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The implementation and evaluation of a best practice physiotherapy protocol in a surgical ICUHanekom, Susan January 2010 (has links)
Bibliography / Thesis (PhD ( Interdisciplinary Health))--University of Stellenbosch, 2010. / Bibliography / ENGLISH ABSTRACT: Introduction: It is increasingly being recognized that how intensive care services are delivered may have a greater impact on patient outcome than the individual therapies. Uncertainty regarding the optimal physiotherapy service provision model in a surgical intensive care unit (ICU) exists. Methodology: The aims of this study were to 1) develop an evidence-based physiotherapy protocol; 2) validate the content of the protocol; and 3) conduct an explorative intervention trial to compare usual care to the estimated effects of providing a physiotherapy service guided by an evidence-based physiotherapy protocol by a dedicated physiotherapist. A systematic review process was used to synthesize the evidence in eight subject areas. The GRADE system was used to formulate best practice recommendations and algorithm statements. Forty-two experts from a variety of disciplines were invited to participate in a Delphi process. Finally, the evidence-based physiotherapy protocol was implemented in a surgical ICU over four three-week intervention periods by a group of research therapists. The outcomes measured included ventilator time, ventilation proportions, failed extubation proportions, length of ICU and hospital stay, mortality, functional capacity, functional ability and cost (using nursing workload as proxy). Results: Fifty-three research reports in eight subject areas were identified, 23 draft best-practice recommendations and 198 algorithm statements were formulated. The draft protocol consisted of five clinical management algorithms. Fifteen international research experts and twelve national academics in the field of critical care agreed to participate in the Delphi process. Consensus was reached on the formulation of 87% (20/23) recommendations and the rating of 66% (130/198) statements. The risk of an adverse event during the protocol care intervention period was 6:1000 treatment sessions (p=0.34). Patients admitted to the unit during the protocol care intervention period were less likely to be intubated (RR 0.16 95%CI 0.07 – 0.71; RRR 0.84 NNT 5.02; p=0.005) or fail extubation (RR 0.23 95%CI 0.05 – 0.98; RRR =0.77 NNT 6.95; p=0.04). The mean difference in the daily unit TISS-28 score between the two condition periods was 1.99 95%CI 0.65 – 3.35 (p=0.04). Patients managed by the protocol tended to remain in the hospital for a shorter time after unit discharge (p=0.05). There was no difference in the time spent on the ventilator (p=0.50), mortality (p=0.52) or in the six minute walk distance (p=0.65). In addition there was no difference in the proportion of patients who reached independence in any of the Barthel Index activities measured within 48 hours of discharge from the unit. Conclusions: The use of an evidence-based physiotherapy protocol for the comprehensive physiotherapeutic management of patients in a surgical ICU was feasible and safe. The preliminary results of this study suggest that a physiotherapy service, which is guided by an evidence-based protocol and offered by a dedicated unit therapist, has the potential to lower the cost of ICU care and facilitate the functional recovery of patients after unit discharge. This information can now be considered by administrators to optimize the physiotherapy service provided in ICU. / AFRIKAANSE OPSOMMING: Inleiding: Daar word toenemend erken dat die wyse waarop dienste gelewer word, ‘n groter impak mag hê op die uitkoms van pasiënte as die spesifieke modaliteite in gebruik. Onsekerheid heers tans oor die optimale fisioterapie diens model om te volg in ‘n chirurgiese intensiewe sorg eenheid (ISE). Metodologie: The doel van hierdie projek was om 1) ‘n bewysgesteunde protokol te ontwikkel; 2) die geldigheid van die protokol te bevestig; en 3) om deur middel van ‘n eksploratiewe studie die uitkoms van pasiënte te vergelyk wanneer die fisioterapie diens gelewer word aan die hand van die bewysgesteunde protokol deur ‘n toegewyde fisioterapeut, teenoor wanneer die gewone fisioterapie diens gelewer word. Die empiriese bewyse in agt onderwerp areas is gesintetiseer na afloop van ‘n sistematiese literatuur oorsig proses. Die GRADE sisteem is gebruik om beste praktyk aanbevelings en algoritme stellings te formuleer. Twee en veertig kundige persone van verskeie disiplines is genooi om deel te neem aan die Delphi proses om die geldigheid van die protokol te bevestig. Uiteindelik is die geldige bewysgesteunde protokol oor ‘n tydperk van vier drie weke intervensie periodes deur ‘n groep navorsings terapeute in ‘n chirurgiese ISE geïmplementeer. Die tyd wat pasiënte geventileer is, die proporsie pasiënte wat geïntubeer en geherintubeer is in die tydperk, die lengte van ISE en hospitaal verblyf, mortaliteit, funksionele kapasiteit asook funksionele vaardigheid en koste (deur die verpleeg werkslading te gebruik as ‘n indikasie van koste) is gemeet. Resultate: Drie en vyftig navorsings verslae in agt onderwerp areas is geïdentifiseer, 23 konsep aanbevelings en 198 algoritme stellings is geformuleer. Die konsep protokol het uit vyf algoritmes bestaan. Vyftien internasionale en twaalf nasionale kundiges het die uitnodiging aanvaar om aan die delphi proses deel te neem. Konsensus is bereik vir die formulering van 87% (20/23) van die aanbevelings en die gradering van 66% (130/198) van die algoritme stellings. Die risiko vir ‘n ongunstige episode tydens die protokol intervensie periode was 6:1000 sessies (p=0.34). Pasiënte wat tydens die protokol intervensie periode tot die eenheid toegelaat is was minder geneig om geïntubeer te word (RR 0.16 95%CI 0.07 – 0.71; RRR 0.84 NNT 5.02; p=0.005) of om ‘n ekstubasie te faal (RR 0.23 95%CI 0.05 – 0.98; RRR =0.77 NNT 6.95; p=0.04). Die gemiddelde verskil in die daaglikse eenheid TISS-28 telling tussen die twee intervensie periodes was 1.99 95%CI 0.65 – 3.35 (p=0.04). Patiente wat tydens die protokol intervensie periode behandel is was geneig om vinniger uit die hospitaal ontslaan te word nadat hul uit die eenheid ontslaan is (p=0.05). Daar was geen verskil in die ventilasie tyd, (p=0.50) die mortaliteit (p=0.52) of die afstand wat pasiente in ses minute kon aflê binne 48 uur na ontslag uit die eenheid (p=0.65) nie. Daar was ook geen verskil in die proporsie pasiente wat onafhanklikheid bereik het in enige van die kategorieë van die Barthell Index instrument nie. Gevolgtrekking: Die gebruik van die protokol vir die omvattende hantering van pasiënte in ‘n chirurgiese eenheid is haalbaar en veilig. Die voorlopige resultate van hierdie studie dui daarop dat wanneer ‘n fisioterapie diens in ‘n chirurgiese ISE gelewer word aan die hand van ‘n bewysgesteunde protokol deur ‘n toegewyde fisioterapeut dit die potensiaal het om ISE koste te verminder en die funksionele herstel van pasiente na ontslag uit die eenheid te fasiliteer. Hierdie inligting kan nou deur administrateurs oorweeg word om ‘n optimale fisioterapie diens in ‘n chirurgiese ISE te verseker.
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A study of right ventricular function during one lung anesthesiaLevin, Andrew Ian 04 1900 (has links)
Dissertation (PhD)--University of Stellenbosch, 2003. / ENGLISH ABSTRACT: Background to the study
OLA can give rise to certain problems:
1. A significant decrease in lung volume is reported to occur in the dependent lung during OLA in the LDP.
This decrease in lung volume can result in an acute increase in opposition to RV ejection. The potential
problem is that the right ventricle is a thin walled structure that can generate considerably less work than
the thicker walled LV. It possesses little reserve to deal with an acute rise in afterload as may occur during
acute lung injury or after lung resection. Therefore, this increase in afterload during OLA may potentially
impair RV-PA coupling. Albeit this potential problem exists, the changes in RV afterload and how the right
ventricle performs during OLA have not been well studied.
2. Arterial hypoxemia, due mainly to venous blood being shunted via the non-ventilated lung, may present a
clinical problem during one lung ventilation.
a. The relative resistances of the pulmonary vascular beds of the dependent ventilated and nondependent
non-ventilated lungs are an important factor governing shunting and thus arterial
oxygenation during one lung anesthesia. A high non-ventilated lung PVR and low ventilated lung
PVR will facilitate good arterial oxygenation during OLA. An increase in non-ventilated lung PVR
is governed predominantly by hypoxic pulmonary vasoconstriction. A low opposition to
pulmonary blood flow in the dependent lung is facilitated predominantly by a high alveolar oxygen
tension and normal lung volume, albeit other factors also play a role in this regard.
b. The saturation and oxygen content of mixed venous blood will contribute significantly to the
arterial oxygenation in the presence of a large shunt as occurs during OLA.
i. On the one hand, venous desaturation as a cause of hypoxemia during one lung
anesthesia has not as yet been systematically addressed in the literature.
ii. On the other hand, if RV afterload increases to such a degree that it leads poor RV
performance, this may cause impairment of global circulatory efficiency and lead to
mixed venous desaturation. The question that has been raised is whether inotrope
infusions could improve RV and LV performance, cardiac output, and thereby the
efficiency of the circulation. Increases in the efficiency of the circulation will result in an
improvement in mixed venous and arterial oxygenation in the presence of a large
shunt. Nonetheless, the administration of inotrope infusions in the presence of a shunt
and during OLA has been reported to aggravate hypoxemia. Thus at the time of
conducting the study, conflicting reports of whether increasing cardiac output and
thereby mixed venous oxygenation would increase or decrease arterial oxygenation
during OLA
In the light of the above, the researcher thus investigated RV afterload, RV performance and coupling to its load
during OLA. The study also addressed the question whether different levels of inotrope infusion or PEEP hadbeneficial or deleterious effects on RV afterload, RV performance and coupling to its load during OLA. Furthermore,
if cardiac output increased during OLA secondary to the infusion of inotropes, would this improve the efficiency of the
circulation, mixed venous oxygenation and thus the arterial oxygenation during OLA, or would it worsen shunt and
arterial oxygenation during OLA?
Control group: OLA and the opposition to pulmonary flow
Pulmonary arterial elastance increased by between 18 to 36% during OLA and mean PAP rose by 32% after
initiation of OLA This increase in mean PAP on initiation of OLA is greater than that observed by certain
investigators but similar to that seen previously in patients with damaged lungs. The question arose as to why
pulmonary artery pressure rises during OLA? From consideration of Ohm’s law, pressure may be regarded as the
product of flow and resistance (Mark, Slaughter et al. 2000). The increase in mean PAP during OLA is due to two
reasons.
1. Firstly, the pressure versus flow curve is likely to be steeper during OLA. This is because pulmonary
vascular recruitment and dilatation (pulmonary vascular reserve) is more limited in scope in these patients
than is usual and most likely accounts for the increase in pulmonary artery pressure during OLA. The
reasons for the limited pulmonary vascular reserve in the DL during OLA include:
a. The pulmonary vascular bed of patients subjected to OLA is frequently abnormal because of its
underlying pathology,
b. During OLA in the lateral decubitus position, lung volume decreases to a greater degree than
during two-lung anesthesia (Klingstedt, Hedenstierna et al. 1990).
c. This decrease in lung volume will be further aggravated by DLT malpositions, secretions and
blood, and absorption atelectasis due to the use of high concentrations of oxygen (Hedenstierna
1998; Krucylak, Naunheim et al. 1996).
d. Excessive amounts of extrinsic or intrinsic PEEP during OLA can compress the intra-alveolar
capillaries and deleteriously affect the pulmonary vascular resistance (Ducros, Moutafis et al.
1999; Inomata, Nishikawa et al. 1997; Bardoczky, Yernault et al. 1996; Yokota, Toriumi et al.
1996).
2. Secondly, there is greater flow through this vascular bed that possesses a higher resistance.
It is noteworthy that the increase in mean PAP did not exceed a value of 25 mm Hg during OLA, even though cardiac
output increased by 30%. However, in studies conducted in patients with “damaged lungs”, greater increases in PA
pressure (accompanied by a decrease in RVEF) have been reported to occur on PA ligation. A question arises as to
why differences exist between PA clamping and OLA? The answer may well be that the observed plateau in the rise
of PA pressure during OLA is as a result of progressive diversion of flow to the NDL as PA pressure rises. Support
for such a suggestion comes from the observation that concomitant with increases in PA pressure during OLA, HPV
is progressively inhibited and shunt fraction progressively rises. This increase in shunt fraction that has been
observed to occur as PA pressure rises, reflects an increase in diversion of pulmonary blood flow to the NDL. The
impact of diversion of this blood to the NDL is that it possibly acts as a safety mechanism limiting increases in PA
pressure and other indices of opposition to pulmonary flow during OLA. This “blow-off effect” will protect the RV until
PA clamping occurs.Control group: OLA and RV function
The current study represented the opportunity to investigate the significance of the abovementioned increases in PA
pressures and elastance on RV performance during OLA. The current study indicates that at the moderate (30%)
increases in PAP that accompanied the initiation of OLA, RV performance, as judged by stroke volume, cardiac
index, RVEF and RVSWI, did not deteriorate compared to the baseline awake status. In fact, cardiac output
increased following surgical incision: this was probably due to sympathetic nervous system stimulation. This
observation also fits in with other studies in which RV performance usually only begins to deteriorate when indices of
opposition to RV ejection reach 200 to 250% of baseline. Furthermore, a constant preload, as indicated by
unchanged central venous and pulmonary artery wedge pressures, and right ventricular end-diastolic volumes were
observed throughout the study period. In other words, this increase in RV afyterlad did not cuse the RV to dilate
durign OLA.
The relationship between stroke work and afterload will vary, depending on the contractile reserve of the ventricle. In
this regard, it could be concluded that under the conditions operative in the current study, the RV was operating on
the upslope of the RVSWI versus Ea relationship. This supports the observation that RV function is well preserved
during OLA.
In conclusion, regarding the indices of opposition to pulmonary flow and RV performance during OLA, it can be
concluded that:
1. Opposition to RV ejection increases. This is evidenced by a 30% rise in mean PAP and 18 to 36%
increase in pulmonary arterial elastance.
2. Right ventricular performance as indicated by RVSWI, RVEF and stroke volume does not decrease during
OLA compared with when the patients awake or subjected to two-lung anesthesia.
3. Furthermore, coupling between the RV and its load is well preserved during OLA. This would imply that
the RV operates at close to maximal efficiency during OLA and that RV stroke work reserve is present
during OLA. It is likely that the RV, which continues operating as a flow pump as it does in normal life,
easily copes with the small increases in RV afterload during OLA.
Dobutamine during OLA: opposition to pulmonary flow and RV
performance
The effects of dobutamine infusions on RV performance during OLA can be summarised as follows:
1. Low rates of dobutamine infusion (3 ug.kg-1.min-1) increased cardiac output, stroke volume, and RVSWI.
The administration of dobutamine 3 ug.kg-1.min-1 was not accompanied by increases in RV afterload.
Therefore, low infusion rates of dobutamine did benefit RV-PA coupling during OLA.
2. However, administration of higher dosages of dobutamine (5 and 7 ug.kg-1.min-1) during OLA was
associated with increases in certain indices of opposition to pulmonary blood flow. For example, PA
elastance, mean PA pressure, and PVR increased by 30% to 40% compared to both when the patients
were awake and when both lungs were being ventilated. Furthermore, PA compliance decreased by up to
61% when dobutamine 5 and 7 ug.kg-1.min-1 were infused compared to the OLA step when dobutaminewas not administered. The increases in mean PAP and PVR are considered to be of limited clinical
significance. However, the decrease in PA compliance during the infusion of the highest dosage of
dobutamine is clinically significant. PA compliance represents one of the factors determining vascular
impedance in the Windkessel model of the circulation. The increases in opposition to pulmonary flow and
lack of progressive increase in indices of RV performance are in contrast to what is expected to occur on
administration of increasing dosages of the inotrope and pulmonary vasodilator, dobutamine. The reasons
for the increase in opposition to pulmonary flow include exhaustion of the pulmonary vascular reserve
during OLA at the high cardiac indices of 5 to 5.5 l.min-1.m-2. This aspect overshadowed the expected
pulmonary vasodilator effects of dobutamine. Moreover, it is probable that the increase in RV afterload
was significant enough to prevent right ventricular performance increasing as would be expected
with the administration of progressively higher dosages of inotrope.
While dobutamine was being administered during OLA, mean PAP increased to a maximum of 24.9 ± 6.2 mm Hg at
a cardiac index of 5.5 ± 1.2 l.min-1.m-2. However during OLA, in the control group, mean PAP was 24.0 ± 7.7 mm Hg
at the maximum cardiac index of 4.4 ± 1.1 l.min-1.m-2. This represented a relatively limited rise in PA pressure
compared with administration of dobutamine alone. The most likely reason why there may have been a limited
increase in mean PAP while dobutamine was being administered is that the “blow off” effect of the NDL vasculature
limited the rise in PA pressure.
Oxygenation during OLA
With regard to oxygen flux, venous and arterial oxygenation during OLA in the control group, the following was
observed:
1. Induction of anesthesia and the approximately 1O Celsius decrease in temperature induced an
approximately 40% decrease in VO2 that continued during OLA.
2. Initiation of OLA resulted in an increase in cardiac output compared to baseline OLA and awake states.
3. The consequence was an increase in S��������O2 from 75% and P��������O2 from 5.4 kPa when the patients were
awake to a P��������O2 of 9.0 ± 1.7 kPa and S��������O2 of 90.6 ± 4.7% during one-lung anesthesia.
4. During OLA, the significant increase in venous oxygenation resulted in an increase in arterial oxygenation
compared to the awake state in spite of the approximately 37% shunt occuring during OLA.
5. Under conditions in the present study, dobutamine administration during OLA did not improve, but
maintained the already high venous and arterial oxygenation compared with OLA alone. Therefore, the
study hypothesis, that dobutamine would induce improvement in RVF and the increase in cardiac output
during OLA would improve arterial oxygenation, does not hold in the current study. The hypothesis that
dobutamine administration and improving cardiac output during OLA would increase arterial oxygenation
was therefore rejected.
However, the rejection of the hypothesis means that the findings of the current study are in contrast to the findings of
Mathru et al, and Nomoto and Kawamura. These authors demonstrated that inotrope administration resulted in an
increase in arterial oxygenation. Nonetheless, the different results are not at odds with each other. In fact, these
differences help to clarify the effect of increases in cardiac output on arterial oxygenation in the presence of asignificant shunt. The differences between the studies can be explained in the following way. Conditions in the
current study resulted in a favourable DO2/VO2 ratio and a high starting P��������O2 even before dobutamine administration
was commenced. Therefore the venous saturations were on the flat part of the oxygen dissociation curve and also
on the flat part of the relationship between cardiac output and arterial oxygen content originally described by Kelman,
Nunn and colleagues. Further increases in cardiac output and the DO2/VO2 ratio would not be expected to, and did
not, increase P��������O2, S��������O2, or C��������O2. Thus, arterial oxygenation content and saturation did not change subsequent
to the increase in cardiac output associated with the administration of dobutamine in the current study. In contrast, in
the Mathru study, the low starting venous saturations and tensions were improved by increases in the DO2/VO2 ratio.
As the starting venous saturation was “low,” significant benefit in arterial oxygenation was obtained on increasing
cardiac output in that study.
One significant concern for the clinician regarding the administration of the inotrope dobutamine during OLA is that it
may increase shunt fraction (Qs/Qt) and thereby decrease arterial oxygenation during one lung ventilation. The
influence of dobutamine on arterial oxygenation during OLA may theoretically be related to the balance of the
following divergent effects:
1. By improving the relationship between oxygen delivery and consumption, dobutamine increases P��������O2.
This increase will benefit arterial oxygenation in the presence of a large shunt,
2. The above has to be weighed against possible increases in VO2 induced by dobutamine, the consequence
of which will be a decrease in P��������O2. Such increases in VO2 were not seen on administration of
dobutamine in the current study,
3. An increase in PA pressure accompanying the increased cardiac output will oppose HPV and increase
shunt in both the dependent and non-dependent lungs,
4. Direct inhibition of HPV by dobutamine and,
5. The influence of P��������O2 on HPV (i.e. high levels of venous oxygenation will inhibit whereas low levels will
potentiate HPV).
Nonetheless, in spite of the concerns (risk) of hypoxemia on administering dobutamine during OLA, dobutamine
administration did not decrease PaO2 or arterial oxygen saturation, and neither did it increase the cost of oxygenation
compared to when OLA was conducted in the absence of dobutamine infusions. In addition, the findings of studies
conducted by Mathru and colleagues, Nomoto and Kawamura and the current study indicate that under usual clinical
conditions present during OLA in the LDP, the administration of low dosages of dobutamine do not increase shunt
fraction. In fact, the beneficial effect of the increase in cardiac output on venous oxygenation resulted in an increase
in arterial oxygenation in the study by Mathru and colleagues; similar mechanisms were most likely operative in the
study conducted by Nomoto and Kawamura.
Therefore, there is currently no evidence that the administration of dobutamine in dosages of up to 7 ug.kg-1.min-1
increases shunt and worsens arterial oxygenation in humans subjected to OLA in the LDP. It is apparent that the
vasodilatory effects of dobutamine resulting in a possible increase in shunt fraction (Qs/Qt) is therefore not the only
factor to consider when studying its effects on arterial oxygenation. What is also of great relevance whenconsidering the effects of an inotrope on arterial oxygenation is the effect of inotropic drugs on the venous oxygen
content. It is possible that Qs/Qt could be increased by the administration of inotrope. Nonetheless, if venous
oxygenation is favourably affected by the administration of dobutamine, then a depressant effect on arterial
oxygenation by an increase in the amount of blood passing via the shunt may be negated. If the increase in venous
oxygenation is very significant, there may even be benefits in terms of arterial oxygenation, as was the case in the
current study.
This approach to how the quality of the blood passing via the shunt affects arterial oxygenation shifts the emphasis
on prevention and treatment of hypoxemia during OLA from the lung to the efficacy of the circulation. In other words,
the emphasis is shifted from what predominantly happens to the non-ventilated lung (HPV) to primarily the efficacy of
oxygen flux during OLA.
Extrinsic and intrinsic PEEP and OLA
The effects of PEEP on hemodynamics and oxygenation observed during OLA in the current study may be
summarised as follows. When PEEP5 was applied to the DL during OLA in the current study:
1. Neither right ventricular function, hemodynamics, oxygen flux nor arterial oxygenation was affected by the
application of PEEP5 compared to the step when no external PEEP was applied.
2. Significant amounts of intrinsic PEEP were present during OLA in the control group patients. The degree
of intrinsic PEEP was weakly related to the degree of obstructive airways disease present on preoperative
LFT’s.
3. The most likely reason why PEEP5 did not make a difference to oxygenation or hemodynamics was the
existence of similar amounts of intrinsic PEEP during OLA. These findings confirm Myles’s contention that
low levels of intrinsic PEEP may have salutary effects on oxygenation during OLA.
When PEEP10 was applied to the DL during OLA in the current study, it led to a decrease in stroke volume. This
decrease is predominantly due to a decrease in preload, as PVR does not increase to levels that are known to impair
RV performance. The decrease in the DO2/VO2 ratio that was induced by PEEP10 predictably decreases P��������O2 and
can potentially lead to impairment of arterial oxygenation. It can therefore be concluded that greater (excessive)
amounts of PEEP under more unfavourable circulatory conditions than were observed in the current study, may have
deleterious cardio-respiratory effects.
In summary, optimising DL volume plays an important role in determining arterial oxygenation. However, the
therapeutic index for PEEP is narrow and the anesthesiologist needs to know firstly when the lung volume of the DL
approaches FRC and secondly, how to avoid dynamic hyperinflation of that lung. One significant problem is that the
best method of monitoring FRC during OLA is not clear at present. / AFRIKAANSE OPSOMMING: Agtergrond tot die studie
Eenlongnarkose mag tot sekere probleme aanleiding gee.
’n Betekenisvolle afname in volume van die onderlong vind in die laterale decubitus posisie tydens eenlongnarkose
plaas. Hierdie afname in longvolume mag egter ’n akute verhoging in regter ventrikulêre nalading tot stand bring.
Die probleem is egter dat die regter ventrikel ’n dunwandige struktuur is wat potensieel baie minder werk as die
dikwandige linker ventrikel kan genereer. Die regter ventrikel het min reserwe om ’n akute verhoging in nalading te
weerstaan soos wat gebeur met akute longbesering of na longreseksie. Dus die verhoging in nalading wat gepaard
gaan met eenlongnarkose mag die koppeling tussen die regter ventrikel en die pulmonale arterie belemmer.
Alhoewel hierdie potensiële probleem bestaan, is die verandering albei in regter ventrikulêre nalading en hoe die
regter ventrikel funksioneer tydens eenlongnarkose nog nie goed bestudeer nie.
1. Arteriële hipoksemie, hoofsaaklik te wyte aan die groot aftakking via die long wat nie geventileer word nie,
mag kliniese probleme tydens eenlongnarkose teweegbring.
2. Die weerstand wat die pulmonale vaskulêre beddens van die geventileerde en nie-geventileerde longe bied
teen bloedvloei is belangrike faktore wat aftakking en dus arteriële oksigenasie tydens eenlongnarkose
beheer. ’n Hoë weerstand van die nie-geventileerde long en ’n lae weerstand van die geventileerde long
se pulmonale vaskulêre beddens sal bevredigende arteriële oksigenasie tydens eenlongnarkose fasiliteer.
’n Verhoging in die pulmonale vaskulêre weerstand van die nie-geventileerde long is hoofsaaklik te wyte
aan hipoksiese pulmonale vasokonstriksie. ’n Lae pulmonale vaskulêre weerstand in die geventileerde
onderlong is hoofsaaklik gefasiliteer deur ’n hoë alveolêre suurstofspanning en ’n normale long volume,
alhoewel alle faktore ook ’n rol in hierdie verband speel.
3. In die teenwoordigheid van die groot aftakking wat bestaan tydens eenlongnarkose, sal die saturasie en
suurstof inhoud van gemeng veneuse bloed ’n betekenisvolle bydrae aan arteriële oksigenasie maak.
a. Veneuse saturasie as ’n oorsaak van hipoksemie tydens eenlongnarkose, is nog nie sistematies
in die literatuur ondersoek nie.
b. Indien regter ventrikulêre nalading tot so ’n mate verhoog dat dit tot swak ventrikulêre uitwerp lei,
mag dit ’n oorsaak wees van ontoereikendheid van die globale bloedsomloop en tot gemeng
veneuse desaturasie lei. Die vraag is dus of verhoging van die kardiale omset deur inotrope
ondersteuning die toereikendheid van die sirkulasie kan verbeter. Verbeterde sirkulasie
toereikendheid sal tot ’n verhoging in gemeng veneuse en arteriële oksigenasie lei in die
teenwoordigheid van ’n groot aftakking. Nietemin, die toediening van inotrope in die
teenwoordigheid van ’n groot aftakking tydens eenlongnarkose gerapporteer om hipoksemie te
vererger tydens eenlongnarkose. Dus ten tye van die uitvoer van dié studie, is daar uitdrukking
gegee tot teenstrydige opinies in die literatuur oftewel verhoging in kardiale omset arteriële
oksigenasie sal verbeter of versleg tydens eenlongnarkose.In die lig van die agtergrond hierbo, het die navorser dus regter ventrikulêre nalading, regter ventrikulêre funksie en
koppeling van die regter ventrikel met sy lading tydens eenlongnarkose ondersoek. Die studie het ook die vraag
benader of inotroop infusies of PEEP goeie of slegte gevolge sou hê op regter ventrikulêre nalading, regter
ventrikulêre funksie en koppeling van die regter ventrikel aan sy lading tydens eenlongnarkose. Sou die kardiale
omset en die toereikendheid van die sirkulasie sou verbeter sekondêr tot die toediening van inotrope tydens
eenlongnarkose, gemeng veneuse oksigenasie en dus arteriële oksigenasie tydens eenlongnarkose verbeter, of sou
dit aftakking en arteriële oksigenasie versleg tydens eenlongnarkose?
Kontrole groep
Pulmonêre elastansie het tussen 18 en 36% verhoog en gemene pulmonale arterie druk het met 32% tydens
eenlongnarkose vermeerder. Die verhoging in gemene pulmonale arterie druk met die aanvang van eenlongnarkose
is groter as die waardes gesien deur sekere navorsers maar gelyk met waardes gevind in pasiënte met beskadigde
longe. Die vraag ontstaan dan hoekom styg pulmonale arterie druk tydens eenlongnarkose? volgens Ohm se Wet,
mag druk as die veelvoud van vloei en weerstand beskou word. Die verhoging in gemene pulmonale arterie druk
tydens eenlongnarkose is daarvolgens hoofsaaklik te wyte aan twee redes.
1. Eerstens, die kurwe van druk teenoor vloei is waarskynlik styler tydens eenlongnarkose. Hierdie is omdat
pulmonale vaskulêre werwing en verwyding (pulmonale vaskulêre reserwe) is meer beperk as nornaal in
pasiënte met longsiekte. Hierdie is die waarskynlikste rede hoekom pulmonale arterie druk tydens
eenlongnarkose verhoog. Die redes hoekom die pulmonale vaskulêre reserwe in die onderste long tydens
eenlongnarkose beperk is sluit in die volgende:
1.1 Die pulmonale vaskulêre bed van pasiënte onderwerp aan eenlongnarkose mag abnormaal wees weens
die onderliggende long patologie,
1.2 Tydens eenlongnarkose in die laterale decubitus posisie, is long volume in hoë mate verminder as tydens
tweelongnarkose,
1.3 Die voorafgenoemde vermindering in longvolume sal verder verminder word deur wanposisies van die
dubbellumenbuis, sekresies en bloed, en absorpsie atelektase.
1.4 Te hoë vlakke van PEEP, oftewel intrinsiek of ekstrensiek van oorsprong, sal die intraalveolêre vate
toedruk en so die pulmonale vaskulêre weerstand verhoog.
2. Tweedens, is daar groter vloei deur hierdie vaskulêre bed wat ‘n hoër weerstand bevat.
Dit is opmerkingswaardig dat die verhoging in gemene pulmonale arterie druk ‘n waarde van 25 mmHg nie oorskry
het nie tydens eenlongnarkose, alhoewel kardiale omset met 30% verhoog het. In pasiënte met beskadigde longe,
het vorige studies egter bewys dat groter verhoging in PA druk gebeur tydens afbinding van die pulmonale arterie.
Die vraag ontstaan dus hoekom daar verskille bestaan tussen wat gebeur tydens afbind van die pulmonale arterie en
eenlongnarkose? Die antwoord mag wees dat die beperking in die styging in PA druk tydens eenlongnarkose as
gevolg van ‘n progressiewe afleiding van bloedvloei na die nie-geventileerde long gebeur sodra pulmonale arterie
druk styg tydens eenlongnarkose. Die implikasie van die afleiding van bloed na die nie geventileerde long is dat dit
as ‘n veiligheids meganisme optree en verdere styging in pulmonale arterie druk beperk tydens eenlongnarkose.
Hierdie afblaas meganisme sal die regter ventrikel beskerm tot en met PA afbind.Kontrole groep: eenlongnarkose en regter ventrikulêre funksie
Die huidige studie bied die geleentheid om die betekenis van die voorafgenoemde verhoging in PA drukke en
elastansie op regter ventrikulêre funksie tydens eenlongnarkose te ondersoek. Die huidige studie dui aan dat die
30% verhoging in pulmonale arterie druk wat met die aanvang van eenlongnarkose plaasvind, glad nie regter
ventrikulêre funksie belemmer nie indien dit vergelyk word met die basislyn wakker staat. In teendeel, kardiale
omset het verhoog na chirurgiese insnyding: hierdie verhoging is waarskynlik te wyte aan simpatiese senuwee
stimulasie na die chirurgiese insnyding. Hierdie waarnemings pas in ook met ander studies waartydens regter
ventrikulêre ejeksie alleenlik begin om af te neem indien die indekse van opposisie tot regter ventrikulêre ejeksie 200
tot 250% van basislyn bereik. Verder, die induksie van voorlading, naamlik sentrale veneuse druk, pulmonale arterie
wigdruk en regter ventrikulêre einddiastoliese volumes is onveranderd tydens die huidige studie; dit beteken die
ventrikel het nie gedilateer het nie tydens die verhoging in regter ventrikulêre nalading.
Die verband tussen slagwerk en nalading sal varieer, afhanklik van die kontraktiele status van die ventrikel. In
hierdie opsig, kon ons aflei dat die regter ventrikel, onder omstandighede wat tydens diė studie plaasgevind het,
gefunksioneer het op die stygende been van die verband tussen regter ventrikulêre slagwerk en pulmonale arterie
elastansie. Hierdie waarneming ondersteun die argument in die vorige paragraaf dat die regter ventrikel funksie
behoue is tydens eenlongnarkose.
Ter opsomming omtrent die indekse van opposisie tot pulmonale vloei en regter ventrikulêre funksie tydens
eenlongnarkose:
1. Opposisie tot regter ventrikulêre uitwerp verhoog. Die bewys hiervoor is ’n 30% verhoging in gemene
pulmonale arterie druk en ’n 36% verhoging in pulmonale arterie elastansie.
2. Ten spyte van die verhoging in weerstand teen RV uitwerping, het regter ventrikulêre funksie (soos bepaal
deur regter ventrikulêre slagwerk indeks, regter ventrikulêre ejeksie fraksie en slag volume), nie verminder
tydens eenlongnarkose in vergelyking met die waardes verkry wanneer die pasiënte wakker is of aan
tweelongnarkose onderwerp is.
3. Ons kon ook aflei dat die koppeling tussen die regter ventrikel en sy lading goed behoue is tydens
eenlongnarkose. Die implikasie hiervan is dat regter ventrikulêre slagwerk reserwe teenwoordig is tydens
eenlongnarkose. Tydens eenlongnarkose funksioneer die regter ventrikel as ’n vloeipomp, net soos in
normale lewe; dit beteken dat en die klein verhoging in regter ventrikulêre nalading wat ondervind word
tydens eenlongnarkose maklik getolereer word.
Dobutamien tydens eenlongnarkose: opposisie tot pulmonale vloei en
regter ventrikulêre funksie
Die uitwerking van dobutamien op regter ventrikulêre funksie tydens eenlongnarkose kan as volg opgesom word:
1. Lae dosisse dobutamien (3 μg.kg-1.min-1) verhoog kardiale omset, slagvolume en regter ventrikulêre
slagwerkindeks. Die toediening van dobutamien 3 μg.kg-1.min-1 het nie saamgegaan met ‘n verhoging in
regter ventrikulêre nalading nie. Dus, lae dosisse van dobutamien het wel die koppeling tussen die regter
ventrikel en die pulmonale vaskulatuur tydens eenlongnarkose verbeter.2. Nietemin, albei die hoër dosisse van dobutamien (5 en 7 μg.kg-1.min-1) tydens eenlongnarkose het
verhogings in die opposisie tot pulmonale bloedvloei teweeggebring. Byvoorbeeld, PA elastansie, gemene
PA druk en pulmonale vaskulêre weerstand het met 30 tot 40% verhoog in vergelyking met die waardes
gekry toe die pasiënte wakker was en toe albei longe geventileer is. ’n Belangrike opmerking in hierdie
opsig is dat pulmonale arterie vervormbaarheid tydens eenlongnarkose met 61% verminder het tydens
albei dobutamien 5 en 7 μg.kg-1.min-1. Die verhogings in gemene pulmonale arterie druk en pulmonale
vaskulêre weerstand is, volgens mening, nie van kliniese of statistiese betekenis nie, alhoewel die
vermindering in PA vervormbaarheid tydens die dobutamien 7 μg.kg-1.min-1 infusie wel van kliniese
betekenis is. PA vervormbaarheid weerspieël een van die faktore wat vaskulêre impedansie in die 3-
element Windkessel model van sirkulasie het. Die verhoging in opposisie tot pulmonale vloei en die
afwesigheid van progressiewe verhogings in indekse van regter ventrikulêre funksie is nie wat verwag word
indien die dosisse van die inotroop en pulmonale vasodilator dobutamien, progressief verhoog word. Die
redes hoekom die opposisie tot pulmonale vloei verhoog tydens die toediening van dobutamien sluit in die
uitwissing van die pulmonale vaskulêre reserwe tydens eenlongnarkose. Tydens die hoë kardiale indekse
van 5 tot 5.5 μg.kg-1.min-1. is die pulmonale vaskulêre reserwe uitgeput en die meganisme het die
verwagte pulmonale vaskulêre vasodilatasie van dobutamien oorskadu. Bowendien is dit waarskynlik dat
die verhoging in regter ventrikulêre nalading betekenisvol genoeg was om te verhoed dat regter
ventrikulêre funksie progressief verhoog soos sou verwag word met die administrasie van hoër dosisse
inotroop.
Die administrasie van dobutamien tydens eenlongnarkose het gemene pulmonale arterie druk verhoog tot ’n
maksimum van 24,9 ± 6.2 mm Hg teen ’n kardiale indeks van 5.5 ± 1.2 l.min-1.m2. Nietemin is gemene pulmonale
arterie druk 24.0 ± 7.7 mm Hg teen die maksimum kardiale indeks in die kontrole groep van 4.4 ± 1.1 l.min-1.m-2
tydens eenlongnarkose in die kontrole groep. Hierdie weerspieël dus ’n relatief beperkte verhoging in pulmonale
arterie druk in vergelyking met die verhoging in pulmonale arterie druk wat gebeur het tydens die administrasie van
dobutamien. Die waarskynlikste rede hoekom daar ’n beperkte verhoging in pulmonale arterie druk sou gewees het
tydens die infusie van dobutamien is die afblaas effek van die nie-geventileerde long wat die verhoging in PA druk
beperk het.
Oksigenasie tydens eenlongnarkose
Die volgende waarnemings is gemaak in verband met suurstof vloed, veneuse en arteriële oksigenasie tydens
eenlongnarkose in die kontrole groep:
1. Die kombinasie van Induksie van narkose en die 1ºC vermindering in temperatuur het saamgegaan met ’n
40% vermindering in suurstof verbruik tydens twee long narkose. Hierdie vermindering in suurstof verbruik
het voortgegaan tydens eenlongnarkose.
2. Die aanvang van eenlongnarkose is geassosieerd met ’n verhoging in kardiale omset in vergelyking met
albei die basislyn eenlongnarkose en wakker state.
3. Die gevolge van punte 1 en 2 hierbo is dat die gemengde veneuse suurstof saturasie vanaf 75% en die
gemeng veneuse suurstof spanning vanaf 5.4 kPa (toe die pasiënte wakker was) gestyg het tydens4. Tydens eenlongnarkose het die betekenisvolle verhoging in veneuse oksigenasie veroorsaak dat daar ’n
verhoging in arteriële oksigenasie was in vergelyking met wanneer die pasiënte wakker was. Hierdie
styging in arteriele oksigenasie was ten spyte van die 37% aftakking wat teenwoordig was tydens
eenlongnarkose.
5. Onder toestande in die huidige studie, het dobutamien tydens eenlongnarkose nog arteriële nog veneuse
oksigenasie verbeter nie, maar die arteriele oksigenasie het konstant gebly. ’n Belangrike observasie wat
daarmee saamgaan is dat dobutamien toediening nie met ’n daling in arteriële suurstof spanning
geassosieer is nie. Vervolgens, die hipotese dat die verhoging in kardiale omset geassosieer met
dobutamien toediening tydens eenlongnarkose ’n verhoging in arteriële oksigenasie beweeg bring, is dus
verwerp.
Die verwerping van die hipotese van die deel van die studie beteken dat die bevindinge die teenoorgestelde is van
die studies gepubliseer deur Mathru en sy kollegas en Nomoto en Kawamura. Hierdie outeurs het gedemonstreer
dat die toediening van inotrope ’n verhoging in arteriële oksigenasie teweeg gebring het. Nietemin is die
teenoorgestelde gevolgtrekkinge nie teenstrydig met mekaar nie. Inteendeel hierdie verskille help ons om die effek
van ’n verhoging in kardiale omset of arteriële oksigenasie in die teenwoordigheid van ’n betekenisvolle aftakking
duidelik te maak. Die verskille tussen die studies kan op die volgende manier verduidelik word. Toestande wat in
die huidige studie teenwoordig was het veroorsaak dat die verband tussen suurstof lewering en verbruik baie hoog
was en dat die gemeng veneuse suurstof spanning baie hoog was om mee te begin alvorens dobutamien geinfuseer
is. Dus is die veneuse saturasies op die plat deel van albei die suurstof dissosiasie kurwe en ook van die verband
tussen kardiale omset en arteriële suurstof inhoud oorspronklik deur Kelman, Nunn en kollegas beskryf. Verdere
verhogings in kardiale omset sou dus nie verwag word, en het nie, verhogings in gemeng veneuse suurstof
spanning, gemeng veneuse suurstof saturasie of gemeng veneuse suurstof inhoud teweeg gebring. Dus, arteriële
suurstof inhoud en saturasie het nie verander na die verhoging in kardiale omset wat teweeg gebring is deur die
toediening van dobutamien in die huidige studie. Inteendeel, in die studie deur Mathru en kollegas, is die lae
aanvanklike veneuse saturasie en spanning verbeter deur verhogings in die verband tussen suurstoflewering en
suurstofverbruik. Omdat die veneuse saturasie aan die begin van die Mathru studie laag was, is betekenisvolle
voordeel in arterieël oksigenasie teweeg gebring deur om die kardiale omset te verhoog.
’n Groot bekommernis vir die klinikus is dat die aftakking mag verhoog met die toediening van die inotroop
dobutamien tydens eenlongnarkose en, op die manier, arteriële oksigenasie mag verminder. Die invloed van
dobutamien op arteriële oksigenasie tydens eenlongnarkose mag teoreties te wyte wees aan die balans van die
volgende uiteenlopende faktore:
1. Deur om die verband tussen suurstof lewering en verbruik te verbeter, sal dobutamien gemeng veneuse
suurstof spanning verhoog. Hierdie verhoging sal arteriële oksigenasie verbeter in die teenwoordigheid
van ’n groot aftakking,
2. Die bogenoemde moet teenoor potensiële verhogings in suurstofverbruik deur dobutamien oorweeg word.
Die gevolge hiervan sou potensieel ’n vermindering in gemeng veneuse suurstof spanning wees. Sulke
verhogings in suurstof verbruik is nie tydens die huidige studie gesien nie,3. ’n Verhoging in pulmonale arterie druk wat saamgaan met die verhoogde kardiale omset sal hipoksiese
pulmonale vasokonstriksie teenwerk wat die aftakking in albei die geventileerde en nie geventileerde longe
sal verhoog,
4. Direkte inhibisie van hipoksiese pulmonale vasokonstriksie deur dobutamien en,
5. Die invloed van gemeng veneuse suurstof spanning op hipoksiese pulmonale vasokonstriksie moet ook
oorweeg word (d.i. hoe gemeng veneuse suurstof parsiele druk sal hipoksiese pulmonale vasokonstriksie
inhibeer).
Nietemin, ten spyte van die bekommernisse rondom hipoksemie tydens die toediening van dobutamien tydens
eenlongnarkose, het dobutamien toediening nie ’n verlaging in arteriële suurstof spanning teweeg gebring nie, en
ook het dit nie die koste van oksigenasie verhoog nie. Verder, die bevindinge van studies tydens eenlongnarkose in
die laterale decubitus posisie deur Mathru en sy kollegas, Nomota en Kawamura en ook die huidige studie, dui aan
dat die toediening van lae dosisse van dobutamien nie toe ’n verhoging in aftakking lei nie. Inteendeel, die
voordelige effekte van die verhoging in kardiale omset op veneuse saturasie het veroorsaak dat daar ’n verhoging in
arteriële saturasie is in die studie deur Mathru en sy kollegas soortgelyke meganismes is waarskynlik ook van
toepassing in die studie wat gedoen is deur Nomoto en Kawamura.
Dus, dwars deur die literatuur, is daar geen huidiglike bewys dat die toediening van dobutamien tot en met dosisse
van 7μg.kg-1.min-1 aftakking verhoog of arteriële oksigenasie versleg in mense onderworpe aan eenlongnarkose in
die laterale decubitus posisie. Dit is duidelik dat die vasodilatoriese effekte van dobutamien wat moontlik ’n
verhoging in aftakking fraksie teweeg kan bring, nie die enigste faktore is om te oorweeg wanneer die middel se
invloed op arteriële oksigenasie bestudeer word nie. Dit is ook van kliniese belang om die invloed van inotrope
middels op veneuse suurstof inhoud te oorweeg. Dit is moontlik dat ’n aftakking verhoog kan word deur die
toediening van ’n inotroop. Nietemin, mag die negatiewe effek wat die toediening van ’n inotroop sal inhou op
arteriële oksigenasie deur middel van sy verhoging in aftakking, negeer word indien veneuse oksigenasie voordelig
beïnvloed is. Verder, indien die verhoging in veneuse oksigenasie wat teweeggebring word deur die toediening van
inotrope baie betekenisvol is, mag die gevolg hiervan wees dat arteriële oksigenasie voordelig beïnvloed word soos
die geval in die huidige studie was.
Die huidige benadering waar die kwaliteit van die bloed wat deur die aftakking vloei die arteriële oksigenasie
beïnvloed, skuif die klem van voorkoming en behandeling van hipoksemie tydens eenlongnarkose van die long na
die toereikendheid van die sirkulasie. Met ander woorde, die klem is geskuif van wat gebeur in die nie-geventileerde
long (hipoksie pulmonale vasokonstriksie) tot primêr die toereikendheid van suurstof flux tydens eenlongnarkose.
Ekstrinsieke en intrinsieke PEEP tydens eenlongnarkose
Die invloed van PEEP op hemodinamika en oksigenasie tydens eenlongnarkose in die huidige studie mag as volg
opgesom word. Toe PEEP5 tydens eenlongnarkose toegedien is:
1. Nie regter ventrikulêre funksie, hemodinamika, suurstof flux nog arteriële oksigenasie is beïnvloed deur die
toediening van PEEP5 in vergelyking met die stap wanneer geen eksterne PEEP toegedien is nie.
2. Betekenisvolle hoeveelhede intrinsieke PEEP is teenwoordig tydens eenlongnarkose in die kontrole groep.Die hoeveelheid intrinsieke PEEP wat teenwoordig was, is swak maar betekenisvol verwant aan die graad
obstruktiewe lugwegsiekte wat teenwoordig was gemeet deur pre-operatiewe longfunksie toetse.
3. Die waarskynlikste rede hoekom PEEP5 nie ’n verskil gemaak het aan oksigenasie of hemodinamika nie is
die teenwoordigheid van soortgelyke hoeveelhede intrinsieke PEEP tydens eenlongnarkose. Hierdie
bevinding bevestig Myle’s se beweringe dat lae vlakke intrinsieke PEEP voordelige effekte op oksigenasie
tydens eenlongnarkose mag hê.
PEEP10 toediening aan die onderlong tydens eenlongnarkose in die huidige studie het tot ’n vermindering in
slagvolume gelei. Hierdie vermindering is primêr veroorsaak deur ’n vermindering in voorlading en nie die gevolg
van ’n verhoging in pulmonale vaskulêre weerstand nie. Die gevolgtrekking is gemaak omdat regerventrikulere
enddiastoliese volume verlaag het maar pulmonale vaskulêre weerstand het nie verhoog tot vlakke wat bekend is om
regter ventrikulêre funksie te belemmer nie. Die vermindering in die verhouding tussen suurstof lewering en suurstof
verbruik wat geïnduseer is deur PEEP10 het (voorspelbaar) gemeng veneuse suurstof spanning verminder en kon
potensieël gelei het tot belemmering in arteriële oksigenasie. Indien minder voordelige sirkulatoriese toestande
geheers het tydens die huidige studie, sou groter (oorbodige) hoeveelhede PEEP slegter kardiorespiratoriese
gevolge tot gevolg gehad het.
Ter opsomming, optimalisering van die volume van die onderlong tydens eenlongnarkose speel ’n belangrike rol in
die bepaling van arteriële oksigenasie. Nietemin, die terapeutiese indeks vir PEEP is nou en die narkotiseur het die
behoefte om te weet wanneer die volume van die onderlong optimaal is. In die opsig, is ’n betekenisvolle probleem
tydens eenlongnarkose dat meting van funksionele residuele kapasiteit nie huidiglik maklik is nie
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73 |
The effect of an in utero high fat diet on the expression of transcription factors and glucose sensing in the developing rat pancreasCerf, Marlon Eugene 12 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2005. / ENGLISH ABSTRACT: A high fat diet (HFD) reduces beta-cell mass, impairs glucose signalling and is
involved in the development of Type 2 diabetes. Malnutrition during gestation is
hypothesized to irreversibly damage beta-cell development. The transcription
factors Pdx-1 and Pax 4 are involved in islet cell development. Pdx-1 is reported
to regulate expression of GLUT-2, glucokinase (GK) and the insulin gene.
Aims
The aim of this study is to investigate, in the neonatal and weanling rat, the effect
of exposure to a HFD in utero and/or lactation on weight, glucose and insulin
concentrations, islet cell development, pancreatic transcription factors and
glucose sensing genes.
Methods
Neonatal and weanling rats were exposed to a maternal HFD for defined periods
of gestation and/or lactation. After termination, pups were weighed and glucose
and insulin concentrations determined. mRNA expression of Pdx-1, Pax 4,
GLUT-2 and GK was quantified by LightCycler PCR. Pancreatic sections were
immunostained for insulin and glucagon (islet cell development), and for Pdx-1,
GLUT-2 and GK (beta-cell function) followed by image analysis.
Results:
Exposure to an in utero HFD throughout gestation resulted in hyperglycaemic
pups with reduced beta-cell volume and number, Pdx-1 and GK
immunoreactivity. In contrast the alpha-cell volume, number and size were
augmented in neonates exposed to a HFD throughout gestation.
Most weanlings were hyperglycaemic and hypoinsulinaemic. In some weanlings,
reduced beta-cell number and beta- and alpha-cell size was observed. Pdx-1
mRNA was overexpressed in weanlings exposed to a maternal HFD for the final
week of gestation or throughout both gestation and lactation, but reduced in
those only exposed throughout lactation. Pax 4 mRNA was reduced in weanlings
exposed to a maternal HFD for the first or final week of gestation, throughout
gestation or throughout lactation. In most of the weanlings, GLUT-2 mRNA
expression was reduced whereas immunoreactivity for GLUT-2 was increased.
Both GK mRNA expression and immunoreactivity were reduced in most of the
weanlings.
Conclusions
• Exposure to an in utero HFD throughout gestation induced
hyperglycaemia in neonates. The reduced Pdx-1 expression appears to
play a role in the compromised beta-cell development, and concomitant
with the reduced GK levels, contributes to the hyperglycaemia in these
neonates and may make them susceptible to beta-cell failure.
• In most weanlings exposed to a HFD in utero and/or during lactation the
hyperglycaemia and hypoinsulinaemia suggest compromised beta-cell
function. The GK mRNA expression and immunoreactivity were reduced
thereby impairing glycolysis which would result in reduced insulin
secretion contributing to the hyperglycaemia. Furthermore, beta-cell
development is adversely affected by the HFD in some weanlings. This
would contribute to reduced beta-cell function and may eventually result in
beta-cell failure. GLUT-2 immunoreactivity was increased in some,
suggesting a compensatory adaptative mechanism to restore glucose
homeostasis.
• A maternal HFD has adverse effects both in neonates and weanlings on
beta-cell development, transcription factor and glucose sensing gene
expression and induced hyperglycaemia and hypoinsulinaemia in some of
the offspring. Ways to ameliorate the HFD-induced attenuation of key
beta-cell genes to ensure normal beta-cell function are important for future
research in Type 2 diabetes. / AFRIKAANSE OPSOMMING:
‘n Hoe vet diet (HVD) verminder beta-sel masse, glukose signale en speel ‘n rol
in Tipe 2 diabetes. Die hipothese is dat wanvoeding gedurende swangerskap lei
tot onomkeerbare betasel beskadiging. Die transkripsiefaktore Pdx-1 en Pax 4
speel rolle in eilandselontwikkeling. Daar is bewyse dat Pdx-1 die uitdrukking van
die GLUT-2, glucokinase (GK) en insulin gene reguleer.
Doelstelling:
Die doel van hierdie studie is om, in die pasgebore en gespeende rot, die effek
van ’n HVD in utero en/of laktasie op gewig, glukose en insulin konsentrasies,
eilandselontwikkeling, pankreatiese transksripsiefaktore en op glukosewaarnemingsgene
te ondersoek.
Metodes:
Pasgebore en gespeende rotte is vir bepaalde periodes van gestasie en/of
laktasie blootgestel aan ’n HVD van die moeder. Na terminase, is kleinjies
geweeg en die glukose- en insulienkinsentrasies bepaal. mRNA uitdrukking van
Pdx-1, Pax 4, GLUT-2 en GK is geoes met LightCycler PCR. Snitte van die
pankreas is gekleur met insulien en glukagon (eilandsontwikkeling) en vir Pdx-1,
GLUT-2 en GK (betaselfunksie) gevolg deur beeldanalise.
Resultate:
Bloodstelling aan ’n in utero HVD regdeur gestasie het hiperglisemie versoorsaak
in pasgebore rotte met verlaagde betasel volume en aantal, Pdx-1 en GK
immunoreaktiwiteit. In teenstelling daarmee was die alfasel se volume, aantal en
grootte verhoog in pasgebore rotte wat regdeur gestasie aan 'n HVD blootgestel
was.
Meeste van die gespeende rotte was hiperglisemies en hipoinsulinemies. In
sommige gespeende rotte, was daar ’n verlaging van betasel hoeveelheid en
grootte en in alfasel groote. Oormatige uitdrukking van Pdx-1 mRNA het
plaasgevind in speenlinge wat aan ’n HVD van die moeder vir die laaste week
van gestasie of regdeur gestasie en laktasie blootgestel was, maar dit was
verlaag in die speenlinge wat net tydens laktasie blootgestel was. Pax 4 mRNA
was verlaag in speenlinge wat aan ’n HVD van die moeder blootgestel was vir
die eerste of laaste week van gestasie, regdeur gestasie of regdeur laktasie. In
meeste van die speenlinge is onder-uitdrukking van GLUT-2 mRNA, maar ’n
verhoging van GLUT-2 immunoreaktiwiteit gevind. Beide GK mRNA uitdrukking
en immunoreaktiwiteit was laer in meeste van die speenlinge.
Gevolgtrekkings:
• Blootstelling aan ’n in utero HVD regdeur gestasie lei tot hiperglisemie in
pasgebore rotte. Die verlaagde Pdx-1 immunoreaktiwiteit speel
klaarblyklik ’n rol by die geaffekteerde betaselontwikkeling. Dit, saam met die verlaagde immunoreaktiwiteit vir GK, kan bydra tot die hiperglisemie in
hierdie pasgebore rotte.
In die meeste van die speenlinge wat aan ’n HVD blootgestel was, dui die
hiperglisemie en hipoinsulinemie op geaffekteerde betaselfunksie. Die GK
mRNA uitdrukking en immunoreaktiwiteit is verlaag, wat weer glikolise
benadeel, en dit sal lei tot verminderde insulienafskeiding wat bydra tot die
hiperglisemie. Betaselontwikkeling word voorts negatief beinvloed deur
die HVD, wat blyk uit die verlaagde aantal en grootte van betaselle. Dit sal
bydra tot verminderde betaselfunksie. Dit kan uiteindelik tot
betaselversaking lei. GLUT-2 immunoreaktiwiteit was verhoog in hierdie
speenlinge, wat dui op ’n kompenserende aanpassingsmeganisme om
glukose homeostase te herstel.
’n HVD van die moeder het ’n negatiewe uitwerking op
betaselontwikkeling, transkripsiefaktor en glukosewaarneming
geenuitdrukking in beide die pasgebore en gespeende rotte, en
geinduseerde hiperglisemie en hipoinsulinemie in sommige kleintjies. Dis
belangrik vir toekomstige Tipe 2 diabetes navorsing dat daar na gekyk
moet word om die HVD-geinduseerde verlaging van sleutel betaselgene
te verbeter vir optimale betaselfunksie.
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Development and validation of a scale to measure patient satisfaction with antenatal careSteyn, Petrus Schonken 03 1900 (has links)
Thesis (MA)--Stellenbosch University, 1999. / ENGLISH ABSTRACT: There is no standardised instrument available in South Africa to measure patient satisfaction
with antenatal care. The measurement of patient satisfaction is especially important after the
implementation of a free antenatal care service in the South African health system.
The purpose of this study was to develop and validate an appropriate scale to measure patient
satisfaction. Several methods to measure patient satisfaction are described in the literature. A
questionnaire was developed for the Tygerberg Hospital patients. This questionnaire was tested
in 200 antenatal patients through a structured interview.
The importance of cross-cultural research is emphasised in the validation of the measuring
instrument. Factor analysis was used to validate the instrument. This showed that a single factor
accounted for most of the total variance. All the items had to do with the process of antenatal
care.
The findings of this survey showed the following:
• One cannot use overseas measuring instruments without adjusting for cross-cultural
differences.
• The patient satisfaction score is negatively skewed with a high mean.
• Social desirability response sets may play an important role in these questionnaires.
• There is a statistically significant difference in patient satisfaction with antenatal care
between the different antenatal clinics, even after controlling for socio-demographic
differences.
• That the satisfaction score is a reflection of the service rendered to the patient and not of the
socio-demographic differences.
This research identified the difficulties of developing a standardised instrument to measure
patient satisfaction with antenatal care and opens the way for future research into patient
satisfaction with medical services. / AFRIKAANSE OPSOMMING: Daar is geen gestandaardiseerde meetinstrument om pasiente se tevredenheid met
voorgeboortesorg in Suid Afrika te bepaal nie. Die noodsaaklikheid van die bepaling van
tevredenheid met voorgeboortesorg het nou belangriker geword nadat 'n stelsel van gratis
voorgeboortesorg in Suid-Afrika gei"mplementeer is.
Die doel van hierdie navorsing was om 'n skaal te ontwikkel om pasiente se tevredenheid met
voorgeboortesorg te bepaal en om die geldigheid van hierdie meetinstrument plaaslik te toets. In
die literatuur is daar verskeie metodes om pasiente se tevredenheid te bepaal. 'n Vraelys is
ontwikkel vir Tygerberg Hospitaal se voorgeboorte pasiente. Hierdie vraelys is getoets by 200
pasiente in die voorgeboorte klinieke in Tygerberg Hospitaal deur middel van 'n gestruktureerde
onderhoud.
In die geldigheidsbepaling van die meetinstrument 1s die belangrikheid van kruiskulturele
navorsing beklemtoon. Faktoranalise is gebruik vir die bepaling van geldigheid. Met
faktoranalise is aangetoon dat een onderliggende faktor, naamlik die voorgeboortesorgsisteem,
pasiente se tevredenheid verklaar.
Die bevindings in hierdie ondersoek het die volgende getoon:
• Dat aile meetinstrumente nie summier transkultureel toegepas kan word nie .
• Dat die tevredenheidsmeting van voorgeboortesorg 'n negatiewe skewe verspreiding het, met
'n hoe gemiddelde telling.
• Sosiaal-aanvaarbare antwoorde speel waarskynlik 'n groat rol in hierdie vraelyste.
• Dat daar 'n statistiese betekenisvolle verskil is in die tevredenheidsgraad van pasiente met
voorgeboortesorg tussen sommige klinieke; selfs nadat gekontroleer is vir sosiodemografiese
verskille tussen pasiente.
• Dat die tevredenheidsmeting 'n weerspieeling is van die diens gelewer aan die pasient, en nie
net 'n weerspieeling is van die pasient se sosio-demografiese verskille nie.
Hierdie navorsmg identifiseer die probleme met die opstel van 'n gestandaardiseerde
meetinstrument vir die bepaling van pasente se tevredenheid met voorgeboortesorg en baan die
weg vir verdere navorsing oor pasiente se tevredenheid met mediese dienste.
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Evaluation of gamete dysfunction as a cause of failed human in vitro fertilizationEsterhuizen, Aletta Dorothea 12 1900 (has links)
Thesis (D.Phil.)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Chapter 1 provides literature based background information on the clinical
importance of sperm morphology as recorded by strict criteria during the
diagnostic approach of the infertile couple. Furthermore, the use of a sequential
diagnostic schedule for couples in an assisted reproductive programme is
emphasized. The author revisited the literature on chromatin packaging of
spermatozoa and addresses this issue as an additional semen parameter
providing information relating to DNA damaged spermatozoa. The chapter also
includes evidence underlining the growing need for the implementation of the
acrosome reaction as an important contribution to the assisted reproductive
programme. Chapter 2 provides detailed descriptions of the material and
methods used during the study. Chapter 3 is sub-divided into 5 sections, each of
which represents a separate study that was prepared as a scientific paper. The
study included 338 couples consulting for infertility treatment at various
gynaecologists in Pretoria and Johannesburg. The diagnostic assisted
reproductive laboratory support was provided by the Andrology laboratory of Drs
du Buisson and partners from Pretoria. In the first study the role of chromatin
packaging as an indicator of in vitro fertilization rates, the semen samples from
72 men were used to record their chromatin packaging quality as well as their
sperm morphology classification. Significant different percentages CMA3staining
(mean±SE) were recorded among the 2 morphology groups, namely 65.9%±3.5
and 44.5%±1.7 (p=0.001). Using cut off values for chromatin packaging
established during the first study, the second study utilized semen from 140 men in the in vitro fertilization (IVF) and intracytoplasmic sperm injection programme
(ICSI) to analyze for sperm concentration, motility, morphology and chromatin
packaging (CMA3).IVF and ICSI data were stratified using 3 basic cut off values
for CMA3staining, namely <44%, >44-60% and >60%. The study concluded that
results on the chromatin packaging quality of spermatozoa could be used as an
additional parameter of sperm quality since it could provide valuable information
on decondensation status of a given sperm population. The third study aimed to
establish zona pellucida induced acrosome reaction response (ZIAR) among 35
couples with normal and G-pattern sperm morphology and repeated poor
fertilization results during assisted reproduction treatment. Interactive dot
diagrams, divided patients into 2 groups i.e. ZIAR<15% and ZIAR>15% with
mean fertilization rates of 49% and 79%, respectively. The study concluded that
the ZIAR test has diagnostic potential, since it can assist the clinician to identify
couples that will benefit from ICSI therapy. The forth study revisited the
importance of micro-assay for acrosome reaction determinations in a diagnostic
andrology laboratory. The micro-assay not only allows the use of a single zona
pellucida, but also facilitates the future possibility of using recombinant zona
pellucida proteins in a diagnostic test system. The final study in Chapter 3
includes results obtained from 49 couples (172 oocytes) and aimed to evaluate
the role of chromatin packaging and sperm morphology during sperm-zona
binding, sperm decondensation and the presence of polar bodies among 170
oocytes that failed in vitro fertilization (IVF). Odds ratio analyses indicated that
being in the a group with elevated CMA3 staining i.e. >60%, the risk of decondensation failure increases 15.6 fold relative to normal CMA3 staining
<44%. Chapter 4 underlines the validity of the sequential diagnostic approach
and summarizes the results and value of a multistep diagnostic scheme. The
chapter concludes with the recommendation that both chromatin packaging
quality and zona pellucida mediation of the acrosome reaction should be part of
the diagnostic tools in the assisted reproductive programme. / AFRIKAANSE OPSOMMING: Die literatuuroorsig in Hoofstuk 1 konsentreer in hoofsaak op die kliniese belang
van sperm morfologie en die uitbreiding van die diagnostiese toetse en hantering
van die egpaar in die reproduktiewe ondersteuningsprogram. Die kromatien
pakkingskwaliteit van die spermsel word onderskryf as In belangrike toevoeging
tot die diganostiese program, aangesien ONS skade dikwels saam met
kromatiendefekte aangetref word. Die rol van die akrosoomreaksie word ook in
detail literatuuroorsigtelik beklemtoon. Hoofstuk 2 bevat volledige inligting
omtrent materiaal en metodes wat in die studie gebruik is. Hoofstuk 3 bevat die
eksperimentele gegewens wat in 5 afsonderlike sub-afdelings as wetenskaplike
publikasies aangebied word. Die studies bestaan uit data van 338 pasiënte, wat
deur verskillende ginekoloë van Pretoria en Johannesburg gekonsulteer is
waartydens drs. du Boisson en vennote van Pretoria die diagnostiese
reproduktiewe laboratoriumdienste verskaf het. Die eerste studie stel dit ten doel
om die belang en korrelasie van die spermsel kromatienpakkingskwaliteit van 72
mans te vergelyk met die morfologiese bou van sie sel. Aangesien morfologie
reeds gevertig is as 'n kliniese voorspeller van bevrugting was dit nodig om
hierdie parameter te vergelyk met die kromatienpakking van die sel. Twee
afsnypunte word vir die normo-en teratozoospermiese mans identifiseer naamlik,
44.5%±1.7 en 65.9%±3.5 (p=O.001),respektiewelik. Die tweede studie gebruik
die afsnypunte 44% en 66% om die in vitro bevrugting en intrasellulêre sperm
inspuiting (ICSI) data te ontleed. Die resultate dui aan dat kromatienpakking In
waardevolle bydrae tot die diagnostiek van die pasiënte lewer. Die derde studie stel dit ten doelom die waarde van die zona pellucida geinduseerde
akrosoomreaksie (ZIAR) te bepaal. Die studie sluit die data van 35 egpare in wat
almal normale of G-patroon morfologie het en verder onverklaarde swak
bevrugtings resultate tydens in vitro bevrugtingsterapie. Interaktiewe punt
diagram (interactive dot diagrams) verdeel die data in twee groepe naamlik,
ZIAR<15% en ZIAR>15% met gemiddelde bevrugtingssyfers van 49% en 79%,
respektiewelik. Die studie sluit af met die gedagte dat die ZIAR toets 'n groep
pasiënte identifiseer met 'n besondere fisiologiese afwyking d.i. subnormale
akrosoom respons op zona pellucida blootstelling. Die vierde afdeling van die
hoofstuk onderstreep die belang van die mikro-tegniek vir die bepaling van die
akrosoom reaksie, wat tydens die projek gebruik is Die vyfde afdeling van
Hoofstuk 3 stel dit ten doelom 170 onbevrugde eierselle van 49 pasiënte te
ontleed vir moontlike oorsake vir die mislukte bevrugting. Ondersoeke sluit in die
kromatienpakking, sperm-zona binding, sperm dekondensasie en die
teenwoordigheid van polêre liggaampies. Statisties blyk dit dat indien 'n
kromtienpakking nie normaal is nie (>66%) het die spermsel 'n 15 keer groter
kans om nie te dekondenseer nie. Hoofstuk 4 bespreek die noodsaaklikheid van
die diagnostiese skedule by die hantering van die onvrugbare egpaar in.
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Obsessive-compulsive disorder : serotonergic and dopaminergic system involvement in symptom generation and treatment responseCarey, Paul D. (Paul Dermot) 03 1900 (has links)
Thesis (PhD)--Stellenbosch University, 2008. / ENGLISH ABSTRACT: Investigations into the neurobiology of obsessive-compulsive disorder (OCD) have provided useful insights into this prevalent and disabling disorder in recent decades. Encouraging advances have also been made in the pharmacological treatment of OCD. This has improved the quality of life for many who typically endure chronic unremitting symptoms. Despite the widespread use of first-line agents selective for the serotonergic system in OCD, relatively little is known about the neurobiology of treatment response, the specific components of the serotonin system involved in symptom modulation, and the overlapping and distinct brain regions impacted by alternative treatment options. Despite the advance that selective serotonin re-uptake inhibitors have been, a significant proportion of patients still fail to respond adequately to these agents, and alternative pharmacological interventions are required. The use of dopamine antagonists, a strategy which until recently has had only limited supporting data, presents one such alternative. Little however, is known about which subsets of patients are most likely to respond to these agents.
In this thesis, I will present a series of six studies that use pharmacological treatments and single photon emission computed tomography (SPECT) to make contributions to three primary areas in OCD namely; neurobiology, treatment and the intersection of the two. First, I address OCD neurobiology by examining the impact of OCD on resting brain function. I then examine the effects of pharmacological challenge of the serotonin 1B receptor using sumatriptan on regional cerebral blood flow (rCBF) and clinical symptomatology. Second, I examine the intersection of neurobiology and treatment as I explore the changes in rCBF in response to treatment with inositol, a precursor of the phosphoinositol second messenger system. I then examine the distinct and overlapping effects on rCBF of treatment for 12 weeks with the selective serotonin re-uptake inhibitor (SSRI) citalopram across anxiety disorders. Third, I address treatment of OCD by examining the efficacy of controlled augmentation of serotonin re-uptake inhibitors with quetiapine, a dopamine antagonist, in treatment refractory OCD. I then combine this data with a second similar dataset to derive a predictive model for treatment outcome with quetiapine augmentation of SRIs. I demonstrate that rCBF in OCD differs significantly from normal controls, is correlated with severity in frontal brain regions, and remains an important line of investigation for OCD pathophysiology that has yet to fully delineated. Pharmacological challenge of the 5HT1B autoreceptor with the selective agonist sumatriptan results in heterogeneous behavioural and regional brain perfusion changes in OCD. Attenuation of pre-frontal perfusion following 5HT1B agonist administration is in line with the effects of SRIs. This work suggests that direct or indirect effects of SRIs on the 5HT1B receptor may be involved in mediating a clinical response in OCD.
In the section exploring the intersection of neurobiology and treatment, I show that changes in rCBF partially parallel treatment response to SSRIs across a range of anxiety disorders. These data suggest that a degree of overlap exists in the neurobiology of treatment response or indeed core neurobiology across different anxiety disorders. I then show that effective treatment with inositol in OCD results in rCBF changes that are partially in line with the effects of SRIs on brain perfusion. These data support suggestions that second messengers may form part of the common pathway of action for effective anti-obsessional compounds.
In the study in which we augmented SRIs with quetiapine, no advantage over placebo was found. This data has, however, recently been combined with similar data in meta-analyses and demonstrated a benefit over placebo. Finally, we found that patients who have failed fewer SRI trials, have more severe illness, and clinical dimensions with a putative dopaminergic underpinning, may derive preferential benefit from serotonin/dopamine antagonist augmentation of SRIs.
Through this series of clinical treatment and functional brain imaging studies in OCD, I have contributed to the neurobiological understanding of OCD, and its treatment in refractory populations. In addition I have explored the intersection of these two domains using novel as well as conventional treatment across other anxiety disorders. Treatment and pharmacological challenges used, either directly or indirectly impacted the monoamine systems serotonin and dopamine and advanced our understanding of their involvement in symptom generation. Future work should focus on the functional intersection of brain function, treatment response, and functional genetic polymorphisms within the monoamine systems of the brain. / AFRIKAANSE OPSOMMING: Ondersoek na die neurobiologie van obsessief-kompulsiewe steuring (OKS) het in die afgelope dekades sinvolle bydraes gelewer tot die begrip van hierdie algemene en verminkende steuring. Bemoedigende vordering is ook in die farmakologiese behandeling van OKS gemaak. Dit het tot ’n verbetering in kwalitiet van lewe van meeste pasiënte gelei wat normaalweg kronies en onophoudelike simptome moet verduur. Ten spyte van die uiteenlopende gebruik van eerste-linie behandeling wat spesifiek inwerk op die serotonien sisteem in OKS, is relatief min bekend oor die neurobiologie van respons op behandeling. So ook is min bekend oor; eerstens die spesifieke komponente van die serotonien sisteem wat betrokke is by simptoom modulasie, en tweedens die gedeeltelik samevallende en afsonderlike brein streke wat deur alternatiewe farmakologiese behandelings beïnvloed word. Ten spyte van die vooruitgang wat die selektiewe serotonien heropname inhibeerders tot gevolg gehad het, is daar nog altyd ‘n betekenisvolle proporsie van pasiënte wat nie voldoende respondeer op hierdie behandelings opsie nie. Dus word alternatiewe opsies benodig. Een so ‘n opsie is die klas dopamien reseptor blokkeerders wat tot onlangs min ondersteunende data gehad het. So ook, is min bekend oor die subgroepe van pasiënte wat die meeste voordeel uit hierdie alternatief sal trek.
In hierdie proefskrif sal ek ‘n reeks van ses studies wat farmakologiese middels en enkel foton emissie rekenaar tomografie (EFERT) gebruik om ‘n bydra tot kennis in drie primêre areas van OKS te maak. By name; neurobiologie, behandeling, en die kruispunt van die twee. Eerstens spreek ek neurobiologie aan deur middel van ’n studie wat rustende brein bloed vloei (rBBV) in OKS ondersoek. Hierna ondersoek ek veranderings op rBBV en simptome na eenmalige toediening van ‘n serotonien 1B reseptor agonis, sumatriptan. Tweedens ondersoek ek die kruispunt van neurobiologie en behandeling deur die effek van behandeling met inositol, ‘n voorloper van die fosfoinositol tweedeboodskapper sisteem, op rBBV. Ek ondersoek dan die rBBV patroon van veranderinge in brein streke wat deur twaalf weke van behandeling met die selektiewe serotonien heropname inhibeerder citalopram in verskeie angversteurings bewerkstellig word. Laastens, spreek ek behandeling van OKS aan deur middel van ‘n gekontroleerde studie wat ondersoek instel na die effektiwiteit van die byvoeging van quetiapien, ‘n dopamien reseptor antagonis, tot serotonien heropname inhibeerders in behandelingsweerstandige OKS. Ek kombineer dan hierdie data met ’n soortgelyke datastel om ‘n model af te lei wat kliniese uitkoms vir hierdie behandelings opsie voorspel.
Ek het gedemonstreer dat rBBV in OKS betekenisvol verskil van gesonde vergelykbare kontroles. Hierdie verskille het gekorreleer met ernstigheid van OKS in frontale brein streke. Dus bly hierdie tipe studies ’n belangrike rigting van ondersoek in OKS patofisiologie wat tot op hede nie tenvolle uitgewerk is nie. Eenmalige toediening van sumatriptan, het heterogene gedrags en rBBV veranderings in OKS tot gevolg gehad. Pre-frontale verhogings in rBBV voor behandeling is met 5HT1B sumatriptan toediening verminder, ’n effek wat in lyn staan met die effek van selektiewe serotonien heropname inhibeerders. Hierdie werk stel voor dat direkte of indirekte effekte van selektiewe serotonien heropname inhibeerders op die 5HT1B reseptore betrokke mag wees by die meganisme van behandelingsrespons in OKS.
In die afdeling waarin ek die kruispunt van neurobiologie en behandeling ondersoek, demonstreer ek dat rBBV veranderings gedeeltelik oorvleuel met dié wat deur selektiewe serotonien heropname inhibeerders veroorsaak word in verskeie angsversteurings. Hierdie data stel voor dat oorvleueling in die neurbiologie van beide behandelingsrespons en kern neurobiologie van hierdie angversteurings ’n waarskynlikheid is. Ek wys ook dat effektiewe behandeling met inositol in OKS ook veranderings in rBBV bewerkstellig wat gedeeltelik in lyn staan met dié van die selektiewe serotonien heropname inhibeerders. Hierdie data ondersteun dus hipoteses van ‘n gemeenskaplike meganisme, wat tweede boodskapper sisteme insluit, wat in die behandelings respons van effektiewe anti-obsessionale middels betrokke is.
Die finale deel van hierdie proefskrif handel oor behandeling van OKS. Ten spyte van die onvermoë om ‘n verskil tussen quetiapien en plasebo te demonstreer, het ons onlangs met hierdie data in ‘n reeks meta-analises wel ‘n voordeel vir hierdie intervensie getoon. Ten slote, het ons gevind dat (1) pasiënte wat minder kursusse selektiewe serotonien heropname inhibeerders gefaal het; (2) voor behandeling ‘n erger vorm van OKS gehad het, en (3) ook voordoen met simptoom dimensies wat oënskynlik ‘n dopaminerge basis het, die grootste waarskynlikheid toon om met quetiapien byvoeging tot selektiewe serotonien heropname inhibeerders te respondeer.
Met hierdie reeks behandelings en funksionele breinbeeldings ondersoeke, lewer ek ‘n bydra tot die begrip van OKS. Spesifiek dra ek by tot die begrip van die neurobiologie, hantering van behandelingsweerstandige OKS asook die kruispunt van die twee. Farmakologiese middels wat ons óf eenmalig óf vir ‘n volle behandelingskursus toegedien het, het direkte of indirekte uitwerkings op die serotonien and dopamien sisteme gehad, en dus dra hierdie werk ook by tot kennis oor dié se betrokkenheid al dan nie in simptoom modulasie in OKS.
Toekomstige werk in die area sal in die breë fokus op die kruispunt van breinfunksie, behandelingsrespons en funksionele genetiese polimorfismes van die monoamien sisteem.
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The effects of physical and psychological stress on the behaviour and neurochemistry of ratsVan Vuuren, Petra J. 12 1900 (has links)
Thesis (MSCMedSc (Biomedical Sciences. Medical Physiology))--University of Stellenbosch, 2005. / Stress is considered one of the major factors involved in the pathogenesis of affective disorders, for example, direct and indirect exposure to terrorist attacks or being subjected to subtle victimization. There is a long history of development of procedures to determine anxiety responses in animals in order to find new or better treatments for patients. Prior stress exposure is known to alter the activation response to a subsequent stressor and the means of coping with stress can influence health and disease. This orchestrated process, usually referred to as the “stress response”, involves various mechanisms, which allow the body to make the necessary physical, psychological and the neuro-endocrine adjustments required to cope with the demands of a homeostatic challenge.
The communication box method is a useful model to investigate the physiological changes that occur under psychological stress, since it can produce an experimental anxiety based on psychological communication between two or more animals, without the direct physical stress. In this animal model, the psychologically stressed rats are exposed to the visual, olfactory, auditory stimuli (such as struggling, vocalization, defecating, urinating and jumping) from the foot shock rat (Oishi et al., 2003). In the present study, we examined the neuro-endocrine and behavioural responses after different durations of inescapable foot shock and the subsequent effect of citalopram (10 milligram/kilogram, intraperitoneal once a day for 10 days), a selective serotonin reuptake inhibitor in reversing these responses. We have subjected rats to a number of stress paradigms (varying in duration), and assessed the effects thereof on behaviour at two different time points. Physically stressed rats were subjected to 10 unpredicted electric foot shocks (0.5 milliampere), in 10 minutes, while the psychologically stressed rats witnessed everything. The behavioural responses were assessed 5 days and 10 days after the last stress session. The rats were decapitated and corticosterone concentrations were determined one day after the open field and elevated plus-maze tests were performed.
The behavioural and endocrine responses in the rats subjected to physical and psychological stress in this study showed that single stress exposure may lead to different outcomes as repetitive stress exposure and that the consequences of stress exposure develop over time and persist for an extended time period. These consequences of direct stress exposure versus indirect stress exposure show a grading in stress intensity and perception, similar to that observed in humans. In the experiment where the rats where treated with citalopram, it showed that citalopram is effective in reversing anxious-like behaviours, but not locomotor deficits. In all the animals basal plasma corticosterone concentrations were comparable and physically and psychologically stressed rats displayed a hyposensitive hypothalamic-pituitary-adrenal axis following acute restraint stress. These findings are interesting in a number of ways. It showed that our stress models propose to be useful in elucidating the complex interrelationship between an external event or stressor, and the organism experiencing it. Simultaneously it presents a promising platform for the finding of new or better treatments for patients.
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The trafficking of the Mycobacterium tuberculosis PE and PPE proteinsMahasha, Phetole Walter 12 1900 (has links)
Thesis (MScMed (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2007. / The expansion of the Mycobacterium tuberculosis PE and PPE gene families seems to be linked to that
of the immunologically-important ESAT-6 (esx) gene clusters secretion system, as the ancestral
members of these families are found only within the ESAT-6 gene cluster regions. These ancestral
members are also the only copies in the earlier mycobacteria like M. smegmatis. The later duplications
of the PE and PPE families belonging to the PGRS and MPTR subgroups, have been implicated in
virulence and are only found within the genomes of the pathogenic mycobacteria closely related to the
M. tuberculosis complex. The aim of this study was to compare the subcellular localization of the later
duplications of the PE and PPE gene families belonging to the PGRS and MPTR subgroups with that of
the ancestral PE and PPE proteins found in M. smegmatis and to investigate whether the ESX secretion
apparatus is involved in the trafficking of these proteins. The PE (Rv3872) and PPE (Rv3873) genes
from M. smegmatis were PCR amplified with a C-terminal HA tag using M. smegmatis genomic DNA as
template. Two PPE-MPTR genes, Rv0442c and Rv0878c, and one PE_PGRS gene, Rv2615c, were
also PCR amplified with a C-terminal HA tag using M. tuberculosis genomic DNA as template. All
genes were cloned into the mycobacterial expression vector p19Kpro. Expression and localization was
investigated using SDS-PAGE and Western blotting. The PE and PPE genes expressed in M.
smegmatis were found to be present within the cell wall, membrane, and cytosol fractions, but not in the
culture filtrate, indicating no secretion. The PPE-MPTR and PE_PGRS genes expressed in M.
smegmatis, were also found to be present within the cell wall, membrane and cytosol fractions, but not
in the culture filtrate, indicating that they are also not secreted. We hypothesize that their secretion is
dependent on ESAT-6 gene cluster region 5, which is absent from the genome of M. smegmatis.
Ancestral PE and PPE proteins are secreted efficiently in M. tuberculosis. The ESAT-6 gene cluster
Region 3 and Region 4 of M. smegmatis were knocked out, and these knockout mutants could be used
in future studies to investigate if the ESAT-6 gene cluster region 1 is involved in the secretion of the
ancestral and recent PE and PPE proteins.
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Identification of the modulators of cardiac ion channel functionCarstens, Johanna J. 03 1900 (has links)
Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009. / The human ether-à-go-go-related gene (HERG) encodes the protein underlying the
cardiac potassium current IKr. Mutations in HERG may produce defective channels and
cause Long QT Syndrome (LQTS), a cardiac disease affecting 1 in 2500 people. The
disease is characterised by a prolonged QT interval on a surface electrocardiogram and
has a symptomatic variability of sudden cardiac death in childhood to asymptomatic
longevity. We hypothesised that genetic variation in the proteins that interact with HERG
might modify the clinical expression of LQTS. Yeast two-hybrid methodology was used
to screen a human cardiac cDNA library in order to identify putative HERG N-terminus
ligands. Successive selection stages reduced the number of putative HERG ligandcontaining
colonies (preys) from 268 to 8. Putative prey ligands were sequenced and
identified by BLAST-search. False positive ligands were excluded based on their
function and subcellular location. Three strong candidate ligands were identified: Rhoassociated
coiled-coil containing kinase 1 (ROCK1), γ-sarcoglycan (SGCG) and
microtubule-associated protein 1A (MAP1A). In vitro co-immunoprecipitation (Co-IP)
and mammalian two-hybrid (M2H) analyses were used to validate these proposed
interactions, but failed to do so. This should be further investigated. Analysis of
confirmed interactions will shed light on their functional role and might contribute to
understanding the symptomatic variability seen in LQTS.
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An in vitro investigation of the anti-inflammatory and immunosuppressive effects of the synthetic contraceptives medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A)Kriek, W. J. 03 1900 (has links)
Thesis (MScMedSc (Pathology. Medical Microbiology))--University of Stellenbosch, 2005. / The aim of this study was to investigate the anti-inflammatory and
immunosuppressive effects of the synthetic progestins, MPA and NET-A on human
cells in vitro. These injectable contraceptives are used extensively throughout the
world, including Africa. The potential of these two synthetic hormones to have
certain immunosuppressive and GC properties have previously been shown.
Therefore, it was of concern to us to investigate whether these two hormones could
possibly demonstrate any of these GC-like properties at contraceptive doses. This
was achieved by determining the effects of these two synthetic hormones in vitro on
certain immunologic parameters.
Chapter 1 is a literature review on MPA, NET and GCs. This chapter starts with a
short introduction that sets the scene. The mode of action, effectiveness, sideeffects
as well as previously reported relevant data on both MPA and NET-A is
portrayed in this review. Research on the known GC, Dex, is also included in the
section dealing with GCs, because this synthetic hormone was used as a
comparative GC in all our experiments. This chapter soon makes the reader realize
how much evidence exists that indicate the possible immunosuppressive effects
these two contraceptive hormones, in particular MPA, could have.
The possible anti-inflammatory or pro-inflammatory effects of MPA and NET-A are
investigated in Chapter 2. This was done in vitro by measuring the effects of these
two synthetic hormones on the inflammatory markers, IL-6 and TNFα, by means of ELISA. In this chapter we demonstrate that MPA, even at contraceptive doses,
exhibits significant anti-inflammatory properties on both cytokines tested, while NETA
displayed considerably less anti-inflammatory tendencies. In its true antiinflammatory
manner, we found that Dex significantly inhibited the release of both
inflammatory markers from human monocytes.
In Chapter 3, we investigated the effects of MPA and NET-A on the activation of
human lymphocytes. This was achieved by flow cytometric measurement of the
expression of the activation membrane marker CD69 by CD4 and CD8 T cells. Here
we discovered that MPA had a very significant inhibitory effect on the activation of
both CD4+ and CD8+ T cells, while NET-A only significantly inhibited the activation of
CD8+ T cells. In addition, we found that the inhibition of CD4+ and CD8+ T cell
activation by MPA was more or less the same as the known GC, Dex, and in some
cases even more potent.
Chapter 4 consists of an investigation of the effects of MPA and NET-A on the
cytokines belonging to TH1 and TH2 subsets of CD4 T cells. This was achieved by
determining whether MPA and/or NET-A targeted specific subsets of T helper cells
by measuring the distinct regulatory cytokines, IFNγ and IL-4. The mechanism and
role of the T helper subsets are discussed in the introduction of this chapter. Our
results were portrayed as a ratio of TH2: TH1 on which the statistical analysis was
done. In addition to the analysis done on the ratio, we analyzed the helper subsets
separately in order to determine which subset(s) were influenced. The results of this chapter showed that neither MPA nor NET-A significantly affected either one of the
helper subsets, while Dex significantly decreased this ratio.
After our observed effects of MPA and NET-A on CD8 T cells, it became of interest
in Chapter 5 to investigate the effects of these two synthetic hormones on the CD8 T
cell-specific chemokine, RANTES. This was achieved by measuring the effects
MPA and NET-A had on RANTES production in vitro by means of ELISA.
Surprisingly, we discovered in this chapter that MPA and NET-A enhanced RANTES
production before and after activation of CD8 T cells. We also found that Dex had
the same effect on RANTES production, but to a lesser degree.
Finally, a general conclusion depicting the significance and implications of our
results as well as possible future research that is required is presented in Chapter 6.
It was of great importance to discuss and interpret the magnitude of data generated
out of all our experiments to the utmost of our capabilities. We found that MPA,
even at contraceptive doses, displayed significant immunosuppressive as well as
anti-inflammatory properties. NET-A, on the other hand, demonstrated weaker
immunosuppressive properties in our research and no significant anti-inflammatory
properties. These findings could have clinical implications in females being treated
with these synthetic contraceptives. We also demonstrated significant variation
found amongst genders in response to MPA, NET-A and Dex.
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