The studies documented here have demonstrated that similar to joint arthroplasty, VP causes FE with cardiovascular changes. Following the augmentation of each VB there is a transient acute response affecting the homeostasis of the cardiovascular system. This response is biphasic. Phase 1 was seen within 3 s after the beginning of bone cement injection and is likely to be due to a autonomous nerve reflex. Phase 2 was observed within ~16 s, reaching a peak response after ~30 s returning to a steady state between I and 5 minutes (approximately 10 % below pre-injection baseline). Consequently multiple VP caused baseline cardiovascular variables to progressively deteriorate. This fundamental response occurred whether bone cement or bone wax was used. A vent-hole did not prevent the peak response but attenuated the progressive deterioration of the baseline. Pathomechanism of Fat Embolism: The exact mechanism(s) responsible for the cardiovascular responses to FE are still not entirely clear. However several theories have been put forward in the literature (see Chapter 1). The present studies have eluciated the role of some of these variables. The primary mechanism responsible for FE has been attributed to an increase in IMP (Breed, 1974; Engesaeter et al., 1984; Orsini et al., 1987, Hofmann et al., 1999). The present investigation measured the IMP during VP and found that the peak increase in IMP (>500mmHg) was similar to that reported for arthroplasty. The consequences of an increase in IMP are 1) a release of bone marrow content into the venous system and 2) a likely stimulation of nerve endings within the bone marrow cavity. By using transoesophageal echocardiography, this thesis provides evidence that the emboli originate from the bone marrow cavity and not from the agglutination of plasma fat. Because the cardiovascular response was seen in the first seconds after the pressurisation (phase 1) and before the bone marrow content had reached the lung, it is most likely that this reaction was triggered by a nerve reflex. On the basis of either an up regulation of the vagus or a down regulation of the sympathetic tone. Pressurisation with bone cement and bone wax caused similar cardiovascular deterioration, which clearly gives evidence that bone cement monomer is not the only factor in this process. In the vent-hole group there was also a similar phase 1. Although the IMP was not measured in this group it is likely that the peak IMP was less in the vent hole group but still exceeding the threshold for nerve reflex stimulation. After the initial cardiovascular response (fall in HR and MABP) a secondary cardiovascular response occurred (phase 2). Two possible mechanisms responsible for phase 2 are: 1) the effect of the released bone marrow content and its mediators on the pulmonary and systemic vascular system and 2) continuous stimulation of nerve endings within the VB caused by the pressure of the injected material. Phase 2 was characterised by an increase in PAP and CVP and a decrease in MABP starting ~16 seconds after the beginning of the bone cement / bone wax injection. The time and response pattern for phase 2 was similar for each augmentation (VP1-VP2) and similar between the groups. This similarity gives evidence that the peak responses were a result of a reflex vasoconstriction of the lung vessels to the microembolisation of bone marrow particles (Byrick et al., 1989; Woo et al., 1995). Other authors also have reported that an increase in PVR was observed during FE (Wheelwright et al., 1993; Byrick et al., 1994), but this work is the first to suggest that a pulmonary vasoconstriction reflex may be involved. This is the first study which measured the cardiovascular responses during FE continuously, unlike other studies which measured responses after 3 to 5 minutes (Wheelwright et al., 1993; Byrick et al., 1994). In the vent-hole group, Q was also measured during the transient response and therefore it was possible to calculate the PVR. The results showed that PVR was increased 3 to 5 times the pre-injection value at the peak response proving evidence that an increase in PVR is likely to be responsible for the increase in PAP and CVP and the decrease in MBP Based on the observation that the wax and non-vent hole groups had similar peak responses to the vent hole group for PAP, CVP and MBP it can be concluded that PVR responses are also similar for all the groups. The bone cement and the bone wax group had similar peak responses, therefore bone cement monomer can not solely be responsible for the vasoconstriction of the lung vessels. Although the amount of the fat was likely to be reduced by using a vent-hole the peak responses were similar. This suggests that even a reduced amount of bone marrow content released in the vent-hole group exceeded the 'threshold' for initiating a reflex response. The fact that a certain threshold has to be reached to initiate a reflex response may explain why only a small percentage of patients develop FE during arthroplasty. Small amounts of bone marrow may not trigger the reflex. This finding is of significant clinical relevance as far as VP is concerned. To prevent the initiation of the reflex during injection of bone cement for VP or implantation of a prosthesis has to be performed as slowly as possible to reduce the amount of bone marrow content released into the circulation which reduces the risk of triggering reflex pulmonary vasoconstriction. The problem with medium viscosity bone cement used in this study is that it cures too rapidly. Therefore it is essential to find a bone cement material which can be injected much slower to reduce the amount of bone marrow content released and, consequently, the chance of triggering a nerve reflex. These findings are also relevant for joint arthroplasty. By reducing the injection pressure less bone marrow content is released into the circulation and the chances of initiating this reflex mechanism are minimised. Future studies are required to measure the cardiovascular changes by injecting bone cement at low speed. Because such bone cement is not yet available, it would be possible to use calcium phosphate cements instead. A similar amount of fat would be released but whether the magnitude of the cardiovascular effect is altered would be interesting to explore. The recovery of PVR was responsible for the recovery of MABP. This was quicker in the bone wax group compared to the group where bone cement was used. It is therefore likely that the bone cement monomer has a vasoconstrictor effect on the vascular system of the lung. Alternatively bone cement has been implicated in the increase of circulation levels of coagulating substances such as thrombin or fibrinopeptides (Dahl et al., 1988; Sharrock et al., 1995). However we could not demonstrate that bone cement monomer altered the peak reflex response. Several authors have implicated bone cement monomer as having an effect on the cardiovascular system (Berman et al., 1974). This is the first study which provides compelling evidence that bone cement plays a role during FE. The peak response for HR was different in the bone wax group compared to the cement groups. With bone wax HR decreased during phase 2 whereas with bone cement HR gradually increased. From the previous study we know that the fall in MABP and HR in phase 1 is caused by a nerve reflex (Chapter 3). This would normally result in an increase in sympathetic activity. In the bone cement group the primary peripheral vasoconstriction response was attenuated resulting in a secondary increase in HR in order to restore MABP. This dulled response may be attributed to the bone cement monomer. However in the bone wax group the sympathetic response caused a severe and rapid vasoconstriction to restore MABP. Therefore an increase in HR did not happen and HR dropped further in phase 2. This result may have a major impact on the clinical use of bone cement in the future, especially when treating patients with cardiovascular risk factors. Baseline Changes: The injection of five consecutive VB in the same animal caused a progressive decrease in MABP in all groups. The fall in MABP was primarily correlated to SVR. The fall in SVR is mostly likely caused either by: 1) vasoactive substances, or 2) a decrease in sympathetic tone. A vent hole was able to attenuate the progressive decrease in MABP. Because the quantity of bone marrow content released into the circulation was lower in the vent-hole group, compared to the bone cement group, the amount of vasoactive substances would also be lower in this group. This suggests that vasoactive substances are responsible for the decrease in SVR. The quantity of injected PMMA was not different between the vent hole and bone cement group. Therefore, the methylmethacrylate monomer does not seem to play a major role in the development of the fall in baseline MABP during multiple VP. The fact that the decrease in MABP was similar in the bone cement and bone wax group supports this theory as well, since a similar amount of bone marrow is released. Blood Gas Changes: In the present study, multiple VP induced prolonged hypoxaemia, hypercapnia and acidosis. According to the literature, the likely cause for these changes in arterial blood gases is ventilation-perfusion (V/Q) mismatch and pulmonary shunting, which is a consequence of the fat and marrow particles causing microembolisation of the pulmonary vessels (Modig et al., 1974; Pitto et al., 1998). The V/Q mismatching may also be accentuated by mediators causing pulmonary vasoconstriction (Woo et al., 1995). The severity of V/Q mismatch is likely to be correlated to the amount of bone marrow reaching the lung which was similar in the bone wax and bone cement group. A vent hole reduced the amount of fat released and therefore the mismatch. Consequently, PaCO2 and pHa did not significantly change and the fall in PaO2 in the vent hole group was less than the bone cement group. Similarly, Pitto et al. (1999) reported that the hypoxaemia that normally develops during hip arthroplasty, can be prevented if a vent hole is drilled into the distal femur and a vacuum applied. Clinical Implications: Surgeons have to be aware that FE occurs during VP and is similar to what happens during arthroplasty. Therefore VP can potentially cause hypotension, cardiac arrest and even death (personal communication with Prof. Jens R. Chapman). The potential risk increases with the number of augmented VBs. As a result of the current work it has been shown that a maximum of 3 - 4 VBs can be augmented safely in one operation and that cardiovascular monitoring is mandatory. A vent hole is also recommended to attenuate the adverse cardiovascular response. The use of bone substitute material does not reduce or prevent the risk of FE and consequently similar precautions are recommended.

Typewritten copy / 246 p. : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1957

Obesity is a chronic condition that primarily develops from an increase in body fat in the form of white adipose tissue (WAT) mass. The resulting adiposity is a risk factor for many diseases, including type 2 diabetes (T2D), cardiovascular diseases, and some forms of cancer. Reducing WAT mass by targeted modulation of metabolic enzymes in fat cell metabolism is an attractive molecular therapeutic alternative to dietary approaches. In the present study, we exogenously up-regulate a novel respiratory uncoupling protein to increase substrate oxidation, and thereby control adipocyte fatty acid content. Increasing molecular evidence points to a family of uncoupling proteins (UCPs) playing an important role in adipocyte fat metabolism. Of specific interest is UCP1, which in brown adipocytes mediates energy dissipation as heat by de-coupling respiration and ATP synthesis. UCP1 is minimally expressed in white adipose tissue (WAT). We hypothesize that controlled expression of UCP1 in WAT will result in enhanced fatty acid oxidation to compensate for reduced ATP synthesis. We used a Tet-Off retroviral transfection system to express UCP1, with doxycycline being used to control the extent of expression. UCP1 cDNA was cloned into pRevTRE and was stably transfected into 3T3-L1 preadipocytes prior to differentiating them into adipocytes. A reporter gene (EGFP) was also transfected in parallel to optimize the transfection and preadipocyte differentiation conditions as well as to demonstrate regulated expression. Metabolite measurements showed that the UCP1-expressing adipocytes accumulated 83% less triglyceride and 85 % free fatty acids while maintaining constant ATP levels. These results suggest UCP1 and other metabolic enzymes as potential targets for development of pharmacological agents for the treatment of obesity and related disorders.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Psychology. Title from title-page of electronic thesis. Bibliography: leaves 90-107.

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Background One of the challenges to public health in Sweden is the consumption of excessive saturated fat and too little unsaturated fat. The National Board of Health and Welfare (NBHW), the Swedish National Food Agency (SNFA) and the health sector work together to tackle such challenges, through educating the public on healthy dietary habits. The SNFA provides guidelines for all nutritional information but some of the guidelines have often been questioned leading to uncertainty and differing attitudes towards the consumption of fat in particular. Aims The study’s aim was to compare healthcare professionals’ attitudes to dietary fat and fat consumption to those of non-health professionals. A further aim was to assess if the named two groups gave advice on dietary habits. Method An online questionnaire survey was carried out with the participation of 260 adults recruited through convenience sampling. The questionnaire comprised 13 questions and the data collected were compiled in Microsoft Excel then imported to IBM SPSS 20.0., for processing and analysis. Results were analyzed using chi-square tests with p<0.05. Results A total of 73 healthcare professionals and 187 non-health professionals took part in the study.  Significantly more healthcare professionals than non-health professionals knew and were positive to established dietary advice regarding fat. There were however no differences between the two groups in the consumption of hard dietary fats. Both groups gave advice on dietary habits. Conclusions Healthcare professionals can be perceived as more knowledgeable than non-health professionals on fat consumption. The sharing of dietary advice by healthcare professionals may therefore lead to positive developments regarding those dietary guidelines that have often been questioned. This however requires that the healthcare professionals act professionally and separate what they do in private from what they advise their patients. / Bakgrund En av utmaningarna för folkhälsan i Sverige är konsumtion av för mycket mättat fett och för lite omättat fett.  Socialstyrelsen, det svenska Livsmedelsverket (SLV) och hälsosektorn arbeta tillsammans för att hantera utmaningen genom att utbilda allmänheten om goda matvanor. SLV ger riktlinjer för all näringsinformation men vissa av dessa har ifrågasatts vilket leder till osäkerhet och varierande inställning till just fett och dess konsumtion. Syfte Studiens syfte var att studera attityder till fett och fettkonsumtion bland hälso- och sjukvårdspersonal och icke-vårdpersonal.  Ytterligare syfte var att se om de två grupperna gav råd om matvanor. Metod En webbaserad enkätundersökning genomfördes med deltagandet av 260 vuxna som rekryterades genom bekvämlighetsurval. Enkäten bestod av 13 frågor.  Data som samlades in sammanställdes i Microsoft Excel och fördes sedan över till IBM SPSS 20.0 för bearbetning och analys. Resultaten analyserades genom att använda chi-två test med p < 0,05. Resultat Totalt deltog 73 hälso- och sjukvårdspersonal och 187 icke-vårdpersonal i studien. Betydligt fler hälso- och sjukvårdspersonal än icke-vårdpersonal visste om och var positiva till etablerade kostråd om fett. Det fanns dock inga skillnader mellan de två grupperna i konsumtionen av hårda fetter i kosten. Båda grupperna gav råd om matvanor. Slutsatser Hälso- och sjukvårdspersonal kan upplevas som mer kunniga än icke-vårdpersonal angående fettkonsumtion. Råden om matvanor från hälso- och sjukvårdspersonal kan därför leda till positiv utveckling när det gäller de kostråd som ofta ifrågasätts. Detta kräver dock att hälso- och sjukvårdspersonalen agerar professionellt och separerar vad de gör privat och råd de ger till patienter.

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