Zur Wahrung der Genomstabilität entwickelten sich verschiedene Reparaturmechanismen, deren Defekte zu diversen Erkrankungen führen. Der 1927 erstmals beschriebenen Fanconi Anämie (FA) (Fanconi 1927) liegt eine fehlerhafte Reparatur der DNA-Doppelstrang-Quervernetzung zugrunde. Als Ursache wurden Defekte innerhalb des FA/BRCA-Weges lokalisiert, welche zur Chromosomeninstabilität führen. Das Krankheitsbild der autosomal rezessiven oder X-chromosomalen Erkrankung wird meist von kongenitalen Fehlbildungen, progressivem Knochenmarkversagen sowie bereits im jugendlichen Alter erhöhten Tumor-raten und Anämien geprägt. Bisher wurden Defekte in 19 verschiedenen Genen als ursächlich für diese Erkrankung diskutiert. Anhand des betroffenen Gens können nur begrenzt Rückschlüsse auf die Ausprä-gung des Phänotyps geschlossen werden, vielmehr scheinen die Art der Mutation und deren Position im Gen mit der Schwere der Erkrankung zu korrelieren. Im Laufe der Zeit wurden immer mehr Patienten mit mild ausgeprägtem Erkrankungsbild beobachtet. Eine mögliche Erklärung hierfür liefern milde Mutationen, eine weitere das Vorhandensein von Mosaiken blutbildender Zellen. Zu letzterem führt die Reversion einer der beiden Mutationen. Diese Art der „natürlichen Gentherapie“ wurde bei 10-30% der FA-Patienten beobachtet. Um die Entwicklung von Reversionen besser zu verstehen, erfolgte im Rahmen dieser Arbeit die Untersuchung verschiedener Zelllinien von 5 Patienten im Alter von 11 (Pat. 5) bis 33 (Pat. 4) Jahren. Die FA-A-Patienten 1 und 2 wurden bereits von Gross et al. 2002 als Mosaikpatienten beschrieben. Für die weiteren Patienten führten unterschiedliche Aspekte, wie normale Blutwerte, MMC-tolerante lympho-blastoide Zelllinien und gDNA-Analysen des Blutes zum Mosaikverdacht. Nähere Analysen bestätigten für die FA-D2-Patienten (Pat. 4, 5) ebenfalls das Vorliegen einer Reversion in den Blutzellen. Allen Patienten gemein war die Reversion in Form einer Rückmutation (Pat. 1: c.971T>G, Pat. 2: c.856 C>T, Pat. 4: c.3467-2A>G, Pat. 5: c.3707G>A), welche meist in einem oder in der Nähe eines Mutationsmotives vorlag. Zur Einschätzung des Mosaikstatus in den Patientenblutzellen wurden, neben der meist mehrjährigen Be-obachtung der Blutwerte (Thrombo-, Mono-, Granulo-, Lymphozyten, Hämoglobin), gDNA-, Chromoso-menbruch- und Zellzyklusanalysen durchgeführt. Chromosomenbruchanalysen von Metaphasen der T-Lymphozyten der Patienten 4 und 5 zeigten nach MMC-Behandlung die mosaik-typische bimodale Vertei-lung der Chromosomenbruchraten. Die nur moderat erhöhten Bruchraten in Metaphasen des Patienten 1 sprachen für eine starke Reversion. Zur besseren Abschätzung des Mosaikstatus wurden Zellzyklusanaly-sen an Mischungsreihen aus FA- und nicht FA- Blut durchgeführt. Die Detektionsgrenze für FA-Mosaike lag bei einem Anteil von 30% Zellen mit spontanem/MMC-induziertem G2-Phasen-Arrest. In Anlehnung an Mischungskurven wurden für die vier Patienten Reversionen von 0% (Pat. 4) bis 90-95% (Pat. 2) ange-nommen. Die gDNA-Analyse MACS-sortierter T-/B-Lympho-, Mono- und Granulozyten sowie von Fib-roblasten und lymphoblastoiden Zelllinien ermöglichte einen detaillierten Einblick in die Mosaikstatus auf molekularer Ebene. Wir fanden bei allen Patienten einen unterschiedlich stark ausgeprägten Mosaikstatus ihrer Blutzellreihen. Tendenziell scheinen die Reversionsgrade mit der Zell-Lebensdauer korrelieren, hier-bei zeigen kurzlebige Zellen (Mono-, Granulo-, B-Lymphozyten) höhere Reversionsgrade als langlebige T-Lymphozyten. Das Auftreten von gleichen Reversionen in allen Zelllinien lässt eine Reversion in einer gemeinsamen Vorläuferzelle vermuten. Als Besonderheit fanden wir, unseren Erachtens erstmalig, eine komplette Reversion einer Knochenmark-Fibroblastenzelllinie (Pat. 1). Häufig in Kultur stattfindende Re-versionen in lymphoblastoiden Zelllinien beobachteten wir für alle vier Patienten. Die Mosaikentstehung im Patientenblut konnte mit allen Methoden bestätigt werden. Jede Methode wies Vor- und Nachteile auf. Zur Abschätzung der Mosaikstatus empfiehlt sich deshalb eine Kombination der Methoden. Ein weiteres Projekt beschäftigte sich mit Interaktionen des FANCO (RAD51C) innerhalb der RAD51 Paraloge (RAD51B, -C, -D, XRCC2, XRCC3) und mit RAD51. Die Analysen erfolgten im Mammalian Two- und Three-Hybrid (M2H/M3H) System. Die Untersuchungen bestätigten die meisten der bisher detektierten Interaktionen, welche zur Ausbildung des RAD51C-XRCC3 Komplexes und des, aus den Subkomplexen RAD51B-RAD51C (BC) und RAD51D-XRCC2 (DX2) bestehenden, BCDX2-Komplex führen. Die M3H-Analysen weisen auf eine wichtige Rolle des RAD51B-Proteins bei der Ausprägung dieses Komplexes hin. Es scheint die Ausbildung der RAD51C-RAD51D-Interaktion erst zu ermöglichen und zusätzlich, anders als bisher beobachtet, auch mit XRCC2 zu interagieren. Diese Interaktion wiederum wird durch die Anwesenheit von RAD51D stark gefördert. Unsere M2H-/M3H-Beobachtungen weisen darauf hin, dass die Ausbildung der Subkomplexe für die Entstehung des BDCX2-Komplexes wichtig ist und dieser vermutlich als Ringstruktur vorliegt. Zusätzlich fanden wir Hinweise auf mögliche Wechselwir-kungen zwischen den BCDX2- und den XRCC3-Komplexproteinen. Aufgrund der Beteiligung der Protei-ne an der Doppelstrangläsionsreparatur wurde die Auswirkung von MMC-induzierten DNA-Schäden un-tersucht. Diese führten innerhalb der Subkomplexe zu gegensätzlichen Änderungen der Interaktionsinten-sität. Während die Substanz im DX2-Komplex zum Sinken der Interaktionsstärke führte, erhöhte sich diese im BC-Komplex. Die in der Literatur beschriebene und charakterisierte RAD51C-FANCN-Interation war im M2H-Test nicht darstellbar. Möglicherweise würde diese jedoch durch die Anwesenheit eines drit-ten Proteins gefördert werden. Zusätzlich wurde ein RAD51C-Protein, welches die Patientenmutation R258H enthielt, überprüft. Es zeigte nur in der M3H-Analyse, mit pMRAD51D und nativem RAD51B, nach Behandlung mit MMC eine reduzierte Interaktionsstärke im Vergleich zum Wildtyp. Dies unter-streicht einmal mehr die als hypomorph beschriebene Mutation des Proteins. Das dritte Projekt, die angestrebte Strukturaufklärung des RAD51C-Proteins erwies sich als schwierig. Eine für eine Kristallisation ausreichende Proteinmenge konnte, weder im E. coli-System noch in Insektenzellen oder in Co-Expression mit seinem Interaktionspartner XRCC3, isoliert und aufgereinigt werden. Elektro-phoretische Mobility Shift Assays des CX3-Proteinkomplexes mit DNA-Strukturen (ssDNA, Open Fork, 3‘-/ 5‘-Überhang-Struktur), zeigten eine Bevorzugung des 3‘-Überhang-DNA-Substrates. Diese Art der Analyse könnte in weiterführenden Analysen zur Abschätzung der Auswirkung von Patientenmutationen herangezogen werden. bb / For maintaining genomic stability several repair mechanisms have evolved. Defects in these mechanisms lead to diverse diseases. One of these Fanconi Anemia (FA), first described in 1927, evoked by deficient mechanism of interstrand crosslinks. As causative reason defects within the FA-BRCA pathway were iden-tified leading to chromosome instability. To date 19 different genes were found to cause Fanconi Anemia. Most commonly for the clinical picture of FA are congenital malformations, progressive bone marrow defects as like an increased tumor rates and anemia at a juvenile age. Knowing the affected gene only lim-ited conclusions could be considered of the phenotypical appearance. More likely the kind of mutation and the affected position within the gene seems to correlate with the severity of the disease. Over the time an elevated number of patients with mild phenotype were observed. One possible explanation may be mild mutations another a mosaic state developed within the blood forming cells. The latter was caused by rever-sion of one of both mutations. This kind of “natural gene therapy” was observed in the blood of 10 up to 30 % FA- patients. To get better insights in to the mosaic development we investigated different cell lines of five patients aged between 11 (pat. 5) and 33 (pat. 4) years. Both FA-A patients (pat. 1, 2) were described as mosaic patients before by Gross et al. 2002. The other patients arouse suspicion for developing mosai-cism by different aspects like normal blood counts, MMC tolerant lymphoblastiode cell lines and analyzing gDNA from blood. Detailed analyses confirmed the reversion of one mutation in blood of the FA-D2 patients (pat. 4, 5). In common for all four mosaic was the kind of reversion, a back mutation (pat. 1: c.971T>G, pat. 2: c.856 C>T, pat. 4: c.3467-2A>G, pat. 5: c.3707G>A) mostly in or near by a mutation motive. To get insights in to the mosaic state of the patients’ blood cells, gDNA, chromosomal breakage and cell cycle analyses were performed and blood cell counts of thrombo-, mono-, granulo-, lymphocytes and haemoglobin were observed for several years. Chromosomal breakage analyses of t-lymphocytes met-aphases (pat. 4, 5) treated with MMC showed a mosaicism typical bimodal distribution. The only moderate increased chromosomal breakage rate in metaphases of patient 1 points out a strong pronounced reversion. For better estimation of the Mosaic state in patient blood we performed cell cycle analysis with mixtures of FA- and non FA-blood. Thereby we observed the border for mosaic detection at a degree of 30 % cells with spontaneous /MMC induced G2-phase arrest. Compared to the mixing study reversion degrees of 0 % (pat. 4) up to 90-95 % (pat. 2) were assumed for four of the patients. At molecular base gDNA analyses of MACS sorted T-/ B- lympho, mono and granulocytes as well as from fibroblasts and lymphoblastoide cell lines allowed a more detailed insight in to the mosaic statuses. In all patients we observed different distinct of mosaic state in their blood cell lines. We observed a tendency of correlation between reversion degree and the longevity of blood cells – cells with short life spans (mono-, granulo-, B-lymphoytes) showed higher reversion degrees than log living T-lymphocytes. The fact that we detected the same rever-sion in the different cell lines of a patient suggests a reversion within a common precursor cell. Further we observed, as we know for the first time, a reversion within a bone marrow fibroblast line (pat. 1). Four of our patients showed commonly observed reversions in cultured lymphoblastoide cell lines. With each of the tested methods we could show mosaic development in blood of our patients. Every of them showed pros and cons. For this reason a combination of the different methods would be recommendable for cal-culation of the mosaic state in patient blood. The second project investigated the interactions of FANCO (RAD51C) within the group of the RAD51 paralogs (RAD51B, -C, -D, XRCC2, XRCC3) and with RAD51. Interactions were tested by Mammalian Two- and Three-Hybrid (M2H/M3H) System. Our investigations confirm most of the up to now detected interactions leading to RAD51C-XRCC3-complex (CX3) and RAD51B-RAD51C-RAD51D-XRCC2 com-plex (BCDX2) formation – latter consisting of the subcomplexes RAD51B-RAD51C (BC) and RAD51D-XRCC2 (DX2). M3H analyses give a hint for the importance of the RAD51B protein for the BCDX2 complex formation. The protein seems to be necessary for RAD51C-RAD51D interaction and also to interact, other than intended before, with XRCC2. In turn this interaction seems to be strongly promoted by RAD51D. In M2H and M3H analyses we found evidence of the importance of subcomplex formation for the formation of the whole BCDX2 complex and that the complex may be a circular structure. Addi-tionaly we observed evidence for interdependency between the BCDX2- and the XRCC3- complex pro-teins. Because of the proteins involvement into the double strand lesion repair the effect of MMC induced DNA lesions were tested. MMC treatment leads to different changes of interaction within the subcom-plexes. We observed a decrease of interaction strength between RAD51D and XRCC2 and an increased interaction within the BC-complex. The interaction between RAD51C and FANCN was not detectable in our M2H assay but may be promoted by another protein in M3H analysis. Additionally we tested a RAD51C protein inherited the patient mutation R258H. Only in M3H analysis with pMRAD51D and native RAD51B and with additional MMC treatment reduced interaction strength was detectable compared to the wildtype RAD51C. This underlines the hypomorphic nature of the mutation described before. The third project – the elucidation of the RAD51C protein structure proved to be difficult. We could not isolate and purify enough protein for crystallization, neither by expression within a E.coli or an insect cell system not even by co-expression of the complex partner XRCC3. Electrophoretic mobility shift assays of the CX3 complex with different DNA-structures (ssDNA, open fork, 3’- and 5’- overhang structures) showed preference for the 3’-overhang DNA substrate. This method may be used for further investiga-tions of mutations in patient DNA in future.

<p>ECT har länge använts som behandlingsmetod inom psykiatrin och är verksam vid psykiska sjukdomar som till exempel depression. För att patienten ska kunna ta ställning till behandlingen utifrån så korrekt information som möjligt, ligger det i sjuksköterskans ansvar att se till att patienten är välinformerad. Därför var syftet med litteraturöversikten att ur ett patientperspektiv beskriva positiva och negativa effekter med behandlingsmetoden ECT vid depression. Litteraturen har sökts i databaser och har resulterat i tretton artiklar som ansågs hålla medel eller hög kvalitet som sedan analyserats enligt innehållsanalys. Resultatet visade att ECT gav en ökad livskvalitet för patienter som svarade på behandlingen. Minnesförlust var den vanligaste biverkningen men drabbade inte alla patienter. Samt visade det sig att minnesproblem kunde vara ett symtom av depressionen och behövde inte bero på ECT-behandlingen. För att minska återfall efter ECT var det viktigt med utvärdering och stödjande behandling. Resultatet har betydelse för att öka kunskapen inom området så att sjuksköterskan kan ge rätt information till patienten. Med denna kunskap kan även omvårdnaden utvecklas för ECT-behandlade patienter.</p>

Background In the past half-century, the prevalence of asthma among children and adolescents has risen and asthma has become an important public health challenge in Sweden as well as in many other countries, necessitating further studies on this complex disease and its risk factor pattern. The studies included in this thesis aimed to investigate the clinical expression of childhood asthma over time, to describe the determinants of new-onset and remission of asthma, and to evaluate possible environmental risk factors in northern Sweden. Methods As the result of a repeated questionnaire survey among primary school children aged 7-8 years in three municipalities in the north of Sweden, two pediatric cohorts were formed, one in 1996 (n=3430) and one in 2006 (n=2585). The cohort created in 1996 was followed annually until the age of 19 years. Skin prick testing was performed on children in both cohorts. Lung function and bronchial hyperreactivity testing were carried out in children with asthma in the first cohort. The study participation and retention rates were very high in both cohorts. Among children in the second cohort living in Luleå, the home addresses were assigned to coordinates in a geographical information system (GIS) to evaluate the impact on respiratory health of living near roads with much traffic, which was measured as the number of vehicles daily. We used a validated reported diagnosis of asthma and International Study of Asthma and Allergies in Childhood (ISAAC) questions were incorporated into the questionnaire. A cross-sectional study of children of the same age ten years apart, longitudinal studies on asthma incidence and remission as well as a cross-sectional study on vehicle traffic were performed. Results While children aged 7-8 years in 2006 more often had a physician-diagnosed asthma compared to children of the same age in 1996 (7.4% vs 5.7%, p&lt;0.001), they had less asthma symptoms, especially severe symptoms. In parallel, a more beneficial environment and a more intense treatment with inhaled corticosteroids (ICS) were observed. The explanation for this change in clinical expression probably includes also an increased awareness and diagnosing of asthma. From age 12 years to age 19 years, the cumulative incidence of physician-diagnosed asthma was 7.2% and of current wheeze 22.0%. The risk of new-onset asthma in adolescence was increased among girls, sensitized and those with heredity for asthma. Smoking and home dampness increased the risk for incident wheeze. The risk for both incident asthma and wheeze was inversely related to number of siblings. Among children with current asthma at age 7-8 years, 21% were in remission, 38% had periodic asthma and 41% had persistent asthma at a follow-up at age 19 years. Subjects in remission and with periodic asthma had significantly less airway obstruction and showed less bronchial hyperreactivity compared to subjects with persistent asthma. The probability of asthma remission from childhood to early adulthood was significantly increased by absence of allergic sensitization, male gender and a low asthma severity scoring at age 7-8 years. Sensitization to furred animals was more important as a determinant of both incidence and remission than sensitization to pollen. Living close to roads with high traffic flows, especially with heavy vehicles, was associated with an increased risk for current wheeze. Stratified analyses showed that the effect of traffic on asthma and wheeze was restricted to non-sensitized subjects. Conclusion Asthma onset in adolescence was more common among girls and remission was more common among boys. Children sensitized to furred animals and children with a more severe asthma were risk groups for persistence of asthma. Environmental factors such as smoking and dampness were associated to onset of asthma symptoms during adolescence, and vehicle traffic was associated with asthma symptoms among children also in a small city with relatively low traffic flows. Preventive measures like smoking reduction programs, improvement of damp housing conditions and separation of areas where many children live from heavily trafficked roads could prove to be beneficial. / OLIN-studierna

No description available.

No description available.

Thesis (Ph.D.)--Cleveland State University, 2009. / Abstract. Title from PDF t.p. (viewed on Dec. 11, 2009). Includes bibliographical references (p. 141-153). Available online via the OhioLINK ETD Center and also available in print.

Major depression is a highly prevalent disorder that affects millions of individuals worldwide each year. Theorists such as Aaron T. Beck (1967; 1976) revolutionized how depression is understood by proposing that cognitive factors are involved in the etiology and maintenance of depression. Inspired by his and other cognitive theories, researchers have documented negative biases in attentional and interpretive cognitive processing of emotional stimuli in individuals with major depressive disorder. However, very little cognitive research has been conducted on individuals with a past history of depression or at different time points since their depressive episode. Also, researchers have not tested whether criticism, a known psychosocial predictor of relapse, exacerbates information-processing biases in people with major depression or reactivates such biases in people in various stages of recovery from the disorder (Butzlaff & Hooley, 1998; Hooley & Gotlib, 2000). As criticism has been implicated in psychiatric relapse, its impact was tested on both formerly depressed persons who are potentially at risk for relapse and recurrence of a depressive episode. The current study was designed to test whether criticism was capable of evoking information-processing biases in attending to and interpreting ambiguous stimuli. Participants (n = 115) at different points in their recovery from depression (i.e. remitted [n = 33] and recovered depressed participants [n = 24]), healthy controls (n = 43) were randomized into either a twenty-second auditory negative mood induction (criticism) or a twenty-second neutral auditory comment. Currently depressed participants (n = 15) were always administered the twenty-second neutral auditory comment. Participants then performed four information-processing tasks: an acoustic word pairs task, a signal detection (probabilistic reward processing) task, a morphing faces task, and a dot probe task. I predicted that the criticism challenge would induce a negative mood state in participants and consequently affect their performance on information-processing tasks by eliciting more negative cognitive biases particularly in the remitted and recovered depressed groups as compared to the control group. I predicted that currently depressed participants would demonstrate the greatest cognitive biases. Consistent with predictions, criticism increased negative mood and decreased positive mood, as compared to no change in mood in the neutral comment condition. Contrary to expectation, criticism did not exacerbate information-processing biases. Clinical status predicted performance on only one information-processing task. Compared to healthy control participants, current and remitted depressed participants demonstrated greater negative interpretive biases by indicating that they more frequently heard negative as compared to neutral words on the acoustic word pairs task. They also more frequently interpreted ambiguous material as neutral rather than positive on the acoustic word pairs task. No significant differences emerged among the clinical groups on the other information-processing tasks. These results suggest that individuals remitted from depression continue to exhibit some interpretive biases even after full recovery. This research also demonstrates significant mood changes in response to criticism, but no effect on information-processing performance. This study suggests that depressed and formerly depressed individuals may not exhibit attentional biases for negative material, but may exhibit interpretive biases irrespective of whether they have undergone a negative mood induction. / Psychology

ECT har länge använts som behandlingsmetod inom psykiatrin och är verksam vid psykiska sjukdomar som till exempel depression. För att patienten ska kunna ta ställning till behandlingen utifrån så korrekt information som möjligt, ligger det i sjuksköterskans ansvar att se till att patienten är välinformerad. Därför var syftet med litteraturöversikten att ur ett patientperspektiv beskriva positiva och negativa effekter med behandlingsmetoden ECT vid depression. Litteraturen har sökts i databaser och har resulterat i tretton artiklar som ansågs hålla medel eller hög kvalitet som sedan analyserats enligt innehållsanalys. Resultatet visade att ECT gav en ökad livskvalitet för patienter som svarade på behandlingen. Minnesförlust var den vanligaste biverkningen men drabbade inte alla patienter. Samt visade det sig att minnesproblem kunde vara ett symtom av depressionen och behövde inte bero på ECT-behandlingen. För att minska återfall efter ECT var det viktigt med utvärdering och stödjande behandling. Resultatet har betydelse för att öka kunskapen inom området så att sjuksköterskan kan ge rätt information till patienten. Med denna kunskap kan även omvårdnaden utvecklas för ECT-behandlade patienter.

BACKGROUND: Previous studies have shown that there are racial disparities in type 2 diabetes (T2DM) remission following bariatric surgery, with African-Americans (AA) in particular experiencing a subsequent relapse. In recent years, some have attributed these findings to racial differences in fasting insulin levels, with AA having higher levels, as increasing evidence for an alternate model of T2DM pathophysiology gains support. In this model, basal hyperinsulinemia is considered a primary event in T2DM disease development, rather than a compensatory response to increased insulin resistance. This study aimed to compare glycemic outcomes after bariatric surgery in different races, namely African-Americans (AA), Hispanic-Americans (HA), and Caucasian-Americans (CA), and to determine whether there were any associated changes in insulin levels and insulin resistance that may lend support to this revised model of T2DM pathophysiology. METHODS: A retrospective medical record review of 1,326 patients (389 AA, 179 HA, and 758 CA) who underwent bariatric surgery at Boston Medical Center (BMC) from 2004 to 2015 was conducted. Baseline characteristics and maximum percent weight loss were compared using one-way ANOVA and Chi-square tests of independence. Changes in mean glycated hemoglobin (HbA1c), insulin levels, insulin resistance (HOMA-IR), and blood glucose levels were analyzed using linear mixed models, overall and by racial group. The same procedures were conducted in both the overall patient population and a T2DM subpopulation. RESULTS: Over an 11-year postoperative observation period, all racial groups underwent a significant decrease in HbA1c (P<0.001) within the first two years following surgery. While HbA1c levels remained stable in CA and HA, they began to rise at 2 years in AA only (P=0.043). Additionally, analyses of covariates, including age at surgery (P=0.005), initial BMI (P<0.001), and maximum weight loss (P=0.049), revealed that all three were significant factors affecting mean HbA1c levels. However, when included in the mixed model, the race x time interaction effect on mean HbA1c remained significant. There was also a significant overall decrease in both insulin and HOMA-IR. When stratified by race, analysis of the T2DM population showed that insulin levels began to increase again by the 2nd year after surgery in AA, while in CA and HA they continued to decrease and subsequently stabilize. Analysis of the total patient population showed that HOMA-IR levels in AA, as well as in CA and HA, continued to decrease at this 2-year time point. Decreases in blood glucose levels after surgery were significant overall (P<0.001), but not significant when stratified by race. CONCLUSIONS: After the initial “metabolic reset” that occurs within the first 2 years after bariatric surgery, during which HbA1c levels normalize in the vast majority of patients, it was observed only in the AA population that there was a steady increase in HbA1c to levels near those recorded at baseline. This coincided with an observation of increasing insulin levels despite decreasing insulin resistance seen in AA only. Our results suggest that current discussions regarding a revised model of T2DM pathophysiology, in which hyperinsulinemia precedes insulin resistance, may help explain the racial disparities in glycemic control observed in both post-surgical and non-surgical contexts of T2DM outcome. However, future prospective studies are needed to further the preliminary results of this study.

At the 2nd Diabetes Surgical Summit in 2015, the world’s leading researchers and professionals in the field of diabetes, surgery, and public health gathered to develop new surgical treatment guidelines for diabetes. This summit led to the recommendation of bariatric surgery as an official treatment for type II diabetes, outlining that the surgery be considered for diabetic patients with a Body Mass Index (BMI) of 30, a much lower threshold BMI than that of typical bariatric surgery patients. Despite incontrovertible evidence that bariatric surgery can reverse the progression of diabetes and even cause remission, the physiological mechanisms chiefly responsible for these effects remain controversial. Peer-reviewed published literature was collected to examine the evidence for mechanisms responsible for metabolic improvements following bariatric surgery, especially Roux-en-Y gastric bypass. This review considered the effects of calorie restriction, appetite modulators, incretins, intestinal adaptations, adipose tissue, gut microbiota, bile acid circulation and composition, and psychosocial and behavioral changes on surgery-induced metabolic improvements and sustained type II diabetes remission. Clinical considerations, such as the surgical risks and improved indicators for bariatric surgery were also explored to contextualize the physiological mechanisms under study. The “hind gut hypothesis” emerged as an important overarching mechanism potentially responsible for many of the observed improvements. The more rapid delivery of food to the distal intestine, as well as the delayed mixing of pancreatic, gastric and bile secretions with food, likely contributes to increased nutrient-stimulation of enteroendocrine cells and greater binding of bile acids with their receptors, farnesoid X receptor and TGR5. These changes in food and secretion delivery also appear to positively affect the gut microbiota to support a non-obese microbiota profile. Calorie restriction may be responsible for the early effects of bariatric surgery, including not just a reduction in fat mass but also epigenetic changes to induce β-cell proliferation and increased insulin secretion. However, long-term benefits of bariatric surgery appear to be more closely correlated to enteroendocrine changes, including the surgery-induced changes to levels of appetite modulators that, unlike pure calorie restriction, promote feelings of satiation and reduce rates of diet failure and weight regain. Fat distribution and adipocyte function are also important contributors to both the pathophysiology of obesity-related diabetes and improvements following bariatric surgery. While reductions in BMI and subcutaneous adipose tissue area were not correlated to diabetes remission, reductions in visceral adipose tissue area and enhanced adiponectin secretions were both independent factors associated with diabetes remission. The important role of adipocytes as endocrine organs has emerged as an important field of inquiry. Adipokines, adipocyte hormones, may either promote a pro-inflammatory profile or an anti-inflammatory profile, impacting the development of obesity-related diabetes or diabetes remission, respectively. The findings of this review support the 2nd Diabetes Surgical Summit’s recommendations of proactive bariatric surgery as a treatment for diabetes. The risks of complications and mortality following bariatric surgery are low, whereas the long-term survival after bariatric surgery is improved relative to non-surgical, matched controls. Single-nucleotide polymorphisms associated with obesity and diabetes may serve as early indicators for surgery, and inform both surgical method and follow-up protocols. Despite the benefits of bariatric surgery, only a small number of eligible candidates undergo treatment. In the United States, barriers such as physician and patient perceptions and cost may limit access to surgery. In places that experience a health workforce shortage, there may be no health care professionals or facilities available to perform bariatric surgery. Therefore, while the surgery amazingly causes diabetes remission, one of its greatest benefits may be to continue to inform the mechanisms responsible for metabolic improvements toward developing new pharmacological treatments. In the future, less invasive drug treatments that seek to replicate the effects of bariatric surgery may be more successful in tackling the global obesity and diabetes crisis.