Poly is a novel, essential protein in Drosophila melanogaster, loss of function of which results in late larval lethality. Importantly, Poly is evolutionarily conserved with a human homologue. poly mutation was isolated in a P-element mutagenesis screen that aimed to generate a larger collection of single P-element induced mutants. Mutant poly larvae are characterized by extreme larval longevity without pupation, formation of melanotic masses, smaller imaginal discs and brains, and abnormal nuclear morphology in neuroblasts. During the course of my project, I attempted to identify cellular processes and pathways that Poly might be involved in. Interestingly, my data suggest that Poly is a novel interactor and regulator of Insulin receptor/target of rapamycin (InR/TOR) signalling in Drosophila. Linking environmental cues to cell growth and metabolism is an essential process that multicellular organisms need to accomplish successfully for normal development. InR/TOR signalling is a highly conserved pathway that mediates the link between the environment and cellular processes such as growth, metabolism and ageing. My analysis in Drosophila suggests that Poly interacts physically with the InR and mutation of Poly leads to an overall down-regulation of InR/TOR signalling in Drosophila as revealed by decreases in the phosphorylation levels of Akt, S6K and 4E-BP - all downstream effectors of this pathway. In addition, loss of poly results in constitutive activation of autophagy in Drosophila fat body and a decrease in stored triglyceride levels. Furthermore, I show that localisation and levels of Poly protein are dependent on insulin action in both Drosophila and human cells. Together, these data suggest that Poly is a novel mediator of InR signalling that promotes an increase in cell growth and metabolism. Taking into consideration the observed poly mutant phenotype, I also investigated the potential involvement of Poly during cell cycle progression and the Drosophila innate immune response. While my analysis suggests that poly loss of function does not have a direct effect on cell cycle progression, alteration of Poly has consequences on various aspects of the Drosophila innate immune response. Therefore, I conclude that the Drosophila innate immune response is a cellular process in which Poly plays a crucial role.

Class of 2010 Abstract / OBJECTIVES: To compare the INR-based results of pharmacist anticoagulation management services to non-pharmacist managed anticoagulation therapy. METHODS: A meta-analysis was performed using studies that reported on pharmacists’ services and interventions in anticoagulation. Two reviewers independently assessed each record retrieved by the literature search, and studies were eliminated if both reviewers agreed that the study did not meet the inclusion criteria. The analysis found eight studies that were eligible for inclusion. The primary independent variable was the presence or absence of pharmacist services. The primary dependent variables were the proportion of patients within INR range, the duration of time within that range, and the time required to achieve that range. Extracted data were pooled and entered into the meta-analysis, and a forest plot was constructed. The a-priori alpha level was 0.05. RESULTS: The eight studies were divided into two groups: The INR group consisted of four studies which used INR test data points as the unit of analysis. The Patient group included four studies which measured the patient’s INR only at the end of the study. The INR group demonstrated a significant difference favoring pharmacist services, with a p-value of 0.02 for the group. There was no significant difference between pharmacist services and the control group with respect to the Patient group. When all eight studies were pooled together, the overall forest plot did demonstrate significant favorability for pharmacist services, with an odds ratio of 1.58, indicating that pharmacist provided services improved care by 58% (Z = 2.8;p p = 0.01). CONCLUSIONS: The advantage of a pharmacist service in reaching goal INR was significant compared to the control group of non- pharmacist care.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2014-10-16T15:13:44Z No. of bitstreams: 2 Dissertacao Ely Rodrigues de Almeida - 2013.pdf: 1560361 bytes, checksum: 153a2514b81e70d5b31e01a1cc0d09b6 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Jaqueline Silva (jtas29@gmail.com) on 2014-10-20T20:06:38Z (GMT) No. of bitstreams: 2 Dissertacao Ely Rodrigues de Almeida - 2013.pdf: 1560361 bytes, checksum: 153a2514b81e70d5b31e01a1cc0d09b6 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-10-20T20:06:38Z (GMT). No. of bitstreams: 2 Dissertacao Ely Rodrigues de Almeida - 2013.pdf: 1560361 bytes, checksum: 153a2514b81e70d5b31e01a1cc0d09b6 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-10-15 / INTRODUCTION: Anticoagulation with warfarin is used in the presence of hypercoagulability and as prophylaxis for thromboembolism. Prothrombin time and activity and the international normalized ratio (PTA/INR) are the standard tests for laboratory follow up of the anticoagulation rate. Hemorrhage is one complication of this therapy. Therefore, one speculates on the possibility of diagnosing cases in which there is excess anticoagulation, by means of the analysis of hematuria in urinalysis and the association with PTA/INR. OBJECTIVE: Analyze the existence of a correlation between hematuria in urinalysis and high PTA/INR, among users of warfarin. METHODOLOGY: This is a descriptive, analytical, primary, quantitative and cross-sectional investigation. The study included 128 patients, 63 of whom were being treated with warfarin, and formed the group of anticoagulated patients (ACG). The remaining 65 patients who were not using anticoagulants formed the non anticoagulated group (NACG). For this study, 152 blood and urine samples were collected; 24 patients of the ACG contributed twice for the PTA/INR and urinalysis, at two different times. All the participants of the NACG also had the PTA/INR and urinalysis tests done. Patients with a clinical suspicion of conditions that might cause hematuria were excluded. The social and demographic data of these individuals were analyzed and the numerical variables of hematuria and of other urinalysis and INR parameters were measured and analyzed. The prevalence and the correlation between hematuria and PTA/INR levels were calculated. Data from the tests, medical appointments and the records of patients recruited in the collection room of the Clinical Laboratory of the HC-UFG were evaluated statistically, and emphasis was placed on the Spearman's correlation for hematuria and PTA/INR (IC 95%; p< 0.05). The study was approved by the Committee on Ethics and Human Research of the HC-UFG, protocol No. 016/2012. RESULTS: The amount of warfarin given on a weekly basis ranged from 10 to 65 mg. If one considers the INR between 2 and 3.9 acceptable for adequate anticoagulation, 59.77% of the individuals were adequately anticoagulated, 35% were insufficiently anticoagulated and 5.75% were excessively anticoagulated. The prevalence of hematuria among the ACG members was 26.44 % (CI 95% 17.98 – 36.43) and among NACG members, 29.23 % (CI 95% 19.16 – 41.11). The correlation coefficient between hematuria and INR was 0.012 (p=0.887). CONCLUSIONS: The most of the patients (59.7%) were within the recommended therapeutic range for controlling patients. There was no correlation between hematuria as measured by urinalysis and anticoagulation levels measured by the INR. / INTRODUÇÃO: A anticoagulação com varfarina é usada na hipercoagubilidade e como profilaxia para o tromboembolismo. O tempo e atividade de protrombina e a relação normatizada internacional (TAP/RNI) são os exames padrões para acompanhamento laboratorial da taxa de anticoagulação. A hemorragia é uma complicação desta terapia. Dessa forma, especula-se a possibilidade de diagnosticar casos em que haja excesso de anticoagulação, por meio da análise da hematúria no exame dos elementos anormais e sedimentoscopia da urina (EAS) e a associação com TAP/RNI. OBJETIVO: Analisar a existência de correlação entre hematúria no EAS e TAP /RNI elevados, nos usuários do anticoagulante varfarina. METODOLOGIA: Estudo descritivo, analítico, primário, quantitativo e transversal. Incluíram-se 128 pacientes, sendo 63 tratados com varfarina, formando um grupo anticoagulado (GAC) e 65 que não faziam uso de anticoagulantes, grupo não anticoagulado (GNAC). Colheram-se 152 amostras de sangue e urina; das quais 24 pacientes do GAC contribuíram duas vezes para exames TAP/RNI e EAS, em dois momentos distintos. Todos os participantes do GNAC também se submeteram aos exames TAP/RNI e EAS. Excluíram-se pacientes com suspeita clínica de condições que causassem hematúria. Analisaram-se os dados sociodemográficos e fez-se a mensuração e a análise das variáveis numéricas hematúria e de outros parâmetros do EAS e RNI. Calculou-se a prevalência e a correlação entre hematúria e níveis de TAP/RNI. Os dados oriundos de exames, consultas médicas e dos prontuários dos pacientes recrutados na sala de coleta do Laboratório Clinico do HC-UFG, foram avaliados estatisticamente, com ênfase na correlação de Spearman para hematúria e TAP/RNI (IC 95%; p<0,05). O projeto foi aprovado pelo Comitê de Ética e Pesquisa Humana do HC-UFG sob o nº 016/2012. RESULTADOS: A quantidade de varfarina semanal variou de 10 a 65 mg. Considerando-se o valor de RNI entre 2 e 3,9, como valor aceitável para adequada anticoagulação, 59,77% estavam adequadamente anticoagulados, 35% insuficientemente e, com efeito anticoagulante excessivo, 5,75%. A prevalência de hematúria no GAC foi de 26,44 % (IC 95% 17,98 – 36,43) e no GNAC, foi de 29,23 % (IC 95% 19,16 – 41,11). O coeficiente de correlação entre hematúria e RNI foi de 0,012 (p=0,887). CONCLUSÕES: A maioria dos pacientes (59,7%) tinha a RNI na faixa terapêutica preconizada para anticoagulação. Não houve correlação entre hematúria ao exame EAS e os níveis de anticoagulação medidos pela RNI.

Waran används sedan 60 år som blodförtunnande läkemedel för att förebygga eller förhindra progress av blodproppssjukdom. I Sverige behandlas årligen cirka 1 % av befolkningen med waran. I Östergötland uppskattas antal waranpatienter till cirka 3000. Waran hämmar enzymet VKORC1 som ansvarar för vitamin K omsättningen i kroppen. Vitamin K behövs som kofaktor för flera koagulationsfaktorer. Behandling med waran är förenad med en svår balansgång och kräver en noggrann dosering. Stora skillnader i dosbehov mellan olika individer, beroende på ärftliga och miljöfaktorer, gör waran till ett svårhanterligt läkemedel. För låg dos medför otillräcklig effekt och därmed risk för minskat skydd mot blodproppssjukdom. För hög dos leder till allvarliga blödningskomplikationer. Uppskattningsvis 1 – 3 % livshotande blödningsfall registreras årligen efter waranbehandling. Därför måste behandlingen kontrolleras noga med analys av protrombinkomplex (PK) och dosjusteringar göras med ledning av resultaten. Två olika metoder finns att använda för mätning av PK. I Norden och i Japan används Owrens metod (utvecklat i Norge under 40- och 50-talet av Paul Owren). I de flesta andra länder används Quickmetoden (utvecklat i USA under 30-talet av Armand Quick). Den senare metoden är förenad med stora variationer mellan olika analyslaboratorier. I Norden, däremot, där Owrens metod används finns det ofta bra överensstämmelse mellan olika laboratorier i PK-resultat. Beroende på vilken PK-metod som används, kan samma patient få olika warandoser vilket ökar risker för under- eller överbehandling. Vi har i samarbete med flera sjukhus och antikoagulationsmottagningar (AK-mottagningar) i sydöstra Sverige studerat dels mekanismerna bakom skillnader i warandos mellan olika patienter, och dels tittat varför de olika PK-metoder skiljer sig så mycket som de gör. I studien har vi identifierat genetiska varianter av enzymet VKORC1. Av de undersökta patienter som gick på waran under längre tid, har vi identifierat en grupp som markant skiljde sig från de övriga. Denna grupp hade warandoser som var betydligt lägre än de övriga. När vi kartlade deras arvsmassa, fann vi att lågdospatienterna hade genvarianten VKORC1*2. Dessutom hade patienter med denna variant svårigheter att få stabila PK-värden. De gjorde också fler besök på AK-mottagningar än andra patienter. Vi har därför konstaterat att en del av de problem som är förenade med waranbehnadlingen kan förklaras av VKORC1*2 varianten. Vetskap om denna variant skulle troligen underlätta behandlingen framför allt under inledningsfasen då patienter med VKORC1*2 riskerar blödningar på grund av överdosering. Vi har identifierat att provförspädning enligt Owrens metod är nödvändig för harmonisering av PK-resultatet mellan olika länder. Quickmetoden använder inte förspädning av patientprov till skillnad från Owrens metod. När vi modifierade en Quickmetod genom att förspäda prover enligt Owrens metod noterade vi en bra överensstämmelse mellan de två olika metoderna. Däremot var resultatet sämre utan provförspädning. Vi anser att Quickmetoder kan uppnå lika bra resultat som Owrens metod om prover förspäds som i Owrens metod. Det skulle gynna patienter som reser mellan olika regioner eller länder och leda till en bättre övervakning av waranbehandling internationellt. I studien har dessutom en metod för mätning av waran i blodet utvecklats. Metoden som är den enda i sitt slag i Norden ger möjlighet att studera hur läkemedlet beter sig i kroppen. Vi har med denna metod kunnat upptäcka patienter som har onormala nedbrytningar av waran. / Warfarin was introduced more than 60 years ago and is used worldwide for the prophylaxis of arterial and venous thromboembolism in primary and secondary prevention. The drug is orally administered as a racemic mixture of (R)- and (S)-enantiomers. The (S)-form is mainly responsible for the anticoagulant effect and is metabolised by CYP2C9 enzyme in the liver microsomes. Warfarin exerts its pharmacological action by inhibiting the key enzyme (VKORC1) that regenerates vitamin K from an oxidised state to a reduced form. The latter is a cofactor for the post-translational modification of a number of proteins including coagulation factors II, VII, IX and X. The vitamin K-dependent modification provides these factors with the calcium-binding ability they require for the interaction with cell membranes of their target cells such as platelets. Warfarin is monitored by measuring prothrombin time (PT) expressed as INR. Two main methods exist for PT analysis. The Owren method is used mainly in the Nordic and Baltic countries, in Japan, whereas the Quick method is employed in most other countries. Warfarin management is associated with some complications. Unlike many other drugs the dose for a given patient cannot be estimated beforehand, dose-response relationship is not predictable, and the prevention of thrombosis must be balanced against the risk of bleeding. Furthermore, the different PT methods used to monitor the drug are sometimes not in agreement and show significant discrepancies in results. In an attempt to clarify the mechanisms influencing the inter-individual variations in warfarin therapy and to detect the factors that contribute to differences between PT methods, studies were conducted in collaboration with hospitals and anticoagulation clinics in the south-eastern region of Sweden. First, a stereo-specific HPLC method for measurement of warfarin enantiomers was developed and validated. With this method, the levels of plasma warfarin following its oral administration can be studied and evaluated. Abnormal clearance in some patients can be detected, and patient compliance can be verified. Furthermore, differing ratios of (S)- and (R)-isomers can be identified. The impact of common VKORC1 polymorphisms on warfarin therapy was investigated. This study has shown that the VKORC1*2 haplotype is an important genetic determinant for warfarin dosage and is associated with difficulties in attaining and retaining therapeutic PT-INR. Further, significant differences in warfarin S/R-ratio was detected between patients with VKORC1*2 and VKORC1*3 or VKORC1*4 variants. This difference was not coupled with CYP2C9 genotype. The effects of predilution of patient plasma samples, sources of thromboplastin and deficient plasma on between PT methods agreement were studied. This study has revealed that sample predilution according to the Owren method is to be preferred for the harmonisation of PT results. Undiluted samples, in contrast, according to the Quick method have shown reduced correlation between two different thromboplastin reagents. Sources of thromboplastin and deficient plasma were only of minor importance.

No description available.

Background Every year about 2,500 patients in Sweden undergo surgery for heart valve disease, primarily in the aortic valve.  In contrast to the mitral valve, which can be repaired in 70% of the cases, the aortic valve is normally replaced by a mechanical or biological prosthesis. A mechanical heart valve (MHV) necessitates lifelong anticoagulation treatment with a vitamin K antagonist, most commonly warfarin, due to the high thrombogenicity of the prosthesis. The quality of the warfarin treatment is crucial in these patients. Compared to other countries, treatment quality in Sweden is very high; nonetheless, there is always room for improvement. One of the ways to achieve this improvement is to implement computerized dosing assistance. Treatment recommendations for anticoagulation intensity are based on few and old studies, making these recommendations uncertain. There is therefore a need for studies designed to establish the appropriate level of anticoagulation therapy. Aim The aim of these studies was to investigate the efficacy and safety of anticoagulation treatment among patients with mechanical heart valve prostheses in Sweden; to assess whether computerized dosing can increase the treatment quality; to investigate the influence of the treatment quality, measured by Time in Therapeutic Range (TTR) and INR variability, on the risk of complications and, finally, to establish the optimal intensity of anticoagulation treatment in this group of patients. Methods Data were obtained from AuriculA – a national quality registry established in 2006, which currently includes approximately 50% of all patients treated with oral anticoagulation in Sweden. Study II used only data from AuriculA. 769,933 warfarin-dosing suggestions proposed by the dosing algorithm in AuriculA were analysed. Accepted dose suggestions (590,939) were compared with 178,994 manually-changed doses in regard to the resultant INR value, measured as mean error (deviation from target INR) and hit rate (number of INR samples within the target range 2-3). In study III, AuriculA was used to identify patients in Sundsvall and Malmö in the period 2008 – 2011 who were receiving warfarin for a mechanical heart valve prosthesis, as well as to retrieve their INR data. Data on background characteristics and bleedings or thromboembolic complications were manually retrieved from medical records by two investigators.  A total of 534 patients with mechanical heart valve prostheses were divided into quartiles based on TTR and were compared regarding the risk of complications. For Studies I and IV, data from AuriculA were merged with the Swedish National Patient Register, SWEDEHEART/ Heart surgery, and the Swedish Cause of Death Register, comprising in total 77,423 patients on warfarin with 217,804 treatment years. Every treatment period registered in AuriculA was given an individual identification number. During the study period a patient could have any number of treatment periods. The number of complications in total and in different patient groups within the study population was investigated. Complications were defined by ICD-10 codes. Major bleeding was defined as an event necessitating hospital treatment and given a discharge diagnosis with one of the ICD-10 codes reflecting bleeding, as listed in the Appendix. Bleeding events were divided into intracranial, gastrointestinal and other bleedings. Thromboembolic complications consist of venous events (deep vein thrombosis, pulmonary embolism, venous stroke) or arterial events (stroke, TIA, acute myocardial infarction, peripheral arterial embolism). Data were analysed using both simple, descriptive statistical methods and various tests such as Mann-Whitney (or two sample Wilcoxon), T-test, Chi 2 test, ANOVA, multivariate analysis with logistic regression and survival analysis with Cox Regression with proportional hazard assumption. Results Treatment quality  Mean TTR among all patients in Study I was 76.5% whereas patients with mechanical heart valve prostheses had a TTR of 74.5%. The annual incidence of major bleeding or thromboembolic events among all patients was 2.24% and 2.65%, respectively. The incidence of intracranial bleeding was 0.37% per year in the general population and 0.51% among patients with mechanical heart valve prostheses, who also had a higher bleeding rate in total (3.37% per year). Both the mean and median errors were smaller (0.44 vs. 0.48 and 0.3 vs. 0.4, respectively) and the hit rate was higher (0.72 vs. 0.67) when the dose suggested by the algorithm was accepted, compared to when it was manually changed. TTR  In Study III there was no significant difference in the risk of thromboembolism regardless of TTR level. Risk of bleeding in quartiles I and II was more than two times higher than in the quartile with TTR &gt;82.9. In Study IV, lower TTR (≤70%) was associated with a significantly higher rate of complications when compared with TTR &gt;70%. Bleeding risk was higher in the group with lower TTR (HR=2.43, CI 2.02-2.89, p&lt;0.001). After dividing patients into TTR quartiles, the rate of complications in total was significantly higher in quartiles I to III compared with quartile IV, which had the highest TTR. Risk of thromboembolism, major bleeding and death was higher in the first and second quartile compared to the quartile with the highest TTR. INR variability  Higher INR variability above mean (≥0.40) was related to a higher rate of complications compared with lower INR variability (&lt;0.40) as shown in Study IV. Bleeding risk was higher in the group with INR variability ≥0.40 (HR = 2.15, CI 1.75-2.61, p&lt;0.001). Comparison of quartile IV, which had the lowest INR variability, with the other three revealed that quartiles I and II, which had the highest INR variability, had significantly worse outcomes for all complications except for thromboembolic events, plus also death in quartile II. TTR and INR variability combined  High variability and low TTR combined was associated with a higher risk of bleedings (HR 2.50, CI 1.99-3.15), death (3.34, CI 2.62-4-27) and thrombosis (1.55, CI 1.21-1.99) compared to the best group. Level of anticoagulation Higher warfarin treatment intensity (mean INR 2.8-3.2 vs. 2.2-2.7) was associated with a higher rate of bleedings (HR 1.29, CI 1.06-1.58), death (1.73, CI 1.38-2.16) and complications in total (1.24, CI 1.06-1.41) after adjustment for MHV position, age and comorbidity. Conclusion Warfarin treatment quality is crucial for patients with mechanical heart valve prostheses. Computerized dosing assistance could help maintain high warfarin treatment quality. Well-managed treatment with TTR ≥70% and INR variability below mean &lt;0.40 is associated with a lower risk of serious complications compared with a lower TTR and higher INR variability. No benefit of higher warfarin treatment intensity was found for any valve type or position.

Regression models for de facto currency regime classification are complemented by inferential techniques for tracking the stability of exchange rate regimes. Several structural change methods are adapted to these regressions: tools for assessing the stability of exchange rate regressions in historical data (testing), in incoming data (monitoring) and for determining the breakpoints of shifts in the exchange rate regime (dating). The tools are illustrated by investigating the Chinese exchange rate regime after China gave up on a fixed exchange rate to the US dollar in 2005 and to track the evolution of the Indian exchange rate regime since 1993. / Series: Research Report Series / Department of Statistics and Mathematics

A unified toolbox for testing, monitoring, and dating structural changes is provided for likelihood-based regression models. In particular, least-squares methods for dating breakpoints are extended to maximum likelihood estimation. The usefulness of all techniques is illustrated by assessing the stability of de facto exchange rate regimes. The toolbox is used for investigating the Chinese exchange rate regime after China gave up on a fixed exchange rate to the US dollar in 2005 and tracking the evolution of the Indian exchange rate regime since 1993. / Series: Research Report Series / Department of Statistics and Mathematics

Intranuclear rodlets (INRs) are poorly understood intranuclear bodies originally identified within neuronal nuclei on the basis of their unique morphology. Their mechanism of formation, biochemical composition and physiological significance are largely unknown. To gain insight into the molecular regulators of INR formation, mice with a conditional adult β cell-specific knockout of the master regulator of β-cell metabolism, Lkb1 protein kinase (LABKO mice) were studied. The proportion of beta cells containing INRs was significantly reduced in LABKO mice. Further examination ruled out mTOR and Mark2 as downstream effectors of Lkb1 knockout INR phenotype. Instead it identified the mTOR pathway as an independent regulator of INR formation. To investigate INR changes in a pathophysiological context, β cell INRs were examined in two models of human metabolic syndrome: (1) mice maintained on a high-fat diet and (2) leptin-deficient ob/ob mice. Significant INR reduction was observed in both models. Taken together, our results support the view that INR formation in pancreatic β cells is a dynamic and regulated process. The substantial depletion of INRs in LABKO and obese diabetic mice suggests their relationship to β cell function and potential involvement in diabetes pathogenesis. The significance of these findings was further underscored by the demonstration of INRs in human endocrine pancreas, suggesting their potential relevance to the development of metabolic syndrome in humans. The existence of biochemically distinct subtypes of INRs has been suggested by previous reports of differential immunological staining of INRs in neurochemically distinct neuronal populations. Here, a novel variant of INR has been identified that is immunoreactive for the 40kDa huntingtin associated protein and ubiquitin; and evidence was provided for the existence of additional INR subtypes sharing ubiquitin immunoreactivity as a common feature. Selective association of these INRs with melanin concentrating hormone and tyrosine hydroxylase immunoreactive neurons of the hypothalamus and the locus coeruleus was described. It was also demonstrated for the first time that biochemically distinct INR subtypes can co-exist within a single nucleus where they engage in non-random spatial interactions. These findings highlight the biochemical diversity and cell type specific expression of these enigmatic intranuclear structures. On the basis of these findings and previous literature a hypothesis is proposed as to the overall functional significance of INRs in the cell nucleus.

Intranuclear rodlets (INRs) are poorly understood intranuclear bodies originally identified within neuronal nuclei on the basis of their unique morphology. Their mechanism of formation, biochemical composition and physiological significance are largely unknown. To gain insight into the molecular regulators of INR formation, mice with a conditional adult β cell-specific knockout of the master regulator of β-cell metabolism, Lkb1 protein kinase (LABKO mice) were studied. The proportion of beta cells containing INRs was significantly reduced in LABKO mice. Further examination ruled out mTOR and Mark2 as downstream effectors of Lkb1 knockout INR phenotype. Instead it identified the mTOR pathway as an independent regulator of INR formation. To investigate INR changes in a pathophysiological context, β cell INRs were examined in two models of human metabolic syndrome: (1) mice maintained on a high-fat diet and (2) leptin-deficient ob/ob mice. Significant INR reduction was observed in both models. Taken together, our results support the view that INR formation in pancreatic β cells is a dynamic and regulated process. The substantial depletion of INRs in LABKO and obese diabetic mice suggests their relationship to β cell function and potential involvement in diabetes pathogenesis. The significance of these findings was further underscored by the demonstration of INRs in human endocrine pancreas, suggesting their potential relevance to the development of metabolic syndrome in humans. The existence of biochemically distinct subtypes of INRs has been suggested by previous reports of differential immunological staining of INRs in neurochemically distinct neuronal populations. Here, a novel variant of INR has been identified that is immunoreactive for the 40kDa huntingtin associated protein and ubiquitin; and evidence was provided for the existence of additional INR subtypes sharing ubiquitin immunoreactivity as a common feature. Selective association of these INRs with melanin concentrating hormone and tyrosine hydroxylase immunoreactive neurons of the hypothalamus and the locus coeruleus was described. It was also demonstrated for the first time that biochemically distinct INR subtypes can co-exist within a single nucleus where they engage in non-random spatial interactions. These findings highlight the biochemical diversity and cell type specific expression of these enigmatic intranuclear structures. On the basis of these findings and previous literature a hypothesis is proposed as to the overall functional significance of INRs in the cell nucleus.