Metabolic and hormonal studies of Type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation

Long-term normalization of glucose metabolism is necessary to prevent or ameliorate diabetic complications. Although pancreatic grafting is able to restore normal blood glucose and glycated haemoglobin, the degree of normalization of the deranged diabetic metabolism after pancreas transplantation is still questionable. Consequently glucose, insulin, C-peptide, glucagon, and pancreatic polypeptide responses to oral glucose and i.v. arginine were measured in 36 Type 1 (insulin-dependent) diabetic recipients of pancreas and kidney allografts and compared to ten healthy control subjects. Despite normal HbA1 (7.2±0.2%; normal <8%) glucose disposal was normal only in 44% and impaired in 56% of the graft recipients. Normalization of glucose tolerance was achieved at the expense of hyperinsulinaemia in 52% of the subjects. C-peptide and glucagon were normal, while pancreatic polypeptide was significantly higher in the graft recipients. Intravenous glucose tolerance (n=21) was normal in 67% and borderline in 23%. Biphasic insulin release was seen in patients with normal glucose tolerance. Glucose tolerance did not deteriorate up to 7 years post-transplant. In addition, stress hormone release (cortisol, growth hormone, prolactin, glucagon, catecholamines) to insulin-induced hypoglycaemia was examined in 20 graft recipients and compared to eight healthy subjects. Reduced blood glucose decline indicates insulin resistance, but glucose recovery was normal, despite markedly reduced catecholamine and glucagon release. These data demonstrate the effectiveness of pancreatic grafting in normalizing glucose metabolism, although hyperinsulinaemia and deranged counterregulatory hormone response are observed frequently

Evaluation of serum iron overload, AST:ALT ratio and log10ferritin:AST ratio among schizophrenia patients in the Kumasi Metropolis, Ghana: A case-control study

Objective: The association between unbalanced iron indices and the conditions of schizophrenia are not well understood. Liver dysfunction which has been linked to iron metabolism might be a contributing factor. This case–control study evaluated serum iron indices and liver function in treatment-naïve schizophrenia patients and those already on treatment at the Psychiatric Department of the Komfo Anokye Teaching Hospital (KATH), Kumasi-Ghana. Results: The mean age of the respondents was 39.6 ± 0.8 years. Increased levels of serum iron, TS, AST, ALT and AST:ALT ratio and lower levels of UIBC, TIBC, Transferrin, and log Ferritin:AST ratio levels were observed among the treatment-naïve group compared to the control. The treatment-naïve and treatment groups showed significantly higher serum AST:ALT ratio, and lower log10ferrtin:AST ratio than the healthy controls. There was a significant correlation between log10ferritin and AST, and log10ferritin and GGT in both treatments (r = 0.343; p = 0.003, and r = 0.502; p = 0.001 respectively) and treatment-naïve groups (r = 0.348; p = 0.002, and r = 0.614; p \u3c 0.001 respectively). Percentage transferrin saturation correlated significantly with GGT only, in the treatment-naïve group (r = 0.667; p \u3c 0.001), and ALT and GGT in the treatment group (r = 0.252; p = 0.030 and r = 0.646; p = 0.014 respectively)

The primary familial brain calcification associated protein MYORG is an α-galactosidase with restricted substrate specificity

Primary familial brain calcification (PFBC) is characterised by abnormal deposits of calcium phosphate within various regions of the brain that are associated with severe cognitive impairments, psychiatric conditions, and movement disorders. Recent studies in diverse populations have shown a link between mutations in myogenesis-regulating glycosidase (MYORG) and the development of this disease. MYORG is a member of glycoside hydrolase (GH) family 31 (GH31) and, like the other mammalian GH31 enzyme α-glucosidase II, this enzyme is found in the lumen of the endoplasmic reticulum (ER). Though presumed to act as an α-glucosidase due to its localization and sequence relatedness to α-glucosidase II, MYORG has never been shown to exhibit catalytic activity. Here, we show that MYORG is an α-galactosidase and present the high-resolution crystal structure of MYORG in complex with substrate and inhibitor. Using these structures, we map detrimental mutations that are associated with MYORG-associated brain calcification and define how these mutations may drive disease progression through loss of enzymatic activity. Finally, we also detail the thermal stabilisation of MYORG afforded by a clinically approved small molecule ligand, opening the possibility of using pharmacological chaperones to enhance the activity of mutant forms of MYORG

Repellency Potential, Chemical Constituents of Ocimum Plant Essential Oils, and Their Headspace Volatiles against Anopheles gambiae s. s., Malaria Vector

African malaria mosquitoes (Anopheles gambiae sensu stricto) transmit a malaria parasite (Plasmodium falciparum) to humans. The current control strategies for the vector have mainly focussed on synthetic products, which negatively impact the environment and human health. Given the potential use of environmentally friendly plant-derived volatiles as a control, this work aims to examine and compare the repellency potential of essential oils and headspace volatiles from Ocimum gratissimum, Ocimum tenuiflorum, and Ocimum basilicum and their chemical compositions. The repellency potential and chemical composition of the plants were achieved by using the protected arm-in-cage method and gas chromatography-mass spectrometry (GC-MS) analysis. Among the three Ocimum species, both the essential oils and the headspace volatiles from O. tenuiflorum achieved the longest repellency time lengths of 90–120 minutes. One hundred and one (101) chemical constituents were identified in the headspace volatiles of the three Ocimum spp. Nonetheless, (−)-camphor, (E)-γ-bisabolene, terpinolene, β-chamigrene, cubedol, (E)-farnesol, germacrene D-4-ol, viridiflorol, γ-eudesmol, tetracyclo [6.3.2.0 (2,5).0(1,8)] tridecan-9-ol, 4,4-dimethyl, α-eudesmol, isolongifolol, and endo-borneol were unique only to O. tenuiflorum headspace volatiles. Either essential oils or headspace volatiles from O. tenuiflorum could offer longer protection time length to humans against An. gambiae. Though field studies are needed to assess the complementarity between the chemical constituents in the headspace volatiles of O. tenuiflorum, our observations provide a foundation for developing effective repellents against An. gambiae

Genome-wide analysis of ivermectin response by Onchocerca volvulus reveals that genetic drift and soft selective sweeps contribute to loss of drug sensitivity

Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread.Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR.This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations

Deletion of parasite immune modulatory sequences combined with immune activating signals enhances vaccine mediated protection against filarial nematodes

&lt;p&gt;Background: Filarial nematodes are tissue-dwelling parasites that can be killed by Th2-driven immune effectors, but that have evolved to withstand immune attack and establish chronic infections by suppressing host immunity. As a consequence, the efficacy of a vaccine against filariasis may depend on its capacity to counter parasite-driven immunomodulation.&lt;/p&gt; &lt;p&gt;Methodology and Principal Findings: We immunised mice with DNA plasmids expressing functionally-inactivated forms of two immunomodulatory molecules expressed by the filarial parasite Litomosoides sigmodontis: the abundant larval transcript-1 (LsALT) and cysteine protease inhibitor-2 (LsCPI). The mutant proteins enhanced antibody and cytokine responses to live parasite challenge, and led to more leukocyte recruitment to the site of infection than their native forms. The immune response was further enhanced when the antigens were targeted to dendritic cells using a single chain Fv-αDEC205 antibody and co-administered with plasmids that enhance T helper 2 immunity (IL-4) and antigen-presenting cell recruitment (Flt3L, MIP-1α). Mice immunised simultaneously against the mutated forms of LsALT and LsCPI eliminated adult parasites faster and consistently reduced peripheral microfilaraemia. A multifactorial analysis of the immune response revealed that protection was strongly correlated with the production of parasite-specific IgG1 and with the numbers of leukocytes present at the site of infection.&lt;/p&gt; &lt;p&gt;Conclusions: We have developed a successful strategy for DNA vaccination against a nematode infection that specifically targets parasite-driven immunosuppression while simultaneously enhancing Th2 immune responses and parasite antigen presentation by dendritic cells.&lt;/p&gt

Ethnicity, voter alignment and political party affiliation - an African case: Zambia

Conventional wisdom holds that ethnicity provides the social cleavage for voting behav-iour and party affiliation in Africa. Because this is usually inferred from aggregate data of national election results, it might prove to be an ecological fallacy. The evidence based on individual data from an opinion survey in Zambia suggests that ethnicity matters for voter alignment and even more so for party affiliation, but it is certainly not the only factor. The analysis also points to a number of qualifications which are partly methodology-related. One is that the degree of ethnic voting can differ from one ethno-political group to the other depending on various degrees of ethnic mobilisation. Another is that if smaller eth-nic groups or subgroups do not identify with one particular party, it is difficult to find a significant statistical correlation between party affiliation and ethnicity - but that does not prove that they do not affiliate along ethnic lines.Wahlverhalten und Mitgliedschaft in politischen Parteien Afrikas ist nur wenig untersucht worden. Gewöhnlich wird argumentiert, dass Ethnizität als soziale Konfliktlinie das Wahlverhalten und die Parteienmitgliedschaft strukturiert. Da dieses Argument auf hoch aggregierten Wahldaten beruht, kann hier ein ökologischer Fehlschuss vorliegen. Die vorliegende Analyse beruht deshalb auf individuellen Umfragedaten aus Sambia. Das Ergebnis ist, dass Ethnizität tatsächlich eine Rolle für das Wahlverhalten und die Parteienmitgliedschaft spielt, aber keineswegs den einzigen Erklärungsfaktor darstellt. Die Analyse offenbart zudem eine Reihe von Einschränkungen und Qualifizierungen, die teilweise methodischer Natur sind. Eine ist, dass ethnisches Wahlverhalten und Parteienmitgliedschaft von einer ethnischen Gruppe zur anderen unterschiedlich ist, dass, wenn sich kleinere ethnische Gruppen oder Untergruppen mit keiner Partei identifizieren, es schwierig wird, statistisch signifikante Korrelationen zu finden - was indessen noch nicht beweist, dass Ethnizität keine Rolle spielt

Hepatitis C Virus Induces the Cannabinoid Receptor 1

BACKGROUND: Activation of hepatic CB(1) receptors (CB(1)) is associated with steatosis and fibrosis in experimental forms of liver disease. However, CB(1) expression has not been assessed in patients with chronic hepatitis C (CHC), a disease associated with insulin resistance, steatosis and metabolic disturbance. We aimed to determine the importance and explore the associations of CB(1) expression in CHC. METHODS: CB(1) receptor mRNA was measured by real time quantitative PCR on extracted liver tissue from 88 patients with CHC (genotypes 1 and 3), 12 controls and 10 patients with chronic hepatitis B (CHB). The Huh7/JFH1 Hepatitis C virus (HCV) cell culture model was used to validate results. PRINCIPAL FINDINGS: CB(1) was expressed in all patients with CHC and levels were 6-fold higher than in controls (P<0.001). CB(1) expression increased with fibrosis stage, with cirrhotics having up to a 2 fold up-regulation compared to those with low fibrosis stage (p<0.05). Even in mild CHC with no steatosis (F0-1), CB(1) levels remained substantially greater than in controls (p<0.001) and in those with mild CHB (F0-1; p<0.001). Huh7 cells infected with JFH-1 HCV showed an 8-fold upregulation of CB(1), and CB(1) expression directly correlated with the percentage of cells infected over time, suggesting that CB(1) is an HCV inducible gene. While HCV structural proteins appear essential for CB(1) induction, there was no core genotype specific difference in CB(1) expression. CB(1) significantly increased with steatosis grade, primarily driven by patients with genotype 3 CHC. In genotype 3 patients, CB(1) correlated with SREBP-1c and its downstream target FASN (SREBP-1c; R=0.37, FASN; R=0.39, p<0.05 for both). CONCLUSIONS/SIGNIFICANCE: CB(1) is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus