Prospective evaluation of gastric neurostimulation for diabetic gastroparesis in Canada

BACKGROUND:

The efficacy of gastric neurostimulation therapy for diabetic gastroparesis (GP) in a ‘real-life’ Canadian setting has not been assessed.

AIMS:

To assess changes in health-related quality of life (QoL), weekly vomiting frequency (WVF), total symptom score (TSS) and health care utilization 12 months before and after gastric neurostimulator implantation in a diabetic GP cohort.

METHODS:

Medication-refractory diabetic GP patients (n=7, four female, mean age 42 years) were prospectively recruited from 2008 to 2012. QoL scores were self-administered and obtained at baseline, 24 and 48 weeks postimplantion. WVF and TSS were assessed similarly. Health care usage, measured as hospitalization frequency and medication cost, was obtained six and 12 months before and after implant. Changes from baseline to six and 12 months for all outcomes were compared.

RESULTS:

The mean (± SD) QoL according to EuroQol was significantly better at 24 weeks after the baseline measurement (baseline 29±5, 24 weeks 52±7; P=0.03). The mean improvement in TSS was significantly better at one year postintervention (baseline score 35±5 versus 12 months 27±3; P=0.03). Changes in Short-Form 36 Health Survey and WVF were not significant. Days of GP-related hospitalization were highly variable but decreased from a median of 71 days (range 0 to 227 days) to 29 days (range two to 334 days) one year before and after surgery, respectively (P=0.735). Outpatient medication costs did not decrease to a significant extent.

CONCLUSION:

Gastric neurostimulation for diabetic GP appeared to show some beneficial palliative effects overall in the present small open-label series, but the effect is highly variable among patients, and placebo effect cannot be ruled out.     

Structural analysis of the minisatellite present at the 3' end of the human apolipoprotein B gene: new definition of the alleles and evolutionary implications

The internal structure of different alleles of the minisatellite present at the 3' end of the apolipoprotein B (ApoB) gene has been analysed by different approaches including sequencing. The repeat unit arrangements of the minisatellite on 570 chromosomes belonging to European and African populations were thus determined. It was possible to group the alleles using this structural criterion much more clearly than by the number of repeat units which can in some cases be misleading in case-control genetic epidemiological studies using such DNA sequences as markers. We were thus able to define five types (a to e) of alleles and their subtypes and to recognize clearly those which are, respectively, specific of the African and Caucasian populations. A phylogeny of the different alleles found in all human populations could also be deduced by this approach. The different putative mutational events leading from one type, or subtype, to the other were simply determined as point mutations, expansion/contraction and conversion events. Sequencing of one chimpanzee's allele suggested that the ApoB minisatellite was present before divergence between great apes and humans. It was determined also that a particular ApoB gene haplotype was in linkage disequilibrium with the minisatellite (a) type of alleles. This and the observation that the potential scaffold attachment regions (SAR) and topoisomerase II binding sites present in this minisatellite have a different distribution between the Caucasian and the African specific alleles suggest that the minisatellite could be involved in the epidemiology of coronary diseases.      

Suicidal behavior: relationship between phenotype and serotonergic genotype

The basis of suicidal behavior (SB) is complex and multifactorial. Numerous risk factors have been identified. Epidemiological genetics studies (family studies, twin studies, adoption studies) suggest that there is a genetic basis to SB and that this genetic basis is specific and independent from the genetic factors implicated in predisposition to psychiatric disorders associated with SB (bipolar disorder, schizophrenia, alcoholism). Recently, new molecular genetics tools have been designed to identify the genetic factors that predispose certain individuals to disorders of complex etiology. Biological psychiatry studies have suggested that the physiopathology of SB involves dysfunctioning of the serotonin system. The first genetic association studies tested candidate genes encoding proteins involved in serotonin metabolism. The results of these studies suggest that the gene coding for the limiting enzyme in the synthesis of serotonin, tryptophan hydroxylase (TPH), and the gene encoding the serotonin transporter are involved in predisposition to SB. Furthermore, it is likely that these genes interact with each other and with environmental factors (early) and that they have different phenotypic consequences. One of the main aims of studies currently underway is to identify the precise phenotypes associated with genes that predispose to SB or intermediate phenotypes (impulsivity, inability to control anger, etc.).     

Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample.

Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study.     

Thrombin receptor: An endogenous inhibitor of inflammatory pain, activating opioid pathways

Serine proteases such as thrombin, trypsin and mast cell tryptase can act on different cell types through protease-activated receptors (PARs). These receptors have been shown to be implicated in several phenomena such as inflammation, platelet activation, immune response and atherosclerosis. Several studies recently reported PARs expression on neurons and some of them demonstrated that these receptors could interfere with nociception. The contribution of PAR₁ to inflammatory pain and the mechanism involved in this phenomenon were investigated. Intraplantar injection of PAR₁ agonist increased withdrawal latency and reduced response frequency to von Frey filaments, thus inhibiting nociceptive response to both mechanical and thermal stimuli in mice. PAR₁ agonist also reduced carrageenan-induced inflammatory hyperalgesia. The anti-nociceptive effects of PAR₁ agonist were mediated by endogenous opioids, as this effect was inhibited by local injection of naloxone methiodide, and because intraplantar injection of PAR₁ agonist increased mRNA expression of the endogenous opioid precursor proenkephalin. However, PAR₁ agonist was not able to inhibit calcium signals in isolated sensory neurons exposed to pro-nociceptive agents. Finally, despite similar inflammatory parameters, PAR₁-deficient mice showed a strong potentiation of inflammatory hyperalgesia induced by the intraplantar injection of either formalin or carrageenan, or in the chronic model of collagen-induced arthritis, compared to wild-type mice. This study highlights a previously unknown endogenous mechanism of analgesia, showing a central role for the thrombin receptor PAR₁ in the regulation of inflammatory pain and as an activator of opioid pathways.     

Association between brain-derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene

Background:  Recent data suggest that brain-derived neurotrophic factor (BDNF) and the serotonergic system are involved and interact in major depressive disorder and suicidal behavior (SB). Several family and population-based studies have reported associations between the BDNF gene and serotonin-related genes, specifically the serotonin transporter (5HTT) gene, with bipolar disorder (BD) and SB. However, despite the fact that gene-by-gene interaction between BDNF and 5HTT has been demonstrated in monoamine deficiencies in animals, this kind of interaction has never been tested in humans. Our hypothesis is that some BDNF and 5HTT polymorphisms might confer increased risk for BD and SB and that both genes may interact with each other.
Methods:  To test this hypothesis, we genotyped the most common BDNF polymorphisms, G196A (Val66Met), A-633T and BDNF-LCPR, as well as 5HTT (5HTT-LPR), in 447 BD patients and 370 controls.
Results:  We replicated the association previously reported between BDNF G196A (Val66Met) polymorphism and BD. We also observed a correlation between the number of G196 alleles and short alleles of 5HTT-LPR and the severity of SB in BD. However, we found no significant interaction between these two markers.
Conclusions:  These results suggest that BDNF G196A as well as 5HTT-LPR polymorphisms confer risk for SB in BD, but we did not observe any evidence for an interaction between them.     

Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts.

BACKGROUND: In the first year following a suicide attempt, patients are at high risk for reattempt and for completed suicide. We aim to determine the predictive value of two serotonin-related genes, the tryptophan hydroxylase (TPH) and serotonin transporter (5-HTTLPR) genes that have been involved in the susceptibility to suicidal behavior. METHODS: After a one-year follow-up study of 103 patients hospitalized after a suicide attempt, patients have been genotyped for both the A218C TPH and the functional S/L 5-HTTLPR polymorphisms. RESULTS: Patients who reattempted suicide during the follow-up period had significantly higher frequencies of the S allele and the SS genotype. The odds ratio for the SS genotype vs. the LL genotype was 6.5 (95% CI [1.18-35.84]). No difference was observed for TPH gene. Patients carrying the SS genotype were more impulsive. However, multivariate analysis suggested an independent effect of both the SS genotype and impulsivity on the risk of repeated suicide attempts. CONCLUSIONS: These results suggest that the 5-HTTLPR SS genotype is associated with further suicide attempts among patients who have previously attempted suicide.     

FOunder effect in patients with Unverricht-Lundborg disease on reunion island

PURPOSE: Unverricht-Lundborg disease (ULD) is the most frequent form of progressive myoclonus epilepsy. ULD is caused mostly by a homozygous expansion of a dodecamer repeat in the cystatin B gene (CSTB) promoter. We present here a clinical and molecular study of 14 ULD patients originating from Reunion Island, a French island in the Indian Ocean. METHODS: These ULD patients were clinically evaluated, and the diagnosis of ULD was confirmed molecularly. We analyzed 12 microsatellites flanking CSTB and estimated the date of introduction of the ULD mutation on Reunion Island. RESULTS: These cases were clinically very similar, with the typical myoclonus syndrome associated with generalized tonic-clonic seizures, cerebellar involvement and, in some cases, mild mental deterioration. The mean age at onset was 9.6 years (range, 5-14 years), and the mean disease duration was 27 years (range, 5-47 years). The 14 patients harbored the typical ULD mutation, with variable degrees of expansion (mean of 56.3 repeats; range, 49-63). A founder effect was detected, with all but one of the Reunion ULD chromosomes displaying expansions belonging to the same haplotype, 1-1-1-2-6-4-3. We estimated the date of arrival of the most recent common ancestor (MRCA) of these patients on Reunion Island to the middle of the eighteenth century. CONCLUSIONS: These Reunion ULD patients displayed a homogeneous phenotype. Our molecular results are compatible with the instability of the repeat expansion and revealed a founder effect in Reunion ULD patients and the existence of a MRCA about 12 generations ago.