Predictive factors in the long term outcome in gastro-oesophageal reflux disease: six years follow up of 107 patients

There is little information concerning the long term outcome of patients with gastro-oesophageal reflux disease (GORD). Thus 109 patients with reflux symptoms (33 with erosive oesophagitis) with a diagnosis of GORD after clinical evaluation and oesophageal testing were studied. All patients were treated with a stepwise approach: (a) lifestyle changes were suggested aimed at reducing reflux and antacids and the prokinetic agent domperidone were prescribed; (b) H2 blockers were added after two months when symptoms persisted; (c) anti-reflux surgery was indicated when there was no response to (b). Treatment was adjusted to maintain clinical remission during follow up. Long term treatment need was defined as minor when conservative measures sufficed for proper control, and as major if daily H2 blockers or surgery were required. The results showed that one third of the patients each had initial therapeutic need (a), (b), and (c). Of 103 patients available for follow up at three years and 89 at six years, respective therapeutic needs were minor in 52% and 55% and major in 48% and 45%. Eighty per cent of patients in (a), 67% in (b), and 17% in (c) required only conservative measures at six years. A decreasing lower oesophageal sphincter pressure (p < 0.001), radiological reflux (p = 0.028), and erosive oesophagitis (p = 0.031), but not initial clinical scores, were independent predictors of major therapeutic need as shown by multivariate analysis. The long term outcome of GORD is better than previously perceived.

Low predictive value of elevated blood pressure during childhood and adolescence

Background: Screening of elevated blood pressure (BP) in children has been advocated to early identify hypertension. However, identification of children with sustained elevated BP is challenging due to the high BP variability. The value of an elevated BP measure during childhood and adolescence for the prediction of future elevated BP is not well described. Objectives: We assessed the positive (PPV) and negative (NPV) predictive value of high BP for sustained elevated BP in cohorts of children of the Seychelles, a rapidly developing island state in the African region. Methods: Serial school-based surveys of weight, height, and BP were conducted yearly between 1998-2006 among all students of the country in four school grades (kindergarten [G0, mean age (SD): 5.5 (0.4) yr], G4 [9.2 (0.4) yr], G7 [12.5 (0.4) yr] and G10 (15.6 (0.5) yr]. We constituted three cohorts of children examined twice at 3-4 years interval: 4,557 children examined at G0 and G4, 6,198 at G4 and G7, and 6,094 at G7 and G10. The same automated BP measurement devices were used throughout the study. BP was measured twice at each exam and averaged. Obesity and elevated BP were defined using the CDC (BMI_95th sex-, and age-specific percentile) and the NHBPEP criteria (BP_95th sex-, age-, and height specific percentile), respectively. Results: Prevalence of obesity was 6.1% at G0, 7.1% at G4, 7.5% at G7, and 6.5% at G10. Prevalence of elevated BP was 10.2% at G0, 9.9% at G4, 7.1% at G7, and 8.7% at G10. Among children with elevated BP at initial exam, the PPV of keeping elevated BP was low but increased with age: 13% between G0 and G4, 19% between G4 and G7, and 27% between G7 and G10. Among obese children with elevated BP, the PPV was higher: 33%, 35% and 39% respectively. Overall, the probability for children with normal BP to remain in that category 3-4 years later (NPV) was 92%, 95%, and 93%, respectively. By comparison, the PPV for children initially obese to remain obese was much higher at 71%, 71%, and 62% (G7-G10), respectively. The NPV (i.e. the probability of remaining at normal weight) was 94%, 96%, and 98%, respectively. Conclusion: During childhood and adolescence, having an elevated BP at one occasion is a weak predictor of sustained elevated BP 3-4 years later. In obese children, it is a better predictor.

Role of HIV-1-specific CD4 T cells.

PURPOSE OF REVIEW: Most of the studies investigating antiviral immunity have predominantly focused on CD8 T cells. However, numerous recent studies have highlighted the importance of HIV-1-specific CD4 T cells in the antiviral immune response, and have also revealed the high level of complexity and heterogeneity of the virus-specific CD4 T-cell responses. An understanding of the role of these key players in the antiviral immune response is of fundamental importance.RECENT FINDINGS: A comprehensive investigation of several features of virus-specific CD4 T-cell responses, including the magnitude, breadth, function and phenotype, has recently been performed. In particular, HIV-1-specific CD4 T-cell responses have been studied in different stages of HIV-1 infection, i.e. acute and chronic phase, under conditions of spontaneous (long-term non-progressors) or antiviral therapy-mediated control of virus replication or uncontrolled virus replication. Different phenotypical and functional patterns of HIV-1-specific CD4 T-cell responses were associated with different conditions of controlled versus uncontrolled virus replication, thus allowing the identification of signatures of protective immune responses. Robust and diverse virus-specific CD4 T-cell responses have been observed. These responses, however, were not predictive of nonprogressive versus progressive HIV-1-associated disease.SUMMARY: There is an urgent need to delineate the immune correlates of protective T-cell responses in order to develop novel immunological markers to evaluate the degree of immune restoration of antiviral therapy as well as the potential effectiveness of HIV vaccine-induced T-cell immune responses.

Alterations of Neuromuscular Function after the World's Most Challenging Mountain Ultra-Marathon

We investigated the physiological consequences of the most challenging mountain ultra-marathon (MUM) in the world: a 330-km trail run with 24000 m of positive and negative elevation change. Neuromuscular fatigue (NMF) was assessed before (Pre-), during (Mid-) and after (Post-) the MUM in experienced ultra-marathon runners (n = 15; finish time = 122.43 hours +/-17.21 hours) and in Pre- and Post- in a control group with a similar level of sleep deprivation (n = 8). Blood markers of muscle inflammation and damage were analyzed at Pre- and Post-. Mean +/- SD maximal voluntary contraction force declined significantly at Mid- (-13+/-17% and -10+/-16%, P<0.05 for knee extensor, KE, and plantar flexor muscles, PF, respectively), and further decreased at Post- (-24+/-13% and -26+/-19%, P<0.01) with alteration of the central activation ratio (-24+/-24% and -28+/-34% between Pre- and Post-, P<0.05) in runners whereas these parameters did not change in the control group. Peripheral NMF markers such as 100 Hz doublet (KE: -18+/-18% and PF: -20+/-15%, P<0.01) and peak twitch (KE: -33+/-12%, P<0.001 and PF: -19+/-14%, P<0.01) were also altered in runners but not in controls. Post-MUM blood concentrations of creatine kinase (3719+/-3045 Ul.1), lactate dehydrogenase (1145+/-511 UI.L-1), C-Reactive Protein (13.1+/-7.5 mg.L-1) and myoglobin (449.3+/-338.2 microg.L-1) were higher (P<0.001) than at Pre- in runners but not in controls. Our findings revealed less neuromuscular fatigue, muscle damage and inflammation than in shorter MUMs. In conclusion, paradoxically, such extreme exercise seems to induce a relative muscle preservation process due likely to a protective anticipatory pacing strategy during the first half of MUM and sleep deprivation in the second half.

Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function

Cholesterol regulates plasma membrane (PM) association and functioning of syntaxin-4 and soluble N-ethylmaleimide-sensitive fusion protein 23 (SNAP23) in the secretory pathway. However, the molecular mechanism and cellular cholesterol pools that determine the localization and assembly of these target membrane SNAP receptors (t-SNAREs) are largely unknown. We recently demonstrated that high levels of annexin A6 (AnxA6) induce accumulation of cholesterol in late endosomes, thereby reducing cholesterol in the Golgi and PM. This leads to an impaired supply of cholesterol needed for cytosolic phospholipase A2 (cPLA2) to drive Golgi vesiculation and caveolin transport to the cell surface. Using AnxA6-overexpressing cells as a model for cellular cholesterol imbalance, we identify impaired cholesterol egress from late endosomes and diminution of Golgi cholesterol as correlating with the sequestration of SNAP23/syntaxin-4 in Golgi membranes. Pharmacological accumulation of late endosomal cholesterol and cPLA2 inhibition induces a similar phenotype in control cells with low AnxA6 levels. Ectopic expression of Niemann-Pick C1 (NPC1) or exogenous cholesterol restores the location of SNAP23 and syntaxin-4 within the PM. Importantly, AnxA6-mediated mislocalization of these t-SNAREs correlates with reduced secretion of cargo via the SNAP23/syntaxin-4¿dependent constitutive exocytic pathway. We thus conclude that inhibition of late endosomal export and Golgi cholesterol depletion modulate t-SNARE localization and functioning along the exocytic pathway.

Relationship between autonomic neuropathy and thermogenesis in non diabetic and diabetic obese patients.

Autonomic neuropathy is a well known complication of diabetes. Diabetes is often superimposed on obesity. A reduction in the variability of the heart rate in the resting state has been demonstrated in 16 obese diabetic subjects as well as in 34 obese non-diabetic subjects. The coefficient of variation (CV) of the heart rate during 30 minutes of resting was significantly decreased in both obese groups (3.9 +/- 0.2% for the diabetics; 5.2 +/- 0.2%, p less than 0.01 for the non diabetics) as compared to their own controls (4.5 +/- 0.6% and 6.5 +/- 0.4%, respectively). Age also contributes to decreased heart rate variability. Furthermore, this defect of autonomic function has been correlated with the blunted glucose-induced thermogenesis (GIT) seen in both obese groups (r = 0.52, p. less than 0.001): the increase in energy expenditure over basal values following a 100 g oral glucose load was only 4.8 +/- 0.8% for the diabetic obese group (p less than 0.001), and 8.5 +/- 0.7% for the non-diabetic obese group (p less than 0.001) as opposed to their own controls (12.4 +/- 1.3% and 13.3 +/- 0.6% respectively). Measurement of the variability of heart rate in obese individuals may be of predictive value in assessing blunted glucose-induced thermogenesis in non diabetic and diabetic obese patients.

Interleukin-1 receptor antagonist gene (IL-1RN) polymorphism is a predictive factor of clinical pregnancy after IVF.

BACKGROUND: Only 25% of IVF transfer cycles lead to a clinical pregnancy, calling for continued technical progress but also more in depth analysis of patients' individual characteristics. The interleukin-1 (IL-1) system and matrix metalloproteinases (MMPs) are strongly implicated in embryo implantation. The genes coding for IL-1Ra (gene symbol IL-1RN), IL-1beta, MMP2 and MMP9 bear functional polymorphisms. We analysed the maternal genetic profile at these polymorphic sites in IVF patients, to determine possible correlations with IVF outcome. METHODS: One hundred and sixty women undergoing an IVF cycle were enrolled and a buccal smear was obtained. The presence of IL-1RN variable number of tandem repeats and IL-1B + 3953, MMP2-1306 and MMP9-1562 single nucleotide substitutions were determined. Patients were divided into pregnancy failures (119), biochemical pregnancies (8) and clinical pregnancies (33). RESULTS: There was a 40% decrease in IL-1RN*2 allele frequency (P = 0.024) and a 45% decrease in IL-1RN*2 carrier status in the clinical pregnancy group as compared to the pregnancy failure group (P = 0.017). This decrease was still statistically significant after a multivariate logistic regression analysis. The likelihood of a clinical pregnancy was decreased accordingly in IL-1RN*2 carriers: odds ratio = 0.349, 95% confidence interval = 0.2-0.8, P = 0.017. The IL-1B, MMP2 and MMP9 polymorphisms showed no correlation with IVF outcome. CONCLUSIONS: IL-1RN*2 allele carriage is associated with a poor prognosis of achieving a pregnancy after IVF.

Dynamic modulation of CCR7 expression and function on naive T lymphocytes in vivo.

The chemokine receptor CCR7 is critical for the recirculation of naive T cells. It is required for T cell entry into secondary lymphoid organs (SLO) and for T cell motility and retention within these organs. How CCR7 activity is regulated during these processes in vivo is poorly understood. Here we show strong modulation of CCR7 surface expression and occupancy by the two CCR7 ligands, both in vitro and in vivo. In contrast to blood, T cells in SLO had most surface CCR7 occupied with CCL19, presumably leading to continuous signaling and cell motility. Both ligands triggered CCR7 internalization in vivo as shown in Ccl19(-/-) and plt/plt mice. Importantly, CCR7 occupancy and down-regulation led to strongly impaired chemotactic responses, an effect reversible by CCR7 resensitization. Therefore, during their recirculation, T cells cycle between states of free CCR7 with high ligand sensitivity in blood and occupied CCR7 associated with continual signaling and reduced ligand sensitivity within SLO. We propose that these two states of CCR7 are important to allow the various functions CCR7 plays in T cell recirculation.

Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A.

Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel CaV2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant CaV2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.