Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study.

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-ß treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-ß-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5).

Dietary alterations due to perceptions in acute viral hepatitis lead to sub-optimal calorie intake and increased length of hospitalization.

Although there are no dietary restrictions recommended in acute viral hepatitis (AVH), there is an altered food intake, probably because of perceptions and traditional nutritional practices, leading to sub-optimal intake and poorer clinical outcome. Therefore, we aimed to determine nutritional intake of AVH patients before and after disease onset and to investigate if optimal intake following nutrition education shortened the length of hospitalization (LOH). Seventy-five patients with AVH were interviewed for foods consumed and avoided because of perceptions during illness. Nutrition education was given to all patients with meal plan. In-patients were monitored for their nutritional intake until discharge. All patients were followed up after 2 weeks to assess compliance to the plan. There was a statistically significant decrease in mean calorie and protein intake in AVH patients during illness [1314 kcal (standard deviation, SD 291) and 27.5 g (SD 8.84)] when compared with that before onset of the disease [1873 kcal (SD 246) and 51.5 g (SD 8.03); P < 0.0001]. Mean LOH in patients consuming a high calorie diet [6.28 days (SD 2.91)] was significantly lower than those consuming low calories [8.36 days (SD 2.59), P = 0.024]. Two-week follow up revealed that 70% of patients modified their diet to a balanced normal diet as per the given plan. Our study showed that AVH patients consumed sub-optimal calories because of perceptions and traditional nutritional practices. Nutrition education played a major role in achieving overall nutritional goals and in decreasing the LOH.

Genome-wide DNA methylation profiling of peripheral blood mononuclear cells in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a stress-sensitive disorder. Environmental factors including stress can trigger epigenetic changes, which have not been well-studied in IBS. We performed a pilot study investigating genome-wide DNA methylation of IBS patients and healthy controls (HCs) to identify potential epigenetic markers and associated pathways. Additionally, we investigated relationships of epigenetic changes in selected genes with clinical traits. METHODS: Twenty-seven IBS patients (59% women; 10 IBS-diarrhea, 8 IBS-constipation, 9 IBS-mixed) and 23 age- and sex-matched HCs were examined. DNA methylation from peripheral blood mononuclear cells (PBMCs) was measured using HM450 BeadChip, and representative methylation differences were confirmed by bisulphite sequencing. Gene expression was measured using quantitative PCR. Gastrointestinal (GI) and non-GI symptoms were measured using validated questionnaires. Associations were tested using non-parametric methods. KEY RESULTS: Genome-wide DNA methylation profiling of IBS patients compared with HCs identified 133 differentially methylated positions (DMPs) (mean difference ≥10%; p < 0.05). These genes were associated with gene ontology terms including glutathione metabolism related to oxidative stress and neuropeptide hormone activity. Validation by sequencing confirmed differential methylation of subcommissural organ (SCO)-Spondin (SSPO), glutathione-S-transferases mu 5 (GSTM5), and tubulin polymerization promoting protein genes. Methylation of two promoter CpGs in GSTM5 was associated with epigenetic silencing. Epigenetic changes in SSPO gene were positively correlated with hospital anxiety and depression scores in IBS patients (r > 0.4 and false discovery rate <0.05). CONCLUSIONS & INFERENCES: This study is the first to comprehensively explore the methylome of IBS patients. We identified DMPs in novel candidate genes which could provide new insights into disease mechanisms; however, these preliminary findings warrant confirmation in larger, independent studies.

Influence of elevated liver fat on circulating adipocytokines and insulin resistance in obese Hispanic adolescents.

OBJECTIVE: We performed this study to examine the metabolic differences arising from higher liver fat accumulation in obese Hispanic adolescents, with a particular focus on circulating levels of adipocytokines and insulin resistance. METHODS: Forty-one obese Hispanic adolescents (15.3 ± 1.0 years, body mass index percentile: 97.0 ± 3.9) were assessed for: visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and hepatic fat fraction (HFF) by magnetic resonance imaging; fasting measures of serum glucose, insulin and adipocytokines; homeostasis model assessment of insulin resistance (HOMA-IR); and insulin sensitivity (SI) and the acute insulin response to glucose (AIR) by intravenous glucose tolerance test. Subjects with normal levels of HFF (below 5%; n = 25) were compared to those with HFF > 5% (n = 16). RESULTS: The two groups differing in HFF were similar for total body fat, VAT and SAT. The group with HFF > 5% had significantly (P < 0.05) higher interleukin-8 (IL-8) (6.1 ± 1.6 vs. 3.2 ± 0.4 pg mL(-1) ), NGF (30.2 ± 9.9 vs. 13.9 ± 1.6 pg mL(-1) ), HOMA-IR (8.8 ± 1.1 vs. 5.5 ± 0.5), AIR (1869 ± 206 vs. 1092 ± 165) and a tendency for lower SI (1.2 ± 0.4 vs. 2.1 ± 0.3; P = 0.06), with no significant differences in any of other factors measured. CONCLUSIONS: These data suggest that elevated liver fat is most closely associated with elevated serum IL-8 and NGF levels as well as increased AIR and HOMA-IR. These elevated factors may play significant roles in the metabolic abnormalities associated with elevated liver fat in obese Hispanics.

Association of cathepsin B gene polymorphisms with tropical calcific pancreatitis.

BACKGROUND AND AIMS: Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to countries in the tropics. Mutations in pancreatic secretory trypsin inhibitor (SPINK1) rather than cationic trypsinogen (PRSS1) explain the disease in only 50% of TCP patients. As cathepsin B (CTSB) is known to activate cationic trypsinogen, we attempted to understand the role of CTSB mutations in TCP. Evidence of epistatic interaction was investigated with the previously associated N34S SPINK1 allele, a variant considered to be a modifier rather than a true susceptibility allele. SUBJECTS AND METHODS: We sequenced the coding region of CTSB gene in 51 TCP patients and 25 controls and further genotyped 89 patients and 130 controls from the same cohort for Leu26Val, C595T, T663C, and Ser53Gly polymorphisms. The positive findings observed in the earlier cohort were re-examined in an ethnically matched replication cohort comprising 166 patients and 175 controls. Appropriate statistical analyses were performed and Bonferroni correction for multiple testing was applied. RESULTS: We found a statistically significant association of the Val26 allele at Leu26Val polymorphism with an odds ratio (OR) of 2.15 (95% confidence interval (CI) 1.60-2.90 (p = 0.009)), after Bonferroni correction (corrected p value = 0.025). This significant association of Leu26Val with TCP was replicated in another cohort (OR 2.10 (95% CI 1.56-2.84); p = 0.013). Val26 allele also showed significantly higher frequency in N34S positive and N34S negative patients than in controls (p = 0.019 and 0.013, respectively). We also found significant differences in the mutant allele frequencies at Ser53Gly and C595T single nucleotide polymorphisms between N34S positive patients and controls (p = 0.008 and 0.001, respectively). Although haplotype analysis did not complement the results of allelic association, it did uncover a unique haplotype protective for TCP (p = 0.0035). CONCLUSION: Our study suggests for the first time that CTSB polymorphisms are associated with TCP. As PRSS1 mutations are absent in TCP and the N34S SPINK1 mutation is proposed to play a modifier role, these variants may be critical as a trigger for cationic trypsinogen activation.

Treatment of severe and moderate hypertension with minoxidil: experience in twenty-eight patients.

1. Twenty patients with severe or moderate hypertension were treated with minoxidil for 284 patient-months. 2. The blood pressure was controlled in all patients, including those refractory to maximal doses of conventional anti-hypertensive agents. 3. In patients with moderate hypertension control with minoxidil was achieved earlier and more easily than with hydrallazine. 4. Three patients developed secondary resistance and required addition of guanethidine or increased doses of diuretics. 5. Fluid retention and hypertrichosis were the main side effects with minoxidil.

Modification of mild proteinuria by postural and other mechanisms affecting haemodynamics.

Changes in urinary protein excretion induced by standing or by the application of venous tourniquets to the thighs while the patient is in the supine position were studied in patients with mild proteinuria and compared with the changes that occur in severe proteinuria (greater than 1 mg/min). Protein excretion decreased in the majority of patients. Irrespective of the initial degree of proteinuria. The increased rate of protein excretion that occurred in a minority of patients when standing may represent a phenomenon analogous to orthostatic proteinuria.

Severe hypertension. Treatment with minoxidil.

Seventeen patients who were partially or totally refractory to maximal doses of conventional antihypertensive agents were treated with minoxidil. Three patients were receiving long-term maintenance dialysis. Propranolol and diuretics were given to prevent reflex tachycardia and fluid retention. Initial control of blood pressure was excellent in 16 patient. In one patient, diastolic blood pressure remained unchanged (120 mm Hg) despite 60 mg of minoxidil and volume depletion. In three other patients, secondary resistance developed, and the addition of guanethidine was necessary. The main side-effects were fluid retention (in eight) and hypertrichosis (in ten), accompanied in some by a peculiar coarsening of the facial features. Renal function stabilized or improved in most, and urine output increased in the three hemodialysis patients. We conclude that minoxidil is a valuable drug in severe hypertension.

Relationship of posture and age to urinary protein excretion.

The influence of posture and age on urinary protein excretion was studied in 120 normal men volunteers. The supine excretion rate was less than 140 mug/min in all but two people (median value 38 mug/min) and tended to increase with age. The excretion rate decreased on quiet standing in 80% of people, which corresponded to a fall in creatinine-clearance. In the remaining 20% protein excretion increased on standing but generally remained within normal limits and was dissociated from changes in creatinine clearances. This increase was more prevalent in younger people and may represent a phenomenon analogous to orthostatic proteinuria, differing only quantitatively.

High-dose bolus urography. A superior technique in advanced renal failure.

High-dose bolus urography was evaluated in 38 patients with severe renal failure. Iothalamate meglumine (Conray 60) (2 ml/kg of body weight) was injected within one minute and nephrotomograms were taken for 30 minutes, with delayed films until 24 hours. Immediate nephrograms were obtained in all cases. The collecting systems, seen in 29 cases, were dilated in three. In the rest, obstruction could be ruled out by a combination of roentgenographic criteria. No untoward reactions occurred, and all the required information was obtained within 30 minutes. The results were superior to plain nephrotomography or infusion pyelography. We conclude that bolus nephrotomography is the procedure of choice in the investigation of severe renal failure.

Role of aluminum in dialysis dementia.

Between September 1972 and January 1976 an outbreak of dialysis dementia affected 20 patients maintained by long-term hemodialysis. The clinical picture was characterized by an insidious onset of altered behaviour, dementia, speech disturbance, myoclonus, and convulsions. Nineteen patients died, but one patient has survived for 16 months. It was later established that in June 1972 the city had altered its method of water purification and that this resulted in higher water aluminum levels. The temporal relation between periods of high water-aluminum content and the appearance of new cases supports the view that aluminum may play a role in the causation of dialysis dementia.

Dialysis dementia -- the Chicago experience.

In the four years between 1972 and 1976 twenty out of 160 maintenance dialysis patients developed dialysis dementia. Their illness was characterized by an insidious onset of mental deterioration, speech disturbance, apraxia, and myoclonus. The disease progressed inexorably to a fatal outcome, the onset of seizures being an ominous sign, and the average duration of the illness being seven months. Routine biochemical studies were unremarkable, and osteodystrophy was not a prominent feature. Serial electroencephalograms (EEG) showed progressive slowing of the rhythm, usually antedating the neurologic symptoms. Brain scan and flow studies were normal. Radio-iodinated serum albumin (RISA) scans in seven patients showed changes suggesting altered cerebrospinal fluid (CSF) dynamics. Treatment was generally ineffective, but ventriculo-peritoneal shunting produced transient neurologic improvement in one patient. Epidemiologic investigations showed high aluminum levels in city water during the period of the outbreak.

Electroencephalographic and radionuclide studies in dialysis dementia.

Six maintenance hemodialysis patients with dialysis dementia (severe mental deterioration, speech disturbances, apraxia, facial grimacing, and myoclonus) were studied. They were matched with respect to age, duration of dialysis, and underlying renal disease with six patients who had no dementia and who acted as controls for the electroencephalographic (EEC) studies. The dementia patients had marked slowing of the EEG rhythm to 5--7 Hz with high voltage biphasic or triphasic spikes, and were clearly separated by frequency distribution analysis from the controls. Radio-iodinated serum albumin (RISA) cisternography in dementia patients demonstrated ventricular reflux, prolonged stasis, late appearance of the parasagittal strip, and persistence of RISA for up to 72--96 hr, which suggest an alteration in cerebrospinal fluid (CSF) dynamics.

Removal of amantadine hydrochloride by dialysis in patients with renal insufficiency.

Two patients with Parkinson's disease and renal insufficiency had excessively high concentrations of amantadine hydrochloride in the blood. The amounts of the drug removed by hemodialysis and peritoneal dialysis were small. However, since extrarenal elimination is negligible in such patients, frequently repeated dialysis may be required to remove the drug.

Communicative and cognitive deterioration in dialysis dementia: two case studies.

We studied the cognitive and communicative deterioration of two patients who were treated by maintenance dialysis and developed a fatal progressive encephalopathy, "dialysis dementia." Detailed language, speech, and psychological evaluations support the contention that this neurologic syndrome is in fact a dementia. Stuttering and intermittent mutism characterize the disorder and may be valuable in the differentiation of dialysis dementia from other neuropsychiatric syndromes. Some of the speech and language defects are not explicable on the basis of intellectual deterioration and probably represent involvement of the cortical language centers.