Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

Mohebbi N, Vargas‐Poussou R, Hegemann SCA, Schuknecht B, Kistler AD, Wüthrich RP, Wagner CA. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near‐normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non‐consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.     

Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.     

Immunohistochemical localization of membrane and alpha-granule proteins in human megakaryocytes: application to plastic-embedded bone marrow biopsy specimens

Using a new technique for antigen localization, we have demonstrated platelet proteins in megakaryocytes in plastic-embedded biopsy specimens of normal human bone marrow. In a series of 25 specimens, megakaryocytes showed labeling with antibodies to the integral membrane glycoproteins IIIa, IIb, and the IIb-IIIa complex; granule membrane protein 140; and five alpha-granule matrix proteins: thrombospondin, factor VIII-related antigen, beta-thromboglobulin, platelet factor 4, and fibrinogen. The antibodies to the membrane glycoproteins IIIa, IIb, and IIb-IIIa produced diffuse cytoplasmic staining and heavier staining on the plasma membrane, whereas the antibodies to the alpha-granule matrix proteins produced a distinct granular staining within the cytoplasm. Staining for granule membrane protein 140 was also granular in distribution. Rare mononuclear cells consistent with megakaryocyte precursors were labeled with these markers. Other enzyme histochemical and lectin-binding studies showed that the enzyme alpha-naphthyl acetate esterase, the lectin Ulex europaeus I, and the periodic-acid Schiff reaction were consistent, but not specific, markers of megakaryocytes. This immunohistochemical technique should facilitate the examination of qualitative and quantitative changes in megakaryocytes in a variety of physiologic and pathologic processes.     

Vasoactive intestinal peptide and pituitary adenylate cyclase- activating polypeptides (PACAP27) and PACAP38) protect CD4+CD8+ thymocytes from glucocorticoid-induced apoptosis

In the present study, the effects of vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptides, PACAP27 and PACAP38, in a concentration range from 10(-13) to 10(-6) mol/L were studied in vitro on the spontaneous and dexamethasone (DEX)- induced apoptosis in rat thymocytes. The results show that VIP and both PACAPs inhibit significantly and in a similar way the DNA fragmentation characteristic of glucocorticoid-induced apoptosis and increase the cell survival of thymocytes, with a maximal effect observed at 10(-8) to 10(-9) mol/L. This study showed the ability of the VIP-receptor (VIP- R) antagonist [N-Ac-Tyr1,D-Phe2]-GRF(1-29) amide to partially reverse the inhibitory effect of VIP and both PACAPs on DEX-induced apoptosis, providing evidence for a specific VIP1-R-mediated response and supporting the involvement of a single receptor for the three neuropeptides. Phenotypic analysis showed that VIP, PACAP27, and PACAP38 protect predominantly CD4+CD8+ thymocytes from glucocorticoid- induced apoptosis. These findings suggest that these neuropeptides could be involved in intrathymic T-cell maturation.     

Circulating peroxiredoxin 4 and type 2 diabetes risk: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

Aims/hypothesis

Oxidative stress plays a key role in the development of type 2 diabetes mellitus. We previously showed that the circulating antioxidant peroxiredoxin 4 (Prx4) is associated with cardiometabolic risk factors. We aimed to evaluate the association of Prx4 with type 2 diabetes risk in the general population.

Methods

We analysed data on 7,972 individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (49% men, aged 28–75 years) with no diabetes at baseline. Logistic regression models adjusted for age, sex, smoking, waist circumference, hypertension and family history of diabetes were used to estimate the ORs for type 2 diabetes.

Results

During a median follow up of 7.7 years, 496 individuals (288 men; 58%) developed type 2 diabetes. The median (Q1–Q3) Prx4 level was 0.84 (0.53–1.40) U/l in individuals who developed type 2 diabetes and 0.68 (0.43–1.08) U/l in individuals who did not develop type 2 diabetes. For every doubling of Prx4 levels, the adjusted OR (95% CI) for type 2 diabetes was 1.16 (1.05–1.29) in the whole population; by sex, it was 1.31 (1.14–1.50) for men and 1.03 (0.87–1.21) for women. Further adjustment for other clinical measures did not materially change the results. The addition of Prx4 to a validated diabetes risk score significantly improved the prediction of type 2 diabetes in men (p?=?0.002 for reclassification improvement).

Conclusions/interpretation

Our findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes. For men, taking Prx4 into consideration can improve type 2 diabetes prediction over a validated diabetes risk score; in contrast, there is no improvement in risk prediction for women.     

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

Aims/hypothesis

Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately.

Methods

From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7?years.

Results

In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p _interaction?p?=?0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p?Conclusions/interpretation The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women.     

Quantifying daily physical activity and determinants in sedentary patients with Parkinson's disease

BackgroundAlthough physical activity is beneficial for Parkinson's disease (PD) patients, many do not meet the recommended levels. The range of physical activity among sedentary PD patients is unknown, as are factors that determine this variability. Hence, we aimed to (1) assess daily physical activity in self-identified sedentary PD patients; (2) compare this with criteria of a daily physical activity guideline; and (3) identify determinants of daily physical activity.MethodsDaily physical activity of 586 self-identified sedentary PD patients was measured with a tri-axial accelerometer for seven consecutive days. Physical fitness and demographic, disease-specific, and psychological characteristics were assessed. Daily physical activity was compared with the 30-min activity guideline. A linear mixed-effects model was estimated to identify determinants of daily physical activity.ResultsAccelerometer data of 467 patients who fulfilled all criteria revealed that >98% of their day was spent on sedentary to light-intensity activities. Eighty-two percent of the participants were ‘physically inactive’ (0 days/week of 30-min activity); 17% were ‘semi-active’ (1–4 days/week of 30-min activity). Age, gender, physical fitness, and scores on the Unified Parkinson's Disease Rating Scale explained 69% of the variability in daily physical activity.ConclusionsPerformance-based measurements confirmed that most self-identified sedentary PD patients are ‘physically inactive’. However, the variance in daily physical activity across subjects was considerable. Higher age, being female, and lower physical capacity were the most important determinants of reduced daily physical activity. Future therapeutic interventions should aim to improve daily physical activity in these high-risk patients, focusing specifically on modifiable risk factors.