Reduced cell surface levels of GPI‐linked markers in a new case with PIGG loss of function

Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early‐onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI‐anchored proteins (GPI‐APs) that can be measured by flow cytometry. No significant differences in GPI‐APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI‐linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI‐anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.     

Polymorphisms in the calcineurin genes are associated with the training responsiveness of cardiac phenotypes in Chinese young adults

We studied the association of 55 polymorphisms in the PPP3CA, PPP3CB, PPP3CC, PPP3R1 and PPP3R2 genes with both (1) the pre-training levels and (2) responsiveness to endurance training (18 weeks), of echocardiographic variables. The latter were measured both before and after the training program at each of the following time points: before (rest), during and after cycle-ergometry exercise. Subjects were healthy young Chinese men of Han origin [n = 102; mean (SD) age: 19 ± 1 years]. To assess genotype:phenotype associations at pre-training, we used a one-factor (genotype) ANOVA for each polymorphism. To assess the association between each polymorphism and the training responsiveness of cardiac phenotypes, we used a two-factor (genotype x training) ANOVA with repeated measures. All multiple comparisons were corrected for mass significance. For genotype:phenotype associations at pre-training, we only found a significant association between the rs3763679 polymorphism (PPP3CB) and resting heart rate. As for genotype associations with trainability of cardiac phenotypes, we found the following significant associations (i.e. significant genotype × training interaction effect): (1) rs1879793, rs1075534, rs7430, rs2461483 and rs10108011 (PPP3CC) and cardiac output/stroke volume after exercise; and (2) rs1407877 (PPP3R2) and ejection fraction at 50 W. The findings suggest that polymorphisms in the calcineurin genes might be among the numerous potential genetic variant candidates that can help explaining human variations in the pre-training levels or trainability of cardiac phenotype traits.     

Attitude of involved epidemiologists toward the first European outbreak of rhinosporidiosis

Rhinosporidiosis occurs extremely seldom in Europe. Until recently, the disease was unknown in Serbia (Yugoslavia). An outbreak that began in January 1992, affected 21 individuals. All of them had been exposed to the same source of stagnant water. The purpose of this study was to assess which control measures would be selected by epidemiologists potentially involved in the control of the disease. Most respondents (20 of 32 or 62.5%) opted only for an information release as the most appropriate control measure. The reasons listed by the epidemiologists to justify their choice of optimal control measures showed that the political and economic hardships, including an embargo imposed upon rump Yugoslavia, did not hamper their judgment. The turmoil associated with the disintegration of Yugoslavia, however, appears to have significantly affected the information level of the participants.     

Sulfenic Acid Modification of Endothelin B Receptor is Responsible for the Benefit of a Nonsteroidal Mineralocorticoid Receptor Antagonist in Renal Ischemia

AKI is associated with high mortality rates and the development of CKD. Ischemia/reperfusion (IR) is an important cause of AKI. Unfortunately, there is no available pharmacologic approach to prevent or limit renal IR injury in common clinical practice. Renal IR is characterized by diminished nitric oxide bioavailability and reduced renal blood flow; however, the mechanisms leading to these alterations are poorly understood. In a rat model of renal IR, we investigated whether the administration of the novel nonsteroidal mineralocorticoid receptor (MR) antagonist BR-4628 can prevent or treat the renal dysfunction and tubular injury induced by IR. Renal injury induced by ischemia was associated with increased oxidant damage, which led to a cysteine sulfenic acid modification in endothelin B receptor and consequently decreased endothelial nitric oxide synthase activation. These modifications were efficiently prevented by nonsteroidal MR antagonism. Furthermore, we demonstrated that the protective effect of BR-4628 against IR was lost when a selective endothelin B receptor antagonist was coadministered. These data describe a new mechanism for reduced endothelial nitric oxide synthase activation during renal IR that can be blocked by MR antagonism with BR-4628.     

HELLP syndrome as a cause of unexpected rapid maternal death–A case report and review of the literature

Unexpected rapid death after delivery due to HELLP syndrome (HS) may become the subject of a forensic expertise. Since this syndrome is rarely encountered in forensic pathology, our objective was to point to some specific findings which might present forensic aspects of HS. These include unexpectedness, suddenness and fulminant course of this syndrome, which may confuse physicians, and on the other hand these characteristics cast doubt on violent injury, diagnostic oversights or iatrogenic injuries. Absence of classical signs of preeclampsia and non-specific clinical symptoms cause considerable differential diagnostic problems leading to a diagnostic delay or initial wrong non-obstetric diagnosis. A definitive postmortem diagnosis of HS in questionable cases of maternal death and consecutive forensic expertise of suspected medical malpractice should be based on accepted laboratory criteria and characteristic histopathological alterations.     

Nutritional support and oral intake after gastric resection in five northern European countries

BACKGROUND: A comprehensive evidence base for perioperative care in upper gastrointestinal (GI) surgery is lacking. Little is known about the routines currently practiced in the absence of such evidence. We describe postoperative practice after gastric resections in five northern European countries. METHOD AND SETTING: Questionnaire survey in all major digestive surgical centres in Scotland, the Netherlands, Denmark, Sweden and Norway. RESULTS: 76% of all centres (n = 200/263) responded. Routines varied extensively both nationally and between countries. No uniformity was traced although a conservative trend was noticeable in the use of nasogastric decompression tubes and 'nil-by-mouth' regimens. Nutritional support during the first 5 days is generally offered in Denmark, but not in Scotland. Drinking at will is generally allowed in Denmark and Norway by the first postoperative day. Eating at will is uniformly restricted. CONCLUSION: The paucity of evidence is reflected by the marked heterogeneity in practice. Large groups of patients may be treated suboptimally. Best perioperative care for these patients must be defined and documented. Especially, the role of early oral intake at will in upper GI surgery needs to be clarified by sufficiently powered trials.     

Ten years' experience in subtotal parathyroidectomy of hemodialysis patients

Secondary hyperparathyroidism (SHP) is a frequent complication of long-term dialysis patients, and surgical parathyroidectomy remains necessary in patients resistant to medical therapy. The present paper reports single center results in subtotal parathyroidectomy, presenting diagnostic procedure, indications for parathyroidectomy, and postoperative course of metabolic and endocrine disorders. Forty-seven patients (25 males and 22 females), aged 25-60 years, regularly hemodialyzed between 3-23 years, have undergone parathyroidectomy at our Clinical Center during the last 10 years. The patients had plasma iPTH levels 8-45 times higher than the top normal limit, high values of alkaline phosphatase, calcemia on the upper normal level, and hyperphosphatemia. Radiographic changes characteristic for SHP were seen in all patients before parathyroidectomy, and the most common were subperiosteal resorptions (100%), bone cysts and periosteal neostosis (66%), and extraskeletal calcifications (98%). Enlarged parathyroid glands were seen by ultrasound in 62% of patients. All patients manifested pruritus and bone pain, 89% of them had myopathy, while other symptoms and signs were present in lower proportions. After parathyroidectomy, pruritus and myopathy reduced significantly, while pain in bones and joints remained. One patient had brown tumor at the maxillary bone that regressed gradually after parathyroidectomy. Significant decreases of phosphate and calcium levels were recorded in all but two patients on the very first postoperative day. Regular peroral and parenteral supplementations of calcium and vitamin D metabolites were used, but calcemia was not normalized until the end of the third week of the postoperative period. Serum alkaline phosphatase showed an increase after the surgery, thereupon a sudden and then slower decrease up to 1 year from the surgery. Plasma iPTH levels, checked on the 21st postoperative day, were close to the lower normal limit in all but two (4.3%) patients with persistent SHP, who required reoperation. In conclusion, subtotal parathyroidectomy was proved as a successful and safe treatment for patients with SHP resistant to medical therapy, and treatment was followed by improvement of clinical symptoms and metabolic disorders.     

Relations of total physical activity and intensity to fitness and fatness in children: the European Youth Heart Study

BACKGROUND: It is unclear how the amount and intensity of physical activity (PA) are associated with cardiovascular fitness (CVF) and body fatness in children. OBJECTIVE: We aimed to examine the associations of total PA and intensity levels to CVF and fatness in children. DESIGN: A cross-sectional study of 780 children aged 9-10 y from Sweden and Estonia was conducted. PA was measured by accelerometry and was expressed as min/d of total PA, moderate PA, and vigorous PA. CVF was measured with a maximal ergometer bike test and was expressed as W/kg. Body fat was derived from the sum of 5 skinfold-thickness measurements. Multiple regression analysis was used to determine the degree to which variance in CVF and body fat was explained by PA, after control for age, sex, and study location. RESULTS: Lower body fat was significantly associated with higher levels of vigorous PA, but not with moderate or total PA. Those children who engaged in >40 min vigorous PA/d had lower body fat than did those who engaged in 10-18 min vigorous PA/d. Total PA, moderate PA, and vigorous PA were positively associated with CVF. Those children who engaged in >40 min vigorous PA/d had higher CVF than did those who accumulated <18 min vigorous PA/d. CONCLUSIONS: The results suggest that PA of vigorous intensity may have a greater effect on preventing obesity in children than does PA of lower intensity, whereas both total and at least moderate to vigorous PA may improve children's CVF.