Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health

Maintenance of glycolytic metabolism is postulated to be required for health of the spinal column. In the hypoxic tissues of the intervertebral disc and glycolytic cells of vertebral bone, glucose is metabolized into pyruvate for ATP generation and reduced to lactate to sustain redox balance. The rise in intracellular H⁺/lactate concentrations are balanced by plasma-membrane monocarboxylate transporters (MCTs). Using MCT4 null mice and human tissue samples, complemented with genetic and metabolic approaches, we determine that H⁺/lactate efflux is critical for maintenance of disc and vertebral bone health. Mechanistically, MCT4 maintains glycolytic and tricarboxylic acid (TCA) cycle flux and intracellular pH homeostasis in the nucleus pulposus compartment of the disc, where hypoxia-inducible factor 1α (HIF-1α) directly activates an intronic enhancer in SLC16A3. Ultimately, our results provide support for research into lactate as a diagnostic biomarker for chronic, painful, disc degeneration. © 2019 American Society for Bone and Mineral Research.     

Health-related quality of life in a sample of HIV-infected South Africans

The study aims to assess the health-related quality of life and HIV symptoms of a sample of people living with HIV (PLHIV) in South Africa. The sample included 607 PLHIV from all districts of the Eastern Cape Province, recruited either through a health facility, from the community through key informants, or through support groups. At the time of the study, 66% of the respondents reported having been given an AIDS diagnosis (advanced stage of HIV disease), 48% were on antiretroviral therapy (ART), and 35% were receiving a disability grant. The findings indicate a low degree of overall quality of life, with a mean score of 13.4 on the WHOQOL-HIV measure. Among the WHOQOL-HIV BREF subscales, logistic regression identified spirituality, environment, psychological health, and level of independence as predictors for overall quality of life. Among medical variables and HIV symptoms, CD4 cell count and having fewer HIV symptoms but not an AIDS diagnosis were identified as predictors for overall quality of life; among socio-economic variables, having sufficient food and a higher educational level were identified as predictors. The results highlight the need for better access to psychosocial support and medical services for PLHIV in South Africa, as well as the need to consider a patient's general health perceptions during the course of ART.     

Understanding Workplace Processes and Factors that Influence Exposures to Engineered Nanomaterials

Abstract

There is a critical need to understand the factors that influence engineered nanomaterial (ENM) exposures in the workplace. Such an understanding would aid in: identifying and prioritizing control measures; targeting future exposure measurements; and predicting worker exposures for work scenarios. This information could also be used in epidemiological studies. We propose a multitiered model in which information on exposure factors can be obtained at the macrolevel (examining differences in exposures between different ENM sectors or product types); the midlevel (examining differences in exposures between workplaces within the same ENM sector or product type); and the microlevel (examining differences in exposure between tasks or between ENM types during the same task). Further, within the microlevel, potential exposure factors are defined by a source-receptor model. We recommend that auxiliary data be collected systematically, along with exposure measurements, to enable analysis of exposure factors as well as the pooling of data across studies.     

Orphan Adhesion GPCR GPR64/ADGRG2 Is Overexpressed in Parathyroid Tumors and Attenuates Calcium‐Sensing Receptor‐Mediated Signaling

Abnormal feedback of serum calcium to parathyroid hormone (PTH) secretion is the hallmark of primary hyperparathyroidism (PHPT). Although the molecular pathogenesis of parathyroid neoplasia in PHPT has been linked to abnormal expression of genes involved in cell growth (e.g., cyclin D1, retinoblastoma, and β‐catenin), the molecular basis of abnormal calcium sensing by calcium‐sensing receptor (CaSR) and PTH hypersecretion in PHPT are incompletely understood. Through gene expression profiling, we discovered that an orphan adhesion G protein‐coupled receptor (GPCR), GPR64/ADGRG2, is expressed in human normal parathyroid glands and is overexpressed in parathyroid tumors from patients with PHPT. Using immunohistochemistry, Western blotting, and coimmunoprecipitation, we found that GPR64 is expressed on the cell surface of parathyroid cells, is overexpressed in parathyroid tumors, and physically interacts with the CaSR. By using reporter gene assay and GPCR second messenger readouts we identified Gαs, 3′,5′‐cyclic adenosine monophosphate (cAMP), protein kinase A, and cAMP response element binding protein (CREB) as the signaling cascade downstream of GPR64. Furthermore, we found that an N‐terminally truncated human GPR64 is constitutively active and a 15–amino acid–long peptide C‐terminal to the GPCR proteolysis site (GPS) of GPR64 activates this receptor. Functional characterization of GPR64 demonstrated its ability to increase PTH release from human parathyroid cells at a range of calcium concentrations. We discovered that the truncated constitutively active, but not the full‐length GPR64 physically interacts with CaSR and attenuates the CaSR‐mediated intracellular Ca²⁺ signaling and cAMP suppression in HEK293 cells. Our results indicate that GPR64 may be a physiologic regulator of PTH release that is dysregulated in parathyroid tumors, and suggest a role for GPR64 in pathologic calcium sensing in PHPT. © 2016 American Society for Bone and Mineral Research.     

Bone Mineral Density and Parathyroid Hormone as Independent Risk Factors for Mortality in Community‐Dwelling Older Adults: A Population‐Based Prospective Cohort Study in Brazil. The São Paulo Ageing & Health (SPAH) Study

Previous studies have shown a relationship between osteoporosis and increased mortality risk. However, none of these studies performed a concomitant evaluation of the parathyroid hormone (PTH)‐calcium‐vitamin D axis and bone mass to accurately determine the contribution of each of these parameters to survival in older subjects. Thus, we sought to investigate the association between bone parameters and mortality in a longitudinal, prospective, population‐based cohort of 839 elderly subjects. Clinical data (including history of fractures and cardiovascular events) were assessed using a specific questionnaire. Laboratory exams, including serum 25OHD and PTH, were also performed. Bone mineral density (BMD) at the lumbar spine and hip were evaluated using DXA. All analyses were performed at baseline (2005 to 2007). Mortality was recorded during follow‐up. Multivariate Cox proportional regression was used to compute hazard ratios for all‐cause and cardiovascular mortality. Over a mean 4.06 ± 1.07 years, there were 132 (15.7%) deaths. These individuals were compared to 707 subjects who were alive at the end of the coverage period for mortality data collection. In a multivariate Cox proportional hazards model, age (HR 1.32; 95% CI, 1.13 to 1.55; p = 0.001, for each 5‐year increase), male gender (HR 1.90; 95% CI, 1.30 to 2.79; p = 0.001), recurrent falls (more than two in the previous year; HR 1.65; 95% CI, 1.06 to 2.56; p = 0.026), diabetes mellitus (HR 2.17; 95% CI, 1.46 to 3.21; p < 0.001), low physical activity score (HR 1.78; 95% CI, 1.14 to 2.79; p = 0.011), prior cardiovascular event (HR 1.76; 95% CI, 1.18 to 2.63; p = 0.006), total hip BMD (HR 1.41; 95% CI, 1.15 to 1.72; p = 0.001, per each 1 SD decrease), and intact PTH (iPTH) (HR 1.06; 95% CI, 1.04 to 1.08; p < 0.001, per each 10 pg/mL increase) were independently associated with all‐cause mortality. The subjects in the highest quartile of PTH (>49 pg/mL) were at a higher risk of cardiovascular death (HR 3.09; 95% CI, 1.36 to 6.99; p = 0.007) compared with the subjects in the lowest quartile (<26 pg/mL). Low BMD and higher PTH were significantly associated with mortality in community‐dwelling older adults. These findings support the notion that careful screening of these bone parameters might lead to better management of older patients and improve outcomes in this population. © 2016 American Society for Bone and Mineral Research.     

The prevalence of G6PD deficiency in blood transfusion recipients

G6PD deficiency is the most common metabolic disorder of red blood cells, involving about 35 million people worldwide. Tropical and subtropical regions in the eastern hemisphere have the highest prevalence, up to 35% in some areas. The prevalence varies in different parts of the world. According to WHO, there is a 10–14.9% prevalence of G6PD deficiency in Iran. With this high prevalence, blood products are not still checked for G6PD deficiency. So, they may be used for transfusion in neonates with jaundice or for patients using oxidants.

In this cross-sectional study, we have observed the effects of using this kind of blood in patients receiving blood in the Pediatric and Neonatology Departments of Imam Sajjad's Hospital in Yasuj. Samples were taken from 261 blood bags used for transfusion or exchange, and examined by spot fluorescence for G6PD deficiency. All of the patients receiving blood were examined for hemoglobin, hematocrit, and bilirubin before and after transfusion. They were also examined for hemoglobinuria, factors involved in hemolysis due to G6PD deficiency, and oxidants.

Results: From the 261 blood transfusions, 37 (14.17%) blood bags had G6PD deficiency. About 81 % of these transfusion recipients had at least one risk factor for hemolysis. The complications associated with receiving these red cells were: insufficient rise in hemoglobin (55.9%), hemoglobinuria (35.3%) and rise in bilirubin (8.8%), which were significantly higher than the control group.

Conclusion: Considering the high prevalence and complications of transfusing G6PD deficient blood to high risk patients, it is recommended that in the form used for requesting blood products, there should be a place for checking G6PD enzyme so that the physician requesting blood could request the test to be done, depending on the risk factors.     

Recovery from neuromuscular blockade. A comparison between old and young patients

Thirteen young and thirteen elderly patients undergoing elective surgery were given an anaesthetic using tubocurarine as the sole muscle relaxant. Following reversal with neostigmine, the time taken to recover from neuromuscular blockade was measured. No significant difference was found between the two groups of patients.     

Hereditary angioneurotic oedema

Hereditary angioedema (HAE) is characterised by episodic swelling of the extremities, face, larynx and recurrent abdominal pain, which can mimic the acute abdomen. Trauma of the larynx may result in acute airway obstruction. The management of emergency anaesthesia for Caesarean section of a patient with documented HAE is described and the special problems presented discussed. The methods of prophylaxis available are considered and the use of fresh frozen plasma advocated.