The effects of physical inactivity on skeletal muscle metabolic function

Bed rest leads to multiple adverse physiological consequences, comparable to the effects of physical inactivity. The role of cellular metabolism in the regulation of these physiological changes during bed rest has not been studied in detail. The aim of this study was to test if prolonged bed rest decreases mitochondrial function, muscle mass and impacts upon mitochondrial dynamics in healthy young men. We also evaluated the impact a micronutrient cocktail supplement had in mitigating these changes. 60 days bed rest resulted a number of anthropometric changes including reduction in lean muscle mass (p<0.05) and an increase in fat mass (p<0.05). These changes were accompanied by an increase in RQ indicative of a switch from fat to carbohydrate oxidation at rest (p<0.05). Mitochondrial respiration, expressed per mg of wet muscle weight, was lower during ETS (CI), ETS (CII) and CII respiration following 60 days of bed rest (p<0.05), a change which was not evident when normalised to mitochondrial content. We concluded that the adaptations in the regulators of mitochondrial density/amount may explain these changes. In particular, we observed a significant decrease in mitochondrial fusion marker, OPA1 and fission marker, Drp1 (p<0.05). Our intervention mitigated these changes, increasing OPA1:Drp1 ratio (p<0.05) suggesting our intervention increased mitochondrial elongation. A comparison between our 60-day study and a previously conducted 21-day bed rest study emphasised the important role OPA1 may be having throughout bed rest epitomised by a shift in mitochondrial dynamics over time from a fragmented phenotype (21-day BR) to a rebalancing of fusion-fission (60-day BR). Further in-vitro analysis uncovered the novel role SIRT4 has on these processes with knockdown increasing OPA1-mediated mitochondrial fusion while increasing ADP-stimulated OXPHOS (p<0.05) indicative of SIRT4s regulation of free fatty acid oxidation. Bed rest leads to a series of adverse physiological and cellular adaptations which may be limited by micronutrient supplementation. Although further clarification is needed, SIRT4 may have a role in this regard with mechanisms linking mitochondrial dynamics and function

Calcium stone lithoptysis in primary ciliary dyskinesia

An association between lithoptysis and primary ciliary dyskinesia (PCD) has not been previously reported. However, reports of lithoptysis from 2 older patients (>60 yr) prompted a study of this association. We performed a prospective study of all PCD patients presenting to our institution between August 2003 and March 2006, seeking the symptom of lithoptysis or calcium deposition on radiology. A retrospective analysis of all PCD patients presenting prior to August 2003 was also performed. Patients age > or = 40 previously reviewed were recontacted. If a history of lithoptysis or calcium deposition was present, we further reviewed radiographic, microbiologic, and biochemical data, including serum calcium and phosphate. Broncholiths were analyzed by light and electron microscopy- and electron-dispersive X-ray analysis. In total, 142 patients (n=28 age > or = 40) were included, 41 in the prospective and 91 in the retrospective study. Lithoptysis was reported in 5 patients (all age > or = 40). Chest CT scans identified calcification (4/5), involving bronchiectatic airways in 3 patients and focal nodular calcification in 1 patient. Two other patients (age 46, 59) were identified with airway calcification without lithoptysis. Available broncholiths from 2 of these patients were composed of calcite, whereas a broncholith from 1 patient with focal nodular calcification contained calcium phosphate. Sputum was positive for Pseudomonas aeruginosa in all 7 patients, but negative for mycobacterial and fungal cultures. There is an association between lithoptysis and PCD in patients age > or = 40. We hypothesize that calcite stone formation is a biomineralization response to chronic airway inflammation and retention of infected airway secretions in PCD in a subset of PCD patients

Calcium stone lithoptysis in primary ciliary dyskinesia

An association between lithoptysis and primary ciliary dyskinesia (PCD) has not been previously reported. However, reports of lithoptysis from 2 older patients (>60 yr) prompted a study of this association. We performed a prospective study of all PCD patients presenting to our institution between August 2003 and March 2006, seeking the symptom of lithoptysis or calcium deposition on radiology. A retrospective analysis of all PCD patients presenting prior to August 2003 was also performed. Patients age > or = 40 previously reviewed were recontacted. If a history of lithoptysis or calcium deposition was present, we further reviewed radiographic, microbiologic, and biochemical data, including serum calcium and phosphate. Broncholiths were analyzed by light and electron microscopy- and electron-dispersive X-ray analysis. In total, 142 patients (n=28 age > or = 40) were included, 41 in the prospective and 91 in the retrospective study. Lithoptysis was reported in 5 patients (all age > or = 40). Chest CT scans identified calcification (4/5), involving bronchiectatic airways in 3 patients and focal nodular calcification in 1 patient. Two other patients (age 46, 59) were identified with airway calcification without lithoptysis. Available broncholiths from 2 of these patients were composed of calcite, whereas a broncholith from 1 patient with focal nodular calcification contained calcium phosphate. Sputum was positive for Pseudomonas aeruginosa in all 7 patients, but negative for mycobacterial and fungal cultures. There is an association between lithoptysis and PCD in patients age > or = 40. We hypothesize that calcite stone formation is a biomineralization response to chronic airway inflammation and retention of infected airway secretions in PCD in a subset of PCD patients

Assessing the value of orphan drugs using conventional cost-effectiveness analysis:Is it fit for purpose?

Conventional cost-effectiveness analysis-i.e., assessing pharmaceuticals through a cost per quality-adjusted life year (QALY) framework-originated from a societal commitment to maximize population health given limited resources. This "extra-welfarist" approach has produced pricing and reimbursement systems that are not well- aligned with the unique considerations of orphan drugs. This framework has been slow to evolve along with our increased understanding of the impact of rare diseases, which in turn has complicated the assessment of orphan drugs meant to treat rare diseases. Herein, we (i) discuss the limitations of conventional cost-effectiveness analysis as applied to assessing access to, as well as the pricing and reimbursement of, orphan drugs, (ii) critically appraise alternative and supplemental approaches, and (iii) offer insights on plausible steps forward

A multicentre study of thromboprophylaxis in pregnancy

Venous thromboembolism (VTE) is a leading cause of maternal mortality. The risk increases with increasing maternal age, mode of delivery and medical co-morbidities. Thromboprophylaxis with low molecular weight heparin (LMWH) has been shown to be both safe and efficacious. The aim of this study was to prospectively investigate the incidence of maternal risk factors in pregnant women admitted to hospital, to calculate their VTE risk status and to investigate if they were receiving appropriate thromboprophylaxis. All patients admitted to the participating hospitals on the day of investigation were assessed for risk of VTE on the basis of hospital chart review. Five Hundred and forty women were recruited from 16 hospitals. Almost 32% (31.7%) were receiving thromboprophylaxis with LMWH. Just under 80% of patients were on the correct thromboprophylaxis strategy as defined by the RCOG guideline but 49% were under-dosed. The odds of receiving appropriate thromboprophylaxis were significantly increased if the woman was >35 years 0or with parity>3