Age-Related Changes in Concentric and Eccentric Isokinetic Peak Torque of the Trunk Muscles in Healthy Older Versus Younger Men.

This study investigated age-related changes in trunk muscle function in healthy men and the moderating effect of physical activity. Twelve older (67.3 ± 6.0 years) and 12 younger (24.7 ± 3.1 years) men performed isokinetic trunk flexion and extension tests across a range of angular velocities (15°/s-180°/s) and contractile modes (concentric and eccentric). For concentric trunk extension, mixed-effects analysis of covariance revealed a significant interaction between Angular velocity × Age group (p = .026) controlling for physical activity. Follow-up univariate analysis of covariance revealed that the younger group produced significantly greater peak torque for all concentric extension conditions. Eccentric trunk strength was somewhat preserved in the older group. Age-related changes in trunk strength were independent of physical activity. The normal loss of trunk muscle strength in older age is muscle- and contractile-mode specific. These findings provide guidance for effective intervention strategies to offset adverse health outcomes related to trunk strength loss in older adults.

Experience from the selection and nutritional preparation for Expedition ICE MAIDEN: the first successful all-female unassisted Antarctic traverse.

INTRODUCTION: Expedition ICE MAIDEN (Ex IM) was the first all-female unsupported crossing of Antarctica. We describe the prerequisite selection and training, comparing those who formed the final team with other participants, and discuss how the expedition diet was established. METHODS: All women serving in the British Army were invited to participate. Following initial assessments, successful women completed three training/selection ski expeditions. Between expeditions 1 and 2, participants completed 6 months rigorous UK-based training. Weight was measured before and after the 6 months UK-based training, expeditions 2 and 3, and body composition by skinfold before and after expedition 2. Participant feedback, body composition and weight changes were applied to modify the expedition diet and provide weight gain targets prior to Ex IM. RESULTS: Following 250 applications, 50 women were assessed and 22, 12 and seven women attended training expeditions 1, 2 and 3, respectively. The final team of six women lost more weight than other participants during UK-based training (mean (SD) change -1.3 (1.5) kg vs -0.5 (1.6) kg, respectively, p=0.046) and during training expedition 2 (-2.8 (0.8) kg vs -1.7 (0.4) kg, respectively, p=0.048), when they also gained more lean mass (+2.1 (0.8) kg vs +0.4 (0.7) kg, respectively, p=0.004). The Ex IM diet provided 5000 kCal/day, comprising approximately 45% carbohydrate, 45% fat and 10% protein. Median (range) weight change between expedition 3 and Ex IM was +8.7 (-1.9 to +14.3) kg. CONCLUSIONS: The selected Ex IM team demonstrated favourable training-associated body composition changes. Training-associated weight loss informed the expeditionary diet design.

Age-related degeneration of the lumbar paravertebral muscles: Systematic review and three-level meta-regression.

BACKGROUND: Morphological changes of the lumbar spine muscles are not well characterised with ageing. To further the understanding of age-related degeneration of the lumbar spine musculature, normative morphological changes that occur within the paravertebral muscles must first be established. METHODS: A systematic review and meta-regressions were conducted adhering to PRISMA guidelines. Searches for published and unpublished data were completed in June 2019. RESULTS: Searches returned 4781 articles. 34 articles were included in the quantitative analysis. Three-level meta-analyses showed age-related atrophy (r = -0.26; 95% CI: -0.33, -0.17) and fat infiltration (r = 0.39; 95% CI: 0.28, 0.50) in the lumbar paravertebral muscles. Degenerative changes were muscle-specific and men (r = -0.32; 95% CI: -0.61, 0.01) exhibited significantly greater muscle atrophy than women (r = -0.24; 95% CI: -0.47, 0.03). Imaging modality, specifically ultrasound, also influenced age-related muscle atrophy. Measurements taken across all lumbar levels revealed the greatest fat infiltration with ageing (r = 0.58, 95% CI: 0.35, 0.74). Moderators explained a large proportion of between-study variance in true effects for muscle atrophy (72.6%) and fat infiltration (79.8%) models. CONCLUSIONS: Lumbar paravertebral muscles undergo age-related degeneration in healthy adults with muscle, lumbar level and sex-specific responses. Future studies should use high-resolution imaging modalities to quantify muscle atrophy and fat infiltration.

Describing the effectiveness of immunosuppression drugs and apheresis in the treatment of transplant patients.

When any foreign object is found in the human body antibodies are generated that mark it for removal by the immune system. In most cases these are natural and healthy responses; however, when considering organ transplants the immune response to the implanted organ must be kept to a minimum to avoid host rejection. To reduce the host's immune response to the implant, clinicians are able to manipulate the antibody dynamics through drug therapy, to minimise the antibody synthesis (immunosuppression), and by the removal of antibodies directly from the patients' blood, a process known as apheresis. In this paper models are presented that describe the in vivo kinetics of three immune complexes which are routinely measured pre- and post-operatively in implant patients, namely IgA, IgG and IgM. These models are then used to analyse the effective clearance rates of different apheresis methods (plasmapheresis, plasma absorption or plasma exchange) and to quantify the impact immune-suppression drugs have on the underlying antibody synthesis. It is hoped that the simplicity of the mathematical models, and associated implementation, will allow the translation of knowledge gained of the process dynamics to positively impact future patient diagnosis and treatment.

Indistinguishability and identifiability of kinetic models for the MurC reaction in peptidoglycan biosynthesis.

An important question in Systems Biology is the design of experiments that enable discrimination between two (or more) competing chemical pathway models or biological mechanisms. In this paper analysis is performed between two different models describing the kinetic mechanism of a three-substrate three-product reaction, namely the MurC reaction in the cytoplasmic phase of peptidoglycan biosynthesis. One model involves ordered substrate binding and ordered release of the three products; the competing model also assumes ordered substrate binding, but with fast release of the three products. The two versions are shown to be distinguishable; however, if standard quasi-steady-state assumptions are made distinguishability cannot be determined. Once model structure uniqueness is ensured the experimenter must determine if it is possible to successfully recover rate constant values given the experiment observations, a process known as structural identifiability. Structural identifiability analysis is carried out for both models to determine which of the unknown reaction parameters can be determined uniquely, or otherwise, from the ideal system outputs. This structural analysis forms an integrated step towards the modelling of the full pathway of the cytoplasmic phase of peptidoglycan biosynthesis.

The use of deconvolution techniques to identify the fundamental mixing characteristics of urban drainage structures.

Mixing and dispersion processes affect the timing and concentration of contaminants transported within urban drainage systems. Hence, methods of characterising the mixing effects of specific hydraulic structures are of interest to drainage network modellers. Previous research, focusing on surcharged manholes, utilised the first-order Advection-Dispersion Equation (ADE) and Aggregated Dead Zone (ADZ) models to characterise dispersion. However, although systematic variations in travel time as a function of discharge and surcharge depth have been identified, the first order ADE and ADZ models do not provide particularly good fits to observed manhole data, which means that the derived parameter values are not independent of the upstream temporal concentration profile. An alternative, more robust, approach utilises the system's Cumulative Residence Time Distribution (CRTD), and the solute transport characteristics of a surcharged manhole have been shown to be characterised by just two dimensionless CRTDs, one for pre- and the other for post-threshold surcharge depths. Although CRTDs corresponding to instantaneous upstream injections can easily be generated using Computational Fluid Dynamics (CFD) models, the identification of CRTD characteristics from non-instantaneous and noisy laboratory data sets has been hampered by practical difficulties. This paper shows how a deconvolution approach derived from systems theory may be applied to identify the CRTDs associated with urban drainage structures.

Response to mucosal antigen challenge in IgA nephropathy.

While IgA nephropathy (IgAN) is characterized by the deposition of glomerular IgA, the source of the deposited IgA is not known, with both the mucosal and systemic IgA systems being implicated. In order to investigate mucosal and systemic antibody production to mucosal antigen challenge in IgAN, 9 patients and 11 controls were immunized intranasally with tetanus toxoid (TT). There was no significant difference in the serum or saliva IgG, IgA, IgA1, or IgA2 antibody production to TT. However, in IgAN there was an increase of in vitro IgA anti-TT production in Epstein-Barr virus transformed cultures of peripheral blood lymphocytes taken after mucosal immunization. This increase in traffic of immunocompetent cells between the systemic and mucosal systems could play a role in the link between the mucosa and glomerulus in IgAN. Systemic immunization with TT following mucosal priming did not result in any difference in the antibody response between patients and controls. There was no evidence from this study that mucosal immunization results in an enhanced antibody response in IgAN or that mucosal priming alters the subsequent systemic antibody response.

Metabolic acidosis is a potent stimulus for cellular inorganic phosphate generation in uraemia.

1. During metabolic acidosis, significant fluxes of inorganic phosphate (Pi) may occur from cellular to extracellular fluid. In this study Pi was measured in erythrocytes of uraemic patients before and after haemodialysis and was related to their plasma pH (acidosis), plasma Pi (hyperphosphataemia) and cellular organic phosphate concentrations. 2. Before dialysis, the ratio of cellular to extracellular Pi concentration correlated inversely with plasma pH, increasing 2.5-fold as pH fell from 7.4 to 7.2. 3. An increase in cellular Pi similar to that seen in the patients was observed within 90 min of adding acid to normal erythrocytes in vitro. 4. The total Pi content of the cell suspension increased 25% on decreasing plasma pH from 7.4 to 7.2, largely as a result of generation of Pi from 2,3-bisphosphoglycerate in the cells. This was accompanied by net efflux of Pi into plasma. 5. In addition, the increase in the steady-state cellular Pi concentration on adding a constant extracellular Pi load was 50% greater at pH 7.2 than at 7.4, implying that alterations in the regulation of the transmembrane Pi gradient also contribute to the rise in cellular Pi observed at low pH. 6. At normal plasma Pi concentration (1 mM), glycolytic flux (lactate production) was inhibited by 20% when pH was lowered from 7.4 to 7.2. However, this inhibition was blocked when cellular Pi was increased by adding Pi to the plasma in vitro. 7. Metabolic acidosis is therefore a potent stimulus for Pi generation in erythrocytes, and this Pi may serve to stimulate glycolysis which is normally inhibited by low pH.

Increased immunoglobulin A and immunoglobulin A1 cells in bone marrow trephine biopsy specimens in immunoglobulin A nephropathy.

The origin of mesangial immunoglobulin A (IgA) in IgA nephropathy remains unknown. To investigate potential abnormalities within the bone marrow in this condition, bone marrow trephine biopsy specimens from seven patients and matched controls were studied using two-color immunofluorescence. In addition, serum levels of IgA and IgA1 were determined by radial immunodiffusion. Serum levels of IgA and IgA1 were higher in patients than in controls (4.53 +/- 1.38 g/L v 2.56 +/- 1 g/L, P < 0.01 and 3.68 +/- 1.11 g/L v 1.92 +/- 0.7 g/L, P < 0.005, respectively). In addition, patient trephine biopsy specimens contained an increased percentage of IgA plasma cells (61.6% +/- 4.4%) compared with controls (47.3% +/- 2.5%) (P < 0.02). The proportion of IgA plasma cells bearing subclass IgA1 was also greater in the patient biopsy specimens (91.6% +/- 1.9%) compared with controls (81.4% +/- 2.7%) (P < 0.01). In patients a positive correlation between the percentage of marrow IgA plasma cells and serum IgA levels was found (r = 0.94, P < 0.002). However, our studies failed to demonstrate a similar correlation between serum IgA1 levels and IgA1 marrow cells. These findings support the hypothesis that mesangial IgA may derive from the bone marrow.

Expression of J chain mRNA in duodenal IgA plasma cells in IgA nephropathy.

Glomerular IgA in IgA nephropathy (IgAN) is at least in part polymeric, and is thought to derive from the mucosal IgA system in view of the association between mucosal infection and haematuria in this condition. To investigate this hypothesis, an in situ hybridization (ISH) technique was developed for the detection of J chain mRNA, the expression of which has been correlated with the secretion of high level polymeric immunoglobulin (pIg). Endoscopic duodenal biopsies from ten patients and matched controls were examined by: (i) two color immunofluorescence (IF); (ii) ISH; and (iii) combined ISH and IF, to permit simultaneous identification of plasma cell type. IF revealed a reduction in the percentage of IgA plasma cells (P < 0.02) and increased absolute numbers of IgG cells (P < 0.02) in patient biopsies. ISH demonstrated fewer J chain mRNA expressing plasma cells (P < 0.005) with lower signal intensity (P < 0.002) in patients' biopsies compared with controls. Combined ISH and IF confirmed a reduction in J chain mRNA-positive IgA plasma cells in the patient biopsies (P < 0.02). The reduction in J chain mRNA expression in duodenal IgA plasma cells in IgAN argues against the gastrointestinal lamina propria as the source of glomerular pIgA.

Plasma amino acid profile in the elderly with increasing uraemia.

Abnormalities in plasma amino acid profiles have been reported in severe uraemia and dialysis patients and may be a consequence of altered protein metabolism in the presence of metabolic acidosis. We studied plasma amino acid profiles in 7 control subjects [GFR 92.7 +/- (SEM) 14.5 ml/min/1.73 m2] and 7 elderly patients with renal failure (GFR 16.5 +/- 1.3 ml/min/1.73 m2). Uraemic patients had significantly reduced plasma levels of valine, tyrosine, phenylalanine, tryptophan and elevated histidine compared to controls. There was no correlation between arterial pH or bicarbonate and plasma amino acid levels.

Low antibody affinity restricted to the IgA isotype in IgA nephropathy.

Antibody affinity affects the handling and behaviour of immune complexes, and experimental studies have shown that animals which produce predominantly low-affinity antibody are prone to immune complex deposition resulting in glomerulonephritis. In order to investigate the potential role of antibody affinity in the pathogenesis of IgA nephropathy, affinity of both IgA and IgG antibody isotypes during secondary response to systemic immunization with tetanus toxoid was studied in 20 patients with IgA nephropathy. Patients with IgA nephropathy produced IgA antibodies of significantly lower affinity than controls (P < 0.001), whereas IgG antibody affinities were similar. Contrasting with controls, patients' IgA antibody affinity was inversely related to antibody concentration, with higher responders producing large amounts of low-affinity antibody. IgG antibody affinity increased with time, and maturation of IgG antibody affinity was similar in both controls and patients. IgA affinity in controls decreased with time, and this lack of IgA affinity maturation may explain the relative unimportance of IgA in normal systemic immunity. This temporal decrease in IgA affinity was not observed in patients with IgA nephropathy. The production of low-affinity IgA in IgA nephropathy may provide an explanation for the predominant deposition of IgA in this disease.

Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria.

Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were "definitely" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.

Deficiency of IgG subclass antibody response to tetanus toxoid associated with high serum IgA levels in IgA nephropathy.

In order to investigate IgG subclass response in IgA nephropathy (IgAN), 20 patients and 20 age and sex matched controls were systemically immunized with tetanus toxoid (TT). Nineteen/20 controls and 19/20 IgAN made a serum IgG anti-TT response of similar magnitude. However, significantly more patients with IgAN had undetectable amounts of at least one IgG subclass antibody to this antigen than controls (7/19 IgAN, 1/19 controls, p < 0.05). All individuals with an IgG subclass anti-TT deficiency lacked IgG1 and/or IgG4. Two patients made no IgG3 anti-TT (as well as no IgG1 and IgG4 anti-TT) but all individuals who responded to TT made IgG2 anti-TT. Total IgG subclass levels in IgAN did not differ from controls and no patient with IgAN had a total IgG subclass deficiency. Total serum IgA was significantly raised in IgAN (p < 0.002) and 6/7 IgAN with an IgG anti-TT subclass deficiency had a serum IgA level of over 3.2 milligrams compared to only 2/12 IgAN with no IgG subclass anti-TT deficiency (p < 0.01). The association of high serum IgA levels with IgG subclass deficiency to TT may be due to an abnormality in switching from IgG to IgA production in IgAN, or a manifestation of a defect of immunoregulation analogous to that proposed in IgA deficiency.

Elevation of IgA in IgA nephropathy is localized in the serum and not saliva and is restricted to the IgA1 subclass.

Glomerular deposits in IgA nephropathy (IgAN) are predominantly IgA1 but their origin is not known. Previous studies have analysed serum or saliva IgA, but not in the same patients. To investigate whether IgA and IgA subclass anomalies occur in IgAN at both mucosal and systemic sites, blood and saliva from 20 patients and 20 age- and sex-matched controls were studied. Patients with IgAN had significantly increased serum IgA (P < 0.002), and this elevation was restricted to the IgA1 subclass. Serum IgA1 was also increased significantly (P < 0.001) but IgA2 was not. By contrast salivary IgA, IgA1, and IgA2 did not differ significantly from the controls. These results demonstrate that the elevated serum IgA is predominantly IgA1 and is likely to be of systemic origin. Further studies should consider the bone marrow as a potential source of the elevated IgA1.

Increased and prolonged production of specific polymeric IgA after systemic immunization with tetanus toxoid in IgA nephropathy.

IgA nephropathy (IgAN) is a chronic form of glomerulonephritis which is characterized by the deposition in the glomerular mesangium of polymeric IgA (pIgA), the source of which is unknown. In order to investigate the production of pIgA in IgAN, patients were immunized systemically with tetanus toxoid (TT). Two weeks after immunization patients and controls responded to TT with an IgA response of similar magnitude. HPLC separation of sera showed that patients with IgAN produce significantly more pIgA anti-TT than controls (7.7 versus 2.88 arbitrary units; P less than 0.04). At this time, 33% of serum IgA anti-TT produced by patients with IgAN was polymeric, compared with 21% produced by controls (P less than 0.02). Monomeric IgA (mIgA) anti-TT levels were similar in both groups. Four weeks after immunization the proportion of pIgA anti-TT in controls and patients was significantly reduced from the 2 week level (from 21% to 0%, P less than 0.02 for controls; and from 33% to 8%, P less than 0.001, for patients). Only four out of 12 controls had any detectable pIgA anti-TT at this time compared with nine out of 10 patients with IgAN (P less than 0.05), and IgAN patients produced proportionally more pIgA anti-TT than did controls (median 8%, interquartile ranges (IQR) 4-10% versus 0% IQR 0-3%; P less than 0.01). HPLC analysis under acid conditions did not alter the pattern of pIgA and mIgA anti-TT, suggesting that the high molecular weight IgA fraction was not due to complexes. These data indicate that circulating pIgA results (at least in part) from a systemic response to antigen, which may be exaggerated in IgAN.

Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia.

To maintain nitrogen equilibrium when prescribed a low protein diet (LPD), metabolic adaptations occur involving a reduction protein turnover, principally decreased muscle protein degradation. Studies suggest that in patients with chronic renal failure (CRF) uncomplicated by metabolic acidosis (MA), these adaptive responses are intact. Because MA stimulates muscle proteolysis, this study examined the hypothesis that in CRF complicated by MA, the adaptation to LPD may be impaired, inducing a nitrogen wasting state. Six adults with CRF (mean GFR: 12.8 +/- 1.5 ml/min) and MA (mean serum bicarbonate: 17.0 +/- 1.0 mM/liter) receiving an unrestricted diet (protein intake: 1.2 g/kg body wt/day) were converted to an isocaloric LPD (protein: 0.6 g/kg body wt/day). Two weeks later total urinary nitrogen losses decreased, but skeletal muscle protein catabolism (SMPC), assessed from the urinary 3-methyl histidine:creatinine ratio, increased, demonstrating impairment in the adaptive down-regulation of SMPC. The LPD was continued for a further two weeks and MA was corrected with oral sodium bicarbonate (mean serum bicarbonate: 24.3 +/- 1.2 mM/liter). Correcting MA decreased SMPC to a level below that measured prior to protein restriction. The decreased SMPC was paralleled by further decreases in urinary nitrogen losses, confirming that MA impaired nitrogen utilization. It is concluded that MA can override the expected metabolic adaptive response to a LPD. The associated impairment of nitrogen utilization not only diminishes the efficacy of the diet, but also accelerates the loss of lean body mass.

Acute renal failure associated with haematological malignancies: a review of 10 years experience.

Patients with ARF and haematological malignancy (excluding myeloma), presenting to a single unit over 10 years were analyzed to see if patients likely to benefit from intensive renal supportive therapy could be identified. 31 episodes of ARF were identified in 29 patients (mean age 51 +/- 2.9 yr): 19 were associated with acute leukaemia (13 AML, 6 ALL); 10 with lymphoma. Acute tubular necrosis (ATN) was identified as the cause of ARF in 26 cases, with sepsis (96%) and exposure to nephrotoxic drugs (88%), especially aminoglycosides, being the commonest precipitating factors. Toxic levels of the latter were commonly documented. Patient survival was 45%. Requirement for mechanical ventilation resulted in a universally fatal outcome; age greater than 55 yr and the presence of CNS symptoms or signs were also significantly associated with a poor outcome. Non-ATN causes (urate nephropathy or obstruction) carried a better prognosis. However, only 4 patients (14%) lived for more than 6 months following ARF. Thus, although a subgroup of patients more likely to benefit from treatment can be identified, the overall prognosis is poor and limited by that of the underlying disease. The potential benefit of avoiding nephrotoxic drugs, especially aminoglycosides, in these patients is highlighted by this study.

Gut permeability in IgA nephropathy.

Gut permeability to small molecules was assessed by the differential absorption of cellobiose and mannitolin 18 patients with IgA nephropathy (IgAN). The urinary cellobiose:mannitol excretion ratio in patients did not differ (P = 0.42) from controls. These findings do not support the hypothesis that chronic increased mucosal permeability allows excessive antigen penetration to the mucosal immune system, predisposing to glomerular IgA deposition in IgA nephropathy. However, the patient with the greatest cellobiose:mannitol ratio developed macroscopic haematuria within 3 weeks of testing, raising the possibility of a transient abnormality in gut permeability.