Evaporative heat loss insufficient to attain heat balance at rest in individuals with a spinal cord injury at high ambient temperature.

The aim of the study was to determine whether climatic limits for achieving heat balance at rest are affected by spinal cord injury (SCI). Twenty-three men [8 able-bodied (AB), 8 with paraplegia (PP), and 7 with tetraplegia (TP)] rested in 37°C and 20% relative humidity (RH) for 20 min. With the ambient temperature held constant, RH was increased by 5% every 7 min, until gastrointestinal temperature (Tgi) showed a clear inflection or increased by >1°C. Tgi, skin temperatures, perceptual responses, and metabolic energy expenditure were measured throughout. Metabolic heat production [AB: 123 (21) W, PP: 111 (15) W, TP: 103 (29) W; means (SD)] and required rate of evaporative cooling for heat balance [Ereq; AB: 113 (20) W, PP: 107 (17) W, TP: 106 (29) W] were similar between groups (P = 0.22 and P = 0.79). Compared with AB, greater increases in Tgi were observed in TP (P = 0.01), with notable increases in mean skin temperature (Tsk) for TP and PP (P = 0.01). A Tgi inflection point was demonstrated by seven AB, only three of eight PP, and no TP. Despite metabolic heat production (and Ereq) being similar between groups, evaporative heat loss was not large enough to obtain heat balance in TP, linked to a shortfall in evaporative cooling potential. Although PP possess a greater sweating capacity, the continual increase in Tgi and Tsk in most PP, although lower than for TP, implies that latent heat loss for PP is also insufficient to attain heat balance.NEW & NOTEWORTHY In the absence of convective heat loss, at temperatures around 37°C evaporative heat loss is insufficient to attain heat balance at rest in individuals with paraplegia and tetraplegia. This finding was directly linked to a shortfall in evaporative cooling potential compared with required evaporative cooling. In this environment, individuals with both paraplegia and tetraplegia cannot subjectively determine the magnitude of their thermal strain; thus perceptual responses should not be relied upon for this population group.

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.

This corrects the article DOI: 10.1038/bjc.2017.85.

Blood lactate and ventilatory thresholds in wheelchair athletes with tetraplegia and paraplegia.

PURPOSE: The purpose of this study was to analyse the influence of spinal cord injury level on blood lactate (BLa) and ventilatory thresholds. METHODS: Ten athletes with tetraplegia (TETRA) and nine athletes with paraplegia (PARA) performed a graded wheelchair propulsion treadmill exercise step test to exhaustion. The aerobic and anaerobic BLa thresholds, the ventilatory threshold and the respiratory compensation point (RCP) were determined. RESULTS: The BLa thresholds were determined in 34 of 38 cases, ventilatory thresholds and RCPs in 31 of 38 cases. The anaerobic BLa threshold (76 ± 7 % [Formula: see text]) and the RCP (77 ± 8 % [Formula: see text]) did not differ significantly from each other (P = 0.92), with a coefficient of variation of 4.8 ± 3.4 % between thresholds. All other thresholds differed significantly from each other (P < 0.05). Thresholds expressed as the percentage of peak oxygen uptake did not differ between TETRA and PARA (P > 0.05) despite altered breathing in TETRA, which included a higher ventilatory equivalent for oxygen and a lower tidal volume. CONCLUSION: Measuring BLa leads to a higher threshold determination rate compared with ventilatory data and the anaerobic BLa threshold can be used to predict the RCP. The altered breathing in TETRA does not seem to have a pronounced effect on the ventilatory threshold or the RCP.

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumour originating in the thoracic mesothelium. Prognosis remains poor with 9- to 12-month median survival, and new targets for treatments are desperately needed. METHODS: Utilising an RNA interference (RNAi)-based screen of 40 genes overexpressed in tumours, including genes involved in the control of cell cycle, DNA replication and repair, we investigated potential therapeutic targets for MPM. Following in vitro characterisation of the effects of target silencing on MPM cells, candidates were assessed in tumour samples from 154 patients. RESULTS: Gene knockdown in MPM cell lines identified growth inhibition following knockdown of NDC80, CDK1 and PLK1. Target knockdown induced cell-cycle arrest and increased apoptosis. Using small-molecule inhibitors specific for these three proteins also led to growth inhibition of MPM cell lines, and Roscovitine (inhibitor of CDK1) sensitised cells to cisplatin. Protein expression was also measured in tumour samples, with markedly variable levels of CDK1 and PLK1 noted. PLK1 expression in over 10% of cells correlated significantly with a poor prognosis. CONCLUSION: These results suggest that RNAi-based screening has utility in identifying new targets for MPM, and that inhibition of NDC80, CDK1 and PLK1 may hold promise for treatment of this disease.

Risk Adjustment In Neurocritical care (RAIN)--prospective validation of risk prediction models for adult patients with acute traumatic brain injury to use to evaluate the optimum location and comparative costs of neurocritical care: a cohort study.

OBJECTIVES: To validate risk prediction models for acute traumatic brain injury (TBI) and to use the best model to evaluate the optimum location and comparative costs of neurocritical care in the NHS. DESIGN: Cohort study. SETTING: Sixty-seven adult critical care units. PARTICIPANTS: Adult patients admitted to critical care following actual/suspected TBI with a Glasgow Coma Scale (GCS) score of < 15. INTERVENTIONS: Critical care delivered in a dedicated neurocritical care unit, a combined neuro/general critical care unit within a neuroscience centre or a general critical care unit outside a neuroscience centre. MAIN OUTCOME MEASURES: Mortality, Glasgow Outcome Scale - Extended (GOSE) questionnaire and European Quality of Life-5 Dimensions, 3-level version (EQ-5D-3L) questionnaire at 6 months following TBI. RESULTS: The final Risk Adjustment In Neurocritical care (RAIN) study data set contained 3626 admissions. After exclusions, 3210 patients with acute TBI were included. Overall follow-up rate at 6 months was 81%. Of 3210 patients, 101 (3.1%) had no GCS score recorded and 134 (4.2%) had a last pre-sedation GCS score of 15, resulting in 2975 patients for analysis. The most common causes of TBI were road traffic accidents (RTAs) (33%), falls (47%) and assault (12%). Patients were predominantly young (mean age 45 years overall) and male (76% overall). Six-month mortality was 22% for RTAs, 32% for falls and 17% for assault. Of survivors at 6 months with a known GOSE category, 44% had severe disability, 30% moderate disability and 26% made a good recovery. Overall, 61% of patients with known outcome had an unfavourable outcome (death or severe disability) at 6 months. Between 35% and 70% of survivors reported problems across the five domains of the EQ-5D-3L. Of the 10 risk models selected for validation, the best discrimination overall was from the International Mission for Prognosis and Analysis of Clinical Trials in TBI Lab model (IMPACT) (c-index 0.779 for mortality, 0.713 for unfavourable outcome). The model was well calibrated for 6-month mortality but substantially underpredicted the risk of unfavourable outcome at 6 months. Baseline patient characteristics were similar between dedicated neurocritical care units and combined neuro/general critical care units. In lifetime cost-effectiveness analysis, dedicated neurocritical care units had higher mean lifetime quality-adjusted life-years (QALYs) at small additional mean costs with an incremental cost-effectiveness ratio (ICER) of £14,000 per QALY and incremental net monetary benefit (INB) of £17,000. The cost-effectiveness acceptability curve suggested that the probability that dedicated compared with combined neurocritical care units are cost-effective is around 60%. There were substantial differences in case mix between the 'early' (within 18 hours of presentation) and 'no or late' (after 24 hours) transfer groups. After adjustment, the 'early' transfer group reported higher lifetime QALYs at an additional cost with an ICER of £11,000 and INB of £17,000. CONCLUSIONS: The risk models demonstrated sufficient statistical performance to support their use in research but fell below the level required to guide individual patient decision-making. The results suggest that management in a dedicated neurocritical care unit may be cost-effective compared with a combined neuro/general critical care unit (although there is considerable statistical uncertainty) and support current recommendations that all patients with severe TBI would benefit from transfer to a neurosciences centre, regardless of the need for surgery. We recommend further research to improve risk prediction models; consider alternative approaches for handling unobserved confounding; better understand long-term outcomes and alternative pathways of care; and explore equity of access to postcritical care support for patients following acute TBI. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Chronic kidney disease: cardiac and renal angiotensin-converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition.

Renin-angiotensin system blockade slows but does not prevent the cardiovascular complications of chronic kidney disease (CKD). Angiotensin-converting enzyme (ACE) 2 is differentially regulated in acute kidney injury, with increased cardiac ACE2 but decreased kidney ACE2 levels. This study investigated the effect of long-term ACE inhibition on cardiac and renal ACE2 in rats with CKD induced by subtotal nephrectomy (STNx). Sprague-Dawley rats had sham (control) or STNx surgery. Control rats received vehicle (n = 9) and STNx rats ramipril (1 mg kg(-1) day(-1); n = 10) or vehicle (n = 10) for 28 days. Subtotal nephrectomy resulted in impaired creatinine clearance (P < 0.05), proteinuria (P < 0.05), renal fibrosis (P < 0.05) and reduced renal cortical ACE2 mRNA (P < 0.05) and activity (P < 0.05). In rats with CKD, ramipril improved creatinine clearance (P < 0.05) and was associated with an increase in cortical but not medullary ACE2 activity (P < 0.05). Compared with control rats, STNx rats were hypertensive (P < 0.01), with increased left ventricular end-diastolic pressure (LVEDP; P < 0.01), left ventricular hypertrophy (LVH; P < 0.05) and interstitial (P < 0.05) and perivascular fibrosis (P < 0.01). In rats with CKD, ramipril decreased blood pressure (P < 0.001) and reduced LVEDP (P < 0.01), LVH (P < 0.01) and perivascular fibrosis (P < 0.05) but did not significantly reduce interstitial fibrosis. There was no change in cardiac ACE2 in rats with CKD compared with control rats. In rats with CKD, ACE inhibition had major benefits to reduce blood pressure and cardiac hypertrophy and to improve creatinine clearance, but did not significantly impact on cardiac ACE2, cardiac interstitial fibrosis, renal fibrosis or proteinuria. Thus, in rats with CKD, renal ACE2 deficiency and lack of activation of cardiac ACE2 may contribute to the progression of cardiac and renal tissue injury. As long-term ACE inhibition only partly ameliorated the adverse cardio-renal effects of CKD, adjunctive therapies that lead to further increases in ACE2 activity may be needed to combat the cardio-renal complications of CKD.

Long-term follow-up of upper extremity implanted venous access devices in oncology patients.

PURPOSE: To evaluate function and assess incidence of complications relating to upper extremity implanted venous access devices placed in oncology patients primarily for chemotherapy. MATERIALS AND METHODS: The authors retrospectively evaluated the clinical course of 205 upper extremity implanted venous access devices placed with fluoroscopic and sonographic guidance in 204 patients during a 2-year period. All patients had a diagnosis of malignancy for which chemotherapy was planned. Follow-up data were collected by patient examination, direct evaluation of device function, as well as chart review and review of relevant imaging procedures. A modified technique for device placement is described. RESULTS: The devices were placed successfully on the initial attempt in all cases. Clinical follow-up was obtained for 195 devices (95.1%) for a total device service period of 33,619 days (mean service interval = 169 days). Seventy-eight devices (40%) had service intervals greater than 180 days. Thirty-seven devices (19% of total devices) led to 39 complications (0.116 event/100 days). No immediate procedural complications were incurred. Eight complications occurred after 180 days of port service. Nineteen devices (9.7% of total devices followed) required removal as a result of complication. Common complications included port malfunction requiring urokinase to clear (n = 10; 0.030 event/100 days), ipsilateral upper extremity deep venous thrombosis (n = 9; 0.027), and local infection (n = 7, 0.021). A comparison of these results relative to other published series of similar devices placed for mixed indications is presented. CONCLUSIONS: Implanted venous access devices are an effective means of long-term venous access in oncology patients. Complication rates in this large series compared favorably to other published radiologic and surgical series. Analysis of complications in a subgroup of extended use implanted venous access devices (greater than 180 days follow-up) showed no statistically significant (P < .05) difference from the larger group of devices.

Intrinsic tone and passive mechanics of isolated renal arteries from virgin and late-pregnant rats.

The purpose of this study was to investigate whether there are alterations in the intrinsic properties of renal interlobar arteries during pregnancy. Renal interlobar arteries (internal diameter approximately 250 microns) from virgin and late-pregnant rats were mounted in a pressurized arteriograph system. Intrinsic tone was quantified as the percent difference in luminal diameter of each artery in the presence of physiological saline solution and while pharmacologically relaxed with papaverine. At pressures between 75 and 125 mmHg, tone was 35-50% less in arteries from pregnant rats (P < 0.05). Endothelial removal reduced tone in arteries from virgin rats but had no effect on arteries from pregnant rats. Analysis of stress-strain curves (rate constants: pregnant, 6.31 +/- 0.38; virgin, 7.81 +/- 0.78; P < 0.05) indicate that there is a decrease in arterial stiffness in gestation. Thus pregnancy is associated with a reduced intrinsic tone, possibly because of a reduction in an endothelial constrictor influence on the vascular smooth muscle in isolated rat renal interlobar arteries. This effect, coupled with the decreased arterial stiffness, demonstrates the significant arterial adaptation occurring during pregnancy.

Sterile versus clean technique in postoperative wound care of patients with open surgical wounds: a pilot study.

PURPOSE: This study was completed to determine whether there were differences between sterile versus clean dressing change technique for open surgical wounds in the postoperative period with respect to (1) rate of wound healing and (2) cost of supplies. METHODS: A two-group design was used for this pilot study. Of a sample of 30 patients undergoing elective gastrointestinal operations with wounds healing by secondary intention, 15 were men and 15 were women. Mean age was 40.6 years (SD 13.0 years). Patients were randomly assigned to receive clean or sterile dressings, and the intervention was begun on the first postoperative day and repeated three times a day until discharge from the hospital. Analysis of rate of healing was performed with the Mann-Whitney U test: cost analysis was completed with a t test. FINDINGS: Subjects were studied for 3 to 9 days. Groups were homogeneous of the start of treatment with respect to age, length of operation, wound volume, nutritional status, and perfusion. There was no difference in rate of wound healing between the clean and sterile groups. Mean cost was significantly less for the clean group than for the sterile group. CONCLUSION: These pilot study data show no difference in rate of wound healing with clean versus sterile technique, and clean technique is less expensive. These findings need to be confirmed with a larger sample; type II error cannot be ruled out.

Myositis, lameness, and paraparesis associated with use of an oil-adjuvant bacterin in beef cows.

Right hind limb lameness, progressing to bilateral paraparesis, was observed in 56 of 610 (9%) beef cows. Lameness began 6 days to 4 weeks after vaccination in the right longissimus lumborum (loin) muscle with an Escherichia coli/Campylobacter bacterin in an oil adjuvant. Postmortem examination of 5 affected cows revealed a large inflammatory mass at the site of vaccination. In each cow, the mass spread through adjacent intervertebral foramina into the vertebral canal and compressed the lumbar portion of the spinal cord. Microbiologic procedures did not reveal a microbial agent in affected tissues or in an unopened bottle of bacterin from the same lot used in the herd. Histologic examination revealed pyogranulomatous inflammation of the vaccination site and adjacent epidural tissue, with inflammatory nodules centered around large clear spaces that probably represented remnant emulsion from the oil adjuvant in the bacterin. As evident in these cows, IM injection of irritating products may cause severe myositis. Vaccination into paravertebral muscles is risky because of possible extension of inflammation through intervertebral foramina.

Iatrogenic compressive lumbar myelopathy and radiculopathy in adult cattle following injection of an adjuvanted bacterin into loin muscle: histopathology and ultrastructure.

Compressive lumbar myelopathy is a recognized iatrogenic complication of injecting water-in-oil vaccines into paravertebral sites of laboratory animals and chickens. Herein, we report the histologic and ultrastructural features of a similar complication in a herd of cattle. Iatrogenic posterior paresis developed over 34 days in 56 of 610 cows (9.2%) following injection of a commercial bacterin 11-34 days earlier into M. longissimus lumborum. The bacterin was composed of inactivated Escherichia coli and Campylobacter fetus ssp. venerealis in a proprietary adjuvant. Tissues were collected for histopathology from 9 affected cattle that died or were euthanized after clinical signs lasting 6-38 days. A range of tissues, including the injection site lesion and lumbar spinal nerve roots, was obtained for ultrastructural examination from a cow with paresis of 31 days duration. There was locally extensive pyogranulomatous myositis with fibrosis and necrosis in right M. longissimus lumborum. Extension of the lesion into the vertebral canal via spinal nerve foramina resulted in focal pyogranulomatous inflammation in epidural fat and in adjacent dura mater. There was axonal degeneration in dorsal, lateral, and ventral columns and chromatolysis of spinal motor neurons in lumbar spinal cord, secondary to compression. A distinctive histologic and ultrastructural feature of pyogranulomata was the presence of osmiophilic material at the center of inflammatory foci, surrounded by macrophages and giant cells that contained intracytoplasmic lipid droplets. Ultrastructural examination of entrapped spinal nerves revealed axonal degeneration and loss of myelinated and unmyelinated fibers, segmental demyelination with remyelination, axonal spheroid formation, and early axonal regeneration.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelial modulation of renal interlobar arteries from pregnant rats.

The purpose of this study was to determine whether there are gestational effects on 1) the response of resistance arteries from the renal vasculature to phenylephrine and 2) the endothelial modulation of these arteries. Interlobar arteries (200-300 microns ID) were isolated from the kidneys of virgin and pregnant rats at 18-20 days of gestation (term, 22 +/- 1 days) and studied in a pressurized arteriograph system. Intact arteries from virgin and pregnant rats did not differ in sensitivity to phenylephrine. Arteries without endothelium from both groups were more sensitive to phenylephrine than arteries with endothelium. Sensitivity was increased 3.4-fold by endothelial removal in arteries from virgin rats and 1.5-fold in the pregnant group. Concentration-response relationships to phenylephrine were determined in arteries with endothelium and then repeated in the presence of 2.5 x 10(-4) M N omega-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase. All arteries were more sensitive to phenylephrine in the presence of L-NNA, with an average increase of 3.2-fold for the arteries from virgin rats and 1.6-fold from pregnant rats. These results indicate that the increased sensitivity to phenylephrine is primarily due to elimination of endothelium-derived relaxing factor (EDRF) and that basal EDRF activity is decreased during late gestation. To determine whether stimulated endothelium-dependent relaxation is enhanced in pregnancy, arteries with endothelium were constricted with phenylephrine to 50% of their maximum and relaxed to increasing concentrations of methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipid peroxidation and altered vascular function in vitamin E-deficient rats.

Female rats deprived of dietary vitamin E for 35 wk postweaning were analyzed for changes in vascular function. A functional state of vitamin E deficiency was indicated by a marked increase in spontaneous hemolysis of washed red cells by 22 wk of feeding. Elevated thiobarbituric acid-reactive material in aorta, liver, and plasma samples from vitamin-E deficient rats indicated increased lipid hydroperoxide formation. Systolic blood pressures and heart rates measured biweekly were unaltered by diet. Before being killed, the rats were catheterized and allowed to recover from anesthesia (methohexital sodium ip). The pressor response to graded doses of angiotensin II was significantly increased in the vitamin E-deficient group relative to its control. Isolated superior mesenteric artery segments from vitamin E-deficient rats demonstrated significantly decreased relaxation responses to acetylcholine. In contrast, artery contractile responses to 50 mM potassium and to graded doses of extracellular calcium did not differ, indicating that contractile capability was maintained. Surface blebbing of the femoral artery endothelium was observed by scanning electron microscopy. These data support a proposed link between lipid peroxidation and development of altered vascular function.

Toxic metal fumes from mantle-type camp lanterns.

The mantle of a gas lantern contains about 600 micrograms of toxic beryllium metal. Most of the beryllium is volatilized and becomes airborne during the first 15 minutes of use of a new mantle. The inhalation of this quantity of beryllium can be hazardous.