The relationship between acute alcohol consumption and consequent injury type

Aims: The aim of this study was to quantify the relationship between acute alcohol consumption and injury type (nature of injury, body region injured), while adjusting for the effect of known confounders (i.e. demographic and situational variables, usual drinking patterns, substance use and risk-taking behaviour). Methods: A cross-sectional study was conducted between October, 2000 and October, 2001 of patients aged >= 15 years presenting to a Queensland Emergency Department for treatment of an injury sustained in the preceding 24 h. There were three measures of acute alcohol consumption: drinking setting, quantity, and beverage type consumed in the 6 h prior to injury. Two variables were used to quantify injury type: nature of injury (fracture/dislocation, superficial, internal, and CNS injury) and body part injured (head/neck, facial, chest, abdominal, external, and extremities). Both were derived from patient medical records. Results: Five hundred and ninety three patients were interviewed. Logistic regression analyses indicated that, after controlling for relevant confounding variables, there was no significant association between any of the three measures of acute alcohol consumption and injury type. Conclusions: The effects of acute alcohol consumption are not specific to injury type. Interventions aimed at reducing the incidence of alcohol-related injury should not be targeted at specific injury types.

Nephron number, hypertension, renal disease, and renal failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed.

An integrated biopsychosocial approach to understanding awareness deficits in Alzheimer's disease and brain injury

Considerable emphasis has been placed upon cognitive neuropsychological explanations of awareness disorders in brain injury and Alzheimer's disease (AD), with relatively few models acknowledging the role of psychosocial factors. The present paper explores clinical presentations of unawareness in brain injury and AD, reviews the evidence for the influence of psychosocial factors alongside neuropsychological changes, and considers a number of key issues that theoretical models need to address, before going on to discuss some recently-developed models that offer the potential for developing a comprehensive biopsychosocial account. Building on these developments, we present a framework designed to assist clinicians to identify the specific factors contributing to an individual's presentation of unawareness, and illustrate its application with a case example.

Reduced nephron number and glomerulomegaly in Australian Aborigines: A group at high risk for renal disease and hypertension

Aborigines in remote areas of Australia have much higher rates of renal disease, as well as hypertension and cardiovascular disease, than non-Aboriginal Australians. We compared kidney findings in Aboriginal and non-Aboriginal people in one remote region. Glomerular number and mean glomerular volume were estimated with the disector/fractionator combination in the right kidney of 19 Aborigines and 24 non-Aboriginal people undergoing forensic autopsy for sudden or unexpected death in the Top End of the Northern Territory. Aborigines had 30% fewer glomeruli than non-Aborigines-202000 fewer glomeruli per kidney, or an estimated 404000 fewer per person (P=0.036). Their mean glomerular volume was 27% larger (P=0.016). Glomerular number was significantly correlated with adult height, inferring a relationship with birthweight, which, on average, is much lower in Aboriginal than non-Aboriginal people. Aboriginal people with a history of hypertension had 30% fewer glomeruli than those without-250000 fewer per kidney (P=0.03), or 500000 fewer per person, and their mean glomerular volume was about 25% larger. The lower nephron number in Aboriginal people is compatible with their susceptibility to renal failure. The additional nephron deficit associated with hypertension is compatible with other reports. Lower nephron numbers are probably due in part to reduced nephron endowment, which is related to a suboptimal intrauterine environment. Compensatory glomerular hypertrophy in people with fewer nephrons, while minimizing loss of total filtering surface area, might be exacerbating nephron loss. Optimization of fetal growth should ultimately reduce the florid epidemic of renal disease, hypertension, and cardiovascular disease.

Parental information needs in chronic renal failure and diabetes mellitus

The information needs of parents of children with end stage renal failure (ESRF) or with insulin dependent diabetes mellitus (IDDM) were assessed by questionnaires over a 2-year period. Questionnaires were posted on seven occasions at 4-monthly intervals and were sent to both mothers and fathers. Most information needs were reported to be for detailed test results, for new information about the condition and about the child's future social development. Questions responsible for the three highest scores were concerned with the future: the child's fertility; their social, career and marriage prospects; and the hope for a new improved treatment. For the IDDM mothers, scores were significantly different depending on age of the child (P = 0.02). Change in treatment mode had no significant effect on the information needs of parents of children with ESRF (P = 0.81). Occupation was significantly associated with the mean general information needs scores for parents, with occupations of a lower socioeconomic status associated with higher information needs scores. There were no significant differences between the reported mean general information needs scores of parents of children with ESRF and of parents of children with IDDM (P = 0.69) or between mothers and fathers mean general information needs scores (P = 0.58). CONCLUSION: Multidisciplinary team members need to tailor information to the needs of the individual families and be sensitive to socioeconomic factors and communication issues.

Renal dopamine and salt-retaining states

Although generally regarded as a neurotransmitter, dopamine is also known to be secreted by the kidney whereby it promotes sodium excretion in its role as a natriuretic honnone. Peripheral dopamine may be formed by two alternative pathways; the decarboxylation of circulating L-Dopa by L-aromatic amino acid decarboxylase (LAAAD), and the desulphation of dopamine sulphate by arylsulphatase A (ASA), the latter being poorly represented in the literature. In many conditions and diseases with which sodium retention is associated, a reduced urinary excretion of dopamine has been noted implicating the involvement of dopamine in the maintenance of sodium homeostasis.This study investigates renal dopamine production via the desulphation of dopamine sulphate in a sample cohort during normal unregulated dietary sodium intake and following a low sodium regimen. After dietary salt restriction urinary dopamine sulphate levels were significantly increased, indicating that dopamine sulphate is indeed a physiological reservoir of active free dopamine, the necessity for which is reduced during self depletion. This confirmed the dopamine/dopamine sulphate pathway as one which may be relevant to the maintenance of sodium homeostasis. The activity of urinary ASA was investigated in diabetes mellitus as an example of a sodium-retaining state, and compared with that in a matched normal control group. A decreased ASA activity was anticipated, given the blunted dopamine excretion observed in many sodium-retaining states, however an unexpected increase in activity in the diabetic group was observed. Enzyme kinetic analysis of ASA showed that this was not due to the existence of an isoform having an altered affinity for dopamine sulphate. This rather paradoxical situation, that urinary-dopamine is decreased while ASA activity is increased, may be explained by the sequestering of free dopamine by autoxidation to 6-hydroxydopamine as has been hypothesised recently to occur in diabetes mellitus. To confirm the homogeneity of ASA in the normal and diabetic groups, four amplicons spanning the 3637bp intronic and exonic regions of the gene were generated by PCR. These were sequence utilising a fluorescent-dye terminator reaction using the forward PCR primer as sequencing primer. Although single nucleotide polymorphisms were observed between the two groups these occurred either in intronic regions or, when exonic, generated silent mutations, supporting the enzyme kinetic data. The expression of ASA was investigated to determine the basis of the increased activity observed in diabetes mellitus. Although a validated comparative RT-PCR assay was developed for amplification of arsa transcripts from fresh blood samples, expression analysis from archived paraffin-embedded renal tissue was complicated by the low yield and degradation of unprotected mRNA. Suggestions for the development of this work using renal cell-culture are discussed.

Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization

Reactive oxygen species (ROS) are increased in ischemic tissues and necessary for revascularization; however, the mechanism remains unclear. Exposure of cysteine residues to ROS in the presence of glutathione (GSH) generates GSH-protein adducts that are specifically reversed by the cytosolic thioltransferase, glutaredoxin-1 (Glrx). Here, we show that a key angiogenic transcriptional factor hypoxia-inducible factor (HIF)-1α is stabilized by GSH adducts, and the genetic deletion of Glrx improves ischemic revascularization. In mouse muscle C2C12 cells, HIF-1α protein levels are increased by increasing GSH adducts with cell-permeable oxidized GSH (GSSG-ethyl ester) or 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanyl thiocarbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), an inhibitor of glutathione reductase. A biotin switch assay shows that GSSG-ester-induced HIF-1α contains reversibly modified thiols, and MS confirms GSH adducts on Cys520 (mouse Cys533). In addition, an HIF-1α Cys520 serine mutant is resistant to 2-AAPA–induced HIF-1α stabilization. Furthermore, Glrx overexpression prevents HIF-1α stabilization, whereas Glrx ablation by siRNA increases HIF-1α protein and expression of downstream angiogenic genes. Blood flow recovery after femoral artery ligation is significantly improved in Glrx KO mice, associated with increased levels of GSH-protein adducts, capillary density, vascular endothelial growth factor (VEGF)-A, and HIF-1α in the ischemic muscles. Therefore, Glrx ablation stabilizes HIF-1α by increasing GSH adducts on Cys520 promoting in vivo HIF-1α stabilization, VEGF-A production, and revascularization in the ischemic muscles

The relationship of systemic markers of renal function and vascular function with retinal blood vessel responses

Purpose: To test the hypothesis of a significant relationship between systemic markers of renal and vascular function (processes linked to cardiovascular disease and its development) and retinal microvascular function in diabetes and/or cardiovascular disease.Methods: Ocular microcirculatory function was measured in 116 patients with diabetes and/or cardiovascular disease using static and continuous retinal vessel responses to three cycles of flickering light. Endothelial function was evaluated by von Willebrand factor (vWf), endothelial microparticles and soluble E selectin, renal function by serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR). HbA1c was used as a control index.Results: Central retinal vein equivalence and venous maximum dilation to flicker were linked to HbA1c (both p<0.05). Arterial reaction time was linked to serum creatinine (p=0.036) and eGFR (p=0.039), venous reaction time was linked to creatinine clearance (p=0.018). Creatinine clearance and eGFR were linked to arterial maximum dilatation (p<0.001 and p=0.003 respectively) and the dilatation amplitude (p=0.038 and p=0.048 respectively) responses in the third flicker cycle. Of venous responses to the first flicker cycle, HbA1c was linked to the maximum dilation response (p=0.004) and dilatation amplitude (p=0.017), vWf was linked to the maximum constriction response (p=0.016), and creatinine clearance to the baseline diameter fluctuation (p=0.029). In the second flicker cycle, dilatation amplitude was linked to serum creatinine (p=0.022). Conclusions: Several retinal blood vessel responses to flickering light are linked to glycaemia and renal function, but only one index is linked to endothelial function. Renal function must be considered when interpreting retinal vessel responses.

Potential for Cell-Transplant Therapy with Human Neuronal Precursors to Treat Neuropathic Pain in Models of PNS and CNS Injury: Comparison of hNT2.17 and hNT2.19 Cell Lines

Effective treatment of sensory neuropathies in peripheral neuropathies and spinal cord injury (SCI) is one of the most difficult problems in modern clinical practice. Cell therapy to release antinociceptive agents near the injured spinal cord is a logical next step in the development of treatment modalities. But few clinical trials, especially for chronic pain, have tested the potential of transplant of cells to treat chronic pain. Cell lines derived from the human neuronal NT2 cell line parentage, the hNT2.17 and hNT2.19 lines, which synthesize and release the neurotransmitters gamma-aminobutyric acid (GABA) and serotonin (5HT), respectively, have been used to evaluate the potential of cell-based release of antinociceptive agents near the lumbar dorsal (horn) spinal sensory cell centers to relieve neuropathic pain after PNS (partial nerve and diabetes-related injury) and CNS (spinal cord injury) damage in rat models. Both cell lines transplants potently and permanently reverse behavioral hypersensitivity without inducing tumors or other complications after grafting. Functioning as cellular minipumps for antinociception, human neuronal precursors, like these NT2-derived cell lines, would likely provide a useful adjuvant or replacement for current pharmacological treatments for neuropathic pain.

Speaking with different voices: the problems with English law and psychiatric injury

Private law courts in the UK have maintained the de minimis threshold as a condition precedent for a successful claim for the infliction of mental harm. This de minimis threshold necessitates the presence of a ‘recognised psychiatric illness’ as opposed to ‘mere emotion’. This standard has also been adopted by the criminal law courts when reading the Offences Against the Person Act 1861 to include non-physical injury. In determining the cut-off point between psychiatric injury and mere emotion, the courts have adopted a generally passive acceptance of expert testimony and the guidelines used by mental health professionals to make diagnoses. Yet these guidelines were developed for use in a clinical setting, not a legal one. This article examines the difficulty inherent in utilising the ‘dimensional’ diagnostic criteria used by mental health professionals to answer ‘categorical’ legal questions. This is of particular concern following publication of the new diagnostic manual, DSM-V in 2013, which will further exacerbate concerns about compatibility. It is argued that a new set of diagnostic guidelines, tailored specifically for use in a legal context, is now a necessity.

Renal effects and vascular reactivity induced by Tityus serrulatus venom

Tityus serrulatus, popularly known as yellow scorpion, is one of the most studied scorpion species in South America and its venom has supplied some highly active molecules. The effects of T. serrulatus venom upon the renal physiology in human showed increased renal parameters, urea and creatinine. However, in perfused rat kidney the effects were not tested until now. Isolated kidneys from Wistar rats, weighing 240-280 g, were perfused with Krebs-Henseleit solution containing 6% (g weight) of previously dialysed bovine serum albumin. The effects of T. serrulatus venom were studied on the perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), sodium tubular transport (%TNa+), potassium tubular transport (%TK+) and chloride tubular transport (%TCl-). Tityus serrulatus venom (TsV; 10 mu g/mL) was added to the system 30 min after the beginning of each experiment (n = 6). This 30 min period was used as an internal control. The mesenteric bed was perfused with Krebs solution kept warm at 37 T by a constant flow (4 mL/min), while the variable perfusion pressure was measured by means of a pressure transducer. The direct vascular effects of TsV (10 mu g/mL/min; n=6), infused at a constant rate (0.1 mL/min), were examined and compared to the infusion of the vehicle alone at the same rate. TsV increased PP (PP30'= 127.8 +/- 0.69 vs PP60' = 154.2 +/- 14 mmHg*, *p < 0.05) and RVR (RVR30' = 6.29 +/- 0.25 vs RVR60' = 8.03 +/- 0.82 mmHg/mL g(-1) min(-1)*, *p < 0.05), decreased GFR (GFR(30') =0.58 +/- 0.02 vs GFR(60') = 0.46 +/- 0.01 mL g(-1) min(-1)*, *p < 0.05) and UF (UF30' = 0.135 +/- 0.001 vs UF60' = 0.114 +/- 0.003 mL g(-1)min(-1)*, *p < 0.05). Tubular transport was not affected during the whole experimental period (120 min). on the other hand, the infusion of TsV (10 mu g/mL/min) increased the basal perfusion pressure of isolated arteriolar mesenteric bed (basal pressure: 74.17 +/- 3.42 vs TsV 151.8 +/- 17.82 mmHg*, *p < 0.05). TsV affects renal haemodynamics probably by a direct vasoconstrictor action leading to decreased renal flow. (c) 2005 Elsevier Ltd. All rights reserved.

Early markers for myocardial ischemia and sudden cardiac death.

The post-mortem diagnosis of acute myocardial ischemia remains a challenge for both clinical and forensic pathologists. We performed an experimental study (ligation of left anterior descending coronary artery in rats) in order to identify early markers of myocardial ischemia, to further apply to forensic and clinical pathology in cases of sudden cardiac death. Using immunohistochemistry, Western blots, and gene expression analyses, we investigated a number of markers, selected among those which are currently used in emergency departments to diagnose myocardial infarction and those which are under investigation in basic research and autopsy pathology studies on cardiovascular diseases. The study was performed on 44 adult male Lewis rats, assigned to three experimental groups: control, sham-operated, and operated. The durations of ischemia ranged between 5 min and 24 h. The investigated markers were troponins I and T, myoglobin, fibronectin, C5b-9, connexin 43 (dephosphorylated), JunB, cytochrome c, and TUNEL staining. The earliest expressions (≤30 min) were observed for connexin 43, JunB, and cytochrome c, followed by fibronectin (≤1 h), myoglobin (≤1 h), troponins I and T (≤1 h), TUNEL (≤1 h), and C5b-9 (≤2 h). By this investigation, we identified a panel of true early markers of myocardial ischemia and delineated their temporal evolution in expression by employing new technologies for gene expression analysis, in addition to traditional and routine methods (such as histology and immunohistochemistry). Moreover, for the first time in the autopsy pathology field, we identified, by immunohistochemistry, two very early markers of myocardial ischemia: dephosphorylated connexin 43 and JunB.