Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study.

In 2010, a tissue-engineered trachea was transplanted into a 10-year-old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti-HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross-sectional area analysis showed restriction of growth within an area of in-stent stenosis. This report demonstrates the long-term viability of a decellularized tissue-engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs.

Influence of polyhydramnios on perinatal outcome in pregestational diabetic pregnancies.

OBJECTIVE: This study was carried out to evaluate the perinatal outcomes of pregnancy with pregestational diabetes mellitus complicated by polyhydramnios. METHODS: This was a retrospective study of singleton pregnancies, with an antepartum diagnosis of polyhydramnios, seen at the maternal fetal medicine department of Mater Mothers' Hospital, a tertiary-level facility. All pregnancies in women with pregestational diabetes with a singleton pregnancy beyond 24 weeks of gestation, from 1996 to 2006, were reviewed (n = 314), and pregnancies complicated by polyhydramnios were identified (n = 59). Pregnancy outcomes of women whose pregnancy was complicated with polyhydramnios were compared to those without this complication. RESULTS: The incidence of polyhydramnios in the study population was 18.8%. Women with polyhydramnios had increased hemoglobin A1c (HbA1c) levels throughout the pregnancy, and the difference was significant during the prepregnancy period and in the third trimester (P = 0.003 and P = 0.025, respectively). Significantly more mothers in the polyhydramnios group delivered preterm (54.2% vs. 33.3%, P = 0.004), the majority of which were iatrogenic preterm deliveries (44.1%). More pregnancies with polyhydramnios were delivered by Cesarean section (83.0% vs. 62%; P = 0.006), with the majority being performed electively in both groups (79.6% and 70.3%, respectively). Regardless, there were no significant differences in perinatal mortality rates, congenital abnormality rates, the incidences of low Apgar score, acidemia, hypoglycemia requiring intravenous therapy, phototherapy and ventilatory needs between the babies of the two groups. CONCLUSION: Pregestational diabetic pregnancy with polyhydramnios is associated with poor diabetic control. Despite this, there is no significant increase in adverse perinatal outcome in these pregnancies, apart from a higher iatrogenic preterm birth rate.

Pattern recognition of MRSI data shows regions of glioma growth that agree with DTI markers of brain tumor infiltration.

Gliomas are the most common primary brain tumors and the majority are highly malignant, with one of the worst prognoses for patients. Gliomas are characterized by invasive growth into normal brain tissue that makes complete surgical resection and accurate radiotherapy planning extremely difficult. We have performed independent component analysis of magnetic resonance spectroscopy imaging data from human gliomas to segment brain tissue into tumor core, tumor infiltration, and normal brain, with confirmation by diffusion tensor imaging analysis. Our data are consistent with previous studies that compared anomalies in isotropic and anisotropic diffusion images to determine regions of potential glioma infiltration. We show that coefficients of independent components can be used to create colored images for easy visual identification of regions of infiltrative tumor growth.

Polymers: synthesis and characterization of extremely high-molecular-weight polystyrene.

Polystyrenes with molecular weights up to 44 x 10(6) grams per mole have been characterized by light-scattering and equilibrium ultracentrifugation methods. The Mark-Houwink equation, which relates the molecular weight and the intrinsic viscosity of flexible polymers, can be used only if the measurements are made in a theta solvent at the theta temperature.

Development of a subsurface LIBS sensor for in situ groundwater quality monitoring with applications in CO2 leak sensing in carbon sequestration.

Sub-surface activity such as geologic carbon sequestration (GCS) has the potential to contaminate groundwater sources with dissolved metals originating from sub-surface brines or leaching of formation rock. Therefore, a Laser Induced Breakdown Spectroscopy (LIBS) based sensor is developed for sub-surface water quality monitoring. The sensor head is built using a low cost passively Q-switched (PQSW) laser and is fiber coupled to a pump laser and a gated spectrometer. The prototype sensor head was constructed using off the shelf components and a custom monolithic, PQSW laser and testing has verified that the fiber coupled design performs as desired. The system shows good calibration linearity for tested elements (Ca, Sr, and K), quick data collection times, and Limits of Detection (LODs) that are comparable to or better than those of table top, actively Q-switched systems. The fiber coupled design gives the ability to separate the PQSW LIBS excitation laser from the pump source and spectrometer, allowing these expensive and fragile components to remain at the surface while only the low-cost, all optical sensor head needs to be exposed to the hostile downhole environment.

A needs-based approach to equitable allocation of district primary healthcare expenditure in North West Province, South Africa.

BACKGROUND: Inequity in resource allocation and expenditure exists in the South African (SA) health system at provincial and district level. Needs-based resource allocation has been utilised in developed and developing countries to promote equity. OBJECTIVES: To assess current spending patterns on primary healthcare (PHC)-level care at district level, and ultimately to promote equity in district PHC spending using a needs-based resource allocation approach in North West Province, SA. METHODS: Data on PHC expenditure in 2013/14 were derived from the Vulindlela system. Data on key indicators of need for health services in each district were collated from various sources published online. Alternative needs-based formulae were calculated, and sensitivity analyses were conducted to assess the impact of key assumptions. RESULTS: The analysis produced four possible needs-based formulae. The districts of Bojanala and Dr Kenneth Kaunda in North West are relatively under-resourced, while Ngaka Moderi Molema and Dr Ruth Segomotsi Mompati are relatively over-resourced. The results suggest that, in moving towards each district's equity target, a relative redistribution of resources should be undertaken over several years, preferably in the context of an annual increase in the real overall provincial PHC health budget, to avoid any absolute budget cuts for relatively over-resourced districts. CONCLUSIONS: Inequity in PHC expenditure exists between the districts of North West. A needs-based resource allocation approach can promote equity across districts. Any formula selected by the Department of Health will need to be refined over time as more up-to-date and accurate data become available. It is recommended that for the initial phase the formula be based on population size, which will need to be updated at regular intervals. The same would apply to other indicators of need selected for the formula. Important areas for refining the formula over time are: (i) estimating the differential cost of providing care in rural v. urban areas, as assumptions were used in this study; and (ii) identifying a more comprehensive burden of disease indicator for which data are available at district level in the province.

Young adult pregnancy status and the risk of developing overweight and obesity among women and men.

Pregnancies can end in miscarriage, birth or termination. Although it is well known that pregnancy results in weight gain across the life course, it is unknown whether pregnancies which end in termination and miscarriage contribute to this. The study used a sub-sample of 3630 adult offspring from the original cohort of the Mater University of Queensland Study of Pregnancy (MUSP) and its outcomes, in Brisbane, Australia. Anthropometric data were measured at 5, 14 and 21 years of age and experience of pregnancy including termination, miscarriage and births were self-reported at 21 years. Multivariable analyses were conducted to determine whether pregnancy status of young people independently associated with overweight or obesity status. The women who had at least one birth were more likely to have overweight (odds ratio [OR] 1.52; 95% confidence interval [CI]: 1.01, 2.27) or obese (OR 2.38; 95% CI: 1.58, 3.59) compared to women who did not experience any pregnancy. Women whose pregnancies were terminated or miscarried were at the same risk of overweight or obesity as women who did not experience any pregnancy. For men, there is no association between the pregnancies in their partners and the mean difference in their body mass index. Young women whose pregnancies result in a birth, but not terminations or miscarriages, are at greater risk of having overweight or obesity following the birth.

Utilizing original XPC™ in feed to reduce stress susceptibility of broilers.

Reduction of stress is an important factor in improving poultry welfare, especially during periods of heat stress. A study was conducted to evaluate the effects of feeding the functional metabolites of Diamond V Original XPCTM to broilers reared under ambient or heat stress temperatures. Dietary treatments included: control feed (CON) and Original XPC fed continuously at 1.25 kg/MT (XPC). Half the birds in each dietary treatment were subjected to either no heat stress (24°C constant) or heat stress (35°C:24°C for 18:6 h daily) from 28 to 42 d. At the end of the heat stress period, blood was collected from 40 birds/treatment. Blood was analyzed for plasma corticosterone (CORT), plasma HSP70 (HSP70), and heterophil/lymphocyte ratios (H/L). At 42 d, bilateral metatarsal traits were also measured in 40 birds/treatment to assess physical asymmetry. Birds fed XPC had significantly lower CORT levels than CON (P < 0.001; 5,129 ± 617 vs. 8,433 ± 730, respectively). Physical asymmetry scores were also significantly higher in CON compared to XPC fed broilers (P < 0.001; 1.50 ± 0.13 vs. 0.54 ± 0.05, respectively). H/L ratios were significantly greater in CON than for XPC birds (P = 0.01; 0.81 ± 0.05 mm vs. 0.62 ± 0.05 mm, respectively). No differences were observed between CON and XPC fed broilers in HSP70. However, heat stress did increase (P < 0.0001) HSP70 compared to no heat stress birds (5.65 ± 0.12 vs. 4.78 ± 0.11 pg/mL, for heat stress and no heat stress, respectively). Feeding XPC to broiler chickens improved animal welfare via reduced stress indicators while under heat stress or no heat stress conditions. These results indicate that feeding XPC may improve poultry welfare by reducing heat stress susceptibility.

Zincergic innervation of the forebrain distinguishes epilepsy-prone from epilepsy-resistant rat strains.

Zinc is released from a subset of cerebral cortical neurons whereupon it exerts a powerful modulatory influence on excitatory and inhibitory neurotransmission. A number of studies have suggested that alterations in the regulation of zinc may contribute to the genesis of epilepsy. Here, we tested this hypothesis by examining the distribution of zinc-containing axon terminals in rats selectively bred for an innate susceptibility (FAST) or resistance (SLOW) to the development of kindling-induced seizures. Zinc was stained histochemically and levels of staining were quantitatively assessed. We found that the levels of synaptic zinc were significantly lower in the SLOW rats throughout the telencephalon. This relative reduction was most pronounced in limbic cortices where levels were less than 30% of FAST rats. These results suggest that innate differences in the homeostatic regulation of synaptic zinc, particularly in limbic cortices, may underlie differences in epileptogenicity.

The neurosteroid THDOC differentially affects spatial behavior and anesthesia in Slow and Fast kindling rat strains.

Rats selectively bred for "Fast" or "Slow" kindling epileptogenesis express different GABA(A) receptor subunits that may account for differences in their miniature inhibitory postsynaptic currents (mIPSCs). The neurosteroid tetrahydrodeoxycorticosterone (THDOC), an endogenous modulator of GABA-mediated inhibition with anesthetic properties and effects on mnemonic processes, preferentially enhances the mIPSCs recorded from the interneurons of Fast rats. Here we show that the anesthetic effect of 20 mg/kg THDOC was reduced in Fast compared to Slow rats. Further, as the strains have previously been shown to differ in their spatial learning abilities, we subsequently examined the effect of a lower dose (5 mg/kg) of THDOC on their performance in the Morris water maze using a matching-to-place paradigm. THDOC injection deteriorated the usually superior mnemonic capabilities of the Slow rats, i.e., concept learning as well as working and reference memory, while marginally improving these behaviors in Fast rats. These outcomes may reflect the divergent expression of GABAA receptors or disinhibition on interneurons versus principal cells that have been observed between the two strains. Possible mechanisms are discussed.

The relationship between white matter brain metabolites and cognition in normal aging: the GENIE study.

Magnetic resonance spectroscopy (MRS) has demonstrated age-related changes in brain metabolites that may underlie micro-structural brain changes, but few studies have examined their relationship with cognitive decline. We performed a cross-sectional study of brain metabolism and cognitive function in 82 healthy adults (aged 50-90) participating in the GENIE (St GEorge's Neuropsychology and Imaging in the Elderly) study. Absolute metabolite concentrations were measured by proton chemical shift imaging within voxels placed in the centrum semiovale white matter. Cognitive abilities assessed were executive function, working memory, information processing speed, long-term memory and fluid intelligence. Correlations showed that all cognitive domains declined with age. Total creatine (tCr) concentration increased with age (r=0.495, p<0.001). Regression analyses were performed for each cognitive variable, including estimated intelligence and the metabolites, with age then added as a final step. A significant relationship was observed between tCr and executive function, long-term memory, and fluid intelligence, although these relationships did not remain significant after age was added as a final step in the regression. The regression analysis also demonstrated a significant relationship between N-acetylaspartate (NAA) and executive function. As there was no age-related decline in NAA, this argues against axonal loss with age; however the relationship between NAA and executive function independent of age and estimated intelligence is consistent with white matter axonal integrity having an important role in executive function in normal individuals.

Effects of feeding Original XPC™ to broilers with a live coccidiosis vaccine under industrial conditions: Part 2. Cecal microbiota analysis.

Biological supplements in poultry feed are of continued interest due to the improvements in growth performance, protection from pathogen invasion, and benefits in overall host health. The fermentation metabolites of Diamond V Original XPC™ (XPC) have previously been shown to improve commercial performance and reduce Salmonella in poultry. The current study sought to characterize the cecal microbiota using culture-independent analysis based on 16S rRNA gene in Coccivac-D sprayed broilers supplemented with XPC and/or Salinomycin (SAL). Ross 708 male broilers (n = 640) were assigned to one of 4 treatments: Cocci-vaccine (T1), Cocci-vaccine + XPC (T2), Cocci-vaccine + SAL (in the grower diet only) (T3), and Cocci-vaccine + SAL (in the grower diet only) + XPC (T4). Analysis with a PCR-based denaturing gradient gel electrophoresis (DGGE) indicated a shift in the microbial populations present at the various sampling ages - 16, 28, and 42 days. Phylogenetic analysis indicated further consistency in microbial communities directly related to bird age. Identification of microbial communities present and the assessment of their respective quantities using an Illumina MiSeq indicated treatment with XPC had no significant impact on microbial diversity (Chao1 index, observed operational taxonomic unit (OTU) and phylogenetic diversity (PD) whole tree). Sampling age revealed significantly greater diversity at 16 and 28 d (P < 0.05) as compared to the 42 d for the Shannon diversity index, while showing significantly decreased richness and diversity in the 42 d sampling age (Chao1 and observed OTU; P < 0.05). The results of the current study indicate that the chicken intestinal microbiota are impacted more by temporal changes rather than by the feed additive studied.

Effects of feeding Original XPC™ to broilers with a live coccidiosis-vaccine under industry conditions: Part 1. Growth performance and Salmonella inhibition.

Supplementation of poultry diets with Diamond V Original XPC™ (XPC) has been proposed as a means to ameliorate the commonly observed loss of appetite and depression of growth in birds given a live coccidiosis vaccine. A study was conducted to compare the effects on bird performance of a live coccidiosis vaccine in broilers, with and without the dietary inclusion of XPC (1.25 g/kg). Ross 708 male broilers (n = 1,280) were allocated to one of 4 feed treatments: cocci-vaccine (T1), cocci-vaccine + XPC (T2), cocci-vaccine + salinomycin in the grower diet only, (T3), and cocci-vaccine + salinomycin in the grower diet + XPC (T4). Birds consuming diets containing XPC (T2 and T4) and salinomycin (T3) exhibited increased (P < 0.05) feed intake and significantly heavier body weights at 28 d (1.70, 1.74, and 1.67 kg, respectively) and 42 d (3.29, 3.31, and 3.26 kg, respectively). Feed conversion ratio at 28 d was improved (P < 0.05) by adding XPC to diets (T2: 1.47 and T4: 1.44) compared to control diets (T1: 1.50 and T3: 1.47). Salmonella prevalence determined via selective media indicated the inclusion of XPC in the diet resulted in a significant reduction of Salmonella when compared to treatments lacking XPC. Molecular confirmation of Salmonella species indicated S. Kentucky to be present in 38 of the 39 positive samples. Results revealed the ability of XPC in reducing the prevalence of Salmonella. Results from this study also suggest that XPC could be used in conjunction with a live coccidiosis-vaccine to increase growth rate and improve feed conversion of broilers. However, further work is needed to delineate more specific effects directly attributable to XPC.

Preconception care for women with type 2 diabetes mellitus: A mixed-methods study of provider knowledge and practice.

AIMS: Preconception care may decrease adverse pregnancy outcomes associated with pre-existing diabetes mellitus. Aboriginal Australians are at high risk of type 2 diabetes mellitus (T2DM), with earlier onset. We explored practitioner views on preconception care delivery for women with T2DM in the Northern Territory, where 31% of births are to Aboriginal women. METHODS: Mixed-methods study including cross-sectional survey of 156 health practitioners and 11 semi-structured interviews. RESULTS: Practitioners reported low attendance for preconception care however, 51% provided counselling on an opportunistic basis. Rural/remote practitioners were most likely to find counselling feasible. The majority (69%) utilised appropriate guidelines and addressed lifestyle modifications including smoking (81%), weight management (79%), and change medications appropriately such as ceasing ACE inhibitors (69%). Fewer (40%) prescribed the recommended dose of folate (5mg) or felt comfortable recommending delaying pregnancy to achieve optimal preconception glucose control (42%). Themes identified as barriers to care included the complexity of care setting and infrequent preconception consultations. There was a focus on motivation of women to make informed choices about conception, including birth spacing, timing and contraception. Preconception care enablers included cross-cultural communication, a multi-disciplinary care team and strong client-based relationships. CONCLUSIONS: Health practitioners are keen to provide preconception counselling and reported knowledge of evidence-based guidelines. Improvements are needed in recommending high dose folate and optimising glucose control. Cross-cultural communication and team-based care were reported as fundamental to successful preconception care in women with T2DM. Continued education and policy changes are required to support practitioners in opportunities to enhance pregnancy planning.

Vagus nerve stimulation does not affect spatial memory in fast rats, but has both anti-convulsive and pro-convulsive effects on amygdala-kindled seizures.

Vagus nerve stimulation (VNS) is an adjunctive treatment for refractory epilepsy. Using a seizure-prone Fast-kindling rat strain with known comorbid behavioral features, we investigated the effects of VNS on spatial memory, epileptogenesis, kindled seizures and body weight. Electrodes were implanted in both amygdalae and around the left vagus nerve of 17 rats. Following recovery, rats were tested in the Morris water-maze utilizing a fixed platform paradigm. The VNS group received 2 h of stimulation prior to entering the Morris water-maze. Rats were then tested in the kindling paradigm wherein the VNS group received 2 h of stimulation prior to daily kindling stimulation. Finally, the abortive effects of acute VNS against kindling-induced seizures were determined in fully kindled rats by applying VNS immediately after the kindling pulse. Body weight, water consumption and food intake were measured throughout. Memory performance in the Morris water-maze was not different between control and vagus nerve stimulation rats. Similarly, kindling rate was unaffected by antecedent VNS. However, pro-convulsive effects (P<0.05) were noted, when VNS was administered prior to the kindling pulse in fully kindled rats. Yet, paradoxically, VNS showed anti-convulsant effects (P<0.01) in those rats when applied immediately after the kindling stimulus. Body weight was significantly lower throughout kindling (P<0.01) in VNS-treated rats compared with controls, which was associated with reduced food intake (P<0.05), but without difference in water consumption. VNS appears to be devoid of significant cognitive side effects in the Morris water-maze in Fast rats. Although VNS exhibited no prophylactic effect on epileptogenesis or seizure severity when applied prior to the kindling stimulus, it showed significant anti-convulsant effects in fully kindled rats when applied after seizure initiation. Lastly, VNS prevented the weight gain associated with kindling through reduced food intake.

Inhibition of the virulence, antibiotic resistance, and fecal shedding of multiple antibiotic-resistant Salmonella Typhimurium in broilers fed Original XPC™.

Salmonella carriage is an insidious problem for the poultry industry. While most Salmonella serotypes are avirulent in poultry, these bacteria can contaminate chicken meat during processing, leading to one of the most important food safety hazards. In this study, we examined the anti-Salmonella effects of Diamond V Original XPC™ (XPC) included in the finisher diet fed to commercial broilers. On 3 occasions between day one (D1) and D20, broilers were experimentally infected with multiple antibiotic-resistant Salmonella Typhimurium. After confirming that the chicks were shedding Salmonella in the feces on D21, broiler chicks were fed a diet containing XPC (n = 57 birds; 1.25 kg/MT) or an XPC-free control diet (CON) (n = 57 birds) to D49. Fecal samples were obtained weekly and subjected to selective culture for enumerating and determining the antibiotic resistance of the Salmonella Salmonella isolates were then subjected to an in vitro virulence assay, which predicts the ability of Salmonella to cause illness in a mammalian host. Broilers were euthanized on D49 and a segment of the large intestine was removed and subjected to the same assays used for the fecal samples. When compared to the birds fed the CON diet, Salmonella fecal shedding, virulence (invasion and invasion gene expression), and antibiotic resistance were significantly decreased in birds fed XPC (5-fold, 7.5-fold, 6-fold, and 5.3-fold decreases, respectively). Birds fed XPC exhibited heavier body weight (BW) and greater BW gains than those fed the CON diet. The decrease in virulence was associated with a decreased expression of a genetic regulator of Salmonella invasion into cells (hilA), while the decrease in antibiotic resistance was due to a loss of an integron (SGI1) from the input strain. This study revealed that Original XPC™ inhibits the shedding, downstream virulence, and antibiotic resistance of Salmonella residing in broilers.

Differential expression of alpha1, alpha2, alpha3, and alpha5 GABAA receptor subunits in seizure-prone and seizure-resistant rat models of temporal lobe epilepsy.

Temporal lobe epilepsy remains one of the most widespread seizure disorders in man, the etiology of which is controversial. Using new rat models of temporal lobe epilepsy that are either prone or resistant to develop complex partial seizures, we provide evidence that this seizure susceptibility may arise from arrested development of the GABAA receptor system. In seizure-prone (Fast kindling) and seizure-resistant (Slow kindling) rat models, both the mRNA and protein levels of the major alpha subunit expressed in adult brain (alpha1), as well as those highly expressed during development (alpha2, alpha3, and alpha5), were differentially expressed in both models compared with normal controls. We found that alpha1 subunit mRNA expression in the Fast kindling strain was approximately half the abundance of control rats, whereas in the Slow kindling strain, it was approximately 70% greater than that of controls. However, Fast rats overexpressed the alpha2, alpha3, and alpha5 ("embryonic") subunits, having a density 50-70% greater than controls depending on brain area, whereas the converse was true of Slow rats. Using subunit-specific antibodies to alpha1 and alpha5 subunits, quantitative immunoblots and immunocytochemistry revealed a concordance with the mRNA levels. alpha1 protein expression was approximately 50% less than controls in the Fast strain, whereas it was 200% greater in the Slow strain. In contrast, alpha5 subunit protein expression was greater in the Fast strain than either the control or Slow strain. These data suggest that a major predispositional factor in the development of temporal lobe epilepsy could be a failure to complete the normal switch from the GABAA receptor alpha subunits highly expressed during development (alpha2, alpha3, and alpha5) to those highly expressed in adulthood (alpha1).

Attenuation of ischemia-induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus.

Transient forebrain ischemia produced by four-vessel occlusion (4-VO) triggers the delayed death of CA1 neurons in the hippocampus, resulting in behavioral deficits of spatial learning performance. We demonstrate that CA1 neuronal loss induced by 4-VO (12 min) is preceded by a selective and marked elevation of catalytically active caspase-3 in these neurons, indicative of apoptosis. Virally mediated overexpression of the anti-apoptotic gene X chromosome-linked inhibitor of apoptosis protein (XIAP) prevented both the production of catalytically active caspase-3 and degeneration of CA1 neurons after transient forebrain ischemia. CA1 neurons protected in this manner appeared to function normally, as assessed by immunohistochemical detection of the neuronal activity marker nerve growth factor inducible-A and by spatial learning performance in the Morris water maze. These findings indicate that caspase-3 activation is a key event in ischemic neuronal death and that blockade of this event by XIAP overexpression permits CA1 neurons to survive and operate properly after an ischemic insult.

Neuro-overprotection? A functional evaluation of clomethiazole-induced neuroprotection following hypoxic-ischemic injury.

Hypoxic-ischemic (H-I) injury produces extensive damage to the hippocampus of young rats. We have recently shown that administration of 125 mg kg-1 clomethiazole (CMZ), a GABA(A)-agonist, provides complete histological protection against H-I injury if administered 3 h post-H-I (Brain Res 1035 (2005) 194). However, whether that histological protection translates into lasting functional preservation is unclear. To determine whether hippocampal-based circuits remain functionally intact in CMZ-protected H-I rats, we administered 125 mg kg-1 (high dose [CMZ-HD]) or 65 mg kg-1 (low dose [CMZ-LD]) CMZ, 3 h post-H-I, and examined numerous kindling parameters in the dorsal hippocampus 60 days following H-I. Kindling parameters included afterdischarge (AD) thresholds (ADTs), AD durations and kindling rates. Additional groups assessed included vehicle-injected H-I (VIH), hypoxic, ligated and naive rats. VIH, CMZ-HD, CMZ-LD and hypoxic rats all exhibited significantly faster kindling rates than naive rats. Thus, a previous traumatic event, even hypoxia alone, facilitated subsequent seizure propagation. Still, a significantly slower kindling rate was evident in CMZ-HD rats than in hypoxic, VIH or CMZ-LD rats. Moreover, while longer pre-kindling AD durations were observed in the damaged hippocampus of VIH compared with naive rats, this was not true for either CMZ-treated groups, hypoxic or ligated rats. Collectively, these findings suggest CMZ can suppress the epileptogenic effects of H-I. Surprisingly, however, both groups of CMZ-treated rats exhibited a four to nine times greater ADT than any other group and this effect was most profound in the CMZ-protected hippocampus. Thus, CMZ administration protected local neurons against terminal insult and left network excitability relatively normal with respect to seizure offset mechanisms but also caused profound elevation of local ADTs, which suggests a local hypoexcitability/increased inhibition. Finally, this study demonstrates, for the first time, that the kindling model can serve as a sensitive measure of function-related neuroprotective efficacy in animal models of ischemia.

Polyuric prerenal failure.

Prerenal failure is traditionally accompanied by oliguria and represents the normal renal adaptation to retain salt and water and correct the prerenal state. Nonoliguria occurring in the setting of acute renal failure usually represents acute tubular necrosis (ATN) since the kidney has lost its ability to extract salt and water. We report nine cases of patients with acute renal failure occurring in the setting of impaired systemic hemodynamic states and yet who were nonoliguric without strong evidence for ATN. The common defect in these subjects with "polyuric prerenal failure" was a blunted urinary concentrating ability. Polyuria and renal failure occurring despite evidence for impaired systemic hemodynamics may not necessarily be ATN, may still be prerenal, and should be recognizable and promptly reversible if treated appropriately.