Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau

The R406W tau mutation found in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) causes a hereditary tauopathy clinically resembling Alzheimer's disease. Expression of modest levels of the longest human tau isoform with this mutation under the control of the alpha-calcium-calmodulin-dependent kinase-II promoter in transgenic (Tg) mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. These inclusions appeared as early as 18 months of age. As with human cases, tau inclusions were composed of both mutant and endogenous wild-type tau, and were associated with microtubule disruption and flame-shaped transformations of the affected neurons. Straight tau filaments were recovered from Sarkosyl-insoluble fractions from only the aged Tg brains. Behaviorally, aged Tg mice had associative memory impairment without obvious sensorimotor deficits. Therefore, these mice that exhibit a phenotype mimicking R406W FTDP-17 provide an animal model for investigating the adverse properties associated with this mutation, which might potentially recapitulate some etiological events in Alzheimer's disease.     

Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease

Melatonin is an endogenous antioxidant and free radical scavenger. A transgenic (Tg) mouse model for Alzheimer's disease mimics the accumulation of senile plaques, neuronal apoptosis and memory impairment. Previous studies indicated that melatonin reduced beta-amyloid (Abeta)-induced neurotoxicity. In this study, after giving melatonin at 10 mg/kg to APP 695 transgenic (APP 695 Tg) mice for 4 months, we evaluated the long-term influence of melatonin on behavior, biochemical and neuropathologic changes in APP 695 Tg mice. Step-down and step-through passive avoidance tests suggested that 8-month-old APP 695 Tg mice showed decreases in step-down latency and step-through latency and increases in count of error throughout the entire learning trial and memory session, which suggested learning and memory impairment. However, melatonin alleviated learning and memory deficits. Additionally, choline acetyltransferase (ChAT) activity also decreased in the frontal cortex and hippocampus of APP 695 Tg mice compared with non-Tg littermates. Melatonin supplementation increased ChAT activity in the frontal cortex and hippocampus. DNA fragmentation was present in the frontal cortex of the APP 695 Tg mice; melatonin reduced the number of apoptotic neurons. Congo Red staining and Bielschowsky silver impregnation both showed the apparent extracellular Abeta deposition in frontal cortex of APP 695 Tg mice. However, melatonin decreased the Abeta deposits. Our results indicate that neuroprotection by melatonin is partly related to modulation of apoptosis and protection of the cholinergic system. Early rational melatonin interventions may be one of the most promising strategies in the development of approaches to retard or prevent Abeta-mediated disease progression.     

Elevated cerebrospinal fluid tau protein levels in Wernicke's encephalopathy

Objective:  Limited neuronal cell loss is seen in the neuropathology of Wernicke's encephalopathy (WE), but the extent of neuronal damage has not been well studied. Moreover, there is still a debate as to whether alcohol itself causes brain damage in humans. Although, it is difficult to examine the extent of neuronal damage in living patients, recent studies have revealed that total tau protein levels in the cerebrospinal fluid (CSF) reflect the rate of neuronal degeneration. Therefore, we hypothesized that the elevated CSF total tau in patients with WE was due to neuronal damage and thus we examined CSF total tau protein in patients with WE, as well as in those with alcohol withdrawal delirium (WD) and Korsakoff syndrome (KS). We also examined CSF total tau in nonalcohol dependent patients with Alzheimer's disease (AD) as a disease control.
Methods:  CSF samples were obtained from 13 acute WE patients with alcohol dependence, 9 WD patients with alcohol dependence and 16 KS patients with alcohol dependence, and from 20 nonalcohol dependent AD patients. CSF was also obtained from 10 of the WE patients after their disease had progressed to the chronic stage. CSF tau protein levels in all samples were determined by sandwich enzyme-linked immunosorbent assay. Tau phosphorylated at threonine 181 (p-tau₁₈₁) and amyloid β-protein ending at amino acid 42 (Aβ42) in CSF were also determined for comparison between acute WE with AD.
Results:  Total tau was significantly elevated in acute WE and decreased on long-term follow-up, but was not elevated in WD or KS. The patterns of p-tau₁₈₁ and Aβ42 differed between acute WE and AD.
Conclusions:  Intense neuronal cell death occurs transiently in WE, and the mechanism differs from that in AD. Neuronal damage is generally unaccompanied in WD. These results suggest that CSF total tau is a useful biological marker for WE.     

Binding and safety profile of novel benzoxazole derivative for in vivo imaging of amyloid deposits in Alzheimer's disease

Background:   In vivo detection of amyloid deposits in the brain is potentially useful for early diagnosis of Alzheimer's disease (AD) and tracking the efficacy of anti-amyloid therapy.
Methods:   To develop an amyloid-binding agent for positron emission tomography, we screened over 2600 compounds.
Results:   We found benzoxazole derivatives as candidate compounds for in vivo amyloid imaging probes. One of these agents, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), displays high binding affinity to Aβ fibrils. BF-227 binding increased linearly with increasing Aβ fibril formation. In temporal and hippocampal AD brain sections, BF-227 selectively bound to amyloid plaques. In contrast, no staining was evident in the cerebellum. Compared with the previously reported compound BF-168, ¹⁸F-labeled BF-227 displayed selective in vivo labeling of amyloid fibrils and rapid washout from white matter areas in an Aβ-injected rat model. An acute and subacute toxicity study of BF-227 indicated sufficient safety for clinical use as a positron emission tomography probe.
Conclusions:   These findings suggest that BF-227 is feasible as an in vivo imaging probe of amyloid deposits in AD patients.     

Alzheimer's disease: Mechanisms and development of therapeutic strategies

Senile plaques are the most characteristic change in Alzheimer's disease (AD). In senile plaques, β amyloid is deposited, which is composed of aggregated amyloid β protein (Aβ) derived from amyloid precursor protein (APP). Therefore, it is suggested that there exists a mechanism of increase of Aβ production or a decrease of Aβ degradation and/or clearance of β amyloid in AD. Mutations in familial Alzheimer's disease (FAD) genes such as APP , presenilin 1 ( PS1 ) and presenilin 2 ( PS2 ) result in an increase of Aβ production. Apolipoprotein E (ApoE), a genetic risk factor for AD, is involved in Aβ production and/or its clearance. Thus, it is suggested that an inhibition of Aβ production and a facilitation of β amyloid degradation and clearance delay the clinical onset and progression of AD, and it is possible to cure AD even after an onset of the disease, if it is still at an early phase. Researchers studied the fine mechanisms of Aβ production and identified enzymes that cleave-out Aβ from APP. Inhibitors of the cleaving enzymes are proven to be effective in ameliorating AD-like conditions in its animal models and are now being applied to humans. Researchers also found an efficient way of clearing β amyloid deposits using the immune system, which was effective in animal models. When it was applied to humans, some patients developed meningoencephalitis as a side-effect. Therefore, safer vaccines are now being developed. It did not require 20 years for researchers to develop therapeutic strategies since the discovery of Aβ in 1984. Now that AD is becoming a treatable disease, early diagnosis and early treatment will soon become the rule. Notably, AD may not be a psychiatric disorder any more, and mainly neurologists and geriatricians will see patients. Thus, neurogeriatrics will become more and more important.     

Synergistic premalignant effects of chronic ethanol exposure and insulin receptor substrate-1 overexpression in liver

Aim:  Insulin receptor substrate, type 1 (IRS-1) transmits growth and survival signals, and is overexpressed in more than 90% of hepatocellular carcinomas (HCCs). However, experimental overexpression of IRS-1 in the liver was found not to be sufficient to cause HCC. Since chronic alcohol abuse is a risk factor for HCC, we evaluated potential interactions between IRS-1 overexpression and chronic ethanol exposure by assessing premalignant alterations in gene expression.
Methods:  Wild-type (wt) or IRS-1 transgenic (Tg) mice, constitutively overexpressing the human (h) transgene in the liver, were pair-fed isocaloric liquid diets containing 0% or 24% ethanol for 8 weeks. The livers were used for histopathologic study and gene expression analysis, focusing on insulin, insulin-like growth factor (IGF) and wingless (WNT)–Frizzled (FZD) pathways, given their known roles in HCC.
Results:  In wt mice, chronic ethanol exposure caused hepatocellular microsteatosis with focal chronic inflammation, reduced expression of proliferating cell nuclear antigen (PCNA) and increased expression of IGF-I and IGF-I receptor. In hIRS-1 Tg mice, chronic ethanol exposure caused hepatic micro- and macrosteatosis, focal chronic inflammation, apoptosis and disordered lobular architecture. These effects of ethanol in hIRS-1 Tg mice were associated with significantly increased expression of IGF-II, insulin, IRS-4, aspartyl–asparaginyl β hydroxylase (AAH), WNT-1 and FZD 7, as occurs in HCC.
Conclusion:  In otherwise normal liver, chronic ethanol exposure mainly causes liver injury and inflammation with impaired DNA synthesis. In contrast, in the context of hIRS-1 overexpression, chronic ethanol exposure may serve as a cofactor in the pathogenesis of HCC by promoting expression of growth factors, receptors and signaling molecules known to be associated with hepatocellular transformation.     

Micronutrient status indicators in individuals single- or double-infected with HIV and Wuchereria bancrofti before and after DEC treatment

Objective  To identify possible associations between selected micronutrient status indicators (serum ferritin, retinol, β-carotene, α-tocopherol, and the acute phase reactant α-1 antichymotrypsin) and infection with human immunodeficiency virus (HIV) or Wuchereria bancrofti , and to assess the effect of the antifilarial drug diethylcarbamazine (DEC) on the micronutrient status indicators in individuals positive for one or both of the two infections.
Methods  Serum concentrations of ferritin, retinol, β-carotene, α-tocopherol and the acute phase reactant α-1 antichymotrypsin were examined in 59 individuals with HIV, W. bancrofti infection, or both, in Tanga Region, Tanzania, before and 12 weeks after treatment with DEC.
Results  HIV infection, but not W. bancrofti infection, was associated with higher serum ferritin concentrations and lower β-carotene and α-tocopherol. Neither HIV infection nor W. bancrofti infection was associated with serum retinol. The four micronutrient status indicators and α-1 antichymotrypsin were generally lower at 12 weeks after treatment both in the DEC and the placebo groups.
Conclusions  The negative association between HIV infection and the antioxidant vitamins β-carotene and α-tocopherol may be due to infection-induced oxidative stress, whereas W. bancrofti infection seemed not to be associated with oxidative stress. The drop in antioxidant vitamin concentrations after treatment may be due to oxidative stress induced by HIV progression (HIV infected) and inflammation around dead adult worms and microfilariae ( W. bancrofti infected) rather than to an effect of DEC.     

Polymorphisms of Interleukin-1β and β3-Adrenergic Receptor in Japanese Patients With Nonalcoholic Steatohepatitis

Background: Obesity, hypertriglyceridemia, and diabetes have been reported as frequent complications observed in patients with nonalcoholic steatohepatitis (NASH) in Western countries. The aim of this study was to investigate the genetic predisposition on NASH pathogenesis in the Japanese population.
Methods: Genotypes of two previously described functional polymorphisms—β3-adrenergic receptor 190 T/A polymorphism, which results in Trp64Arg (W64R) amino acid replacement, and interleukin-1β-511 T/C polymorphism in the promoter sequence—were determined in 63 Japanese NASH patients and 100 healthy volunteers using polymerase chain reaction and restriction fragment length polymorphism.
Results: β3-adrenergic receptor R allele frequency and the R/− (W/R and R/R) genotype frequency were significantly higher in NASH patients than those in control subjects. Interleukin-1β-511 T allele frequency and the T/T genotype frequency were significantly higher in NASH patients than those in control subjects. Obesity, hypertriglyceridemia, and hyperinsulinemia were associated with NASH patients with the R/− genotype, whereas an increase in fasting plasma glucose level and a decrease in insulinogenic index were associated with NASH patients with the W/W genotype.
Conclusion: This study confirmed the contribution of obesity, glucose intolerance, and hypertriglyceridemia to NASH development in the Japanese population. In addition to these factors, genetic predispositions to obesity and inflammation in the Japanese population were shown to contribute much to the development of NASH.     

Age-related loss of noradrenergic neurons in the brains of triple transgenic mice

Microscopic findings in Alzheimer’s disease (AD) at autopsy include a wide cortical distribution of beta amyloid (Aβ)-containing plaques and diminished numbers of pyramidal neurons in CA1 of hippocampus and tyrosine hydroxylase-positive (TH+) neurons in the locus coeruleus (LC). To better understand the neuropathology underlying cognitive decline in AD, we analyzed the AD-type neuropathology in brains of triple transgenic (3×Tg) mice harboring mutations for APP_swe, PS1_M146V, and tau_P301L. Histochemical and immunohistochemical staining and computerized stereology were carried out in age-matched young, early middle age, and late middle age 3×Tg mice. The 3×Tg mice showed an intracellular Aβ deposition in subiculum and CA1 pyramidal neurons and an extracellular distribution of amyloid plaques specifically in the subiculum of hippocampal formation and in neocortical layer V. The 3×Tg mice also showed an age-related loss of TH+ neurons in LC, with a loss of 37% of these neurons at 15 months of age. There was no loss of CA1 neurons at any age examined. Reduced AD-type neuropathology in CA1 of 3×Tg mice suggests a possible neuroprotective role for high intracellular-to-extracellular ratios of insoluble Aβ deposits. Understanding the neurobiology of this apparent neuroprotection could lead to an improved understanding of age-related cognitive function in general, and the development of novel strategies for the therapeutic management of AD patients.     

Time of the day for 11β-HSD1 inhibition plays a role in improving glucose homeostasis in DIO mice

Aims:  The physiological effects of glucocorticoids in a given tissue are driven by the local level of the active glucocorticoid, which is determined by two sources: the plasma cortisol in human (or corticosterone in rodents) and the cortisol produced locally through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. Because of the circadian variation of plasma glucocorticoids, the pharmacological efficacy of 11β-HSD1 inhibition may depend on the time of the day for inhibitor administration.
Methods:  The circadian profile of corticosterone was established in lean and diet-induced obesity (DIO) C57BL/6 mice from blood collected at different time of the day. 11β-HSD1 enzyme activity was also measured throughout the day in DIO mice. To determine the optimal timing for administration of an 11β-HSD1 inhibitor to obtain maximum efficacy, we used a DIO mouse model and a small molecule inhibitor of 11β-HSD1 from our thiazolinone series. Based on the circadian profile of corticosterone obtained, we administered the 11β-HSD1 inhibitor to these animals at different times of the day and evaluated the effects on plasma glucose levels and glucose tolerance.
Results:  We report that corticosterone circadian rhythm was similar between lean and DIO C57BL/6 mice, and 11β-HSD1 enzyme activity undergoes minimal variations throughout the day. Interestingly, the compound exhibited maximum efficacy if dosed in the afternoon when plasma corticosterone is high; the morning dosing when plasma corticosterone is low did not lead to efficacy.
Conclusion:  These data suggest that because of the circadian rhythm of circulating glucocorticoids, the time of the day for 11β-HSD1 inhibitor administration is important in achieving efficacy.     

Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology

Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid β (Aβ) peptide, the major constituent of AD plaques. We expressed human APP₇₅₁ containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes Aβ deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of Aβ in the pathogenesis of the disease.     

They just don't get enough! Variable intern experience in bedside procedural skills

Background: Medical school and resident training programmes offer different learning opportunities and outcomes. The aim of the study was to assess medical student and intern experience in common clinical procedures.
Methods: Interns employed in a metropolitan teaching hospital from 2000 to 2004 completed a survey of experience and confidence in clinical procedures at the beginning and end of their intern year. Attendance at and the contribution to procedural confidence of a voluntary procedural skill-training programme were examined.
Results: For the 314 interns, clinical experience before and during internship varied for each procedure and between year cohorts as did training programme attendance (44–84%). Student procedural confidence was predicted by pre-intern experience either on patients or by simulation ( β  = 0.17, 95% confidence interval (CI) 0.02–0.21, P  = 0.03) and age >30 years on commencing internship ( β  = 8.44, 95%CI 3.03–14.06, P  = 0.003. Adjusted R ² = 0.08, P  = 0.002). Intern procedural confidence by year's end was predicted by attendance at the training programme ( β  = 0.48, 95%CI 0.34–0.62, P  < 0.001), intern experience with patient procedures ( β  = 0.34, 95%CI 0.21–0.47, P  < 0.001) and a clear decision to enter a postgraduate training programme ( β  = 0.13, 95%CI 0.04–0.22, P  = 0.007, Adjusted R ² = 0.50, P  < 0.001).
Conclusion: Interns and students receive variable experience to carry out procedural skills on patients. This makes designing training programmes difficult as training needs vary each year. Both mandatory supervision of key skills and opportunities to supplement limited experience are needed during the intern year to ensure a uniform experience.     

An insight into the protection of rat liver against ischemia/reperfusion injury by 2-selenium-bridged β-cyclodextrin

Aim:  The reperfusion following liver ischemia results in the damage and apoptosis of hepatocytes. The aim of this study was to investigate the possible effects and mechanism of a new synthesized glutathione peroxidase (GPX) mimic, 2-selenium-bridged β-cyclodextrin (2-SeCD), on rat liver ischemia-reperfusion (I/R) injury.
Methods:  Male Wistar rats ( n  = 32) were randomly divided into four groups: I. sham-operated group, II. I/R group, III. I/R +2-SeCD group, IV. I/R + Ebselen group. Hepatic I/R was administered by 90 min of ischemia and 12 h of reperfusion. Liver tissues were collected at the end of reperfusion period for measurement of various biochemical parameters.
Results:  The serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) activity and tissue malondialdehyde, myeloperoxidase levels were increased in I/R group, while the increase was significantly reduced by 2-SeCD treatment. The glutathione level, depressed by I/R, was elevated back to normal levels by treatment with 2-SeCD. Severe hepatic damage were observed by light and transmission electron microscopy whilst pretreatment with 2-SeCD resulted in tissue and cellular preservation. Furthermore, 2-SeCD reduced cytochrome c release from mitochondria and subsequent DNA fragmentation by regulating Bcl-2/Bax expression ratio. Results suggested that 2-SeCD was more effective than ebselen in the reversal of the alteration in tissue structural and biochemical parameters caused by I/R injury.
Conclusion:  2-selenium-bridged β-cyclodextrin playes an important role in the protection of liver against I/R injury and this treatment may be a novel pharmacological agent for liver surgery.     

Comparing the protective effects of ciprofloxacin, moxifloxacin and levofloxacin in mice with lipopolysaccharide-induced acute lung injuries

Background and objective:   Ciprofloxacin, moxifloxacin and levofloxacin are recognized immunomodulators. Their effects in acute lung injuries have not been tested. This study compared the immunoprotective effects of these agents in mice with lung injuries induced by LPS by measuring the cytokine profiles in the injured lung and the associated mortality.
Methods:   The development of lung injury and mortality was compared in mice pretreated with either ciprofloxacin, levofloxacin, moxifloxacin or saline (control group) after the intratracheal administration of LPS. BALF and serum were collected at 1, 3 and 6 h to measure the concentrations of tumour necrosis factor-α (TNF-α), IL-1β, IL-6, IL-10 and macrophage inflammatory protein-2 (MIP-2) using enzyme-linked immunoassay.
Results:   Levels of TNF-α, IL-1β and MIP-2 in the BAL of the ciprofloxacin group were significantly lower compared with those of controls (all P  < 0.0083) at 3 and 6 h after LPS challenge. There were no significant differences in the levels of these cytokines in the moxifloxacin and levofloxacin groups compared with controls. Overall, the 96-h survival for the mice pretreated with ciprofloxacin, but not for those pretreated with moxifloxacin or levofloxacin, was significantly greater than that of the control animals ( P  = 0.019).
Conclusions:   In the setting of LPS-induced lung injuries, ciprofloxacin appears to provide better anti-inflammatory properties and survival benefits than the other fluoroquinolones tested.     

Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function

Multiple independent mutations in neuroligin genes were identified in patients with familial autism, including the R451C substitution in neuroligin-3 (NL3). Previous studies showed that NL3(R451C) knock-in mice exhibited modestly impaired social behaviors, enhanced water maze learning abilities, and increased synaptic inhibition in the somatosensory cortex, and they suggested that the behavioral changes in these mice may be caused by a general shift of synaptic transmission to inhibition. Here, we confirm that NL3(R451C) mutant mice behaviorally exhibit social interaction deficits and electrophysiologically display increased synaptic inhibition in the somatosensory cortex. Unexpectedly, however, we find that the NL3(R451C) mutation produced a strikingly different phenotype in the hippocampus. Specifically, in the hippocampal CA1 region, the NL3(R451C) mutation caused an ～1.5-fold increase in AMPA receptor-mediated excitatory synaptic transmission, dramatically altered the kinetics of NMDA receptor-mediated synaptic responses, induced an approximately twofold up-regulation of NMDA receptors containing NR2B subunits, and enhanced long-term potentiation almost twofold. NL3 KO mice did not exhibit any of these changes. Quantitative light microscopy and EM revealed that the NL3(R451C) mutation increased dendritic branching and altered the structure of synapses in the stratum radiatum of the hippocampus. Thus, in NL3(R451C) mutant mice, a single point mutation in a synaptic cell adhesion molecule causes context-dependent changes in synaptic transmission; these changes are consistent with the broad impact of this mutation on murine and human behaviors, suggesting that NL3 controls excitatory and inhibitory synapse properties in a region- and circuit-specific manner.     

Hepatic 11beta-HSD1 mRNA expression in fatty liver and nonalcoholic steatohepatitis

Context  Nonalcoholic fatty liver disease represents the hepatic manifestation of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury. The pathophysiology that leads to NASH is not well understood.
Objective  We hypothesize that an altered cortisol metabolism in the liver may be a pathogenetic factor.
Design and patients  75 patients (28 men, 47 women) underwent liver biopsy for elevation in liver enzymes. Histological diagnosis identified normal liver in eight, fatty liver in 20, NASH grade 1 in 22, grade 2 in nine, grade 3 in three patients, and other forms of hepatitis or cirrhosis in 13 patients. We quantified hepatic 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1) and hexose-6-phosphate-dehydrogenase (H6PDH) mRNA expression by real-time PCR. In addition, analysis of 24 h urinary excretion of cortisol metabolites using GCMS was performed and compared with healthy controls.
Results  11β-HSD1 mRNA expression correlated significantly ( R ²= 0·809; P  < 0·001) with H6PDH mRNA expression, negatively with waist-to-hip ratio in women ( R ²= 0·394; P = 0·005), but not with urinary (THF + 5α-THF)/THE ratio, total cortisol metabolite excretion, age, BMI, degree of fatty liver or NASH stages. Total cortisol metabolite excretion was increased in patients with fatty liver or NASH compared with healthy controls.
Conclusions  Our data suggest that expression of hepatic 11β-HSD1 and H6PDH are closely interlinked. 11β-HSD1 gene expression does not seem to be involved in the pathogenesis of fatty liver or NASH. However, those patients showed an increased 5α- and 5β-reduction of cortisol leading to an increased cortisol turnover rate and an activation of the HPA axis.     

Enhanced immediate inflammatory response to Streptococcus pneumoniae in the lungs of mice with pulmonary emphysema

Background and objective:   Pulmonary emphysema is associated with frequent respiratory infections but little is known about the reasons for this susceptibility to bacterial infection. We previously demonstrated an impaired inflammatory response to Streptococcus pneumoniae in an experimental emphysema mouse model at 24 h, or longer following bacterial inoculation. Toll-like receptors (TLR) have been recognized as regulators in the inflammatory response. We examined the expression of TLR on alveolar macrophages in experimental emphysema mice and evaluated the immediate inflammatory response of the emphysematous lung to streptococcal infection.
Methods:   Elastase was administered once into mice trachea to induce pulmonary emphysema. Three weeks later, expression of TLR-2 and TLR-4 in the BAL cells was examined by immunostaining. Following the intratracheal inoculation of Streptococcus pneumoniae , pro-inflammatory cytokine concentrations were measured in the BAL fluids of the control and emphysema mice.
Results:   The expression of TLR-2 and TLR-4 was significantly elevated in the alveolar macrophages of emphysema mice. Six hours after infection, neutrophils in the BAL fluid of emphysema mice were significantly increased, and the levels of tumour necrosis factor-α, IL-1β and IL-6 were significantly elevated, compared with the control mice. At 3 h post inoculation, macrophage inflammatory protein-2 levels were significantly elevated.
Conclusions:   The immediate inflammatory response in the emphysematous lung is significantly enhanced in response to streptococcal infection. This may be partly attributed to the increased expression of TLR in the alveolar macrophages of emphysema mice.     

Socio-environmental predictors of Barmah forest virus transmission in coastal areas, Queensland, Australia

Objective  To assess the socio-environmental predictors of Barmah forest virus (BFV) transmission in coastal areas, Queensland, Australia.
Methods  Data on BFV notified cases, climate, tidal levels and socioeconomic index for area (SEIFA) in six coastal cities, Queensland, for the period 1992–2001 were obtained from the relevant government agencies. Negative binomial regression models were used to assess the socio-environmental predictors of BFV transmission.
Results  The results show that maximum and minimum temperature, rainfall, relative humidity, high and low tide were statistically significantly associated with BFV incidence at lags 0–2 months. The fitted negative binomial regression models indicate a significant independent association of each of maximum temperature (β = 0.139, P  = 0.000), high tide (β = 0.005, P  = 0.000) and SEIFA index (β = −0.010, P  = 0.000) with BFV transmission after adjustment for confounding variables.
Conclusions  The transmission of BFV disease in Queensland coastal areas seemed to be determined by a combination of local social and environmental factors. The model developed in this study may have applications in the control and prevention of BFV disease in these areas.     

BK channel subunit composition modulates molecular tolerance to ethanol

Background:  The large conductance calcium-activated potassium channel (also called BK channel or Slo channels) is a well-studied target of alcohol action, and plays an important role in behavioral tolerance.
Methods:  Using patch clamp electrophysiology, we examined human BK channels expressed in HEK293 cells to test whether tolerance to ethanol occurs in excised patches and whether it is influenced by subunit composition. Three combinations were examined: hSlo, hSlo + β₁, and hSlo + β₄.
Results:  The 2 components of BK alcohol adaptation (Component 1: rapid tolerance to acute potentiation, and Component 2: a more slowly developing decrease in current density) were observed, and varied according to subunit combination. Using a 2-exposure protocol, Component 1 tolerance was evident in 2 of the 3 combinations, because it was more pronounced for hSlo and hSlo + β₄.
Conclusions:  Thus, rapid tolerance in human BK occurs in cell-free membrane patches, independent of cytosolic second messengers, nucleotides or changes in free calcium. Alcohol pretreatment for 24 hours altered subsequent short-term plasticity of hSlo + β₄ channels, suggesting a relationship between classes of tolerance. Finally, Component 2 reduction in current density showed a striking dependency on channel composition. Twenty-four hour exposure to 25 mM ethanol resulted in a down-regulation of BK current in hSlo and hSlo + β₄ channels, but not in hSlo + β₁ channels. The fact that hSlo + β₁ channels show less sensitivity to acute challenge, in conjunction with less Component 1 and Component 2 tolerance, suggests subunit composition is an important factor for these elements of alcohol response.