Search

In Australia, there are no current national estimates of the risks of transmission of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or human T-lymphotrophic virus (HTLV) by musculoskeletal tissue transplantation. We determined the prevalence rates of antibodies against HIV (anti-HIV), HCV (anti-HCV) and HTLV (anti-HTLV) and Hepatitis B surface antigen (HBsAg) for 12,415 musculoskeletal tissue donors from three major bone tissue banks across Australia for the period 1993-2004. The prevalence (per 100,000 persons) was 64.44 for anti-HIV, 407.13 for HBsAg, 534.63 for anti-HCV and 121.88 for anti-HTLV. The estimated probability of viremia at the time of donation was 1 in 128,000, 1 in 189,000, 1 in 55,000 and 1 in 118,000, respectively. With the addition of nucleic acid amplification testing (NAT), the probability of donor viremia would be reduced to 1 in 315,000 for HIV, 1 in 385,000 for HBV and 1 in 500,000 for HCV. The prevalence of HIV, HBV, HCV and HTLV although low, are higher among musculoskeletal tissue donors than among first-time blood donors. The risks associated with musculoskeletal donation will be reduced with NAT, though further cost analysis is required prior to its implementation.

It is now widely accepted, given the current weight of experimental evidence, that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage caused by glucolipotoxicity in diabetes. The source of ROS in the insulin secreting pancreatic beta-cells and in the cells which are targets for insulin action has been considered to be the mitochondrial electron transport chain. While this source is undoubtably important, we provide additional information and evidence for NADPH oxidase-dependent generation of ROS both in pancreatic beta-cells and in insulin sensitive cells. While mitochondrial ROS generation may be important for regulation of mitochondrial uncoupling protein (UCP) activity and thus disruption of cellular energy metabolism, the NADPH oxidase associated ROS may alter parameters of signal transduction, insulin secretion, insulin action and cell proliferation or cell death. Thus NADPH oxidase may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in diabetes.

Vaccination with Abeta(1-42) and treatment with NCX-2216, a novel nitric oxide releasing flurbiprofen derivative, have each been shown separately to reduce amyloid deposition in transgenic mice and have been suggested as potential therapies for Alzheimer's disease. In the current study we treated doubly transgenic amyloid precursor protein and presenilin-1 (APP+PS1) mice with Abeta(1-42) vaccination, NCX-2216 or both drugs simultaneously for 9 months. We found that all treatments reduced amyloid deposition, both compact and diffuse, to the same extent while only vaccinated animals, with or without nonsteroidal anti-inflammatory drug (NSAID) treatment, showed increased microglial activation associated with the remaining amyloid deposits. We also found that active Abeta vaccination resulted in significantly increased cerebral amyloid angiopathy and associated microhemorrhages, while NCX-2216 did not, in spite of similar reductions in parenchymal amyloid. Co-administration of NCX-2216 did not attenuate this effect of the vaccine. This is the first report showing that active immunization can result in increased vascular amyloid and microhemorrhage, as has been observed with passive immunization. Co-administration of an NSAID agent with Abeta vaccination does not substantially modify the effects of Abeta immunotherapy. The difference between these treatments with respect to vascular amyloid development may reflect the clearance-promoting actions of the vaccine as opposed to the production-modifying effects proposed for flurbiprofen.

Aims/hypothesis: Acute or chronic exposure of beta cells to glucose, palmitic acid or pro-inflammatory cytokines will result in increased production of the p47(phox) component of the NADPH oxidase and subsequent production of reactive oxygen species (ROS)., Methods: Rat pancreatic islets or clonal rat BRIN BD11 beta cells were incubated in the presence of glucose, palmitic acid or pro-inflammatory cytokines for periods between 1 and 24 h. p47(phox) production was determined by western blotting. ROS production was determined by spectrophotometric nitroblue tetrazolium or fluorescence-based hydroethidine assays., Results: Incubation for 24 h in 0.1 mmol/l palmitic acid or a pro-inflammatory cytokine cocktail increased p47(phox) protein production by 1.5-fold or by 1.75-fold, respectively, in the BRIN BD11 beta cell line. In the presence of 16.7 mmol/l glucose protein production of p47(phox) was increased by 1.7-fold in isolated rat islets after 1 h, while in the presence of 0.1 mmol/l palmitic acid or 5 ng/ml IL-1beta it was increased by 1.4-fold or 1.8-fold, respectively. However, palmitic acid or IL-1beta-dependent production was reduced after 24 h. Islet ROS production was significantly increased after incubation in elevated glucose for 1 h and was completely abolished by addition of diphenylene iodonium, an inhibitor of NADPH oxidase or by the oligonucleotide anti-p47(phox). Addition of 0.1 mmol/l palmitic acid or 5 ng/ml IL-1beta plus 5.6 mmol/l glucose also resulted in a significant increase in islet ROS production after 1 h, which was partially attenuated by diphenylene iodonium or the protein kinase C inhibitor GF109203X. However, ROS production was reduced after 24 h incubation., Conclusions/interpretation: NADPH oxidase may play a key role in normal beta cell physiology, but under specific conditions may also contribute to beta cell demise.

Objective: To determine the aetiology of genital ulcers and discharges in rural south western Uganda and to assess response to syndromic treatment., Method: A longitudinal, prospective study using laboratory testing and questionnaires to evaluate 561 adult men and women presenting with clinically verified genital ulcers, urethral, or vaginal discharge at a general outpatient clinic and two health centres between December 1999 and July 2001., Results: One third of patients had genital ulcers and two thirds discharges. There was good response to treatment in 461/508 patients (90.7%). Herpes simplex virus type 2 was found in 95/217 (43.8%) genital ulcers. In 24.1% of ulcer cases there was also a genital discharge. HIV seropositivity was high in ulcer cases (63.2%), with significantly more HSV2 and secondary bacterial infection than in seronegative cases. Neisseria gonorrhoeae was found in 135/204 (66.2%) male genital discharges. Female genital discharges were mostly associated with bacterial vaginosis (36.1%), Trichomonas vaginalis (18.9%), and candidiasis (18.6%)., Conclusions: The aetiological pattern of STI syndromes reported will help inform revision of national STI guidelines. The importance of herpes simplex virus type 2, the variation in causes of genital ulcers according to HIV serostatus, the high frequency of multiple infections and secondary bacterial contamination of genital ulcers are notable. These results help explain the lack of effect of an STI intervention on HIV incidence in a recent trial in this area.

This study reviews whether patients with artificial joints need antibiotic cover for dental treatment. Generally in Australia the practice has developed of giving most patients with artificial joints antibiotic prophylaxis for a wide range of dental procedures. This is partly on anecdotal grounds, partly historical and partly for legal concerns. It has been encouraged by some guidelines. Scientifically, the risk and the benefit of each step in the process needs to be analysed. This review shows that the risk of an artificial joint becoming infected from a bacteraemia of oral origin is exceedingly low whereas the risk of an adverse reaction to the antibiotic prophylaxis is higher than the risk of infection. If all patients with artificial joints receive antibiotic prophylaxis then more will die from anaphylaxis than develop infections. Factors which balance the risk benefit are if the patient is seriously immunocompromised, if the joint prosthesis is failing or chronically inflamed and if the dental procedures, such as from extractions and deep periodontal scaling, produce high level bacteraemias. Recommendations to rationalize antibiotic prophylaxis for patients with artificial joints are presented.

Background: Collection of audit data about epidural blood patches has traditionally relied on voluntary reporting, which is notoriously incomplete. The records of Medicare-funded Australian private obstetric practice, which represents 30% of all deliveries, allow a novel method of central data collection and retrieval., Method: Data relating to all deliveries, epidurals and blood patches in private practice in Australia over a two-year period were retrieved from the Health Insurance Commission., Results: The overall rate of epidural analgesia in labour was estimated at 30% and the proportion of epidurals that progressed to blood patching was 0.35%. The rate of epidural blood patching varied between states from 0.18% to 0.56%., Conclusion: Despite certain limitations of our data interpretation, we regard this technique as a useful audit tool capable of generating accurate and robust audit data that might otherwise be unobtainable.

Dielectric (dielectric constant (ε(')) and loss factor (ε″)) and thermal (heat capacity (c), thermal conductivity (k) and thermal diffusivity (α))) properties of two meat batters (pork luncheon roll (PLR) and white pudding (WP)) were measured between 5 and 85 °C. Radio frequency (RF) and microwave (MW) ε″ values varied across 5-85 °C (P<0.05). MW ε(') and ε″ values for WP tended to peak at 45 °C and decrease thereafter, whereas for PLR, ε(') and ε″ peaked at 65 °C which appeared to match potato starch gelatinisation within this product. WP and PLR had significantly higher c values at 25 °C, which corresponded to the MP of pork fat. For PLR, an additional c peak was noted at 65 °C, which appeared to correspond to potato starch gelatinisation. At 85 °C, k values were higher (P<0.05) than at 5, 25 and 45 °C but were not higher than values at 65 °C. α values increased with temperature (P<0.05).

To determine the effects of the recessive retinal degeneration (rd) gene on behavioral performance, three Alzheimer's transgenic lines (APPsw, P301L, APPsw + P301L) and non-transgenic littermates were evaluated in a comprehensive behavioral battery between 5 and 8.5 months of age. For all four genotypes collectively, rd homozygosity resulted in profound impairment in spatial cognitive tasks requiring visual acuity (Morris maze, platform recognition, and radial arm water maze). Non-transgenic and P301L mutant tau mice contributed most to this rd effect since heterozygous and wild type mice performed well. By contrast, spatial cognitive performance of both APPsw-expressing lines was often impaired, irrespective of rd status. Sensorimotor performance was unaffected by rd homozygosity, while rd effects on anxiety were genotype-dependent (less anxiety in NT, APPsw; more anxiety in P301L, APPsw + P301L). Our results strongly encourage rd screening of genetically manipulated mouse lines produced from rd-carrying strain backgrounds to avoid serious potential confounds in the interpretation of spatially based cognitive performance.

Previously, we showed that blueberry (BB) supplementation reversed the deleterious effects of aging on motor behavior and neuronal signaling in senescent rodents. We now report that BB-fed (from 4 months of age) APP + PS1 transgenic mice showed no deficits in Y-maze performance (at 12 months of age) with no alterations in amyloid beta burden. It appeared that the protective mechanisms are derived from BB-induced enhancement of memory-associated neuronal signaling (e.g. extracellular signal-regulated kinase) and alterations in neutral sphingomyelin-specific phospholipase C activity. Thus, our data indicate for the first time that it may be possible to overcome genetic predispositions to Alzheimer disease through diet.

Prior work demonstrated that beta-amyloid (A beta) immunotherapy for 8 months prevented cognitive impairment in 16-month-old APP + PS1 transgenic mice. In the present study, 4 immunizations administered biweekly to cognitively impaired 16-month-old transgenic mice could not reverse deficits in working memory or reference memory in the radial arm water maze or in visual platform recognition, possibly because of inadequate antibody exposure. Nontransgenic mice showed cognitive savings between the 16- and 18-month test periods, but the transgenic groups did not. These results suggest that a longer period of active immunotherapy, or passive immunization, may be required to provide sufficient antibody titers to improve cognition in older transgenic mice. A beta-based immunotherapy for Alzheimer's disease will likely be more successful prophylactically than therapeutically.

Aims: Ultrasound is a non-invasive, non-ionising radiation modality which is highly successful at soft tissue imaging. Groin pain from an occult hernia can be a difficult clinical diagnosis made easier by good imaging. The aim of this study was to demonstrate the accuracy of ultrasound in diagnosing and typing the groin hernia, which could lead to its justification of use in the imaging of the occult hernia., Patients and Methods: A total of 118 patients with a clinical diagnosis of a groin hernia, prospectively underwent a blinded, ultrasound examination of the groin. All patients underwent surgery and these findings were compared with the ultrasound results., Results: 120 symptomatic groins in 118 patients underwent surgery. Ultrasound diagnosed 118 hernias and there were two normal ultrasound examinations. Surgery confirmed the same two patients to be normal - ultrasound sensitivity for all hernias was 100% with 100% specificity. Two femoral hernias were seen in this study, both correctly identified at ultrasound. Of the inguinal hernias, ultrasound identified 36 of 42 direct hernias (sensitivity 86%, specificity 97%) and 72 of 74 indirect hernias (sensitivity 97%, specificity 87%), Conclusions: This study confirms that ultrasound can accurately diagnose groin hernias and this may justify its use in the assessment of the occult hernia.

Mutations in the presenilin-1 (mutPS-1) gene, a cause of familial Alzheimer's disease, increase the susceptibility of neurons to apoptotic death. Using the trimethyltin model of hippocampal neurodegeneration, mice expressing the human mutPS-1 gene (M146L) exhibited increased neurodegeneration and mortality relative to non-transgenic littermates. Activation of NF-kappaB p50 was found to be impaired in transgenic mice with unaltered expression levels suggesting that mutPS-1 expression inhibits p50 activation to adversely affect neuronal resistance to injury.

Behavioural surveillance programmes have enabled the description of population patterns of risk behaviours for STI and HIV transmission and aid in the understanding of how epidemics of STI are generated. They have been instrumental in helping to refine public health interventions and inform the targeting of sexual health promotion and disease control strategies. The formalization and coordination of behavioural surveillance in England and Wales could optimise our ability to measure the impact of interventions and health promotion strategies on behaviour. This will be particularly useful for monitoring the progress towards specific disease control targets set in the Department of Health's new Sexual Health and HIV Strategy.

In humans, the progression to cocaine addiction presumably involves increases in the effectiveness of cocaine to function as a reinforcer. Here we use breakpoints assessed using the progressive ratio (PR) schedule as an index of the efficacy of cocaine as a reinforcer. To date, no preclinical studies have demonstrated an increase in breakpoint as a consequence of self-administration history. In the current study, baseline performances on fixed ratio (FR) and PR schedules were determined. Rats were then exposed to different self-administration histories and deprivation periods, and responding under FR and PR schedules was reassessed. Exposure to a discrete-trials procedure (access to cocaine 4 times/hour, 24 hours/day; DT4) for 7 or 10 days, coupled with a deprivation period of 7 days, resulted in increases in breakpoint on a PR schedule, with no change in FR1 schedule responding. Exposure to an FR1 schedule for 72 consecutive hours followed by 7 days of deprivation, failed to change breakpoints, but increased rates of intake assessed with an FR1 schedule. Thus, the type of self-administration history and the length of deprivation experienced contribute to changes in the reinforcing efficacy of cocaine as measured by a PR schedule.

We report a de novo, apparently balanced (2;8)(q35;q21.2) translocation in a boy with developmental delay and autism. Cross species (colour) paint (Rx) and SKY FISH, forward and reverse chromosome painting, and FISH with subtelomeric probes were used to examine the patient's karyotype, but further rearrangements were not detected. FISH with region specific clones mapping near 2q35 and 8q21.2 breakpoints and STS mapping performed on the isolated derivative chromosomes were used to refine the location of the breakpoints further. A cryptic deletion of between 4.23 and 4.41 Mb in extent and involving at least 13 complete genes or transcription units was found at the breakpoint on 2q35. The deletion includes the promoter and 5' untranslated region of the paired box 3 (PAX3) gene. The child has very mild dystopia canthorum which may be associated with the PAX3 haploinsufficiency. The 8q21.2 breakpoint is within MMP16 which encodes matrix metalloproteinase 16. We postulate that the cryptic deletion and rearrangement are responsible for the patient's phenotype and that a gene (or genes) responsible for autism lies at 2q35 or 8q21.2. The results present a step towards identifying genes predisposing to autism.

The paper applies artificial neural networks (ANNs) to the analysis of heart sound abnormalities through auscultation. Audio auscultation samples of 16 different coronary abnormalities were collected. Data pre-processing included down-sampling of the auscultated data and use of the fast Fourier transform (FFT) and the Levinson-Durbin autoregression algorithms for feature extraction and efficient data encoding. These data were used in the training of a multi-layer perceptron (MLP) and radial basis function (RBF) neural network to develop a classification mechanism capable of distinguishing between different heart sound abnormalities. The MLP and RBF networks attained classification accuracies of 84% and 88%, respectively. The application of ANNs to the analysis of respiratory auscultation and consequently the development of a combined cardio-respiratory analysis system using auscultated data could lead to faster and more efficient treatment.

Viral haemorrhagic fevers (VHF) have attracted the attention of the medical world and general public for many reasons, some based in reality and more on misinformation. They are amongst the highest profile infections in the public mind, because they are thought to be highly infectious and to kill most of their victims in a dramatic way (1,2). To add to the intrigue, mysteries remain about the source of some of the viruses involved. They emerge and re-emerge in many countries, most recently Ebola in Uganda in 2000 (3) and Gabon in 2001/02 (4), and Congo Crimean Haemorrhagic Fever (CCHF) in Kosovo (5) and Pakistan in 2001 (6). Large outbreaks have affected populations in endemic areas, living mainly in inaccessible areas or refugee camps where living conditions are very difficult. Poorly resourced medical facilities have played a role in amplifying transmission and infection control measures have been difficult or virtually impossible to establish. These viruses are likely to remain a threat until the reservoir is identified and as long as endemic areas are afflicted with ecological change, poverty and social instability. Recent events since September 11 2001 remind us of their potential to be used as weapons, and that fear can present a risk to public health.

In the UK, suspected and confirmed cases of viral haemorrhagic fever are currently managed according to the 1996 Guidance of the Advisory Committee on Dangerous Pathogens, which describes an approach to the risk categorisation of suspected cases. It also provides guidance on patient management including transfer, laboratory investigations, infection control, and monitoring of contacts based on the risk assessment. Confirmed cases are managed in bed isolators ("Trexler units"), two of which are available in high security infectious disease units in the UK. This guidance is under review and may change. Recent experience has shown that communication and reassurance for health care workers and the public are major tasks in managing such cases.

Osteogenic proteins (OPs), also referred to as bone morphogenetic proteins (BMPs), are a family of bone matrix polypeptides that induce a sequence of cellular events that lead to the formation of new bone. This article reports the use of recombinant human OP-1 (rhOP-1, rhBMP-7) in preclinical animal models and initial human clinical experience in hip reconstructive surgery. The use of rhOP-1 in conjunction with morcellized cancellous bone and cortical strut allograft in preclinical models dramatically improved the biologic activity of the graft, resulting in greater and earlier new bone formation and graft incorporation. The clinical use of rhOP-1 in hip reconstructive procedures also resulted in greater and earlier new bone formation in the more challenging biologic environment compared with allograft bone alone.

Modification of the P(1)' substituent of macrocyclic matrix metalloproteinase (MMP) inhibitors provided compounds that are selective for inhibition of tumor necrosis factor-alpha converting enzyme (TACE) over MMP-1 and MMP-2. Several analogues potently inhibited the release of TNF-alpha in a THP-1 cellular assay. Compounds containing a trimethoxyphenyl group in the P(1)' substituent demonstrated TACE selectivity across several series of hydroxamate-based inhibitors.

Sclerosing mesenteritis is an uncommon benign condition that should be included in the differential diagnosis of abdominal masses. We present the first reported case of this condition in association with idiopathic bile duct fibrosis simulating Klatskin's tumor. A review of the literature regarding both clinical entities is presented.

Long-term vaccinations with human beta-amyloid peptide 1-42 (Abeta1-42) have recently been shown to prevent or markedly reduce Abeta deposition in the PDAPP transgenic model of Alzheimer's disease (AD). Using a similar protocol to vaccinate 7.5-month-old APP (Tg2576) and APP+PS1 transgenic mice over an 8-month period, we previously reported modest reductions in brain Abeta deposition at 16 months. In these same mice, Abeta vaccinations had no deleterious behavioral effects and, in fact, benefited the mice by providing partial protection from age-related deficits in spatial working memory in the radial arm water maze task (RAWM) at 15.5 months. By contrast, control-vaccinated transgenic mice exhibited impaired performance throughout the entire RAWM test period at 15.5 months. The present study expands on our initial report by presenting additional behavioral results following long-term Abeta vaccination, as well as correlational analyses between cognitive performance and Abeta deposition in vaccinated animals. We report that 8 months of Abeta vaccinations did not reverse an early-onset balance beam impairment in transgenic mice. Additionally, in Y-maze testing at 16 months, all mice showed comparable spontaneous alternation irrespective of genotype or vaccination status. Strong correlations were nonetheless present between RAWM performance and extent of "compact" Abeta deposition in both the hippocampus and the frontal cortex of vaccinated APP+PS1 mice. Our results suggest that the behavioral protection of long-term Abeta vaccinations is task specific, with preservation of hippocampal-associated working memory tasks most likely to occur. In view of the early short-term memory deficits exhibited by AD patients, Abeta vaccination of presymptomatic AD patients could be an effective therapeutic to protect against such cognitive impairments.

The experience of autumn 2001, when anthrax spores were released in the postal system, had considerable consequences in the United States and in Europe. The threat of covert deliberate releases against civilians has become a reality. In Europe, despite the growing number of criminal hoaxes, no cases of anthrax linked to deliberate releases have been reported, and the only contaminated letters were addressed to American embassies abroad. Nevertheless, the time has come for Europe to set up efficient and timely plans to respond to bioterrorism, under the coordination of the European Commission.

Multiple lines of evidence indicate that inflammatory processes are involved in the pathogenesis of Alzheimer's disease. Lipopolysaccharide (LPS) is widely used to induce inflammation in experimental systems. Consequently we injected LPS or saline intrahippocampally in 11 and 16 months old APP+PS1 transgenic mice to induce brain inflammation, then used immunocytochemistry to examine amyloid pathology 7 days later. As expected, LPS activated microglia as indicated by a significant increase in the area covered by major histocompatibility complex-II (MHC-II) immunostaining in the mice injected with LPS compared to the saline injected. Simultaneously, Abeta immunostaining showed an unexpected reduction of the Abeta load in the mice injected with LPS compared to the saline injected. This effect of LPS on the Abeta load in APP+PS1 mice strengthens the hypothesis that moderate amounts of microglial activation may be beneficial in Alzheimer's disease, by increasing the clearance of Abeta.

There have been several reports on the use of beta-amyloid (Abeta ) vaccination in different mouse models of Alzheimer's disease (AD) and its effects on pathology and cognitive function. In this report, the histopathologic findings in the APP+PS1 doubly transgenic mouse were compared after three, five, or nine Abeta inoculations. The number of inoculations influenced the effects of vaccination on Congo red levels, microglia activation, and anti-Abeta antibody titers. After three inoculations, the antibody titer of transgenic mice was substantially lower than that found in nontransgenic animals. However, after nine inoculations, the levels were considerably higher in both genotypes and no longer distinguishable statistically. The number of inoculations influenced CD45 expression, an indicator of microglial activation. There was an initial upregulation, which was significant after five inoculations, but by nine inoculations, the extent of microglial activation was equivalent to that in mice given control vaccinations. Along with this increased CD45 expression, there was a correlative reduction in staining by Congo red, which stains compact plaques. When data from the mice from all groups were combined, there was a significant correlation between activation of microglia and Congo red levels, suggesting that microglia play a role in the clearance of compact plaque.

Arterial compliance measurements using intraarterial pulse contour analysis and a modified Windkessel model were carried out in 19 patients with isolated systolic hypertension (> or = 160/< or = 90 mm Hg) and compared to measurements in 29 patients with essential hypertension (diastolic blood pressure [BP] > or = 95 mm Hg) and 47 normotensive control subjects. Arterial capacitive compliance was significantly lower in isolated systolic hypertension than in essential hypertension (P < .0002) and significantly lower in essential hypertension than in normotensive control subjects (P < .0001). Although the isolated systolic hypertension group was older than the essential hypertension group, the reduction of capacitive compliance in isolated systolic hypertension persisted even when comparison was made with a more nearly age-matched group of essential hypertension. In contrast, oscillatory compliance was reduced similarly in isolated systolic hypertension and essential hypertension compared to normotensive control subjects (P < .0001). Although pulse pressure was greater in isolated systolic hypertension than in essential hypertension, only a weak correlation (r = -0.34) existed between pulse pressure and capacitive compliance. These data indicate that both essential hypertension and isolated systolic hypertension patients exhibit comparably abnormal structure or tone of the small vessels that are the site of oscillations or reflections in the arterial vasculature. In isolated systolic hypertension there is a profound reduction in large artery or capacitive compliance that accounts for the increase in systolic BP and decrease in diastolic BP. This abnormality cannot be accurately assessed by pulse pressure alone.

During the "respiratory burst," the NADPH oxidase complex of phagocytes produces reactive oxygen species that kill bacteria and other invaders (Babior, B. M. (1999) Blood 93, 1464-1476). Electron efflux through NADPH oxidase is electrogenic (Henderson, L. M., Chappell, J. B., and Jones, O. T. G. (1987) Biochem. J. 246, 325-329) and is compensated by H(+) efflux through proton channels that reportedly are contained within the gp91(phox) subunit of NADPH oxidase. To test whether gp91(phox) functions as a proton channel, we studied H(+) currents in granulocytes from X-linked chronic granulomatous disease patients lacking gp91(phox) (X-CGD), the human myelocytic PLB-985 cell line, PLB-985 cells in which gp91(phox) was knocked out by gene targeting (PLB(KO)), and PLB-985 knockout cells re-transfected with gp91(phox) (PLB(91)). H(+) currents in unstimulated PLB(KO) cells had amplitude and gating kinetics similar to PLB(91) cells. Furthermore, stimulation with the phorbol ester phorbol 12-myristate 13-acetate increased H(+) currents to a similar extent in X-CGD, PLB(KO), and PLB(91) cells. Thus, gp91(phox) is not the proton channel in unstimulated phagocytes and does not directly mediate the increase of proton conductance during the respiratory burst. Changes in H(+) channel gating kinetics during NADPH oxidase activity are likely crucial to the activation of H(+) flux during the respiratory burst.

To determine the prevalence and correlates of left ventricular systolic dysfunction in hypertensive patients in a biracial population-based sample, clinical evaluation and echocardiography were performed in 2086 participants in the Hypertension Genetic Epidemiology Network (HyperGEN) examination; 86% had normal ejection fraction (>54%), 10% had mild ventricular dysfunction (ejection fraction 41% to 54%), and 4% had severe ventricular dysfunction (ejection fraction

It is difficult to assess the proportion of individuals who experience an acute seroconversion illness after infection with HIV-1. We found that five out of 27 recent HIV-1 seroconverters (18.5%) in a population-based cohort in rural Uganda and four out of 22 HIV-negative controls (18.2%) reported a flu-like illness. More symptoms were reported by seroconverters, but the duration of illness was similar in both groups. We found no association between symptoms and infection with HIV-1 subtype A or D.

Background: Genital ulcer disease (GUD) is documented as a significant risk factor for HIV acquisition. Its prompt recognition and effective treatment are important components of HIV control in sub-Saharan Africa., Goals: To determine the rate and risk factors for GUD, and to describe sexual and treatment-seeking behavior., Study Design: A longitudinal follow-up study of 525 individuals, both those infected with HIV and those uninfected, was conducted in a population-based, clinical cohort over 9 years., Results: The rate of GUD in this population was 16/100 person years, and 30% of the participants reported an episode during the follow-up period. The rates were almost four times higher in participants infected with HIV than in those who were HIV-negative. Half of the participants with a regular sexual partner reported engaging in sex while symptomatic, and only 16% informed their partner. Treatment was sought for only 12% of the genital ulcer disease episodes, despite open access to doctors at a free clinic. A self-diagnosis of genital herpes did not affect treatment-seeking or sexual behavior., Conclusions: Genital ulcer disease is very common in this rural population, especially among those infected with HIV. Few seek treatment, and many continue sexual activity despite symptoms without informing their partners. The implications of these findings for HIV control are a cause for concern.

Cholinergic basal forebrain (CBF) projection systems are defective in late Alzheimer's disease (AD). We examined the brains of 12-month-old singly and doubly transgenic mice overexpressing mutant amyloid precursor protein (APP(swe)) and/or presenilin-1 (PS1(M146L)) to investigate the effects of these AD-related genes on plaque and tangle pathology, astrocytic expression, and the CBF projection system. Two types of beta-amyloid (Abeta)-immunoreactive (ir) plaques were observed: type 1 were darkly stained oval and elongated deposits of Abeta, and type 2 were diffuse plaques containing amyloid fibrils. APP(swe) and PS1(M146L) mouse brains contained some type 1 plaques, while the doubly transgenic (APP(swe)/PS1(M146L)) mice displayed a greater abundance of types 1 and 2 plaques. Sections immunostained for the p75 NGF receptor (p75(NTR)) revealed circular patches scattered throughout the cortex and hippocampus of the APP(swe)/PS1(M146L) mice that contained Abeta, were innervated by p75(NTR)-ir neurites, but displayed virtually no immunopositive neurons. Tau pathology was not seen in any transgenic genotype, although a massive glial response occurred in the APP(swe)/PS1(M146L) mice associated with amyloid plaques. Stereology revealed a significant increase in p75(NTR)-ir medial septal neurons in the APP(swe) and PS1(M146L) singly transgenic mice compared to the APP(swe)/PS1(M146L) mice. No differences in size or optical density of p75(NTR)-ir neurons were observed in these three mutants. p75(NTR)-ir fibers in hippocampus and cortex were more pronounced in the APP(swe) and PS1(M146L) mice, while the APP(swe)/PS1(M146L) mice showed the least p75(NTR)-ir fiber staining. These findings suggest a neurotrophic role for mutant APP and PS1 upon cholinergic hippocampal projection neurons at 12 months of age., (Copyright 2001 Academic Press.)

The suitability of ten diets for the development and reproduction of Franklinothrips orizabensis Johansen, the key natural enemy of Scirtothrips perseae Nakahara, a pest of California grown avocados, was determined in the laboratory. The experimental diets evaluated were: (i) irradiated Ephestia kuehniella Zeller eggs; (ii) irradiated E. kuehniella eggs and avocado pollen; (iii) Tetranychus pacificus McGregor eggs; (iv) T. pacificus eggs and avocado pollen; (v) irradiated E. kuehniella eggs and T. pacificus eggs; (vi) irradiated E. kuehniella eggs, T. pacificus eggs and avocado pollen; (vii) Scirtothrips perseae; (viii) Heliothrips haemorrhoidalis (Bouchè); (ix) avocado pollen; and (x) a young avocado leaf. Franklinothrips orizabensis larvae were unable to develop to adulthood on diets 9 and 10. The remaining eight diets supported complete development of F. orizabensis, but only diets 1, 2, 5, 6, 7 and 8 produced fecund females. On diet 5, F. orizabensis exhibited high larval to adult survivorship (90%), mated females exhibited highest daily and lifetime fecundity, and the progeny of mated females were female biased (53%). Analysis of jackknife estimates of net reproduction (Ro), intrinsic rate of increase (rm), and finite rate of increase (lambda) were all significantly greater for F. orizabensis reared on irradiated E. kuehniella eggs and T. pacificus eggs (i.e. diet 5) than corresponding values for other diets on which female F. orizabensis were able to complete development and reproduce. Incorporation of avocado pollen into diets had an adverse effect on demographic statistics for F. orizabensis, and low quality diets resulted in male biased sex ratios for this predator.

Partial opioid agonists can produce their actions at opioid as well as some non-opioid sites. Although the receptor systems underlying these non-opioid effects are not completely clear, recent studies indicate the possible involvement of activity at the dopamine uptake site. One purpose of the present investigation was to examine the ability of selected partial opioid agonists (dezocine, meperidine and [+]-propoxyphene) with non-opioid actions to produce cocaine-like stimulus effects. Because non-opioid effects can be apparent under conditions in which opioid-mediated effects are blocked or at doses that markedly decrease responding, these opioids were also examined in combination with the opioid antagonist naltrexone. A second purpose was to determine the ability of these opioids to inhibit [3H]dopamine uptake in rat caudate putamen. Cocaine and the direct-acting dopamine agonist (-)-quinpirole, but not (+)-propoxyphene, butorphanol, morphine, U50,488 and pentobarbital, substituted completely for the cocaine stimulus. Dezocine substituted for the cocaine stimulus in the majority of the rats tested only when administered in combination with naltrexone. Meperidine also substituted for the cocaine stimulus in the majority of the rats tested, although this pattern of substitution was not consistently altered by naltrexone. Dezocine and meperidine inhibited [3H]dopamine uptake in a manner consistent with that produced by cocaine. The results suggest that dezocine and meperidine can produce cocaine-like stimulus effects and that these effects are likely mediated by activity at the dopamine uptake site.

Doubly transgenic mAPP+mPS1 mice (15-16 months) had impaired cognitive function in a spatial learning and memory task that combined features of a water maze and a radial arm maze. Nontransgenic mice learned a new platform location each day during 4 consecutive acquisition trials, and exhibited memory for this location in a retention trial administered 30 min later. In contrast, transgenic mice were, on average, unable to improve their performance in finding the hidden platform over trials. The cognitive performance of individual mice within the transgenic group were inversely related to the amount of Abeta deposited in the frontal cortex and hippocampus. These findings imply that mAPP+mPS1 transgenic mice develop deficits in cognitive ability as Abeta deposits increase. These data argue that radial arm water maze testing of doubly transgenic mice may be a useful behavioral endpoint in evaluating the functional consequences of potential AD therapies, especially those designed to reduce Abeta load.

Although punishment contingencies are widely used with human drug users, basic research on the effectiveness of these procedures is limited. The present study evaluated the effects of a negative punishment contingency, response-contingent timeout (TO) presentation, on cocaine-maintained responding. Rhesus monkeys were trained under a multiple fixed-interval (FI) 5-min cocaine, conjoint FI 5-min cocaine, variable-interval (VI) 30-sec TO schedule. TO values were either 0 (baseline), 10, 30, or 60s in length. During the TO periods, the FI clock continued to operate but the discriminative stimuli signaling cocaine availability were removed, and responding had no scheduled consequence. Cocaine maintained responding in all monkeys and the dose-effect curve was characterized as an inverted U-shaped function. The response-contingent TO presentations reduced response rates maintained by cocaine in all monkeys compared to baseline. The magnitude of the reduction in response rates was not a function of the length of the TO period (i.e. intensity of the punisher), and the punishment effect was enhanced by increases in cocaine dose. When responding was punished, response rates in the unpunished components either also decreased (i.e. response induction; approximately 30% of the cases) or were not affected (approximately 60%). These results demonstrate that cocaine-maintained behavior can be decreased by environmental manipulations involving negative punishment contingencies.

Between September 1986 and June 1998, 32 patients with relapsed or refractory intermediate or high grade lymphoma received intensified preparative therapy and underwent allogeneic transplantation at a single institution. Patients were considered for allogeneic transplantation if they failed to respond to initial therapy, failed to respond to salvage therapy, relapsed after autologous transplantation, had bone marrow involvement, or failed attempts to harvest autologous stem cells. Patients had a median age of 39 years and had generally received at least two chemotherapy regimens. Five year actuarial survival (S) was 16% +/- 6%; median survival was 4 months. Survival was significantly worse in patients who had received high intensity brief duration chemotherapy prior to transplantation and was also significantly worse in patients who did not receive total body irradiation (TBI). This likely reflects the fact that the patients with the most resistant disease had required local radiotherapy and could not receive TBI. While treatment related mortality played a major role in limiting the effectiveness of allogeneic transplantation, in this heavily pre-treated population of patients with resistant disease, only 39% of patients achieved a complete response following allogeneic transplantation, and in only 40% of that group was long term disease free survival achieved.

Nicotine is known to modulate immune function, but reports have produced conflicting evidence as to whether nicotinic acetylcholine (nACh) receptors are responsible for these effects. This study was designed to examine the identity of nicotine-binding sites on immune cells using a human leukaemic monocytic cell line, THP-1, that is known to have functions that are modulated by nicotine. Binding studies were performed on THP-1 whole cells using [3H]nicotine as a probe to analyse any possible nicotine-binding sites on these cells. Saturation analysis of THP-1 cells revealed the presence of 2 distinct binding sites; one with a K(d1) of 3.5 +/- 2.1 x 10(-9) M and a B(max1) of 4100 +/- 560 sites/cell (designated the high-affinity site) and the other with a K(d2) of 27 +/- 9.2 x 10(-9) M and a B(max2) of 11,600 +/- 630 sites/cell (low-affinity site). Competition analysis revealed that one site had an affinity to a range of cholinergic ligands including epibatidine and cytisine. When saturation analysis of [3H](-)-nicotine to THP-1 cells was performed in the presence of 1 x 10(-6) M epibatidine, only one binding site was detected. Comparisons of K(d) and B(max) values showed that the high-affinity site was not occluded by epibatidine. No drugs tested displayed any affinity for the high-affinity site except the two enantiomers of nicotine. The high-affinity site was shown to be stereoselective for the (+)-enantiomer of nicotine as shown by K(i) values produced by competition analysis in the presence of 1 x 10(-6) M epibatidine. These values were 5.7 +/- 0.32 x 10(-11) M and 1.9 +/- 4.9 x 10(-9) M for (+)-nicotine and (-)-nicotine, respectively. This study presents evidence for a possible non-cholinergic binding site that may play a role in the mechanism of immunomodulation by nicotine.

Apolipoprotein E (apoE) is a 299 amino acid protein that is associated with risk of developing Alzheimer's Disease (AD) and outcome after acute brain injury. To investigate the possibility that apoE modulates glial activation we studied the effect of endogenous apoE on inflammatory gene regulation in vitro and in vivo. Our results indicate that apoE downregulates CNS production of TNFalpha, Il-1beta, and Il-6 mRNA following stimulation with lipopolysaccharide (LPS). This effect of endogenous apoE on inflammatory gene regulation appears to be specific, and may account for the biological role that apoE plays in acute and chronic human neurological disease.

Alpha(1)-antichymotrypsin (ACT), an acute-phase inflammatory protein, is an integral component of the amyloid deposits in Alzheimer's disease (AD) and has been shown to catalyze amyloid beta-peptide polymerization in vitro. We have investigated the impact of ACT on amyloid deposition in vivo by generating transgenic GFAP-ACT-expressing mice and crossing them with the PDGF-hAPP/V717F mice, which deposit amyloid in an age-dependent manner. The number of amyloid deposits measured by Congo Red birefringence was increased in the double ACT/amyloid precursor protein (APP) transgenic mice compared with transgenic mice that only expressed APP, particularly in the hippocampus where ACT expression was highest, and the increase was preceded by elevated total amyloid beta-peptide levels at an early age. Our data demonstrate that ACT promotes amyloid deposition and provide a specific mechanism by which inflammation and the subsequent upregulation of astrocytic ACT expression in AD brain contributes to AD pathogenesis.

Background: The state of California, like every other state, has no system for assessing the quality of prehospital emergency medical services (EMS) care. As part of a statewide project, a process was designed for the evaluation and quality improvement (QI) of EMS in California. Local EMS agency (LEMSA) representatives made a commitment to submit data from both the providers and the hospitals they work with., Indicator Selection and Development: For conditions such as cardiac chest complaints, standardized indicators had already been developed, but for many other areas of interest there was either little literature or little consensus in the literature. Definitional differences were often linked to local-practice protocol differences. A related comparison challenge lay in the fact that care protocols may differ across systems. Some aspects of care may not be offered at all, which may reflect resource shortages or variable medical direction., Data Collection Procedures: Each indicator was precisely defined, and definition sheets and data troubleshooting report forms were provided to participants in three data-collection rounds. Participants were given 1 month to collect the data, which consisted of summary-level elements (for example, average time to defibrillation for all patients 15 years or older who received defibrillation in 1998). Data were then aggregated, analyzed, and prepared for display in graphs and tables., Access and Measurement Issues: Numerous data collection problems were encountered. For example, not all participants could actually access data that they thought would be available. Linking data on patients as they travel through the continuum of EMS care (dispatch, field, hospital) and linking EMS data to hospital outcomes was also difficult. Yet even when data were easily available, challenges arose. The need for specificity, the potential misfit between definitions and the available data, and the challenges of data retrieval remained salient for the duration of the project and made cross-LEMSA and cross-provider comparison problematic., Recommendations and Lessons Learned: The project led to formal policy recommendations regarding development of a state-defined minimum data set of structure, process, and outcome indicators and their associated data elements; provision in the minimum data set for both local-level and statewide indicators; and provision of technical assistance at the local-provider level., Epilogue: Since the project's conclusion in June 2000, many regional and local EMS groups have begun to collect data on indicators. Many of the project's recommendations have been incorporated into the work plan of the state's System Review and Data Committee.

Objective: To investigate the role of HIV-1 envelope subtypes on disease progression in a rural cohort of Ugandan adults where two major HIV-1 subtypes (A and D) exist., Methods: Participants of a clinical cohort seen between December 1995 and December 1998 had blood collected for HIV-1 subtyping. These included prevalent cases (people already infected with HIV at the start of the study in 1990) and incident cases (those who seroconverted between 1990 and December 1998). HIV-1 subtyping was carried out by heteroduplex mobility assay and DNA sequencing in the V3 env region. Disease progression was measured by the rate of CD4 lymphocyte count decline, clinical progression for the incident cases as time from seroconversion to AIDS or death, to first CD4 lymphocyte count < 200 x 10(6)/l and to the World Health Organization clinical stage 3. All analyses were adjusted for age and sex., Results: One hundred and sixty-four individuals, including 47 prevalent and 117 incident cases, had V3 env subtype data of which 65 (40%) were subtyped as A and 99 as D. In the incident cases, 44 (38%) were subtyped as A and 73 as D. There was a suggestion that for most end-points A had a slower progression than D. The cumulative probability of remaining free from AIDS or death at 6 years post-seroconversion was 0.72 [95% confidence interval (CI), 0.50 to 0.85] for A and 0.58 (95% CI, 0.42 to 0.71) for D, and the adjusted hazard ratio of subtype D compared to A was estimated to be 1.39 (95% CI, 0.66 to 2.94; P = 0.39). The estimated difference in rates of decline in square root CD4 lymphocyte counts was -0.41 per year (95% CI, -0.98 to 0.15; P = 0.15)., Conclusion: This study suggests that although subtype A may have a slower progression than D, HIV-1 envelope subtype is not a major factor in determining the progression of HIV-1 disease in a rural population in Uganda.