Is routine pre-entry chest radiograph necessary in a high tuberculosis prevalence country?

CONTEXT: Chest radiographs have been used worldwide as a screening tool before employment and training, by various healthcare and other government and nongovernment institutions. Many studies done in the past have demonstrated a relatively low yield for tuberculosis detection and therefore, the authors have questioned this practice. AIMS: To compare the value of the preadmission/employment chest radiograph in two groups, namely, those who have been previously exposed to a healthcare setting (post-exposure group) and those who have not been exposed (pre-exposure group) and to determine if there is a significant difference in tuberculosis detection between these two groups. SETTINGS AND DESIGN: A retrospective review of the reports of the chest radiographs of all candidates appearing for admission to various undergraduate and postgraduate courses in our institute between 2014 and 2017 was performed. MATERIALS AND METHODS: The various abnormalities detected were recorded and the findings in the two groups were compared. STATISTICAL ANALYSIS USED: Chi-square test was used to compare between two group proportions. RESULTS: Thirty out of 4333 (0.69%) candidates in the pre-exposure group and 53 out of 3379 (1.57%) candidates in the post-exposure group showed abnormalities on chest radiographs involving the lung parenchyma, mediastinum, heart, or pleura. In the pre-exposure group, six (0.14%) were found to have underlying cardiac disease and one (0.02%) had tuberculosis. Among the six candidates in the post-exposure group who underwent further investigations in our institute, five (0.15%) were diagnosed to have tuberculosis. Although there was no statistically significant difference in tuberculosis detection between the groups (P = 0.051), there is a trend towards higher detection of tuberculosis in the post-exposure group. CONCLUSIONS: In a country where the prevalence of tuberculosis is high, the pre-employment chest radiograph may still have a role in detecting tuberculosis in the post-exposure group.

High resolution approaches for the identification of amyloid fragments in brain.

BACKGROUND: It is now widely recognized that endogenous, picomolar concentrations of the 42 amino acid long peptide, amyloid-ß (Aß42) is secreted under normal physiological conditions and exerts important functional activity throughout neuronal intracellular compartments. Transgenic animal models that overexpress Aß42 and its precursor, amyloid precursor protein (APP), have not provided predictive value in testing new treatments for Alzheimer's disease (AD), resulting in failed clinical trials. While these results are discouraging, they underscore the need to understand the physiological roles of Aß42 and APP under normal conditions as well as at early pre- symptomatic stages of AD. New method: We describe the use of acrolein-perfusion in immunoelectron microscopy in combination with novel antibodies directed against endogenous murine Aß42 and APP fragments to study abnormalities in the endolysosomal system at early stages of disease. The specific requirements, limitations and advantages of novel antibodies directed against human and murine Aß42, APP and APP fragments are discussed as well as parameters for ultrastructural analysis of endolysosomal compartments. RESULTS: Novel antibodies and a detailed protocol for immunoelectron microscopy using acrolein as a fixative are described. Acrolein is shown to preserve intraneuronal Aß42 species, as opposed to paraformaldehyde fixed tissue, which primarily preserves membrane bound species. Comparison with existing method(s): Technology sensitive enough to detect endogenous Aß42 under physiological conditions has not been widely available. We describe a number of novel and highly sensitive antibodies have recently been developed that may facilitate the analysis of endogenous Aß42. CONCLUSIONS: Using novel and highly specific antibodies in combination with electron microscopy may reveal important information about the timing of aberrant protein accumulation, as well as the progression of abnormalities in the endolysosomal systems that sort and clear these peptides.

Outbreak of Notozothecium bethae (Monogenea: Dactylogyridae) in Myleus schomburgkii (Actinopterygii: Characiformes) cultured in the Peruvian Amazon.

The presence of Notozothecium bethae was investigated in 76 black band myleus (Myleus schomburgkii [Actinopterygii: Charasiformes]) born and kept in captivity in two semi-intensive breeding cages in the northern region of Peru. Among the 76 cultivated specimens of M. schomburgkii examined in the present study, 100 % had monogenean on the gill and the parasites were identified as Notozothecium bethae. During the survey no bacteria was isolated, and no protozoan or other metazoan parasites were found. The prevalence of N. bethae remained constant throughout the present study. Mean intensity of N. bethae in the months of April and May was exceptionally high in both facilities. The massive infection of N. bethae on the gills of M. schomburgkii was associated with mortality. This is the first report of N. bethae in M. schomburgkii born in captivity and cultured in the Amazon region. The mortality due the presence of this parasite emphasise the need for disease control strategies of cultured M. schomburgkii.

Synergistic effects of A1896, T1653 and T1762/A1764 mutations in genotype c2 hepatitis B virus on development of hepatocellular carcinoma.

The effects of genomic changes in hepatitis B virus (HBV) on the occurrence of hepatocellular carcinoma (HCC) are still unclear, especially in relation to the genotype of HBV. In this study, we examined the effects of genomic changes in HBV of genotype C2 on the development of HCC. A total of 318 patients with HBV-associated HCC and 234 patients with chronic hepatitis B (CHB) were studied. All of HCC cases were diagnosed histologically and treated with surgical resection. The whole of the X, S, basal core promoter (BCP) and precore regions of the viral genome from sera or liver tissues were sequenced. All subjects had HBV of genotype C2. The prevalence of the T1653 mutation in the X region and the A1896 mutation in the precore region of HBV was significantly higher in the HCC group than in the control CHB group (22% vs 11%, P = 0.003; 50% vs 23%, P < 0.001, respectively). Moreover, the T1762/A1764 mutations in the BCP region in combination with either T1653 or A1896 were more common in the HCC compared with the CHB group (BCP+X1653: 18% vs 11%, P = 0.05; BCP+PC, 40% vs 15%, P < 0.001, respectively). In multivariate analysis, T1653 and A1896 were revealed to be independent risk factors for HCC development. G1896A in the precore region and C1653T mutation in the X region of genotype C2 HBV are important risk factors for HCC development. Also, the A1762T/G1764A double mutation may act in synergy with C1653T to increase the risk of HCC in patients chronically infected with HBV genotype C2.

Does solid culture for tuberculosis influence clinical decision making in India?

SETTING: Medical units at an academic tertiary referral hospital in Southern India. OBJECTIVE: To investigate the impact of solid culture on Löwenstein-Jensen medium on clinical decision making. DESIGN: In a retrospective review of 150 culture-positive and 150 culture-negative consecutively sampled tuberculosis (TB) suspects, treatment decisions were analysed at presentation, after the availability of culture detection results and after the availability of drug susceptibility testing (DST) culture results. RESULTS: A total of 124 (82.7%) culture-positive patients and 35 (23.3%) culture-negative patients started anti-tuberculosis treatment prior to receiving their culture results; 101 patients (33.7%) returned for their results; two (1.3%) initiated treatment based on positive culture and no culture-negative patients discontinued treatment. DST was performed on 119 (79.3%) positive cultures: 30 (25.2%) showed any resistance, eight (6.7%) showed multidrug resistance and one (0.84%) showed extensively drug-resistant TB. Twenty-eight patients (23.5%) returned for their DST results. Based on DST, treatment was modified in four patients (3.4%). CONCLUSION: Using solid culture, 150 cultures need to be tested for one treatment modification and 30 for DST. The cost of the widespread application of culture will need to be balanced against its impact on treatment decisions in India.

BACE (beta-secretase) modulates the processing of APLP2 in vivo.

BACE is an aspartyl protease that cleaves the amyloid precursor protein (APP) at the beta-secretase cleavage site and is involved in Alzheimer's disease. The aim of our study was to determine whether BACE affects the processing of the APP homolog APLP2. To this end, we developed BACE knockout mice with a targeted insertion of the gene for beta-galactosidase. BACE appeared to be exclusively expressed in neurons as determined by differential staining. BACE was expressed in specific areas in the cortex, hippocampus, cerebellum, pons, and spinal cord. APP processing was altered in the BACE knockouts with Abeta levels decreasing. The levels of APLP2 proteolytic products were decreased in BACE KO mice, but increased in BACE transgenic mice. Overexpression of BACE in cultured cells led to increased APLP2 processing. Our results strongly suggest that BACE is a neuronal protein that modulates the processing of both APP and APLP2.

Baculoviruses expressing the human familial Alzheimer's disease presenilin 1 mutation lacking exon 9 increase levels of an amyloid beta-like protein in Sf9 cells.

Presenilin 1 (PS1) plays a pivotal role in the production of the amyloid-beta protein (Abeta) that is central to the pathogenesis of Alzheimer's disease. PS1 regulates the intramembranous proteolysis of a 99-amino-acid C-terminal fragment of the amyloid precursor protein (APP-C99), a cleavage event that releases Abeta following a reaction catalyzed by an enzyme termed 'gamma-secretase'. The molecular mechanism of PS1-mediated, gamma-secretase cleavage remains largely unresolved. In particular, controversy surrounds whether PS1 includes the catalytic site of the gamma-secretase protease or whether instead PS1 mediates gamma-secretase activity indirectly, perhaps by regulating the trafficking or presentation of substrates to the 'authentic' protease, which may be a molecule distinct from PS1. To address this issue, the baculovirus expression system was used to co-express: (i) APP-C99; (ii) a pathogenic, constitutively active mutant form of PS1 lacking exon 9 (PS1DeltaE9); (iii) nicastrin and (iv) tropomyosin in Spodoptera frugiperda (Sf9) cells. Cells infected with APP-C99 alone produced an Abeta-like species, and levels of this species were enhanced by the addition of baculoviruses bearing the PS1DeltaE9 mutation. The addition to APP-C99-infected cells of baculoviruses bearing nicastrin, also a transmembrane protein, had a neutral or inhibitory effect on the reaction; tropomyosin viruses had the same effect as nicastrin viruses. These results suggest that PS1DeltaE9 molecules expressed in Sf9 cells retain the ability to modulate Abeta levels. Baculoviral-expressed PS1DeltaE9 provides a source of microgram quantities of bioactive molecules for use as starting material for purifying and reconstituting gamma-secretase activity from its individual purified component parts.

Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP.

Presenilin 1-null mice die at birth from brain and skeletal developmental deformities due to disrupted Notch signaling. Presenilin 1-null mice also have severely reduced gamma-secretase cleavage of betaAPP. The assumption has been that facilitation of Notch signaling and betaAPP processing by presenilin 1 are analogous functions. Here we describe a presenilin 1-targetted mouse model that expresses extremely low levels ( approximately 1% of normal) of mutant PS1-M146L. Homozygous mice have significantly reduced viability due to a Notch-like phenotype. The animals that survive have severe axial skeletal deformities and markedly diminished gamma-secretase activity and accumulation of betaAPP-C100, but no obvious abnormalities in brain development. These results suggest that, in mice, a marked reduction of PS1-facilitated gamma-secretase activity is not detrimental to normal brain development.

Compartment syndrome of the well leg as a result of the hemilithotomy position: a report of two cases and review of literature.

Compartment syndrome in the well leg as a complication of prolonged positioning in a hemilithotomy position is a serious complication that is rarely reported in the orthopaedic literature. A similar entity has been well described in urologic, gynecologic, and general surgery literature but, to the authors' knowledge, has been reported in only seven patients in the orthopaedic literature. The authors report two cases of unilateral compartment syndrome in a well leg during femoral nailing of the contralateral leg. Risk factors, theories of pathogenesis, and preventive measures are identified and discussed.

Hyperleptinemia in pregnant bats is characterized by increased placental leptin secretion in vitro.

Hyperleptinemia is a common feature of pregnancy in mammals. The source of increased plasma leptin is uncertain. We examined leptin secretory rates in vitro to test the hypothesis that leptin secretion is upregulated during pregnancy. Two species of insectivorous bats were examined, Myotis lucifugus and Eptesicus fuscus, because of their unique reproductive cycle. Body mass and plasma leptin significantly increased with gestation and decreased during lactation. Adiposity increased in midgestation, then decreased in late gestation and lactation and was not significantly correlated with plasma leptin in pregnant or early lactating individuals. Leptin secretion in vitro per gram of adipose tissue tended to increase with gestation but was not significantly correlated with plasma leptin in the same individuals. Leptin secretion from placentae, however, increased with gestation and was significantly correlated with plasma leptin from the same individuals. In suckling pups, plasma leptin was high shortly after birth, then decreased to low levels that were not correlated with adiposity thereafter. We conclude that in bats, the placenta is a major source of circulating leptin during pregnancy, and that adiposity and plasma leptin levels are decoupled during three different periods of intense metabolic demand (pregnancy, early lactation, and neonatal growth).

Penile metastasis arising from transitional cell carcinoma of the urinary bladder.

Metastatic spread of transitional cell carcinoma of the bladder to the penis is very rare. We present 1 such case in a 63-year-old man that was treated by total penectomy and adjuvant systemic chemotherapy.

Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease.

BACKGROUND: Mutations in the presenilin proteins cause early-onset, familial Alzheimer's disease (FAD). MATERIALS AND METHODS: We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer's disease (AD). RESULTS: Amino-terminal antibodies to both presenilins predominantly decorated large neurons. Regional differences between the broad distributions of the two presenilins were greatest in the cerebellum, where most Purkinje cells showed high levels of only PS2 immunoreactivity. PS2 endoproteolysis in brain yielded multiple amino-terminal fragments similar in size to the PS1 amino-terminal fragments detected in brain. In addition, two different PS2 amino-terminal antibodies also detected a prominent 42 kDa band that may represent a novel PS2 form in human brain. Similar to PS1 findings, neither amino-terminal nor antiloop PS2 antibodies revealed substantial full-length PS2 in brain. Immunocytochemical examination of brains from individuals with the N141I PS2 mutation or eight different PS1 mutations, spanning the molecule from the second transmembrane domain to the large cytoplasmic loop domain, revealed immunodecoration of no senile plaques and only neurofibrillary tangles in the M139I PS1 mutation stained with PS1 antibodies. CONCLUSIONS: Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenilin FAD cases were similar to control cases and sporadic AD cases. Thus, accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined.

The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review.

A prominent feature of brain pathology in Alzheimer's disease is a robust activation of the neuronal lysosomal system and major cellular pathways converging on the lysosome, namely, endocytosis and autophagy. Recent studies that identify a disturbance of the endocytic pathway as one of the earliest known manifestation of Alzheimer's disease provide insight into how beta-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal dysfunction has historically been linked to neurodegeneration. New data now directly implicate cathepsins as proteases capable of initiating, as well as executing, cell death programs in certain pathologic states. These and other studies support the view that the progressive alterations of lysosomal function observed during aging and Alzheimer's disease contribute importantly to the neurodegenerative process in Alzheimer's disease.

Reducing the risks of ventilator-associated infections.

Mechanically ventilated patients are at high risk for developing nosocomial pneumonia. This article reviews the pathogenesis of ventilator-associated infections and ways nurses can intervene to reduce the risks to patients and to themselves.

Steroid-dependent up-regulation of adipose leptin secretion in vitro during pregnancy in mice.

Circulating leptin levels are elevated during the later stages of pregnancy in mammals, suggesting that maternal leptin may play a role in maintenance of pregnancy and/or preparation for parturition and lactation. The regulation and source of circulating leptin during pregnancy remains undetermined, but leptin mRNA levels increase in adipose tissue during this time in some species. Considerable controversy exists whether placenta is also a leptin-secreting tissue during pregnancy. Here, we directly demonstrate that leptin secretion rates from mouse adipose tissue in vitro are decreased during early pregnancy and up-regulated during late pregnancy and lactation. Changes in leptin secretion rates in vitro paralleled those of circulating leptin in vivo during gestation. Subcutaneous implants of estradiol or corticosterone into lactating mice for 48 h stimulated adipose leptin secretion rates in vitro to the level of that in pregnant mice. However, corticosterone, but not estradiol, increased leptin secretion when added to isolated adipose tissue in vitro. Placentae obtained at two stages of pregnancy did not secrete leptin in vitro, either when acutely isolated or when dissociated into cells for long-term cultures. Placental tissue (or cells) secreted progesterone, however, demonstrating placental viability. We conclude that hyperleptinemia during late pregnancy in mice primarily results from corticosterone-dependent up-regulation of leptin secretion from adipose tissue, and that the placenta does not contribute to leptin secretion. The initial decrease in leptin secretory rates from adipose tissue during early pregnancy may facilitate energy storage for the subsequent, increased metabolic demands of later pregnancy and lactation.

D(2), but not D(1) dopamine receptor agonists potentiate cannabinoid-induced sedation in nonhuman primates.

In primates, CB(1) cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D(1) or D(2) dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys (Macaca fasicularis) alone and after administration of a low dose of the CB(1) agonist levonantradol. Alone, the CB(1) cannabinoid receptor agonist levonantradol (0.01-0. 3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D(2)-type dopamine agonists quinelorane (0. 001-1.0 mg/kg; n = 4) or pergolide (0.01-1.0 mg/kg) or a D(1) dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3-3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after administration of a threshold dose of levonantradol (0.03 mg/kg), D(2)-type agonists, but not the D(1) agonist, precipitated marked sedation, ptosis, and decreased general activity and locomotor activity. These data inducate the following: 1) D(2,) but not D(1) dopamine agonists, potentiate sedation in monkeys treated with a CB(1) cannabinoid agonist, at doses of agonists that alone do not produce sedation; 2) the threshold dose for cannabinoid-induced sedation is reduced by D(2) agonists, but not by a D(1) dopamine agonist, differentiating D(1) and D(2) dopamine receptor linkage to cannabinoid receptors; and 3) modulation of D(2) dopamine receptor activity by a nonsedating dose of a cannabinoid agonist has implications for the pathophysiology and treatment of dopamine-related neuropsychiatric disorders and drug addiction. Cannabinoid agonists and D(2) dopamine agonists should be combined with caution.