Adenosine deaminase activity (ADA) was estimated in cerebrospinal fluid (CSF) of 30 patients of tuberculous meningitis (TBM) and 10 patients each of partially treated pyomeningitis (PTM), aseptic meningitis (AM) and pyogenic meningitis (PM). Mean ADA levels in CSF of TBM patients were higher (18.22 U/L) as compared to 6.28 U/L, 3.43 U/L and 7.98 U/L in PTM, AM and PM respectively. This difference of ADA values in CSF between TBM and other types of meningitis was statistically significant (p<0.01) different. Sensitivity and specificity of ADA levels in CSF of children to diagnose tuberculous meningitis was 66.6% and 90% respectively at 10 U/L cut off of ADA levels in CSF. ADA levels in CSF could also differentiate PTM, AM and PM from TBM with a specificity of 90%, 100% and 80% respectively.

Adenosine deaminase (ADA) activity was measured in the cerebrospinal fluid (CSF) of 27 subjects suffering from tuberculous meningitis (TBM), 19 from bacterial meningitis, 10 from encephalitis, and 10 control subjects. The mean CSF ADA level was significantly raised (P < 0.001) in TBM patients as compared to other study groups. A cut-off CSF ADA level of>> 5 IU/1 was considered for the diagnosis of TBM, and the test had sensitivity and specificity of 89 and 92 per cent, respectively. Overall, it was found to be a better test in comparison to any other single test for the diagnosis of TBM. Confirmed TBM patients had significantly higher CSF ADA activity when compared with clinical TBM (P < 0.01) and the levels did not differ significantly among different stages of disease. The ADA level in TBM cases had significant correlation with CSF cell count (P < 0.01), lymphocyte percentage (P < 0.02) and protein concentration (P < 0.02). Thus, the CSF ADA activity assay was found to be a simple, useful and rapid diagnostic test for the early recognition of TBM in children.

Adenosine deaminase (ADA) activity measurement and C-reactive protein (C-RP) detection were done in CSF of 27 tuberculous meningitis (TBM) and 8 patients of partially treated bacterial meningitis, apart from routine biochemical tests. Both the groups had comparable CSF cell count, protein and sugar concentrations. The mean CSF ADA activity was significantly raised in TBM as compared to partially treated bacterial meningitis patients (p < 0.05). A cut-off ADA level < or = 5 IU/L and C-RP positively were used for differentiation of partially treated bacterial from TBM cases. Based on this, the sensitivity and specificity of ADA and C-RP were 62.5%, 88.9% and 75%, 100%, respectively. Since both the tests are simple and take lesser time to perform, they can be used as rapid diagnostic tests to remove diagnostic dilemma between the two diseases.

The target site for inhaled vapor-induced injury often differs in mouth-breathing humans compared with nose-breathing rats, thus complicating the use of rat inhalation toxicity data for assessment of human risk. We sought to examine sensitivity of respiratory/transitional nasal (RTM) and tracheobronchial (TBM) mucosa to two electrophilic irritant vapors: diacetyl and acrolein. Computational fluid dynamic physiologically based pharmacokinetic modeling was coupled with biomarker assessment to establish delivered dose-response relationships in RTM and TBM in male F344 rats following 6 h exposure to diacetyl or acrolein. Biomarkers included glutathione status, proinflammatory and antioxidant gene mRNA levels, and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Modeling revealed that 0.0094-0.1653 μg acrolein/min-cm(2) and 3.9-21.6 μg diacetyl/min-cm(2) were deposited into RTM/TBM. Results indicate RTM and TBM were generally of similar sensitivity to diacetyl and acrolein. For instance, both tissues displayed induction of antioxidant and proinflammatory genes, and nuclear accumulation of Nrf2 after electrophile exposure. Hierarchical cellular response patterns were similar in RTM and TBM but differed between vapors. Specifically, diacetyl exposure induced proinflammatory and antioxidant genes concomitantly at low exposure levels, whereas acrolein induced antioxidant genes at much lower exposure levels than that required to induce proinflammatory genes. Generally, diacetyl was less potent than acrolein, as measured by maximal induction of transcripts. In conclusion, the upper and lower extrapulmonary airways are of similar sensitivity to inhaled electrophilic vapors. Dosimetrically based extrapolation of nasal responses in nose-breathing rodents may provide an approach to predict risk to the lower airways of humans during mouth-breathing.

A 57-year-old man was admitted because of headache, nausea, and fever up (38 degrees C). He showed nuchal rigidity slightly. CSF analysis showed 833 white blood cells (WBC) (80% monocyte), protein value of 68 mg/dl, glucose level of 36 mg/dl and ADA level of 11.8 IU/l. Brain pre-contrast CT indicated high density area in right parietal lobe, and it showed slightly homogeneously enhancement with contrast medium. MRI on T2 WI demonstrated hypointense lesion with bright central core in right parietal lobe. The lesion showed isointense on T1WI, and indicated homogeneous enhancement with Gd-DTPA. He was sent to our hospital after one week. With only antibiotics the symptoms were relieved and the CSF findings improved during the previous hospital. However, Mycobacterium tuberculosis (M. tuberculosis) DNA was detected in CSF by PCR amplification, and he recovered completely with anti-tuberculous treatment. This case was interesting to reveal atypical features of spontaneous recovery. Since Shankar's study using polymerase chain reaction (PCR) for detection of M. tuberculosis in cerebrospinal fluid (CSF), the PCR assay have been recognized to be a rapid method for diagnosis of tuberculous meningitis (TBM). But there are problems of PCR sensitivity when dealing with CSF samples containing small amount of M. tuberculosis DNA. Comparing direct PCR with nested PCR, we studied on the evaluation of PCR for diagnosis of TBM. In this study the nested PCR was positive in all CSF specimens from 4 patients with TBM, but we could not detect M. tuberculosis DNA by only the direct PCR. Nested PCR amplification improved the sensitivity and specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the present study was to evaluate the enhancement of tolbutamide (TBM) oral bioavailability and hypoglycaemic activity through complexation with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). TBM and its freeze-dried inclusion complexes were administered to rabbits (New zealand breed; n=6), in a dose of 20 mg/kg. TMB plasma levels were measured by HPLC and glucose levels were analysed according to Trinder (Trinder, P., 1969. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann. Clin. Biochem. 6, 24-28). The pure drug attained a maximum of plasma concentration (C(max)) of 18.58+/-3.27 microg/ml at 8.5 h (T(max)), whereas with inclusion complexes, C(max) increased about two times and appeared at ca. 4 h. AUC(0-24) of complexes was about 1.6 times as much as that of the pure drug. Thus, the extent of oral absorption of TBM from inclusion complexes was significantly greater and faster when compared with drug alone. In addition, without cyclodextrins the maximum hypoglycaemic effect (CVG(max)) of TBM (34. 1%) was observed at 5.6 h (Tg(max)). CVG(max) of TBM/beta-CD and TBM/HP-beta-CD inclusion complexes were 34.1% (at 6.5 h) and 37.7% (at 5.1 h), respectively. AAC(0-24) of inclusion complexes was 1.4 times larger than that of pure drug. Hence, the oral administration of complexed TBM not only improved the drug absorption, but also the TBM hypoglycaemic activity.

In the present prospective study, a dot immunobinding assay (Dot-Iba) was standardized to measure the circulating mycobacterial antigen in cerebrospinal fluid (CSF) specimens for the laboratory diagnosis of tuberculous meningitis (TBM). Immunoglobulin G antibody specific for Mycobacterium tuberculosis in a CSF specimen from a patient with culture-proven TBM was isolated and was coupled with activated cyanogen bromide-Sepharose 4B. By immunosorbent affinity chromatography, a 14-kDa antigen was isolated from the culture filtrate of M. tuberculosis. Antibody to the 14-kDa mycobacterial antigen was raised in rabbits. The Dot-Iba in this study gave no false-positive results with CSF specimens from patients with nontuberculous neurological diseases. The assay gave positive results for all five patients with culture-proven TBM. The Dot-Iba described in the present report is simple, rapid, sensitive, specific, and, more importantly, suitable for routine application in laboratories in developing countries.

BACKGROUND: Epidemiological studies have linked the consumption of chlorinated surface waters to an increased risk of two major causes of human mortality, colorectal and bladder cancer. Trihalomethanes (THMs) are by-products formed when chlorine is used to disinfect drinking water. The purpose of this study was to examine the ability of the THMs, trichloromethane (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and tribromomethane (TBM), to induce DNA strand breaks (SB) in (1) CCRF-CEM human lymphoblastic leukemia cells, (2) primary rat hepatocytes (PRH) exposed in vitro, and (3) rats exposed by gavage or drinking water. METHODS: DNA SB were measured by the DNA alkaline unwinding assay (DAUA). CCRF-CEM cells were exposed to individual THMs for 2 hr. Half of the cells were immediately analyzed for DNA SB and half were transferred into fresh culture medium and incubated for an additional 22 hr before testing for DNA SB. PRH were exposed to individual THMs for 4 hr then assayed for DNA SB. F344/N rats were exposed to individual THMs for 4 hr, 2 weeks, and to BDCM for 5 wk then tested for DNA SB. RESULTS: CCRF-CEM cells exposed to 5- or 10-mM brominated THMs for 2 hr produced DNA SB. The order of activity was TBM)DBCM>BDCM; TCM was inactive. Following a 22-hr recovery period, all groups had fewer SB except 10-mM DBCM and 1-mM TBM. CCRF-CEM cells were found to be positive for the GSTT1-1 gene, however no activity was detected. No DNA SB, unassociated with cytotoxicity, were observed in PRH or F344/N rats exposed to individual THMs. CONCLUSION: CCRF-CEM cells exposed to the brominated THMs at 5 or 10 mM for 2 hr showed a significant increase in DNA SB when compared to control cells. Additionally, CCRF-CEM cells exposed to DBCM and TBM appeared to have compromised DNA repair capacity as demonstrated by an increased amount of DNA SB at 22 hr following exposure. CCRF-CEM cells were found to be positive for the GSTT1-1 gene, however no activity was detected. No DNA SB were observed in PRH or F344/N rats exposed to individual THMs.

A 25-year-old woman was diagnosed to have tubercular meningitis (TBM) with a right parietal infarct. She responded well to four-drug anti-tubercular treatment (ATT), systemic steroids and pyridoxine. Steroids were tapered off in one and a half months; she was put on two-drug ATT after two months. Six months after initial diagnosis she presented with sudden, bilateral visual loss. Vision was 3/200 with afferent pupillary defect and un-recordable field in the right eye; vision was 20/60 in the left eye, pupillary reaction was sluggish and the field showed a temporal hemianopia. On reintroduction of systemic corticosteroids vision improved (20/120 in right eye and 20/30 in left eye) within three days; the field defects improved sequentially to a left homonymous hemianopia, then a left homonymous inferior quadrantonopia. A diagnosis of TBM, on treatment, with bilateral optic neuritis, and right optic radiation involvement was made. Since the patient had been off ethambutol for four months, the optic neuritis and optic radiation lesion were attributed to a paradoxical reaction to tubercular allergen, corroborated by prompt recovery in response to corticosteroids. This is the first report of optic radiation involvement in a paradoxical reaction in neuro-tuberculosis in a young adult.

The nicotinic acetylcholine receptor α1 (nAChRα1) was investigated as a potential proinflammatory molecule in the kidney, given a recent report that it is an alternative urokinase plasminogen activator (uPA) receptor, in addition to the classical receptor uPAR. Two animal models and in vitro monocyte studies were involved: (1) In an ApoE(-/-) mouse model of chronic kidney disease, glomerular-resident cells and monocytes/macrophages were identified as the primary cell types that express nAChRα1 during hypercholesterolemia/uninephrectomy-induced nephropathy. Silencing of the nAChRα1 gene for 4 months (6 months on Western diet) prevented the increases in renal monocyte chemoattractant protein-1 and osteopontin expression levels and F4/80+ macrophage infiltration compared with the nonsilenced mice. These changes were associated with significantly reduced transforming growth factor-β1 mRNA (50% decrease) and α smooth muscle actin-positive (αSMA+) myofibroblasts (90% decrease), better glomerular and tubular basement membranes (GBM/TBM) preservation (threefold less disintegration), and better renal function preservation (serum creatinine 40% lower) in the nAChRα1-silenced mice. The nAChRα1 silencing was also associated with significantly reduced renal tissue calcium deposition (78% decrease) and calpain-1 (but not calpain-2) activation (70% decrease). (2) The nAChRα1 was expressed in vitro by mouse monocyte cell line WEHI-274.1. The silencing of nAChRα1 significantly reduced both calpain-1 and -2 activities, and reduced the degradation of the calpain substrate talin. (3) To further explore the role of calpain-1 activity in hypercholesterolemic nephropathy, disease severities were compared in CAST(-/-)ApoE(-/-) (calpain overactive) mice and ApoE(-/-) mice fed with Western diet for 10 months (n=12). Macrophages were the main cell type of renal calpain-1 production in the model. The number of renal F4/80+ macrophages was 10-fold higher in the CAST(-/-)ApoE(-/-) mice (P<0.05), and was associated with a significantly higher level of αSMA+ cells, increased GBM/TBM destruction, and higher serum creatinine levels. Our studies suggest that the receptor nAChRα1 is an important regulator of calpain-1 activation and inflammation in the chronic hypercholesterolemic nephropathy. This new proinflammatory pathway may also be relevant to other disorders beyond hyperlipidemic nephropathy.

The objective of the present work is to apply the plasma clearance parameters to strontium, previously determined in our laboratory, to improve the biokinetic and dosimetric models of strontium-90 ((90)Sr) used in radiological protection; and also to apply this data for the estimation of the radiation doses from strontium-89 ((89)Sr) after administration to patients for the treatment of the painful bone metastases. Plasma clearance and urinary excretion of stable strontium tracers of strontium-84 ((84)Sr) and strontium-86 ((86)Sr) were measured in GSF-National Research Center for Environment and Health (GSF) in 13 healthy German adult subjects after intravenous injection and oral administration. The biological half-life of strontium in plasma was evaluated from 49 plasma concentration data sets following intravenous injections. This value was used to determine the transfer rates from plasma to other organs and tissues. At the same time, the long-term retention of strontium in soft tissue and whole body was constrained to be consistent with measured values available. A physiological urinary path was integrated into the biokinetic model of strontium. Parameters were estimated using our own measured urinary excretion values. Retention and excretion of strontium were modeled using compartmental transfer rates published by the International Commission on Radiological Protection (ICRP), the SENES Oak Ridge Inc. (SENES), and the Urals Research Center for Radiation Medicine (TBM). The results were compared with values calculated by applying our GSF parameters (GSF). For the dose estimation of (89)Sr, a bone metastases model (GSF-M) was developed by adding a compartment, representing the metastases, into the strontium biokinetic model. The related parameters were evaluated based on measured data available in the literature. A set of biokinetic parameters was optimized to represent not only the early plasma kinetics of strontium but also the long-term retention measured in soft tissue and whole body. The ingestion dose coefficients of (90)Sr were computed and compared with different biokinetic model parameters. The ingestion dose coefficients were calculated as 2.8 x 10(-8), 2.1 x 10(-8), 2.5 x 10(-8) and 3.8 x 10(-8) Sv Bq(-1) for ICRP, SENES, TBM and GSF model parameters, respectively. Moreover, organ absorbed dose for the radiopharmaceutical of (89)Sr in bone metastases therapy was estimated based on the GSF and ICRP biokinetic model parameters. The effective doses were 3.3, 1.8 and 1.2 mSv MBq(-1) by GSF, GSF-M, and ICRP Publication 67 model parameters, respectively, compared to the value of 3.1 mSv MBq(-1) reported by ICRP Publication 80. The absorbed doses of red bone marrow and bone surface, 17 and 21 mGy MBq(-1) calculated by GSF parameters, and 7.1 and 8.8 mGy MBq(-1) by GSF-M parameters, are comparable to the clinical results of 3-19 mGy MBq(-1) for bone marrow and 16 mGy MBq(-1) for bone surface. Based on the GSF-M model, the absorbed dose of (89)Sr to metastases was estimated to be 434 mGy MBq(-1). The strontium clearance half-life of 0.25 h from the plasma obtained in the present study is obviously faster than the value of 1.1 h recommended by ICRP. There are no significant changes for ingestion dose coefficients of (90)Sr using different model parameters. A model including the metastases was particularly developed for dose estimation of (89)Sr treatment for the pain of bone metastases.

Tracheobronchomalacia, as a whole, is likely misdiagnosed and underestimated as a cause of respiratory compromise in pediatric patients. Currently, there is no standardized approach for the overall evaluation of pediatric tracheobronchomalacia (TBM) and the concept of excessive dynamic airway collapse (EDAC); no grading score for the evaluation of severity; nor a standardized means to successfully approach TBM and EDAC. This paper describes our experience standardizing the approach to these complex patients whose backgrounds include different disease etiologies, as well as a variety of comorbid conditions. Preoperative and postoperative evaluation of patients with severe TBM and EDAC, as well as concurrent development of a prospective grading scale, has allowed us to ascertain correlation between surgery, symptoms, and effectiveness on particular tracheal-bronchial segments. Long-term, continued collection of patient characteristics, surgical technique, complications, and outcomes must be collected given the overall heterogeneity of this particular population.

OBJECTIVE

The aim of this work is to provide a theoretical framework which is sufficiently expressive to describe temporal evolution of diseases, and also to propose a diagnostic process for building explanations of patient's observed temporal evolution based on these disease descriptions.

BACKGROUND

Model-based diagnosis (MBD) tackles the problem of troubleshooting systems by starting from a description of their structure and function (or behaviour). It is in this area where the use of deep causal models, as part of MBD systems, has shown its greater efficiency over classical rule based systems. From its beginnings, the temporal dimension was considered as an important component in MBD, since it makes it possible to define the dynamic behaviour. Several approaches have been proposed to represent time in MBD, enabling the representation of temporal concepts and relations, as well as the use of temporal reasoning mechanisms.

METHODS

We first propose a temporal behavioural model (TBM), which allows us to capture the dynamics underlying temporal evolution of diseases and to include contextual information. Contextual information is required to model how contextual factors change the temporal evolution of diseases. The temporal component is modelled by fuzzy temporal constraints networks (FTCN), which makes the representation of quantitative and qualitative imprecise temporal information possible. We also provide a diagnostic process, which is based on a temporal adaptation of classical cover and differentiate method.

RESULTS

The TBM and diagnostic process proposed provides a unique framework which addresses three problems not dealt with together so far: (a) the inclusion of contextual information, (b) the expressivity of the solution provided, and (c) the evaluation of the diagnostic hypotheses. This proposal demonstrates that the FTCN formalism provides mechanisms sufficiently expressive to cope with the intrinsic imprecision in the description of diseases' temporal evolution. The explanation generated provides the user with a complete picture of the temporal evolution of diseases and its causal links, thus allowing the appearance of repeated instances of the same disease through time. Mechanisms are provided which evaluate the credibility of alternative hypotheses, based on possibility theory. A prototype is presented along with a knowledge acquisition tool that guides medical experts in the model building process.

CONCLUSIONS

In this paper, we propose a model that tightly couples methods from MBD area with constraint-based temporal reasoning techniques. The proposed model allows us to model complex contextual relationships in a compact way as well as providing solutions expressive enough to be used for decision support purposes. The solution provided conforms a causal network entailing the abnormal observations, including pathophysiological and etiological states. Furthermore, different instances of the same diagnostic hypotheses, located at different time instants, are also possible in the final solution. Finally, we provide an analysis of related and future works.

Paradoxical manifestation is worsening of pre-existing tuberculous lesion or appearance of new lesions in patients whose condition initially improved with antituberculous treatment. Our hypothesis was that paradoxical manifestation in non-HIV tuberculous meningitis (TBM) patients was underestimated and this could contribute to patients' prognosis. This was the first systemic study of paradoxical manifestation in HIV-negative TBM patients. Between 2009 and 2014, TBM patients were studied prospectively in 2 hospitals. Clinical features, cerebrospinal fluid, and radiological findings were monitored. Paradoxical manifestation was divided into definite (4 weeks or more) and probable (between 14 and 27 d) after commencement of antituberculous treatment. Forty-one non-HIV TBM patients were recruited. Definite paradoxical manifestation occurred in 23/41 (56%) of the patients. Time to onset of paradoxical manifestation was between 28 days and 9 months, and majority was between 28 and 50 days. Neuroimaging manifestation in the brain (22/41 patients, 54%) and clinical manifestation (22/41 patients, 54%) were most commonly seen, followed by cerebrospinal fluid manifestation (7/41 patients, 17%). Neuroimaging changes most commonly seen were worsening of leptomeningeal enhancement, new infarcts, new tuberculomas, and enlargement of tuberculoma. Initial Computed Tomography Angiography/magnetic resonance angiography brain showed vasculitis in 14 patients, with 2 (12.5%) showing paradoxical vasculitis during follow-up. Recurrence of the paradoxical manifestation was seen in 7/23 (30%) of the patients. More than half (14/23, 61%) of the patients improved, 6 (26%) patients died, and 3 (13%) patients had persistent neurological deficit. Paradoxical manifestation was very common in non-HIV TBM patients. Neuroimaging paradoxical manifestation of 2-4 weeks may not be paradoxical manifestation but could be delayed treatment response.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are infectious neurological disorders of man and animals, characterised by abnormal disease-associated prion protein (PrP(d)) accumulations in the brain and lymphoreticular system (LRS). Prior to neuroinvasion, TSE agents often accumulate to high levels within the LRS, apparently without affecting immune function. However, our analysis of scrapie-affected sheep shows that PrP(d) accumulations within the LRS are associated with morphological changes to follicular dendritic cells (FDCs) and tingible body macrophages (TBMs). Here we examined FDCs and TBMs in the mesenteric lymph nodes (MLNs) of scrapie-affected mice by light and electron microscopy. In MLNs from uninfected mice, FDCs could be morphologically categorised into immature, mature and regressing forms. However, in scrapie-affected MLNs this maturation cycle was adversely affected. FDCs characteristically trap and retain immune complexes on their surfaces, which they display to B-lymphocytes. In scrapie-affected MLNs, some FDCs were found where areas of normal and abnormal immune complex retention occurred side by side. The latter co-localised with PrP(d) plasmalemmal accumulations. Our data suggest this previously unrecognised morphology represents the initial stage of an abnormal FDC maturation cycle. Alterations to the FDCs included PrP(d) accumulation, abnormal cell membrane ubiquitin and excess immunoglobulin accumulation. Regressing FDCs, in contrast, appeared to lose their membrane-attached PrP(d). Together, these data suggest that TSE infection adversely affects the maturation and regression cycle of FDCs, and that PrP(d) accumulation is causally linked to the abnormal pathology observed. We therefore support the hypothesis that TSEs cause an abnormality in immune function.

The authors report on a infant who presented with an auto-immune enteropathy characterized by the association of a protracted diarrhea, a neonatal insulin-dependent diabetes, and a dermatitis and who developed a nephrotic syndrome at 4 months of age. A renal biopsy showed a membranous glomerulonephritis (MGN) with IgG linear deposits along the tubular basement membranes (TMB). By indirect immunofluorescence anti-enterocyte antibodies together with anti-TMB antibodies and anti-renal brush border (BB) antibodies were found in the serum of the patient. The patient received various immunosuppressive drugs that failed to improve the disease. In the course of the disease the anti-TBM antibodies disappeared progressively but the BB antibodies persisted. A review of the literature indicates that renal involvement is not uncommon in auto-immune enteropathy and in 5 cases it has been reported as being characterized by a nephrotic syndrome related to the presence of a MGN. In 4 of these cases MGN was associated with the presence of anti-TBM antibodies and in the remaining one with anti-BB antibodies. This case report shows that in human pathology, auto-antibodies to BB proteins may, as well as in experimental models, be responsible for the development of a MGN. It suggests a close relationship (probably a common epitope) between the renal BB proteins and the proteins of the gut epithelium.

The taxonomic placement of freshwater and marine Savoryella species has been widely debated, and the genus has been tentatively assigned to various orders in the Sordariomycetes. The genus is characterized as possessing paraphyses that deliquesce early, elongate, clavate to cylindrical asci with a poorly developed apical ring and versicolored, three-septate ascospores. We performed two combined phylogenetic analyses of different genes: (i) partial small subunit rRNA (SSU), large subunit rRNA (LSU), DNA-dependent RNA polymerase II largest subunit (rpb2) dataset and (ii) SSU rDNA, LSU rDNA, DNA-dependent RNA polymerase II largest subunit (rpb1 and rpb2), translation elongation factor 1-alpha (tef1), the 5.8S ribosomal DNA (5.8S rDNA) dataset. Our results indicate that Savoryella species formed a monophyletic group within the Sordariomycetes but showed no affinity to the Hypocreales, Halosphaeriales (now Microascales), Sordariales and Xylariales, despite earlier assignments to these orders. Savoryella, Ascotaiwania and Ascothailandia (and its anamorph, Canalisporium) formed a new lineage that has invaded both marine and freshwater habitats, indicating that these genera share a common ancestor and are closely related. Because they show no clear relationship with any named order we erect a new order Savoryellales in the subclass Hypocreomycetidae, Sordariomycetes. The genera Savoryella and Ascothailandia are monophyletic, while the position of Ascotaiwania is unresolved. All three genera are phylogenetically related and form a distinct clade similar to the unclassified group of marine ascomycetes comprising the genera Swampomyces, Torpedospora and Juncigera (TBM clade: Torpedospora/Bertia/Melanospora) in the Hypocreomycetidae incertae sedis.

Gradually-changing shocks associated with potable water quality deficiencies are anticipated for urban drinking-water distribution systems (UDWDS). The impact of structural UDWDS features such as, the number of pipe leaking incidences on the formation of water trihalomethanes (THM) at the geocoded household level has never been studied before. The objectives were to: (i) characterize the distribution of water THM concentrations in households from two district-metered areas (DMAs) with contrasting UDWDS characteristics sampled in two seasons (summer and winter), and (ii) assess the within- and between-household, spatial variability of water THM accounting for UDWDS characteristics (household distance from chlorination tank and service pipe leaking incidences). A total of 383 tap water samples were collected from 193 households located in two DMAs within the UDWDS of Nicosia city, Cyprus, and analyzed for the four THM species. The higher intraclass correlation coefficient (ICC) values for water tribromomethane (TBM) (0.75) followed by trichloromethane (0.42) suggested that the two DMAs differed with respect to these analytes. On the other hand, the low ICC values for total THM levels between the two DMAs suggested a large variance between households. The effect of households nested under each DMA remained significant (p<0.05) for TBM (not for the rest of the THM species) in the multivariate mixed-effect models, even after inclusion of pipe network characteristics. Our results could find use by water utilities in overcoming techno-economic difficulties associated with the large spatiotemporal variability of THM, while accounting for the influence of UDWDS features at points of water use.

The accumulation of excessive extracellular matrix (ECM) following tubular injury likely represents an imbalance between ECM production and degradation. We assessed the temporal relationship between the accumulation of ECM, cell adhesion molecules, matrix degrading proteinases, and their inhibitors in a rat model of anti-tubular basement membrane (TBM) antibody-associated tubulointerstitial nephritis (TIN) by the RNase protection assay and immunohistochemistry. There was an increase in the steady state expression of fibronectin (FN) and alpha 2(IV) collagen mRNAs beginning on day 7 with the onset of neutrophil infiltration. An increase in alpha 1(III) collagen and alpha 1-integrin did not occur until days 9 and 10, respectively, at which time mononuclear leukocytes were the predominant infiltrating cell. Increased levels of FN, alpha 1(III), alpha 2(IV) and alpha 1-integrin mRNAs occurred through day 14. By immunohistochemistry, increased accumulation of collagen IV, heparan sulfate proteoglycan, and laminin were detected along the thicken TBM; collagens I and III were immunolocalized within the tubulo-interstitium, while FN was present in both the TBM and interstitium in rats with TIN on day 14. The increase in matrix accumulation was associated with little or no increase in proteinases. u-PA transcripts fell beginning on day 8, with recovery to control values by day 12. Transin mRNA was found at low levels only on days 8 and 9, and the protein could not be detected by Western blotting. In contrast, these changes were associated with an increase in proteinase inhibitors, so that TIMP and PAI-1 mRNAs increased beginning on day 7 and persisted through day 14.(ABSTRACT TRUNCATED AT 250 WORDS)

Exposure to mercuric chloride induces the development of a membranous glomerulopathy with high proteinuria in DZB rats, in which immunoglobulin (Ig)G1 and IgG2a bound in the glomeruli were previously found to react with laminin of the EHS tumor and several unidentified glomerular basement membrane components. Monoclonal antibodies were prepared by fusing cervical and mandibular lymph node cells from a HgCl2-treated DZB rat with a nonsecreting mouse myeloma. Monoclonal antibodies were screened for reactivity with collagenase-digested glomerular basement membrane and kidney sections; upon subcloning, eight stable hybridomas were obtained, named MEC1 to MEC8. MEC2 (IgG1, kappa), MEC3 (IgM, kappa), and MEC5 (IgG1, kappa), as well as the polyclonal glomerular eluate, reacted preferentially with the P1 fragment of the laminin-1 (alpha 1 beta 1 gamma 1) isoform. MEC8 (IgM, kappa) reacted with the P1 and the E4 fragment of laminin. Both MEC6 (IgM, kappa) and MEC8 bound to actin and to various other, unidentified cellular antigens, indicating that MEC6 and MEC8 are polyreactive antibodies. MEC7 (IgM, kappa) bound to a cytoskeleton-linked cell membrane antigen, present on various epithelial cells and between heart muscle fibers and associated with small peripheral, intramuscular nerves. Several of the MEC monoclonal antibodies bound in vivo along the glomerular capillary wall. Although discrete electron-dense subepithelial immune aggregates were not detected and proteinuria was not induced, MEC3 localization changed from a continuous pattern into a fine granular pattern along the glomerular basement membrane, and focally along the TBM, upon passive transfer into naive DZB rats. These findings suggest a pathogenetic role for the P1 fragment of laminin either in the induction phase of HgCl2-induced membranous glomerulopathy as an immunogen or in the effector phase as a target antigen.

To supplement a previous analysis of spontaneous tandem-base mutations (TBM) in the lacI gene of Big Blue((R)) mice, 2658 additional mutants were sequenced from 13 tissues and 44 spontaneous TBM were identified (tripling the sample size). Previous findings were confirmed and generalized and several new observations were made. TBM differ from single and other double mutations in that TBM frequency varies dramatically with tissue type. In certain tissues, most notably male germ cells, no TBM are observed despite screening as many as 26 million plaque forming units. TBM are most frequent in kidney and liver (3.45 and 2x10(-6), respectively), accounting for 7.6 and 4.8% of all mutational events in kidney and liver, respectively. There is a trend for elevated TBM frequency in thymic lymphomas in p53-deficient mice. TBM are more frequent in old age in both liver and kidney. TBM differ from single mutations and other double mutations because they display a marked difference in pattern and dramatic tissue specificity for target sequence. Five of the 78 possible TBM outcomes comprise 79% of those observed, and mutations at GG/CC predominate. TBM in mice were compared with TBM found in human mutation databases. TBM are also rare in the human germline (one in 5133 germline mutations reported in five human mutation databases). In general, the types of somatic TBM are similar in mice and humans except for an excess of TG/CA to CA/TG TBM in humans (TBM related to ultraviolet light-induced skin cancer were excluded). TBM may be the result of unknown mechanisms that may have some similarities in mice and humans.

An age- and gender-dependent biokinetic model for strontium was developed based on the study of a population living along the Techa River exposed to effluents from the Mayak Production Association (MPA). To estimate the parameters of a new model (Techa biokinetic model, TBM) many data sets have been assembled: our whole-body counter data on long-term retention of 90Sr in humans, data from studies during the period of global fallout, data resulting from deliberate injection of strontium radionuclides and non-radiological data regarding bone formation and resorption, mineral content of the body, etc. The model was developed using the basic structure of the ICRP biokinetic model for strontium, but new age- and gender-specific parameters were derived. This paper discusses the approaches applied to develop the new model.

The mineralocorticoid receptor displays equal affinity for aldosterone and corticosterone. It has been proposed that aldosterone selectivity in vivo is achieved by the conversion of corticosterone into its inactive metabolite 11-dehydrocorticosterone by 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). To test this hypothesis, we transfected rat liver 11 beta HSD cDNA into TBM cells, a sodium-transporting cell line. These cells respond equally well to aldosterone and corticosterone, indicating that endogenous 11 beta HSD is expressed at low levels in TBM cells. Although exogenous rat liver 11 beta HSD was expressed at high levels in transfected cells, mineralocorticoid selectivity was not observed. By contrast, the biologically inactive 11-dehydrocorticosterone was readily converted into corticosterone, a potent agonist for sodium transport. Our results indicate that rat liver 11 beta HSD behaves predominantly as a reductase in TBM cells. Another 11 beta HSD isoform is likely to be responsible for the dehydrogenase reaction in aldosterone-responsive cells.

Tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are two of the most common types of chronic meningitis. This study aimed to assess whether chronic neuro-psychological sequelae are associated with micro-structure white matter (WM) damage in HIV-negative chronic meningitis. Nineteen HIV-negative TBM patients, 13 HIV-negative CM patients, and 32 sex- and age-matched healthy volunteers were evaluated and compared. The clinical relevance of WM integrity was studied using voxel-based diffusion tensor imaging (DTI) magnetic resonance imaging. All of the participants underwent complete medical and neurologic examinations, and neuro-psychological testing. Differences in DTI indices correlated with the presence of neuro-psychological rating scores and cerebrospinal fluid (CSF) analysis during the initial hospitalization. Patients with CM had more severe cognitive deficits than healthy subjects, especially in TBM. There were changes in WM integrity in several limbic regions, including the para-hippocampal gyrus and cingulate gyrus, and in the WM close to the globus pallidus. A decline in WM integrity close to the globus pallidus and anterior cingulate gyrus was associated with worse CSF analysis profiles. Poorer DTI parameters directly correlated with worse cognitive performance on follow-up. These correlations suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities. Abnormalities in the limbic system and globus pallidus, with their close relationship to the CSF space, may be specific biomarkers for disease evaluation.