HIV and viral hepatitis coinfection analysis using surveillance data from 15 US states and two cities.

Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.

Pharmacokinetics and pharmacodynamics of BB-10153, a thrombin-activatable plasminogen, in healthy volunteers.

BACKGROUND: BB-10153 is an engineered variant of human plasminogen that is activated to plasmin by thrombin. Thrombus-selective induction of reperfusion and prevention of reocclusion have been demonstrated following bolus administration in animal models of thrombosis. OBJECTIVE AND METHODS: The objective of the study was to examine the pharmacokinetics and pharmacodynamics of BB-10153 administered as an intravenous bolus to healthy male human volunteers. Cohorts of four were dosed with BB-10153 (n = 3) or placebo (n = 1). In total, placebo was received by eight volunteers and 0.08, 0.2, 0.6, 1.2, 1.8, 2.4, 3.6 and 4.8 mg kg(-1) BB-10153 by three volunteers each. RESULTS: There was a linear relationship between AUC/Cmax and dose. The half-life of BB-10153 was approximately 3-4 h and all the BB-10153 in the circulation retained the ability to be activated by thrombin. There was a dose-related increase in plasma fibrin D-dimers. Ex vivo plasma clot lysis was observed at doses of 3.6 and 4.8 mg kg(-1), whereas lysis of clots formed from euglobulin-fractionated plasma was first evident at 0.6 mg kg(-1) and activity increased with dose. This activity decreased with time in line with the half-life. BB-10153 had no effect on plasma alpha2-antiplasmin or fibrinogen levels, coagulation assays or bleeding time. An increase in plasminogen was observed as BB-10153 was detected by the enzyme-linked immunosorbent assay (ELISA) for human plasminogen. CONCLUSIONS: BB-10153 was well tolerated and had a 3-4-h plasma half-life. Fibrinolytic activity was demonstrated by dose-related ex vivo clot lysis and in vivo production of fibrin D-dimers. These effects were not accompanied by consumption of alpha2-antiplasmin or fibrinogen.

Thrombolytic activity of BB-10153, a thrombin-activatable plasminogen.

BACKGROUND: BB-10153 is an engineered variant of human plasminogen, modified to be activated to plasmin by thrombin. Thrombin-activatable plasminogen was designed as a novel thrombolytic agent which would persist in the blood as a prodrug and be activated to plasmin only at fresh or forming thrombi by the thrombin that is tightly localized there. We previously described the construction of several thrombin-activatable plasminogens and their in vitro clot lysis activity. OBJECTIVES AND METHODS: The current study was an examination of the thrombolytic properties of BB-10153 in vivo; comparison was made with tissue-type plasminogen activator (t-PA) in a femoral artery copper coil thrombosis model in the anesthetized dog and rabbit. Heparin was not coadministered so that the fundamental activity of the agents could be compared. RESULTS: BB-10153, administered as an intravenous bolus of 5 mg kg(-1) in the dog and 10 mg kg(-1) in the rabbit, produced a comparable incidence of reperfusion to 3 mg kg(-1) t-PA. Reocclusion at these doses occurred in 4/4 dogs and 5/7 rabbits treated with t-PA and in 2/6 dogs and 0/10 rabbits treated with BB-10153. There was no reocclusion in three dogs dosed with 10 mg kg(-1) BB-10153. BB-10153 did not affect plasma alpha2-antiplasmin levels or the bleeding time, whereas 3 mg kg(-1) t-PA caused marked depletion of alpha2-antiplasmin and fibrinogen and increased the bleeding time. The plasma half-life of BB-10153 was 3-4 h. CONCLUSIONS: The long half-life and thrombus-selective thrombolytic activity of BB-10153 might allow it to overcome the bleeding and reocclusion shortfalls in the performance of current thrombolytics.

Clinical features and surgical management of retinal detachment secondary to round retinal holes.

AIMS: The majority of rhegmatogenous retinal detachments result from pathological posterior vitreous detachment (PVD) and secondary horseshoe or giant retinal tears. Retinal detachment without PVD is usually associated with either retinal dialysis or round retinal holes. This study characterises the features, surgical outcome, and incidence of bilateral involvement of detachment associated with round retinal holes. METHODS: In all, 110 retinal detachments from 96 consecutive patients with retinal detachment secondary to round retinal holes were studied. Analysis of patient age, sex, refraction, preoperative visual acuity, presented symptoms, position and extent of detachment, number and distribution of holes present, posterior hyaloid membrane status, surgical management, outcome of surgery, and postoperative visual acuity were studied. RESULTS: The mean age for patients was 34 years with a marked female preponderance (64%) and myopia (83%). The posterior hyaloid membrane remained attached in 95 eyes (86%). In all, 45% patients had bilateral pathology, of which 33% had 'mirror image' distribution. Detachments were predominantly shallow (93%) and slow in progression (17%). A total of 100 detachments were repaired with cryotherapy and scleral buckling, eight with cryotherapy alone, and one with laser retinopexy. In all, 99% detachments were successfully reattached with a single procedure. The mean follow-up period was 2 years. There were no instances of redetachment. CONCLUSIONS: Round hole detachments are slowly evolving detachments with attached vitreous gel in young, predominantly female myopes. Examination of the fellow eye should be mandatory as there is a high incidence of bilateral pathology. Scleral buckling procedures remained highly effective in this selected group of patients.

Pharmacology of the selective 5-HT(1B/1D) agonist frovatriptan.

OBJECTIVE: To determine the pharmacological profile of frovatriptan. BACKGROUND: Frovatriptan is a new 5-HT(1B/1D) agonist developed for the treatment of migraine. METHODS: Pharmacological studies were performed using in vitro and in vivo techniques. RESULTS: Radioligand-binding studies showed that frovatriptan has a high affinity for 5-HT(1B) and 5-HT(1D) receptors, and moderate affinity for 5-HT(1A), 5-HT(1F), and 5-HT(7) receptors. In vitro, frovatriptan acts as a potent full agonist at human cloned 5-HT(1B) and 5-HT(1D) receptors, and as a moderately potent full agonist at 5-HT(7) receptors. Studies of frovatriptan in isolated human arteries demonstrated a lower threshold for constriction of cerebral than coronary vasculature and a bell-shaped dose-response curve was apparent in the coronary arteries. In anesthetized dogs, frovatriptan administration produced no measurable effect on cardiac function or on blood pressure. Frovatriptan had no effects on coronary blood flow following transient coronary artery occlusion, whereas sumatriptan produced a prolonged and significant decrease in coronary blood flow. CONCLUSION: The pharmacology of frovatriptan suggests that it should be an effective agent for the acute treatment of migraine, with a low potential for undesirable peripheral effects.

Who should manage primary retinal detachments?

PURPOSE: To determine whether the outcome of primary retinal reattachment surgery in a subregion is improved by surgery being performed in a specialist vitreoretinal unit (VRU). METHODS: A subregional, population-based, retrospective audit cycle of primary retinal reattachment surgery was conducted by independent investigators. The subregion was defined as the catchment area of a teaching hospital (TH) with a specialist VRU and three neighbouring district general hospitals (DGHs). During the initial audit period (January 1989 to December 1990), 142 cases were treated at all four hospitals: TH/VRU (83), DGH-A (15), DGH-B (13), and DGH-C (31). Policy changes after the initial audit led to primary retinal reattachment surgery being predominantly performed by the VRU. During the re-audit period (September 1995 to August 1997), 160 cases were treated at two hospitals: VRU (148) and DGH-C (12). The outcome measure employed was complete retinal reattachment after a single procedure with a minimum follow-up of 12 months. RESULTS: The success rate for primary retinal reattachment surgery in the subregion improved from 76.1% to 88.8% (p = 0.006) following the policy changes. The success rate of the vitreoretinal specialists in the VRU (90%) was greater than the general ophthalmologists in the DGHs (ranging from 47% to 77%), despite case selection by the general ophthalmologists. The number of cases treated by the VRU increased by 156% in the 6.5 year interval between the two audits due to a widespread change in the model of care for primary retinal detachments (both within and outside the subregion). During the re-audit period, the VRU treated 348 primary retinal detachments (including referrals from outside the subregion), achieving a success rate of 86.8% with a single procedure and 97.4% with further surgery. This primary success rate included 35 cases (10%) treated by vitrectomy with silicone oil tamponade who did not undergo silicone oil removal. CONCLUSIONS: The outcome of primary retinal reattachment surgery can be improved if surgery is performed by a specialist VRU. It is suggested that the current standard for retinal reattachment with a single procedure should be set in the region of 85% to 90%. Changing the model of care so that primary retinal reattachment surgery is predominantly performed by a specialist VRU has important resource implications.

The EM/MPM algorithm for segmentation of textured images: analysis and further experimental results.

In this paper we present new results relative to the "expectation-maximization/maximization of the posterior marginals" (EM/MPM) algorithm for simultaneous parameter estimation and segmentation of textured images. The EM/MPM algorithm uses a Markov random field model for the pixel class labels and alternately approximates the MPM estimate of the pixel class labels and estimates parameters of the observed image model. The goal of the EM/MPM algorithm is to minimize the expected value of the number of misclassified pixels. We present new theoretical results in this paper which show that the algorithm can be expected to achieve this goal, to the extent that the EM estimates of the model parameters are close to the true values of the model parameters. We also present new experimental results demonstrating the performance of the EM/MPM algorithm.

Application of a marker of ciliated epithelial cells to gynaecological pathology.

BACKGROUND: The assessment of neoplastic disease in gynaecological histopathology can be complicated by the high incidence of metaplasia seen in tissues of the female genital tract. There is a need to identify specific tissue markers which can be applied in routine histopathological practice. AIM: To examine the clinical potential of a monoclonal antibody, LhS28, which reacts with basal bodies of ciliated epithelial cells. METHODS: A panel of normal and pathological gynaecological tissues was processed and labelled with LhS28. RESULTS: LhS28 immunoreactivity was found in the normal Fallopian tube where it was confined to ciliated rather than secretory epithelial cells. In the remaining specimens, LhS28 was associated exclusively with ciliated cells in tubal metaplasias of the cervix and endometrium and in benign serous lined inclusion cysts. CONCLUSIONS: LhS28 may be a valuable marker for identifying metaplasia of tubal type and may find application in distinguishing tubal metaplasia from low grade cervical glandular intraepithelial neoplasia.

Expression of an antigen associated with basal bodies of human ciliated epithelial cells.

The process and regulation of ciliogenesis in human epithelia is little understood and many components of the cilium and associated structures have not been characterised. We have identified a monoclonal antibody, LhS28, which recognises a 44,000-45,000 M(r) protein specifically associated with human ciliated epithelial cells. Immunoperoxidase labelling of formalin-fixed paraffin wax-embedded human tissues showed that LhS28 was expressed in the sub-apical zone of ciliated epithelial cells of the Fallopian tube and upper respiratory tract, but not ciliated ependyma, non-ciliated epithelia or testis containing developing spermatozoa. Immunoelectron microscopy demonstrated that the antigen recognised by LhS28 was associated with the basal body structure of the cilium and specifically with the 9 + 0 microtubule arrays. LhS28 should be a useful tool in the identification of ciliated cells in pathological specimens and for investigating mechanisms of ciliogenesis.

Segmentation of textured images using a multiresolution Gaussian autoregressive model.

We present a new algorithm for segmentation of textured images using a multiresolution Bayesian approach. The new algorithm uses a multiresolution Gaussian autoregressive (MGAR) model for the pyramid representation of the observed image, and assumes a multiscale Markov random field model for the class label pyramid. The models used in this paper incorporate correlations between different levels of both the observed image pyramid and the class label pyramid. The criterion used for segmentation is the minimization of the expected value of the number of misclassified nodes in the multiresolution lattice. The estimate which satisfies this criterion is referred to as the "multiresolution maximization of the posterior marginals" (MMPM) estimate, and is a natural extension of the single-resolution "maximization of the posterior marginals" (MPM) estimate. Previous multiresolution segmentation techniques have been based on the maximum a posterior (MAP) estimation criterion, which has been shown to be less appropriate for segmentation than the MPM criterion. It is assumed that the number of distinct textures in the observed image is known. The parameters of the MGAR model-the means, prediction coefficients, and prediction error variances of the different textures-are unknown. A modified version of the expectation-maximization (EM) algorithm is used to estimate these parameters. The parameters of the Gibbs distribution for the label pyramid are assumed to be known. Experimental results demonstrating the performance of the algorithm are presented.

Induction of a differentiated ciliated cell phenotype in primary cultures of Fallopian tube epithelium.

Human Fallopian tubal epithelial cells in culture lose morphological features associated with the epithelium in situ and the extent to which they retain their in-vivo phenotype or function is unknown. In order to address this question, immunocytochemical markers were identified which distinguish secretory (HMFG2+, LhS28-) from ciliated (HMFG2-, LhS28+) epithelial cells in tissue sections of Fallopian tube. These markers were used to analyse the phenotype of tubal cells in vitro. Primary cultures of human tubal epithelial cells were seeded onto glass and grown to confluence before addition of oestradiol-17beta. In the absence of hormone, tubal epithelial cells expressed cytokeratins and nuclear receptors for oestrogen and progesterone and adopted a homogeneous (HMFG2+, LhS28-) secretory cell phenotype. Following the addition of oestradiol-17beta, a proportion of cells became positive for LhS28. The induction of a ciliated epithelial cell phenotype was confirmed by scanning electron microscopy, where on permeable collagen membranes, approximately one-third of tubal epithelial cells became ciliated in the presence of oestradiol-17beta. We suggest that in vitro, tubal epithelial cells adopt an immature secretory-like phenotype and that oestrogen can induce differentiation to a ciliated epithelial cell phenotype.

Transcriptional regulation of the GluR2 gene: neural-specific expression, multiple promoters, and regulatory elements.

To understand how neurons control the expression of the AMPA receptor subunit GluR2, we cloned the 5' proximal region of the rat gene and investigated GluR2 promoter activity by transient transfection. RNase protection and primer extension of rat brain mRNA revealed multiple transcription initiation sites from -340 to -481 bases upstream of the GluR2 AUG codon. The relative use of 5' start sites was different in cortex and cerebellum, indicating complexity of GluR2 transcript expression among different sets of neurons. When GluR2 promoter activity was investigated by plasmid transfection into cultured cortical neurons, cortical glia, and C6 glioma cells, the promoter construct with the strongest activity, per transfected cell, was 29.4-fold (+/- 3.7) more active in neurons than in non-neural cells. Immunostaining of cortical cultures showed that >97% of the luciferase-positive cells also expressed the neuronal marker MAP-2. Evaluation of internal deletion and substitution mutations identified a functional repressor element I RE1-like silencer and functional Sp1 and nuclear respiratory factor-1 (NRF-1) elements within a GC-rich proximal GluR2 promoter region. The GluR2 silencer reduced promoter activity in glia and non-neuronal cell lines by two- to threefold, was without effect in cortical neurons, and could bind the RE1-silencing transcription factor (REST) because cotransfection of REST into neurons reduced GluR2 promoter activity in a silencer-dependent manner. Substitution of the GluR2 silencer by the homologous NaII RE1 silencer further reduced GluR2 promoter activity in non-neuronal cells by 30-47%. Maximal positive GluR2 promoter activity required both Sp1 and NRF-1 cis elements and an interelement nucleotide bridge sequence. These results indicate that GluR2 transcription initiates from multiple sites, is highly neuronal selective, and is regulated by three regulatory elements in the 5' proximal promoter region.

The acute effects of exercise on bone turnover.

Exercise is known to have long-term benefits on bone mass, but little is known about the short-term effects of exercise on bone turnover. The purpose of this study was to investigate whether acute effects of exercise on bone remodelling could be detected by measuring blood and urinary markers of bone turnover. We measured biochemical markers of bone turnover in ten healthy, young men before and up to 32 hours after 30 minutes of brisk treadmill walking. Blood samples were taken before, immediately after and at 0.5, 1, 8, 24 and 32 hours after the exercise. These were assayed for osteocalcin and bone specific alkaline phosphatase. Twenty-four hour urine samples were taken over three days (day before, day of and day after exercise) and measured for pyridinoline and deoxypyridinoline crosslinks. Crosslink excretion was standardised for total body bone mineral content (TBBMC) and urinary creatinine. Total body bone mineral density (and content) and body composition were measured by dual energy X-ray absorptiometry. No changes in the levels of either osteocalcin or alkaline phosphatase were seen at any time point following the exercise. Both urinary crosslinks exhibited an increase in levels on the day of the exercise and a further significant increase the day after (pyridinoline 38.7%, p = 0.05; deoxypyridinoline 42.3%, p = 0.025; median, corrected for TBBMC). There were significant negative correlations between the crosslinks, osteocalcin and body fat percentage. In conclusion, the exercise appears to have stimulated bone resorption within 32 hours of moderate exercise, but there was no measurable effect on bone formation after 32 hours. A longer study period may be necessary to detect changes in bone formation.

Acute proptosis in relation to activated protein C resistance: a case report.

Activated Protein C resistance is a recently described clotting disorder, accounting for several previously undiagnosed thrombophilic states. Initially this defect had been associated with leg vein thromboses, but it is now recognised that other vascular beds are also prone to clotting in this disorder. We report a case of acute proptosis in a patient with Activated Protein C resistance, due to cavernous sinus thrombosis.

Growth rate-dependent control, feedback regulation and steady-state mRNA levels of the threonyl-tRNA synthetase gene of Escherichia coli.

The expression of the gene thrS encoding threonyl-tRNA synthetase is under the control of two apparently different regulatory loops: translational feedback regulation and growth rate-dependent control. The translational feedback regulation is due to the binding of threonyl-tRNA synthetase to a site located in the leader RNA of thrS, upstream of the initiation codon, which mimics the anticodon stem and loop of tRNA(Thr). This binding competes with that of the ribosome and thus inhibits translation initiation. Here, we investigate the mechanism of growth rate-dependent control, i.e. the mechanism by which the synthetase accumulates at high growth rates. We show that growth rate-dependent control acts at the level of translation and requires feedback regulation since mutations that abolish feedback regulation also abolish growth rate-dependent control. We also show that tRNA(Thr), which accumulates at high growth rates, is one of the effectors of growth rate-dependent control since its accumulation can cause derepression independently of growth rate. We show that this tRNA(Thr)-dependent derepression is also dependent on feedback regulation since mutations which abolish feedback also prevent derepression. Based on these results and previous data concerning the mechanism of translational feedback regulation, we propose that threonyl-tRNA synthetase growth rate-dependent control is the consequence of the accumulation at high growth rates of two effectors, the ribosome and tRNA(Thr). We also study the growth rate-dependence of the steady state level of thrS mRNA and show that the steady state level of thrS mRNA increases at high growth rates. This increase is dependent on the translational feedback regulation and can also be detected, independently of growth rate, when thrS mRNA translation is derepressed. Consistently with the model of growth rate-dependent control above, we propose that at high growth rates, the mRNA is well translated and thus stabilised and that, at low growth rates, because of its low translation, thrS mRNA is rapidly degraded.

Pneumonitis in a lupus twin pregnancy: a case report.

We describe a patient with systemic lupus erythematosus (SLE), whose pregnancy was complicated by fulminant lupus pneumonitis and pericarditis. Maternal disease responded to therapy and twin girls were delivered, both with thrombocytopenia, one of whom died of an intraventricular haemorrhage. Pneumonitis is a rare complication of lupus in pregnancy which may be fatal. We suggest patients with previous severe pneumonitis should have lung function tests at the onset of pregnancy, and treatment be modified to suppress flare if there is any indication of severe pneumonitis in early pregnancy.

Human Fallopian tubal epithelial cells in vitro: establishment of polarity and potential role of intracellular calcium and extracellular ATP in fluid secretion.

A pure population of human Fallopian tubal epithelial cells has been isolated by enzyme digestion, grown in primary culture and used to explore the biochemical basis of oviduct fluid secretion. Confluence was achieved in 3-7 days. Immunocytochemical labelling for cytokeratins indicated that the cells were epithelial in nature and formed extensive desmosomal contacts, producing a polarized layer in culture. By growing the cells on collagen-impregnated filters, a small transepithelial electrical potential difference could be recorded, with the apical side of the cells negative with respect to the basal side. In addition, the consumption of glucose and the appearance of lactate were greater on the basal than on the apical side of the cells. Because intracellular Ca2+ ([Ca2+]i) is well established as a signal transduction agent in epithelial fluid secretion, the effect of a wide range of agonists on [Ca2+]i in isolated tubal epithelial cells was studied using Fura-2. The only agent which induced a change in [Ca2+]i was extracellular ATP. The transients induced were dependent on both intracellular and extracellular calcium. ATP added to the basal side of the cells of the polarized layer induced a transient increase in the potential difference. The data are consistent with a potential role for extracellular ATP in the regulation of human tubal fluid formation.

Clinical implications of patients' knowledge.

We evaluated the effectiveness of current strategies for educating patients in routine clinical practice in three related studies. (1) A study of overall knowledge in 100 patients with rheumatoid arthritis (RA) and osteoarthritis (OA) showed knowledge of diagnosis and treatment effects were high (86% and 83% respectively) but only a minority (37%) were well informed about side effects. (2) Patients' detailed knowledge of drug therapy was assessed in 50 RA and OA patients. Between 56%-92% knew why drugs were given, their use and their likely effects. But many patients were unaware of the main adverse reactions and also how to avoid or limit them. (3) The relationship of patient education to overall disease management was evaluated in 89 RA patients with 5-10 years disease duration using validate guidelines for specialist care. Those patients who had been give inadequate education about drug therapy had a reduced level of overall care. Although education is considered important by patients, it is often inadequate, and this is associated with a less effective overall treatment.