Miracle-dz/UniFAR-FTUs huggingface dataset:
IgM‐enriched human intravenous immunoglobulin strongly inhibits complement‐dependent porcine cell cytotoxicity mediated by human xenoreactive antibodies

Abstract: Treatment with intravenous immunoglobulin preparations consisting of human IgG (IVIgG) prevents hyperacute rejection of pig xenografts transplanted into primates by inhibition of the classical complement pathway. Recent studies indicate that IVIg preparations mainly consisting of human IgM (IVIgM) have a stronger capacity than IVIgG to inhibit the complement system. IVIg preparations also contain xenoreactive antibodies (XAb) binding to pig cells. In the present study, we compared IVIgG and IVIgM for their capacity to inhibit xenogeneic complement activation, with special reference to the roles of IgG and IgM XAb present in these preparations. Xenogeneic complement activation was studied by exposure of pig cells (PK15) to human serum. For some experiments, IVIgG and IVIgM were depleted from XAb by immune absorption. Exposure of PK15 cells to human serum induced surface deposition of C4 and C3 and cytotoxicity, which could be inhibited in a dose‐dependent fashion by both IVIgM and IVIgG. The efficacy of IVIgM was more than 10 times higher than that of IVIgG. IgG XAb were detected in both IVIgG and IVIgM whereas IgM XAb were only present in IVIgM. Depletion of XAb from the IVIg preparations did not modify the protective properties of IVIgG against cytotoxicity induced by human serum, whereas the IVIgM‐mediated protection against xenogeneic cytotoxicity was only slightly improved. IgM‐enriched IVIg is a potent inhibitor of xenogeneic complement activation and complement‐dependent cytotoxicity of human serum to pig cells, irrespective of the presence of cytotoxic xenoreactive IgM antibodies in this preparation. Therefore, IVIgM has a promising therapeutic significance for the treatment of (hyper)acute xenograft rejection.
Observational studies of a one year self-management program and a two year pulmonary rehabilitation program in patients with COPD

Objective: To describe the outcome of a one year self-management program (SMG) and a two year pulmonary rehabilitation program (PRG). Methods: Two open prospective observational studies with 30 patients in each study. SMG had 46 hours over 12 months. PRG had in addition three weekly exercise sessions parallel which lasted an additional year. Results: In SMG, health-related quality of life (HRQoL, measured by St. George’s Respiratory Questionnaire) had an improvement of −3.6 points (95% CI −6.7 to −0.5) one year after the end of the intervention, but there was no change in the six minutes walking test (6MWT). The PRG had an improvement in HRQoL at the end of the intervention of −11.2 points (95% CI −13.9 to −8.4) and the 6MWT was clinically significant improved with 86 metres (95% CI 63 to 109). None of the groups showed any clinical relevant change in lung function. Conclusion: Participants in the SMG had had an improvement in quality of life and no deterioration in exercise tolerance one year after the end of the program compared to the start. Participants in the PRG significantly improved their quality of life and exercise tolerance the first year, but had no further clinical relevant improvement the second year.
Waitlist‐controlled trial of cognitive behavior therapy for hoarding disorder

Objective: This study investigated a multicomponent cognitive behavioral treatment (CBT) for hoarding based on a model proposed by Frost and colleagues and manualized in Steketee and Frost (2007). Method: Participants with clinically significant hoarding were recruited from the community and a university‐based anxiety clinic. Of the 46 patients randomly assigned to CBT or waitlist (WL), 40 completed the 12‐week assessment and 36 completed 26 sessions. Treatment included education and case formulation, motivational interviewing, skills training for organizing and problem solving, direct exposure to nonacquiring and discarding, and cognitive therapy. Measures included the Saving Inventory‐Revised (self‐report), Hoarding Rating Scale‐Interview, and measures of clinical global improvement. Between group repeated measures analyses using general linear modeling examined the effect of CBT versus WL on hoarding symptoms and moodstate after 12 weeks. Within group analyses examined pre‐post effects for all CBT participants combined after 26 sessions. Results: After 12 weeks, CBT participants benefited significantly more than WL patients on hoarding severity and mood with moderate effect sizes. After 26 sessions of CBT, participants showed significant reductions in hoarding symptoms with large effect sizes for most measures. At session 26, 71% of patients were considered improved on therapist clinical global improvement ratings and 81% of patients rated themselves improved; 41% of completers were clinically significantly improved. Conclusions: Multicomponent CBT was effective in treating hoarding. However, treatment refusal and compliance remain a concern, and further research with independent assessors is needed to establish treatment benefits and durability of gains. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.
Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg‐negative and anti‐HBc antibodies‐positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer

Summary. We studied clinical outcome and clinico‐virological factors associated with hepatitis B virus reactivation (HBV‐R) following cancer treatment in hepatitis B virus surface antigen (HBsAg)‐negative/anti‐hepatitis B core antibodies (anti‐HBcAb)‐positive patients. Between 11/2003 and 12/2005, HBV‐R occurred in 7/84 HBsAg‐negative/anti‐HBcAb‐positive patients treated for haematological or solid cancer. Virological factors including HBV genotype, core promoter, precore, and HBsAg genotypic and amino acid (aa) patterns were studied. Patients presenting with reactivation were men, had an hepatitis B virus surface antibody (HBsAb) titre <100 IU/L and underwent >1 line of chemotherapy (CT) significantly more frequently than controls. All were treated for haematological cancer, 3/7 received haematopoietic stem cell transplantation (HSCT), and 4/7 received rituximab. Using multivariate analysis, receiving >1 line of CT was an independent risk factor for HBV‐R. Fatal outcome occurred in 3/7 patients (despite lamivudine therapy in two), whereas 2/4 survivors had an HBsAg seroconversion. HBV‐R involved non‐A HBV genotypes and core promoter and/or precore HBV mutants in all cases. Mutations known to impair HBsAg antigenicity were detected in HBV DNA from all seven patients. HBV DNA could be retrospectively detected in two patients prior cancer treatment and despite HBsAg negativity. HBV‐R is a concern in HBsAg‐negative/anti‐HBcAb‐positive patients undergoing cancer therapy, especially in males presenting with haematological cancer, a low anti‐HBsAb titre and more than one chemotherapeutic agent. HBV DNA testing is mandatory to improve diagnosis and management of HBV‐R in these patients. The role of specific therapies such as rituximab or HSCT as well as of HBV aa variability deserves further studies.
Alcohol and Substance Abuse among Schizophrenic Patients Presenting to an Emergency Psychiatric Service

To obtain information regarding patterns of alcohol and substance use, portions of the Diagnostic Interview Schedule (DIS) were administered to 53 schizophrenic patients who presented to the crisis service of an emergency room in a major general hospital. The number of individuals in the sample qualifying for a lifetime diagnosis of an alcohol abuserelated disorder was quite high (47%), and there was a strong correlation between disorders of alcohol abuse and the use of other drugs. Other than alcohol, marijuana was the most frequently abused drug. Individuals who qualified for a diagnosis of an alcohol-related disorder were compared with those who did not on a variety of diagnostic and demographic variables. The authors conclude by suggesting that the high-risk rates of drug use-related disorders reported in this sample may be due to the preferential use of emergency services by schizophrenic patients with alcohol and drug abuse-related disorders.
In vivo angiogenic activity of neuroblastoma correlates with MYCN oncogene overexpression

Neuroblastoma (NB) is the most common malignant solid tumor in early childhood. Amplification of the MYCN oncogene is associated with a more malignant course of disease and poor outcome. The role that MYCN plays in the regulation of angiogenesis in NB remains unclear. To better elucidate this matter, fresh biopsy samples from 21 patients, 10 with MYCN‐amplified tumors (defined as having >10 copies of the oncogene) and 11 with nonamplified tumors, were tested for their angiogenic capacity using the chick embryo chorioallantoic membrane assay, a useful model for such investigation. Moreover, using the same experimental model, conditioned media obtained from 5 different human NB cell lines MYCN‐amplified (HTLA‐230, LAN‐5 and GI‐LI‐N) or nonamplified (ACN and SH‐SY5Y) and biopsy fragments obtained from xenografts derived from 4 NB cell lines (HTLA‐230, GI‐LI‐N, ACN and SH‐SY5Y) injected in nude mice were assayed for angiogenic potential. Our results clearly demonstrated that MYCN amplification parallels angiogenesis in NB. When fresh biopsy samples from patients, CM derived from NB cell lines and biopsy fragments derived from xenografts of the same cell lines injected in nude mice were tested, the response was univocal: the angiogenic response, evaluated both macroscopically and microscopically, was significantly higher in the MYCN‐amplified specimens compared to the nonamplified ones. © 2002 Wiley‐Liss, Inc.
Behavioral Oscillations in Attention: Rhythmic α Pulses Mediated through θ Band

Neuronal oscillations are ubiquitous in the brain and contribute to perception and attention. However, most associated evidence derives from post hoc correlations between brain dynamics and behavior. Although a few recent studies demonstrate rhythms in behavior, it remains largely unknown whether behavioral performances manifest spectrotemporal dynamics in a neurophysiologically relevant manner (e.g., the temporal modulation of ongoing oscillations, the cross-frequency coupling). To investigate the issue, we examined fine spectrotemporal dynamics of behavioral time courses in a large sample of human participants (n = 49), by taking a high time-resolved psychophysical measurement in a precuing attentional task. We observed compelling dynamic oscillatory patterns directly in behavior. First, typical attentional effects are demonstrated in low-pass (0–2 Hz) filtered time courses of behavioral responses. Second, an uninformative peripheral cue elicits recurring α-band (8–20 Hz) pulses in behavioral performances, and the elicited α pulses for cued and uncued conditions are in a temporally alternating relationship. Finally, ongoing α-band power is phase locked to ongoing θ-bands (3–5 Hz) in behavioral time courses. Our findings constitute manifestation of oscillations at physiologically relevant rhythms and power-phase locking, as widely observed in neurophysiological recordings, in behavior. The findings suggest that behavioral performance actually consists of rich dynamic information and may reflect underlying neuronal oscillatory substrates. Our data also speak to a neural mechanism for item attention based on successive cycles (θ) of a sequential attentional sampling (α) process.
Therapeutic potential of endothelin receptor modulators: lessons from human clinical trials

The endothelin system, and in particular endothelin receptors, are targets for therapeutic intervention in human diseases. Endothelin receptor antagonists have reached clinical use for treating pulmonary arterial hypertension, and are under clinical investigation for several other diseases, such as cancer, vasospasm or fibrogenic diseases. We review the molecules that have been evaluated in the main clinical trials, from the point of view of receptor selectivity and of their chemical characteristics which were important for efficacy in pulmonary hypertension. We will also discuss future use of antagonists to endothelin receptor(s) in several human diseases and what should be the necessary properties of the future molecules for efficacy in diseases where the presently tested molecules displayed suboptimal efficacy.
The determination of the relevance of basic sciences learning objectives to clinical practice using a questionnaire survey

Objectives Facilitating sufficient understanding of the basic sciences to underpin clinical practice is important in producing the good doctor. However, the inclusion of irrelevant material in the curriculum not only wastes valuable learning time, but may also hinder learning. The aim of this study was to determine how relevant staff and students thought respiratory basic science learning objectives were to medical practice.
Evaluation of Cardiovascular Parameters of a Selenium‐Based Antihypertensive Using Pulsed Doppler Ultrasound

&NA; The pharmacology of selenium is of much interest because selenium deficiency has been linked to cardiovascular diseases, cancer, and arthritis, and selenoenzymes are critical cellular antioxidants. We have previously reported that phenyl‐2‐aminoethylselenide (PAESe) and its derivatives represent a novel class of selenium‐based antihypertensive agents that exhibit unique biochemical and pharmacologic properties. We now report on experiments designed to probe the hemodynamic mechanism of action of these compounds in spontaneously hypertensive rats (SHR). A noninvasive pulsed Doppler ultrasound probe was used to measure peak blood flow velocity in the aortic arch from the right second intercostal space. PAESe was found to increase peak aortic blood flow velocity (+44%), heart rate (+16%), and blood flow acceleration (+105%), while decreasing left ventricular ejection time (LVET) (‐37%) concomitant with a decrease in mean arterial pressure (‐54%). These results were compared with the known vasodilator hydralazine, which had similar effects on mean arterial pressure (MAP) and peak velocity but caused an increase in LVET (+42%) and a decrease in heart rate (‐18%). Taken together, our results suggest that PAESe decreases blood pressure via a decrease in peripheral resistance, which overcomes the initial increase in heart rate and acceleration to give a net decrease in MAP.
Oligodendroglial tau filament formation in transgenic mice expressing G272V tau

Genetic evidence indicates that several mutations in tau, including G272V, are linked to frontotemporal dementia with parkinsonism. We expressed this mutation in mouse brains by combining a prion protein promoter‐driven expression system with an autoregulatory transactivator loop that resulted in high expression of human G272V tau in neurons and in oligodendrocytes. We show that G272V tau can form filaments in murine oligodendrocytes. Electron microscopy established that the filaments were either straight or had a twisted structure; these were 17–20 nm wide and had a periodicity of ≈ 75 nm. Filament formation was associated with tau phosphorylation at distinct sites, including the AT8 epitope 202/205 in vivo. Immunogold electron microscopy of sarcosyl‐extracted spinal cords from G272V transgenic mice using phosphorylation‐dependent antibodies AT8 or AT100 identified several sparsely gold‐labelled 6‐nm filaments. In the spinal cord, fibrillary inclusions were also identified by thioflavin‐S fluorescent microscopy in oligodendrocytes and motor neurons. These results establish that expression of the G272V mutation in mice causes oligodendroglial fibrillary lesions that are similar to those seen in human tauopathies.
Effect of Vacuum Profile on Breast Milk Expression Using an Electric Breast Pump

The authors compared milk expession using 5 experimental vacuum patterns and a commercially available vacuum pattern ranging in cycle times (20 to 78 cycles/min) and vacuum curve dynamics in 30 mothers using an experimental, software-controlled electric breast pump. The volume of milk removed over 5 minutes differed (P= .0072) between patterns (range = 62.8 ± 6.6m Lto 47.2 ± 5.1 mL). However, therewas no difference in the percentage of available milk removed (range = 99.4% ± 15.1% to 70.6% ± 8.6%). The rate of milk removal differed between patterns at both the beginning (1 minute) and end (1.5 minutes) of the expression period (P< .05). Peak vacuum chosen differed between patterns (P= .0085) butwas not related to either the volume or percentage of available milk expressed. Breastfeeding characteristics did not differ between poor and successful expressers. These results showthat breast milk expression by an electric breast pump can be influenced by the vacuum pattern.
Antiphospholipid Antibodies and the Antiphospholipid Syndrome: Clinical Significance and Treatment

This article provides a review of the various types of antiphospholipid (aPL) antibodies and antiphospholipid syndromes, their prevalence, presumed origin, relationship to autoimmunity in general, and their role in the body's defenses and apoptosis. New hypotheses such as the role of antibodies to beta2 glycoprotein I (beta2GPI) and the signaling of toll-like receptors are also discussed, as is the spectrum of clinical manifestations associated with the demonstration of these antibodies, now assumed to be "pathogenic. " A distinction is made between antibodies present in sera of patients with a variety of microangiopathic syndromes (MAPS; e.g., HELLP syndrome, thrombotic thrombocytopenic purpura, and thrombotic microangiopathic syndromes). In these conditions, the antibodies might not be "pathogenic" but, alternatively, generated by small vessel endothelial damage. These conditions are differentially referred to as microangiopathic antiphospholipid-associated syndromes, and they should be differentiated from the microvascular occlusions that are seen in the antiphospholipid syndrome. Current treatments of the antiphospholipid syndrome are briefly reviewed.
Functional assays testing pathogenicity of 14 cystathionine‐beta synthase mutations

In this study, 14 CBS alleles from homocystinuric patients were expressed heterologously in E. coli and their enzyme activities were assayed in vitro. Additionally, mutant CBS proteins were visualized by Western blot from denaturing and non‐denaturing polyacrylamide gels. The 14 mutations characterized were: p.R125W (c.373C>T), p.G148R (c.442G>A), p.M173V (c.517A>G), p.T191M (c.572C>T), p.A226T (c.676G>A), p.C275Y (c.824G>A), p.R336C (c.1006C>T), p.R336H (c.1007G>A), p.L338P (c.1013T>C), p.S349N (c.1046G>A), p.R379Q (c.1136G>A), p.L456P (c.1367T>C), p.G522fsX540 (c.1566delG), and p.R548Q (c.1643G>A). Eleven of the mutant alleles exhibited an activity lower than 4% of the wild‐type protein. In contrast, mutations p.A226T and p.M173V presented 20% and 40% of the wild‐type activity, respectively, whereas the activity of p.R548Q was up to 60% of the wild‐type. This suggests that it is a new rare variant rather than a pathogenic mutation. Most of the mutated proteins exhibited a decreased signal in Western blot analyses. The non‐denaturing PAGE revealed that the wild‐type protein retained the capacity to form a multimeric quaternary structure, whereas in the mutations p.M173V, p.A226T, and p.G548Q, this structure grade was dramatically reduced and was completely absent in the rest of the mutations. © 2006 Wiley‐Liss, Inc.
Immune response of Brazilian children to a Neisseria meningitidis serogroup B outer membrane protein vaccine: comparison with efficacy

Since 1986, serogroup B Neisseria meningitidis has caused approximately 80% of the meningococcal disease in Brazil. In 1988, an epidemic caused by N. meningitidis B:4:P1.15 was recognized in the greater São Paulo area of Brazil. The São Paulo state government decided to vaccinate children from 3 to 83 months of age with a vaccine consisting of serotype 4 outer membrane protein and group C meningococcal polysaccharide that was produced in Cuba. About 2.7 million children were vaccinated during two immunization campaigns conducted in 1989 and 1990. Because of this, a case-control study was designed to determine vaccine efficacy against group B meningococcal disease. The purpose of our study was to compare the antibody response with the protection from disease estimated from the case-control study. We measured the immune responses of vaccinees by enzyme-linked immunosorbent assay (ELISA), immunoblot, and bactericidal assay. The development of bactericidal antibodies was age dependent and in good agreement with the results of the case-control study. Only 40% of vaccinees showed fourfold or greater increases in bactericidal antibody titers after vaccination. A poor correlation between antibody levels detected by ELISA and those by bactericidal assay was found. Immunoblot analysis showed that about 50% of the serum samples with bactericidal titers higher than 1:4 were reactive with class 1 outer membrane protein. We conclude that the bactericidal assay is a good, laboratory-based, functional assay for the study of vaccine immunogenicity and that an effective solution to group B meningococcal disease remains to be demonstrated.
Formulation Studies and In Vivo Evaluation of a Flurbiprofen-Hydroxypropyl β-Cyclodextrin System

The purpose of this study was 1) to investigate in vivo advantages of a flurbiprofen (FPN)-hydroxypropyl β-cyclodextrin (HPβCD) solid dispersion (SD) in rats, 2) to study factors affecting the drug release from SD formulations, and 3) to evaluate the pharmacokinetic profile of the drug when administered as SD, in humans. The solubility of FPN in water and dissolution media was evaluated as a function of HPβCD concentration. The SD was prepared by coevaporation from dilute aqueous NH3 and evaluated in rats. The release of the drug from tablet formulations and capsules of SD was studied in simulated gastric fluid and phosphate buffer, pH 7.2. The bioavailability of drug when administered as SD was evaluated in humans. HPβCD enhanced the solubility of the drug, and SD improved bioavailability and reduced ulcerogenicity of the drug in rats. The type of excipient used affected drug release from tablets. Presence of microcrystalline cellulose, a hydrophilic polymeric excipient, resulted in uptake of water and stabilization of the resulting gels-like structure of HPβCD–containing tablets. This adversely affected drug release. The release from capsules filled with SD was comparable to that obtained from plain SD powder. The drug–HPβCD association constant in water was much lower than the values reported in literature. The bioavailability (which could suffer in case of higher association constant) was enhanced on administration of SD-filled capsules to humans.
Graphene-on-silicon hybrid plasmonic-photonic integrated circuits

Graphene surface plasmons (GSPs) have shown great potential in biochemical sensing, thermal imaging, and optoelectronics. To excite GSPs, several methods based on the near-field optical microscope and graphene nanostructures have been developed in the past few years. However, these methods suffer from their bulky setups and low GSP-excitation efficiency due to the short interaction length between free-space vertical excitation light and the atomic layer of graphene. Here we present a CMOS-compatible design of graphene-on-silicon hybrid plasmonic-photonic integrated circuits that achieve the in-plane excitation of GSP polaritons as well as localized surface plasmon (SP) resonance. By employing a suspended membrane slot waveguide, our design is able to excite GSP polaritons on a chip. Moreover, by utilizing a graphene nanoribbon array, we engineer the transmission spectrum of the waveguide by excitation of localized SP resonance. Our theoretical and computational study paves a new avenue to enable, modulate, and monitor GSPs on a chip, potentially applicable for the development of on-chip electro-optic devices.