Intratubular germ cell neoplasia of the human testis: heterogeneous protein expression and relation to invasive potential.
Testicular germ cell cancer develops from premalignant intratubular germ cell neoplasia, unclassified cells that are believed to arise from failure of normal maturation of fetal germ cells from gonocytes (OCT4(+)/MAGEA4(-)) into pre-spermatogonia (OCT4(-)/MAGEA4(+)). Intratubular germ cell neoplasia cell subpopulations based on stage of germ cell differentiation have been described, however the importance of these subpopulations in terms of invasive potential has not been reported. We hypothesized that cells expressing an immature (OCT4(+)/MAGEA4(-)) germ cell profile would exhibit an increased proliferation rate compared with those with a mature profile (OCT4(+)/MAGEA4(+)). Therefore, we performed triple immunofluorescence and stereology to quantify the different intratubular germ cell neoplasia cell subpopulations, based on expression of germ cell (OCT4, PLAP, AP2γ, MAGEA4, VASA) and proliferation (Ki67) markers, in testis sections from patients with preinvasive disease, seminoma, and non-seminoma. We compared these subpopulations with normal human fetal testis and with seminoma cells. Heterogeneity of protein expression was demonstrated in intratubular germ cell neoplasia cells with respect to gonocyte and spermatogonial markers. It included an embryonic/fetal germ cell subpopulation lacking expression of the definitive intratubular germ cell neoplasia marker OCT4, that did not correspond to a physiological (fetal) germ cell subpopulation. OCT4(+)/MAGEA4(-) cells showed a significantly increased rate of proliferation compared with the OCT4(+)/MAGEA4(+) population (12.8 versus 3.4%, P<0.0001) irrespective of histological tumor type, reflected in the predominance of OCT4(+)/MAGEA4(-) cells in the invasive tumor component. Surprisingly, OCT4(+)/MAGEA4(-) cells in patients with preinvasive disease showed significantly higher proliferation compared to those with seminoma or non-seminoma (18.1 versus 10.2 versus 7.2%, P<0.05, respectively). In conclusion, this study has demonstrated that OCT4(+)/MAGEA4(-) cells are the most frequent and most proliferative cell population in tubules containing intratubular germ cell neoplasia, which appears to be an important factor in determining invasive potential of intratubular germ cell neoplasia to seminomas.


Couple relationship quality and the infant home language environment: Gender-specific findings.
Couple relationship quality is known to drop significantly across the transition to parenthood (Ahlborg & Strandmark, 2001; Doss, Rhoades, Stanley, & Markman, 2009), yet individual differences in the amount of parent-to-infant talk have rarely been studied in relation to variation in couple relationship quality. Addressing this gap, the current study of 93 first-time parents with 4-month-old infants included multimeasure reports of couple relationship quality from both mothers and fathers and examined associations between couple relationship quality and the home language environment, assessed via the Language Environment Analysis (LENA), when infants were approximately 7 months old. LENA consists of a wearable talk pedometer that records a full day of naturalistic parent-infant talk and is coupled to software that provides automated analysis. Given the covariation between depression and both couple relationship quality and parental infant-directed talk, both maternal and paternal depression were controlled for in all analyses. Results showed that, for mothers of sons, frequency of infant-directed talk was inversely related to couple relationship quality. Consistent with family systems theory, this finding provides partial support for the compensation hypothesis. However, variation in couple relationship quality was unrelated to infant-directed speech in fathers or in mothers of daughters. Together, these findings demonstrate that the gender composition of the parent-infant dyads plays a moderating role on the association between couple relationship quality and parent-infant talk. (PsycINFO Database Record (c) 2020 APA, all rights reserved).


Mechanisms and classification of deranged distal urinary acidification.
Distal renal tubular acidosis has been thought to be the consequence of an impaired ability to maintain a large pH gradient between distal nephron urine and blood. Recent evidence suggests that the classification of deranged distal nephron acidification requires expansion. These mechanisms whereby the urine is acidified in the distal nephron include an active component, a passive component, and a component of bicarbonate secretion. Active proton secretion is influenced by the integrity of the pump and the nature of the electrical chemical gradient against which it operates. The passive component relates either to the backleak of acid from lumen to blood or the leak of bicarbonate from blood to lumen; under ordinary circumstances this passive component is negligible. Aldosterone also influences distal acidification. A defect in most of these components can be identified experimentally. We propose a classification of deranged distal acidification that will allow identification of the mechanism responsible for the defect. This classification, which employs measurement of the urinary carbon dioxide gradient, the response of the kidney to sulfate or phosphate administration, the urinary pH during acidosis, and the state of potassium and sodium excretion, can easily be performed in human subjects.


Total elbow arthroplasty for primary and metastatic tumor.
Prostheses can be used in elbow reconstruction in both primary and metastatic lesions. Several authors have reported their experience with different types of implant, but not with modular prostheses. Limb salvage using an elbow prosthesis is effective in obtaining good functional results and reliable local tumor control. Forty-seven patients treated at the Rizzoli Institute for elbow neoplasm from 1990 to 2012 were evaluated. There were 30 primary tumors (64%), 24 bone tumors and 6 soft tissue sarcomas, and 17 bone metastases. Elbow reconstruction used a modular prosthesis in 25 patients and a standard prosthesis in 22. Reconstruction was primary in 30 patients and secondary in 17. At last control, 15 (32%) were dead of disease (DOD) at a mean follow-up of 35 months, 12 (25%) were alive with disease (AWD) at a mean follow-up of 29 months, 19 (40%) showed no evidence of disease (NED) at a mean follow-up of 80 months. Early complications were related to unexpected neurological damage, observed in 12 patients (25%): in 5 cases the deficit resolved in a mean 6 months; in the others, no or only partial recovery was observed. Two implants (4%) developed infection: 1 was treated with antibiotic therapy, and the other required implant revision. One implant showing cement extrusion was revised. In 3 patients (6%) radiography showed a radiolucent halo around the stem (2 humeral, 1 ulnar); no measures were taken, as the patients were completely asymptomatic at every follow-up. In 3 patients (6%) partial resorption of the allograft was observed on X-ray, but remained unchanged at last follow-up, without pain or functional impairment. Seven local recurrences (15%) were observed, at a mean of 16 months after surgery; 5 were treated by resection and/or radiotherapy, and 2 by amputation. Mean functional scores on MEPS and MSTS were respectively 84% and 22/30 (73%). Elbow prostheses provided better function in primary than in metastatic tumor. Elbow prosthesis reconstruction after tumor resection is a viable option both for primary and secondary bone neoplasms. Therapeutic. IV, retrospective study.


Effect of diet and absence of protozoa on the rumen microbial community and on the representativeness of bacterial fractions used in the determination of microbial protein synthesis.
Accurate estimates of microbial synthesis in the rumen are vital to optimize ruminant nutrition. Liquid- (LAB) and solid-associated bacterial fractions (SAB) harvested from the rumen are generally considered as microbial references when microbial yield is calculated; however, factors that determine their composition are not completely understood. The aim of this study was to evaluate the effect of diet and absence or presence of rumen protozoa on the rumen microbial community. It was hypothesized that these treatments could modify the composition and representativeness of LAB and SAB. Twenty twin lambs (Ovis aries) were used; one-half of the twins were kept protozoa-free, and each respective twin sibling was faunated. At 6 mo of age, 5 animals from each group were randomly allocated to the experimental diets consisting of either alfalfa hay as the sole diet, or 50:50 mixed with ground barley grain. After 15 d of adaptation to the diet, animals were euthanized, rumen and abomasum contents were sampled, and LAB and SAB isolated. The presence of protozoa buffered the effect of diet on the rumen bacterial population. Faunated animals fed alfalfa hay had a greater abundance of F. succinogenes, anaerobic fungi and methanogens, as well as an enhanced rumen bacterial diversity. Cellulolytic bacteria were more abundant in SAB, whereas the abomasal abundance of most of the microorganisms studied was closer to those values observed in LAB. Rumen and abomasal samples showed similar bacterial DNA concentrations, but the fungal and protozoal DNA concentration in the abomasum was only 69% and 13% of that observed in the rumen, respectively, suggesting fungal and protozoal sequestration in the rumen or possible preferential degradation of fungal and protozoal DNA in the abomasum, or both. In conclusion, absence of protozoa and type of diet extensively modified the chemical composition of LAB and SAB as a consequence of changes in the microbial composition of these fractions.


Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo.
This paper aims to investigate the effects of artesunate (ART) on growth and apoptosis in human osteosarcoma HOS cell line in vitro and in vivo and to explore the possible underlying mechanisms. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The induction of apoptosis was detected by light and transmission electron microscopy and flow cytometry. Western blot analysis was used to investigate the related mechanisms. Nude mice were further employed to investigate the antitumour activity of ART in vivo. MTT assay results demonstrated that ART selectively inhibits the growth of HOS cells in a dose- and time-dependent manner. Based on the findings of light and transmission electron microscopy, Hoechst 33258 staining, and fluorescein isothiocyanate (FITC)-annexin V staining, the cytotoxicity of ART in HOS cells occurs through apoptosis. With ART treatment, cytosolic cytochrome c was increased, Bax expression was gradually upregulated, Bcl-2 expression was downregulated, and caspase-9 and caspase-3 were activated. Thus, the intrinsic apoptotic pathway may be involved in ART-induced apoptosis. Cell cycle analysis by flow cytometry indicated that ART may induce cell cycle arrest at G(2)/M phase. In nude mice bearing HOS xenograft tumours, ART inhibited tumour growth and regulated the expressions of cleaved caspase-3 and survivin, in agreement with in vitro observations. ART has a selective antitumour activity against human osteosarcoma HOS cells, which may be related to its effects on induction of apoptosis via the intrinsic pathway. The results suggest that ART is a promising candidate for the treatment of osteosarcoma.


[HPV prophylactic vaccines].
Since 2007, two prophylactic vaccines against Human Papillomavirus (HPV) infection and HPV. induced lesions (both precancerous dysplasia and cancer) have been registered in Belgium. In multicentre randomized trials including more than 64,000 patients, these vaccines were shown to be highly efficient against the occurrence of condyloma and of dysplastic lesion in the cervix, vagina and vulva in females and in the anus in males. These vaccines display an excellent tolerance and safety profile, the most common adverse event being minor and transient side effects at the injection site. The protection given by these vaccines is more important in subjects that have not been in contact with HPV previously ; moreover the title of neutralizing antibodies against HPV are significantly higher in children vaccinated before 15 years-old age compared to young person vaccinated after this age. For these two reasons, it is recommended to vaccinate before the first sexual relationships. Recently, several studies have demonstrated that vaccination by two doses given at 0 and 6 months in children before 15 years-old was equivalent to the three doses scheme that should be given at 0, 1 or 2 and 6 months in subjects aged 15 years or more. In the countries that have achieved a high vaccine coverage among their young female population, the prevalence of HPV infection and the incidence of high grade cervical dysplasia have significantly decreased while condyloma has almost disappeared four years after the implementation of HPV vaccination. In HIV-positive subjects who are particularly susceptible to infection and lesions induced by HPV, vaccination brings levels of antibody comparable to what is found in the general population with similar safety.


Metallic mesh devices-based terahertz parallel-plate resonators: characteristics and applications.
The capability to design, fabricate, and optimize metamaterials based on various structures and material platforms has been crucial for the rapid development of modern terahertz (THz) technology. While the detailed structures of artificial unit cells within a metamaterial is certainly worth investigating, there has been increasing demand to integrate novel metamaterials with a traditional functional photonic device to form a hybrid device, whose performance is so significantly improved as to be promising for real-world applications. In this study, we proposed, for the first time, a THz parallel-plate resonator based on metallic mesh devices (MMDs) for chemical sensing applications. We studied the influences of various structural parameters through simulations, fabricated MMD-based resonator devices, and fully characterized the device performance through THz spectroscopy experiments. Furthermore, we experimentally demonstrated that our device can detect a doxycycline hydrochloride aqueous solution whose concentrations is as low as 1 mg L-1 through resonance frequency shifts, evidencing the device sensitivity capable of delicate chemical sensing tasks. Our work presents a practical and low cost architecture for chemical sensing using THz radiation, which opens new avenues for numerous useful THz devices based on metamaterials.


Update: Medicare patient records in physicians' offices.
We have become aware of a growing concern among physicians who are under the impression that review of Medicare patients' records in physicians' offices is imminent. Our current activity of reviewing care provided by health maintenance organizations (HMOs) may have caused some physicians to believe that such review had already started. HMO review may, at times, include a request for office records, but such requests are made to the HMO. The review does not take place at the physician's office.


Early Clinical Features, Time to Secondary Progression, and Disability Milestones in Polish Multiple Sclerosis Patients.
Background and Objectives: Determining the clinical course of multiple sclerosis (MS) and prediction of long-term disability can be a big challenge. To determine early clinical features of MS, their influence on long-term disability progression, and time to transition from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS), a cohort of Polish patients was studied. Materials and Methods: We retrospectively evaluated 375 Polish MS patients based on data from available medical records. We assessed early clinical MS features and the relationship between demographics and time from disease onset to attainment of 4 and 6 points on the Expanded Disability Status Scale (EDSS), as well as time to conversion from RRMS to SPMS. Results: The differences between initial MS variants were significantly associated with gender, age at disease onset, number and type of the first symptoms, and rate of the disability accrual. Mean times from disease onset to attainment of EDSS 4 and 6 were significantly influenced by the disease variant, age at onset, gender, degree of recovery from the initial symptoms, and first inter-bouts interval. The mean time to secondary progression was significantly influenced by the number and type of the first symptoms of RRMS. Conclusions: Early clinical features of MS are important in determining the disease variant, the time to transition from RRMS to SPMS, as well as predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Polish patients are similar to other regions of the world.


Nonlinearity- and dispersion- less integrated optical time magnifier based on a high-Q SiN microring resonator.
The ability to measure optical signals with fast dynamics is of significant interest in many application fields. Usually, single-shot measurements of non-periodic signals can be enabled by time magnification methods. Like an optical lens in the spatial domain, a time magnifier, or a time lens, stretches a signal in the time domain. This stretched signal can then be further processed with low bandwidth photonics and electronics. For a robust and cost-effective measurement device, integrated solutions would be especially advantageous. Conventional time lenses require dispersion and nonlinear optical effects. Integration of a strong dispersion and nonlinearities is not straightforward on a silicon photonics platform and they might lead to signal distortions. Here we present a time magnifier based on an integrated silicon nitride microring resonator and frequency-time coherence optical sampling, which requires neither a dispersion, nor a nonlinearity. Sampling of signals with up to 100 GHz bandwidth with a stretching factor of more than 100 is achieved using low bandwidth measurement equipment. Nevertheless, with already demonstrated integrated 100 GHz modulators, the method enables the measurement of signals with bandwidths of up to 400 GHz. Since amplitude and phase can be sampled, a combination with the spectrum slicing method might enable integrated, cost-effective, small-footprint analog-to-digital converters, and measurement devices for the characterization of single irregular optical signals with fast dynamics and bandwidths in the THz range.


Run-time reconfigurable adaptive LDPC coding for optical channels.
In this paper, we proposed a class of large-girth QC-LDPC codes designed to maximize the girth property with code rates ranging from 0.5 to 0.8, which leads to well-structured parity-check matrix and generator matrix. Instead of implementing several FEC encoder and decoder engines in hardware, we design an efficient unified FPGA-based architecture enabling run-time reconfigurable capability. Apart from four principle LDPC codes being incorporated into a unified design, shortening is adopted to bridge the rate gap between principle codes. With our proposed unified LDPC engine, the signal-to-noise ratio (SNR) limits of -1 dB to 2.2 dB have been demonstrated at BER of 10-12 in additive white Gaussian noise (AWGN) channel by FPGA emulation. It is desirable for the application to both free-space optical (FSO) and fiber optics communications. Large code rate range is preferred to deal with various channel impairments. To further verify the proposed unified code engine for FSO applications, we tested the scheme through a spatial light modulator (SLM)-based FSO channel emulator. We showed that in medium atmospheric turbulence regime, a post-FEC BER below 10-8 can be achieved without any interleaver and adaptive optics.


Docetaxel/anthracycline combinations for breast cancer treatment.
Anthracyclines and taxanes represent the most active group of cytotoxic agents for the treatment of breast cancer. Combining docetaxel with anthracyclines is widely used in the clinic, but, due to an overlap in toxicities this strategy remains somewhat challenging. Combinations of docetaxel with doxorubicin, epirubicin or liposomal doxorubicin in conventional or dose-dense cycles are reviewed in this article. A specific focus is given to the three-drug combination of docetaxel, doxorubicin and cyclophosphamide (TAC regimen), as it is registered for the adjuvant treatment of node-positive breast cancer. Febrile neutropenia and associated toxicities are frequently associated with the TAC combination. However, when used as primary prophylaxis with granulocyte growth factors, as well as antibiotics, this regimen is considered as a safely-applicable standard option for early breast cancer treatment.


Melting transition of Lennard-Jones fluid in cylindrical pores.
Three-stage pseudo-supercritical transformation path and multiple-histogram reweighting technique are employed for the determination of solid-liquid coexistence of the Lennard-Jones (12-6) fluid, in a structureless cylindrical pore of radius, R, ranging from 4 to 20 molecular diameters. The Gibbs free energy difference is evaluated using thermodynamic integration method by connecting solid and liquid phases under confinement via one or more intermediate states without any first order phase transition among them. The thermodynamic melting temperature, Tm, is found to oscillate for pore size, R < 8, which is in agreement with the behavior observed for the melting temperature in slit pores. However, Tm for almost all pore sizes is less than the bulk case, which is contrary to the behavior seen for the slit pore. The oscillation in Tm decays at around pore radius R = 8, and beyond that shift in the melting temperature with respect to the bulk case is in line with the prediction of the Gibbs-Thomson equation.


Trends and prescribing patterns of oral anti-neoplastic drugs: a retrospective longitudinal study.
Cancer as a global public health problem, imposes a heavy disease burden. With the rapid development of oral anti-neoplastic drugs, there has been a paradigm shift in the treatment of cancer from intravenous to oral administration. This study was conducted to investigate the trends and prescribing patterns of oral anti-neoplastic drugs in an academic tertiary hospital in China. A single-center and retrospective analysis was performed based on the prescriptions of outpatients treated with oral anti-neoplastic drugs from 2017 to 2022. Yearly prescriptions and expenditure were calculated according to their pharmacological classes, and trends were further analyzed. Defined daily doses (DDDs) and defined daily cost (DDC) of oral targeted anti-neoplastic drugs were also determined. Both the number of prescriptions and expenditure of oral anti-neoplastic drugs increased progressively. There was a significant upward trend in the number and proportion of prescriptions for the older adult group, male group, and patients with gynecologic/genitourinary and respiratory cancer. Hormonal therapy agents accounted for the highest proportion of prescriptions, and letrozole was initially the most frequently prescribed drug. The number of DDDs of total oral targeted anti-neoplastic drugs showed a continuously ascending trend, primarily driven by the usage of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and BCR-ABL TKIs. The prescriptions and expenditure of oral anti-neoplastic drugs, and the number of DDDs of oral targeted anti-neoplastic drugs all showed a progressively ascending trend. Further studies are needed to evaluate the long-term health and financial outcomes, and the factors influencing these prescribing patterns.


Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum.
The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies. Therefore, we attempted to determine if glial cell-type specific markers may be altered in autistic brain tissue in a manner that is consistent with known cellular findings, such that they could serve as a proxy for glial cell numbers and/or activation patterns. We assessed the relative expression of five glial-specific markers and two neuron-specific markers via qRT-PCR. We studied tissue samples from the prefrontal cortex (PFC) and cerebellum of nine post-mortem autistic brain samples and nine neurologically-normal controls. Relative fold-change in gene expression was determined using the ΔΔCt method normalized to housekeeping gene β-actin, with a two-tailed Student's t-test P <0.05 between groups considered as significant. Both astrocyte- and microglial-specific markers were significantly more highly expressed in autistic PFC as compared to matched controls, while in the cerebellum only astrocyte markers were elevated in autistic samples. In contrast, neuron-specific markers showed significantly lower expression in both the PFC and cerebellum of autistic patients as compared to controls. These results are in line with previous findings showing increased glial cell numbers and up-regulation of glial cell gene expression in autistic post-mortem brain tissue, particularly in the PFC, as well as decreased number of neurons in both the PFC and cerebellum of autistic patients. The concordance of these results with cell-level studies in post-mortem autistic brain tissue suggests that expression of glial cell-type specific markers may serve as a useful alternative to traditional cellular characterization methods, especially when appropriately-preserved post-mortem tissue is lacking. Additionally, these results demonstrate abnormal glial-specific gene expression in autistic brains, supporting previous studies that have observed altered glial cell numbers or activation patterns in ASDs. Future work should directly assess the correlation between cell-type specific marker levels and cell number and activation patterns.


Depth dependent stress revealed by aftershocks.
Characterising the state of stress in the brittle upper-crust is essential in mechanics of faulting, industrial production processes, and operational earthquake forecasting. Nevertheless, unresolved questions concern the variation of pore-fluid with depth and the absolute strength on tectonically active faults. Here we show that, along the San Andreas fault system, the time-delay before the onset of the power-law aftershock decay rate (the c-value) varies by three orders of magnitude in the first 20 km below the surface. Despite the influence of the lithostatic stress, there is no continuous change in c-value with depth. Instead, two decay phases are separated by an abrupt increase at an intermediate depth range of 2-5 km. This transitional regime is the only one observed in fluid-injection-induced seismic areas. This provides strong evidence for the role of fluid and a porosity reduction mechanism at depth of few kilometres in active fault zones. Aftershock statistics can then be used to predict changes in differential shear stress with depth until the brittle-ductile transition is reached.


Variation among United States hospitals in inpatient mortality for cirrhosis.
Little is known about geographic variations in health care for patients with cirrhosis. We studied geographic and hospital-level variations in care of patients with cirrhosis in the United States by using inpatient mortality as an outcome for comparing hospitals. We also aimed to identify features of patients and hospitals associated with lower mortality. We used the 2009 U.S. Nationwide Inpatient Sample to identify patients with cirrhosis, which were based on the International Classification of Diseases, 9th Revision-Clinical Modification diagnosis codes for cirrhosis or 1 of its complications (ascites, hepatorenal syndrome, upper gastrointestinal bleeding, portal hypertension, or hepatic encephalopathy). Multilevel modeling was performed to measure variance among hospitals. There were 102,155 admissions for cirrhosis in 2009, compared with 74,417 in 2003. Overall inpatient mortality was 6.6%. On multivariable-adjusted logistic regression, patients hospitalized in the Midwest had the lowest odds ratio (OR) of inpatient mortality (OR, 0.54; P < .001). Patients who were transferred from other hospitals (OR, 1.49; P < .001) or had hepatic encephalopathy (OR, 1.28; P < .001), upper gastrointestinal bleeding (OR, 1.74; P < .001), or alcoholic liver disease (OR, 1.23; P = .03) had higher odds of inpatient mortality than patients without these features. Those who received liver transplants had substantially lower odds of inpatient mortality (OR, 0.21; P < .001). Multilevel modeling showed that 4% of the variation in mortality could be accounted for at the hospital level (P < .001). Adjusted mortality among hospitals ranged from 1.2% to 14.2%. Inpatient cirrhosis mortality varies considerably among U.S. hospitals. Further research is needed to identify hospital-level and provider-level practices that could be modified to improve outcomes.


Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain.
Resiniferatoxin (RTX) is the most potent among all known endogenous and synthetic agonists for the transient receptor potential vanilloid 1 (TRPV1) receptor, which is a calcium-permeable nonselective cation channel, expressed on the peripheral and central terminals of small-diameter sensory neurons. Prolonged calcium influx induced by RTX causes cytotoxicity and death of only those sensory neurons that express the TRPV1 ion channel leading to selective targeting and permanent deletion of the TRPV1-expressing C-fiber neuronal cell bodies in the dorsal root ganglia. The goal of this project was to provide preclinical efficacy data, that intrathecal RTX could provide effective pain relief and improve function in dogs with bone cancer without significant long-term side effects. In a single-blind, controlled study, 72 companion dogs with bone cancer pain were randomized to standard of care analgesic therapy alone (control, n = 36) or 1.2 μg/kg intrathecal RTX in addition to standard of care analgesic therapy (treated, n = 36). Significantly more dogs in the control group (78%) required unblinding and adjustment in analgesic protocol or euthanasia within 6 weeks of randomization, than dogs that were treated with RTX (50%; P < 0.03); and overall, dogs in the control group required unblinding significantly sooner than dogs that had been treated with RTX (P < 0.02). The analgesic effect was documented in these dogs without any evidence of development of deafferentation pain syndrome that can be seen with neurolytic therapies.


Comparative analysis of transcriptomic profile, histology, and IDH mutation for classification of gliomas.
Gliomas are currently classified through integration of histology and mutation information, with new developments in DNA methylation classification. However, discrepancies exist amongst the major classification methods. This study sought to compare transcriptome-based classification to the established methods. RNAseq and microarray data were obtained for 1032 gliomas from the TCGA and 395 gliomas from REMBRANDT. Data were analyzed using unsupervised and supervised learning and other statistical methods. Global transcriptomic profiles defined four transcriptomic glioma subgroups with 91.4% concordance with the WHO-defined mutation subtypes. Using these subgroups, 168 genes were selected for the development of 1000 linear support vector classifiers (LSVC). Based on plurality voting of 1000 LSVC, the final ensemble classifier confidently classified all but 17 TCGA gliomas to one of the four transcriptomic profile (TP) groups. The classifier was validated using a gene expression microarray dataset. TP1 cases include IDHwt, glioblastoma high immune infiltration and cellular proliferation and poor survival prognosis. TP2a is characterized as IDHmut-codel, oligodendrogliomas with high tumor purity. TP2b tissue is mostly composed of neurons and few infiltrating malignant cells. TP3 exhibit increased NOTCH signaling, are astrocytoma and IDHmut-non-codel. TP groups are highly concordant with both WHO integrated histology and mutation classification as well as methylation-based classification of gliomas. Transcriptomic profiling provides a robust and objective method to classify gliomas with high agreement to the current WHO guidelines and may provide additional survival prediction to the current methods.


Quasistatic work processes: When slowness implies certainty.
Two approaches are outlined to characterize the fluctuation behavior of work applied to a system by a slow change of a parameter. One approach uses the adiabatic theorems of quantum and classical mechanics, and the other one is based on the behavior of the correlations of the generalized coordinate that is conjugate to the changed parameter. Criteria are obtained under which the work done on small thermally isolated as well as on open systems ceases to fluctuate in a quasistatic process.


Key determinants of induced abortion in women seeking postabortion care in hospital facilities in Ouagadougou, Burkina Faso.
Despite the universal recognition of unsafe abortion as a major public health problem, very little research has been conducted to document its precipitating factors in Burkina Faso. Our aim was to investigate the key determinants of induced abortion in a sample of women who sought postabortion care. A cross-sectional household survey was carried out from February to September 2012 in Ouagadougou, Burkina Faso. Data of 37 women who had had an induced abortion and 267 women who had had a spontaneous abortion were prospectively collected on sociodemographic characteristics, pregnancy and birth history, abortion experience, including previous abortion experience, and selected clinical information, including the type of abortion. A two-step regression analysis consisting of a univariate and a multivariate logistic regression was run on Stata version 11.2 in order to identify the key determinants of induced abortion. The findings indicated that 12% of all abortions were certainly induced. Three key factors were significantly and positively associated with the probability of having an induced abortion: whether the woman reported that her pregnancy was unwanted (odds ratio [OR] 10.45, 95% confidence interval [CI] 3.59-30.41); whether the woman reported was living in a household headed by her parents (OR 6.83, 95% CI 2.42-19.24); and if the woman reported was divorced or widowed (OR 3.47, 95% CI 1.08-11.10). On the contrary, being married was protective against induced abortion, with women who reported being married having an 83% (OR 0.17, CI 0.03-0.89) lower chance of having an induced abortion, even when the pregnancy was unwanted. This study has identified three major determinants of induced abortion in Ouagadougou, Burkina Faso. Improved targeted programs on family planning counseling, methods of contraception, and availability of contraceptives should be widely promoted.


Early clinical exposure to geriatric medicine in second-year medical school students--the McGill experience.
This study examined the effect of a curriculum change on early clinical exposure to geriatrics for second-year medical students at McGill University and its effects on learning and students' appreciation of geriatrics as a subspecialty. Second-year medical students (N = 200) were exposed to a change in the curriculum involving the integration of 10 weekly sessions into one integrated week in geriatric medicine. Students participating in 10 weekly sessions were Group 1 and students participating in one integrated week were Group 2. Students rated their rotation using two different scales. The students completed 12-item questionnaires during their feedback sessions at the end of the 10-week session experience or the integrated week. The first six items assessed the students' appreciation of their improvement of knowledge in the subject of geriatrics and aging. The second and third part of the survey (questions 7 and 8) included the students' opinions about the quality of the instruction (teaching feedback) and evaluation. Students in Group 2 found their rotation more effective as a learning experience and expressed greater satisfaction with interaction with the tutors, community settings, and multidisciplinary team sessions. Grades obtained on final examinations showed a better and more-effective acquisition of knowledge by Group 2. The integrated week is a more-effective learning tool in the early clinical experience for medical students in geriatric medicine than 10 weekly sessions as the first introductory experience to the field of geriatric medicine.


A hybrid system for simultaneous velocity and distance measurements in dynamic experiments.
The accurate measurement of an object's motion requires knowledge of both its position and its velocity. The commonly used photonic Doppler velocimetry and broadband laser ranging techniques are ideal for conducting simultaneous dynamic experiments. Instead of employing two distinct measurement systems, we developed a hybrid system that can simultaneously measure velocity and distance in dynamic experiments. This reduces cost and complexity, particularly for multi-channel tests, by using only one probe, photodetector, and oscilloscope channel. By precisely synchronizing the velocity and distance data in time, the system can assist with interpreting the target's position and orientation.


Subjective social status and health: A meta-analysis of community and society ladders.
To derive a robust estimate of the relation between health and subjective status in society versus subjective status in one's community, and to identify moderators of these effects, using meta-analysis. Thirty-eight independent studies, which included both subjective status ladders and collectively provided data from 142,836 participants, met criteria for inclusion. Information on sample characteristics (e.g., age, gender, continent), methodological factors (e.g., scale type, methodological quality), and statistical factors (e.g., model type, inclusion of objective socioeconomic status covariates) were extracted from each study. Random-effects meta-analysis was used to aggregate data across studies. Both the community ladder and the society ladder yielded small but statistically significant associations with health behavior (r = .06 and r = .06), mental health (r = .13 and r = .11), physical health (r = .05 and r = .04), and self-rated health (r = .08 and r = .09) that were comparable in size and were qualified in a similar way by the type of health outcome, sample age, continent, and methodological quality. Additionally, community and society ladders remained significantly associated with health both when considered simultaneously and following the inclusion of objective socioeconomic status covariates. This meta-analysis is the first to establish a unique association of the community ladder with health. It also supports social comparison theories highlighting the importance of comparisons with proximal others and may promote greater use of the community ladder in future research. (PsycINFO Database Record


Relationship between self-reported listening and communication difficulties and executive function: a protocol for a systematic review and meta-analysis.
Listening and communication difficulties can limit people's participation in activity and adversely affect their quality of life. Hearing, as well as listening and communication difficulties, can be measured either by using behavioural tests or self-report measures, and the outcomes are not always closely linked. The association between behaviourally measured and self-reported hearing is strong, whereas the association between behavioural and self-reported measures of listening and communication difficulties is much weaker, suggesting they assess different aspects of listening. While behavioural measures of listening and communication difficulties have been associated with poorer cognitive performance including executive functions, the same association has not always been shown for self-report measures. The objective of this systematic review and meta-analysis is to understand the relationship between executive function and self-reported listening and communication difficulties in adults with hearing loss, and where possible, potential covariates of age and pure-tone audiometric thresholds. Studies will be eligible for inclusion if they report data from both a self-report measure of listening difficulties and a behavioural measure of executive function. Eight databases are to be searched: MEDLINE (via Ovid SP), EMBASE (via Ovid SP), PsycINFO (via Ovid SP), ASSIA (via ProQuest), Cumulative Index to Nursing and Allied Health Literature or CINAHL (via EBSCO Host), Scopus, PubMed and Web of Science (Science and Social Science Citation Index). The JBI critical appraisal tool will be used to assess risk of bias for included studies. Results will be synthesised primarily using a meta-analysis, and where sufficient quantitative data are not available, a narrative synthesis will be carried out to describe key results. No ethical issues are foreseen. Data will be disseminated via academic publication and conference presentations. Findings may also be published in scientific newsletters and magazines. CRD42022293546.


Full-length sequence and mosaic structure of a human immunodeficiency virus type 1 isolate from Thailand.
Human immunodeficiency virus type 1 isolates of envelope genotype E are contributing substantially to the global pandemic. These strains appear to be mosaics, with the gag gene from clade A and the envelope from clade E; the parental clade E strain has not been found. Here we report the first full genomic sequence of one such mosaic virus, isolate CM240 from Thailand. Multiple breakpoints between the two parental genotypes have been found in a CM240 virus. The entire gag-pol region and most, if not all, of the accessory genes vif, vpr, tat, rev, and vpu appear to derive from clade A. The genotype switches to E shortly after the signal peptide of the envelope and back to clade A near the middle of gp41; thus, the portion of the envelope that lies on the cytoplasmic side of the membrane appears to be principally derived not from clade E, as previously thought, but from clade A. Another small segment not belonging to any recognized clade and presumably also contributed by the parental E strain has been found in the long terminal repeat. It may be significant that the implied virion structure resembles a pseudotype virus with the matrix and core from one clade and the outer envelope from another. In the long terminal repeat, differences were observed between CM240 and other clades in the number of NF-kappa B binding sites, the sequence of the TATA box, and the putative secondary structure of the transactivation response region stem-loop. The mosaic structure of a CM240 virion is suggestive of phenotypic differences which might have contributed to the emergence of this variant.


SARS-CoV-2 Antibodies in Breast Milk After Vaccination.
Passive and active immunity transfer through human milk (HM) constitutes a key element in the infant's developing immunity. Certain infectious diseases and vaccines have been described to induce changes in the immune components of HM. We conducted a prospective cohort single-institution study from February 2 to April 4, 2021. Women who reported to be breastfeeding at the time of their coronavirus disease 2019 (COVID-19) vaccination were invited to participate. Blood and milk samples were collected on day 14 after their second dose of the vaccine. Immunoglobulin G (IgG) antibodies against nucleocapsid protein as well as IgG, immunoglobulin M and immunoglobulin A (IgA) antibodies against the spike 1 protein receptor-binding domain against severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2 RBD-S1) were analyzed in both serum and HM samples. Most of the participants (ie, 94%) received the BNT162b2 messenger RNA COVID-19 vaccine. The mean serum concentration of anti-SARS-CoV-2 RBD-S-IgG antibodies in vaccinated individuals was 3379.6 ± 1639.5 binding antibody units per mL. All vaccinated study participants had anti-SARS-CoV-2 RBD-S1-IgG, and 89% of them had anti-SARS-CoV-2 RBD-S-IgA in their milk. The antibody concentrations in the milk of mothers who were breastfeeding 24 months were significantly higher than in mothers with breastfeeding periods <24 months (P < .001). We found a clear association between COVID-19 vaccination and specific immunoglobulin concentrations in HM. This effect was more pronounced when lactation periods exceeded 23 months. The influence of the lactation period on immunoglobulins was specific and independent of other variables.


[Studies on MDM2 oncogene expression and its effect on pancreatic carcinoma cells].
In order to study the interrelation and interaction between MDM2 oncogene and wild type p53 in human pancreatic cancer, we studied the expression and amplification of MDM2 oncogene and its antagonistic effect on wild type p53 by use of gene recombination, gene transduction and molecular hybridization techniques. The results showed that MDM2 oncogene could be detected in all 5 pancreatic cell lines, but MDM2 mRNA expression varied in the different cell lines. The recombinant vector pCMV-MDM2 was transduced into PC-2/s-wtp53 cell line (a transformed PC-2 pancreatic carcinoma cell line containing wild type p53 gene). The resultant cell line, PC-2/s-wtp53/pCMV-MDM2 showed rapid cell growth, a rate similar to that of the parent cell line PC-2. Our results verify the fact that MDM2 gene can abrogate the cell growth arrest mediated by wild type p53 and the antagonistic function of wild type p53.


The LNT model is the best we can do--today.
The form of the dose-response curve for radiation-induced cancers, particularly at low doses, is the subject of an ongoing and spirited debate. The present review describes the current database and basis for establishing a low dose, linear no threshold (LNT) model. The requirement for a dose-response model to be used for risk assessment purposes is that it fits the great majority of data derived from epidemiological and experimental tumour studies. Such is the case for the LNT model as opposed to other nonlinear models. This view is supported by data developed for radiation-induced mutations and chromosome aberrations. Potential modifiers of low dose cellular responses to radiation (such as adaptive response, bystander effects and genomic instability) have not been shown to be associated with tumour development. Such modifiers tend to influence the slope of the dose-response curve for cellular responses at low doses and not the shape--thereby resulting in a quantitative modification rather than a qualitative one. Additional data pertinent to addressing the shape of the tumour dose-response relationship at low doses are needed.


Computer-based and paper-based reading comprehension in adolescents with typical language development and language-learning disabilities.
With the global expansion of technology, our reading platform has shifted from traditional text to hypertext, yet little consideration has been given to how this shift might help or hinder students' reading comprehension. The purpose of this study was to compare reading comprehension of computer-based and paper-based texts in adolescents with and without language-learning disabilities (LLD). Fourteen adolescents with LLD and 25 adolescents with typical language development (TLD) read literary texts in computer-based and paper-based formats and then answered reading comprehension questions. The LLD group scored significantly lower than the TLD group on the reading comprehension measure, but there were no significant between-group differences for reading or answering time. In addition, there were no significant within-group differences for the computer-based or paper-based conditions. Predictors for reading comprehension varied by group and condition. Neither group appeared to be affected by the additional cognitive load imposed by hypertext in the computer-based condition; however, the load between conditions may not have been sufficient to differentially impact reading comprehension. Based on the regression analyses, it appears that working memory, oral language, and decoding differed in their contribution to reading comprehension for each group and condition.


Multiplexed SNP genotyping using primer single-base extension (SBE) and microsphere arrays.
Single-nucleotide polymorphisms (SNPs), genome sites with single-base sequence differences between individual chromosomes, are the most common type of genetic variation. Single-base changes can result in disease phenotypes, confer susceptibility or resistance to toxins or pathogens, or serve as markers for distinct allelic segments of DNA, making SNPs an important emerging tool in both basic and clinical research. This unit presents detailed protocols for multiplexed SNP genotyping using primer single-base extension (SBE) adapted to microspheres and flow cytometry. The methods described are best suited for typing a modest number of SNPs in a large number of samples. The Basic Protocol describes extension of the genotyping primers by one nucleotide, a labeled dideoxyribonucleotide that reveals the nucleotide base at that position on the template strand. The extended primers are then captured onto microspheres bearing an oligonucleotide "address" that is the reverse complement of a sequence on the 5' end of the genotyping primers and subsequently measured using flow cytometry.


Life, the genome and everything.
In this issue of the Journal of Bacteriology, N. J. Bonde, E. A. Wood, K. S. Myers, M. Place, J. L. Keck, and M. M. Cox (J Bacteriol 205:e00184-23, 2023, https//doi.org/10.1128/jb.00184-23) used an unbiased transposon-sequencing (Tn-seq) screen to identify proteins required for life when cells lose the RecG branched-DNA helicase (synthetic lethality). The proteins' identities indicate pathways that prevent endogenous DNA damage, pathways that prevent its homology-directed repair (HDR) "strand-exchange" intermediates between sister chromosomes, and pathways that resolve those intermediates. All avoid intermediate pile-up, which blocks chromosome segregation, causing "death-by-recombination." DNA damage is managed to regulate crucial but potentially lethal HDR.


Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data.
Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by an increased risk of thrombosis and progression to acute myeloid leukemia. MPN are associated with driver mutations in JAK2, CALR and MPL which are crucial for the diagnosis and lead to a constitutive activation of the JAK-STAT signaling, independent of cytokine regulation. Moreover, most patients have concomitant mutations in genes involved in DNA methylation, chromatin modification, messenger RNA splicing, transcription regulation and signal transduction. These additional mutations may arise before, in the context of clonal hematopoiesis of indeterminate potential (CHIP), or after the acquisition of the driver mutation. The clinical phenotype of MPN results from complex interactions between mutations and host factors. The increased application of next-generation sequencing (NGS) techniques to a large series of patients with MPN has expanded the knowledge of mutational landscape and contributed to define the clinical significance of mutations. This molecular information is being increasingly used to refine diagnosis, risk stratification, monitoring of residual disease and response to treatment. ASXL1, SRSF2, EZH2, IDH1/IDH2 and U2AF1 mutations are associated with a more advanced disease and reduced overall survival in primary myelofibrosis (PMF), whereas spliceosome mutations in Polycythemia vera (PV) and essential thrombocythemia (ET) adversely affect both overall (SF3B1, SRSF2 in ET and SRSF2 in PV) and myelofibrosis-free (U2AF1, SF3B1 in ET) survival. This review discusses current knowledge of the molecular landscape of MPN, and how the availability of those molecular information may impact patient management.


A residential aged care end-of-life care pathway (RAC EoLCP) for Australian aged care facilities.
The objective of this study was to develop, implement and evaluate an end-of-life (terminal) care pathway and associated infrastructure suitable for Australian residential aged care facilities that improves resident and health system outcomes. The residential aged care end-of-life care pathway was developed by a multidisciplinary collaboration of government and non-government professionals and incorporated best clinical management for dying residents to guide care and increase palliative care capacity of generalist staff. Implementation included identifying and up-skilling Link Nurses to champion the pathway, networking facilities with specialist palliative care services, delivering education to generalists and commencing a Palliative Care Medication Imprest System in each facility. The primary outcome measure for evaluation was transfer to hospital; secondary measures included staff perceived changes in quality of palliative care provided and family satisfaction with care. Results indicated that the pathway, delivered within a care framework that guides provision of palliative care, resulted in improved resident outcomes and decreased inappropriate transfers to acute care settings.


Bile acid metabolism in rats fed two levels of corn oil and brans of oat, rye and barley and sugar beet fiber.
High concentrations of fecal bile acids are associated with a higher incidence of colon cancer. Dietary changes that alter bile acid metabolism are therefore of interest. Here, we report the effect of feeding diets containing four fiber sources and two fat levels for 7 wk on bile acid excretion and small intestinal bile acids (an index of pool size) in rats. The fiber sources were oat bran, rye bran, barley bran and sugar beet fiber. Fiber-containing diets were 8% dietary fiber and contained either 5 or 20% corn oil. All fiber sources caused significantly greater fecal output compared with the fiber-free basal diet. All fiber sources also resulted in significantly (P less than 0.05) lower fecal bile acid concentration compared with the fiber-free basal diet. Only rye bran resulted in significantly (P less than 0.05) higher total fecal bile acid excretion. Oat bran resulted in a slightly but significantly (P less than 0.05) higher quantity of small intestine bile acids compared with the other diets. Dietary fat level had no significant effect on fecal bile acid concentration or excretion or quantity of small intestinal bile acids. We conclude that all four fiber sources tested resulted in lower fecal bile acid concentration, by effectively causing greater fecal mass. Changes in dietary fat level as corn oil had no effect on fecal bile acids.


The nature of the sex-linked differences in glutathione peroxidase activity and aerobic oxidation of glutathione in male and female rat liver.
1. Glutathione peroxidase activity in the livers of sham-operated female rats was about 60% higher than in similarly treated male rats. The value in the ovariectomized female was about the same as that in the castrated or sham-operated male. 2. Glutathione peroxidase activity changed during the oestrous cycle. The highest value was in oestrus, and was about 50% higher than the lowest activity, which was found in dioestrus. The activity in proestrus and in metoestrus was respectively about 20 and 30% higher than in dioestrus. 3. In the pregnant female 1 or 2 days before term, glutathione peroxidase activity was about 20% higher than that in the female in oestrus. 4. Subcutaneous implants of both oestra-diol and progesterone in the gonadectomized rats increased the glutathione peroxidase activity approximately to the values found in the female at oestrus. 5. The rate of aerobic oxidation of GSH in the female rat liver was about 80% higher than in the male and about 110% higher than in the gonadectomized rats. Treatment of gonadectomized rats with subcutaneous implants of oestradiol and of progesterone increased the rate of oxidation of GSH by about 100%. 6. In the presence of azide the rate of GSH oxidation in the male and in the female was respectively about 3.5- and 2.1-fold that in the absence of azide. In castrated or ovariectomized rats the increase due to the presence of azide was about 2.4-fold. In the gonadectomized rats treated with oestradiol or progesterone the rate of GSH oxidation in the presence of azide was about 2.2-fold that in its absence. 7. The rate of lipid peroxidation in female was 15-30-fold that in male or in gonadectomized rats. Treatment of the gonadectomized rats with oestradiol or with progesterone increased the rate of lipid peroxidation up to values that were even higher than in the female. In the presence of GSH the formation of malonaldehyde from peroxides was virtually eliminated. 8. The results suggest that the sex-linked differences in glutathione peroxidase activity, in the rate of GSH oxidation and in the rate of lipid peroxidation are due to the female sex hormones. 9. It is suggested that both the catalase activity and the rate of hydrogen peroxide formation are higher in the male than in the female. 10. Sex-linked changes in glutathione peroxidase, in the rate of GSH oxidation and in the rate of lipid peroxide formation are discussed in relation to the metabolism of oestrogens in the liver and also to the possible nature of those sex-linked changes.


Adverse effects of cytomegalovirus vaccination in mice.
Studies of live attenuated cytomegalovirus (CMV) vaccine have recently been initiated in man. The possibilities of latent infection and disease resulting from reactivation of vaccine virus are major concerns. Because markers for attenuation of tissue culture-passaged mouse CMV (MCMV) exist, studies of potential adverse effects of vaccination were initiated in mice. Plaque-purified MCMV was passed 12 times in cell culture ("vaccine virus") and shown to be attenuated by virtue of loss of lethality and diminished replication in reticuloendothelial organs of normal mice. Although subcutaneous inoculation of 10(5) plaque-forming units of wild virus was lethal for mice immunosuppressed with antilymphocyte serum (18/18 died), "vaccine MCMV" killed only 3/18 (P < 0.05) and was thus shown to be highly attenuated even in immunosuppressed animals. 4 mo after subcutaneous inoculation of vaccine MCMV, no infectious virus was detectable in the tissues of normal C(3)H mice. However, immunosuppression with anti-lymphocyte serum and cortisone caused MCMV reactivation, dissemination, and wide-spread cytomegalic inclusion disease in 19 of 20 animals. Characterization of the reactivating virus recovered from salivary glands indicated that reversion to virulence had occurred. Thus, vaccine MCMV, although markedly attenuated initially, established latent infection, reactivated after immunosuppression, and reverted to virulence, at least in salivary gland tissue. These data from the murine model substantiate the need for careful surveillance and virologic study of patients given experimental CMV vaccine.


Electromyographic activity of the shoulder muscles during rehabilitation exercises in subjects with and without subacromial pain syndrome: a systematic review.
Subacromial pain syndrome (SPS) is a common cause of shoulder pain and muscle activity deficits are postulated to contribute to the development and progression of the disorder. The purpose of this systematic review was to definitively determine whether evidence exists of differences in electromyography (EMG) characteristics between subjects with and without SPS. Six key databases were searched: MEDLINE, EMBASE, CINAHL, SPORTdiscus, PEDro and The Cochrane Library (inception to May 2016). The search yielded 1414 records using terms relating to shoulder impingement, EMG, scapular and rotator cuff muscles. Twenty-two papers remained once duplicates were removed and selection criteria applied. Data extraction, quality assessment and data synthesis were performed. Effect sizes and 95% confidence intervals were calculated. There was limited evidence that serratus anterior has lower amplitude, delayed activation and earlier termination in SPS participants. For the majority of muscles, regardless of task, load or arm position, significant differences were not demonstrated or results were contradictory. The understanding of SPS is changing and EMG appears unable to capture the complexities associated with this condition. Addressing aberrant movement patterns and facilitating balanced activation of all shoulder muscles may be a more appropriate treatment direction for the future.


A homogeneous cell-based bicistronic fluorescence assay for high-throughput identification of drugs that perturb viral gene recoding and read-through of nonsense stop codons.
Recoding mechanisms are programmed protein synthesis events used commonly by viruses but only very rarely in cells for cellular gene expression. For example, HIV-1 has an absolute reliance on frameshifting to produce the correct ratio of key proteins critical for infectivity. To exploit such recoding sites as therapeutic targets, a simple homogeneous assay capable of detecting small perturbations in these low-frequency (<5%) events is required. Current assays based on dual luciferase reporters use expensive substrates and are labor-intensive, both impediments for high-throughput screening. We have developed a cell-based bifluorophore assay able to measure accurately small recoding changes (<0.1%) with a high Z'-factor in 24- or 96-well formats that could be extended to 384 wells. In cases of nonsense mutations arising within coding regions of genes, the assay is suitable for assessing the potential of screened compounds to increase read-through at these nonprogrammed stop signals of variable termination efficiency.


Cost consequences of elimination of the routine group B streptococcus culture at a teaching hospital.
To evaluate the cost consequence of the elimination of routine Group B streptococcus (GBS) cultures in pregnancy utilizing risk factor assessment management recommendations of the Center for Disease Control. This retrospective study cohort population included all delivering patients from June 1, 1996, to May 31, 1997, managed by the Morbidity Mortality Weekly Report (MMWR) guidelines May 31, 1996, for GBS in pregnancy compared to the previous 29 months cohort from January 1, 1994, to May 31, 1996, managed with routine GBS cultures done at 35-37 weeks. Of the 7,681 culture management control cohort patients, there were four neonates with culture-positive GBS sepsis (1/1,900). The cost for detection of a single positive culture in an affected neonate was $8,627 ($34,509/4) and there were 2,875 personnel hours expended. In contrast, of the 2,011 patients in the risk factor management cohort, there were two cases of neonatal GBS sepsis ($111,005). The cost for detection of a positive culture in an affected neonate was $1,579 ($3,159/2) and there were 263 personnel hours expended in the risk factor management group. In spite of these significant laboratory savings, we noted a concurrent increase in the total cost in the newborn nursery for septic work-ups and treatment from $2.4 million to $3.1 million. Risk assessment management of GBS provided a savings of both money ($7,048/positive neonatal culture) and laboratory time (586 personnel hours/positive neonatal culture). However, these savings were more than offset by cost increases occurring in the newborn nursery ($400,000), demonstrating the necessity of practice patterns to undergo concurrent evaluation to verify cost savings and prevent shifting of expenses.


Methylation mechanism of tin(II) by methylcobalamin in aquatic systems.
The methylation reaction of tin(II) with methylcobalamin (CH(3)B(12)) in aquatic systems was modeled in the laboratory. The products were detected by a sensitive gas chromatography-flame photometric detector (GC-FPD), and further identified by gas chromatography-mass spectrometry (GC-MS). Both monomethyltin (MMT) and dimethyltin (DMT) were found as methylation products. Three important effecting factors during the methylation reaction, salinity, pH and aerobic or anaerobic, were studied. The results showed that methyl group can be transferred from CH(3)B(12) to tin in aquatic solutions as a radical or carbonium, as well as a carbanion. Two explanations for the pH-dependency of the methylation reaction between tin(II) and CH(3)B(12) were proposed: pH-dependency of the equilibrium states of CH(3)B(12), and pH-dependency of inorganic tin(II) species whose reactivity vary with the redox potential in the solution. Salinity can influence the activity of the methyl donor, which cause changes in the methylation efficiency. Kinetic experiments showed that the methylation reaction was pseudo-first-order for CH(3)B(12).


Considerations on implications of risk behavior in mental condition at students.
Social and family factors significantly influence somatic and psychical development of children and young people, differentiated by social gradient. Their behavior externalizes their capacities to adapt to family and social environment. It is the result of positive or negative influences of actions of factors in these environments. In adolescence, the social motivation of these behaviors is determined by their social relations (family, school, friends, entourage). By our conducted study we aimed to identify such behaviors, which, under various influences may gain risk or impact on health condition. 160 students, by random sex and aged between 11 and 18, were investigated anthropometric and physiometric were asked to respond to a complex set of questionnaires. The research has shown that subjects with reduced anthropometric and physiometric parameters (of the head) have serious school concerns, they are frequently extracurricular pursuits with a good academic situation, they meet the program of rest, have a peaceful sleep, have a balanced diet, no violent events, do not smoke or consume alcohol.


A review of the safety of tooth bleaching.
This article considers the safety of tooth bleaching based on a Medline search of clinical, animal and in vitro studies between 1986 and 2007. Bleaching is the least invasive option for improving tooth colour compared to alternatives such as crowns and veneers. However, no dental procedure is without risk and the clinician should be aware of the safety issues and adverse effects of tooth bleaching so that patients can be fully informed.


Towards a North Pacific long-term monitoring program for ocean plastic pollution: A systematic review and recommendations for shorelines.
Increased organized monitoring is key to improving our understanding of marine debris on shorelines. Shorelines are demonstrated sinks for marine debris but efforts to quantify debris often fail to capture and report core variables and survey design techniques necessary to ensure study repeatability, comparability and to provide meaningful results. Here, we systematically review the available literature regarding marine debris distribution and abundance on shorelines of countries bordering the North Pacific Ocean (NPO), which are demonstrated to have unusually high marine debris abundance and diversity both at the ocean surface and stranded on shorelines. The majority of the 81 papers documenting shoreline debris in the NPO were studies that took place for less than one year (76.5%). Additionally, most sampling sites were visited only once (57.3%). Precise site locations (GPS coordinates) were provided in only 44.4% of the evaluated studies. Debris quantities were reported using nine different measurement units, with item counts per area and item counts per mass being most commonly reported for macro- and microplastics, respectively. Taken together, most of the reviewed studies could not be repeated by others given the information provided. We propose a series of guidelines with regard to marine debris shoreline sampling metrics, indicators, methods, and target goals in the NPO in order to improve comparability and repeatability. These follow the basic tenets of environmental survey design, which when not accounted for, can limit the applicability and value of large-scale shoreline monitoring efforts.


Successful Use of Subcutaneous Stimulation for Bilateral Sacroiliac Joint Pain.
Sacroiliac joint pain (SIJP) has been difficult to properly manage in the medical field. Patients are initially managed with medications and physical therapy but may require further interventions including intra-articular corticosteroid injections, radiofrequency ablation, and sacroiliac joint fusion. Although peripheral nerve stimulation (PNS) and peripheral field nerve stimulation (PFNS) have been used with varying success, subcutaneous spinal cord stimulation (SCS) has not yet been utilized. We present the case of a patient with bilateral SIJP who had successful resolution with the use of subcutaneously-implanted SCS electrode leads. A 74-year-old female patient with a history of lumbar stenosis status post epidural steroid injection and minimally invasive lumbar decompression presented with year-long chronic low back pain (LBP) with unsuccessful pain relief from medical management and physical therapy. On physical exam, pain elicited with tenderness over both sacroiliac joints with positive Patrick's and Gaenslen's test bilaterally. After successful pain relief from a diagnostic SI joint injection, the patient underwent an SCS trial. Trial SCS leads were placed epidurally at T7 and subcutaneously next to bilateral SI joints. Epidural stimulation provided no pain relief after three days. Stimulation was then changed to the subcutaneous leads, with subsequent 90% pain relief. The patient then underwent a permanent implant with subcutaneous lead placement without complications. She reported pain relief ongoing for two years. SIJP is a difficult condition to treat despite various modalities. Recent advances in neuromodulation have shown anecdotal success with PNS. SCS involves electrode leads placed in the epidural space to provide axial back and radicular pain coverage. In this case, however, SCS leads were placed subcutaneously with excellent pain relief. Our case showcases the successful use of subcutaneous-implanted SCS which can provide another viable minimally invasive treatment option in the management of this pain source.


Isolation and Immunological Detection of Mycobacterium Tuberculosis from HIV and Non-HIV Patients in Benue State, Nigeria.
Immunological techniques are important tools for tuberculosis epidemiology; although its use is underutilized in Nigeria. In this study, we report the epidemiological outlook of Mycobacterium tuberculosis among HIV patients in Benue State, Nigeria. Sputum samples were collected from 425 suspected TB patients from July 2016 to February 2018 and subjected to acid-fast microscopy, GeneXpert MTB/RIF, processed using NALC-NaOH and cultured on Lowenstein-Jensen media. The isolates obtained were identified by SD-Bioline® assay. The prevalence of TB by acid-fast microscopy was 35(15.9%). The prevalence of TB by acid-fast bacilli was significantly (χ2 = 8.458; P = 0.003) highest among the 15-34 years age group (22.0%) compared with other age groups. TB prevalence was significantly (χ2 = 4.751; P = 0.029) higher among patients from rural areas than those from urban center (23.8% vs 14.1%). GeneXpert assay detected 64(15.1%) TB cases of which patients from rural areas had significantly (χ2 = 8.104; P = 0.017) higher prevalence of TB than patients from urban areas (23.8% vs 12.9%). The overall rifampicin resistance TB was 3.1%. Also, patients from rural areas had significantly (χ2 = 10.625; P = 0.005) higher rifampicin resistance compared with patient from urban areas (8.3% vs 1.3%). Of the 126(29.7%) mycobacterial isolates, 42(33.33%) were identified as MTBC and 84 (66.67%) as NTM by SD-Bioline® assay. The study revealed that Mycobacterium tuberculosis infection is still a major public health problem, with relatively high prevalence rate of rifampicin resistance among HIV positive patients. Further studies are needed for early detection and treatment intervention necessary for infection control.


Synthesis, antimicrobial activity and cytotoxicity of novel oxadiazole derivatives.
In the present study, 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) were synthesized via the ring closure reactions of appropriate acid hydrazides with carbon disulphide. N-(Benzothiazol-2-yl)-2-[[5-substituted-1,3,4-oxadiazol-2-yl]sulfanyl]acetamide derivatives (3a-j) were obtained by the nucleophilic substitution reactions of 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) with N-(benzothiazol-2-yl)-2-chloroacetamides. The chemical structures of the compounds were elucidated by IR, (1)H NMR, (13)C NMR and FAB(+)-MS spectral data and elemental analyses. The synthesized compounds were screened for their antimicrobial activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. All compounds except compound 3h exhibited the highest antibacterial activity against P. aeruginosa. Among all compounds (3a-j), the compounds bearing 4-methoxyphenoxymethyl moiety on oxadiazole ring (3a-e) exhibited the highest inhibitory activity against C. albicans. Although compound 3j did not possess 4-methoxyphenoxymethyl moiety on oxadiazole ring, this derivative also exhibited the same level of anti-candidal activity. The compounds were also investigated for their cytotoxic effects using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Compound 3a exhibited the highest cytotoxic activity, whereas compound 3g possessed the lowest cytotoxic activity against NIH/3T3 cells.


Effects of clonidine and tricyclic antidepressants on gastric smooth muscle contractility.
To determine if and how clonidine and tricyclic antidepressants affect gastric contractility. Guinea pig fundic and antral circular muscle strips were studied in vitro. The effects of clonidine or amitriptyline added in graded concentrations on contractions to electric field stimulation (EFS), acetylcholine (ACh), and SP in the presence of N(epsilon)-nitro-l-arginine methyl ester (l-NAME) were studied. EFS produced frequency dependent contractions of fundic and antral muscle that were abolished by atropine or tetrodotoxin (TTX). ACh contractions were abolished by atropine but not TTX. Clonidine reduced contractile response to EFS but had no effect on ACh contractions. The threshold concentration of clonidine to inhibit EFS contractions was lower in the fundus than in the antrum. Amitriptyline reduced contractions to both EFS and ACh but not to SP. The threshold concentration of amitriptyline to inhibit EFS contractions was lower in the antrum than in the fundus. Both clonidine and amitriptyline affect gastric contractility. At threshold concentrations, clonidine affects fundic contractility whereas amitriptyline affects antral contractility. Clonidine affects gastric contractility in response to EFS but not to ACh, suggesting alpha-2 receptors on cholinergic nerves that reduce ACh release. Amitriptyline inhibits gastric contractility to EFS and ACh suggesting an inhibitory muscle effect.


High number of chromosomal copy number aberrations inversely relates to t(11;19)(q21;p13) translocation status in mucoepidermoid carcinoma of the salivary glands.
Although rare, mucoepidermoid carcinoma (MEC) is one of the most common malignant salivary gland tumors. The presence of the t(11;19)(q21;p13) translocation in a subset of MECs has raised interest in genomic aberrations in MEC. In the present study we conducted genome-wide copy-number-aberration analysis by micro-array comparative-genomic-hybridization on 27 MEC samples. Low/intermediate-grade MECs had significantly fewer copy-number-aberrations compared to high-grade MECs (low vs high: 3.48 vs 30; p = 0.0025; intermediate vs high: 5.7 vs 34.5; p = 0.036). The translocation-negative MECs contained more copy-number-aberrations than translocation-positive MECs (average amount of aberrations 15.9 vs 2.41; p =0.04). Within all 27 MEC samples, 16p11.2 and several regions on 8q were the most frequently gained regions , while 1q23.3 was the most frequently detected loss. Low/intermediate-grade MEC samples had copy-number-aberrations in chromosomes 1, 12 and 16, while high-grade MECs had a copy-number-aberration in 8p. The most commonly observed copy-number-aberration was the deletion of 3p14.1, which was observed in 4 of the translocation-negative MEC samples. No recurrent copy-number-aberrations were found in translocation-positive MEC samples. Based on these results, we conclude that MECs may be classified as follows: (i) t(11;19)(q21;p13) translocation-positive tumors with no or few chromosomal aberrations and (ii) translocation-negative tumors with multiple chromosomal aberrations.


The assessment of time-dependent changes in human performance.
This paper discribes a series of experiments to illustrate the use of various methods of time series analysis in the delineation of the effects of circadian and ultradian cycles on human performance. These experiments are concerned with measures of both human performance and physiology. They illustrate how the parameters of these time series analytic techniques can be used to postulate physiological mechanisms where time-dependent changes have been shown to be significant. The use of analytic techniques in both the time and frequency domain is illustrated.


[Clonal origin of intrahepatic recurrence after resection of hepatocellular carcinoma].
Using integrated hepatitis B virus (HBV) DNA in the cancer cells as a genetic marker, clonal origin of intrahepatic recurrence of hepatocellular carcinoma was studied by Southern blot technique. Comparing 5 cases of postoperative recurrent hepatocellular carcinoma with their primary tumors, it was found that 1 case had identical HBV DNA integration patterns, 3 cases were of different clonality and 1 case with multiple nodular recurrences contained either a unicentric origin or a new distinctive clone origin. The results suggest that, in addition to recurrence from residual cancer cells, in some cases, hepatocellular carcinoma may develop repeatedly during a continuous process of carcinogen action, even after a radical resection.


A functional model for the Rieske center: full characterization of a biomimetic N-ligated [2Fe-2S] cluster in different protonation states.
Give and take both: A bis(benzimidazolate)-capped biomimetic [2Fe-2S] cluster has been characterized in different protonation states, both in the diferric and mixed-valent forms. Protonation does not lead to structural changes of the [2Fe-2S] core, but facilitates its reduction and causes pronounced valence localization in the mixed-valent state. Concerted proton and electron transfer back to the diferric cluster emulates a key step in the function of mitochondrial Rieske proteins (see scheme).


Regulation of the renal Na-HCO(3) cotransporter. XI. Signal transduction underlying CO(2) stimulation.
We have previously shown that CO(2) stimulation of the renal Na-HCO(3) cotransporter (NBC) activity is abrogated by general inhibitors of protein tyrosine kinases. The more selective inhibitor herbimycin also blocked this effect at concentrations known to preferentially inhibit Src family kinases (SFKs). We therefore examined a role for SFKs in CO(2)-stimulated NBC activity. To this end, we engineered OK cells to express the COOH-terminal Src kinase (Csk), a negative regulator of SFKs. CO(2) stimulated NBC activity normally in beta-galactosidase-expressing and untransfected control cells. In contrast, Csk-expressing cells had normal baseline NBC activity that was not stimulated by CO(2). CO(2) stimulation increased both total SFK activity and specific tyrosine phosphorylation of Src. The specific MEK1/2 inhibitor PD-98059 completely inhibited the CO(2) stimulation of NBC activity as well as the accompanying phosphorylation and activation of ERK1/2. Our data suggest the involvement of both SFKs, probably Src, and the "classic" MAPK pathway in mediating CO(2)-stimulated NBC activity in renal epithelial cells.


Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever.
Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a β-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (P < .0001). IL-6 levels were elevated to clinically relevant levels at delivery in IL-6 compared to vehicle-treated animals (mean ± standard deviation: 923 ± 97 vs 143 ± 94 pg/mL, P = .0006). ED-1-stained cells were present in significantly higher numbers in fetal brains from IL-6 compared to saline-treated dams (median [interquartile range]: caudal hippocampus, 99 [94-104] and 64 [57-68], respectively, P = .002; lateral septum, 102 [96-111] and 68 [65-69], respectively, P = .002), as well as COX-2 immunostaining (lateral septum, 22 [20-26] and 17 [15-18], respectively, P = .005; dorsal hippocampus, 27 [22-32] and 16 [14-19], respectively, P = .013) and quantitative COX-2 Western blotting activity (mean ± standard error of the mean: vehicle, 0% of β-actin intensity versus IL-6, 41.5% ± 24%, P < .001). Noninfectious inflammatory fever is inducible in the near-term pregnant rat by injection of IL-6 at levels comparable to those observed during human epidural labor analgesia. Maternal IL-6 injection causes neuroinflammation in the fetus.


[Peptide receptor radionuclide therapy for patients with somatostatin receptor expressing tumours. German Guideline (S1)].
This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.


SSLpheno: a self-supervised learning approach for gene-phenotype association prediction using protein-protein interactions and gene ontology data.
Medical genomics faces significant challenges in interpreting disease phenotype and genetic heterogeneity. Despite the establishment of standardized disease phenotype databases, computational methods for predicting gene-phenotype associations still suffer from imbalanced category distribution and a lack of labeled data in small categories. To address the problem of labeled-data scarcity, we propose a self-supervised learning strategy for gene-phenotype association prediction, called SSLpheno. Our approach utilizes an attributed network that integrates protein-protein interactions and gene ontology data. We apply a Laplacian-based filter to ensure feature smoothness and use self-supervised training to optimize node feature representation. Specifically, we calculate the cosine similarity of feature vectors and select positive and negative sample nodes for reconstruction training labels. We employ a deep neural network for multi-label classification of phenotypes in the downstream task. Our experimental results demonstrate that SSLpheno outperforms state-of-the-art methods, especially in categories with fewer annotations. Moreover, our case studies illustrate the potential of SSLpheno as an effective prescreening tool for gene-phenotype association identification. https://github.com/bixuehua/SSLpheno.


Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study.
BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease. Uncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.


Strain differentiation in Bacteroides fragilis by ribotyping and computer-assisted gel analysis.
It is important to distinguish between Bacteroides fragilis strains as their virulence may vary and as B. fragilis seems to be a heterogeneous species. The aim of our study was to evaluate ribotyping for differentiation of 46 strains of B. fragilis and for assessment of strain heterogeneity within and between the two DNA-DNA homology strain groups established in this species. Twenty-seven strains belonged to Johnson's DNA homology group I and eight to group II. Eleven strains had not been assigned to any group (NI group). DNA from all strains was cut with BglI, EcoRI and HindIII. Restriction fragment length polymorphisms were investigated using a non-radioactive digoxigenin-labelled cDNA probe transcribed from Escherichia coli 16S+23S rRNA. Ribotyping with BglI was most discriminatory, revealing a total of 26 different patterns by visual inspection of gels. EcoRI followed with 20 patterns and HindIII with 13 patterns. The gels from ribotyping were processed using the Dendron computer-assisted program. Strain clusters established using Dendron were not always in agreement with homology-based strain groups. Strains of the NI group fell into both homology groups. Ribotyping, as it is based on a relatively small portion of the genome, is useful for strain distinction in epidemiological studies with B. fragilis, whereas DNA-DNA homology, using the entire genome, is more reliable for taxonomy. The Dendron computer-assisted program, which enabled objective assessment of multiple banding patterns, increased the reliability of ribotyping.


Socioeconomic status and health inequalities for cardiovascular prevention among elderly Spaniards.
Although it is known that social factors may introduce inequalities in cardiovascular health, data on the role of socioeconomic differences in the prescription of preventive treatment are scarce. We aimed to assess the relationship between the socioeconomic status of an elderly population at high cardiovascular risk and inequalities in receiving primary cardiovascular treatment, within the context of a universal health care system. Cross-sectional study of 7447 individuals with high cardiovascular risk (57.5% women, mean age 67 years) who participated in the PREDIMED study, a clinical trial of nutritional interventions for cardiovascular prevention. Educational attainment was used as the indicator of socioeconomic status to evaluate differences in pharmacological treatment received for hypertension, diabetes, and dyslipidemia. Participants with the lowest socioeconomic status were more frequently women, older, overweight, sedentary, and less adherent to the Mediterranean dietary pattern. They were, however, less likely to smoke and drink alcohol. This socioeconomic subgroup had a higher proportion of coexisting cardiovascular risk factors. Multivariate analysis of the whole population found no differences between participants with middle and low levels of education in the drug treatment prescribed for 3 major cardiovascular risk factors (odds ratio [95% confidence interval]): hypertension (0.75 [0.56-1.00] vs 0.85 [0.65-1.10]); diabetic participants (0.86 [0.61-1.22] vs 0.90 [0.67-1.22]); and dyslipidemia (0.93 [0.75-1.15] vs 0.99 [0.82-1.19], respectively). In our analysis, socioeconomic differences did not affect the treatment prescribed for primary cardiovascular prevention in elderly patients in Spain. Free, universal health care based on a primary care model can be effective in reducing health inequalities related to socioeconomic status.


Construct validity of the Impact of Weight on Quality of Life Questionnaire.
The Impact of Weight on Quality of Life questionnaire (IWQOL) is a 74-item self-report, condition-specific instrument that (1) assesses the effect of weight on quality of life in eight key areas, and (2) may be used as a treatment outcome measure and/or an evaluation tool for healthcare policy makers and third-party payers. This study explores IWQOL construct validity and provides new information on internal consistency, treatment effects, and differences between men and women. IWQOL total scores correlated highly with other measures of overall quality of life, and subscale scores correlated well with counterparts in the assessment battery. Internal consistency estimates for the IWQOL scales generally were high. For the women, 4-week participants, and the total sample, pretreatment-posttreatment differences were significant for all IWQOL scales and total score. For men, treatment differences were significant for the total score and all subscales except for Work and Mobility. Treatment differences for 2-week participants were significant for all scales except for Work. Consistent with previous IWQOL study results, the Comfort With Food scale scores reflected more discomfort at posttreatment as compared with pretreatment. The IWQOL, already translated into French and Italian, currently is demonstrating clinical and research utility as a quality-of-life outcome measure for clinical trials of antiobesity drugs and surgical treatments for patients with obesity.


Effect of retinoic acid on phorbol ester-stimulated differentiation and protein kinase C-dependent phosphorylation in the U937 human monoblastoid cell.
Phorbol esters stimulate differentiation of certain human leukemic cell lines. Although activation of protein kinase C may mediate certain effects of phorbol esters, controversy exists as to the role of protein kinase C activation in phorbol ester-induced differentiation. Retinoic acid modulates responses to phorbol esters in several cell types. Retinoic acid has also been found to alter protein kinase C-dependent phosphorylation in leukemic cells. We correlated the effects of retinoic acid on protein kinase C-dependent phosphorylation and differentiation stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a phorbol ester, in the human monoblastoid U937 cell line. At concentrations less than 1 nM, which were 100-fold less than those directly stimulating differentiation, retinoic acid potentiated TPA-induced differentiation of the U937 cell as assessed by enhanced adherence to plastic and acquisition of nonspecific esterase activity. TPA-stimulated decreases in cellular proliferation were not affected by retinoic acid treatment. Without altering the sensitivity to TPA, retinoic acid increased the maximal response to this agent. Retinoic acid enhanced TPA-stimulated phosphorylation of a Mr 48,000 substrate in intact 32P-labeled U937 cells and also increased the protein kinase C-dependent phosphorylation of a similar Mr 48,000 substrate and a Mr 80,000 substrate in cellular extracts. In cellular extracts the retinoic acid-induced enhancement of protein kinase C-dependent phosphorylation was predominantly localized to the cytosolic fraction. Increases in protein kinase C-dependent phosphorylation were evident within a 12-h exposure to 1 nM retinoic acid and were observed at retinoic concentrations of 0.01 to 1 nM. A retinoic acid-induced increase in the protein kinase C-dependent phosphorylation of an exogenous substrate, histone, was observed following diethylaminoethyl extraction of cytosol, but not a solubilized particulate fraction. The conditions of retinoic acid treatment increasing protein kinase C activity and enhancing protein kinase C-dependent phosphorylation of endogenous substrates were similar to those conditions potentiating phorbol ester-induced differentiation. Thus, the retinoic acid-induced amplification of phorbol ester signal transduction at the level of protein kinase C activation could mediate the effects of this vitamin on phorbol ester-induced differentiation.


The development of tropisetron in its clinical perspective.
This review discusses the development of tropisetron as an antiemetic drug with the patient in mind. The original aims of the programme and the progress achieved towards them to date are described. The efficacy and safety data from two dose-ranging studies and four comparative-treatment studies with tropisetron were combined in a prospectively planned meta-analysis of 799 patients. An integrated safety summary is presented which includes all patients from the six studies. Tropisetron at a dose of 5 mg once daily is an effective and well-tolerated, single-agent, antiemetic treatment, which can be given without special precautions to all patients receiving highly emetogenic chemotherapy. In comparison with metoclopramide, tropisetron is more effective in the prevention of nausea and vomiting. When compared with the most potent cocktail treatments currently in use (containing high-dose metoclopramide, dexamethasone and lorazepam or diphenhydramine), tropisetron is equally effective in the prevention of acute vomiting and somewhat less effective in the prevention of nausea. Overall, tropisetron is an effective and well-tolerated antiemetic treatment that is simple to administer, comparing well with currently available antiemetic cocktails. Tropisetron remains effective for the prevention of nausea and vomiting during multiple chemotherapy courses. The simple dosing schedule (5 mg i.v. day 1; one 5 mg capsule daily, days 2-6) makes tropisetron ideal for both inpatient or outpatient use.