Effect of Donor Lymphocyte Infusion From Two Types of Donors on Mixed Chimerism With Secondary Graft Failure After Allogeneic Hematopoietic Stem Cell Transplantation.
Mixed chimerism (MC) and secondary graft failure (SGF) with recipient- or donor-type chimerism is a major obstacle in allogeneic hematopoietic stem cell transplantation (HSCT). Donor lymphocyte infusion (DLI) can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions after HSCT. This study aimed to analyze the efficacy and immune mechanism of DLI from the original and alternative donor for patients of mixed donor chimerism with SGF. The alternative donor refers to the candidate relative donor who did not initially provide stem cells and includes HLA-matched sibling donor or HLA-haploidentical donor. We conducted a retrospective study of 246 patients with a median age of 37 (9-58) years who had regularly detected MC, complete donor chimera (CC), and regulatory T cells (Treg). The median diagnosis time of SGF was 69 (39-141) days after transplantation. Sixteen patients with SGF received DLI from the alternative donor, including 3 patients who chose DLI from the original donor with no initial response and 13 patients who directly chose DLI from the alternative donor. Sixteen patients with SGF existed mixed chimerism synchronously and the rate calculated overall chimerism of MC was 63% (range 42%-85%) after transplantation. The proportion of Treg decreased significantly in SGF patients from a median of 2.66% ± 0.80% to 0.93% ± 0.57% at a time point after transplantation (P = .02). The DLI of the alternative donor in 14 patients achieved complete response and MC gradually convert to CC state, simultaneously there was significant increase in the Treg fraction (SGF versus complete response: 0.93% ± 0.57% versus 3.61% ± 0.82% [P = .01]). For the clinical nonresponders from 2 types of donors, there was no significant change in MC and Treg cells. The OS and disease-free survival at 2 years after DLI were 69.7% ± 3.19% and 61.3% ± 4.80%, respectively. DLI from the alternative donor may be an effective treatment for MC with SGF, and the mechanism is closely related to the activation of Treg cells level.


Variation in the cholesteryl ester transfer protein (CETP) gene does not influence individual plasma cholesterol response to changes in the nature of dietary fat.
Some individuals respond to a greater extent than others to changes in dietary fat and cholesterol even when dietary intake is consistent. A prospective study has been undertaken in which two groups of individuals according to cholesteryl ester transfer protein (CETP) genotype were compared in terms of plasma lipid response to altering the nature of dietary fat in a free-living situation. Following genotyping, 35 individuals with the CETP Taq1 B1B1 genotype were paired with age and sex-matched individuals with one or two CETP B2 alleles, to undertake a single crossover trial with a diet high in saturated fat and a diet high in polyunsaturated fat. There was no washout period between the two 4-week phases. Plasma lipoproteins were measured at the beginning and end of each phase. The difference (95% CI) in plasma LDL-cholesterol concentration at the end of the PUFA and SAFA diets was 0.95 (0.71, 1.19) mmol/l in the CETP B1B1 group and 0.80 (0.57, 1.04) mmol/l in the group with at least one CETP B2 allele. The dietary induced changes in the two genotype groups were not significantly different (p=0.38) from each other. Comparable results were observed for plasma total cholesterol. The high PUFA and SAFA diets did not significantly alter plasma HDL concentration in either of the CETP genotype groups. Response was also similar according to apolipoprotein E genotype (E3E3 vs E4+) and lipoprotein lipase genotype (S447X). The results of this study do not support previous studies in which CETP genotype predicted plasma LDL-cholesterol response to diet. CETP genotype does not significantly affect the change in plasma total and LDL-cholesterol concentrations that occur when altering the nature of dietary fat. These data suggest that the influence of genetic factors on total and LDL-cholesterol may be relatively small in comparison with the effect of dietary manipulation.


Post COVID-19 condition and its physical, mental and social implications: protocol of a 2-year longitudinal cohort study in the Belgian adult population.
Since the onset of the COVID-19 pandemic, most research has focused on the pathophysiology and management of the acute symptoms of COVID-19, yet some people tend to experience symptoms beyond the acute phase of infection, that is, Post COVID-19 condition (PCC). However, evidence on the long-term health impacts of a COVID-19 infection are still scarce. The purpose of this paper is to describe the COVIMPACT study, which aims to set up a cohort of people who have been tested positive for COVID-19 and study the evolution of their physical, mental and social health over the medium (3 months) and long term (two years), and the factors associated with an (un)favorable evolution. COVIMPACT is a longitudinal cohort study organised over a two-years period between April 2021 and April 2023. The eligible population is all people aged 18 years and older, living in Belgium, with a recent COVID-19 infection and contacted by the health authorities for contact tracing. Two questionnaires are used: a baseline questionnaire that aims to assess the initial health status of the participants and their status during the acute phase of the illness, and a follow-up questionnaire that is sent every three months after participants enter into the cohort. A matched non-COVID-19 control group was also selected. As of November 1, 2021, 10,708 people completed the baseline questionnaire (5% of the eligible population) and the follow-up participation rate was 79%. In total, 48% of the cohort participants appeared to fit the proposed case definition of PCC (i.e. report at least one symptom related to their COVID-19 infection three months afterwards). This study was designed to provide timely information on the short and long term impact of a COVID-19 infection, to stakeholders such as policymakers, health practitioners and people with PCC. Although the follow-up participation rate was good (79%), the participation rate of the eligible population was low (5%). Compared to other studies, this study has a large sample, of non-hospitalised and hospitalised people, who will be followed over a long period of 3 months to two years post infection, and with a global approach to their health.


Obsessive-compulsive symptoms and attentional bias: An eye-tracking methodology.
Cognitive models suggest that attentional biases are integral in the maintenance of obsessive-compulsive symptoms (OCS). Such biases have been established experimentally in anxiety disorders; however, the evidence is unclear in Obsessive Compulsive disorder (OCD). In the present study, an eye-tracking methodology was employed to explore attentional biases in relation to OCS. A convenience sample of 85 community volunteers was assessed on OCS using the Yale-Brown Obsessive Compulsive Scale-self report. Participants completed an eye-tracking paradigm where they were exposed to OCD, Aversive and Neutral visual stimuli. Indices of attentional bias were derived from the eye-tracking data. Simple linear regressions were performed with OCS severity as the predictor and eye-tracking measures of the different attentional biases for each of the three stimuli types were the criterion variables. Findings revealed that OCS severity moderately predicted greater frequency and duration of fixations on OCD stimuli, which reflect the maintenance attentional bias. No significant results were found in support of other biases. Interpretations based on a non-clinical sample limit the generalisability of the conclusions, although use of such samples in OCD research has been found to be comparable to clinical populations. Future research would include both clinical and sub-clinical participants. Results provide some support for the theory of maintained attention in OCD attentional biases, as opposed to vigilance theory. Individuals with greater OCS do not orient to OCD stimuli any faster than individuals with lower OCS, but once a threat is identified, these individuals allocate more attention to OCS-relevant stimuli..


Making no bones about it: Transcription factors in vertebrate skeletogenesis and disease.
Skeletogenesis is a complex multi-step process, which involves many genes and pathways. The tightly regulated interplay between these genes in these pathways ensures a correct and timely organogenesis and it is imperative that we have a fair understanding of the major genes and gene families involved in the process. This review aims to give a deeper insight into the roles of 3 major transcription factor families involved in skeleton formation: Sox, Runx and Pax and to look at the human skeleotogenic phenotypes associated with mutations in these genes.


Atmospheric deposition and trajectories of antimony in Central Europe.
Antimony (Sb) concentrations were measured in wet atmospheric deposition at 10 high-elevation sites in the Czech Republic (Central Europe) during three winter seasons (2009-2011). Soluble and insoluble Sb forms were quantified in snow (vertical deposition) and rime (horizontal deposition) on mountain summits located equidistantly near the Czech borders with Austria, Germany and Poland. The highest Sb concentrations were found in the soluble form in rime (0.47 μg L-1), while the lowest Sb concentrations were those in the insoluble form in snow (0.017 μg L-1). The estimated average Sb deposition rate in Central Europe amounted to 1.3. 10-4 g m-2 yr-1. Most Sb was deposited in the soluble form in snow (7.9. 10-5 g m-2 yr-1), followed by the soluble form in rime (3.5. 10-5 g m-2 yr-1). The corresponding insoluble fraction contained less Sb, namely 1.2. 10-5 g m-2 yr-1 in snow and 2.3. 10-6 g m-2 yr-1 in rime. The average Sb deposition in Central Europe, measured at an altitude of 1000 m a.s.l., was by six orders of magnitude higher compared to Sb deposition in the Arctic (7. 10-10 g m-2 yr-1), and by four orders of magnitude lower compared to Sb deposition in a Sb-Hg mining district in China (7 g m-2 yr-1). Using the HYSPLIT model, backward trajectories of air masses indicated that the Sb sources were predominantly situated in Upper and Lower Silesia.


[Ecological data on the interstitial meiofauna of the lower part of the beaches of the gulf of Tunis].
The density of the meiofauna in the mediolittoral zone can exceed 4.10(6) ind./m2; the Nematoda are the most important group but their percentage is lower as in constantly immersed biotops; the population has a great vertical extension. Near the mouth of Medjerda river, the low salinity brings about a strong impoverishment.


Antioxidant activity of banana flavonoids.
The antioxidant activity of flavonoids from banana (Musa paradisiaca) was studied in rats fed normal as well as high fat diets. Concentrations of peroxidation products namely malondialdehyde, hydroperoxides and conjugated diens were significantly decreased whereas the activities of catalase and superoxide dismutase were enhanced significantly. Concentrations of glutathione were also elevated in the treated animals.


Functionally distinct NMDA receptors mediate horizontal connectivity within layer 4 of mouse barrel cortex.
In sensory areas of neocortex, thalamocortical afferents project primarily onto the spiny stellate neurons of Layer 4. Anatomical evidence indicates that these cells receive most of their excitatory input from other cortical neurons, including other spiny stellate cells. Although this local network must play an important role in sensory processing, little is known about the properties of the neurons and synapses involved. We have produced a slice preparation of mouse barrel cortex that isolates Layer 4. We report that excitatory interaction between spiny stellate neurons is largely via N-methyl-D-aspartate receptors (NMDARs) and that a given neuron contains more than one type of NMDAR, as distinguished by voltage dependence. Thus, spiny stellate cells act as effective integrators of powerful and persistent NMDAR-mediated recurrent excitation.


Complete Genome Sequence of Helicobacter pylori Strain 3192, Isolated from a Chinese Patient with Chronic Nonatrophic Gastritis.
Here, we present the complete genome sequence of Helicobacter pylori 3192, isolated from a patient diagnosed with nonatrophic gastritis in China. The genome is 1.6 Mbp long and encompasses 1,566 genes, including cagA and vacA genes.


Prevention of Sport-related Facial Injuries.
There is evidence that eye protection, mouth guards, helmets, and face guards are effective in reducing the risk of facial injury; however, such safety practices are not adopted universally by all athletes playing high-risk sports. Underlying beliefs about risk perception, comfort, ineffectiveness, utility, and a lack of awareness or enforcement have been identified as reasons people may not adopt preventive measures. There are several high-risk sports that have not mandated or do not enforce use of protective equipment. Valid evidence can assist with addressing the resistance caused by prevailing beliefs and could be essential in influencing rule changes.


A simple chlorophyll fluorescence parameter that correlates with the rate coefficient of photoinactivation of photosystem II.
A method of partitioning the energy in a mixed population of active and photoinactivated Photosystem II (PS II) complexes based on chlorophyll fluorescence measurements is presented. There are four energy fluxes, each with its quantum efficiency: a flux associated with photochemical electron flow in active PS II reaction centres (JPS II), thermal dissipation in photoinactivated, non-functional PS IIs (JNF), light-regulated thermal dissipation in active PS IIs (JNPQ) and a combined flux of fluorescence and constitutive, light-independent thermal dissipation (Jf,D). The four quantum efficiencies add up to 1.0, without the need to introduce an 'excess' term E, which in other studies has been claimed to be linearly correlated with the rate coefficient of photoinactivation of PS II (kpi). We examined the correlation of kpi with various fluxes, and found that the combined flux (JNPQ + Jf,D= Jpi) is as well correlated with kpi as is E. This combined flux arises from Fs/Fm ', the ratio of steady-state to maximum fluorescence during illumination, which represents the quantum efficiency of combined non-photochemical dissipation pathways in active PS IIs. Since Fs/Fm ' or its equivalent, Jpi, is a likely source of events leading to photoinactivation of PS II, we conclude that Fs/Fm ' is a simple predictor of kpi.


Building from the Ground up: Basement Membranes in Drosophila Development.
Basement membranes (BMs) are sheetlike extracellular matrices found at the basal surfaces of epithelial tissues. The structural and functional diversity of these matrices within the body endows them with the ability to affect multiple aspects of cell behavior and communication; for this reason, BMs are integral to many developmental processes. The power of Drosophila genetics, as applied to the BM, has yielded substantial insight into how these matrices influence development. Here, we explore three facets of BM biology to which Drosophila research has made particularly important contributions. First, we discuss how newly synthesized BM proteins are secreted to and assembled exclusively on basal epithelial surfaces. Next, we examine how regulation of the structural properties of the BM mechanically supports and guides tissue morphogenesis. Finally, we explore how BMs influence development through the modulation of several major signaling pathways.


Rearing is critical for forming spatial representations in pre-weanling rats.
Rearing, i.e., standing on the hind limbs in an upright posture, is part of a rat's innate exploratory motor program. Here, we examined in developing rats whether rearing is critical for the pup's capability to form spatial representations based on distal environmental cues. Pups (male) were tested at PD18, i.e., the first day they typically exhibit stable rearing, on a spatial habituation paradigm comprising a Familiarization session (with the pup exposed to an arena with a specific configuration of distal cues) followed, 3 h later, by a Test session where the pups were either re-exposed to the identical distal cue configuration (NoChange) or a changed configuration (DistalChange). In Experiment 1, rearing activity (rearing events, duration) decreased from Familiarization to Test in the NoChange pups but, remained elevated in the DistalChange group indicating that these pups recognized the distal novelty. Recognition of distal novelty was associated with increased c-Fos expression in hippocampal and medial prefrontal cortex (mPFC) areas, compared with NoChange pups. Analysis of GAD67+ cells suggested a parallel increase in excitation and inhibition specifically in prelimbic mPFC networks in response to distal cue changes. In Experiment 2, the pups were mechanically prevented from rearing while still seeing the distal cues during Familiarization. Rearing activity in the Test session of these pups did not differ between groups that were or were not exposed to a changed distal cue configuration at Test. The findings evidence a critical role of rearing for the emergence of allocentric representations integrating distal space during early development.


Enthalpy, entropy and heat capacity changes induced by binding of calcium ions to cardiac troponin C.
Microcalorimetric titrations have been used to study the binding of Ca2+ to cardiac troponin C. Measurements were made both in the presence and in the absence of Mg2+, and at temperatures of 5 degrees, 15 degrees and 25 degrees C. Changes in enthalpy, entropy and heat capacity of troponin C associated with Ca binding have been determined. Cardiac troponin C exhibited a decrease in enthalpy and an increase in entropy associated with Ca binding. Enthalpy changes increased linearly with temperature, indicating that the Ca binding causes negative changes in the heat capacity of troponin C. These results show that the Ca binding causes a strong hydrophobic effect and a tightening of the molecular structure of cardiac troponin C.


Pharmacophore identification of Raf-1 kinase inhibitors.
A three-dimensional pharmacophore model was developed based on 25 currently available Raf-1 kinase inhibitors. The best pharmacophore hypothesis (Hypo1), consisting of four chemical features (one hydrogen-bond acceptor, one hydrogen-bond donor, and two hydrophobic groups), has a correlation coefficient of 0.972. The results of our study provide a valuable tool in designing new leads with desired biological activity by virtual screening.


Nipple reconstruction with banked costal cartilage after vertical-type skin-sparing mastectomy and deep inferior epigastric artery perforator flap.
We recently used skin-sparing mastectomy (SSM), the deep inferior epigastric artery perforator (DIEP) flap, and delayed nipple reconstruction with banked costal cartilage. Eight patients who underwent these reconstructions between 2008 and 2010 were reviewed. SSM was performed by vertical-type incision. We transferred the DIEP flap using an internal thoracic vessel and banked costal cartilage into an abdominal wound. Three to 6 months later, we removed the cartilage and cut it into a cylindrical shape. We fixed the cartilage on the dermal base of a modified C-V flap. No flap necrosis or exposure of cartilage was seen and the scar was acceptable in all cases. At a mean follow-up of 12.6 months, 59% of the nipple projection was maintained in comparison to immediately postoperatively. Our new concept is the combination of SSM, DIEP, and banked cartilage, and furthermore putting the cartilage on a dermal base. With support from the dermis, a large, complicated cartilage form is unnecessary.


Abscess Formation in a Nonfunctioning Pituitary Adenoma.
Pituitary abscesses are rare clinical entities that can occur in the setting of a normal gland or underlying disease, including adenoma, craniopharyngioma, or Rathke cleft cyst. Although once believed to be indolent, when these secondary abscesses occur in the setting of an adenoma, they can be associated with significant clinical morbidity. Most patients present with visual disturbances or headache without fever or meningitis. We present the case of a 63-year-old woman with remote history of Staphylococcus osteomyelitis who presented with 1 week of diplopia, partial left third nerve palsy, and bitemporal hemianopsia who was found to have a pituitary abscess in the setting of an adenoma. She underwent drainage of the abscess and resection of her adenoma followed by complete resolution of her symptoms. This case highlights the need for prompt treatment of pituitary abscesses, with the possibility of excellent neurologic recovery.


Ru-catalyzed dehydrogenative coupling of carboxylic acids and silanes--a new method for the preparation of silyl ester.
Ru(3)(CO)(12)/EtI has been found to be an efficient catalyst system for the dehydrosilylation of carboxylic acids with silanes. In the presence of 1 mol% Ru(3)(CO)(12) and 4 mol% EtI, dehydrosilylation reactions in toluene afforded the corresponding silyl esters at 100 degrees C in good and high yields.


Role of Notch signaling in regulating innate immunity and inflammation in health and disease.
The Notch signaling pathway is conserved from Drosophila to mammals and is critically involved in developmental processes. In the immune system, it has been established that Notch signaling regulates multiple steps of T and B cell development in both central and peripheral lymphoid organs. Relative to the well documented role of Notch signaling in lymphocyte development, less is known about its role in regulating myeloid lineage development and function, especially in the context of acute and chronic inflammation. In this review article, we will describe the evidence accumulated during the recent years to support a key regulatory role of the Notch pathway in innate immune and inflammatory responses and discuss the potential implications of such regulation for pathogenesis and therapy of inflammatory disorders.


Morphine-induced analgesia and exposure to low-intensity 60-Hz magnetic fields: inhibition of nocturnal analgesia in mice is a function of magnetic field intensity.
In 2 experiments male CF-1 mice were exposed for 60 min, during the mid-dark period of the day-night cycle, to low-intensity (0.5-1.5 gauss, rms) 60-Hz magnetic fields and then tested for levels of analgesia induced by morphine (10 mg/kg) injections. The magnetic field exposures inhibited the degree of morphine-induced analgesia in a field intensity-dependent manner in both experiments (P less than 0.01) with the largest inhibitory effect after exposure to the 1.5-gauss field. Analysis of the combined data from the two experiments revealed a significant (P less than 0.001) linear relationship between level of analgesia and magnetic field intensity. Thus, these data demonstrated a functional relationship between the behavioral effects of morphine in mice and the strength of the 60-Hz magnetic field. Possible mechanisms underlying these effects are discussed.


Modulation of Ca2+ efflux and rebounding Ca2+ transport in rat liver mitochondria.
The independent pathway for Ca2+ efflux of rat liver mitochondria exhibits a sharp temperature and pH dependence. The Arrhenius plot displays a break at 18 degrees C, activation energy being about 117 kJ/mol below 18 degrees C and 59 kJ/mol above 18 degrees C. The pH profile is bell-shaped, with a broad optimum at pH 7.0. These properties of the efflux pathway, together with the membrane potential modulation recently described (Bernardi, P. and Azzone, G.F. (1983) Eur. J. Biochem. 134, 377-383), suggest an explanation for the phenomenon of rebounding Ca2+ transport. Addition of a Ca2+ pulse to respiring mitochondria causes (i) a phase of rapid Ca2+ uptake, leading to a decrease of extramitochondrial free Ca2+ to a lower level with respect to that maintained before Ca2+ addition, and (ii) a slower phase of net Ca2+ efflux, leading to restoration of the steady-state extramitochondrial free Ca2+ preceeding Ca2+ addition. Evidence is provided that the excess Ca2+ uptake is linked to transient inactivation of the efflux pathway due to membrane depolarization. Conversely, the efflux phase is linked to reactivation of the efflux pathway upon repolarization. The efflux component of the rebound cycle and the isolated efflux pathway exhibit similar dependence on temperature, pH and membrane potential.


Disparities in health information quality across the rural-urban continuum: where is coded data more reliable?
The growing application of evidence-based medicine practices across U.S. healthcare has created greater dependence on information resources, especially related to quality and consistency of data. The manipulation of data through coding and classification of patient information presents a critical process where the quality of information, as well as perceived quality of care, could potentially suffer. Where recent regulatory standards, such as HIPAA, create additional requirements for consistency in coding of health information, it becomes apparent that meaningful health outcomes assessment is, in part, an indicator of data quality as well as clinical quality. In a national survey of 16,000+ accredited health information managers we found most respondents reported that significant coding errors existed in 5% or less of the records in their institutions. Within specific organizations, however, coding errors existed in six to ten percent of their records, and at times exceeded 20%. Regional variation in reported coding error and inconsistency ranged widely, occurring across organizations as well as population concentrations. Metropolitan-based organizations tended to have somewhat worse reported overall coding accuracy, compared to suburban and rural areas. At a national level there will need to be some degree of coding and classification uniformity across population areas, if healthcare professionals are expected to rely on comparative evidence benchmarks to fully assess medical outcomes data. Related impacts on comparative cost and clinical performance assessment are discussed.


Cronobacter sakazakii clinical isolates overcome host barriers and evade the immune response.
Cronobacter sakazakii is the most frequently clinically isolated species of the Cronobacter genus. However the virulence factors of C. sakazakii including their ability to overcome host barriers remains poorly studied. In this study, ten clinical isolates of C. sakazakii were assessed for their ability to invade and translocate through human colonic carcinoma epithelial cells (Caco-2) and human brain microvascular endothelial cells (HBMEC). Their ability to avoid phagocytosis in human macrophages U937 and human brain microglial cells was investigated. Additionally, they were tested for serum sensitivity and the presence of the Cronobacter plasminogen activation gene (cpa) gene, which is reported to confer serum resistance. Our data showed that the clinical C. sakazakii strains invaded and translocated through Caco-2 and HBMEC cell lines and some strains showed significantly higher levels of invasion and translocation. Moreover, C. sakazakii was able to persist and even multiply in phagocytic macrophage and microglial cells. All strains, except one, were able to withstand human serum exposure, the single serum sensitive strain was also the only one which did not encode for the cpa gene. These results demonstrate that C. sakazakii clinical isolates are able to overcome host barriers and evade the host immune response indicating their capacity to cause diseases such as necrotizing enterocolitis (NEC) and meningitis. Our data showed for the first time the ability of C. sakazakii clinical isolates to survive and multiply within human microglial cells. Additionally, it was shown that C. sakazakii clinical strains have the capacity to translocate through the Caco-2 and HBMEC cell lines paracellularly.


Opioid Use Among Veterans of Recent Wars Receiving Veterans Affairs Chiropractic Care.
To examine patient sociodemographic and clinical characteristics associated with opioid use among Veterans of Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND) who receive chiropractic care, and to explore the relationship between timing of a chiropractic visit and receipt of an opioid prescription. Cross-sectional analysis of administrative data on OEF/OIF/OND veterans who had at least one visit to a Veterans Affairs (VA) chiropractic clinic between 2004 and 2014. Opioid receipt was defined as at least one prescription within a window of 90 days before to 90 days after the index chiropractic clinic visit. We identified 14,025 OEF/OIF/OND veterans with at least one chiropractic visit, and 4,396 (31.3%) of them also received one or more opioid prescriptions. Moderate/severe pain (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.72-2.03), PTSD (OR = 1.55, 95% CI = 1.41-1.69), depression (OR = 1.40, 95% CI = 1.29-1.53), and current smoking (OR = 1.39, 95% CI = 1.26-1.52) were associated with a higher likelihood of receiving an opioid prescription. The percentage of veterans receiving opioid prescriptions was lower in each of the three 30-day time frames assessed after the index chiropractic visit than before. Nearly one-third of OEF/OIF/OND veterans receiving VA chiropractic services also received an opioid prescription, yet the frequency of opioid prescriptions was lower after the index chiropractic visit than before. Further study is warranted to assess the relationship between opioid use and chiropractic care.


Comparison of Cumulative Live Birth Rate (CLBR) According to Patient Oriented Strategies Encompassing Individualized Oocyte Number (POSEIDON) Stratification Among Low Prognosis Women Undergoing IVF-ICSI Cycles.
The purpose of the current study was to evaluate patient-oriented strategies encompassing individualized oocyte number (POSEIDON) criteria, validate stratification of low prognosis women, and prognosticate their reproductive potential in terms of cumulative live birth rate (CLBR) in Indian women. Out of 4048 women who underwent IVF/ICSI, 3287 women met the criteria for final evaluation of CLBR. They criteria were divided into (a) group 1a as cases with <4 oocytes retrieved and 1b with 4-9 oocytes retrieved; (b) group 2a as cases with <4 oocytes retrieved and 2b with 4-9 oocytes retrieved; (c) group 3 (<35 years, AMH <1.2 ng/ml, AFC <5); and (d) group 4 (≥35 years, AMH <1.2 ng/ml, AFC <5). Non-POSEIDON group was sub-divided into normo-responders (10-20 oocytes) and hyper-responder (>20 oocytes). Overall CLBR was two-fold lower in POSEIDON group as compared to non-POSEIDON group (p<0.001). For every one-year increase in the age, the odds of CLBR decreased by 4% (OR 0.96, CI 0.93-0.99) in POSEIDON group and by 5% (OR 0.95, CI 0.92-0.98) in non-POSEIDON group. For every unit increase in number of oocytes retrieved, the odds of CLBR increased by 1.22 times (OR1.22, CI 1.16-1.28) in POSEIDON group and by 1.08 times (OR 1.08, CI 1.05-1.11) in non-POSEIDON group. Among POSEIDON groups, the highest values in CLBR belonged to group 1b followed by 3, 2b, 4, 1a, and 2a. POSEIDON stratification of low-prognosis women undergoing IVF may be considered valid to prognosticate and counsel women undergoing IVF. Prospective studies will strengthen its validity among different ethnic populations.


Serum bilirubin fractionation using multilayer film method in hepatobiliary diseases in comparison with high performance liquid chromatography.
The Ektachem multilayer film method (Ektachem) and high performance liquid chromatography (HPLC) were employed to fractionate and evaluate serum bilirubin species in 45 serum samples. The false-positive or false-high levels of bilirubin close-bonded with albumin (i.e. the delta bilirubin fraction (B delta] was obtained by Ektachem in sera of cases with normal bilirubin concentration and cases with unconjugated hyperbilirubinemia when compared with the results of HPLC. In the sera of cases with conjugated hyperbilirubinemia, Ektachem gave comparable levels of total bilirubin (TB), and unconjugated bilirubin (Bu) to those of HPLC, but underestimated conjugated bilirubin (Bc) and slightly overestimated B delta. To investigate the clinical significance of B delta in 113 cases of various hepatobiliary diseases with conjugated hyperbilirubinemia, the ratios of B delta to TB (B delta/TB) and to directly-reacting bilirubin fractions (B delta/(Bc + B delta] and that of Bc to B delta (Bc/B delta) were calculated based on the results of Ektachem and compared with each other during the course of jaundice. The mean B delta/TB was below 40% in various hepatobiliary diseases but became as high as approximately 60% in the convalescence stage. The mean B delta/(Bc + B delta) was below 50% in acute hepatitis (the serum bilirubin-elevating stage) and obstructive jaundice, and it increased to above 80% in the recovery stage. In decompensated liver cirrhosis and intrahepatic cholestasis the mean B delta/(Bc + B delta) was about 60%, indicating continuous backflow of Bc from liver cells. The changes in B delta/(Bc + B delta) were much greater than in B delta/TB.(ABSTRACT TRUNCATED AT 250 WORDS)


The luteinizing hormone-releasing hormone pulse generator in men: abnormalities and clinical management.
Most men with hypogonadotropic eunuchoidism have absent luteinizing hormone and presumably absent luteinizing hormone-releasing hormone pulses. Pulsatile luteinizing hormone-releasing hormone therapy is effective in restoring normal gonadotropin secretion and testicular function and inducing fertility in men with hypogonadotropic eunuchoidism. Furthermore, pulsatile (versus continuous) luteinizing hormone-releasing stimulation of the pituitary gland is an absolute requirement for normal gonadotropin secretion. Men with idiopathic oligoazoospermia and selective elevation of follicle-stimulating hormone levels have slow luteinizing hormone and presumably luteinizing hormone-releasing pulse frequency. In these men, pulsatile luteinizing hormone--releasing treatment is effective in decreasing serum follicle-stimulating hormone levels, but it is unclear whether spermatogenesis and fertility are improved.


Prevalence and analysis of potential risk factors for Cryptosporidium parvum infection in lambs in Zaragoza (northeastern Spain).
An epidemiologic study was carried out to investigate the prevalence of and to identify factors associated with the risk of Cryptosporidium infection in sheep in Zaragoza (northeastern Spain). Faecal samples from 583 lambs aged from 1 day to 3 months and 205 ewes older than 1 year were collected at 89 farms in the two regions of the province of Zaragoza with the highest sheep population (Zaragoza and Ejea de los Caballeros). In every sheep farm, data of the factors potentially associated with the likelihood of C. parvum infection were analysed: geographical location, season, size of herd, number of lambs in the herd at sampling time, lambing period, cleaning of lambing area and presence of diarrhoeic lambs in the farm. C. parvum oocysts were identified by using the Ziehl-Neelsen technique in 344 lambs (59%) from 75 farms (84.4%). Infected lambs ranged from less than 7 days to 90 days of age, although the percentage of animals shedding oocysts peaked at 8-14 days of age (76.2%). Statistical analysis showed that infection rates were significantly higher in lambs aged between 1 and 21 days (66.4%) than in those aged between 22 and 90 days (23%) (P<0.0001, chi(2)). Analysis of correlation between excretion of oocysts and diarrhoea revealed a relationship in all age groups and the probability of presenting diarrhoea was significantly higher for lambs shedding oocysts (86.3%) than for those which did not excrete the parasite (32.2%) (P<0.0001, chi(2)). Similarly, cryptosporidial infection rates were significantly higher in diarrhoeic (79.4%) than in non-diarrhoeic lambs (22.4%). Furthermore, infection intensity was correlated with the presence of clinical symptoms. Presence of diarrhoeic lambs in the farm was the only factor significantly associated with an increased risk of infection since the percentage of herds testing positive was significantly higher in farms with diarrhoeic lambs (91.3%) than in those without cases of neonatal diarrhoea (12.5%) (P<0.0001, chi(2)). Factors associated with a decreased risk of C. parvum infection in lambs included low numbers of lambs in the farm and cleaning of the lambing area. Additionally, lambs 8-14 days of age were less likely to be infected at the first lambing period and in spring/autumn. Cryptosporidial infection was also detected in 16 ewes (7.8%) which excreted few oocysts and without diarrhoea.


Athermal Robotic Technique of prostatectomy in patients with large prostate glands (>75 g): technique and initial results.
To report our experience with robotic radical prostatectomy (rRP) for prostate glands of >75 g, as this technique is developing rapidly. Between January 2005 and November 2005, 30 men with prostates of >75 g had rRP. Their clinicopathological and operative data were reviewed. Technical considerations for successful rRP in patients with large glands are discussed, including the importance of surgical exposure and multiple traction sutures. The mean (range) specimen weight was 116.1 (75.3-346.0) g, the patient age 65.0 (56-72) years, the body mass index 28.4 (21-41) kg/m2, the preoperative International Prostate Symptom Score 10 (0-32), and the prostate-specific antigen (PSA) level 7.54 (1.9-20.1) ng/mL. The clinical stage was T1c in 26 men and T2a in four. The biopsy Gleason scores were 3 + 3 = 6 in 25 men, 3 + 4 = 7 in four and 4 + 3 = 7 in one. The mean (range) estimated blood loss was 208 (100-600) mL and the operative duration 193 (150-270) min. The cancer was organ-confined in all patients and all surgical margins were negative. The mean (range) duration of indwelling catheterization was 12.7 (11-14) days. There were no complications during or after rRP, and the PSA level was undetectable in all patients after surgery. RP for patients with large prostates is technically challenging. The robotic approach does not appear to compromise oncological control. We show the feasibility of rRP for men with large glands.


[Diagnostic and therapeutic management of primary and recurrent patellar dislocations - analysis of a nationwide survey and the current literature].
Patellar dislocations are a common injury of the knee joint. During patella dislocations injuries of soft-tissue structures can occur that can destabilise the patella and lead to recurrent dislocations. There are also congenital pathologies that predispose to patella dislocations. In the current literature, diagnostics and treatment of patellar dislocations are frequently discussed. Therefore the aim of our survey was to analyse and summarise actual diagnostic and therapeutic strategies regarding primary and recurrent patella dislocations. An online questionnaire form was sent to 735 orthopaedic and/or trauma departments in Germany. The departments were invited to participate in an anonymous survey concerning diagnostics and treatment of primary and recurrent patellar dislocations. The questionnaire consisted of multiple choice questions and was divided into three sections. The first section included questions concerning the department structure. The second part contained questions regarding diagnostics and treatment of primary patella dislocations. The third part involved diagnostic and treatment strategies for recurrent patella dislocations. A systematic review of outcome after treatment of patellar dislocation was performed and discussed with the results of the survey. 245 hospitals (33.3 %) returned the questionnaire. Among the participants were 23 % orthopaedic surgery departments, 32 % trauma surgery departments and 45 % combined departments. 12 % were university hospitals and 53 % academic teaching hospitals. Clinical examination was performed by nearly all participants after primary and recurrent patella dislocations. MRI was used as diagnostic tool in 81 % after primary patella dislocation and in 85 % after recurrent patella dislocation. Conventional X-rays were performed in 58 % (primary) and 51 % (recurrent patella dislocations). Computed tomography scans for measurement of the tuberositas tibiae-trochlea groove distance were used in 35 % after recurrent dislocations and in 20 % after primary patella dislocations. 69 % of the participating departments performed non-operative therapies after primary patella dislocations, especially when no associated injuries and no congenital pathologies were observed. Reconstruction of the medial retinaculum was the most frequent surgical therapy (52 %) followed by the reconstruction of the medial patellofemoral ligament (36 %) after primary patella dislocation. Following recurrent patella dislocations reconstruction of the medial patellofemoral ligament (58.5 %) was the most performed surgery and a tuberositas transfer was done in 58 % of participating departments after recurrent patella dislocation. The results of our survey showed diagnostic and therapeutic procedures in the participating departments which are in accordance with recommendations in recent publications. The clinical importance of the MPFL reconstruction was observed for primary and recurrent patella dislocation. In addition, conservative treatment is still the most common treatment after primary dislocation of the patella.


Clinical sequelae and sacroiliac joint changes by computed tomography after recovery from septic sacroiliitis.
Nine cases of septic sacroiliitis were re-examined clinically and by CT after a follow-up period of 1.5-7 years. At the final check-up, six of the patients were asymptomatic, while pain could be provoked by palpation or compression in three cases. The sacroiliac joint CT findings were considered normal in two cases. Joint space narrowing, subchondral sclerosis, cysts, erosions, ankylosis and/or osteophytes were detected in seven cases. We conclude that recovery from septic sacroiliitis is good although destructive and degenerative changes often develop as sequelae of an osteolytic involvement.


Delta and Omicron: protective measures and SARS-CoV-2 infections in day care centres in Germany in the 4th and 5th wave of the pandemic 2021/2022.
During the five waves of the SARS-CoV-2 pandemic so far, German early childhood education and care (ECEC) centres implemented various protective measures, such as wearing a face mask, fixed children-staff groups or regular ventilation. In addition, parents and ECEC staff were increasingly vaccinated throughout 2021. During the 4th wave, variant of concern (VOC) Delta-driven transmission indicators reached record values at the end of 2021. Those values were even exceeded in the 5th wave at the beginning of 2022 when Omicron dominated. We examine which factors facilitated or prevented infection with SARS-CoV-2 in ECEC centres, and if these differed between different phases within wave 4 (Delta) and 5 (Omicron). Since August 2020, a weekly online survey among approximately 8000 ECEC managers has been conducted, monitoring both incident SARS-CoV-2 infections and protective measures taken. We included data from calendar week 26/2021 to 05/2022. We estimate the probability of any infections and the number of SARS-CoV-2 infections in children, parents and staff using random-effect-within-between (REWB) panel models for binomial and count data. While children, parents and staff of ECEC centres with a high proportion of children from families with low socioeconomic status (SES) have a higher risk of infections in the beginning of wave 4 (OR up to 1.99 [1.56; 2.56]), this effect diminishes for children and parents with rising incidences. Protective measures, such as wearing face masks, tend to have more extensive effects with rising incidences in wave 5 (IRR up to 0.87 [0.8; 0.93]). Further, the protective effect of vaccination against infection among staff is decreasing from wave 4 to wave 5 (OR 0.3 [0.16; 0.55] to OR 0.95, [0.84; 1.07, n.s.]). The degree of transmission from staff to child and from staff to parent is decreasing from wave 4 to wave 5, while transmission from child to staff seems to increase. While Omicron seems to affect children and parents from ECEC centres with families with all SES levels more equally than Delta, the protective effect of vaccination against infection is decreasing and the effect of protective measures like face masks becomes increasingly important. In order to prevent massive closures of ECEC centres due to infection of staff, protective measures should be strictly adhered to, especially to protect staff in centres with a high proportion of children from families with low socioeconomic status.


Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy.
Antiretroviral treatment (ART) significantly reduces cerebrospinal fluid (CSF) HIV-1 RNA levels and residual viremia is less frequently found in CSF than in blood. However, persistent intrathecal immunoactivation is common, even after several years of ART. To investigate whether low-level CSF viremia and residual immunoactivation within the central nervous system (CNS) derive from ongoing local viral replication, we conducted a study of treatment intensification in patients on effective ART. Ten patients on ART with plasma HIV RNA <50 copies per milliliter for >18 months were included. Intensification was given for in total 8 weeks: 4 weeks with maraviroc or lopinavir/ritonavir (good CNS penetration), and 4 weeks with enfuvirtide (poor CNS penetration). Lumbar punctures were performed 4 weeks before, at intensification commencement, at switchover after 4 weeks, at the conclusion of, and 4 weeks after the intensification period. No significant changes in HIV RNA, neopterin, β2-microglobulin, immunoglobulin G index, albumin ratio, and CD4(+) T-cell count were observed, either in CSF or blood, neither before, during, nor after the intensification periods. ART intensification did not reduce residual CSF HIV RNA levels or intrathecal immunoactivation in patients on ART. These findings do not support an ongoing viral replication in CNS.


The Association of the Lymphocyte-to-C-Reactive-Protein Ratio With Gastric Cancer Patients Who Receive Curative Treatment.
We investigated the association of the preoperative lymphocyte-to-C-reactive-protein ratio (LCR) with gastric cancer survival and recurrence after curative treatment. This study included 480 patients who underwent curative surgery followed by adjuvant treatment for gastric cancer between 2013 and 2017. The prognostic factors for overall survival (OS) and recurrence-free survival (RFS) were identified. A LCR of 7,000 was regarded as the optimal critical point of classification, considering the 1-, 3- and 5-year survival rates. The OS rates at 3 and 5 years after surgery were 84.4% and 73.9% in the low-LCR group, respectively, and 92.4% and 87.0% in the high-LCR group, respectively, and were statistically significantly different. The RFS rates at 3 and 5 years after surgery were 78.8% and 68.7% in the low-LCR group, respectively, and 89.3% and 86.6% in the high-LCR group, respectively, with a statistically significant difference. A multivariate analysis showed that the LCR was a significant independent prognostic factor for both OS and RFS. The LCR was a significant prognostic factor for survival in patients who underwent curative treatment for gastric cancer.


High prevalence of clindamycin resistance in Staphylococcus aureus blood culture isolates in São Paulo, Brazil.
Clindamycin has become an important antimicrobial option for the treatment of Staphylococcus aureus. However, little is known about the current patterns of clindamycin-susceptibility in S. aureus invasive isolates, both in our country and in other developing countries in the world. The aim of this study was to determine the prevalence of constitutive and inducible clindamycin resistance in methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) blood culture isolates in São Paulo, Brazil. From July 2011 to June 2012, all S. aureus isolates from blood cultures collected at our hospital were included in the study. Antimicrobial susceptibility testing was performed according to recommendations of the Clinical and Laboratory Standards Institute. Total prevalence of clindamycin resistance was 68%, including 7.2% with inducible resistance. In MRSA resistance rate was 90.8% whereas in MSSA the rate was 32.7%. Our high prevalence of clindamycin resistance highlights the importance of performing D-test in a routine base, as well of maintaining continued surveillance for the prevalence of clindamycin resistance.


The young Göttingen minipig as a model of childhood and adolescent obesity: influence of diet and gender.
Gender and sex hormones influence the development of obesity and metabolic syndrome in humans and Göttingen minipigs. The aim of this study was to investigate possible gender differences in the metabolic response to a high energy diet in young Göttingen minipigs as a model of childhood/adolescent obesity. Nine-week-old male and female Göttingen minipigs were fed restrictedly on either a low energy diet (LED) or a high energy diet (HED) for 4 months (n = 5-7). Parameters of interest were fat percentage, visceral fat mass, plasma lipids and glucose tolerance, insulin resistance, and β-cell function measured by oral and intravenous glucose tolerance tests. At 11 to 12 weeks of age, after 2 weeks diet feeding, both genders on HED had increased fat percentage, glucose intolerance, decreased insulin sensitivity, and increased plasma levels of cholesterol and triglycerides (TGs). There was no gender difference in body weight (BW) or fat percentage, but males had lower glucose tolerance than females. After 3.5 to 4 months on the diets, the pigs on HED had increased BW, fat percentage, and visceral fat mass and were more glucose intolerant and insulin resistant than pigs on LED. Also increases in plasma cholesterol and TG levels were observed in the pigs on HED. Females had higher fat percentage and more visceral fat, were more insulin resistant, and had a more unfavorable lipid profile compared with males independent of diet. In conclusion, the young Göttingen minipig, and especially the female gender, seems to be a potential model for diet induced childhood/adolescent obesity and metabolic syndrome.


Community control of hypertension- experiences from Finland.
The improvement in the hypertension control in Finland started in the 1970s by the activities of the North Karelia Project, a comprehensive programme for the control of cardiovascular diseases. The blood pressure level of the population has had a continuous downward trend according to the population surveys conducted every fifth year since 1972 and the rule of halves has changed to the rule of two-thirds. The serum cholesterol level has decreased among hypertensives, even though it is still higher than among normotensives; the patients with antihypertensive drug treatment smoke less than the rest of the population. However, the situation is far from optimal; BP levels are high and body mass index is continuously increasing among the patients. The need for intensifying both pharmacological and nonpharmacological treatment among the hypertensives on a large scale is obvious.


The influence of substance P on the response of guinea-pig isolated ileum to periarterial nerve stimulation.
1 The effects of substance P (SP) on the responses of the guinea-pig isolated ileum to periarterial nerve stimulation were studied. Electrical stimulation (2-50 Hz) of mesenteric periarterial nerves resulted in contraction of preparations pretreated with guanethidine. The responses were abolished by atropine and morphine, but unaffected by hexamethonium. 2 SP in a high concentration (0.65 mumol) inhibited reversibly, by about 40%, the responses of the guinea-pig isolated ileum to periarterial nerve stimulation. 3 SP in a very low concentration (0.18 pmol) potentiated (by about 20%) the responses of the guinea-pig isolated ileum to periarterial nerve stimulation. 4 In the presence of low concentrations (0.06-0.32 pmol) of SP, morphine (2.65 mumol) produced less inhibition of the responses to periarterial nerve stimulation, and recovery from morphine inhibition of contraction was accelerated. 5 These results indicate that SP may act as a modulator on prejunctional acetylcholine release in the guinea-pig ileum.


Heterogeneous intracellular expression of B-cell receptor components in B-cell chronic lymphocytic leukaemia (B-CLL) cells and effects of CD79b gene transfer on surface immunoglobulin levels in a B-CLL-derived cell line.
B-cell chronic lymphocytic leukaemia (B-CLL) cells display low amounts of surface immunoglobulins (sIg). To investigate the mechanisms underlying this phenomenon, we performed a thorough study of surface and intracellular expression of the B-cell receptor (BCR) components in B-CLL cells using flow cytometry. There was an heterogeneous pattern of expression. Overall, 20 of 22 samples showed reduced sIgM levels, compared with normal B cells. Among them, three (15%) had very low to undetectable intracellular IgM levels and variable amounts of CD79a and CD79b; nine (45%) had low intracellular CD79b levels but appreciable levels of IgM and CD79a; and eight (40%) had relatively normal intracellular levels of all BCR components. To investigate whether surface BCR levels could be controlled by the rate of CD79b synthesis, adenoviral vectors encoding CD79b were generated and used for gene transfer experiments. Delivery of CD79b to non-B cells transfected with IgM and CD79a lead to high-level expression of a functional BCR. Moreover, CD79b gene transfer in a B cell line derived from a B-CLL patient and characterised by low intracellular levels of endogenous CD79b consistently increased sIgM levels. These findings indicate that the phenotype of B-CLL cells in a subset of patients may depend primarily on poor CD79b expression, and suggest that upregulation of CD79b expression may correct the phenotype of these cells.


Human metabolism and excretion kinetics of benzotriazole UV stabilizer UV-327 after single oral administration.
UV-327 (2-(5-chloro-benzotriazol-2-yl)-4,6-di-(tert-butyl)phenol) is used as an ultraviolet (UV) absorber in plastic products and coatings. Due to its ubiquitous distribution in the environment, human exposure is conceivable. In the study presented herein, initial information on the human in vivo metabolism of UV-327 was obtained by single oral administration to three volunteers. Urine and blood samples were collected up to 72 h after exposure. One study participant additionally donated plasma samples. Maximum blood and plasma levels of UV-327 and its two monohydroxylated metabolites UV-327-6-mOH and UV-327-4-mOH were reached 6 h post-exposure. Almost the entire amount found in blood and plasma samples was identified as UV-327, whereas the two metabolites each accounted for only 0.04% of the total amount, indicating that UV-327 is well-absorbed from the intestine, but only partially metabolized. Plasma to blood ratios of UV-327, UV-327-6-mOH, and UV-327-4-mOH ranged from 1.5 to 1.6. Maximum urinary excretion rates of UV-327, UV-327-6-mOH, UV-327-4-mOH, and UV-327-4 + 6-diOH were reached 9-14 h post-exposure. However, only about 0.03% of the orally administered dose of UV-327 was recovered as UV-327 and its metabolites in urine, indicating that biliary excretion may be the major route of elimination of UV-327 and its hydroxylated metabolites. The present study complements the insight in the complex absorption, distribution, metabolism, and elimination (ADME) processes of benzotriazole UV stabilizers (BUVSs).


Gas chromatographic retention behaviour of polychlorinated naphthalenes on non-polar, polarizable, polar and smectic capillary columns.
Six commercially available gas chromatography columns were investigated for performance in separating polychlorinated naphthalenes (PCNs). Retention behaviour on the investigated phases is compared and retention data for 40 congeners on a 5% phenyl-methylpolysiloxane column is reported. For all columns, except the octylmethylpolysiloxane and the smectic, a relation between substitution pattern and retention was found, where substitution in adjacent positions as well as alpha-substitution increase the retention time. A mathematical model based on these findings was developed and used to predict the relative retention of all congeners from di- up to octachloronaphthalene, on a 5% phenyl-methylpolysiloxane column.


Roles of growth hormone and testosterone in the synthesis of mouse kidney glucuronidase.
Mouse kidney beta-glucuronidase production is under multihormonal control. In normal mice, kidney glucuronidase is induced over 100-fold by testosterone. However, hypophysectomy reduces this induction to about 5% of normal. This loss in inducibility was in part restored by growth hormone. Simultaneous administration to hypophysectomized female mice of growth hormone and testosterone, but not of prolactin and testosterone, restored kidney glucuronidase concentration to half that found in testosterone-treated normal female mice. Growth hormone alone had no effect in hypophysectomized females nor did it enhance glucuronidase activity in testosterone-treated normal females. Radiolabeling experiments demonstrated that the enhancement by growth hormone of glucuronidase activity was accompanied by a corresponding increase in its rate of synthesis. Kidney hypertrophy and kidney glucuronidase production may be under common hormonal regulation. Testosterone or growth hormone treatment alone of hypophysectomized mice had little or no effect on either process, but combined treatment with the two hormones significantly enhanced both. The rate of synthesis of kidney glucuronidase is controlled by the Gur gene. Relative differences in kidney glucuronidase synthesis in mice of different Gur genotype were maintained in testosterone-treated hypophysectomized mice. This suggests that control of glucuronidase synthesis by the Gur locus is exerted by interaction with androgens rather than pituitary products.


Myristoylated alanine-rich C kinase substrate (MARCKS) regulates the expression of proinflammatory cytokines in macrophages through activation of p38/JNK MAPK and NF-κB.
MARCKS, a substrate of protein kinase C, is involved in various processes associated with cytoskeletal movement. Although the expression of MARCKS is highly induced in macrophages, its role in macrophage function has not been studied in detail. Notably, the suppression of MARCKS expression in macrophage cell lines blocked LPS-induced expression of TNF-α at the transcriptional level. Treatment of macrophages with MARCKS N-terminus sequence (MANS) and effector domain (ED) peptides, which mimic functional domains and block the phosphorylation of MARCKS, suppressed the LPS-induced expression of TNF-α through suppression of p38 and JNK MAPKs and NF-κB. Treatment of mice with MANS peptide reduced serum TNF-α and IL-6 levels and resulted in 40% survival of mice after the administration of a lethal dose of LPS. These data demonstrate that MARCKS is involved in the regulation of proinflammatory cytokine expression in macrophages and that MARCKS-derived peptides can be used to suppress inflammatory responses.


Barriers to participation in surgical randomized controlled trials in pediatric urology: A qualitative study of key stakeholder perspectives.
Randomized controlled trials (RCTs) are considered the gold standard for assessing treatment efficacy. However, pediatric surgical RCTs have been limited in their ability to recruit patients. The purpose of this study was to identify barriers and motivators to pediatric participation in surgical RCTs. We conducted a series of two focus groups with parents and one focus group with urology providers for children aged <2 years of age with a diagnosis of Society for Fetal Urology grade 3 or 4 hydronephrosis. We then administered a survey to referring pediatricians based on the initial analysis of focus group findings. Theme analysis was used for all qualitative transcribed text data obtained from focus groups and open-ended survey questions using team-based inductive approaches. Descriptive statistics were obtained for the remainder of the provider survey. Using qualitative text from stakeholders (n = 38) we identified four key themes across the data: responsibility to my child; responsibility to my patient; responsibility to the field; and irreversibility of surgery. Participants felt there was an obligation to be informed of relevant scientific research within a clinic research culture. However, there remains a disconnect for parents between randomized research studies that may ultimately benefit their child, depending on their age and concern their child is being treated as a 'guinea pig'. Some parents were willing to participate in RCTs but all were more open to participate in an observational study where the treatment decisions were felt to be under their control even when there was no "right answer" or multiple equivalent options for treatment. There was mixed opinion across the parents and providers whether research trial education and enrollment should be provided by the pediatrician or urologist. Active physician decisions were seen as critical within the context of a long term clinical relationship and provision of information of risks and benefits without pressure were considered essential for ethical research by both parents and providers. While some parents are open to participation in surgical RCTs, providers and parents of children with hydronephrosis feel discomfort with the element of chance in surgical randomized trials. Parents and providers are more likely to participate in observational studies where treatment decisions may be made jointly by the physician and the parent. These findings suggest that pragmatic trial strategies with the option for participation in an observational cohort may improve recruitment of pediatric patients into surgical clinical trials.


Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial.
Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting. We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416). Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9-44·4). Median overall survival was 35·0 months (95% CI 31·1-39·0) in the S-1 group and 37·2 months (33·0-40·1) in the taxane group (HR 1·05 [95% CI 0·86-1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group. S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho.


Vasectomy and lowering surgeon's risk of liability.
The increased demand for vasectomy as a method of fertility control has resulted in an increase in professional liability suits against those surgeons performing this procedure. In some instances this litigation appears to arise from vague or casual instructions from the surgeon, but an additional causative factor is a misunderstanding on the part of the patient regarding the operative and postoperative periods and his responsibility for utilizing alternative contraceptive methods. I suggest some means for addressing these problems, and comment on the factors to consider when the surgeon finds himself the defendant in a lawsuit on "failed" vasectomy.


[Progress in the surgical treatment of cervix carcinoma].
The radioisotope radical operation may cause an improvement of results in carcinoma of the cervix stage I b, II, and IV. The increased yield of lymph nodes enables a more reliable prognosis in advanced cases. Recurrent tumors at the pelvic wall may be detected earlier by isotope nephrography.


Enantioselective synthesis of alcohols and amines by iridium-catalyzed hydrogenation, transfer hydrogenation, and related processes.
The preparation of chiral alcohols and amines by using iridium catalysis is reviewed. The methods presented include the reduction of ketones or imines by using hydrogen (hydrogenations), isopropanol, formic acid, or formate (transfer hydrogenations). Also dynamic and oxidative kinetic resolutions leading to chiral alcohols and amines are included. Selected literature reports from early contributions to December 2012 are discussed.


An evaluation of two heavier-than-water internal limiting membrane-specific dyes during macular hole surgery.
To evaluate the staining characteristics and effect on internal limiting membrane (ILM) histology of two heavier-than-water ILM-specific dyes during macular hole surgery: acid violet 17 combined with 5 % mannitol (AV17-M) and brilliant blue G with 4 % polyethylene glycol (BBG-P). Single-centre observational comparative cohort study. The ILM of consecutive patients undergoing surgery for idiopathic macular hole were stained with BBG-P and AV17-M for 10 s each. The ILMs were retrieved and examined with electron microscopy. The extent of retinal and vitreous side debris was scored. Surgical videos were used to assess the staining contrast effect by measuring the Euclidean distance in the CIELAB colour space between stained and unstained retinas after peeling. 51 consecutive patients were studied with 25 in the AV17-M group and 26 in the BBG-P group. The mean age was 71 years with no significant difference between the groups. The amount of retinal side tissue was greater on the BBG-P-stained ILMs compared to the AV17-M-stained ILMs (30.2 versus 19.6 %, p < 0.001). There was a difference in the CIELAB colour space separation distance between stained and peeled retinas (5.89 versus 3.97, p = 0.01) in favour of BBG-P. Visual outcomes between the two groups were similar (logMAR visual acuity 0.40 versus 0.38, p = 0.74). Both stains were successfully used to peel the ILM with comparable outcomes. AV17-M resulted in less retinal debris than BBG-P, suggesting an altered and potentially beneficial ILM cleavage plane from the retina but with lowered staining contrast than BBG-PEG.


Supercontinuum generation in quasi-phase-matched LiNbO3 waveguide pumped by a Tm-doped fiber laser system.
We demonstrate self-referencing of a Tm-doped fiber oscillator-amplifier system by performing octave-spanning supercontinuum generation in a periodically poled lithium niobate waveguide. We model the supercontinuum generation numerically and show good agreement with the experiment.


Left-handed Z-DNA and intramolecular triplex formation at the site of an unequal sister chromatid exchange.
An unequal sister chromatid exchange (USCE) in the mouse myeloma cell line MPC-11 between 3' regions of the C gamma 2a and C gamma 2b heavy chain genes results in duplication of the C gamma 2a heavy chain gene and generation of a novel recombination joint. The USCE occurs between (TC)n tracts adjacent to alternating purine-pyrimidine tracts. We have investigated the capacity of both the donor regions and the recombinant product involved in this event to adopt left-handed Z-DNA and intramolecular triplexes. The results of chemical probing with diethylpyrocarbonate and osmium tetroxide at the base pair level demonstrate that under the influence of negative supercoiling the alternating purine-pyrimidine regions of these plasmids can adopt Z-DNA at neutral pH, and the oligopurine.oligopyrimidine (pur.pyr) regions of these regions can adopt intramolecular triplexes at low pH (less than or equal to pH 6.0). At intermediate pH values, mixtures of both structures are present. Increasing the negative superhelical density of the plasmid does not increase the amount of triplex present at neutral pH indicating that the presence of long Z-DNA segments adjacent to pur.pyr tract prevents intramolecular triplex formation. In summary, we conclude that the sequences involved in the USCE can form either an intramolecular triplex in the (TC)n tract or Z-DNA in the alternating purine-pyrimidine tract and that Z-DNA will predominate under physiological conditions. The presence of segments which adopt Z-DNA at a site of USCE suggests that formation of this structure may enhance recombination between adjacent pur.pyr tracts.


Comparative study of four interleukin 17 cytokines of tongue sole Cynoglossus semilaevis: Genomic structure, expression pattern, and promoter activity.
The interleukin (IL)-17 cytokine family participates in the regulation of many cellular functions. In the present study, we analyzed the genomic structure, expression, and promoter activity of four IL-17 members from the teleost fish tongue sole (Cynoglossus semilaevis), i.e. CsIL-17C CsIL-17D, CsIL-17F, and IL-17F like (IL-17Fl). We found that CsIL-17C, CsIL-17D, CsIL-17F, and CsIL-17Fl share 21.2%-28.6% overall sequence identities among themselves and 31.5%-71.2% overall sequence identities with their counterparts in other teleost. All four CsIL-17 members possess an IL-17 domain and four conserved cysteine residues. Phylogenetic analysis classified the four CsIL-17 members into three clusters. Under normal physiological conditions, the four CsIL-17 expressed in multiple tissues, especially non-immune tissues. Bacterial infection upregulated the expression of all four CsIL-17, while viral infection upregulated the expression of CsIL-17D and CsIL-17Fl but downregulated the expression of CsIL-17C and CsIL-17F. The 1.2 kb 5'-flanking regions of the four CsIL-17 exhibited apparent promoter activity and contain a number of putative transcription factor-binding sites. Furthermore, the promoter activities of CsIL-17C, CsIL-17D, and CsIL-17F, but not CsIL-17Fl, were modulated to significant extents by lipopolysaccharide, PolyI:C, and PMA. This study provides the first evidence that in teleost, different IL-17 members differ in expression pattern and promoter activity.


Tyrosine sulfation site is located in the C-terminal fibrin-binding domain in secreted fibronectin from rat embryo fibroblasts, line 3Y1.
Tryptic fragments of [35S]sulfate-labeled 3Y1 secreted fibronectin were fractionated by hydroxylapatite column chromatography and examined using sodium dodecyl sulfate gel electrophoresis, followed by autoradiography. Radioactive bands containing tyrosine-O-[35S]sulfate were detected at 17- and 40-kDa positions under reducing conditions. Under nonreducing conditions, the 17-kDa band was no longer present and new bands at 57- and 80-kDa positions appeared, indicating a disulfide linkage between the two smaller fragments in the native state. These fragments exhibited binding affinity toward fibrin and could be immunoprecipitated by the monoclonal antifibronectin Fib-2 domain antibody. These results suggested that the tyrosine sulfation site in 3Y1 secreted fibronectin is located in the C-terminal fibrin-binding (Fib-2) domain, being within 17 kDa of the C-terminus.


Inferotemporal cortex subserves three-dimensional structure categorization.
We perceive real-world objects as three-dimensional (3D), yet it is unknown which brain area underlies our ability to perceive objects in this way. The macaque inferotemporal (IT) cortex contains neurons that respond selectively to 3D structures defined by binocular disparity. To examine the causal role of IT in the categorization of 3D structures, we electrically stimulated clusters of IT neurons with a similar 3D-structure preference while monkeys performed a 3D-structure categorization task. Microstimulation of 3D-structure-selective IT clusters caused monkeys to choose the preferred structure of the 3D-structure-selective neurons considerably more often. Microstimulation in IT also accelerated the monkeys' choice for the preferred structure, while delaying choices corresponding to the nonpreferred structure of a given site. These findings reveal that 3D-structure-selective neurons in IT contribute to the categorization of 3D objects.


Control of the hypothalamus-pituitary-adrenal axis in young and older rats injected with thyroxine.
Administration of T4 on alternate weeks for 30 weeks at a dosage which does not alter body weight depresses basal serum corticosterone levels in older rats (575 days), but not in young animals (260 days). Similar serum corticosterone response to HPA axis stimulation occurs regardless of age or T4 injection.


Inhibition of C5AR1 impairs osteoclast mobilization and prevents bone loss.
Age-related and chemotherapy-induced bone loss depends on cellular senescence and the cell secretory phenotype. However, the factors secreted in the senescent microenvironment that contribute to bone loss remain elusive. Here, we report a central role for the inflammatory alternative complement system in skeletal bone loss. Through transcriptomic analysis of bone samples, we identified complement factor D, a rate-limiting factor of the alternative pathway of complement, which is among the most responsive factors to chemotherapy or estrogen deficiency. We show that osteoblasts and osteocytes are major inducers of complement activation, while monocytes and osteoclasts are their primary targets. Genetic deletion of C5ar1, the receptor of the anaphylatoxin C5a, or treatment with a C5AR1 inhibitor reduced monocyte chemotaxis and osteoclast differentiation. Moreover, genetic deficiency or inhibition of C5AR1 partially prevented bone loss and osteoclastogenesis upon chemotherapy or ovariectomy. Altogether, these lines of evidence support the idea that inhibition of alternative complement pathways may have some therapeutic benefit in osteopenic disorders.


Nystagmus only with fixation in the light: a rare central sign due to cerebellar malfunction.
Fixation nystagmus refers to the nystagmus that appears or markedly increases with fixation. While relatively common in infantile (congenital) nystagmus, acquired fixation nystagmus is unusual and has been ascribed to lesions involving the cerebellar nuclei or the fibers projecting from the cerebellum to the brainstem. We aimed to report the clinical features of patients with acquired fixation nystagmus and discuss possible mechanisms using a model simulation and diagnostic significance. We describe four patients with acquired fixation nystagmus that appears or markedly increases with visual fixation. All patients had lesions involving the cerebellum or dorsal medulla. All patients showed direction-changing gaze-evoked nystagmus, impaired smooth pursuit, and decreased vestibular responses on head-impulse tests. The clinical implication of fixation nystagmus is that it may occur in central lesions that impair both smooth pursuit and the vestibulo-ocular reflex (VOR) but without creating a spontaneous nystagmus in the dark. We develop a mathematical model that hypothesizes that fixation nystagmus reflects a central tone imbalance due to abnormal function in cerebellar circuits that normally optimize the interaction between visual following (pursuit) and VOR during attempted fixation. Patients with fixation nystagmus have central lesions involving the cerebellar circuits that are involved in visual-vestibular interactions and normally eliminate biases that cause a spontaneous nystagmus.


Effects of D-cycloserine on the behavior and ERK activity in the amygdala: role of individual anxiety levels.
Low dose of D-cycloserine (DCS), a partial agonist of glycine binding site on N-methyl-D-aspartate (NMDA) receptors, can facilitate extracellular signal-regulated kinase1/2 (ERK1/2) activity in the amygdala and modulate emotional behavior. However, the relationship between ERK1/2 activation, individual anxiety levels, and DCS is unknown. Therefore, based on open arm time in the elevated plus-maze, male Wistar rats were divided into subgroups with either low (LOA) or high open arm (HOA) time. Open arm time is usually accepted as a critical index of unconditioned anxiety-like/avoidance behavior. On the following day, DCS (30 mg/kg, i.p.) was administered 30 min before the second elevated plus-maze test. On day 8 and 9, the rats were subjected to a 2-day session of the forced swim test, receiving the DCS treatment again 30 min before the 2nd day. On the 16th day, 30 min after the administration of DCS, the rats were sacrificed in order to detect the phosphorylation of ERK1/2 (p-ERK1/2) in the amygdala by Western blots. The results showed that: (1) DCS decreased the open arm time in HOA but not LOA rats. (2) DCS suppressed the immobility in the day-2 trial of the forced swim test and increased the p-ERK1/2 level in the amygdala in LOA but not HOA rats. This is the first instance data has been found indicating different sensitivities of p-ERK1/2 and behavioral responses to the treatment of DCS between HOA and LOA rats. The results suggest that the activity of NMDA receptor-mediated ERK1/2 signaling is mediated by individual behavioral differences which are related to the antidepressant-like activity of DCS. This study provides first insight into the pathophysiological role of ERK signaling with regard to individual differences in emotional behavior.


Detection of Lymph Node Metastases with SERRS Nanoparticles.
The accurate detection of lymph node metastases in prostate cancer patients is important to direct treatment decisions. Our goal was to develop an intraoperative imaging approach to distinguish normal from metastasized lymph nodes. We aimed at developing and testing gold-silica surface-enhanced resonance Raman spectroscopy (SERRS) nanoparticles that demonstrate high uptake within normal lymphatic tissue and negligible uptake in areas of metastatic replacement. We evaluated the ability of SERRS nanoparticles to delineate lymph node metastases in an orthotopic prostate cancer mouse model using PC-3 cells transduced with mCherry fluorescent protein. Tumor-bearing mice (n = 6) and non-tumor-bearing control animals (n = 4) were injected intravenously with 30 fmol/g SERRS nanoparticles. After 16-18 h, the retroperitoneal lymph nodes were scanned in situ and ex vivo with a Raman imaging system and a handheld Raman scanner and data corroborated with fluorescence imaging for mCherry protein expression and histology. The SERRS nanoparticles demonstrated avid homing to normal lymph nodes, but not to metastasized lymph nodes. In cases where lymph nodes were partially infiltrated by tumor cells, the SERRS signal correctly identified, with sub-millimeter precision, healthy from metastasized components. This study serves as a first proof-of-principle that SERRS nanoparticles enable high precision and rapid intraoperative discrimination between normal and metastasized lymph nodes.


Risk assignment in pediatric soft-tissue sarcomas: an evolving molecular classification.
Pediatric soft-tissue sarcomas are increasingly being defined by both histologic appearance and underlying chromosomal abnormalities to determine their biologic behavior. Most sarcomas of this type have specific chromosomal translocations that create unique fusion genes. Expression of such fusion genes may have diagnostic, prognostic, and surveillance implications for the patient. This review analyzes the fusion gene expressions seen with seven of the major types of pediatric soft-tissue tumors and their impact on biologic behavior. In nearly 50% of the malignancies discussed, the diagnostic, prognostic, and surveillance implications of their specific fusion gene expressions are already defined or becoming established (alveolar rhabdomyosarcoma, Ewing sarcoma/primitive neuroectodermal tumor, and synovial sarcoma). In the remainder of the tumors, these questions are rapidly being addressed. To facilitate future fusion gene studies, pediatric surgeons, pathologists, and oncologists need to work as a coordinated team to ensure proper tumor procurement. Large clinical cooperative trials involving biologic studies of pediatric soft-tissue sarcomas could facilitate advancement of knowledge in this area of pediatric oncology.


Growth-dependent signals drive an increase in early G1 cyclin concentration to link cell cycle entry with cell growth.
Entry into the cell cycle occurs only when sufficient growth has occurred. In budding yeast, the cyclin Cln3 is thought to initiate cell cycle entry by inactivating a transcriptional repressor called Whi5. Growth-dependent changes in the concentrations of Cln3 or Whi5 have been proposed to link cell cycle entry to cell growth. However, there are conflicting reports regarding the behavior and roles of Cln3 and Whi5. Here, we found no evidence that changes in the concentration of Whi5 play a major role in controlling cell cycle entry. Rather, the data suggest that cell growth triggers cell cycle entry by driving an increase in the concentration of Cln3. We further found that accumulation of Cln3 is dependent upon homologs of mammalian SGK kinases that control cell growth and size. Together, the data are consistent with models in which Cln3 is a crucial link between cell growth and the cell cycle.


Modeling of vapor sorption in polymeric film studied by surface plasmon resonance spectroscopy.
Sorption process by surface plasmon resonance (SPR) was studied by exposing polymeric film made from anthracene labeled poly(methyl methacrylate) (An-PMMA) chains to various concentrations of saturated chloroform vapor. It was observed that the reflectivity changes were fast and reversible. The changes in reflectivity implied the swelling behavior of polymeric film during adsorbtion and can be explained by capturing of chloroform molecules. When clean air is introduced into gas cell similar behavior is observed but this time in the opposite direction as a result of desorption. Fick's law for diffusion was used to quantify real time SPR data for the swelling and desorption processes. It was observed that diffusion coefficients (D(s)) for swelling obeyed the t(1/2) law and found to be correlated with the amount of chloroform content in the cell. Diffusion coefficients (D(d)) during desorption were also measured and found to be increased as the saturated chloroform vapor content is increased in the cell.


Behavioral management of childhood headache: a pilot study and case history report.
Many chronically recurrent disorders of children and adolescents are often unresponsive to standard medical therapy. The Stress and Headache Management Clinic was established as a prototype behavioral medicine clinic to provide integrated therapeutic modalities. Using biofeedback and relaxation/mental-imagery techniques, 119 patients with the chief complaint of recurrent headache were evaluated. This paper describes the use, application, and efficacy of behavioral techniques for the management of headache in children and adolescents. Relevant treatment factors in behavioral treatment of pediatric headache are also discussed.


Heat shock proteins as markers of neural injury.
Systemic or intracerebral injections of kainic acid induced immunoreactivity for the 72 kDa heat shock protein (HSP72) in individual neurons of the rat brain in patterns matching the known histopathology of the particular injury. HSP72 immunostaining was also induced in and around areas of infarction following experimental strokes. These results suggest that HSP72 immunocytochemistry may be used as a marker of cellular injury in the mammalian brain.


Left ventricular systolic and diastolic flow abnormalities determined by Doppler echocardiography in obstructive hypertrophic cardiomyopathy.
To analyze the relation of systolic anterior motion (SAM) of the mitral valve, peak left ventricular (LV) outflow tract velocity, aortic flow and mitral flow, 17 patients with obstructive hypertrophic cardiomyopathy (HC) (8 men, 9 women), aged 19 to 88 years (mean 45), were studied using M-mode and 2-dimensional echocardiography and pulsed and continuous-wave Doppler echocardiography and results were compared with those from 18 age-matched normal subjects. SAM was present in all patients with HC and absent in normal subjects. Time to peak outflow velocity as a percentage of LV ejection time was 63% in patients with HC and 29% in normal subjects (p less than 0.001). In 13 patients, time from the R-wave peak to the closest approximation of the mitral valve to the ventricular septum or initial contact during SAM was determined and was 242 +/- 66 ms and time from the R-wave peak to the peak LV outflow tract velocity was 242 +/- 73 ms (r = 0.90). In 11 patients time from the R-wave peak to cessation of flow in the ascending aorta was measured and was 286 +/- 80 ms; time from the R-wave peak to the peak LV outflow tract velocity was 246 +/- 75 ms. The ratio of early to late diastolic filling velocities of the left ventricle was 1.47 +/- 0.40 in the normal subjects and 1.26 +/- 0.84 in patients with HC (difference not significant). The early to late ratio of the 12 patients without mitral regurgitation was 0.99 +/- 0.52 (p less than 0.01 vs normal subjects).(ABSTRACT TRUNCATED AT 250 WORDS)


Aminoacyl-tRNA synthetase (AARS) as an attractive drug target in neglected tropical trypanosomatid diseases-Leishmaniasis, Human African Trypanosomiasis and Chagas disease.
TriTryp diseases (Leishmaniasis, Human African Trypanosomiasis (HAT), and Chagas disease) are devastating parasitic neglected tropical diseases (NTDs) that affect billions of people in developing countries, cause high mortality in humans, and impose a large socio-economic burden. The current treatment options against tritryp diseases are suboptimal and challenging due to the emergence of resistance against available tritryp drugs. Hence, designing and developing effective anti-tritryp drugs with novel targets are required. Aminoacyl-tRNA synthetases (AARSs) involved in specific aminoacylation of transfer RNAs (tRNAs), interrupt protein synthesis through inhibitors, and retard the parasite growth. AaRSs have long been studied as therapeutic targets in bacteria, and three aaRS inhibitors, mupirocin (against IleRS), tavaborole AN2690 (against LeuRS), and halofuginone (against ProRS), are already in clinical practice. The structural differences between tritryp and human aaRSs and the presence of unique sequences (N-terminal domain/C-terminal domain/catalytic domain) make them potential target for developing selective inhibitors. Drugs based on a single aaRS target developed by high-throughput screening (HTS) are less effective due to the emergence of resistance. However, designing multi-targeted drugs may be a better strategy for resistance development. In this perspective, we discuss the characteristics of tritryp aaRSs, sequence conservation in their orthologs and their peculiarities, recent advancements towards the single-target and multi-target aaRS inhibitors developed through rational design.


[Seizures revealing phosphocalcic metabolism abnormalities].
Hypocalcemia due to hypoparathyroidism produces a broad spectrum of clinical manifestations, but overt symptoms may be sparse. One unusual presentation is onset or aggravation of epilepsy in adolescence revealing hypoparathyroidism. This situation can lead to delayed diagnosis, with inefficacity of the antiepileptic drugs. We report five cases of adolescence-onset epilepsy with unsuccessful antiepileptic therapy, even with gradually increasing dose. Physical examination revealed signs of hypocalcemia, confirmed biologically. Full testing disclosed the origin of the seizures: hypoparathyroidism in three patients and pseudohypoparathyroidism in the other two. In four of five patients, computed tomography showed calcification of the basal ganglia, defining Fahr's syndrome. The patients were treated with oral calcium and active vitamin D (1-alphahydroxy vitamin D3). Seizure frequency progressively decreased and serum calcium levels returned to normal. These cases illustrate the importance of the physical examination and of routine serum calcium assay in patients with new-onset epileptic seizures in order to detect hypocalcemia secondary to hypoparathyroidism.


Late diagnosis of CHD and its associated factors in Kenya: an analytic cross-sectional study.
Burden of CHD in Africa is generally underestimated mainly due to significant under-reporting and early-related fetal and neonatal mortality. Determine the prevalence and factors associated with late diagnosis of CHD seen at three tertiary care hospitals in Kenya. A cross-sectional study on paediatric patients with CHDs, aged 0-18 years, seen over a 5-year period, between January, 2011 and December, 2016. Aga Khan University Hospital Nairobi, Mater Hospital, and Kenyatta National Hospital. Patients were stratified into those diagnosed late (>1 year of age) and those diagnosed early (<1 year of age). Multiple logistic regression analysis was done to determine factors associated with late diagnosis. The study enrolled 411 patients, with equal gender distribution. Prevalence of late diagnosis (>1 year of age) of CHD was 60.6% (95% CI 55.7-65.3). Median age at diagnosis was 15 (IQR 5-48) months. Presence of a cardiac murmur (OR = 0.87; 95% CI 0.72-0.92, p-value = 0.016) and level of parental education (OR = 4.99; 95% CI 2.25-11.40, p-value <0001) were associated with a decreased odds of late diagnosis. Other factors like cyanosis, an increase in the number of healthcare workers and healthcare facilities per 10,000 population showed some association with decreased odds of late diagnosis of CHD, but these were not statistically significant. Late diagnosis of CHD remains alarmingly high in our setting. Initiatives to enhance early detection and screening of CHD should be adopted to reduce related mortality and morbidity.


Constructing turn-on bioluminescent probes for real-time imaging of reactive oxygen species during cisplatin chemotherapy.
Real-time imaging of reactive oxygen species (ROS) during cisplatin chemotherapy of cancer is imperative to fully reveal their functions in the biological response to cisplatin. Currently, using a bioluminescent probe for real-time imaging of a specific ROS in vivo during cisplatin chemotherapy has not been achieved. Herein, three bioluminescent probes, F Probe, N Probe and P Probe were synthesized for real-time imaging of the primary ROS, O2•-. They all consisted of a bioluminescent emitter D-luciferin (D-LH2) and an O2•--recognition group, and their bioluminescent signal could be turned on in response to O2•-. In vitro results indicated that P Probe was the most suitable one among the three probes for detection of O2•-, with high sensitivity, excellent selectivity and stability. P Probe was then successfully applied for real-time imaging of O2•- in both cancer cells and tumors during cisplatin chemotherapy. The imaging results demonstrated that O2•- amount in cancer cells increased with the increasing dose of cisplatin, and that cisplatin-induced upregulation of O2•- level in cancer cells was upstream of the cancer-killing pathway of cisplatin. We envision that P Probe may serve as an elucidative tool to further explore the role of O2•- in cisplatin chemotherapy.


Quantification methods of folpet degradation products in plasma with HPLC-UV/DAD: application to an in vivo toxicokinetic study in rats.
Solid-phase extractions followed by HPLC-UV/DAD methods were developed for occupational biological monitoring or forensic investigations of the fungicide folpet using its degradation products, phthalimide and phthalamic acid as plasma biomarkers. These methods show good linearity (r>0.9955), precision (CV<15%) and accuracy (bias<14.8%). The lower limits of quantification for phthalimide and phthalamic acid were 10 and 20 ng/ml and the absolute recoveries were higher than 86% and 68%, respectively. Applying these methods, a plasma toxicokinetic study of folpet in rats after intratracheal administration of Folpan 80WG showed that inhalation of folpet could be a route of exposure with an important systemic absorption.


Trade-off between conservation of biological variation and batch effect removal in deep generative modeling for single-cell transcriptomics.
Single-cell RNA sequencing (scRNA-seq) technology has contributed significantly to diverse research areas in biology, from cancer to development. Since scRNA-seq data is high-dimensional, a common strategy is to learn low-dimensional latent representations better to understand overall structure in the data. In this work, we build upon scVI, a powerful deep generative model which can learn biologically meaningful latent representations, but which has limited explicit control of batch effects. Rather than prioritizing batch effect removal over conservation of biological variation, or vice versa, our goal is to provide a bird's eye view of the trade-offs between these two conflicting objectives. Specifically, using the well established concept of Pareto front from economics and engineering, we seek to learn the entire trade-off curve between conservation of biological variation and removal of batch effects. A multi-objective optimisation technique known as Pareto multi-task learning (Pareto MTL) is used to obtain the Pareto front between conservation of biological variation and batch effect removal. Our results indicate Pareto MTL can obtain a better Pareto front than the naive scalarization approach typically encountered in the literature. In addition, we propose to measure batch effect by applying a neural-network based estimator called Mutual Information Neural Estimation (MINE) and show benefits over the more standard maximum mean discrepancy measure. The Pareto front between conservation of biological variation and batch effect removal is a valuable tool for researchers in computational biology. Our results demonstrate the efficacy of applying Pareto MTL to estimate the Pareto front in conjunction with applying MINE to measure the batch effect.


Affinity-driven selection of tripeptide inhibitors of ribonucleotide reductase.
Tripeptide libraries of the type Fmoc(W/F)XF were screened for binding to the large subunit of mouse ribonucleotide reductase (mRR), using a new, affinity chromatography method. A high-affinity tripeptide, FmocWFF, was found that inhibited mRR activity with a K(i) equal to that of AcFTLDADF, the heptapeptide corresponding to the C-terminus of the small subunit of mRR.


Early rheumatoid arthritis is characterised by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin.
A study by Raza et al., published in this journal in 2005, identified that RA patients, within 3 months of symptom onset, had a synovial fluid cytokine profile that was distinct from that of patients with other inflammatory arthritides of similarly short duration. This profile, which was transient, was characterised by cytokines of stromal and T cell origin. These findings suggested that the first few months after symptom onset were associated with changes in the early RA joint that differed from those operating at later stages. The significance of this paper's methodological approach and its findings, and how they relate to subsequent literature, are discussed.


Relationships between specific drinking problems in early adulthood and middle age. An exploratory 20-year follow-up study.
Specific drinking problems were remeasured in a panel study after a 20-year interval. The nature of the problems at both measurement points is assessed and the associations between them explored.