Cryptosporidium hominis Is a Newly Recognized Pathogen in the Arctic Region of Nunavik, Canada: Molecular Characterization of an Outbreak.
Cryptosporidium is a leading cause of childhood diarrhea in low-resource settings, and has been repeatedly associated with impaired physical and cognitive development. In May 2013, an outbreak of diarrhea caused by Cryptosporidium hominis was identified in the Arctic region of Nunavik, Quebec. Human cryptosporidiosis transmission was previously unknown in this region, and very few previous studies have reported it elsewhere in the Arctic. We report clinical, molecular, and epidemiologic details of a multi-village Cryptosporidium outbreak in the Canadian Arctic. We investigated the occurrence of cryptosporidiosis using a descriptive study of cases with onset between April 2013 and April 2014. Cases were defined as Nunavik inhabitants of any age presenting with diarrhea of any duration, in whom Cryptosporidium oocysts were detected by stool microscopy in a specialised reference laboratory. Cryptosporidium was identified in stool from 51 of 283 individuals. The overall annual incidence rate (IR) was 420 / 100,000 inhabitants. The IR was highest among children aged less than 5 years (1290 /100,000 persons). Genetic subtyping for stool specimens from 14/51 cases was determined by DNA sequence analysis of the 60 kDa glycoprotein (gp60) gene. Sequences aligned with C. hominis subtype Id in all cases. No common food or water source of infection was identified. In this first observed outbreak of human cryptosporidiosis in this Arctic region, the high IR seen is cause for concern about the possible long-term effects on growth and development of children in Inuit communities, who face myriad other challenges such as overcrowding and food-insecurity. The temporal and geographic distribution of cases, as well as the identification of C. hominis subtype Id, suggest anthroponotic rather than zoonotic transmission. Barriers to timely diagnosis delayed the recognition of human cryptosporidiosis in this remote setting.


Interventions to Improve Hydration in Older Adults: A Systematic Review and Meta-Analysis.
Dehydration is common in the elderly, especially when hospitalised. This study investigated the impact of interventions to improve hydration in acutely unwell or institutionalised older adults for hydration and hydration linked events (constipation, falls, urinary tract infections) as well as patient satisfaction. Four databases were searched from inception to 13 May 2020 for studies of interventions to improve hydration. Nineteen studies (978 participants) were included and two studies (165 participants) were meta-analysed. Behavioural interventions were associated with a significant improvement in hydration. Environmental, multifaceted and nutritional interventions had mixed success. Meta-analysis indicated that groups receiving interventions to improve hydration consumed 300.93 mL more fluid per day than those in the usual care groups (95% CI: 289.27 mL, 312.59 mL; I2 = 0%, p < 0.00001). Overall, there is limited evidence describing interventions to improve hydration in acutely unwell or institutionalised older adults. Behavioural interventions appear promising. High-quality studies using validated rather than subjective methods of assessing hydration are needed to determine effective interventions.


Evaluation of penetrating keratoplasties with long-term cryopreserved corneas using simplified method.
Since March 1986, the authors have studied and simplified the corneal cryopreservation technique using a self-made QL Bio-freezer. On the basis of successful animal experiments, penetrating keratoplasties with human cadaver corneas cryopreserved 9 to 571 days (averaging 131 days) were performed in 60 patients (61 eyes). The patients were followed up for 1.5 to 50 months. 41 of the corneal grafts remained clear, 9 became translucent and 11 cloudy. A total of 46 eyes had their visual acuity improved significantly. The results show that clinical use of corneal cryopreservation by the simplified two-step method is noteworthy.


The pathology of experimental chronic fibrosing pancreatitis--light microscopic and ultrastructural observations.
The light microscopic and ultrastructural changes seen in a canine model of chronic fibrosing pancreatitis are described. The distribution of the experimental lesion is similar to that of human chronic obstructive pancreatitis. The canine lesion is also compared to that of human chronic calcifying pancreatitis. It is suggested that the common denominator in all these conditions is an increased pressure in the terminal intercalated ducts which produces pressure atrophy of the acinar cells in the periphery of the obstructed lobules.


Pyrimethamine Modulates Interplay between Apoptosis and Autophagy in Chronic Myelogenous Leukemia Cells.
Pyrimethamine (Pyri) is being used in combination with other medications to treat serious parasitic infections of the body, brain, or eye and to also reduce toxoplasmosis infection in the patients with HIV infection. Additionally, Pyri can display significant anti-cancer potential in different tumor models, but the possible mode of its actions remains unclear. Hence, in this study, the possible anti-tumoral impact of Pyri on human chronic myeloid leukemia (CML) was deciphered. Pyri inhibited cell growth in various types of tumor cells and exhibited a marked inhibitory action on CML cells. In addition to apoptosis, Pyri also triggered sustained autophagy. Targeted inhibition of autophagy sensitized the tumor cells to Pyri-induced apoptotic cell death. Moreover, the activation of signal transducer and activator of transcription 5 (STAT5) and its downstream target gene Bcl-2 was attenuated by Pyri. Accordingly, small interfering RNA (siRNA)-mediated STAT5 knockdown augmented Pyri-induced autophagy and apoptosis and promoted the suppressive action of Pyri on cell viability. Moreover, ectopic overexpression of Bcl-2 protected the cells from Pyri-mediated autophagy and apoptosis. Overall, the data indicated that the attenuation of STAT5-Bcl-2 cascade by Pyri can regulate its growth inhibitory properties by simultaneously targeting both apoptosis and autophagy cell death mechanism(s).


Radiation sensitivity of cultured human glioblastoma cells.
Glial cells from 2 normal brains and 9 astrocytomas were cultured in vitro. The most rapidly proliferating cell lines were obtained from Grades III-IV astrocytomas. Normal glia proliferated slowly and growth ceased after 20 to 40 generations. The response of 3 Grade III-IV lines to graded doses of radiation was determined by colony formation and end point dilution technique. Two of the 3 lines were relatively radioresistant compared to other human cell lines; this may partially account for the radiation resistance of high grade astrocytoma tumors.


[Posteriorinstrumental spinal fixation in tuberculous spondylitis and osteomyelitis of the vertebral bodies].
The short- and long-term results of surgical treatment were studied in 74 patients with tuberculous spondylitis and in 20 patients with chronic osteomyelitis of the vertebral column. All the patients underwent radical reconstructive operations on the anterior vertebral column if they had an active inflammatory process. The operations were supplemented by an interstitial posterior instrumental fixation with the Hurrington manipulation reduction frames or the plates, developed at the Central Institute of Traumatology and Orthopedics, in 11 cases and with the Cotrel-Dubosse tools in 28 cases. The Cotrel-Dubosse tools were shown to have significant advantages in correcting kyphosis and preventing graft resorption and chronic pain syndrome in tuberculous spondylitis.


Suppression effects of negative pressure on the proliferation and metastasis in human pancreatic cancer cells.
The aim was to explore the effect of negative pressure on the proliferation and metastasis of human pancreatic cancer SW1990 cells. Three groups were conducted in the work: normal control group (NC group, 0 mm Hg), low negative pressure group (LN group, -300 mm Hg), and high negative pressure group (HN group, -600 mm Hg). Cell morphological assay was conducted using an inverted Nikon TE2000-S microscope. Cell viability was assayed using cell counting kit-8 solution. Cell apoptosis was evaluated with flow cytometry. Cell migration was investigated using transwell assay. Compared to LN and HN groups, SW1990 cells in NC group grew quite well, showing a higher density. The NC group represented the highest cell viability. The HN group represented the lowest cell viability, which was lower than that of the LN group (P < 0.01). The apoptosis rate in NC group, LN group and HN group was 1.91% ± 0.13%, 2.31% ± 0.06% and 15.22% ± 0.81%, respectively (P < 0.05). The average number of migration cells in NC group was 53.60 ± 4.14 (× 200), which was decreased to 18.93 ± 3.67 and 11.07 ± 3.01 in LN group and HN group, respectively (P < 0.01). The negative pressure shows suppression effects on the proliferation and metastasis of human pancreatic cancer SW1990 cells. It is indicated that negative pressure may be involved in the development of human pancreatic cancer by influencing cell biological characteristics.


An oculomotor representation area within the ventral premotor cortex.
We explored the ventral part of the premotor cortex (PMV) with intracortical microstimulation (ICMS) while monkeys performed a visual fixation task, to see whether the PMV is involved in oculomotor control. ICMS evoked saccades from a small-restricted region in the PMV, without evoking movements in the limbs, neck, or body. We found the saccade-evoking site in the PMV in a total of three hemispheres in two monkeys. Quantitative analysis of the effects of eye position on saccades evoked by microstimulation of the PMV characterized the evoked saccades as goal directed. The nature of the saccades evoked in the PMV contrasted with the fixed vector nature of saccades evoked by ICMS of the frontal eye field. We also found that neurons in this restricted area of the PMV were active while the animals were performing a saccade task that required them to make saccades toward targets without arm movements. These data provide evidence for the presence of an oculomotor-specific subregion within the PMV. This subregion and the surrounding skeletomotor-representing regions of the PMV seem to coordinate oculomotor and skeletomotor control in performing goal-directed motor tasks.


Nontraumatic osteonecrosis of the femoral head: ten years later.
The etiology of osteonecrosis of the hip may have a genetic basis. The interaction between certain risk factors and a genetic predisposition may determine whether this disease will develop in a particular individual. The rationale for use of joint-sparing procedures in the treatment of this disease is based on radiographic measurements and findings with other imaging modalities. Early diagnosis and intervention prior to collapse of the femoral head is key to a successful outcome of joint-preserving procedures. The results of joint-preserving procedures are less satisfactory than the results of total hip arthroplasty for femoral heads that have already collapsed. New pharmacological measures as well as the use of growth and differentiation factors for the prevention and treatment of this disease may eventually alter our treatment approach, but it is necessary to await results of clinical research with long-term follow-up of these patients.


Fungal siderophore biosynthesis catalysed by an iterative nonribosomal peptide synthetase.
Siderophores play a vital role in the viability of fungi and are essential for the virulence of many pathogenic fungal species. Despite their importance in fungal physiology and pathogenesis, the programming rule of siderophore assembly by fungal nonribosomal peptide synthetases (NRPSs) remains unresolved. Here, we report the characterization of the bimodular fungal NRPS, SidD, responsible for construction of the extracellular siderophore fusarinine C. The use of intact protein mass spectrometry, together with in vitro biochemical assays of native and dissected enzymes, provided snapshots of individual biosynthetic steps during NPRS catalysis. The adenylation and condensation domain of SidD can iteratively load and condense the amino acid building block cis-AMHO, respectively, to synthesize fusarinine C. Our study showcases the iterative programming features of fungal siderophore-producing NRPSs.


The extracellular signal-regulated kinase 3 (mitogen-activated protein kinase 6 [MAPK6])-MAPK-activated protein kinase 5 signaling complex regulates septin function and dendrite morphology.
Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 5 (MK5) deficiency is associated with reduced extracellular signal-regulated kinase 3 (ERK3) (mitogen-activated protein kinase 6) levels, hence we utilized the MK5 knockout mouse model to analyze the physiological functions of the ERK3/MK5 signaling module. MK5-deficient mice displayed impaired dendritic spine formation in mouse hippocampal neurons in vivo. We performed large-scale interaction screens to understand the neuronal functions of the ERK3/MK5 pathway and identified septin7 (Sept7) as a novel interacting partner of ERK3. ERK3/MK5/Sept7 form a ternary complex, which can phosphorylate the Sept7 regulators Binders of Rho GTPases (Borgs). In addition, the brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. In transfected primary neurons, Sept7-dependent dendrite development and spine formation are stimulated by the ERK3/MK5 module. Thus, the regulation of neuronal morphogenesis is proposed as the first physiological function of the ERK3/MK5 signaling module.


GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation.
Although an extensive body of literature confirmed γ-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine-like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut could not be limited to the maintenance of physiologic intestinal activity. Indeed, a series of interesting studies have suggested a potential key role of GABA in the promising field of neuroimmune interaction, being involved in the modulation of immune cell activity associated with different systemic and enteric inflammatory conditions. Given the urgency of novel therapeutic strategies against chronic immunity-related pathologies, i.e. multiple sclerosis and Inflammatory Bowel Disease, an in-depth comprehension of the enteric GABAergic system in health and disease could provide the basis for new clinical application of nerve-driven immunity. Hence, in the attempt to drive novel researches addressing both the physiological and pathological importance of the GABAergic signalling in the gut, we summarized current evidence on GABA and GABA receptor function in the different parts of the GI tract, with particular focus on the potential involvement in the modulation of GI motility and inflammation.


The SPoRT concept of bracing for idiopathic scoliosis.
The SPoRT (acronym: Symmetrical, Patient-oriented, Rigid, Three-dimensional, active) concept of bracing is a new way to build braces based on our 20 years of experience and the biomechanical principles of scoliosis correction, inclusive of the Sibilla and Sforzesco braces. The concept always requires a custom brace, which is made according to the patient's individual requirements. New technologies such as CAD-CAM can be applied, and often for better results, without the customary use of prebuilt forms whose measurements are stored in databases. Once the initial draft brace is completed, a final test must be made on the patient to modify and adapt it, depending on his or her real interaction between the body and the brace. The results that are today available on the SPoRT concept relate to the Sforzesco brace and are necessarily short-term, because the first treated patients are now reaching the fourth-year follow-up examination and haven't yet completed their treatments. On the basis of the initial evaluations, we can state that the Sforzesco brace is more effective than the Lyon brace after 6 months of treatment and that the Sforzesco brace is equally effective as the Risser Plast brace.


Risk of Acute Myocardial Infarction and Ischemic Stroke in Patients with Asthma Exacerbation: A Population-Based, Self-Controlled Case Series Study.
Patients with asthma have a high incidence of acute myocardial infarction and ischemic stroke. To investigate the acute effect of asthma exacerbation on these cardiovascular events. Using population-based inpatient data of 3 geographically diverse US states (Florida, Nebraska, and New York) during the period 2011 to 2014, we conducted a self-controlled case series study of adults (aged ≥40 years) hospitalized with asthma exacerbation. The primary outcome was a composite of acute myocardial infarction and ischemic stroke. We used conditional Poisson regression to compare each patient's incidence rate of the outcome during 3 sequential risk periods (1-7, 8-14, and 15-28 days after asthma exacerbation) with that of the reference period (ie, summed period before and after the 3 risk periods). We identified 4607 adults hospitalized for asthma exacerbation who had a first episode of acute myocardial infarction or ischemic stroke. During the reference period, the incidence rate of acute myocardial infarction or ischemic stroke was 25.0/100 person-years. Compared with the reference period, the incidence rate significantly increased during the first risk period (129.1/100 person-years), with a corresponding adjusted incidence rate ratio of 5.04 (95% CI, 4.29-5.88; P < .001). In the 2 subsequent risk periods, the incidence rate declined but remained high-50.1/100 person-years (adjusted incidence rate ratio, 1.96; 95% CI, 1.51-2.48; P < .001) and 38.0/100 person-years (adjusted incidence rate ratio, 1.48; 95% CI, 1.20-1.81; P < .001), respectively. The findings were similar when the 2 outcomes were examined separately. In this population-based study of adults with asthma, the risk of acute myocardial infarction and ischemic stroke increased significantly after asthma exacerbation.


Oxidative phosphorylation. The relation between the specific binding of trimethylytin and triethyltin to mitochondria and their effects on various mitochondrial functions.
1. A binding site (site 1) is present in mitochondria with affinity for trimethyltin and triethyltin adequate for a site to which they could be attached when the processes of energy conservation are inhibited. 2. The quantitative relationships between the binding of trimethyltin and triethyltin to site 1 and their effects on various mitochondrial functions have been examined. 3. ATP synthesis linked to the oxidation of pyruvate, succinate and intramitochondrial substrate, ATP synthesis and oxygen uptake (succinate or pyruvate as substrate) stimulated by uncoupling agents are all inhibited by trimethyltin and triethyltin; when inhibition is less than 50% the ratio (percentage inhibition)/(percentage of binding site 1 complexed) is approx. 10:1. 4. ATP synthesis linked to the oxidation of reduced cytochrome c (ascorbate+NNN'N'-tetramethyl-p-phenylenediamine), ATP hydrolysis and oxygen uptake in the presence of low concentrations of trimethyltin and triethyltin approach zero activity as the proportion of binding site 1 complexed approaches 100%. 5. Possible interpretations of these findings are discussed with reference to published arrangements for coupling of electron transport to ATP synthesis and also to our present knowledge of the chemical and biological specificity of trialkyltin compounds.


The Neurospora crassa chs-2 gene encodes a non-essential chitin synthase.
Chitin is a structural component of morphologically distinct structures assembled during various phases of growth and development in filamentous fungi. In Neurospora crassa, at least three different DNA fragments related to chitin synthase have been identified. In this study we cloned, sequenced and characterized the chitin synthase 2 structural gene (designated chs-2). The amino acid sequence deduced from the cloned chs-2 genomic DNA fragments is very similar to that of chitin synthase genes isolated from other fungi. Inactivation of the N. crassa chs-2 gene by repeat-induced point (RIP) mutation produced progeny which under standard growth conditions were indistinguishable from the wild-type. However, a significant reduction in chitin synthase activity and increased sensitivity to the phosphatidylcholine biosynthesis inhibitor edifenphos are characteristic of the chs-2RIP strain.


Entrustment Decision Making in the Core Entrustable Professional Activities: Results of a Multi-Institutional Study.
In 2014, the Association of American Medical Colleges defined 13 Core Entrustable Professional Activities (EPAs) that all graduating students should be ready to do with indirect supervision upon entering residency and commissioned a 10-school, 5-year pilot to test implementing the Core EPAs framework. In 2019, pilot schools convened trained entrustment groups (TEGs) to review assessment data and render theoretical summative entrustment decisions for class of 2019 graduates. Results were examined to determine the extent to which entrustment decisions could be made and the nature of these decisions. For each EPA considered (4-13 per student), TEGs recorded an entrustment determination (ready, progressing but not yet ready, evidence against student progressing, could not make a decision); confidence in that determination (none, low, moderate, high); and the number of workplace-based assessments (WBAs) considered (0->15) per determination. These individual student-level data were de-identified and merged into a multischool database; chi-square analysis tested the significance of associations between variables. The 2,415 EPA-specific determinations (for 349 students by 4 participating schools) resulted in a decision of ready (n = 997/2,415; 41.3%), progressing but not yet ready (n = 558/2,415; 23.1%), or evidence against student progression (n = 175/2,415; 7.2%). No decision could be made for the remaining 28.4% (685/2,415), generally for lack of data. Entrustment determinations' distribution varied across EPAs (chi-square P < .001) and, for 10/13 EPAs, WBA availability was associated with making (vs not making) entrustment decisions (each chi-square P < .05). TEGs were able to make many decisions about readiness for indirect supervision; yet less than half of determinations resulted in a decision of readiness to perform this EPA with indirect supervision. More work is needed at the 10 schools to enable authentic summative entrustment in the Core EPAs framework.


C-Reactive protein predicts acute myocardial infarction during high-risk noncardiac and vascular surgery.
High-sensitivity C-reactive protein predicts cardiovascular events in a wide range of clinical contexts. However, the role of high-sensitivity C-reactive protein as a predictive marker for perioperative acute myocardial infarction during noncardiac surgery is not yet clear. The present study investigated high-sensitivity C-reactive protein levels as predictors of acute myocardial infarction risk in patients undergoing high-risk noncardiac surgery. This concurrent cohort study included patients aged ≥ 50 years referred for high-risk noncardiac surgery according to American Heart Association/ACC 2002 criteria. Patients with infections were excluded. Electrocardiograms were performed, and biomarkers (Troponin I or T) and/or total creatine phosphokinase and the MB fraction (CPK-T/MB) were evaluated on the first and fourth days after surgery. Patients were followed until discharge. Baseline high-sensitivity C-reactive protein levels were compared between patients with and without acute myocardial infarction. A total of 101 patients undergoing noncardiac surgery, including 33 vascular procedures (17 aortic and 16 peripheral artery revascularizations), were studied. Sixty of the patients were men, and their mean age was 66 years. Baseline levels of high-sensitivity C-reactive protein were higher in the group with perioperative acute myocardial infarction than in the group with non-acute myocardial infarction patients (mean 48.02 vs. 4.50, p = 0.005). All five acute myocardial infarction cases occurred in vascular surgery patients with high CRP levels. Patients undergoing high-risk noncardiac surgery, especially vascular surgery, and presenting elevated baseline high-sensitivity C-reactive protein levels are at increased risk for perioperative acute myocardial infarction.


Marketing Healthy Food in an African City: Consumer Motivations for Adopting Orange-Fleshed Sweet Potato in Maputo, Mozambique.
Since the late 1990s, the International Potato Center has promoted orange-fleshed sweet potato (OFSP) cultivars in Mozambique as a healthy food, emphasizing its capacity to reduce the prevalence of vitamin A deficiency among mothers and young children. This article seeks to reveal why consumers in Maputo, the capital city of Mozambique, adopt or reject OFSP looking at the role of food systems and consumer characteristics in access and acceptance of healthy food and at the positioning of OFSP on the market in terms of lifestyle and need satisfaction.The results of 255 street interviews confirm that OFSP is widely known. Information reaches people mainly via informal channels (relatives and retailers). Nonadoption is the result of the positioning of OFSP as food for young children and sick people. The OFSP appeals most to the hedonistic and conservative lifestyle segments. Adoption is associated with the perception of OFSP as a source of vitamins that builds up muscles and improves physical appearance and self-fulfillment. While women are typically responsible for domestic tasks, male adopters emphasize the role of OFSP in family health and well-being more than female adopters. This first attempt to understand the marketing of healthy food in Mozambique exposes many similarities between the urban consumers in Maputo and those in developed countries. The results indicate that future marketing should exploit informal channels such as vendors and emphasize its nutritious value for all consumers instead of focusing on mothers and young children.


Mean hospital stay and treatment with electroconvulsive therapy.
The objective is to analyze if the mean hospital stay is less than the episodes or not in which electroconvulsive therapy (ECT) is applied. With a retrospective design, we studied a sample of 30 patients in whom ECT was applied between 1996 and 2001. These patients were suffering a disorder for which ECT has been shown to be effective (schizophrenia, bipolar disorder and major depression). Each one of the episodes (n = 185) of these patients was studied, comparing the length of stay in the hospital in these patients in which ECT was applied (n = 135) with those where it was not (n = 50). Statistical analysis was carried out by non-parametric Mann-Whitney-U tests. The descriptive level of statistical significance was established at p < 0.05. This work shows statistically significant differences between the treatment groups (p = 0.000), the length of stay being longer when ECT is applied.


Oncology mortality: weekend and summer vacation effect.
In this study, we investigated the effect of the weekend and summer vacation on mortality in patients with cancer. All patient data were obtained from their hospital registry records and the Death Notification System of the Ministry of Health. The majority of patients died in the hospital compared at home, 80.8% versus 19.2%, respectively. Patients aged <65 died mostly in hospital, which was the opposite of those aged ≥65, who died at home. While tumour location and histopathological type had no effect on the place of death, patients with metastasis (including single organ metastasis), diffuse metastases (diffuse metastases: multiple organ metastases) and patients with locally advanced stage disease were found to die more frequently in the hospital. Deaths in the hospital occurred most frequently in August, while deaths at home occurred most frequently in April and October. Deaths in the hospital occurred most frequently on Friday, Saturday and Sunday, while deaths at home occurred more frequently on Monday. It was determined that the deaths in the hospital were significantly higher at the weekend. This study contains data supporting the weekend effect in oncology patients. Moreover, it provides new data on the increased death rates in August, which coincides with the summer vacation leave month.


Jean-Martin Charcot's role in the 19th century study of music aphasia.
Jean-Martin Charcot (1825-93) was a well-known French neurologist. Although he is widely recognized for his discovery of several neurological disorders and his research into aphasia, Charcot's ideas about how the brain processes music are less well known. Charcot discussed the music abilities of several patients in the context of his 'Friday Lessons' on aphasia, which took place at the Salpêtrière Hospital in Paris in 1883-84. In his most comprehensive discussion about music, Charcot described a professional trombone player who developed difficulty copying music notation and playing his instrument, thereby identifying a new isolated syndrome of music agraphia without aphasia. Because the description of this case was published only in Italian by one of his students, Domenico Miliotti, there has been considerable confusion and under-acknowledgement of Charcot's ideas about music and the brain. In this paper, we describe Charcot's ideas regarding music and place them within the historical context of the growing interest in the neurological underpinnings of music abilities that took place in the 1880s.


Determinants of arterial stiffness in chronic kidney disease stage 3.
Early chronic kidney disease (CKD) is associated with increased cardiovascular (CV) risk but underlying mechanisms remain uncertain. Arterial stiffness (AS) is associated with increased CV risk in advanced CKD, but it is unclear whether AS is relevant to CV disease (CVD) in early CKD. Cross-sectional. 1717 patients with previous estimated glomerular filtration rate (eGFR) 59-30 mL/min/1.73 m(2); mean age 73±9y, were recruited from 32 general practices in primary care. Increased arterial stiffness. Medical history was obtained and participants underwent clinical assessment, urine and serum biochemistry testing. Carotid to femoral pulse wave velocity (PWV) was determined as a measure of AS, using a Vicorder™ device. Univariate analysis revealed significant correlations between PWV and risk factors for CVD including age (r = 0.456; p<0.001), mean arterial pressure (MAP) (r = 0.228; p<0.001), body mass index (r = -0.122; p<0.001), log urinary albumin to creatinine ratio (r = 0.124; p<0.001), Waist to Hip ratio (r = 0.124, p<0.001), eGFR (r = -0.074; p = 0.002), log high sensitivity c-reactive protein (r = 0.066; p = 0.006), HDL (r = -0.062; p = 0.01) and total cholesterol (r = -0.057; p = 0.02). PWV was higher in males (9.6 m/sec vs.10.3 m/sec; p<0.001), diabetics (9.8 m/sec vs. 10.3 m/sec; p<0.001), and those with previous CV events (CVE) (9.8 m/s vs. 10.3 m/sec; p<0.001). Multivariable analysis identified age, MAP and diabetes as strongest independent determinants of higher PWV (adjusted R² = 0.29). An interactive term indicated that PWV increased to a greater extent with age in males versus females. Albuminuria was a weaker determinant of PWV and eGFR did not enter the model. Data derived from one study visit, with absence of normal controls. In this cohort, age and traditional CV risk factors were the strongest determinants of AS. Albuminuria was a relatively weak determinant of AS and eGFR was not an independent determinant. Long-term follow-up will investigate AS as an independent risk factor for CVE in this cohort.


Recent surgical management of gliomas.
Refinement of neurosurgical technique has enabled safer operations with more aggressive outcomes. One cornerstone of modern-day practice is the utilization of intraoperative stimulation mapping. In addition to identifying critical motor pathways, this technique can be adapted to reliable identify language pathways, as well. Given the individual variability of cortical language localization, such awake language mapping is essential to minimize language deficits following tumor resection. Our experience suggests that cortical language mapping is a safe and efficient adjunct to optimize tumor resection while preserving essential language sites, even in the setting of negative mapping data. However, the value of maximizing glioma resections remains surprisingly unclear, as there is no general consensus in the literature regarding the efficacy of extent of glioma resection in improving patient outcome. While the importance of resection in obtaining tissue diagnosis and to alleviate symptoms is clear, a lack of Class I evidence prevents similar certainty in assessing the influence of extent of resection. Beyond an analysis of modern intraoperative mapping techniques, we examine every major clinical publication since 1990 on the role of extent of resection in glioma outcome. The mounting evidence suggests that, despite persistent limitations in the quality of available studies, a more extensive surgical resection is associated with longer life expectancy for both low-grade and high-grade gliomas.


Maintenance of Certification Part 4 Credit and recruitment for practice-based research.
Competing priorities in pediatric practice have created challenges for practice-based research. To increase recruitment success, researchers must design studies that provide added value to participants. This study evaluates recruitment of pediatricians into a study, before and after the development and addition of a quality improvement (QI) curriculum approved for American Board of Pediatrics Maintenance of Certification (MOC) Part 4 Credit as an enrollment incentive. Researchers implemented multiple outreach methods to enroll pediatric practices over 28 months. Field note review revealed that many physicians declined enrollment, stating that they prioritized MOC Part 4 projects over research studies. A QI curriculum meeting standards for MOC Part 4 Credit was developed and added to the study protocol as an enrollment incentive. Enrollment rates and characteristics of practitioners enrolled pre- and post-MOC were compared. Pre-MOC enrollment contributed 48% of practices in 22 months; post-MOC enrollment contributed 49% of practices in 6 months. An average of 3.5 practices enrolled per month pre-MOC, compared with 13.1 per month post-MOC (P < .001). Clinicians in pre- and post-MOC groups were similar in age, gender, race, and time spent on patient care; practices enrolled post-MOC were more likely to be located in federally designated Medically Underserved Areas than those enrolled pre-MOC (28.6% vs 12%, P = .03). Addition of MOC Part 4 Credit increased recruitment success and increased enrollment of pediatricians working in underserved areas. Including QI initiatives meeting MOC Part 4 criteria in practice-based research protocols may enhance participation and aid in recruiting diverse practice and patient populations.


Far red/near infrared light-induced protection against cardiac ischemia and reperfusion injury remains intact under diabetic conditions and is independent of nitric oxide synthase.
Far red/near-infrared light (NIR) promotes a wide range of biological effects including tissue protection but whether and how NIR is capable of acutely protecting myocardium against ischemia and reperfusion injury in vivo is not fully elucidated. Our previous work indicates that NIR exposure immediately before and during early reperfusion protects the myocardium against infarction through mechanisms that are nitric oxide (NO)-dependent. Here we tested the hypothesis that NIR elicits protection in a diabetic mouse model where other cardioprotective interventions such as pre- and postconditioning fail, and that the protection is independent of nitric oxide synthase (NOS). NIR reduced infarct size dose dependently. Importantly, NIR-induced protection was preserved in a diabetic mouse model (db/db) and during acute hyperglycemia, as well as in endothelial NOS(-/-) mice and in wild type mice treated with NOS inhibitor L-NAME. In in vitro experiments NIR light liberates NO from nitrosyl hemoglobin (HbNO) and nitrosyl myoglobin (MbNO) in a wavelength-(660-830 nm) and dose-dependent manner. Irradiation at 660 nm yields the highest release of NO, while at longer wavelengths a dramatic decrease of NO release can be observed. Similar wavelength dependence was observed for the protection of mice against cardiac ischemia and reperfusion injury in vivo. NIR-induced NO release from deoxymyoglobin in the presence of nitrite mildly inhibits respiration of isolated mitochondria after hypoxia. In summary, NIR applied during reperfusion protects the myocardium against infarction in an NO-dependent, but NOS-independent mechanisms, whereby mitochondria may be a target of NO released by NIR, leading to reduced reactive oxygen species generation during reperfusion. This unique mechanism preserves protection even during diabetes where other protective strategies fail.


Monitoring of a flame retardant (tetrabromobisphenol A) toxicity on different microalgae assessed by flow cytometry.
Microalgae are key organisms in aquatic ecosystems. Emergent pollutants like the tetrabromobisphenol A (TBBPA) are potential threat for these primary producers at the base of the trophic chain. The effects of this flame retardant on three microalgae (Pseudokirchneriella subcapitata, Nitzschia palea and Chlamydomonas reinhardtii) commonly observed in freshwater ecosystems were studied using a flow cytometer. Each species was exposed to 1.8, 4.8, 9.2, 12.9 and 16.5 µmol L⁻¹ of TBBPA for 72 h. After staining with fluorescein diacetate (FDA), viable cells were discriminated in flow cytogram according to the chlorophyll autofluorescence and the intracellular enzyme activity (esterase) to assess the sensitivity of microalgae to the TBBPA with multi-parametric analysis. For P. subcapitata and N. palea, growth inhibitions of viable cells were lower when the viability was assessed with chlorophyll autofluorescence in comparison with esterase activity. These results are related to the appearance of cells presenting optimal chlorophyll fluorescence without intracellular esterase activity after exposure to TBBPA. Abundance increase of these cells was higher in N. palea than in P. subcapitata. No similar trends were observed in C. reinhardtii populations due to the very high mortality of this microalgal species exposed to TBBPA.


A randomized trial of diagnostic techniques for ventilator-associated pneumonia.
Critically ill patients who require mechanical ventilation are at risk for ventilator-associated pneumonia. Current data are conflicting as to the optimal diagnostic approach in patients who have suspected ventilator-associated pneumonia. In a multicenter trial, we randomly assigned immunocompetent adults who were receiving mechanical ventilation and who had suspected ventilator-associated pneumonia after 4 days in the intensive care unit (ICU) to undergo either bronchoalveolar lavage with quantitative culture of the bronchoalveolar-lavage fluid or endotracheal aspiration with nonquantitative culture of the aspirate. Patients known to be colonized or infected with pseudomonas species or methicillin-resistant Staphylococcus aureus were excluded. Empirical antibiotic therapy was initiated in all patients until culture results were available, at which point a protocol of targeted therapy was used for discontinuing or reducing the dose or number of antibiotics, or for resuming antibiotic therapy to treat a preenrollment condition if the culture was negative. We enrolled 740 patients in 28 ICUs in Canada and the United States. There was no significant difference in the primary outcome (28-day mortality rate) between the bronchoalveolar-lavage group and the endotracheal-aspiration group (18.9% and 18.4%, respectively; P=0.94). The bronchoalveolar-lavage group and the endotracheal-aspiration group also had similar rates of targeted therapy (74.2% and 74.6%, respectively; P=0.90), days alive without antibiotics (10.4+/-7.5 and 10.6+/-7.9, P=0.86), and maximum organ-dysfunction scores (mean [+/-SD], 8.3+/-3.6 and 8.6+/-4.0; P=0.26). The two groups did not differ significantly in the length of stay in the ICU or hospital. Two diagnostic strategies for ventilator-associated pneumonia--bronchoalveolar lavage with quantitative culture of the bronchoalveolar-lavage fluid and endotracheal aspiration with nonquantitative culture of the aspirate--are associated with similar clinical outcomes and similar overall use of antibiotics. (Current Controlled Trials number, ISRCTN51767272 [controlled-trials.com].).


Changes in Physical Performance Throughout Professional Soccer Match-Play.
Oliva-Lozano, JM, Granero-Gil, P, and Panascì, M. Changes in physical performance throughout professional soccer match-play. J Strength Cond Res 38(1): 123-127, 2024-The aim of this study was to explore the changes in physical performance by playing position throughout professional soccer match-play. Global Positioning Systems were used for the collection of external load measures during 35 matches. Each match was divided into 15-minute periods. Physical performance varied according to the period in distance covered ( F = 25.69; p < 0.001; partial eta-squared [ηp 2 ] = 0.11), sprinting distance (SPD, F = 4.35; p < 0.001; ηp 2 = 0.02), sprinting actions (SPAs, F = 5.19; p < 0.001), high-intensity accelerations (Acc+3, F = 2.18; p = 0.05; ηp 2 = 0.01), high-intensity decelerations (Dec+3, F = 4.51; p < 0.001; ηp 2 = 0.02), and high-metabolic load distance (HMLD, F = 5.59; p < 0.001; ηp 2 = 0.03). The period with the greatest mean physical performance was usually from the first half of the matches: 0-15 minutes (distance, Acc+3, and Dec+3) and 30-45 minutes (HMLD, SPA, and SPD). However, the lowest mean physical performance compared with the rest of 15-minute periods was observed in the 60-75-minute period (distance, HMLD, Acc+3, and Dec+3), except for SPA and SPD (15-30 minutes and 75-90 minutes). Overall, no significant differences ( p > 0.05) were observed in the physical performance between the extratime periods. In addition, the playing position had a significant effect on all performance variables ( F = 39.99-133.29; p < 0.001; ηp 2 = 0.14-0.34). Central defenders showed the lowest physical performance throughout the periods of match-play, whereas wide midfielders showed the greatest physical performance in all variables, except for distance covered, in which midfielders had the greatest performance. In conclusion, there were changes in physical performance during the matches depending on the period of match-play and playing position.


Separation of carbohydrates and carbohydrate derivatives by HPLC with cation-exchange columns at high pH.
Cation-exchange columns were found to be stable when used at high pH and high temperature for high-performance liquid chromatographic separations of carbohydrates and carbohydrate derivatives. Pulsed amperometric detection and refractive index detection were found to be suitable detection modes with these cation-exchange columns. Significant differences in carbohydrate separation selectivity were observed between cation-exchange and anion-exchange columns.


Identification of genomic loci regulating grain iron content in aus rice under two irrigation management systems.
Iron (Fe) deficiency is one of the common causes of anaemia in humans. Improving grain Fe in rice, therefore, could have a positive impact for humans worldwide, especially for those people who consume rice as a staple food. In this study, 225-269 accessions of the Bengal and Assam Aus Panel (BAAP) were investigated for their accumulation of grain Fe in two consecutive years in a field experiment under alternative wetting and drying (AWD) and continuous flooded (CF) irrigation. AWD reduced straw Fe by 40% and grain Fe by 5.5-13%. Genotype differences accounted for 35% of the variation in grain Fe, while genotype by irrigation interaction accounted for 12% of the variation in straw and grain Fe in year 1, with no significant interactions detected in year 2. Twelve rice accessions were identified as having high grain Fe for both years regardless of irrigation treatment, half of which were from BAAP aus subgroup 3 which prominently comes from Bangladesh. On average, subgroup 3 had higher grain Fe than the other four subgroups of aus. Genome-wide association mapping identified 6 genomic loci controlling natural variation of grain Fe concentration in plants grown under AWD. For one QTL, nicotianamine synthase OsNAS3 is proposed as candidate for controlling natural variation of grain Fe in rice. The BAAP contains three haplotypes of OsNAS3 where one haplotype (detected in 31% of the individuals) increased grain Fe up to 11%. Haplotype analysis of this gene in rice suggests that the ability to detect the QTL is enhanced in the BAAP because the high Fe allele is balanced in aus, unlike indica and japonica subgroups.


The use of self-retained, cryopreserved amniotic membrane for the treatment of Sjögren syndrome: a case series.
To determine whether signs and symptoms of ocular surface disease improve after placement of a self-retained, cryopreserved amniotic membrane (CAM) in patients with Sjögren syndrome (SS). The medical records of SS patients who received a self-retained CAM implant (Prokera or Prokera Slim; TissueTech Inc, Doral, FL) for the treatment of ocular surface disease between August 2012 and August 2016 at a single, large academic institution were reviewed retrospectively. Visual acuity, results of slit-lamp examination of the cornea and conjunctiva, and dry eye symptoms, were evaluated before and after CAM insertion. A total of 6 eyes of 6 patients (all female; mean age, 62.5 ± 13.0 years [range, 49-86 years]) were included. All patients were on topical medications at the time of the study and had signs of ocular surface dryness. There were reductions in corneal and/or conjunctival staining in 5 eyes (83%) after the CAM dissolved. All patients who completed therapy (5/5) experienced a relapse in their signs and symptoms within 1 month of removal of the CAM, with an average time to relapse of 24.6 days. Mean follow-up time was 54.5 days. Foreign body sensation and blurred vision were the most common complaints associated with the CAM implant. In this small case series, self-retained CAM implantation was found to be beneficial in SS patients with ocular surface disease that is refractory to standard therapies; however, we found that the effects were temporary. Future larger studies are needed to confirm these benefits.


Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation.
The R-diastereomer of phosphorothioate analogs of cGMP, Rp-cGMPS, is one of few known inhibitors of cGMP-dependent protein kinase I (PKG I); however, its mechanism of inhibition is currently not fully understood. Here, we determined the crystal structure of the PKG Iβ cyclic nucleotide-binding domain (PKG Iβ CNB-B), considered a 'gatekeeper' for cGMP activation, bound to Rp-cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iβ CNB-B bound to Rp-cGMPS displays an apo-like structure with its helical domain in an open conformation. Comparison with the cAMP-dependent protein kinase regulatory subunit (PKA RIα) showed that this conformation resembles the catalytic subunit-bound inhibited state of PKA RIα more closely than the apo or Rp-cAMPS-bound conformations. These results suggest that Rp-cGMPS inhibits PKG I by stabilizing the inactive conformation of CNB-B.


IL-28B genetic variant is associated with the risk of schizophrenia in the Chinese Han population.
Schizophrenia is a severe psychiatric disorder. Although its exact cause is unknown, it is widely accepted that environmental factors and genes integrate in the pathogenesis of schizophrenia. 19q13, which contains IL-28B, is a newly identified potential susceptibility locus. IL-28B is a cytokine that functionally has anti-viral activity, but, structurally, is related to the interleukin-10 family. Both virus infection and cytokine changes have been documented in schizophrenia. We selected the single-nucleotide polymorphism rs8099917, which is associated with IL-28B gene expression, to study its relationship to the susceptibility to schizophrenia. A total of 256 Chinese patients with schizophrenia and 329 healthy controls were studied. Both genotype and allele frequencies showed significant differences between patients and normal subjects (p=0.03 and p=0.04, respectively). Our study suggested that the frequency of allele T was a risk factor for the susceptibility of schizophrenia (odds ratio [OR]=1.76, 95% confidence interval [CI]=1.03-3.03). When all subjects were grouped by symptoms, both the genotype and the allele frequency were associated with patients having disorganized speech (genotype: χ(2)=5.75, p=0.02; allele: χ(2)=5.41, p=0.02, OR=3.67, 95% CI=1.14-11.82) and negative symptoms (genotype: χ(2)=5.09, p=0.02; allele: χ(2)=4.80, p=0.03, OR=1.95, 95% CI=1.06-3.56) as well as cognitive symptoms (genotype: χ(2)=5.97, p=0.02; allele: χ(2)=5.53, p=0.02, OR=2.04, 95% CI=1.11-3.74). The results in this study may lead to a better understanding of the etiology of schizophrenia.


Two alpha 1b-adrenergic receptor mRNAS expressed in Sprague-Dawley rat liver have distinct 5'-regions.
Previous studies have revealed two size classes of alpha 1b-adrenergic receptor mRNAs, 3.3 kb and 2.7 kb, in the Sprague Dawley rat that are transcribed from a single gene and are expressed in approximately equal amounts in liver. Only the 2.7 kb mRNA is expressed in heart. Both alpha 1b-adrenergic receptor mRNAs appear to share extensive regions of homology, therefore, we used oligonucleotide-directed ribonuclease H mapping to detect sequence differences between the two transcripts. Initial experiments using oligo (dT)-directed RNase H hydrolysis indicated that the two mRNAs have poly [A+] tails of identical length. By using region-specific cDNA probes, we determined that the sequence difference between the two alpha 1b-adrenergic receptor mRNAs lies in the 5' end, upstream from the known initiator AUG in the 2.7 kb transcript. In addition, results from ribonuclease protection assays and Northern blot analysis in which an oligonucleotide was used as the probe suggested that both alpha 1b-adrenergic receptor mRNAs are transcribed from the same DNA strand.


Epigenetic reprogramming and development: a unique heterochromatin organization in the preimplantation mouse embryo.
Fertilization of the oocyte by the sperm results in the formation of a totipotent zygote, in which the maternal and paternal chromatin is enclosed in two pronuclei undergoing distinct programmes of transcriptional activation and chromatin remodelling. The highly packaged paternal chromatin delivered by the sperm is decondensed and acquires a number of specific epigenetic marks, but markedly remains devoid of those usually associated with constitutive heterochromatin. During this period the maternal chromatin remains relatively stable except for marks associated with transcription and/or replication such as arginine methylation and H3/H4 acetylation. The embryo then undergoes a series of mitotic divisions without significant additional growth but differentiation, resulting in the formation of a blastocyst containing distinct cell types. The chromatin remodelling events during these stages are likely to be important in establishing the nuclear foundations required for later triggers of differentiation. Overall, we summarize three important points during these earliest reprogramming events: (i) relatively stable maternal chromatin after fertilization, (ii) rapid acquisition of specific histone marks by the paternal chromatin during the hours that follow fertilization and (iii) rapid remodelling of constitutive heterochromatic marks and modifications in the core of the nucleosome from the first mitotic division. These features are likely to be required for the creation of a chromatin environment compatible with cellular reprogramming and plasticity.


[Research on quality of health care from the Mexican Social Security Institute: a bibliometric study].
OBJECTIVE. To identify studies on quality of health care in the IMSS. MATERIALS AND METHODS. A bibliometric, descriptive cross-sectional and retrospective study was conducted, from 1992 to 2011. RESULTS. We identified 881 research studies related to the issue of quality (CI95% 10.6-12.0) of 7 762 studies presented at the annual research meetings. 10 521 articles were published in this period of time and only 946 (CI95% 8.4-9.5) were linked to the issue of quality. CONCLUSIONS. The results of this study allowed us to identify the interest about research on quality. Further research is needed to establish what has been the impact on the improvement of quality in health care.


Clinical and pathophysiological aspects of bicuspid aortic valve disease.
A bicuspid aortic valve is not only a common congenital heart defect but also an enigmatic condition that can cause a large spectrum of diseases, such as aortic valve stenosis and severe heart failure in newborns whereas aortic dissection in adults. On the contrary, a bicuspid aortic valve can also occur with normal function throughout life and never need treatment. Numerous genetic mechanisms are involved in the abnormal cellular functions that may cause abnormal development of the aortic valve during early foetal life. As several chromosomal disorders are also associated with a bicuspid valve, there does not appear to be an apparent common trigger to the abnormal development of the aortic valve. The clinical care of the bicuspid aortic valve patient has been changed by a significant body of evidence that has improved the understanding of the natural history of the disease, including when to best intervene with valve replacement and when to provide prophylactic aortic root surgery. Moreover, as bicuspid valve disease is also part of various syndromes, we can identify high-risk patients in whom a bicuspid valve is much more unfavourable than in the normal population. This review provides an overview of all aspects of the bicuspid aortic valve condition and gives an updated perspective on issues from pathophysiology to clinical care of bicuspid aortic valve disease and associated aortic disease in asymptomatic, symptomatic, and pregnant patients, as well as our viewpoint on population screening.


Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia.
The striatum is widely viewed as the fulcrum of pathophysiology in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In these disease states, the balance in activity of striatal direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) is disrupted, leading to aberrant action selection. However, it is unclear whether countervailing mechanisms are engaged in these states. Here we report that iSPN intrinsic excitability and excitatory corticostriatal synaptic connectivity were lower in PD models than normal; L-DOPA treatment restored these properties. Conversely, dSPN intrinsic excitability was elevated in tissue from PD models and suppressed in LID models. Although the synaptic connectivity of dSPNs did not change in PD models, it fell with L-DOPA treatment. In neither case, however, was the strength of corticostriatal connections globally scaled. Thus, SPNs manifested homeostatic adaptations in intrinsic excitability and in the number but not strength of excitatory corticostriatal synapses.


A prospective trial comparing Biobrane, Duoderm and xeroform for skin graft donor sites.
Many new dressings have been introduced for use on split-thickness skin graft donor sites in an effort to reduce pain at the donor site and decrease healing time, while maintaining a low infection rate and cost. To assess these factors in two such dressings, Biobrane (temporary wound dressing) (Winthrop) and Duoderm (hydrocolloid dressing) (Convatec), we compared them with a conventional fine mesh gauze dressing, xeroform, in a prospective, randomized study of 30 donor sites in the same number of patients. Wounds were considered healed when they were 100 per cent re-epithelialized and required no further dressings. Patient self-assessment of pain was quantified on a scale of zero to ten, with ten being the most severe pain. Donor sites dressed with xeroform had a healing time of 10.5 days, which was significantly better (p less than 0.05) than Duoderm (15.3 days) or Biobrane (19.0 days), although the protocol for Duoderm use (wound visualization at seven day intervals) extended the apparent healing times in this group. Duoderm was the most comfortable dressing (0.53 grade) when compared with Biobrane (1.44) and xeroform (2.41, p less than 0.05). No infections occurred in donor sites dressed with xeroform, but two developed in patients using Biobrane. One patient with a Duoderm dressing had a donor site infection during a drug-related neutropenic reaction. Xeroform was the least expensive dressing to use ($1.16 per patient), followed by Duoderm ($54.88 per patient) and Biobrane ($102.57 per patient). The results of our study confirm the usefulness of xeroform as a donor site dressing as it promotes relatively rapid healing, is easy to use and is inexpensive. We found Duoderm to be ideal for smaller donor sites when pain could be significantly reduced with minimal increase in cost. Biobrane is too costly and the infection rate too high for it to be used routinely as a skin graft donor site dressing.


Management of male-factor infertility.
For many years, the management of male-factor infertility has been empirical rather than evidence-based. In current clinical practice, assisted reproductive techniques are the most successful methods of alleviating male-factor infertility. To date, it remains unclear what adjuvant actions can be taken to improve the outcome of assisted reproductive techniques for male-factor infertility. Evidence shows that smoking adversely affects sperm quality to some extent, and the genetic make-up of sperm to a greater extent; however, because of the scarcity and heterogeneity of studies, its effect on in-vitro fertilisation outcome remains largely unknown. Although smoking cessation should be part of the assisted reproductive techniques treatment plan, the benefit of antioxidant treatment in either smokers or non-smokers undergoing assisted reproductive techniques is still under scrutiny. Other lifestyle modifications in subfertile men, such as refraining from moderate alcohol and caffeine consumption, are even more controversial. When embarking on assisted reproductive techniques to alleviate male-factor infertility, intrauterine insemination may be considered as a first-line treatment for couples in whom the female partner has a normal fertility status, and at least 0.8 × 10(6) progressively motile spermatozoa are recovered after sperm preparation. If no pregnancy is achieved after three to six cycles of intrauterine insemination, in-vitro fertilisation can be proposed. When too few progressively motile spermatozoa are obtained after sperm processing for in-vitro fertilisation, or when surgically retrieved sperm are to be used, intracytoplasmic sperm injection is preferable. Although the outcome of no other assisted reproductive techniques has been scrutinised so much, and no large-scale 'macro-problems' have yet been observed after intracytoplasmic sperm injection, malformation rates are reported to be higher compared with the general population. Therefore, candidates for intracytoplasmic sperm injection should be rigorously screened before embarking on in-vitro fertilisation or intracytoplasmic sperm injection, and thoroughly informed of the limitations of our knowledge on the hereditary aspects of male infertility and the safety aspects of assisted reproductive techniques.


Stimulation of plasma inactive renin by dexamethasone in the cat.
An inactive form of renin in human plasma is the biosynthetic precursor, prorenin. The cat is a good animal model for studies of inactive renin. The gene for human renin contains sequences homologous to the glucocorticoid consensus sequence. The response of cat plasma (active and inactive renin) and of angiotensinogen to administration of dexamethasone (0.5 mg/kg im, daily) was studied in ketamine-sedated cats (20 mg/kg im). Inactive renin increased by twofold after 7 days of dexamethasone (P less than 0.01). After a 7-day recovery period, it returned to base line. Active renin did not change. Angiotensinogen fell by 35% (P less than 0.01). The time course of the selective increase of plasma inactive renin showed that inactive renin began to rise after 2 days, peaking after 5 days. Ketamine alone induced inactive renin to rise slightly but significantly (P less than 0.05), although the magnitude of the increment was much less than that observed in ketamine-sedated cats receiving dexamethasone (P less than 0.01). Active renin did not change, whereas angiotensinogen was reduced by 25% (P less than 0.01). Our findings support the hypothesis that glucocorticoids might have a selective role in the synthesis and/or secretion of the precursor of renin, at least in the cat.


International expert consensus on the management of bleeding during VATS lung surgery.
Intraoperative bleeding is the most crucial safety concern of video-assisted thoracic surgery (VATS) for a major pulmonary resection. Despite the advances in surgical techniques and devices, intraoperative bleeding is still not rare and remains the most common and potentially fatal cause of conversion from VATS to open thoracotomy. Therefore, to guide the clinical practice of VATS lung surgery, we proposed the International Interest Group on Bleeding during VATS Lung Surgery with 65 experts from 10 countries in the field to develop this consensus document. The consensus was developed based on the literature reports and expert experience from different countries. The causes and incidence of intraoperative bleeding were summarised first. Seven situations of intraoperative bleeding were collected based on clinical practice, including the bleeding from massive vessel injuries, bronchial arteries, vessel stumps, and bronchial stumps, lung parenchyma, lymph nodes, incisions, and the chest wall. The technical consensus for the management of intraoperative bleeding was achieved on these seven surgical situations by six rounds of repeated revision. Following expert consensus statements were achieved: (I) Bleeding from major vascular injuries: direct compression with suction, retracted lung, or rolled gauze is useful for bleeding control. The size and location of the vascular laceration are evaluated to decide whether the bleeding can be stopped by direct compression or by ligation. If suturing is needed, the suction-compressing angiorrhaphy technique (SCAT) is recommended. Timely conversion to thoracotomy with direct compression is required if the operator lacks experience in thoracoscopic angiorrhaphy. (II) Bronchial artery bleeding: pre-emptive clipping of bronchial artery before bronchial dissection or lymph node dissection can reduce the incidence of bleeding. Bronchial artery bleeding can be stopped by compression with the suction tip, followed by the handling of the vascular stump with energy devices or clips. (III) Bleeding from large vessel stumps and bronchial stumps: bronchial stump bleeding mostly comes from accompanying bronchial artery, which can be clipped for hemostasis. Compression for hemostasis is usually effective for bleeding at the vascular stump. Otherwise, additional use of hemostatic materials, re-staple or a suture may be necessary. (IV) Bleeding from the lung parenchyma: coagulation hemostasis is the first choice. For wounds with visible air leakage or an insufficient hemostatic effect of coagulation, suturing may be necessary. (V) Bleeding during lymph node dissection: non-grasping en-bloc lymph node dissection is recommended for the nourishing vessels of the lymph node are addressed first with this technique. If bleeding occurs at the site of lymph node dissection, energy devices can be used for hemostasis, sometimes in combination with hemostatic materials. (VI) Bleeding from chest wall incisions: the chest wall incision(s) should always be made along the upper edge of the rib(s), with good hemostasis layer by layer. Recheck the incision for hemostasis before closing the chest is recommended. (VII) Internal chest wall bleeding: it can usually be managed with electrocoagulation. For diffuse capillary bleeding with the undefined bleeding site, compression of the wound with gauze may be helpful.


Low-intensity exercise can increase muscle mass and strength proportionally to enhanced metabolic stress under ischemic conditions.
Skeletal muscle bulk and strength are becoming important therapeutic targets in medicine. To increase muscle mass, however, intensive, long-term mechanical stress must be applied to the muscles, and such stress is often accompanied by orthopedic and cardiovascular problems. We examined the effects of circulatory occlusion in resistance training combined with a very low-intensity mechanical load on enhancing muscular metabolic stress and thereby increasing muscle bulk. Muscular metabolic stress, as indicated by the increases in inorganic phosphate (P(i)) and a decrease in intramuscular pH, was evaluated by (31)P-magnetic resonance spectroscopy during unilateral plantar-flexion at 20% of the one-repetition maximum (1-RM) with circulatory occlusion for 2 min in 14 healthy, male untrained participants (22 yr) at baseline. Participants performed two sets of the same exercise with a 30-s rest between sets, 2 times/day, 3 days/wk, for 4 wk. The muscle cross-sectional area (MCA) of the plantar-flexors and the 1-RM were measured at baseline and after 2 and 4 wk of training. MCA and 1-RM were significantly increased after 2 and 4 wk (P < 0.05, respectively). The increase in MCA at 2 wk was significantly (P < 0.05) correlated with the changes in P(i) (r = 0.876) and intramuscular pH (r = 0.601). Furthermore, the increases in MCA at 4 wk and 1-RM at 2 wk were also correlated with the metabolic stress. Thus enhanced metabolic stress in exercising muscle is a key mechanism for favorable effects by resistance training. Low-intensity resistance exercise provides successful outcomes when performed with circulatory occlusion, even with a short training period.


Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in extremely preterm infants: a clinical practice guideline incorporating family values and preferences.
ImportanceProphylactic cyclo-oxygenase inhibitors (COX-Is) such as indomethacin, ibuprofen and acetaminophen may prevent morbidity and mortality in extremely preterm infants (born ≤28 weeks' gestation). However, there is controversy around which COX-I, if any, is the most effective and safest, which has resulted in considerable variability in clinical practice. Our objective was to develop rigorous and transparent clinical practice guideline recommendations for the prophylactic use of COX-I drugs for the prevention of mortality and morbidity in extremely preterm infants. The Grading of Recommendations Assessment, Development and Evaluation evidence-to-decision framework for multiple comparisons was used to develop the guideline recommendations. A 12-member panel, including 5 experienced neonatal care providers, 2 methods experts, 1 pharmacist, 2 parents of former extremely preterm infants and 2 adults born extremely preterm, was convened. A rating of the most important clinical outcomes was established a priori. Evidence from a Cochrane network meta-analysis and a cross-sectional mixed-methods study exploring family values and preferences were used as the primary sources of evidence. The panel recommended that prophylaxis with intravenous indomethacin may be considered in extremely preterm infants (conditional recommendation, moderate certainty in estimate of effects). Shared decision making with parents was encouraged to evaluate their values and preferences prior to therapy. The panel recommended against routine use of ibuprofen prophylaxis in this gestational age group (conditional recommendation, low certainty in the estimate of effects). The panel strongly recommended against use of prophylactic acetaminophen (strong recommendation, very low certainty in estimate of effects) until further research evidence is available.


Length-dependent sensitivity of vascular smooth muscle in normotensive and hypertensive animals.
Ring segments were obtained from the aorta of spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar (WST) rats and from the anterior tibial artery of normotensive and hypertensive dogs. Norepinephrine dose-response curves were generated at lengths relative to that for maximum force (Lmax) and at a specific preload (in grams). The doses of stimulus necessary to elicit 10 and 50% maximum force of contraction (ED10 and ED50) are greater at lengths less than Lmax than at Lmax for all groups. When SHR rings are compared with WKY or WST rings, ED10 or ED50 is the same at either length. The same result was found in comparing normal and hypertensive dogs. ED10 and ED50 from hypertensive groups were the same as their respective control groups when compared at the same preload. We conclude that sensitivity of the rat aorta and dog anterior tibial artery to norepinephrine depends on muscle length, this relationship is not altered in hypertension, and the conclusion on sensitivity in hypertension is the same for excised rings compared at the same length or at the same preload. Contractility (active stress) was lower (rats) or the same (dogs) but thickness was greater in the hypertensive groups than in their controls. The results show that a change in the vessel wall that can cause increased flow resistance and pressure is not in sensitivity or contractility but in wall thickness. Apparent differences in sensitivity from normal and hypertensive animals can be explained by an unchanged length-dependent sensitivity. The results also show that differences in body weight will affect a comparison of wall tension but not of sensitivity.


ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds): A pipeline for sample-specific computational modeling of electrical stimulation of peripheral nerves.
Electrical stimulation and block of peripheral nerves hold great promise for treatment of a range of disease and disorders, but promising results from preclinical studies often fail to translate to successful clinical therapies. Differences in neural anatomy across species require different electrodes and stimulation parameters to achieve equivalent nerve responses, and accounting for the consequences of these factors is difficult. We describe the implementation, validation, and application of a standardized, modular, and scalable computational modeling pipeline for biophysical simulations of electrical activation and block of nerve fibers within peripheral nerves. The ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds) pipeline provides a suite of built-in capabilities for user control over the entire workflow, including libraries for parts to assemble electrodes, electrical properties of biological materials, previously published fiber models, and common stimulation waveforms. We validated the accuracy of ASCENT calculations, verified usability in beta release, and provide several compelling examples of ASCENT-implemented models. ASCENT will enable the reproducibility of simulation data, and it will be used as a component of integrated simulations with other models (e.g., organ system models), to interpret experimental results, and to design experimental and clinical interventions for the advancement of peripheral nerve stimulation therapies.


[The headache triggered with ingestion of hot and soft fizzy drinks: similarity with ice cream headache].
Ice cream headache is more frequent in migraineurs. This is probably due to the specific interactions between neural and vascular systems in migraine patients. Two patients suffering from ice cream headache reported us that a similar headache occurred during migraine attacks with various stimuli such as ingesting hot and fizzy drinks. In addition to the pace of ingestion and temperature of the material, central sensitization may also have a role in the occurrence of this pain. We think that various factors play role in this neuro-vascular interaction. Accepting the ice cream headache as a prototype of this neuro-vascular interaction could provide path to new concepts.


A dispersed family of repetitive DNA sequences exhibits characteristics of a transposable element in the genus Lycopersicon.
A segment of DNA 5' to the transcribed region of an auxin-regulated gene, ARPI, from Lycopersicon esculentum Mill. cv. VFN8 contains a sequence with the structural characteristics of a transposable element. The putative element (Lyt1) is 1340 bp long, has terminal inverted repeats of approximately 235 bp and is flanked by 9-bp direct repeats. Lyt1 has a structure similar to the Robertson's Mutator (Mu) family from maize. The terminal inverted repeats are 80% AT-rich, are 96.6% identical, and define a larger family of repetitive elements. Southern analysis and genomic dot-blot reconstructions detected at least 41 copies of Lyt1-hybridizing sequences in red-fruited Lycopersicon spp. (L. esculentum, L. pimpinellifolium and L. cheesmanii), and 2-8 copies in the green-fruited species (L. hirsutum, L. pennellii, L. peruvianum, L. chilense and L. chmielewskii). There were two to four copies in the Solanum spp. closely allied with the genus Lycopersicon (S. lycopersicoides, S. ochranthum and S. juglandifolium), while the more distantly related Solanum spp. showed little (one to two copies in S. tuberosum) to no (S. quitoense) detectable hybridization under stringent conditions. Linkage analysis in the F2 progeny of a cross between L. esculentum and L. cheesmanii indicated that at least six loci that hybridize to the Lyt1 sequence are dispersed in the genome. Polymerase chain reaction and Southern analyses revealed that some red-fruited accessions and L. chmielewskii lacked Lyt1 5' to the transcribed region of ARPI. Subsequent sequence analysis indicated that only one copy of the 9-bp direct repeat (target site) was present, suggesting that transposition of the element into the ARPI gene occurred after the divergence of the red-fruited and green-fruited Lycopersicon species.


Databases for assessing the outcomes of the treatment of patients with congenital and paediatric cardiac disease--the perspective of cardiac surgery.
This review includes a brief discussion, from the perspective of cardiac surgeons, of the rationale for creation and maintenance of multi-institutional databases of outcomes of congenital heart surgery, together with a history of the evolution of such databases, a description of the current state of the art, and a discussion of areas for improvement and future expansion of the concept. Five fundamental areas are reviewed: nomenclature, mechanism of data collection and storage, mechanisms for the evaluation and comparison of the complexity of operations and stratification of risk, mechanisms to ensure the completeness and accuracy of the data, and mechanisms for expansion of the current capabilities of databases to include comparison and sharing of data between medical subspecialties. This review briefly describes several European and North American initiatives related to databases for pediatric and congenital cardiac surgery the Congenital Database of The European Association for Cardio-Thoracic Surgery, the Congenital Database of The Society of Thoracic Surgeons, the Pediatric Cardiac Care Consortium, and the Central Cardiac Audit Database in the United Kingdom. Potential means of approaching the ultimate goal of acquisition of long-term follow-up data, and input of this data over the life of the patient, are also considered.


Locally enhanced relative humidity for scanning probe nanolithography.
The formation of a water meniscus between a sharp tip and a solid surface is one of the prevailing requirements for scanning probe microscope (SPM)-based lithographies, such as dip-pen nanolithography (DPN) and conductive tip induced oxidation. The water meniscus functions as a medium for the oxidation of or mass transfer to the solid surface. Here we report a simple, efficient, and effective approach to enhance the local relative humidity and thus increase the size of the water meniscus by bringing a water-containing capillary tube to the proximity of the tip-surface contact area. The enhancement in local relative humidity is confirmed via an increase in the measured tip-surface adhesion forces and the widths of DPN generated parallel lines. Compared to the global control of relative humidity for the whole lithography system, the short distance between the "water reservoir" and the tip-surface contact area enables rapid increase in the local vapor pressure of water, less perturbation, and minimal erosion to the state-of-the-art electronics. As a result, most scanning probe lithography experiments at high relative humidity can now be performed in a reasonable time frame.


Serine catabolism generates liver NADPH and supports hepatic lipogenesis.
Carbohydrate can be converted into fat by de novo lipogenesis, a process upregulated in fatty liver disease. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor. The feedstocks used to generate acetyl-CoA and NADPH in lipogenic tissues remain, however, unclear. Here we show using stable isotope tracing in mice that de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH. The liver, in contrast, derives acetyl-CoA for lipogenesis from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway in liver running in the opposite direction to that observed in most tissues and tumours, with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. SHMT inhibition decreases hepatic lipogenesis. Thus, liver folate metabolism is distinctively wired to support cytosolic NADPH production and lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are used, opening the door to tissue-specific pharmacological interventions.


[Efficacy of Shenshi Qianghuo Dihuang Decoction in rheumatoid arthritis: a randomized controlled trial].
In China, patients with rheumatoid arthritis (RA) are often treated with traditional Chinese herbal medicine. There are certain advantages of traditional Chinese medicine therapy in treatment of RA. To assess the efficacy and adverse reaction of Shenshi Qianghuo Dihuang Decoction (SQDD), a compound traditional Chinese herbal medicine, in treatment of RA. This was a 24-week prospective, randomized, controlled trial. Ninety RA patients meeting inclusion criteria from Shanghai Municipal Hospital of Traditional Chinese Medicine were randomly assigned to receive SQDD or methotrexate (MTX) with 45 cases in each group. The patients in SQDD group were orally administered with SQDD twice daily, and the patients in MTX control group were treated by oral administration of 15 mg MTX once a week. All the RA patients were treated for 24 weeks. The primary outcome was the number of patients achieving the American College of Rheumatology 20% response. Clinical and laboratory parameters including tender joint count and swollen joint count, patient's global assessment and physician's global assessment (using a 0-10 cm visual analogue scale), duration of morning stiffness, plasma C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR) and value of anti-cyclic citrullinated peptide (CCP) antibody were assessed. After 24-week treatment, the response rates in SQDD group and MTX group were 62.53% (24/41) and 67.5% (28/40) respectively, and there was no statistical difference between the two groups (P>0.05). The patient's global assessment and physician's global assessment, morning stiffness, grip strength, tender joint count, swollen joint count and the levels of ESR, CRP and anti-CCP antibody in SQDD and MTX groups were improved significantly as compared with those before treatment, and there were no significant differences between the two groups. The efficacy of MTX in improving rest pain and joint tenderness was better than that of SQDD (P<0.05). The incidence rate of adverse reactions in SQDD group was 9.75%(4/41), significantly lower than 32.5% (13/40) in MTX group (P<0.05). SQDD has a therapeutic effect on RA, and the adverse reactions are less than MTX.


Revealing the Neural Mechanisms Underlying the Beneficial Effects of Tai Chi: A Neuroimaging Perspective.
Tai Chi Chuan (TCC), a traditional Chinese martial art, is well-documented to result in beneficial consequences in physical and mental health. TCC is regarded as a mind-body exercise that is comprised of physical exercise and meditation. Favorable effects of TCC on body balance, gait, bone mineral density, metabolic parameters, anxiety, depression, cognitive function, and sleep have been previously reported. However, the underlying mechanisms explaining the effects of TCC remain largely unclear. Recently, advances in neuroimaging technology have offered new investigative opportunities to reveal the effects of TCC on anatomical morphologies and neurological activities in different regions of the brain. These neuroimaging findings have provided new clues for revealing the mechanisms behind the observed effects of TCC. In this review paper, we discussed the possible effects of TCC-induced modulation of brain morphology, functional homogeneity and connectivity, regional activity and macro-scale network activity on health. Moreover, we identified possible links between the alterations in brain and beneficial effects of TCC, such as improved motor functions, pain perception, metabolic profile, cognitive functions, mental health and sleep quality. This paper aimed to stimulate further mechanistic neuroimaging studies in TCC and its effects on brain morphology, functional homogeneity and connectivity, regional activity and macro-scale network activity, which ultimately lead to a better understanding of the mechanisms responsible for the beneficial effects of TCC on human health.


Assignment of quinone derivatives as the main compound class composing 'interstellar' grains based on both polarity ions detected by the 'Cometary and Interstellar Dust Analyser' (CIDA) onboard the spacecraft STARDUST.
The 'Cometary and Interstellar Dust Analyser' (CIDA) is a particle impact time-of-flight mass spectrometer onboard the NASA spacecraft STARDUST. A series of positive and negative ion mass spectra from the impact of (apparently) interstellar dust particles has been collected since 1999. In the meantime laboratory work has been performed to better understand the ion formation processes of organic grains impacting at those speeds (>15 km/s) and to relate them to some other ion formation methods. The key ion types were the negative ions, with some additional information from the positive ions. Here, first the principal ion formation rules are briefly reviewed. Secondly, the common substance class is inferred mainly by the application of exclusion principles, and appears to be partly condensed aromatic and quinonoid compounds with high oxygen and low nitrogen content. Oxygen appears to be present in quinone-type structures with condensed aromatic rings, possibly with furan substructures and some hydroxyl moieties. Some nitrogen may be present in pyrrole- or quinoline-type structures. Considerations of thermodynamics and radiation physics of these dust particles within the solar system are consistent with this interpretation. Quinoenzyme cofactors such as the known compound pyrroloquinoline-quinone (PQQ) and its subconstituents would be expected to yield similar mass spectra.


Episodic blindness and ataxia in a horse with cholesterinic granulomas.
An 11-year-old Oldenburg mare presented following three episodes of acute, transient blindness, ataxia, and disorientation within the preceding 7 months. Clinical improvement, including return of vision, occurred within 1 week of initiating corticosteroid therapy for each of the three episodes. However, mild right-sided miosis was a consistent finding on ophthalmic examinations. Routine clinicopathologic testing revealed no significant abnormalities, and testing of cerebral spinal fluid for selected infectious diseases was unrewarding. Computed tomography of the brain demonstrated a hyperattenuating mass with peripheral mineralization in the rostroventral aspect of each lateral ventricle. The mare was euthanized due to a guarded to poor prognosis. On histopathology, the masses consisted of clusters of cholesterol clefts admixed with leukocytes, mineral deposits, and connective tissue. Cholesterinic granulomas of the lateral ventricles and hydrocephaly were diagnosed. Cholesterinic granulomas should be considered a differential diagnosis in horses presenting for intermittent blindness.


Fecundity is impaired in a mouse model of osteogenesis imperfecta.
Osteogenesis imperfecta (OI), or brittle bone disease, is most often caused by mutations in genes encoding type I collagen or proteins that process it. Women with OI have a small, but significant increase in risk of serious pregnancy complications including uterine rupture. Here, the OI mouse, Col1a2oim/oim , was used to examine the effects of collagen mutation on establishment and maintenance of pregnancy. Picrosirius birefringence was faint in Col1a2oim/oim uteri, indicating diminished collagen in the myometrium and endometrium. There was some evidence of increased uterine gland number (p = .055) and size (p = .12) in (p = .055) virgin uteri, though the they were not significantly different than controls. There were no differences in the number of corpora lutea, or the time from pairing to delivery of pups between Col1a2oim/oim and control dams, suggesting that ovulation and conception occur normally. However, when examined at Gestation Day 6.5 (postimplantation), gestation Day 10.5 (midpregnancy), and Postnatal Days 1-2, Col1a2oim/oim dams had significantly fewer viable pups than controls overall. In pairwise comparisons, the loss was only significant in the postnatal group, suggesting the gradual loss of pups over time. Overall, the Col1a2oim/oim mouse data suggest that OI impairs uterine function in pregnancy in a way that affects a small but significant number of fetuses.


Validation of a Post-Transplant Lymphoproliferative Disorder Risk Prediction Score and Derivation of a New Prediction Score Using a National Bone Marrow Transplant Registry Database.
We externally validated Fujimoto's post-transplant lymphoproliferative disorder (PTLD) scoring system for risk prediction by using the Taiwan Blood and Marrow Transplant Registry Database (TBMTRD) and aimed to create a superior scoring system using machine learning methods. Consecutive allogeneic hematopoietic cell transplant (HCT) recipients registered in the TBMTRD from 2009 to 2018 were included in this study. The Fujimoto PTLD score was calculated for each patient. The machine learning algorithm, least absolute shrinkage and selection operator (LASSO), was used to construct a new score system, which was validated using the fivefold cross-validation method. We identified 2,148 allogeneic HCT recipients, of which 57 (2.65%) developed PTLD in the TBMTRD. In this population, the probabilities for PTLD development by Fujimoto score at 5 years for patients in the low-, intermediate-, high-, and very-high-risk groups were 1.15%, 3.06%, 4.09%, and 8.97%, respectively. The score model had acceptable discrimination with a C-statistic of 0.65 and a near-perfect moderate calibration curve (HL test p = .81). Using LASSO regression analysis, a four-risk group model was constructed, and the new model showed better discrimination in the validation cohort when compared with The Fujimoto PTLD score (C-statistic: 0.75 vs. 0.65). Our study demonstrated a more comprehensive model when compared with Fujimoto's PTLD scoring system, which included additional predictors identified through machine learning that may have enhanced discrimination. The widespread use of this promising tool for risk stratification of patients receiving HCT allows identification of high-risk patients that may benefit from preemptive treatment for PTLD. This study validated the Fujimoto score for the prediction of post-transplant lymphoproliferative disorder (PTLD) development following hematopoietic cell transplant (HCT) in an external, independent, and nationally representative population. This study also developed a more comprehensive model with enhanced discrimination for better risk stratification of patients receiving HCT, potentially changing clinical managements in certain risk groups. Previously unreported risk factors associated with the development of PTLD after HCT were identified using the machine learning algorithm, least absolute shrinkage and selection operator, including pre-HCT medical history of mechanical ventilation and the chemotherapy agents used in conditioning regimen.


Interferon in lyssavirus infection.
Rabies is a zoonosis still claiming more than 50 000 human deaths per year. Typically, human cases are due to infection with rabies virus, the prototype of the Lyssavirus genus, but sporadic cases of rabies-like encephalitis caused by other lyssaviruses have been reported. In contrast to rabies virus, which has an extremely broad host range including many terrestrial warm-blooded animals, rabies-related viruses are associated predominantly with bats and rarely infect terrestrial species. In spite of a very close genetic relationship of rabies and rabies-related viruses, the factors determining the limited host range of rabies-related viruses are not clear. In the past years the importance of viral countermeasures against the host type I interferon system for establishment of an infection became evident. The rabies virus phosphoprotein (P) has emerged as a critical factor required for paralysing the signalling cascades leading to transcriptional activation of interferon genes as well as interferon signalling pathways, thereby limiting expression of antiviral and immune stimulatory genes. Comparative studies would be of interest in order to determine whether differential abilities of the lyssavirus P proteins contribute to the restricted host range of lyssaviruses.


Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice.
The ability of interleukin (IL)-12 to prevent tumors when administered to individuals with a genetic risk of cancer was studied in two lines of transgenic mice expressing rat HER-2/neu oncogene in the mammary gland. Female BALB/c (H-2(d)) mice carrying the activated HER-2/ neu oncogene show no morphological abnormalities of the mammary gland until 3 wk of age. They then progress through atypical hyperplasia to in situ lobular carcinoma and at 33 wk of age all 10 mammary glands display invasive carcinomas. Adult FVB mice (H-2(q)) carrying the HER-2/neu protooncogene develop mammary carcinomas with a longer latency (38-49 wk) and a lower multiplicity (mean of 2.6 tumors/mice). Treatment with IL-12 (5 daily intraperitoneal injections, 1 wk on, 3 wk off; the first course with 50 ng IL-12/day, the second with 100 ng IL-12/day) begun at 2 wk of age in BALB/c mice and at 21 wk of age in FVB mice markedly delayed tumor onset and reduced tumor multiplicity. Analogous results were obtained in immunocompetent and permanently CD8(+) T lymphocyte-depleted mice. In both transgenic lines, tumor inhibition was associated with mammary infiltration of reactive cells, production of cytokines and inducible nitric oxide synthase, and reduction in microvessel number, in combination with a high degree of hemorrhagic necrosis.


Tospoviruses Induce Small Interfering RNAs Targeting Viral Sequences and Endogenous Transcripts in Solanaceous Plants.
Tospoviruses infect numerous crop species worldwide, causing significant losses throughout the supply chain. As a defence mechanism, plants use RNA interference (RNAi) to generate virus-derived small-interfering RNAs (vsiRNAs), which target viral transcripts for degradation. Small RNA sequencing and in silico analysis of capsicum and N. benthamiana infected by tomato spotted wilt virus (TSWV) or capsicum chlorosis virus (CaCV) demonstrated the presence of abundant vsiRNAs, with host-specific differences evident for each pathosystem. Despite the biogenesis of vsiRNAs in capsicum and N. benthamiana, TSWV and CaCV viral loads were readily detectable. In response to tospovirus infection, the solanaceous host species also generated highly abundant virus-activated small interfering RNAs (vasiRNAs) against many endogenous transcripts, except for an N. benthamiana accession lacking a functional RDR1 gene. Strong enrichment for ribosomal protein-encoding genes and for many genes involved in protein processing in the endoplasmic reticulum suggested co-localisation of viral and endogenous transcripts as a basis for initiating vasiRNA biogenesis. RNA-seq and RT-qPCR-based analyses of target transcript expression revealed an inconsistent role for vasiRNAs in modulating gene expression in N. benthamiana, which may be characteristic of this tospovirus-host pathosystem.


Sanjin tablets for acute uncomplicated lower urinary tract infection (syndrome of dampness-heat in the lower jiao): protocol for randomized, double-blind, double-dummy, parallel control of positive drug, multicenter clinical trial.
Acute uncomplicated lower urinary tract infection (UTI) is one of the most common bacterial infections. Patients usually present with dysuria, urinary urgency, urinary frequency, and suprapubic pain or tenderness. Approximately 150 million people are diagnosed with UTI each year worldwide. The high recurrence rate of lower UTI is a common problem of clinical treatment. The misuse of antibiotics has led to the emergence of a number of resistant bacterial strains. Thus, traditional Chinese medicine is considered as an alternative option for treating acute uncomplicated lower UTI. Thus, this study aims to evaluate the efficacy and safety of Sanjin tablets (SJT) for the treatment of acute uncomplicated lower UTI, explore whether SJT can reduce or substitute the use of antibiotics, and reduce the recurrence rate in the treatment of acute uncomplicated lower UTI. In this study, a randomized, double-blind, double-dummy, parallel control of positive drug, multicenter clinical study will be established. A total of 252 patients with acute uncomplicated lower UTI (syndrome of dampness-heat in the lower jiao) will be randomly allocated in the ratio of 1:1:1 to three groups: experimental group; control group 1; and control group 2. The experimental group receives Sanjin tablets plus levofloxacin tablets (LT) placebo; the control group 1 receives LT plus SJT placebo; and the control group 2 receives SJT plus LT on the first five days, SJT plus LT placebo on the last two days. Each group will be treated for seven days and followed-up 1-2 times. The primary outcome measures of effective rate and recurrence rate are symptoms. Secondary outcome measures of effective rate and recurrence rate are the urine leukocytes, bacteriology examination, and safety assessment. Outcomes will be assessed at baseline and after treatment. This study protocol will provide the research data of efficacy and safety of SJT for the treatment of acute uncomplicated lower UTI. The first aim is to determine whether Sanjin tablets can reduce the use of antibiotics; the second aim is to determine whether Sanjin tablets can substitute the use of antibiotics. The recurrence rate will be assessed after cured to determine whether SJT can reduce the recurrence rate. The results of this study will improve the rational use of drugs, especially the rational application of antibiotics. It will also enable safety evaluation from laboratory indices and adverse events, which will provide reliable evidence for clinical treatment. ClinicalTrials.gov, NCT03658291 . Registered on 4 September 2018.


Hope, counselling and complicated bereavement reactions.
This paper examines the relationship between hope and complicated bereavement, and then considers if current bereavement counselling theory addresses this issue. Bereavement can be considered to have a number of phases or stages which need not occur in a linear fashion, but this does not make bereavement a mechanistic process. Whilst there are commonalities in people's experience of bereavement and loss, the experience of bereavement is unique to each individual. A person needs to reach a state of acceptance, to resolve conflicts related to grieving in order to complete the bereavement. Yet all individuals do not achieve this resolution naturally. Some individuals appear to experience delay in this process, and this can be described as a complicated grief reaction. Unequivocally bound up with bereavement are hope and hopelessness, with a completed bereavement process being bound up with the re-emergence of hope and complicated bereavement process being bound up with continued hopelessness. There are many theories of bereavement counselling, and commonalities exist between these theories. Whilst the theories indicate implicitly the re-emergence of hope in the bereft individual as a result of the counselling, there is a dearth of specific reference to how this inspiration occurs. Since the reemergence of hope appears to be linked to a person's movement towards a completed bereavement reaction, and this movement is facilitated by means of bereavement counselling, this paper concludes that there is a clear need to examine how this resolution occurs.