Sotorasib for Lung Cancers with KRAS p.G12C Mutation.
Sotorasib showed anticancer activity in patients with KRAS p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).


Preclinical to clinical translation for intervertebral disc repair: Effects of species-specific scale, metabolism, and matrix synthesis rates on cell-based regeneration.
A significant hurdle for potential cell-based therapies is the subsequent survival and regenerative capacity of implanted cells. While many exciting developments have demonstrated promise preclinically, cell-based therapies for intervertebral disc (IVD) degeneration fail to translate equivalent clinical efficacy. This work aims to ascertain the clinical relevance of both a small and large animal model by experimentally investigating and comparing these animal models to human from the perspective of anatomical scale and their cellular metabolic and regenerative potential. First, this work experimentally investigated species-specific geometrical scale, native cell density, nutrient metabolism, and matrix synthesis rates for rat, goat, and human disc cells in a 3D microspheroid configuration. Second, these parameters were employed in silico to elucidate species-specific nutrient microenvironments and predict differences in temporal regeneration between animal models. This work presents in silico models which correlate favorably to preclinical literature in terms of the capabilities of animal regeneration and predict that compromised nutrition is not a significant challenge in small animal discs. On the contrary, it highlights a very fine clinical balance between an adequate cell dose for sufficient repair, through de novo matrix deposition, without exacerbating the human microenvironmental niche. Overall, this work aims to provide a path towards understanding the effect of cell injection number on the nutrient microenvironment and the "time to regeneration" between preclinical animal models and the large human IVD. While these findings help to explain failed translation of promising preclinical data and the limited results emerging from clinical trials at present, they also enable the research field and clinicians to manage expectations on cell-based regeneration. Ultimately, this work provides a platform to inform the design of clinical trials, and as computing power and software capabilities increase in the future, it is conceivable that generation of patient-specific models could be used for patient assessment, as well as pre- and intraoperative planning.


Maternal Healthcare Providers in Uttar Pradesh, India: How to Position Informal Practitioners within the System?
To understand the knowledge and services of informal providers and to explore their role in addressing the human resource gap in Uttar Pradesh, India, within the context of maternal health. The study is exploratory in nature, conducted in four blocks of four districts of Uttar Pradesh state, India. Semi-structured interviews were conducted with 114 informal providers. More than one-third (38%) providers have some formal education and unrecognized degrees. Approximately three-fourths (74%) of them have more than 5 years of work experience. They also provide delivery and in-patient services and have basic equipment available. However, they lack essential knowledge about maternal health. They have mixed opinion about their contribution towards maternal health but the only ones available. Therefore, despite lacking requisite knowledge, training and services, they become indispensable due to lack of emergency and timely public health services, and being the only ones existing in the community. Informal sector practitioners are a critical link in reaching out to population for health services in developing countries. As opposed to the general notion, they possess years of formal education, experience, informal trainings along with trust of communities. Thus, it becomes important to accept their presence and manage them to the best of their abilities even for specialized care like maternal health.


[Perinatal bioethics: euthanasia or end-of-life decisions? Analysis of the Groningen Protocol].
The so called "Groningen Protocol" was conceived as a framework to discuss the euthanasia in neonates. Originally, it presents three groups of babies who might be candidates to this option. We analyzed the protocol in its original context and that of the Dutch society in which it was created. The analysis started with a careful reading of the protocol in both English and Dutch versions, translated later into Spanish. The medical and nursing staff participated in discussing it. A final consensus was reached. The Institutional Ethics Committee at our hospital discussed it freely and made recommendations for its application as a guideline to honestly discuss with parents the clinical condition of their babies, without permitting the option included literally in the word euthanasia. We selected four extremely ill infants. Their parents were interviewed at least twice daily: three stages were identified: the initial one of promoting all possible treatments; a second one of guarded and cautious request for the staff to evaluate "suffering", and a last one where requests were made to reduce therapeutic efforts to provide dignified death. A week after the death of their infants, they were presented with the facts of the protocol and the limits of our legal system. In all four cases the parents suggested that they would have chosen ending the life of their infants, in order to avoid them undue suffering. They clearly pointed out that this option emerged as a viable one to them once the ultimate outcome was evident. The protocol must not be viewed as a guideline for euthanasia in newborns, but rather as a mean to discuss the critical condition of an infant with the parents. Its direct implementation in our setting remains difficult. As a clear limitation for its overall application remains the definition of what is considered "unbearable suffering" in newborns, and how to certify when the infant has "no prospect". We emphasize the benefits of securing the help of the Ethics Committee and of "second opinions" from authorized physicians.


Development of performance tracking for a pediatric hospitalist division.
Our goal was to develop a comprehensive performance tracking process for a large pediatric hospitalist division. We aimed to use established dimensions and theory of health care quality to identify measures relevant to common inpatient diagnoses, reflective of current standards of clinical care, and applicable to individual physician performance. We also sought to implement a reproducible data collection strategy that minimizes manual data collection and measurement bias. Washington University Division of Pediatric Hospital Medicine provides clinical care in 17 units within 3 different hospitals. Hospitalist services were grouped into 5 areas, and a task group was created of divisional leaders representing clinical services. The group was educated on the health care quality theory and tasked to search clinical practice standards and quality resources. The groups proposed a broad spectrum of performance questions that were screened for electronic data availability and modified into measurable formulas. Eighty-seven performance questions were identified and analyzed for their alignment with known clinical guidelines and value in measuring performance. Questions were distributed across quality domains, with most addressing safety. They reflected structure, outcome, and, most commonly, process. Forty-seven questions were disease specific, and 79 questions reflected individual physician performance; 52 questions had electronically available data. We describe a systematic approach to the development of performance indicators for a pediatric hospitalist division that can be used to measure performance on a division and physician level. We outline steps to develop a broad-spectrum quality tracking process to standardize clinical care and build invaluable resources for quality improvement research.


Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity.
Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.


Understanding obstacles to the recognition of and response to dementia in different European countries: a modified focus group approach using multinational, multi-disciplinary expert groups.
Experts from eight European countries (Belgium, France, The Netherlands, Ireland, Italy, Portugal, Spain and the United Kingdom) and the disciplines of clinical psychology, general practice, geriatric medicine, old age psychiatry, medical sociology, nursing and voluntary body organisation met in 2003 to explore obstacles to recognition of and response to dementia in general practice within Europe. A modified focus group methodology was used in this exploratory process. Groups were conducted over a two-day period, with five sessions lasting 1-1.5 hours each. An adapted nominal group method was used to record themes arising from the group discussion, and these themes were used in a grounded theory approach to generate explanations for delayed recognition of and response to dementia. The overarching theme that arose from the focus groups was movement, which had three different expressions. These were: population movement and its consequences for localities, services and professional experience; the journey of the person with dementia along the disease process; and the referral pathway to access services and support. Change is the core issue in dementia care, with multiple pathways of change that need to be understood at clinical and organisational levels. Practitioners and people with dementia are engaged in managing emotional, social and physical risks, making explicit risk management a potentially important component of dementia care. The boundary between generalist and specialist services is a particular problem, with great potential for dysfunctionality. Stigma and ageism are variably distributed phenomena both within and between countries.


Mechanistic basis for suicide inactivation of porphobilinogen synthase by 4,7-dioxosebacic acid, an inhibitor that shows dramatic species selectivity.
4,7-Dioxosebacic acid (4,7-DOSA) is an active site-directed irreversible inhibitor of porphobilinogen synthase (PBGS). PBGS catalyzes the first common step in the biosynthesis of the tetrapyrrole cofactors such as heme, vitamin B(12), and chlorophyll. 4,7-DOSA was designed as an analogue of a proposed reaction intermediate in the physiological PBGS-catalyzed condensation of two molecules of 5-aminolevulinic acid. As shown here, 4,7-DOSA exhibits time-dependent and dramatic species-specific inhibition of PBGS enzymes. IC(50) values vary from 1 microM to 2.4 mM for human, Escherichia coli, Bradyrhizobium japonicum, Pseudomonas aeruginosa, and pea enzymes. Those PBGS utilizing a catalytic Zn(2+) are more sensitive to 4,7-DOSA than those that do not. Weak inhibition of a human mutant PBGS establishes that the inactivation by 4,7-DOSA requires formation of a Schiff base to a lysine that normally forms a Schiff base intermediate to one substrate molecule. A 1.9 A resolution crystal structure of E. coli PBGS complexed with 4,7-DOSA (PDB code ) shows one dimer per asymmetric unit and reveals that the inhibitor forms two Schiff base linkages with each monomer, one to the normal Schiff base-forming Lys-246 and the other to a universally conserved "perturbing" Lys-194 (E. coli numbering). This is the first structure to show inhibitor binding at the second of two substrate-binding sites.


Orbital volumetric analysis: clinical application in orbitozygomatic complex injuries.
Fifteen patients with unilateral orbitozygomatic complex fractures and five with bilateral injuries were analyzed with respect to the differences in orbital volume between the affected and the uninjured, or other, side. The study was conducted using the ALLEGRO Workstation and software package from ISG Technologies, which was capable of calculating volume partitions from either axial or coronal images. Patients without postoperative enophthalmos demonstrated a maximum volume difference of 3.8%; those with enophthalmos demonstrated differences of 4% or greater. The Critical Volume Difference at which enophthalmos becomes clinically apparent (whereby the orbital-corneal distance measured by Hertel exophthalmometry is greater than 3 mm on the affected side) is in the range of 4% to 5%. Volume analysis of the orbits by manipulation of the computed tomography data may allow a better understanding of changes in orbital configuration, which can result in better-directed primary and secondary reconstructions.


Lineage-specific mutation of Lmx1b provides new insights into distinct regulation of suture development in different areas of the calvaria.
The calvaria (top part of the skull) is made of pieces of bone as well as multiple soft tissue joints called sutures. The latter is crucial to the growth and morphogenesis of the skull, and thus a loss of calvarial sutures can lead to severe congenital defects in humans. During embryogenesis, the calvaria develops from the cranial mesenchyme covering the brain, which contains cells originating from the neural crest and the mesoderm. While the mechanism that patterns the cranial mesenchyme into bone and sutures is not well understood, function of Lmx1b, a gene encoding a LIM-domain homeodomain transcription factor, plays a key role in this process. In the current study, we investigated a difference in the function of Lmx1b in different parts of the calvaria using neural crest-specific and mesoderm-specific Lmx1b mutants. We found that Lmx1b was obligatory for development of the interfrontal suture and the anterior fontanel along the dorsal midline of the skull, but not for the posterior fontanel over the midbrain. Also, Lmx1b mutation in the neural crest-derived mesenchyme, but not the mesoderm-derived mesenchyme, had a non-cell autonomous effect on coronal suture development. Furthermore, overexpression of Lmx1b in the neural crest lineage had different effects on the position of the coronal suture on the apical part and the basal part. Other unexpected phenotypes of Lmx1b mutants led to an additional finding that the coronal suture and the sagittal suture are of dual embryonic origin. Together, our data reveal a remarkable level of regional specificity in regulation of calvarial development.


Neural recruitment after mild traumatic brain injury is task dependent: a meta-analysis.
Individuals with mild traumatic brain injury (TBI) often have deficits in processing speed and working memory (WM) and there is a growing literature using functional imaging studies to document these deficits. However, divergent results from these studies revealed both hypoactivation and hyperactivation of neural resources after injury. We hypothesized that at least part of this variance can be explained by distinct demands between WM tasks. Notably, in this literature some WM tasks use discrete periods of encoding, maintenance, and retrieval, whereas others place continuous demands on WM. The purpose of this meta-analysis is to examine the differences in neural recruitment after mTBI to determine if divergent findings can be explained as a function of task demand and cognitive load. A comprehensive literature review revealed 14 studies using functional magnetic resonance imaging to examine brain activity of individuals with mTBI during working memory tasks. Three of the fourteen studies included reported hypoactivity, five reported hyperactivity, and the remaining six reported both hypoactivity and hyperactivity. Studies were grouped according to task type and submitted to GingerALE maximum likelihood meta-analyses to determine the most consistent brain activation patterns. The primary findings from this meta-analysis suggest that the discrepancy in activation patterns is at least partially attributable to the classification of WM task, with hyperactivation being observed in continuous tasks and hypoactivation being observed during discrete tasks. We anticipate that differential task load expressed in continuous and discrete WM tasks contributes to these differences. Implications for the interpretation of fMRI signals in clinical samples are discussed.


Simultaneously Measured Interarm Blood Pressure Difference and Stroke: An Individual Participants Data Meta-Analysis.
We conducted individual participant data meta-analysis to examine the validity of interarm blood pressure difference in simultaneous measurement as a marker to identify subjects with ankle-brachial pressure index <0.90 and to predict future cardiovascular events. We collected individual participant data on 13 317 Japanese subjects from 10 cohorts (general population-based cohorts, cohorts of patients with past history of cardiovascular events, and those with cardiovascular risk factors). Binary logistic regression analysis with adjustments identified interarm blood pressure difference >5 mm Hg as being associated with a significant odds ratio for the presence of ankle-brachial pressure index <0.90 (odds ratio, 2.19; 95% confidence interval, 1.60-3.03; P<0.01). Among 11 726 subjects without a past history of cardiovascular disease, 249 developed stroke during the average follow-up period of 7.4 years. Interarm blood pressure difference >15 mm Hg was associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke (hazard ratio, 2.42; 95% confidence interval, 1.27-4.60; P<0.01). Therefore, interarm blood pressure differences, measured simultaneously in both arms, may be associated with vascular damage in the systemic arterial tree. These differences may be useful for identifying subjects with an ankle-brachial pressure index of <0.90 in the overall study population, and also a reliable predictor of future stroke in subjects without a past history of cardiovascular disease. These findings support the recommendation to measure blood pressure in both arms at the first visit.


Specificity of the imino acid carrier in rat small intestine.
The rat intestinal imino acid carrier is chloride independent, while in guinea pig and rabbit intestine it is chloride dependent. While non-alpha-amino acids do not significantly interact with guinea pig and rabbit imino acid carriers, inhibition studies had indicated that in rat small intestine beta-alanine, gamma-aminobutyric acid (GABA), and probably taurine might be transported by the imino acid carrier. The present study of rat jejunum demonstrates that the half-maximal activation concentration of beta-alanine (K1/2 beta-Ala) is identical to its inhibition constant (Ki beta-Ala) against GABA, that K1/2GABA is identical to KiGABA against beta-alanine, that proline and sarcosine have identical values of Ki against beta-alanine and GABA, and that Ki of beta-alanine and proline against sarcosine are equal to their K1/2 values. Taurine inhibits the transport of beta-alanine, and 300 mM proline and beta-alanine reduce the transport of taurine measured at 80 mM taurine to the level expected for the diffusive contribution, corresponding to Ki values equal to those against sarcosine. Thus the rat imino acid carrier is the principal carrier of taurine and the only carrier of beta-alanine and GABA. It is also demonstrated that alpha-amino-monocarboxylic acids with side chains in excess of one methyl group do not significantly interact with the imino acid carrier, and the lack of stereospecificity is confirmed.


[Effectiveness of computed tomography in the diagnosis of otosclerosis].
Computer-aided tomography (CAT) is the most informative method for imaging the morphologic substrate of an otosclerotic process. In otospongiosis the tomograms show compact bone demineralization sites to the front of the vestibule fenestra (the fenestral form) or round the cochlear osseous capsule (the cochlear form); this latter form is better detectable by densitometry. During the stage of "mature" inactive otosclerosis the labyrynth fenestra are exposed to partial or complete obliteration. Combinations of active and inactive foci in the temporal bone pyramid are seen in 38% of cases. CAT helps accurately define the cause of stapedoplasty failure: anvil necrosis and the prosthesis subdislocation. CAT should be an obligatory diagnostic component in examinations of patients with sound conduction abnormalities.


Algorithm to Diagnose Delayed and Late PJI: Role of Joint Aspiration.
Total Joint Arthroplasty (TJA) continues to gain acceptance as the standard of care for the treatment of severe degenerative joint disease, and is considered one of the most successful surgical interventions in the history of medicine. A devastating complication after TJA is infection. Periprosthetic joint infection (PJI), represents one of the major causes of failure and remains a significant challenge facing orthopaedics today. PJI usually requires additional surgery including revision of the implants, fusion or amputations causing tremendous patient suffering but also a heavy health economics burden. PJI is at the origin of around 20-25 % of total knee arthroplasty (Bozic et al. 2010; de Gorter et al. 2015; Sundberg et al. 2015) and 12-15 % of total hip arthroplasty (Bozic et al. 2009; Garellick et al. 2014; de Gorter et al. 2015) failures.


Diagnosis of systemic lupus erythematosus.
Systemic lupus erythematosus is a multisystem inflammatory disease that is often difficult to diagnose. Before the diagnosis can be established, four of 11 clinical and laboratory criteria must be met. Antinuclear antibody titer is the primary laboratory test used to diagnose systemic lupus erythematosus. Because of the low prevalence of the disease in primary care populations, the antinuclear antibody titer has a low predictive value in patients without typical clinical symptoms. Therefore, as specified by the American College of Rheumatology, this titer should be obtained only in patients with unexplained involvement of two or more organ systems. Patients with an antinuclear antibody titer of 1:40 and characteristic multiorgan system involvement can be diagnosed with systemic lupus erythematosus without additional testing; however, patients with an antibody titer of 1:40 who fail to meet full clinical criteria should undergo additional testing, including tests for antibody to double-stranded DNA antigen and antibody to Sm nuclear antigen. While an antinuclear antibody titer of less than 1:40 usually rules out systemic lupus erythematosus, patients with persistent, characteristic multisystem involvement may be evaluated for possible antinuclear antibody-negative disease.


Inadequate status of iodine nutrition among pregnant women residing in three districts of Niamey, the Niger Republic's capital.
Universal dietary salt iodisation (UDSI) programme was implemented in Niger in 1996. However, since 2000, there has been a slowdown in progress against iodine deficiency. The aim of our study was to assess the iodine status among pregnant women in a context where national controls are not effective at ensuring universal availability of adequately iodised salt. This is mainly to assess the impact of the slowdown in the fight against iodine deficiency in this vulnerable group. The study was centred on 240 healthy pregnant women volunteers recruited in three districts primary health centres. A control group of 60 non-pregnant, non-lactating healthy women was also studied and compared. Median urinary iodine concentration (UIC) of all pregnant women was 119 μg L(-1) , and 61.67% had UIC below 150 μg L(-1) . Median UIC for the first, second and third trimester were 144, 108 and 92 μg L(-1) , respectively. The percentage of pregnant women with UIC below 150 μg L(-1) increased from 52% in the first trimester to 66% in the third trimester. The median UIC of the control group was 166 μg L(-1) , and 28.33% had UIC below 100 μg L(-1) . No significant relationship was found between nutritional iodine status and provenance, age and parity. However, significant relationship was found between iodine status and stage of pregnancy, gestational age and educational level (P < 0.05). Iodine nutrition status thus observed was inadequate in 61.67% of all the pregnant women. It is therefore urgent to revitalise implementation of the UDSI programme, and in the short term to consider iodine supplementation for pregnant women.


Noninvasive visualization of early osteoarthritic cartilage using targeted nanosomes in a destabilization of the medial meniscus mouse model.
Early stage osteoarthritis (OA) is clinically asymptomatic due to the avascular and the aneural nature of the cartilage tissue. Nevertheless, early detection of cartilage tissue is critical in order to impede the progression of OA. Hence, in order to develop effective preventive therapy for OA, diagnosis in the early stages is necessary. To achieve this goal, we have developed targeted, fluorescent nanosomes conjugated with monoclonal anti-type II collagen antibodies (MabCII) for diagnosis of early OA. The MabCII-coated nanosomes (targeted-nanosomes) bind to the damaged cartilage explants in vitro and in vivo in an OA mouse model that mimics early stage OA. The OA mouse model was induced by destabilization of the medial meniscus (DMM) in 9-10 weeks old C57Bl/6 mice. The targeted-nanosomes enhanced the binding specificity to the cartilage tissue according to the severity of damage. We show that MabCII-nanosomes can precisely detect early stage OA in the DMM mouse model. Thus, MabCII-nanosomes have the potential to be used as a non-invasive method for diagnosing the early osteoarthritic lesions.


Ensuring the future of otitis media research: Interest in and feasibility of a mentoring network program within the otitis media research community.
The goal of this study was to assess the feasibility of the implementation of a mentoring network program based on expressed interest and the diverse composition of the otitis media research community in order to address attrition of the scientific workforce. An online survey was sent to basic, translational, and clinical researchers with a known interest in otitis media. Of 509 eligible participants, 119 (23.4%) responded to the survey. Survey respondents had a diverse background by completed education, current job description, and membership in an underrepresented group in science. Most faculty respondents (76.4%) were willing to participate in the proposed program as mentors and faculty lecturers, or had early-career researchers or trainees in their research group who were willing to participate as mentees in the mentoring network. Scientific and non-scientific topics for inclusion in the training program were ranked, with immunology and inflammation, microbiology, science leadership and collaboration, mentoring, and grantsmanship as main foci of interest among respondents. Our survey results showed enthusiastic participation among responding otitis media researchers, indicating the feasibility of implementing a mentoring network program that will address workforce attrition, particularly among underrepresented groups in science.


Meditation programs for veterans with posttraumatic stress disorder: Aggregate findings from a multi-site evaluation.
Interest in meditation to manage posttraumatic stress disorder (PTSD) symptoms is increasing. Few studies have examined the effectiveness of meditation programs offered to Veterans within Department of Veterans Affairs (VA) mental health services. The current study addresses this gap using data from a multisite VA demonstration project. Evaluation data collected at 6 VA sites (N = 391 Veterans) before and after a meditation program, and a treatment-as-usual (TAU) program, were examined here using random effects meta-analyses. Site-specific and aggregate between group effect sizes comparing meditation programs to TAU were determined for PTSD severity measured by clinical interview and self-report. Additional outcomes included experiential avoidance and mindfulness. In aggregate, analyses showed medium effect sizes for meditation programs compared to TAU for PTSD severity (clinical interview: effect size (ES) = -0.32; self-report: ES = -0.39). Similarly sized effects of meditation programs were found for overall mindfulness (ES = 0.41) and 1 specific aspect of mindfulness, nonreactivity to inner experience (ES = .37). Additional findings suggested meditation type and program completion differences each moderated program effects. VA-sponsored meditation programs show promise for reducing PTSD severity in Veterans receiving mental health services. Where meditation training fits within mental health services, and for whom programs will be of interest and effective, require further clarification. (PsycINFO Database Record


Interplay of defective excitation-contraction coupling, energy starvation, and oxidative stress in heart failure.
In chronic heart failure, maladaptive remodeling of the left ventricle (LV) with systolic and diastolic dysfunction underlies the inability of the heart to pump sufficient blood to supply the body with blood and oxygen. Three integral aspects of this maladaptive LV remodeling are (1) defects in excitation-contraction (EC) coupling, particularly of cellular Ca(2+) and Na(+) homeostasis; (2) an energetic deficit; and (3) oxidative stress. Although these three aspects are often investigated separately from each other, their close and dynamic interplay are increasingly recognized. Central to this novel approach are mitochondria, which are the main source for cellular ATP, but also for reactive oxygen species, and their function is critically regulated by Ca(2+) and Na(+). Here, we review recent advances in our understanding of how maladaptive changes of EC coupling can contribute to the energetic deficit and oxidative stress, which may initiate a vicious cycle leading to progressive cardiac dysfunction.


A moving view: subcellular trafficking processes in pattern recognition receptor-triggered plant immunity.
A significant challenge for plants is to induce localized defense responses at sites of pathogen attack. Therefore, host subcellular trafficking processes enable accumulation and exchange of defense compounds, which contributes to the plant on-site defenses in response to pathogen perception. This review summarizes our current understanding of the transport processes that facilitate immunity, the significance of which is highlighted by pathogens reprogramming membrane trafficking through host cell translocated effectors. Prominent immune-related cargos of plant trafficking pathways are the pattern recognition receptors (PRRs), which must be present at the plasma membrane to sense microbes in the apoplast. We focus on the dynamic localization of the FLS2 receptor and discuss the pathways that regulate receptor transport within the cell and their link to FLS2-mediated immunity. One emerging theme is that ligand-induced late endocytic trafficking is conserved across different PRR protein families as well as across different plant species.


New alpha blockers to treat male lower urinary tract symptoms.
To date it is unclear whether the selectivity of new alpha-blockers to alpha-adrenergic receptor subtypes translates into more clinical benefits and less adverse effects in clinical practice. We performed a systematic review of the two new Abs silodosin and naftopidil. With the availability of numerous alpha-blockers to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia, the findings of this review will be highly relevant to the field of urology. Silodosin was found to be more effective than placebo in improving International Prostate Symptom Score (IPSS) and quality of life scores and as effective as other alpha-blockers. Although the incidence of cardiovascular adverse events of silodosin was similar compared with placebo and other alpha-blockers (tamsulosin, naftopidil, alfuzosin), the sexual adverse events were more common with silodosin. No placebo-controlled randomized trial exists investigating the effects of naftopidil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. Naftopidil had similar efficacy with regards to IPSS and quality of life compared with tamsulosin. The rate of adverse events was similar compared with tamsulosin. The two new selective alpha-blockers, silodosin, and naftopidil showed similar efficacy in IPSS and quality of life compared with other alpha-blockers. However, silodosin has more sexual adverse events.


Interaction of interleukin-6, tumour necrosis factor and interleukin-1 during Listeria infection.
Injected recombinant interleukin-6 (IL-6), tumour necrosis factor (TNF) and IL-1 all protect mice against experimental infection with Listeria monocytogenes. We have therefore investigated the interaction of these cytokines during infection. Treatment with recombinant (r)IL-6 enhanced TNF production by spleen cells during the first 2 days of infection. Anti-TNF antibody could totally abolish the protective effect of rIL-6, while the optimal protective function of TNF could not be achieved when IL-6 was neutralized by anti-IL-6 antibody. IL-1 induced a high level of IL-6 in the serum a short time after its administration, and neutralization of IL-6 totally abolished the protective function of rIL-1. The results thus provide further evidence for the complexity of cytokine interaction.


Generation and characterization of a stable cell population releasing fluorescent HIV-1-based Virus Like Particles in an inducible way.
The availability of cell lines releasing fluorescent viral particles can significantly support a variety of investigations, including the study of virus-cell interaction and the screening of antiviral compounds. Regarding HIV-1, the recovery of such biologic reagents represents a very hard challenge due to the intrinsic cytotoxicity of many HIV-1 products. We sought to overcome such a limitation by using a cell line releasing HIV-1 particles in an inducible way, and by exploiting the ability of a HIV-1 Nef mutant to be incorporated in virions at quite high levels. Here, we report the isolation and characterization of a HIV-1 packaging cell line, termed 18-4s, able to release valuable amounts of fluorescent HIV-1 based Virus-Like Particles (VLPs) in an inducible way. 18-4s cells were recovered by constitutively expressing the HIV-1 NefG3C mutant fused with the enhanced-green fluorescent protein (NefG3C-GFP) in a previously isolated inducible HIV-1 packaging cell line. The G3C mutation creates a palmitoylation site which results in NefG3C-GFP incorporation into virions greatly exceeding that of the wild type counterpart. Upon induction of 18-4s cells with ponasterone A and sodium butyrate, up to 4 mug/ml of VLPs, which had incorporated about 150 molecules of NefG3C-GFP per viral particle, were released into the culture supernatant. Due to their intrinsic strong fluorescence, the 18-4s VLPs were easily detectable by a novel cytofluorometric-based assay developed here. The treatment of target cells with fluorescent 18-4 VLPs pseudotyped with different glycoprotein receptors resulted in these becoming fluorescent as early as two hours post-challenge. We created a stable cell line releasing fluorescent HIV-1 based VLPs upon induction useful for several applications including the study of virus-cell interactions and the screening of antiviral compounds.


Comparison of molecular dynamics simulations with triple layer and modified Gouy-Chapman models in a 0.1M NaCl-montmorillonite system.
Molecular dynamics (MD) simulations of a montmorillonite/water interface at the pore scale were carried out at 0.1molL(-1) NaCl concentration in order to constrain cation, anion, and water distribution and mobility influenced by the mineral surface. MD results enabled anion exclusion and cation condensation at the surface to be quantified. MD-derived values could then be compared with macroscopic model results obtained from the Modified Gouy-Chapman (MGC) theory. While the Na concentration profile is well reproduced in the diffuse layer, anion exclusion is overestimated by the MGC theory under our experimental conditions. We also showed that MD simulations can be used to constrain Basic Stern model parameters or, in combination with zeta potential measurements, can be used to constrain triple layer model (TLM) parameters by providing suitable values for the capacitance values. Na sorption intrinsic equilibrium constant values for clay basal surfaces are given accordingly.


Angiotensin converting enzyme inhibitory peptides from a lactotripeptide-enriched milk beverage are absorbed intact into the circulation.
Food products containing angiotensin converting enzyme (ACE) inhibitory peptides reportedly play a role in treatment of mild hypertension. The aim of this placebo-controlled crossover study was to assess the bioavailability of Ile-Pro-Pro and 7 other ACE-inhibiting peptides present in a lactotripeptide (LTP)-enriched yogurt beverage and whether meal intake affects Ile-Pro-Pro bioavailability. Six male and female subjects randomly consumed an LTP-enriched yogurt beverage or a placebo in the fasted state and an LTP-enriched yogurt beverage in the fed or fasted state. The area under the curve (AUC) of Ile-Pro-Pro after the LTP treatment in the fasted state was 2.1-fold of that after the placebo treatment (P < 0.001). The maximum peptide plasma concentration (C(max)) value was greater after consumption of the LTP-enriched beverage (897 +/- 157 pmol/L) than after the placebo treatment (555 +/- 0.09 pmol/L; P < 0.001) with a greater time after ingestion when reaching C(max) (T(max)) in the placebo treatment. Plasma concentrations of the peptides Leu-Trp, Phe-Tyr, Ile-Tyr, and Leu-Pro-Pro increased compared with baseline (P < 0.05) in the LTP-enriched and placebo treatment when consumed in the fasted state. However, DeltaC(max) values differed significantly between the placebo and LTP-enriched treatment only for Leu-Pro-Pro. Meal intake affected Ile-Pro-Pro concentrations. When the beverage was consumed after a meal, the AUC of Ile-Pro-Pro was 1.3-fold (P < 0.05) of the AUC derived from premeal intake. This was due to an increase in the plasma elimination half-life (P < 0.05); C(max) and T(max) were not affected by meal intake. In summary, this is the first demonstration, to our knowledge, that the tripeptide Ile-Pro-Pro selectively escapes from intestinal degradation and reaches the circulation undegraded.


Stark-selected beam of ground-state OCS molecules characterized by revivals of impulsive alignment.
We make use of an inhomogeneous electrostatic dipole field to impart a quantum-state-dependent deflection to a pulsed beam of OCS molecules, and show that those molecules residing in the absolute ground state, X(1)Σ(+), |00(0)0>, J = 0, can be separated out by selecting the most deflected part of the molecular beam. Past the deflector, we irradiate the molecular beam by a linearly polarized pulsed nonresonant laser beam that impulsively aligns the OCS molecules. Their alignment, monitored via velocity-map imaging, is measured as a function of time, and the time dependence of the alignment is used to determine the quantum state composition of the beam. We find significant enhancements of the alignment (<cos(2) θ(2D)> = 0.84) and of state purity (>92%) for a state-selected, deflected beam compared with an undeflected beam.


Predictors of tuberculosis treatment outcomes.
To analyze tuberculosis treatment outcomes and their predictors. This was a retrospective longitudinal cohort study involving tuberculosis patients treated between 2004 and 2006 at the Instituto de Pesquisa Evandro Chagas, in the city of Rio de Janeiro. We estimated adjusted risk ratios (ARRs) for the predictors of treatment outcomes. Among 311 patients evaluated, the rates of cure, treatment abandonment, treatment failure, and mortality were 72%, 19%, 2%, and 6%, respectively. Changes in the treatment regimen due to adverse events occurred in 8%. The factors found to reduce the probability of cure were alcoholism (ARR, 0.30), use of the streptomycin+ethambutol+ofloxacin (SEO) regimen (ARR, 0.32), HIV infection without the use of antiretroviral therapy (ART; ARR, 0.36), and use of the rifampin+isoniazid+pyrazinamide+ethambutol regimen (ARR, 0.58). Being younger and being alcoholic both increased the probability of abandonment (ARR, 3.84 and 1.76, respectively). It was impossible to determine the ARR for the remaining outcomes due to their low prevalence. However, using the relative risk (RR), we identified the following potential predictors of mortality: use of the SEO regimen (RR, 11.43); HIV infection without ART (RR, 9.64); disseminated tuberculosis (RR, 9.09); lack of bacteriological confirmation (RR, 4.00); diabetes mellitus (RR, 3.94); and homosexual/bisexual behavior (RR, 2.97). Low income was a potential predictor of treatment failure (RR, 11.70), whereas disseminated tuberculosis and HIV infection with ART were potential predictors of changes in the regimen due to adverse events (RR, 3.57 and 2.46, respectively). The SEO regimen should not be used for extended periods. The data confirm the importance of ART and suggest the need to use it early.


Familial hypercholesterolemia in French-Canadians: taking advantage of the presence of a "founder effect".
The frequency of familial hypercholesterolemia (FH) in the Province of Quebec is twice that observed in most population samples. In the French-Canadian population, 5 mutations in the low density lipoprotein (LDL) receptor gene account for 76% of FH cases diagnosed using clinical and biochemical criteria. One of these mutations, a > 10 kilobase (kb) deletion at the 5' end of the gene involving the promoter and exon 1, is present in 60% of FH patients studied in Montréal. This high frequency is attributable to a "founder effect." Contribution to this founder effect included strategies in 17th century France for the settlement of a small number of pioneers, local incentives for early marriages and large families, and geographic and cultural isolation; these factors also favored endogamy. The > 10 kb deletion is present on only one haplotype in all patients studied so far (homozygotes and heterozygotes), a major advantage for studies relating phenotypic variation to haplotype variation in the normal LDL receptor allele of these hemizygous patients. Indeed, the presence of founder effects facilitates screening, genetic counseling, and treatment. It also confers a number of advantages for research: (1) the search for new causes of FH in the 24% unaccounted for to date; (2) the study of the geographic distribution of mutations and population movements; (3) the identification of gene-gene interactions in the etiology of disease; (4) the evaluation of factors modulating phenotypic expression and search for LDL-lowering genes; and (5) the study of genetic determinants of therapeutic response.


Robust design and optimization of retroaldol enzymes.
Enzyme catalysts of a retroaldol reaction have been generated by computational design using a motif that combines a lysine in a nonpolar environment with water-mediated stabilization of the carbinolamine hydroxyl and β-hydroxyl groups. Here, we show that the design process is robust and repeatable, with 33 new active designs constructed on 13 different protein scaffold backbones. The initial activities are not high but are increased through site-directed mutagenesis and laboratory evolution. Mutational data highlight areas for improvement in design. Different designed catalysts give different borohydride-reduced reaction intermediates, suggesting a distribution of properties of the designed enzymes that may be further explored and exploited.


Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
The nerve axon is a good model system for studying the molecular mechanism of organelle transport in cells. Recently, the new kinesin superfamily proteins (KIFs) have been identified as candidate motor proteins involved in organelle transport. Among them KIF1A, a murine homologue of unc-104 gene of Caenorhabditis elegans, is a unique monomeric neuron- specific microtubule plus end-directed motor and has been proposed as a transporter of synaptic vesicle precursors (Okada, Y., H. Yamazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769-780). To elucidate the function of KIF1A in vivo, we disrupted the KIF1A gene in mice. KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances. In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease. Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies. Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons. The neuronal death in cultures was blocked by coculture with wild-type neurons or exposure to a low concentration of glutamate. These results in cultures suggested that the mutant neurons might not sufficiently receive afferent stimulation, such as neuronal contacts or neurotransmission, resulting in cell death. Thus, our results demonstrate that KIF1A transports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability, maintenance, and function of neurons, particularly mature neurons.


Identification of dithiolethione-inducible gene-1 as a leukotriene B4 12-hydroxydehydrogenase: implications for chemoprevention.
Cancer chemoprevention is inhibition of neoplastic disease by naturally occurring or synthetic chemical agents. Dithiolethiones inhibit production of experimentally produced tumors by elevating the expression of several genes that encode for known cytoprotective enzymes. In an effort to discover additional molecular mechanisms mediating chemoprevention, cDNA clones representing a gene that is transcriptionally activated by dithiolethiones, hence named dithiolethione-inducible gene-1 (DIG-1), were isolated from rat liver via differential hybridization screening. The deduced amino acid sequence of DIG-1 was found to have 80% identity with the human liver enzyme leukotriene B4 (LTB4) 12-hydroxydehydrogenase. DIG-1, purified >400-fold from the liver of rats dosed with 1,2-dithiole-3-dithiolethione, possessed an NADP+-dependent activity to convert LTB4 to 12-oxo-LTB4. Kinetic analysis of DIG-1 revealed apparent Km and Vmax values of 28 mM and 8.1 nmol 12-oxo-LTB4 formed/min/mg purified protein respectively. Since LTB4 is a potent chemotactic factor and stimulator of production of reactive oxygen species from neutrophils, the effects of DIG-1 on these LTB4-mediated processes were examined. Pre-incubation of LTB4 with purified rat hepatic DIG-1 greatly diminished LTB4-stimulated migration of neutrophils. In addition, pre-incubation of LTB4 with purified rat hepatic DIG-1 reduced LTB4-stimulated production of superoxide anions in neutrophils, as evidenced by decreased lucigenin-derived chemiluminescence. These results suggest that DIG-1-catalyzed dehydrogenation of LTB4 to 12-oxo-LTB4 inhibits the pro-inflammatory actions of LTB4. Consequently, elevation of LTB4 catabolism via enhanced DIG-1 activity may suppress inflammatory processes implicated in tumorigenesis.


Myocardial ischemia, reperfusion and cytoprotection.
The hypothesis proposed is that ischemic cell death is a metabolic event as evidenced by ischemic contracture. There is a protective role for glycolytic ATP and for some drugs. There must be enough coronary flow to deliver the glucose. It appears that provision of glucose and restoration of blood flow have complementary benefits. Such combinations need exploration in patients.


Sequencing and functional analysis of the SNRPN promoter: in vitro methylation abolishes promoter activity.
The gene encoding the small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) maps to the Prader-Willi syndrome critical region on chromosome 15 and is expressed preferentially from the paternal allele. A CpG island encompassing the first exon of SNRPN is methylated on the inactive maternal allele. DNA sequence was determined for a cosmid containing the first three exons of SNRPN and extending 20 kb upstream and 15 kb downstream from the CpG island. This region is extremely rich in Alu elements and other repetitive sequences and contains a single CpG island, which includes numerous short direct repeat sequences. Functional analysis of the first exon revealed strong promoter activity for a 260-bp fragment extending 207 bp upstream from the exon. In vitro methylation of this 260-bp fragment abolished promoter activity completely, suggesting that the silencing of the maternal SNRPN allele may be a direct consequence of methylation of the promoter region.


Do perioperative antibiotics reduce the risk of surgical-site infections following excision of ulcerated skin cancers? A Critically Appraised Topic.
To review the efficacy of perioperative antibiotics in reducing the risk of surgical-site infections (SSIs) following excision of ulcerated skin cancers. Study selection, data extraction and analysis were carried out independently by four authors. Only randomized controlled trials (RCTs) reported in the English language were included. RCTs in the English language in which patients received perioperative topical, intralesional or oral antibiotics for dermatological surgery, including Mohs micrographic surgery in general practice, dermatology or plastic surgery departments, were included. The proportion of participants developing SSI following excision of skin lesions. Thirteen RCTs were identified from our literature search of PubMed and Embase, which evaluated SSI following use of topical (n = 5), oral (n = 3), intramuscular (n = 2), intravenous (n = 1) and intralesional antibiotics (n = 2) in dermatological surgery. Two RCTs specifically investigated SSIs in ulcerated skin cancer excisions; one RCT investigated the SSI rate following surgical treatment specifically for ulcerated skin cancers in individuals randomized to topical antibiotics vs. oral cephalexin; and one RCT compared intravenous cefazolin with no antibiotic, demonstrating significant reduction in SSI rates for ulcerated tumours (P = 0·04). The heterogeneity of the RCTs included in this study makes it difficult to make a direct comparison of the outcomes measured. High-quality evidence demonstrating a beneficial effect of the use of perioperative antibiotics to prevent SSI following excision of ulcerated skin cancers is lacking. In the absence of an evidence base, we propose that a well-designed multicentre RCT could evaluate the effect of perioperative antibiotics following excision of ulcerated tumours, and potentially reduce inappropriate antibiotic prescription.


Cohesion and conflict: family influences on adolescent alcohol use in immigrant Latino families.
This study examines how cohesion and parent–child conflict relate to alcohol use among Mexican-heritage adolescents. The sample consists of 120 adolescents (14 to 18 years) participants from the Southwest sub-sample of the Latino Acculturation and Health Project. Lifetime and recent alcohol use and binge drinking were tested. Results from the logistic regressions identified high and low levels of family cohesion as a risk factor for alcohol use compared to medium levels of cohesion, and parent–child conflict predicted lifetime use and binge drinking. Low and high family cohesion levels appear to be especially problematic among Mexican adolescents who are trying to navigate two different cultural worlds. Although high family cohesion is often a characteristic of Mexican families, Mexican-heritage adolescents may view high family cohesion as a hindrance to their own independence. Unresolved conflict seems to be connected to children's problem behaviors and alcohol misuse could be utilized by adolescents as a mechanism to reduce emotional distress caused by family tensions.


Complications following limb-threatening lower extremity trauma.
Our objective is to report the nature and incidence of major complications after severe lower extremity trauma. Multicenter, prospective, observational study. Eight level-1 trauma centers. Five hundred forty-five patients were followed for 2 years. Amputation or reconstruction. The type and number of complications associated with these injuries were recorded at baseline, 3-, 6-, 12-, and 24-month intervals. One hundred forty-nine underwent amputation during the initial hospitalization. The revision amputation rate was 5.4%. Among the amputation group, a complication was noted most frequently at 3 months (24.8%), and the most commonly seen complication was wound infection (34.2%). Wound complications including dehiscence (13.4%) were seen more commonly in the amputation group. Three hundred seventy-one limb reconstructions were performed with 25 patients (3.9%) requiring late amputation. The most frequently reported complication was at 6 months for the salvage group (37.7%), and the most commonly seen complication was wound infection (23.2%). Not surprisingly, osteomyelitis (8.6%) and nonunions (31%) were seen more commonly in the salvage group. Complications of wound infection, osteomyelitis, nonunion, malunion, and prominent hardware resulted in rehospitalization in at least one-third of patients. However, patients who underwent reconstruction were more likely to be hospitalized for these complications. Patients with severe lower extremity injuries can expect a significant number of complications, most notably wound infection, nonunion, wound necrosis, and osteomyelitis. A large portion of these will require additional inpatient or operative treatment. Patients electing for reconstruction can expect a higher risk of complications.


IONIZING INFLUENCE OF SALTS WITH TRIVALENT AND TETRAVALENT IONS ON CRYSTALLINE EGG ALBUMIN AT THE ISOELECTRIC POINT.
1. While crystalline egg albumin is highly soluble in water at low temperature at the pH of its isoelectric point, it is coagulated by heating. It has long been known that this coagulation can be prevented by adding either acid or alkali, whereby the protein is ionized. 2. It is shown in this paper that salts with trivalent or tetravalent ions, e.g. LaCl(3) or Na(4)Fe(CN)(6), are also able to prevent the heat coagulation of albumin at the isoelectric point (i.e. pH 4.8), while salts with a divalent ion, e.g. CaCl(2), BaCl(4), Na(2)SO(4), or salts like NaCl, have no such effect. 3. This is in harmony with the fact shown in a preceding paper that salts with trivalent or tetravalent ions can cause the ionization of proteins at its isoelectric point and thus give rise to a membrane potential between micellae of isoelectric protein and surrounding aqueous solution, while the above mentioned salts with divalent and monovalent ions have apparently no such effect.


Nanotechnologies for pathogen detection: Future alternatives?
The development of multiplex and flexible tests allowing the simultaneous analysis of pathogens presenting a transfusional risk is a real challenge. Current miniaturized platforms have been particularly marked by microarrays. These microsystems allow the optical detection of hundreds of individual targets simultaneously. However, they suffer from a low sensitivity and their combination with a preliminary target amplification step such as PCR is necessary. The variable level of expression of the infectious genomes of interest and their large diversity complicate multiplex amplification. Finally simultaneous analysis of multiple blood-transmitted agents poses numerous difficulties in diagnosis that remain unresolved by currently available technologies. Until recently, scientific and technological advances for pathogen detection have focused on target amplification and optical detection steps. Today, sample preparation is recognized as a critical area to improve. Nanotechnologies can reach the single-cell or molecular scale and consequently overcome several current technological obstacles. They offer new technological tools for improving sample preparation but also for avoiding target amplification and the current fluorescent labeling. The combination of nano-objects and nano-systems in current technologies offers new possibilities for potential applications in the detection of infectious agents.


Liver progenitor cells fold up a cell monolayer into a double-layered structure during tubular morphogenesis.
Bile ducts are hepatic tubular structures that are lined by cholangiocytes, a type of liver epithelial cell. Cholangiocytes first form a single layer of cells, termed the ductal plate, surrounding the portal vein, which eventually remodels into the branching tubular network of bile ducts. The process of bile duct morphogenesis is not yet clear: a conventional model where cholangiocytes proliferate to duplicate a single layer of the ductal plate before lumen formation seems inconsistent with the observation that proliferation is dramatically reduced when hepatoblasts, liver progenitor cells, differentiate into cholangiocytes. Here, we developed a new culture system in which a liver progenitor cell line, HPPL, reorganizes from a monolayer to tubular structures in response to being overlaid with a gel containing type I collagen and Matrigel. We found that some of the HPPL in the monolayer depolarized and migrated to fold up the monolayer into a double-cell layer. These morphogenetic processes occurred without cell proliferation and required phosphatidylinositol 3-kinase and Akt activity. Later in morphogenesis, luminal space was generated between the two cell layers. This process, in particular enlargement of the apical lumen, involved transcriptional activity of HNF1beta. Thus, using this sandwich culture system, we could segregate tubulogenesis of bile ducts into distinct steps and found that the PI3K/Akt pathway and HNF1beta regulated different steps of the morphogenesis. Although the process of tubulogenesis in culture specifically resembled early bile duct formation, involvement of these two key players suggests that the sandwich culture might help us to find common principles of tubulogenesis in general.


Biological and regulatory roles of acid-induced small RNA RyeC in Salmonella Typhimurium.
Salmonella Typhimurium is an enteric pathogen that has evolved masterful strategies to enable survival under stress conditions both within and outside a host. The acid tolerance response (ATR) is one such mechanism that enhances the viability of acid adapted bacteria to lethal pH levels. While numerous studies exist on the protein coding components of this response, there is very little data on the roles of small RNAs (sRNAs). These non-coding RNA molecules have recently been shown to play roles as regulators of bacterial stress response and virulence pathways. They function through complementary base pairing interactions with target mRNAs and affect their translation and/or stability. There are also a few that directly bind to proteins by mimicking their respective targets. Here, we identify several sRNAs expressed during the ATR of S. Typhimurium and characterize one highly induced candidate, RyeC. Further, we identify ptsI as a trans-encoded target that is directly regulated by this sRNA. From a functional perspective, over-expression of RyeC in Salmonella produced a general attenuation of several in vitro phenotypes including acid survival, motility, adhesion and invasion of epithelial cell lines as well as replication within macrophages. Together, this study highlights the diverse roles played by sRNAs in acid tolerance and virulence of S. Typhimurium.


FDA Approval Summary: Mirvetuximab Soravtansine-Gynx for FRα-Positive, Platinum-Resistant Ovarian Cancer.
On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.


Efficacy and safety of ixekizumab in patients with plaque psoriasis across different degrees of disease severity: results from UNCOVER-2 and UNCOVER-3.
To evaluate short- and long-term efficacy and safety of ixekizumab in patients according to psoriasis severity. Data were integrated from clinical trials (UNCOVER-2, UNCOVER-3). Patients received placebo, 80-mg ixekizumab every 2 weeks (IXEQ2W), every 4 weeks (IXEQ4W), or 50 mg etanercept (ETN) biweekly for 12 weeks, then open-label IXEQ4W (UNCOVER-3). Psoriasis severity was categorized by baseline Psoriasis Area and Severity Index (PASI <20 and ≥20). Efficacy was evaluated by percentage reaching PASI 75, 90, 100, and absolute PASI ≤5, ≤2, and ≤1. Significantly more patients with PASI ≥20 (vs. PASI <20) were male and had higher body weight. After 12 weeks, both severity groups had significantly more IXEQ2W- than ETN-treated patients reach PASI 75, 90, 100, and absolute PASI ≤5, ≤2, ≤1. Fewer PASI ≥20 vs. PASI <20 patients across treatments reached PASI ≤5, ≤2, and ≤1 at week 12. Efficacy was maintained during 156 weeks of ixekizumab treatment with no differences between groups. The IXEQ2W safety profile was similar between groups except for injection-site reactions (significantly higher in PASI <20). Ixekizumab demonstrated a high level of efficacy and had a consistent safety profile in patients with different baseline psoriasis severity levels.


[Ultrastructure of pancreatic acinar cells under the influence of pancreozymin, serotonin and histamine].
The pancreas was removed from male white mice given intraperitoneally pancreozymin (2 i. u./kg and 4 i. u./kg), serotonin (0.2 and 0.4 mg/kg) or histamine (0.1 mg/kg) within 5--10 min. Pancreozymin caused hypertrophy of the Golgi zone and the appearance of multivesicular bodies. Serotonin induced an intensive autophagia in the apical parts of acinar cells. The effect of histamine was revealed in the rapidity of the extrusion of zymogen granules and the dilatation of cisterns of granular cytoplasmatic reticulum. Possible physiological significance of the ultrastructural alterations of acinar cells is discussed.


The fibrotic response of primary liver spheroids recapitulates in vivo hepatic stellate cell activation.
A major obstacle in the development of efficient therapies for progressive liver fibrosis is the lack of representative in vitro models of liver fibrosis to aid in understanding the mechanisms of the disease and to promote the development of pharmaceuticals. Our aim was to develop a relevant in vitro mouse liver fibrosis model, based on the central hypothesis that liver fibrosis in vitro cannot be studied using only hepatic stellate cells (HSCs)-the main producer of scar tissue during fibrosis-, but requires cultures in which at least hepatocytes are integrated. We established robust methods to generate co-culture spheroids from freshly isolated mouse hepatocytes and HSCs. Characteristics and functionality of these spheroids were analyzed by qPCR of cell-type specific markers, CYP induction and immunohistochemistry. Compound toxicity was determined by ATP-assays. Hepatocytes and HSCs maintained their cell-type specific marker expression over a 15-day culture period without major hepatocyte dedifferentiation or HSC activation. Exposure of spheroids to TGFβ can directly activate HSCs, while acetaminophen exposure mounts a hepatocyte damage dependent activation of HSCs. Pharmaceuticals with known anti-fibrotic properties, such as Valproic acid and Verteporfin, reduce HSC activation in response to hepatocyte damage in these cultures. A comparison between the fibrotic response of the spheroid co-cultures and in vivo activated HSCs showed that these 3D co-cultures are more representative than the commonly used 2D HSC monocultures. Finally, we showed that the 3D cultures can be integrated in microfluidic chips. We conclude that our hepatocyte-stellate cell-spheroid cultures are a robust in vitro model of liver fibrosis. This model could be used to further unravel the mechanism of HSC activation and facilitate the discovery of, or testing for novel anti-fibrotic compounds, as these spheroids better reproduce HSC in vivo activation compared to the more traditional 2D mono-culture models.


Repetitive noxious neonatal stimuli increases dentate gyrus cell proliferation and hippocampal brain-derived neurotrophic factor levels.
Neonatal noxious stimulation has been proposed to model pain triggered by diagnostic/therapeutic invasive procedures in premature infants. Previous studies have shown that hippocampal neurogenesis rate and the behavioral repertoire of adult rats may be altered by neonatal noxious stimuli. The purpose of this study was to evaluate whether noxious stimulation during neonatal period alters the nociceptive response and dentate gyrus neurogenesis when compared to rats subjected to a single noxious stimulus in late infancy. Plasma corticosterone and hippocampal brain-derived neurotrophic factor (BDNF) levels were measured. Neurogenesis in the dentate gyrus was evaluated in adolescent rats (postnatal day 40; P40) exposed twice to intra-plantar injections of Complete Freund's adjuvant (CFA) on P1 and P21 (group P1P21) or P8 and P21 (P8P21) or exposed once on P21 (pubertal). On P21, one subset of animals received 5-bromo-2'-deoxyuridine (BrdU) and was euthanized on P40 for identification of proliferating cells in the dentate gyrus. Another subset was sampled for thermal response or plasma corticosterone measurement and hippocampal BDNF levels. Proliferative cell rate in dentate gyrus was the highest in all re-exposed groups (P < 0.001), except for P8 females (P8P21F), revealing also a sex difference, where P8P21 males showed higher rate than females (P < 0.001). Stimulated groups took longer than CTL animals to lick the paws (P < 0.001), regardless of the age when the noxious stimulus was applied. Re-exposed groups had lower corticosterone plasma level (P1P21 M and F, P8P21M) than controls. On the contrary, hippocampal BDNF was increased in males from both re-exposed groups. These results show that infant noxious stimulation in neonatally previously stimulated rats is related to high proliferation in the DG and this association seems to be modified by the animal's sex. The new generated dentate granule cells in the hippocampus may have a role in the long-term behavioral responses to neonatal nociceptive stimulation. Noxious stimulation in the neonatal period results in sex-dependent neurogenic response.


Travel Time to Health Facilities as a Marker of Geographical Accessibility Across Heterogeneous Land Coverage in Peru.
To better estimate the travel time to the most proximate health care facility (HCF) and determine differences across heterogeneous land coverage types, this study explored the use of a novel cloud-based geospatial modeling approach. Geospatial data of 145,134 cities and villages and 8,067 HCF were gathered with land coverage types, roads and river networks, and digital elevation data to produce high-resolution (30 m) estimates of travel time to HCFs across Peru. This study estimated important variations in travel time to HCFs between urban and rural settings and major land coverage types in Peru. The median travel time to primary, secondary, and tertiary HCFs was 1.9-, 2.3-, and 2.2-fold higher in rural than urban settings, respectively. This study provides a new methodology to estimate the travel time to HCFs as a tool to enhance the understanding and characterization of the profiles of accessibility to HCFs in low- and middle-income countries.


[Epidemiology of meningitis, pneumonia and acute otitis due to Streptococcus pneumoniae in pediatric in Italy].
Streptococcus pneumoniae is one of the most important bacterial pathogens in pediatrics, both from a quantitative and from a qualitative point of view. It can cause severe diseases such as occult bacteremia, sepsis, meningitis and it is also involved in the determination of a relevant part of very common illnesses such as pneumonia, acute otitis media and rhinosinusitis. However, most of the data regarding the epidemiology of pneumococcal infections in pediatrics have been collected in the U.S.A. and in other industrialized Countries different from Italy. In Italy only studies concerning meningitis and the carrier state of pneumococcus are at the moment available. They indicate that also in Italy S. pneumoniae seems to play a significant role in the determination of several pediatric diseases and that quite similar are the group of serotypes mainly involved in the determination of both invasive and not invasive diseases.


Examining the Factors Influencing Orthopedic Physician's Decision to Purchase Medical Devices: Evidence from Kuwait.
It is explanatory and descriptive research to explain the relationship among factors influencing the orthopedic physician's decision of purchasing medical devices and equipment. Quantitative method will be used in this study as all heads of departments in MOH hospitals refused to make one-to-one interviews and suggested only questionnaires that will be high in confidentiality. For the first question: What is the ranking of factors that influence orthopedic physician decision in purchasing medical devices and equipment in MOH hospitals in Kuwait? According to HB analysis, the most preferred attribute is implant review in a journal and the lowest preferred factor is product training. Moreover, Brand was the second preferred attribute followed by leader influence. Surprisingly, price came after all these attributes. Physicians ranked technical support and sponsorship in the fifth and sixth places. For the second question: How can marketing and sales management predict orthopedic physicians' decisions before designing product proposals? This will assist M&S department in creating proposals that satisfy orthopedic physicians through expecting their decisions on various alternatives. There is a good opportunity for all medical devices companies, after discussion with SMEs, either for growth or leaving stagnation phase. However, SMEs have no real understanding of what factors matter to the orthopedic physicians' decision in purchasing medical devices and equipment. Thus, one of the goals of this research is to give M&S departments in medical devices companies with recommendations that will help them in forming attractive product offers to orthopedic physicians in MOH hospitals in Kuwait. Moreover, predicting the response from them in the future. In addition, four simulation scenarios have been conducted in this research to reach the best economic offer that maintains physicians attracted.


[Vermilion reconstruction after dog bite injuries].
Dog bite injuries often concern the lips. In children, injuries of the face are most common, but also in adults so-called kissing injuries frequently happen. All-layer defects are treated by wedge excision in minor cases and by myocutaneous flaps in major cases of lower lip injuries, whereas upper lip defects are reconstructed by exchange flaps. If only the vermilion is concerned, mucosal flaps according to the von Esmarch technique yield very good aesthetic results with excellent function and without impairment of the mouth opening.


The tyrosine kinase Csk dimerizes through Its SH3 domain.
The Src family kinases possess two sites of tyrosine phosphorylation that are critical to the regulation of kinase activity. Autophosphorylation on an activation loop tyrosine residue (Tyr 416 in commonly used chicken c-Src numbering) increases catalytic activity, while phosphorylation of a C-terminal tyrosine (Tyr 527 in c-Src) inhibits activity. The latter modification is achieved by the tyrosine kinase Csk (C-terminal Src Kinase), but the complete inactivation of the Src family kinases also requires the dephosphorylation of the activation loop tyrosine. The SH3 domain of Csk recruits the tyrosine phosphatase PEP, allowing for the coordinated inhibition of Src family kinase activity. We have discovered that Csk forms homodimers through interactions mediated by the SH3 domain in a manner that buries the recognition surface for SH3 ligands. The formation of this dimer would therefore block the recruitment of tyrosine phosphatases and may have important implications for the regulation of Src kinase activity.


Monoclonal antibodies for carcinoembryonic antigen and related antigens as a model system: a systematic approach for the determination of epitope specificities of monoclonal antibodies.
A systematic approach for the determination of epitope specificities of monoclonal antibodies to a complex antigen system is described. After initial screening to identify antigen-binding monoclonal antibodies, one or more of the clones are isolated by limiting dilution cloning, grown in ascites, and the resulting antibodies secreted into the ascitic fluid are affinity purified on Sepharose-bound protein A, radiolabeled, and cross-compared with antibodies from other clones by a solid-phase competitive immunoassay. In this work, BALB/c mice were immunized with either purified carcinoembryonic antigen (CEA) or the CEA-producing cell line HC 84S. Spleen cells were fused with the mouse myeloma cell line Sp2/0-Ag14. The supernatants from 25 hybrids showed a significant binding of 125I-CEA (greater than or equal to 15%). Nine hybrids were cloned, resulting in 33 different clones. The antibodies produced by the different cloned hybrids and the remaining uncloned hybrids recognized a total of five different epitopes on CEA. All of the epitopes reside on the protein moiety of the molecule as determined by antibody binding to deglycosylated CEA. The monoclonal antibodies with five different epitope specificities were reacted with tissue sections of normal and cancerous tissues and with peripheral blood smears. Each of the five monoclonal antibodies reacted with tissue sections from colonic, gastric, lung, and mammary carcinomas, as well as from a benign colonic polyp and a resection margin from a colonic carcinoma. Four monoclonals reacted with normal liver tissue. Granulocytes in peripheral blood smears bound three antibodies strongly and one antibody weakly, and one antibody was not bound. One monoclonal antibody that reacted with normal liver tissue was not bound by granulocytes. The ability of these five monoclonal antibodies to differentially detect three different CEA-related antigens in normal and malignant tissues may have clinical utility.


A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19(+) tumor cells.
To harness the potent tumor-killing capacity of T cells for the treatment of CD19(+) malignancies, we constructed AFM11, a humanized tetravalent bispecific CD19/CD3 tandem diabody (TandAb) consisting solely of Fv domains. The molecule exhibits good manufacturability and stability properties. AFM11 has 2 binding sites for CD3 and 2 for CD19, an antigen that is expressed from early B cell development through differentiation into plasma cells, and is an attractive alternative to CD20 as a target for the development of therapeutic antibodies to treat B cell malignancies. Comparison of the binding and cytotoxicity of AFM11 with those of a tandem scFv bispecific T cell engager (BiTE) molecule targeting the same antigens revealed that AFM11 elicited more potent in vitro B cell lysis. Though possessing high affinity to CD3, the TandAb mediates serial-killing of CD19(+) cells with little dependence of potency or efficacy upon effector:target ratio, unlike the BiTE. The advantage of the TandAb over the BiTE was most pronounced at lower effector:target ratios. AFM11 mediated strictly target-dependent T cell activation evidenced by CD25 and CD69 induction, proliferation, and cytokine release, notwithstanding bivalent CD3 engagement. In a NOD/scid xenograft model, AFM11 induced dose-dependent growth inhibition of Raji tumors in vivo, and radiolabeled TandAb exhibited excellent localization to tumor but not to normal tissue. After intravenous administration in mice, half-life ranged from 18.4 to 22.9 h. In a human ex vivo B-cell chronic lymphocytic leukemia study, AFM11 exhibited substantial cytotoxic activity in an autologous setting. Thus, AFM11 may represent a promising therapeutic for treatment of CD19(+) malignancies with an advantageous safety risk profile and anticipated dosing regimen.


Racial discrimination and socioemotional and sleep problems in a cross-sectional survey of Australian school students.
To determine the prevalence of direct and vicarious racial discrimination experiences from peer, school and societal sources, and examine associations between these experiences and socioemotional and sleep outcomes. Data were analysed from a population representative cross-sectional study of n=4664 school students in years 5-9 (10-15 years of age) in Australia. Students reported direct experiences of racial discrimination from peers, school and societal sources; vicarious discrimination was measured according to the frequency of witnessing other students experiences of racial discrimination. Students self-reported on the Strengths and Difficulties Questionnaire, with the total difficulties, conduct, emotional and prosocial behaviour subscales examined. Sleep problems included duration, latency, and disruption. 41.56% (95% CI 36.18 to 47.15) of students reported experiences of direct racial discrimination; Indigenous and ethnic minority students reported the highest levels. 70.15% (95% CI 63.83 to 75.78) of students reported vicarious racial discrimination. Direct and vicarious experiences of racial discrimination were associated with socioemotional adjustment (eg, for total difficulties, total direct racism: beta=3.77, 95% CI 3.11 to 4.44; vicarious racism: beta=2.51, 95% CI 2.00 to 3.03). Strong evidence was also found for an effect of direct and vicarious discrimination on sleep (eg, for sleep duration, total direct: beta=-21.04, 95% CI -37.67 to -4.40; vicarious: beta=-9.82, 95% CI -13.78 to -5.86). Experiences of direct and vicarious racial discrimination are common for students from Indigenous and ethnic minority backgrounds, and are associated with socioemotional and sleep problems in adolescence. Racism and racial discrimination are critically important to tackle as social determinants of health for children and adolescents.


Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia.
Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders. We assayed 276 publicly available 'tag' single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS). Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL. Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.


Evidence-based pathways to intervention for children with language disorders.
Paediatric speech and language therapist (SLT) roles often involve planning individualized intervention for specific children, working collaboratively with families and education staff, providing advice, training and coaching and raising awareness. A tiered approach to service delivery is currently recommended whereby services become increasingly specialized and individualized for children with greater needs. To stimulate discussion regarding delivery of SLT services by examining evidence regarding the effectiveness of (1) intervention for children with language disorders at different tiers and (2) SLT roles within these tiers; and to propose an evidence-based model of SLT service delivery and a flowchart to aid clinical decision-making. Meta-analyses and systematic reviews, together with controlled, peer-reviewed group studies where recent systematic reviews were not available, of interventions for children with language disorders are discussed, alongside the differing roles SLTs play in these interventions. Gaps in the evidence base are highlighted. The service-delivery model presented resembles the tiered model commonly used in education services, but divides individualized (Tier 3) services into Tier 3A: indirect intervention delivered by non-SLTs, and Tier 3B: direct intervention by an SLT. We report evidence for intervention effectiveness, which children might best be served by each tier, the role SLTs could take within each tier and the effectiveness of these roles. Regarding universal interventions provided to all children (Tier 1) and those targeted at children with language weaknesses or vulnerabilities (Tier 2), there is growing evidence that approaches led by education services can be effective when staff are highly trained and well supported. There is currently limited evidence regarding additional benefit of SLT-specific roles at Tiers 1 and 2. With regard to individualized intervention (Tier 3), children with complex or pervasive language disorders can progress following direct individualized intervention (Tier 3B), whereas children with milder or less pervasive difficulties can make progress when intervention is managed by an SLT, but delivered indirectly by others (Tier 3A), provided they are well trained and supported, and closely monitored. SLTs have a contribution to make at all tiers, but where prioritization for clinical services is a necessity, we need to establish the relative benefits and cost-effectiveness at each tier. Good evidence exists for SLTs delivering direct individualized intervention and we should ensure that this is available to children with pervasive and/or complex language disorders. In cases where service models are being provided which lack evidence, we strongly recommend that SLTs investigate the effectiveness of their approaches.


An efficient method to determine double Gaussian fluence parameters in the eclipse™ proton pencil beam model.
To find an efficient method to configure the proton fluence for a commercial proton pencil beam scanning (PBS) treatment planning system (TPS). An in-water dose kernel was developed to mimic the dose kernel of the pencil beam convolution superposition algorithm, which is part of the commercial proton beam therapy planning software, eclipse™ (Varian Medical Systems, Palo Alto, CA). The field size factor (FSF) was calculated based on the spot profile reconstructed by the in-house dose kernel. The workflow of using FSFs to find the desirable proton fluence is presented. The in-house derived spot profile and FSF were validated by a direct comparison with those calculated by the eclipse TPS. The validation included 420 comparisons of the FSFs from 14 proton energies, various field sizes from 2 to 20 cm and various depths from 20% to 80% of proton range. The relative in-water lateral profiles between the in-house calculation and the eclipse TPS agree very well even at the level of 10-4. The FSFs between the in-house calculation and the eclipse TPS also agree well. The maximum deviation is within 0.5%, and the standard deviation is less than 0.1%. The authors' method significantly reduced the time to find the desirable proton fluences of the clinical energies. The method is extensively validated and can be applied to any proton centers using PBS and the eclipse TPS.


Shared heritability and functional enrichment across six solid cancers.
Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10-8), breast and ovarian cancer (rg = 0.24, p = 7 × 10-5), breast and lung cancer (rg = 0.18, p =1.5 × 10-6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.


[Observation on therapeutic effect of moxibustion on temperature-sensitive points for lumbar disc herniation].
To compare therapeutic effects of traditional moxibustion and moxibustion on temperature-sensitive points for lumbar disc herniation. One hundred and twenty cases were randomly divided into a temperature-sensitive point group and a traditional moxibustion group, 60 cases in each group. The temperature-sensitive point group was treated with moxibustion on the temperature-sensitive points in the temperature-sensitive high incidence area such as waist and lower limbs, once each day; the traditional moxibustion group was treated with warming moxibustion at Jiaji (EX-B 2), Ciliao (BL 32), Zhibian (BL 54), Huantiao (GB 30), Weizhong (BL 40), Yanglingquan (GB 34), Kunlun (BI. 60), once each day, 7 days constituting one course. The therapeutic effect and the recurrence rate were observed after one course treatment and six months later. After treatment for one course, the cured-markedly effective rate was 65.00% in the temperature-sensitive point group, superior to 50.0% in the traditional moxibustion group, with a significant difference between the two groups (P < 0.05); all effective cases were followed-up for six months, the cured-markedly effective rate and the recurrence rate were 62.3% and 26.4% in the temperature-sensitive point group, and 34.2% and 46.3% in the traditional moxibustion group, the therapeutic effect of the temperature-sensitive point group being superior to the traditional moxibustion group, and the recurrence rate was lower than the traditional moxibustion group (both P < 0.05). Moxibustion on temperature-sensitive points is a effective therapy for lumbar disc herniation, with stable therapeutic effect and low recurrence rate.


[Characteristics of postural corrective responses before and after long-term spaceflight].
Balance function is dramatically deteriorated after exposure to microgravity. The purpose of the present study was to investigate the role and the contribution of different gravity sensory systems to the development of balance impairment after long-term spaceflights. Postural perturbations (pushes to the chest) of the threshold, medium, and sub-maximal intensities were produced in eight cosmonauts before, and on the day 3, 7, and 11 following spaceflight. Postural corrective responses were analyzed by anterior-posterior body sway fluctuation and electromyographic activity of leg muscles. The characteristics of the postural corrective responses changed significantly on the day 3 following spaceflight: the amplitude of posterior sway caused by perturbation of threshold intensity was increased reaching 135% ofpreflight value; the corrective responses lasted more than 6 s in 50% of all trials, while it did not last more than 4 s in 96% before spaceflight. The EMG responses were characterized by increased contribution of medium- and long-latency reactions. On the day 11 following spaceflight, most of the characteristics of postural corrective responses were close to preflight values. We assumed that the balance alterations after spaceflight are caused by changes in weightlessness of functions of two main gravity sensory systems, namely, weight-bearing and vestibular one. The deficit of weight-bearing afferentation triggers a decline of the extensors' muscle tone, while changes of vestibular function cause a decline of accuracy of postural corrections.


Par3/Par6 polarity complex coordinates apical ectoplasmic specialization and blood-testis barrier restructuring during spermatogenesis.
The Par3/Par6/aPKC and the CRB3/Pals1/PATJ polarity complexes are involved in regulating apical ectoplasmic specialization (ES) and blood-testis barrier (BTB) restructuring in the testis. Par6 was a component of the apical ES and the BTB. However, its level was considerably diminished at both sites at stage VIII of the cycle. Par6 also formed a stable complex with Pals1 and JAM-C (a component of the apical ES) in normal testes. When rats were treated with adjudin to induce apical ES restructuring without compromising the BTB, Par6 staining virtually disappeared at the apical ES in misaligned spermatids before their depletion. Additionally, the Par6/Pals1 complex became tightly associated with Src kinase, rendering a loss of association of the Par6/Pals1 complex with JAM-C, thereby destabilizing apical ES to facilitate spermatid loss. Primary Sertoli cell cultures with established functional BTB, but without apical ES, were next used to assess the Par6-based complex on BTB dynamics. When either Par6 or Par3 was knocked down by RNAi in Sertoli cell epithelium, a significant loss of the corresponding protein by approximately 60% in cells vs. controls was detected, alongside with a decline in aPKC after Par6, but not Par3, knockdown. This Par3 or Par6 knockdown also led to a transient loss of selected BTB proteins at the cell-cell interface, thereby compromising the BTB integrity. These findings illustrate that the Par6/Par3-based polarity complex likely coordinates the events of apical ES and BTB restructuring that take place concurrently at the opposing ends of adjacent Sertoli cells in the seminiferous epithelium during spermatogenesis.


The retention of advanced cardiac life support knowledge among registered nurses.
In an investigation into the retention of advanced cardiac life support (ACLS) knowledge over time, the authors found that ACLS scores significantly decreased for a subgroup of a sample of 40 RNs employed in critical care areas in the first year after certification. Several variables that influenced scores were identified. Recommendations for inservice educators include reconstructing the ways in which ACLS courses are taught, conducting mock mega code scenarios every 6 months, constructing mega code scenarios that reflect the reality of practice, and routinely conducting refresher courses based on problems identified in a particular group.


[The effectiveness of lamotrigine in a case of ring chromosome 14 with refractory epilepsy].
A 25-month old boy was admitted to our hospital due to intractable seizures and developmental retardation. At birth, the patient's head circumference was within normal limits and development appeared normal until approximately six months of age, when symptoms of mental and motor retardation, and microcephaly, gradually appeared. From three months of age, refractory complex partial seizures, secondary generalization of partial seizures, and convulsive status epilepticus occurred. Electroencephalograms (EEGs) taken prior to the patient's referral to our hospital displayed focal spikes at the right occipital region, and at 25 months of age, EEGs showed focal fast activity in the same region. Abnormalities were not detected in the patient's MRI and there was no congenital malformation. Chromosome analysis (G-banding) revealed 46, XY, r (14) (p13q32.3) [28]/45, XY, -14 [2], mosaic ring chromosome 14, and monosomy 14. Clinical experience has shown that even in the absence of malformations, children with developmental delay and refractory seizures may have chromosomal abnormalities, and this was true for our patient. Although consistent clinical characteristics of ring chromosome 14 have not yet been described, the refractory partial seizures that began in early infancy, and the gradual appearance of developmental delay with acquired microcephaly exhibited by our patient are characteristic. However, the patient's refractory seizures have been completely suppressed through an add-on therapy consisting of a relatively low dose of lamotrigine (0.7 mg/kg/day), despite the likely aggravating effect of topiramate.