GOAL: automated Gene Ontology analysis of expression profiles.
One of the most common problems encountered while deciphering results from expression profiling experiments is in relating differential expression of genes to molecular functions and cellular processes. A second important problem is that of comparing experiments performed by different labs using different microarray platforms, or even unrelated techniques. Gene Ontology (GO) is now used to describe biological features, since GO terms are associated with genes, to overcome the apparent distance between expression profiles and biological comprehension. Here we describe the development, implementation and use of GOAL (Gene Ontology Automated Lexicon), a web-based application for the identification of functions and processes regulated in microarray and SAGE (serial analysis of gene expression) experiments. We applied GOAL to a range of experimental datasets related to different biological problems, including cancer and the cell cycle. By using GOAL, reported and novel relevant processes were identified in a number of experiments by our collaborators and by us. Different datasets could also be compared with each other to define conserved functional modules. GOAL allows a seamless and high-level analysis of expression profiles and is implemented as a free WWW resource (http://microarrays.unife.it).


A review of bioanalytical techniques for evaluation of cannabis (Marijuana, weed, Hashish) in human hair.
Cannabis products (marijuana, weed, hashish) are among the most widely abused psychoactive drugs in the world, due to their euphorigenic and anxiolytic properties. Recently, hair analysis is of great interest in analytical, clinical, and forensic sciences due to its non-invasiveness, negligible risk of infection and tampering, facile storage, and a wider window of detection. Hair analysis is now widely accepted as evidence in courts around the world. Hair analysis is very feasible to complement saliva, blood tests, and urinalysis. In this review, we have focused on state of the art in hair analysis of cannabis with particular attention to hair sample preparation for cannabis analysis involving pulverization, extraction and screening techniques followed by confirmatory tests (e.g., GC-MS and LC-MS/MS). We have reviewed the literature for the past 10 years' period with special emphasis on cannabis quantification using mass spectrometry. The pros and cons of all the published methods have also been discussed along with the prospective future of cannabis analysis.


Threat Responsiveness as a Function of Cannabis and Alcohol Use Disorder Severity.
Objective: Two of the most commonly abused substances by adolescents in the United States are alcohol and cannabis, both of which are associated with adverse medical and psychiatric outcomes throughout the lifespan. Both are assumed to impact the development of emotional processing although findings on the direction of this impact have been mixed. Preclinical animal work and some functional magnetic resonance imaging (fMRI) work with humans have suggested cannabis use disorder (CUD) and alcohol use disorder (AUD) are associated with increased threat responsiveness. However, other fMRI work has indicated CUD/AUD are associated with diminished threat responsiveness. In this study, we report on a study examining the relationship of severity of CUD/AUD and threat responsiveness in an adolescent population. Methods: The study involved 87 (43 male) adolescents with varying levels of CUD/AUD symptomatology (N = 45 above clinical cutoffs for CUD or AUD). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding. Results: Increasing levels of CUD symptomatology were associated with decreased responding to looming stimuli within regions, including rostral frontal and fusiform gyrus as well as the amygdala. There were no relationships with AUD symptomatology. Conclusions: These data indicate that CUD in particular is associated with a decrease in responsiveness to the looming threat cue possibly relating to the putative neurotoxic impact of cannabis abuse.


Aromatase/Seladin-1 Interactions in Human Neuronal Cell Culture, the Hippocampus of Healthy Rats and Transgenic Alzheimer's Disease Mice.
Decreasing levels of aromatase and seladin-1 could be one of the molecular mechanisms of Alzheimer's disease (AD). Aromatase is an enzyme that catalyzes estrogen biosynthesis from androgen precursors, and seladin-1 is an enzyme that converts desmosterol to cholesterol, which is the precursor of all hormones. Verifying the potential relationship between these proteins and accordingly determining new therapeutic targets constitute the aims of this study. Changes in protein levels were compared in vitro in aromatase and seladin-1 inhibitor-administered human neuroblastoma (SH-SY5Y) cells in vivo in intracerebroventricular (icv) aromatase or seladin-1 inhibitor-administered rats, as well as in transgenic AD mice in which the genes encoding these proteins were knocked out. In the cell cultures, we observed that seladin-1 protein levels increased after aromatase enzyme inhibition. The hippocampal aromatase protein levels decreased following chronic seladin-1 inhibition in icv inhibitor-administered rats; however, the aromatase levels in the dentate gyrus of seladin-1 knockout (SelKO) AD male mice increased. These findings indicate a partial relationship between these proteins and their roles in AD pathology.


Functional effects of antipsychotic drugs: comparing clozapine with haloperidol.
Using positron emission tomography (PET) with (15)O water, we compared regional cerebral blood flow (rCBF) patterns induced by clozapine or haloperidol in individuals with schizophrenia. Based on the known clinical characteristics of each drug, we hypothesized that brain regions where the drugs show similar rCBF patterns are among those mediating their antipsychotic actions; whereas, regions where the drugs produce different rCBF patterns are among those mediating their different drug actions, namely, haloperidol's motor side effects or clozapine's unique therapeutic action. Persons with schizophrenia were scanned using PET with (15)O water, first after withdrawal of all psychotropic medication (n = 6), then again after treatment with therapeutic doses of haloperidol (n = 5) or clozapine (n = 5). Both drugs increased rCBF in the ventral striatum and decreased rCBF in hippocampus and ventrolateral frontal cortex. The rCBF increase associated with haloperidol was greater than that with clozapine in the dorsal and ventral striatum; the rCBF increase with clozapine was greater than that with haloperidol in cortical regions, including anterior cingulate and dorsolateral frontal cortex. These data suggest that the rCBF increase in ventral striatum and/or the decrease in hippocampus and/or ventrolateral frontal cortex mediate a common component of antipsychotic action of these drugs. The increased rCBF in dorsal striatum by haloperidol could well be associated with its prominent motor side effects, whereas the increased rCBF in the anterior cingulate or dorsolateral frontal cortex may mediate the superior antipsychotic action of clozapine. The proposals based on these preliminary observations require further study.


The structural brain correlates of neurological soft signs in AESOP first-episode psychoses study.
Patients with schizophrenia and related psychoses have an excess of minor neurological abnormalities (neurological soft signs) of unclear neuropathological origin. These include poor motor coordination, sensory perceptual difficulties and difficulties in sequencing complex motor tasks. Neurological soft signs seem not to reflect primary tract or nuclear pathology. It still has to be established whether neurological soft signs result from specific or diffuse brain structural abnormalities. Studying their anatomical correlates can provide not only a better understanding of the aetiopathogenesis of soft signs, but also of the pathophysiology of schizophrenia. Surprisingly few studies have investigated the brain correlates of neurological soft signs. In the present study, we investigated the relationship between brain structure and neurological soft signs in an epidemiologically based sample of 77 first-episode psychosis patients. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and voxel-based methods of image analysis to investigate brain structure. Higher rates of soft neurological signs (both motor and sensory) were associated with a reduction of grey matter volume of subcortical structures (putamen, globus pallidus and thalamus). Signs of sensory integration deficits were additionally associated with volume reduction in the cerebral cortex, including the precentral, superior and middle temporal, and lingual gyri. Neurological soft signs and their associated brain changes were independent of antipsychotic exposure. We conclude that neurological soft signs are associated with regional grey matter volume changes and that they may represent a clinical sign of the perturbed cortical-subcortical connectivity that putatively underlies psychotic disorders.


Coercion: an understudied issue in mental health.
Coercion in mental health services is a controversial practice, yet it is a relatively understudied area. This special themed edition draws upon research from the international community with the aim of addressing issues related to coercion and involuntary admission. The issue covers topics such as community treatment orders, service users' perspectives, alternative models of involving service users in their treatment, and future directions for coercion research. It is hoped that this edition will encourage funding and inspire future research on this important topic.


Serology for hepatitis B and C, HIV and syphilis in the initial evaluation of diabetes patients referred for an external nephrology consultation.
Information is available regarding the prevalence and incidence of positive microbiological serology results both in the general population and in patients on haemodialysis in Spain. Nevertheless, little information is known regarding patients with diabetes attended in external nephrology consultations. To evaluate the percentage of patients with positive serology results for hepatitis B and C, Human Immunodeficiency Virus (HIV), and syphilis in the initial assessment of patients referred to diabetic nephropathy external consultations. Retrospective study of 500 patients assessed over the course of 5 years with the diagnosis of diabetic nephropathy originating in external consultations and for which hepatitis B, C, HIV, and syphilis serology had been requested. With regard to hepatitis B virus, 0.4% of patients had chronic hepatitis B, 10.2% had overcome the hepatitis and were in recovery, and 4.2% had received the hepatitis B vaccine. As for hepatitis C, 2.4% of the patients studied had antibodies against hepatitis C. With regard to syphilis, 0.8% of patients had positive serological results. No patients had positive HIV serology results. Despite major methodological limitations, this would be the first study to evaluate the microbiological serology of diabetic nephropathy patients treated in external consultations.


Effects of native species diversity and resource additions on invader impact.
Theory and empirical work have demonstrated that diverse communities can inhibit invasion. Yet, it is unclear how diversity influences invader impact, how impact varies among exotics, and what the relative importance of diversity is versus extrinsic factors that themselves can influence invasion. To address these issues, we established plant assemblages that varied in native species and functional richness and crossed this gradient in diversity with resource (water) addition. Identical assemblages were either uninvaded or invaded with one of three exotic forbs: spotted knapweed (Centaurea maculosa), dalmatian toadflax (Linaria dalmatica), or sulfur cinquefoil (Potentilla recta). To determine impacts, we measured the effects of exotics on native biomass and, for spotted knapweed, on soil moisture and nitrogen levels. Assemblages with high species richness were less invaded and less impacted than less diverse assemblages. Impact scaled with exotic biomass; spotted knapweed had the largest impact on native biomass compared with the other exotics. Although invasion depressed native biomass, the net result was to increase total community yield. Water addition increased invasibility (for knapweed only) but had no effect on invader impact. Together, these results suggest that diversity inhibits invasion and reduces impact more than resource additions facilitate invasion or impact.


Bioremediation of pharmaceuticals, pesticides, and petrochemicals with gomeya/cow dung.
Use and misuse of pharmaceuticals, pesticides, and petrochemicals by man is causing havoc with nature, as they persist as such or as their toxic metabolites. These pollutants bioaccumulate in environment, and they ultimately reach man through various means. They are hazardous because of potential toxicity, mutagenicity, carcinogenicity, and genotoxicity. To rejuvenate nature, remediation methods currently available are usually expensive and might convert one toxic pollutant to another. Bioremediation methods use naturally occurring microorganisms to detoxify man-made pollutants so that they change pollutants to innocuous products that make soil fertile in the process. Taking cue from Ayurveda, Gomeya/cow dung is used as an excellent bioremediation method. Thus, utilizing freely available cow dung as slurry or after composting in rural areas, is a cheap and effective measure to bioremediate the harmful pollutants. Yet, more research in this direction is warranted to bioremediate nonbiodegradable, potentially toxic pollutants.


Efficacy and safety of supraclavicular and pectoralis nerve blocks as primary peri-procedural analgesia for cardiac electronic device implantation: A pilot study.
Cardiac implantable electronic devices (CIEDs) are routinely implanted using intravenous drugs for sedation. However, some patients are poor candidates for intravenous sedation. We present a case series demonstrating the safety and efficacy of a novel, ultrasound-guided nerve block technique that allows for pre-pectoral CIED implantation. The targets are the supraclavicular nerve (SCN) and pectoral nerve (PECS1). We enrolled 20 patients who were planned for new CIED implantation. Following US-localization of the SCN and PECS1, local anesthetic (LA) was instilled at least 30-60 min pre-procedure. Successful nerve block was determined if < 5 mL of intraprocedural LA was used, along with lack of sensation with skin and deep tissue pinprick. Optional sedation was offered to patients' pre-procedure if discomfort was reported. Seventeen patients (85%) had a successful periprocedural nerve block, with only three patients exceeding 5 mL of LA. SCN and PECS1 success occurred in 19 (95%) and 18 (90%) patients, respectively. The overall success of nerve block by fulfilling all the criteria was demonstrated in 17 out of 20 patients (85%). Patients who reported no pain (VAS score = 0) were distributed as follows: 13 patients (65%) in the immediate post-procedure interval, 18 patients (90%) at the 1 h post-implant interval, and 14 patients (70%) at the 24 h post- implant interval. The median cumulative VAS score was 0 (IQR = 0 - 1). There were no reported significant adverse effects. SCN and PECS1 nerve blocks are safe and effective for patients undergoing CIED implantation to minimize or eliminate the use of intravenous sedation.


Use of nitrogen-fixing bacteria as biofertiliser for non-legumes: prospects and challenges.
The potential of nitrogen-fixing (NF) bacteria to form a symbiotic relationship with leguminous plants and fix atmospheric nitrogen has been exploited in the field to meet the nitrogen requirement of the latter. This phenomenon provides an alternative to the use of the nitrogenous fertiliser whose excessive and imbalanced use over the decades has contributed to green house emission (N2O) and underground water leaching. Recently, it was observed that non-leguminous plants like rice, sugarcane, wheat and maize form an extended niche for various species of NF bacteria. These bacteria thrive within the plant, successfully colonizing roots, stems and leaves. During the association, the invading bacteria benefit the acquired host with a marked increase in plant growth, vigor and yield. With increasing population, the demand of non-leguminous plant products is growing. In this regard, the richness of NF flora within non-leguminous plants and extent of their interaction with the host definitely shows a ray of hope in developing an ecofriendly alternative to the nitrogenous fertilisers. In this review, we have discussed the association of NF bacteria with various non-leguminous plants emphasizing on their potential to promote host plant growth and yield. In addition, plant growth-promoting traits observed in these NF bacteria and their mode of interaction with the host plant have been described briefly.


Automated analysis of cell-matrix adhesions in 2D and 3D environments.
Cell-matrix adhesions are of great interest because of their contribution to numerous biological processes, including cell migration, differentiation, proliferation, survival, tissue morphogenesis, wound healing, and tumorigenesis. Adhesions are dynamic structures that are classically defined on two-dimensional (2D) substrates, though the need to analyze adhesions in more physiologic three-dimensional (3D) environments is being increasingly recognized. However, progress has been greatly hampered by the lack of available tools to analyze adhesions in 3D environments. To address this need, we have developed a platform for the automated analysis, segmentation, and tracking of adhesions (PAASTA) based on an open source MATLAB framework, CellAnimation. PAASTA enables the rapid analysis of adhesion dynamics and many other adhesion characteristics, such as lifetime, size, and location, in 3D environments and on traditional 2D substrates. We manually validate PAASTA and utilize it to quantify rate constants for adhesion assembly and disassembly as well as adhesion lifetime and size in 3D matrices. PAASTA will be a valuable tool for characterizing adhesions and for deciphering the molecular mechanisms that regulate adhesion dynamics in 3D environments.


Methods for evaluation of antiviral efficacy against influenza virus infections in animal models.
Compounds undergoing preclinical development for anti-influenza virus activity require evaluation in small animal models. Laboratory mice are most commonly used for initial studies because of size, cost, and availability. Cotton rats, guinea pigs, and ferrets (particularly) have been used for more advanced studies. Each animal infection model has certain limitations relative to human influenza infections. For example, the fever response that is evident in humans only occurs with consistency in ferrets. Mice infected with mouse-adapted viruses and ferrets infected with highly pathogenic avian influenza viruses suffer severe disease, whereas cotton rats and guinea pigs manifest few symptoms. Thus, for each animal model there is a certain set of disease parameters that can be measured. Here we describe methods for assessing the efficacy of anti-influenza virus compounds in each of these animal species.


Evaluation of the use of blood in surgeries as a tool to change patterns for requesting blood product reserves.
Thirty to sixty percent of prepared blood products are not transfused. Blood reserves for surgeries lead to many unused blood products, which increases hospital costs. The aim of this study is to identify the request and use profiles of blood products for elective surgeries in different surgical specialties, the influence of surgery time and demographic, clinical, and laboratory variables on the number of red blood cells (RBCs) used and to calculate the rate of transfused patients (RTP) and cross-matched and transfused (C/T) RBCs. Observational and prospective studies. Sociodemographic, clinical and quantitative data on the request and use of blood products were collected. The influence of the data on the use of RBCs was examined by binary logistic regression. Chi-square, one-way ANOVA and Kruskal-Wallis tests were utilized to compare the data among the specialties. In total, 822 procedures were included. Most of the requested blood products were not used, even 24 hours postoperatively. Of the 2,483 RBC units, 314 were transfused, leaving 87.6% unused; however, cardiac, digestive tract, vascular, gynecologic, urologic and thoracic surgery procedures transfused 50%, 25%, 16.5%, 11%, 9.5% and 8.1% of requested RBCs, respectively. The factors that influenced the transfusions were age, time of surgery and cardiac surgeries. The RTP was >10% in 22 surgical types and <1% in 24 surgical types, and 88% of samples presented a C/T ratio >2.5. The RTP and C/T ratios can guide RBC requests in the preoperative period. Knowing the standard of use of blood products and developing protocols enables the optimization of reserves, reduction of costs and improvement of care.


How others perceive orthognathic patients: an eye-tracking study.
To test the hypothesis that the faces of patients with a severe Class III are contemplated differently from and assessed more negatively than skeletal Class I patients in direct face-to-face interaction. The eye movements of 24 randomly recruited evaluators were analyzed with a noninvasive, infrared high-speed camera while looking at 18 standardized frontal photographs of adult orthognathic Class III patients and 18 photographs of adults with skeletal Class I relationships as controls. Additionally, all images were assessed for appearance, symmetry, and facial expression. The Class III patients were rated significantly more negatively in terms of appearance, symmetry, and facial expression than the Class I individuals. The eye movement data revealed that orthognathic patients were appraised differently from the Class I individuals, with fewer fixations in the face center, especially around the mouth. Skeletal Class III patients were characterized as less attractive than Class I individuals. Faces of Class III patients were visually perceived with different eye movements. These differences in visual perception are described for the first time in the present study. Although they were small, they are an indication of an objectively different perception of faces that are rated subjectively as less attractive and more asymmetric and exhibiting a more negative expression.


Hepatitis C antibody testing among opioid agonist therapy recipients, Victoria, Australia, 2012 to 2020.
The high burden of hepatitis C among people who inject drugs in Australia underscores the need to increase testing within this population. Understanding hepatitis C screening uptake in primary care settings is therefore critical to the development of effective and targeted strategies to improve hepatitis C testing for people who inject drugs. Primary care services that prescribe OAT are well-positioned to provide hepatitis C testing among a priority population at-risk of hepatitis C. This study used linked data from 5,429 individuals attending ten clinical services participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance (ACCESS) who received their first recorded OAT prescription between 1st January 2012 and 31st December 2019. We estimated the proportion of OAT recipients who received a hepatitis C antibody test within 12 months of their first recorded OAT prescription, and the proportion of individuals tested who received a positive hepatitis C antibody test. Approximately one in five individuals (17%) received a hepatitis C antibody test in the 12 months following their first recorded OAT prescription. Over half of individuals tested (56%) received a positive hepatitis C antibody test result. Hepatitis C antibody testing was higher among individuals who attended 5-8 (aOR:2.98; 95%CI:2.41-3.69) and 9+ (aOR:6.17; 95%CI:5.13-7.43) clinical consultations, were women (aOR:1.20; 95%CI:1.08-1.34) and whose first recorded OAT prescription occurred in 2017 vs. 2012 (aOR:1.39; 95%CI:1.06-1.84). Hepatitis C antibody testing was lower among individuals prescribed methadone (aOR:0.81; 95%CI:0.73-0.91), and individuals aged 60+ years vs. 18-29 years (aOR:0.67; 95%CI:0.48-0.94). Despite high positivity rates, hepatitis C antibody testing among individuals prescribed OAT remains low. There are opportunities for increased testing among populations exhibiting greater proportions of missed testing opportunities. Integrating routine hepatitis C screening in OAT settings will likely increase case-finding and contribute to Australia's hepatitis C elimination targets.


Twelve tips for teaching medical students about female genital mutilation (FGM).
This article was migrated. The article was marked as recommended. Background: Seeing women or girls from FGM practising communities can be a challenge for healthcare professionals, involving a complex interplay of professional duties, legal requirements, social and cultural understanding, and sensitive, skilled communication. Aims and methods: Robust training on how to identify and support women and girlswho have undergone or who are at risk of FGM , including fulfilling FGM-related legal duties,is essential for healthcare professionals. We believe it is important that this training begins in medical school so that junior doctors feel prepared to talk to women and girls from FGM practising communities as soon as they qualify and start work. Results: We have reviewed the limited existing literature on teaching medical and other healthcare students about FGM and have drawn on our many years of providing well-evaluated teaching sessions on FGM at UCL Medical School to design twelve tips as a blueprint for running sensitive and effective undergraduate teaching on FGM. Conclusions: Effective teaching for medical students on FGM is important and feasible . Curricula leads and individual teachers will benefit from a structured, comprehensive and culturally sensitive approach outlined in the twelve tips.


Size Effects of the Anions in the Ionothermal Synthesis of Carbon Nitride Materials.
Semiconducting carbon nitride polymers are used in metal-free photocatalysts and in opto-electronic devices. Conventionally, they are obtained using thermal and ionothermal syntheses in inscrutable, closed systems and therefore, their condensation behavior is poorly understood. Here, the synthetic protocols and properties are compared for two types of carbon nitride materials - 2D layered poly(triazine imide) (PTI) and hydrogen-bonded melem hydrate - obtained from three low-melting salt eutectics taken from the systematic series of the alkali metal halides: LiCl/KCl, LiBr/KBr, and LiI/KI. The size of the anion plays a significant role in the formation process of the condensed carbon nitride polymers, and it suggests a strong templating effect. The smaller anions (chloride and bromide) become incorporated into triazine (C3 N3 )-based PTI frameworks. The larger iodide does not stabilize the formation of a triazine-based polymer, but instead it leads to the formation of the heptazine (C6 N7 )-based hydrogen-bonded melem hydrate as the main crystalline phase. Melem hydrate, obtained as single-crystalline powders, was compared with PTI in photocatalytic hydrogen evolution from water and in an OLED device. Further, the emergence of each carbon nitride species from its corresponding salt eutectic was rationalized via density functional theory calculations. This study highlights the possibilities to further tailor the properties of eutectic salt melts for ionothermal synthesis of organic functional materials.


Neonatal systemic candidiasis in a tertiary care centre.
The purpose of this study was to identify infections causing Candida spp. and to examine their susceptibility to antifungal drugs. The study examined 30 isolates of Candida spp. grown from blood culture samples of neonates. Clinical histories revealed that all 30 infants had received systemic broad-spectrum antibiotic therapy, 27/30 were low birth weight, 21/30 suffered from respiratory distress syndrome and 23/30 were preterm. The three species of Candida isolated were Candida albicans (16/30, 53.3%), C. tropicalis (7/30,23.3%), and C. krusei (7/30, 23.3%). Antifungal susceptibility tests against fluconazole and amphotericin B were done based on the NCCLS guidelines for antifungal susceptibility testing. The fluconazole resistance pattern was as follows: 1/16 (6.25%) strain of C. albicans was susceptible, 12/16 (75%) strains were dose dependent susceptibles, and 3/16 (18.75%) were resistant to fluconazole. Among Candida tropicalis, 2/7(29%) strains were susceptible, 4/7 (55.5%) dose dependent susceptible and 1/7 (14.5%) were resistant. All strains of C. krusei were resistant to fluconazole. There was no resistance to amphotericin B.


Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.
Mutations in the Pfmdr1 gene are reported to be associated with chloroquine resistance in some Plasmodium falciparum isolates. A polymerase chain reaction/restriction fragment length polymorphism method was used for the detection of Pfmdr1 mutations in chloroquine-resistant field isolates of P. falciparum collected in Irian Jaya. The frequency of Pfmdr1 mutations was significantly higher in chloroquine-resistant P. falciparum parasites than background frequencies observed in the same location. The 7G8 mutation was identified in some parasites although always in a mixed genotype status. Chloroquine-resistant P. falciparum specimens were characterized using the World Health Organization 28-day criteria, supplemented by demonstrating adequate chloroquine absorption and genetic analysis.


Perioperative and Long-Term Outcome for Intrahepatic Cholangiocarcinoma: Impact of Major Versus Minor Hepatectomy.
The objective of the current study was to investigate both short- and long-term outcomes of patients undergoing curative-intent resection for intrahepatic cholangiocarcinoma (ICC) stratified by extent of hepatic resection relative to overall final pathological margin status. One thousand twenty-three patients with ICC who underwent curative-intent resection were identified from a multi-institutional database. Demographic, clinicopathological, and operative data, as well as overall (OS) and recurrence-free survival (RFS) were compared among patients undergoing major and minor resection before and after propensity score matching. Overall, 608 (59.4%) patients underwent major hepatectomy, while 415 (40.6%) had a minor resection. Major hepatectomy was more frequently performed among patients who had large, multiple, and bilobar tumors. Roughly half of patients (n = 294, 48.4%) developed a postoperative complication following major hepatectomy versus only one fourth of patients (n = 113, 27.2%) after minor resection (p < 0.001). In the propensity model, patients who underwent major hepatectomy had an equivalent OS and RFS versus patients who had a minor hepatectomy (median OS, 38 vs. 37 months, p = 0.556; and median RFS, 20 vs. 18 months, p = 0.635). Patients undergoing major resection had comparable OS and RFS with wide surgical margin (≥10 and 5-9 mm), but improved RFS when surgical margin was narrow (1-4 mm) versus minor resection in the propensity model. In the Cox regression model, tumor characteristics and surgical margin were independently associated with long-term outcome. Major hepatectomy for ICC was not associated with an overall survival benefit, yet was associated with increased perioperative morbidity. Margin width, rather than the extent of resection, affected long-term outcomes. Radical parenchymal-sparing resection should be advocated if a margin clearance of ≥5 mm can be achieved.


Magnesium supplementation alleviates premenstrual symptoms of fluid retention.
We investigated the effect of a daily supplement of 200 mg of magnesium (as MgO) for two menstrual cycles on the severity of premenstrual symptoms in a randomized, double-blind, placebo-controlled, crossover study. A daily supplement of 200 mg of Mg (as MgO) or placebo was administered for two menstrual cycles to each volunteer, who kept a daily record of her symptoms, using a 4-point scale in a menstrual diary of 22 items. Symptoms were grouped into six categories: PMS-A (anxiety), PMS-C (craving), PMS-D (depression), PMS-H (hydration), PMS-O (other), and PMS-T (total overall symptoms). Urinary Mg output/24 hours was estimated from spot samples using the Mg/creatinine ratio. Analysis of variance for 38 women showed no effect of Mg supplementation compared with placebo in any category in the first month of supplementation. In the second month there was a greater reduction (p = 0.009) of symptoms of PMS-H (weight gain, swelling of extremities, breast tenderness, abdominal bloating) with Mg supplementation compared with placebo. Compliance to supplementation was confirmed by the greater mean estimated 24-hour urinary output of Mg (p = 0.013) during Mg supplementation (100.8 mg) compared with placebo (74.1 mg). A daily supplement of 200 mg of Mg (as MgO) reduced mild premenstrual symptoms of fluid retention in the second cycle of administration.


WAGR syndrome with tetralogy of Fallot and hydrocephalus.
Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome occurs sporadically due to deletion of chromosome 11p13. A variety of other abnormalities involving different systems have been reported in patients with WAGR syndrome. We report on a patient with WAGR syndrome with accompanying tetralogy of Fallot and hydrocephalus.


Effects of extrusion, boiling, autoclaving, and microwave heating on lupine allergenicity.
Lupine flour has been reported as a causative agent of allergic reactions. However, the allergenicity of lupine after thermal processing is not well-known. For this purpose, the allergenic characteristics of lupine seeds after boiling (up to 60 min), autoclaving (121 degrees C, 1.18 atm, up to 20 min and 138 degrees C, 2.56 atm, up to 30 min), microwave heating (30 min), and extrusion cooking were studied. The IgE-binding capacity was analyzed by IgE-immunoblotting and CAP inhibition using a serum pool from 23 patients with lupine-specific IgE. Skin testing was carried out in four patients. An important reduction in allergenicity after autoclaving at 138 degrees C for 20 min was observed. IgE antibodies from two individual sera recognized bands at 23 and 29 kDa in autoclaved samples at 138 degrees C for 20 min. Autoclaving for 30 min abolished the IgE binding to these two components. A previously undetected band at 70 kDa was recognized by an individual serum. Therefore, prolonged autoclaving might have an important effect on the allergenicity of lupine with the majority of patients lacking IgE reactivity to these processed samples.


Site staff perspectives on communicating trial results to participants: Cost and feasibility results from the Show RESPECT cluster randomised, factorial, mixed-methods trial.
Sharing trial results with participants is an ethical imperative but often does not happen. Show RESPECT (ISRCTN96189403) tested ways of sharing results with participants in an ovarian cancer trial (ISRCTN10356387). Sharing results via a printed summary improved patient satisfaction. Little is known about staff experience and the costs of communicating results with participants. We report the costs of communication approaches used in Show RESPECT and the views of site staff on these approaches. We allocated 43 hospitals (sites) to share results with trial participants through one of eight intervention combinations (2 × 2 × 2 factorial; enhanced versus basic webpage, printed summary versus no printed summary, email list invitation versus no invitation). Questionnaires elicited data from staff involved in sharing results. Open- and closed-ended questions covered resources used to share results and site staff perspectives on the approaches used. Semi-structured interviews were conducted. Interview and free-text data were analysed thematically. The mean additional site costs per participant from each intervention were estimated jointly as main effects by linear regression. We received questionnaires from 68 staff from 41 sites and interviewed 11 site staff. Sites allocated to the printed summary had mean total site costs of sharing results £13.71/patient higher (95% confidence interval (CI): -3.19, 30.60; p = 0.108) than sites allocated no printed summary. Sites allocated to the enhanced webpage had mean total site costs £1.91/patient higher (95% CI: -14, 18.74; p = 0.819) than sites allocated to the basic webpage. Sites allocated to the email list had costs £2.87/patient lower (95% CI: -19.70, 13.95; p = 0.731) than sites allocated to no email list. Most of these costs were staff time for mailing information and handling patients' queries. Most site staff reported no concerns about how they had shared results (88%) and no challenges (76%). Most (83%) found it easy to answer queries from patients about the results and thought the way they were allocated to share results with participants would be an acceptable standard approach (76%), with 79% saying they would follow the same approach for future trials. There were no significant effects of the randomised interventions on these outcomes. Site staff emphasised the importance of preparing patients to receive the results, including giving opt-in/opt-out options, and the need to offer further support, particularly if the results could confuse or distress some patients. Adding a printed summary to a webpage (which significantly improved participant satisfaction) may increase costs to sites by ~£14/patient, which is modest in relation to the cost of trials. The Show RESPECT communication interventions were feasible to implement. This information could help future trials ensure they have sufficient resources to share results with participants.


Cerebral Cavernous Malformations: Patient-Reported Outcome Validates Conservative Management.
Cerebral cavernous malformations (CCM) are clusters of dilated sinusoidal channels lined by a single layer of endothelium. In contradistinction to arteriovenous malformations, these lesions do not have smooth muscle or elastin in their lining and they are angiographically occult, and the MRI is the most sensitive test for CCM detection. CCM are one of the most prevalent vascular malformations of the central nervous system, affecting about 0.4-0.6% of the general population. The main complication of this malformation is the risk of bleeding, which may cause neurological deficits that affect the quality of life (QoL) in patients. When symtomatic, they may be surgically treated for relieving the mass effect and seizures refractory to drug uses, hemorrhage and drug-refractory epilepsy. Patient-reported outcome (PRO) may be a strategy that can be used to evaluate QoL of CCM population and was used in a sample of non-operated patients. An observational, cross-sectional analysis to evaluate the PRO using the SF-36 and EuroQol 5 dimensions (EQ-5D) questionnaires of QoL added to functional metrics using the Karnofsky Performance Status (KPS) in 49 patients not submitted to intervention and with long-term follow-up. During the 364 person-years of follow-up, there was an average of individual follow-up of 7.42 years. The mean age was 46.8 years (18-84) - 57% of them were female, 71% had superficial lesions, and 65% had the familial form. Comparisons of SF-36 dimensions with KPS graded <100 had a worse score only in terms of the pain (p = 0.04), vitality (p = 0.001), and general state of health (p = 0.03) domains. The domain mental health was worse in patients without surgical indication (p = 0.032). The functional capacity domain had the highest overall grading in the group. The EQ-5D dimensions of mobility (p = 0.03) and pain/discomfort (p = 0.001) were the ones with lower score compared to KPS <100. The study is the first to evaluate, with validated tools, the PRO of non-operated CCM patients and has demonstrated in a selected group of patients that it was possible to achieve long-term clinical stability, thereby maintaining QoL and functional neurological outcome.


Silver nanoparticle loaded PLGA composite nanoparticles for improving therapeutic efficacy of recombinant IFNγ by targeting the cell surface.
The field of medical science has advanced significantly with the discoveries of new drugs and the development of sophisticated biomedical tools; still cancer therapy remains one of the major hurdles currently. Herein, we report a new approach, which exhibits complementary anti-cancer effects of recombinant IFNγ protein and silver nanoparticles (Ag NPs) when loaded together in PLGA composite NPs (GST IFNγ-Ag PLGA NPs). IFNγ acts as an antiviral and tumoricidal agent. To augment therapeutic efficacy, IFNγ was cloned, purified as GST tagged IFNγ recombinant protein, and immobilized on the composite NPs preloaded with Ag NPs. The NPs were characterized using UV-vis spectroscopy, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM) and dynamic light scattering (DLS) analysis. Finally, the composite NPs were delivered into two different human cancer cell types, HeLa (cervical cancer) and MCF-7 (breast cancer) cells. Our results demonstrated that the recombinant IFNγ could block the cell cycle at the G1 phase and its anticancer activity could be potentiated in the presence of Ag NPs. The interaction between the recombinant IFNγ with its cell surface receptors facilitated the delivery of the composite NPs, and thus the combination of the duos ultimately led to induction of apoptosis in the cancer cells.


Is Post-discharge Rehabilitation Timing Associated with 90-Day Readmission in Primary Total Joint Arthroplasty?
Physical therapy (PT) is an accepted standard of care after total joint arthroplasty (TJA) and essential to maximizing joint functionality and minimizing complications that lead to readmission. However, evidence-based guidelines about appropriate post-discharge rehabilitative care are not well-defined in the orthopedic literature. We sought to determine the average timing for receiving PT rehabilitation and to evaluate the association between PT rehabilitation timing and unplanned readmission within 90 days of a TJA patient being discharged home from acute care. This retrospective study examined 11,545 joint procedures using claims data for the years 2008 to 2013. Outcomes were assessed using a population-averaged approach to regression models. The average time for initiating PT was 4 days for knee arthroplasty and 6 days for hip arthroplasty in patients discharged home from acute care. Most patients (89%) began PT consultation or supervised exercises during the first week after discharge. The type of joint surgery considerably modified the effect of rehabilitation timing on the likelihood of readmission. Later initiation of rehabilitation was associated with a higher probability of 90-day readmission in both knee and hip arthroplasty, with the effect of rehabilitation timing being more pronounced in hip rather than knee arthroplasty 2 weeks post-discharge from acute care. Timing for initiating PT may be an important modifiable factor that can affect readmission in patients discharged home from acute care after TJA. Further exploration of the role of PT timing along with other factors such as dosage and frequency among such patients is needed.


Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke.
Ischaemic stroke is a frequent heterogeneous multifactorial disease that is affected by a number of genetic mutations and environmental factors. We hypothesised the clinical importance of the interactions between common, unfavourable genetic mutations and clinical risk factors in the development of ischaemic stroke. The Factor V Leiden G1691A (Leiden V), the prothrombin G20210A, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutations, the angiotensin converting enzyme I/D (ACE I/D), and apolipoprotein allele e4 (APO e4) genotypes were examined by the polymerase chain reaction (PCR) technique in 867 ischaemic stroke patients and 743 healthy controls. Logistic regression models were used to estimate the roles of the co-occurrences of the clinical risk factors and common genetic mutations in ischaemic stroke. The Leiden V mutation in combination with hypertension or diabetes mellitus increased the risk of ischaemic stroke. We found synergistic effects between the ACE D/D and MTHFR 677TT genotypes and drinking or smoking. The presence of the APO e4 greatly facilitated the unfavourable effects of hypertension, diabetes mellitus, smoking, or drinking on the incidence of ischaemic stroke. In certain combinations, pairing of common unfavourable genetic factors, which alone confer only minor or non-significant risk, with clinical risk factors can greatly increase the susceptibility to ischaemic stroke.


Thymoquinone poly (lactide-co-glycolide) nanoparticles exhibit enhanced anti-proliferative, anti-inflammatory, and chemosensitization potential.
Thymoquinone (TQ), derived from the medicinal spice Nigella sativa (also called black cumin), has been shown to exhibit anti-inflammatory and anti-cancer activities. In this report we employed polymer-based nanoparticle approach to improve upon its effectiveness and bioavailability. TQ was encapsulated with 97.5% efficiency in biodegradable nanoparticulate formulation based on poly (lactide-co-glycolide) (PLGA) and the stabilizer polyethylene glycol (PEG)-5000. Dynamic laser light scattering and transmission electron microscopy confirmed particle diameter between 150 and 200nm. Electrophoretic gel shift mobility assay showed that TQ nanoparticles (NP) were more active than TQ in inhibiting NF-kappaB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), those are markers of cell proliferation, metastasis and angiogenesis, respectively. TQ-NP were also more potent than TQ in suppressing proliferation of colon cancer, breast cancer, prostate cancer, and multiple myeloma cells. Esterase staining for plasma membrane integrity revealed that TQ-NP were more potent than TQ in sensitizing leukemic cells to TNF- and paclitaxel-induced apoptosis. Overall our results demonstrate that encapsulation of TQ into nanoparticles enhances its anti-proliferative, anti-inflammatory, and chemosensitizing effects.


Ability of sagittal kinematic variables to estimate ground reaction forces and joint kinetics in running.
Controlled laboratory study, cross-sectional design. To determine if sagittal kinematic variables can be used to estimate select running kinetics. Excessive loading during running has been implicated in a variety of injuries, yet this information is typically not assessed during a standard clinical examination. Developing a clinically feasible strategy to estimate ground reaction forces and joint kinetics may improve the ability to identify those at an increased risk of injury. Three-dimensional kinematics and ground reaction forces of 45 participants were recorded during treadmill running at self-selected speed. Kinematic variables used to estimate specific kinetic metrics included vertical excursion of the center of mass, foot inclination angle at initial contact, horizontal distance between the center of mass and heel at initial contact, knee flexion angle at initial contact, and peak knee flexion angle during stance. Linear mixed-effects models were fitted to explore the association between the kinetic and kinematic measures, including step rate and sex, with final models created using backward variable selection. Models were developed to estimate peak knee extensor moment (R(2) = 0.43), energy absorbed at the knee during loading response (R(2) = 0.58), peak patellofemoral joint reaction force (R(2) = 0.55), peak vertical ground reaction force (R(2) = 0.48), braking impulse (R(2) = 0.50), and average vertical loading rate (R(2) = 0.04). Our findings suggest that insights into important running kinetics can be obtained from a subset of sagittal plane kinematics common to a clinical running analysis. Of note, the limb posture at initial contact influenced subsequent loading patterns in stance.


The protective effect of character maturity in child aggressive antisocial behavior.
Childhood aggressive antisocial behavior (CD) is one of the strongest predictors of mental health problems and criminal behavior in adulthood. The aims of this study were to describe personality profiles in children with CD, and to determine the strength of association between defined neurodevelopmental symptoms, dimensions of character maturity and CD. A sample of 1886 children with a close to equal distribution of age (9 or 12) and gender, enriched for neurodevelopmental and psychiatric problems were selected from the nationwide Child and Adolescent Twin Study in Sweden. Their parents rated them according to the Junior Temperament and Character Inventory following a telephone interview during which information about the children's development and mental health was assessed with the Autism-Tics, AD/HD and other Comorbidities inventory. Scores on the CD module significantly and positively correlated with scores on the Novelty Seeking temperament dimension and negatively with scores on character maturity (Self-Directedness and Cooperativeness). In the group of children with either neurodevelopmental or behavioral problems, the prevalence of low or very low character maturity was 50%, while when these two problems coexisted the prevalence of low or very low character maturity increased to 70%. Neurodevelopmental problems (such as: oppositional defiant disorder, symptoms of attention deficit/hyperactivity disorder and autism spectrum disorder) and low scores on character maturity emerged as independently significant predictors of CD; in a multivariable model, only oppositional defiant symptoms and impulsivity significantly increased the risk for coexisting CD while a mature self-agency in a child (Self-Directedness) remained a significant protective factor. These results suggest that children's willpower, the capacity to achieve personally chosen goals may be an important protective factor - even in the presence of neurodevelopmental and psychiatric problems - against progressing into persistent negative outcomes, such as aggressive antisocial behaviors.


Women Veterans' Barriers to Care-Seeking for Cardiovascular Disease Prevention.
Women veterans have a high prevalence of traditional and nontraditional risks for cardiovascular disease (CVD) including obesity and posttraumatic stress disorder. Experts from the U.S. Department of Veterans Affairs have called for actions to improve the cardiovascular health of this population. One approach is to assess women veterans' barriers to care-seeking for CVD prevention, to inform future intervention research. The objective of this study was to describe women veterans' barriers to care-seeking for CVD prevention, guided by the theory of care-seeking behavior and concept awareness. Using a cross-sectional, descriptive design, a national sample of 245 women veterans participated in an online survey about barriers to care-seeking. Participants provided narrative responses to open-ended items, endorsements to closed-ended items, and rankings of their top five barriers. Researchers conducted poststratification weighting of numerical data to reflect the women veteran population. Narrative responses described unaffordable and inaccessible services, feeling harassed or not respected in healthcare settings, and lack of awareness of risks for CVD. Frequently endorsed barriers were unaffordable and inaccessible services. Frequently ranked barriers were feeling not respected in healthcare settings and clinicians not recommending CVD prevention. Findings support concepts in theory of care-seeking behavior and concept awareness. Understanding women veterans' barriers to care-seeking for CVD prevention can inform clinicians and researchers as they address these barriers.


[The clinical and evolutional characteristics of visceral leishmaniasis in patients with HIV infection].
To analyze the clinical features, yield of the diagnostic techniques, and therapeutic response of HIV-associated visceral leishmaniasis (VL), and compare the initial episodes to the relapses. Forty-one episodes of leishmaniasis visceral, diagnosed in 31 HIV-positive patients between 1st February 1992 and 31st January 1996 were reviewed. The prevalence of VL in HIV-positive patients in our center was 4.2%. Fifty-eight percent of the patients had AIDS prior to the diagnosis of VL. Fever was more frequent in the initial episodes than in the relapses (90.3% versus 60%; p < 0.05; OR: 6.2; IC 95%: 0.8-51.5), splenomegaly was more frequent in the relapses (100% versus 71%; p = 0.05). The diagnostic delay was longer in the initial episodes (27.2 +/- 22.7 versus 5 +/- 4.8 days; p < 0.05). The diagnostic yield of bone marrow biopsy was 82.1%, of liver biopsy 72.7% and of splenic fine-needle aspiration 87.5%. The indirect immunofluorescence test for Leishmania antibodies was positive in 5.9% of cases. Therapeutic failure occurred in 47.6% of patients treated with antimonials and 3.3% of patients treated with amphotericin B. Those patients who received secondary prophylaxis had less relapses than those who did not (17.6% versus 66.7%; p < 0.05; OR: 0.11; IC 95%: 0.01-1.28). Of the 31 patients, twenty-six (83.8%) died, and in none of them was the cause of the death directly related to LV. HIV-associated VL manifests clinically in a similar fashion to the immunocompetent's disease. It appears in advanced immunosuppression phases, behaving like other AIDS-defining illnesses. In spite of a good therapeutic response the relapse rate is high.


Ubiquitin-Proteasome-Dependent Regulation of Bidirectional Communication between Plastids and the Nucleus.
Plastids are DNA-containing organelles and can have unique differentiation states depending on age, tissue, and environment. Plastid biogenesis is optimized by bidirectional communication between plastids and the nucleus. Import of nuclear-encoded proteins into plastids serves as anterograde signals and vice versa, plastids themselves send retrograde signals to the nucleus, thereby controlling de novo synthesis of nuclear-encoded plastid proteins. Recently, it has become increasingly evident that the ubiquitin-proteasome system regulates both the import of anterograde plastid proteins and retrograde signaling from plastids to the nucleus. Targets of ubiquitin-proteasome regulation include unimported chloroplast precursor proteins in the cytosol, protein translocation machinery at the chloroplast surface, and transcription factors in the nucleus. This review will focus on the mechanism through which the ubiquitin-proteasome system optimizes plastid biogenesis and plant development through the regulation of nuclear-plastid interactions.


Pediatric obesity epidemic: treatment options.
The increasing prevalence of overweight youth in the United States and the associated increase in medical comorbidities has created a growing need for effective weight-management interventions. The recommended treatment for an overweight child to achieve a more healthful weight uses four primary behavioral strategies: (a) reduce energy intake while maintaining optimal nutrient intake to protect growth and development, (b) increase energy expenditure by promoting more physical movement and less sedentary activity, (c) actively engage parents and primary caretakers as agents of change, and (d) facilitate a supportive family environment. Although this approach has the most empirical support, the impact on the pediatric obesity epidemic has been limited, particularly for adolescents with more severe obesity and for African-American, Native-American, and Hispanic children. This has prompted efforts to adapt strategies that have been effective in adult weight management for use in pediatric behavioral intervention programs. These include using motivational interviewing to increase readiness for health behavior changes, modifying the carbohydrate content of children's diets, using culturally appropriate messages and materials, improving cultural competency of health care providers, and using computer-based strategies. Randomized, controlled clinical trials are needed to test the safety and efficacy of these approaches before they can be recommended for clinical practice. Pharmacotherapy and bariatric surgery are more aggressive and historically adult interventions with greater risk that are being considered for severely obese adolescents who have serious obesity-related medical complications and who have failed other more conventional methods.


DNA and protein changes caused by disease in human breast tissues probed by the Kubelka-Munk spectral functional.
Malignant, fibroadenoma, normal and adipose breast tissues were studied using diffuse reflectance spectroscopy. The absorption spectra of the breast tissues were extracted from the diffuse reflectance spectra using the Kubelka-Munk function (K-M function). The spectral features of the K-M function were identified and compared with those of the absorption spectra. The spectral features of the K-M function were assigned to DNA, protein, beta-carotene and hemoglobin (oxygenated and deoxygenated) molecules in the breast tissue. The amplitudes of the K-M function averaged from 275 to 285 nm and from 255 to 265 nm and were found to be different for malignant, fibroadenoma and normal tissues. These differences were attributed to changes in proteins and DNA. A set of critical parameters was determined for separating malignant tissues from fibroadenoma and normal tissues. This approach should hold for other tissue types such as cervix, uterus and colon.


Pitfalls in clinical staging of bladder tumors.
Errors in clinical staging of bladder carcinoma occur in about 50 per cent of patients. Sources of error include (1) a variable assortment of diagnostic studies performed, (2) inexactitudes inherent in the diagnostic measures employed, (3) insufficient corroboration by surgical and pathologic staging, (4) the lack of a satisfactory means for detecting micrometastases, and (5) a generalized confusion regarding the multiple classifications available for clinical staging. More precise clinical staging will be influential in treatment decision-making and in prognosis. Minimum requirements for clinical staging of the primary tumor currently include complete examination, excretory urography, cystoscopy, bimanual examination under anesthesia, and transurethral resection or biopsy. Polycystography, triple contrast cystograpy and arteriography may be helpful occasionally to document muscle invasion. Pedal lymphangiography and lymphography can in selected cases be helpful in detecting otherwise silent nodal involvement in spite of its inability to demonstrate many primary or regional lymph nodes. Familiarity with the above diagnostic options and the advantages and limitations of each is essential for each physician caring for a patient with bladder carcinoma. Conversion to TNM classification for bladder carcinoma that is similar to that of the UICC seems appropriate (1) because of its more rational approach to extent of involement by primary tumor, lymph node and distant sites, and (2) in order for our western hemisphere urologists to communicate better with our colleagues from around the globe. Such a system is now under consideration by a subcommittee of the American Joint Committee on Staging and End Result Reporting.


Hormone replacement and menopausal symptoms following hysterectomy.
Hormone replacement therapy (HRT) is recommended for most women who experience surgical menopause following hysterectomy/oophorectomy for noncancerous conditions; it is also commonly prescribed for postmenopausal women. Beginning in 1992, 1,299 women undergoing hysterectomy in 28 hospitals throughout Maryland were interviewed prior to hysterectomy and were subsequently followed over a 2-year period. Interviews included questions about HRT use and symptoms associated with menopause. The majority of the women (66 percent) were white, 55 percent had a high school education or better, 49 percent were obese (body mass index > or =27.3), and 11 percent were postmenopausal. Over 40 percent of premenopausal women underwent bilateral oophorectomy. At 3 months posthysterectomy, 89 percent of these women were on HRT; this figure dropped to 85 percent at 24 months. Among postmenopausal women, 50 percent were on HRT both at 3 months and at 24 months posthysterectomy. Among premenopausal women who had unilateral oophorectomy, 21 percent were on HRT at 3 months, increasing to 35 percent at 24 months. Among premenopausal women who had no ovaries removed, 5 percent were on HRT at 3 months, increasing to 13 percent at 24 months. There were few within-group differences between HRT users and nonusers, except that among postmenopausal women, HRT users were younger and more likely to be white and had higher income and educational levels. Women who were postmenopausal or who underwent bilateral oophorectomy were less likely to have hot flashes if they were on HRT, but women with 0-1 ovary removed who were on HRT were more likely to have hot flashes than those not on HRT. Black women were significantly more likely to experience hot flashes than were white women, independent of HRT status and weight. Obese women were on HRT at approximately the same rates as nonobese women but were significantly more likely to have hot flashes, even when analyses controlled for HRT and race.


Effects of scanning technique on in vitro performance of CAD/CAM-fabricated fiber posts.
This study assessed push-out strength, cement layer thickness, and interfacial nanoleakage of luted fiber posts fabricated with computer-aided design/computer-assisted manufacture (CAD/CAM) technology after use of 1 of 3 scanning techniques, namely, direct scanning of the post space (DS), scanning of a polyether impression of the post space (IS), and scanning of a plaster model of the post space (MS). Thirty premolars were randomly assigned to three groups corresponding to the scanning technique. Posts were computer-designed and milled from experimental fiber-reinforced composite blocks. The mean (±SD) values for push-out strength and cement thickness were 17.1 ± 7.7 MPa and 162 ± 24 μm, respectively, for DS, 10.7 ± 4.6 MPa and 187 ± 50 μm for IS, and 12.0 ± 7.2 MPa and 258 ± 78 μm for MS specimens. Median (interquartile range) interfacial nanoleakage scores were 3 (2-4) for DS, 2.5 (2-4) for IS, and 3 (2-4) for MS. Post retention was better for fiber posts fabricated by DS technique than for those fabricated by IS and MS. Cement thickness did not differ between DS and IS specimens, but the cement layer was significantly thicker in the MS group than in the other two groups. Scanning technique did not affect sealing ability, as the three groups had comparable nanoleakage values.


Dynamics of Bacterial Signal Recognition Particle at a Single Molecule Level.
We have studied the localization and dynamics of bacterial Ffh, part of the SRP complex, its receptor FtsY, and of ribosomes in the Gamma-proteobacterium Shewanella putrefaciens. Using structured illumination microscopy, we show that ribosomes show a pronounced accumulation at the cell poles, whereas SRP and FtsY are distributed at distinct sites along the cell membrane, but they are not accumulated at the poles. Single molecule dynamics can be explained by assuming that all three proteins/complexes move as three distinguishable mobility fractions: a low mobility/static fraction may be engaged in translation, medium-fast diffusing fractions may be transition states, and high mobility populations likely represent freely diffusing molecules/complexes. Diffusion constants suggest that SRP and FtsY move together with slow-mobile ribosomes. Inhibition of transcription leads to loss of static molecules and reduction of medium-mobile fractions, in favor of freely diffusing subunits, while inhibition of translation appears to stall the medium mobile fractions. Depletion of FtsY leads to aggregation of Ffh, but not to loss of the medium mobile fraction, indicating that Ffh/SRP can bind to ribosomes independently from FtsY. Heat maps visualizing the three distinct diffusive populations show that while static molecules are mostly clustered at the cell membrane, diffusive molecules are localized throughout the cytosol. The medium fast populations show an intermediate pattern of preferential localization, suggesting that SRP/FtsY/ribosome transition states may form within the cytosol to finally find a translocon.


Aquisalibacillus elongatus gen. nov., sp. nov., a moderately halophilic bacterium of the family Bacillaceae isolated from a saline lake.
A novel moderately halophilic, non-motile, rod-shaped bacterium was isolated from a saline lake, Lake Shangmatala, in the Inner Mongolia Autonomous Region, China. This bacterium, designated SH4sT, was strictly aerobic, catalase-positive and oxidase-negative. It grew at salinities of 3-20 % (w/v) NaCl, with an optimum at 10 % (w/v) NaCl. The cell-wall peptidoglycan was of the A4beta type, based on l-Orn-d-Asp, and the major quinone was a menaquinone with seven isoprene units (MK-7). The major fatty acids were iso-C16:0 and iso-C15:0. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, a glycolipid and four different unidentified phospholipids. The DNA G+C content was 45.9 mol%. In a maximum-parsimony phylogenetic tree based on 16S rRNA gene sequences, strain SH4sT was found to belong to the family Bacillaceae and to be most closely related to members of the genera Filobacillus (95.9 % sequence similarity), Piscibacillus (95.7 %) and Tenuibacillus (95.4 %). DNA-DNA hybridization experiments revealed 10 % relatedness (12 %, reciprocally) between strain SH4sT and Filobacillus milosensis DSM 13259T, the sole species of the genus. All of these data show that strain SH4sT represents a novel genus and species in the family Bacillaceae, for which the name Aquisalibacillus elongatus gen. nov., sp. nov. is proposed. The type strain of Aquisalibacillus elongatus is SH4sT (=CCM 7366T =CECT 7149T =DSM 18090T).


Obesity and prostate cancer detection: insights from three national surveys.
Previous studies suggest that obesity is associated with higher prostate cancer progression and mortality despite an association with lower prostate cancer incidence. This study aims to better understand these apparently inconsistent relationships among obese men by combining evidence from 3 nationally representative cross-sectional surveys. We evaluated relationships between obesity and 1) testosterone concentrations in the Third National Health and Nutrition Examination Survey (NHANES III; n=845); 2) prostate-specific antigen (PSA) in NHANES 2001-2004 (n=2458); and 3) prostate biopsy rates in the National Health Interview Survey (NHIS 2000; n=4789) population. Mean testosterone, PSA concentrations, and biopsy rates were computed for Body Mass Index (BMI) categories. Testosterone concentrations were inversely associated with obesity (P-trend <.0001) in NHANES III. In NHANES 2001-2004, obese (BMI >35) versus lean (BMI <25) men were less likely to have PSA concentrations that reached the biopsy threshold of >4 ng/mL (3% vs 8%; P <.0001). Among NHIS participants, all BMI groups had similar rates of PSA testing (P=.24). However, among men who had PSA tests, 11% of men with BMI >30 versus 16% with BMI <25, achieved a PSA threshold of 4 ng/mL; P=.01. Furthermore, biopsy rates were lower among men with BMI >30 versus BMI <25 in NHIS participants (4.6% vs 5.8%; P=.05). Obesity was associated with lower PSA-driven biopsy rates. These data support further studies to test the hypothesis that obesity affects prostate cancer detection independent of prostate cancer risk by decreasing the PSA-driven biopsy rates.


Antimicrobial peptide activity is anticorrelated with lipid a leaflet affinity.
The activity of antimicrobial peptides (AMPs) has significant bacterial species bias, the mechanisms of which are not fully understood. We employed single-molecule tracking to measure the affinity of three different AMPs to hybrid supported bilayers composed of lipid A extracted from four different Gram negative bacteria and observed a strong empirical anticorrelation between the affinity of a particular AMP to a given lipid A layer and the activity of that AMP towards the bacterium from which that lipid A was extracted. This suggested that the species bias of AMP activity is directly related to AMP interactions with bacterial outer membranes, despite the fact that the mechanism of antimicrobial activity occurs at the inner membrane. The trend also suggested that the interactions between AMPs and the outer membrane lipid A (even in the absence of other components, such as lipopolysaccharides) capture effects that are relevant to the minimum inhibitory concentration.


SOHLHs Might Be Gametogenesis-Specific bHLH Transcriptional Regulation Factors in Crassostrea gigas.
The self-renewal and differentiation of germ cells are essential for gametogenesis and reproduction. In mammals, the transcription factors SOHLH1 and SOHLH2, two members of the bHLH family, are specifically expressed in the gonads, and play an important role in spermatocyte and oocyte differentiation. In our previous study, we performed a phylogenetic analysis of the Lophotrochozoa bHLH genes, and two Sohlh were identified in the Pacific oyster Crassostrea gigas. Based on the genomes of other species that have complete genomic information, we further analyzed the phylogenetics of the Sohlh in this study. The results indicate that the Sohlh are ancient genes that were lost in many species during evolution, including in some invertebrates, and lower vertebrates. The phylogenetic tree shows that Sohlh1 and Sohlh2 are located in different scaffolds and that they have low similarity, suggesting early separation in invertebrates. We used RNA-seq and RT-PCR to examine the mRNA expression of the Sohlh in C. gigas (termed Cg-Sohlh), we found that Cg-Sohlh1, and Cg-Sohlh2 are specifically expressed in the gonads. During gonadal development, the mRNA expression levels of both genes increased from the proliferative stage and reached the highest level at the growth stage (P < 0.05). Then, the expression level decreased until the resting stage. In addition, immunohistochemistry was used to determine that the Cg-SOHLH1 protein was specifically expressed in the spermatogonia and spermatocytes. Cg-Sohlh2 mRNA was expressed in both the male and female gonads, while Cg-Sohlh1 mRNA was highly expressed in the female gonads at all developmental stages except for the resting stage. These data indicate that Cg-SOHLH might be gonad-specific regulatory factors, similar to mammalian SOHLH, and that Cg-SOHLH1 might be involved in spermatogonial differentiation. This study lays the foundation to further determine the functional role of SOHLH in mollusk gametogenesis and provides a foundation to better understand the regulatory mechanism of gametogenesis in invertebrates.


Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentration-dependent interaction.
Zidovudine (ZDV) is converted to its active triphosphate (ZDVTP) by intracellular kinases. The intermediate ZDV monophosphate (ZDVMP) is believed to play a major role in ZDV toxicity. Manipulation of ZDV phosphorylation is a possible therapeutic strategy for altering the risk-benefit ratio. Here we investigate whether combining RBV with ZDV is able to modulate efficacy and toxicity of ZDV. We have measured the intracellular activation of ZDV (0.3 microM) in the absence and presence of ribavirin (RBV; 2 and 20 microM) in Molt 4 and U937 cells. MTT cytotoxicity of ZDV (10-1000 microM) was also measured with and without RBV (2 microM) in Molt 4 and U937 cells. Measurement of endogenous deoxythymidine triphosphate (dTTP) allowed investigation of the dTTP/ZDVTP ratio. The antiviral efficacy of ZDV in combination with RBV (2 microM) was assessed by HIV p24 antigen measurements. In the presence of RBV (2 and 20 microM) a decrease in total ZDV phosphates was observed, owing mainly to an effect primarily on ZDVMP rather than the active ZDVTP. RBV also increased endogenous dTTP pools in both cell types, resulting in an increase in the dTTP/ZDVTP ratio. ZDV alone significantly reduced p24 antigen production, with an IC50 of 0.34 microM. Addition of RBV increased the IC50 approximately fivefold (1.52 microM). However, at higher concentrations of ZDV (10 and 100 microM) the antagonistic effect of RBV (2 microM) on ZDV was lost. The RBV-mediated decrease in ZDVMP may explain the reduction in ZDV toxicity when combined with RBV (2 microM). Cytotoxicity of ZDV was reduced in the presence of RBV (2 microM) at all concentrations in both cell lines, probably owing to saturation of ZDVTP formation. The interaction of ZDV and RBV is concentration dependent.


Crystal structure of N-acetyl-gamma-glutamyl-phosphate reductase from Mycobacterium tuberculosis in complex with NADP(+).
The enzyme N-acetyl-gamma-glutamyl-phosphate reductase (AGPR) catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductive dephosphorylation of N-acetyl-gamma-glutamyl-phosphate to N-acetylglutamate-gamma-semialdehyde. This reaction is part of the arginine biosynthetic pathway that is essential for some microorganisms and plants, in particular, for Mycobacterium tuberculosis (Mtb). The structures of apo MtbAGPR in the space groups P2(1)2(1)2(1) and C2 and the structure of MtbAGPR bound to the cofactor NADP(+) have been solved and analyzed. Each MtbAGPR subunit consists of alpha/beta and alpha+beta domains; NADP(+) is bound in the cleft between them. The hydrogen bonds and hydrophobic contacts between the enzyme and cofactor have been examined. Comparison of the apo and the bound enzyme structures has revealed a conformational change in MtbAGPR upon NADP(+) binding. Namely, a loop (Leu88 to His92) moves more than 5 A to confine sterically the cofactor's adenine moiety in a hydrophobic pocket. To identify the catalytically important residues in MtbAGPR, a docking of the substrate to the enzyme has been performed using the present structure of the MtbAGPR/NADP(+) complex. It reveals that residues His217 and His219 could form hydrogen bonds with the docked substrate. In addition, an ion pair could form between the substrate phosphate group and the guanidinium group of Arg114. These interactions optimally place and orient the substrate for subsequent nucleophilic attack by Cys158 on the substrate gamma-carboxyl group. His219 is the most probable general base to accept a proton from Cys158 and an adjacent ion pair interaction with the side-chain carboxyl group of Glu222 could help to stabilize the resulting positive charge on His219. For this catalytic triad to function efficiently it requires a small conformational change of the order of 1 A in the loop containing His217 and His219; this could easily result from the substrate binding.


Targeting methanopterin biosynthesis to inhibit methanogenesis.
This paper describes the design, synthesis, and successful employment of inhibitors of 4-(beta-D-ribofuranosyl)aminobenzene-5'-phosphate (RFA-P) synthase, which catalyzes the first committed step in the biosynthesis of methanopterin, to specifically halt the growth of methane-producing microbes. RFA-P synthase catalyzes the first step in the synthesis of tetrahydromethanopterin, a key cofactor required for methane formation and for one-carbon transformations in methanogens. A number of inhibitors, which are N-substituted derivatives of p-aminobenzoic acid (pABA), have been synthesized and their inhibition constants with RFA-P synthase have been determined. Based on comparisons of the inhibition constants among various inhibitors, we propose that the pABA binding site in RFA-P synthase has a relatively large hydrophobic pocket near the amino group. These enzyme-targeted inhibitors arrest the methanogenesis and growth of pure cultures of methanogens. Supplying pABA to the culture relieves the inhibition, indicating a competitive interaction between pABA and the inhibitor at the cellular target, which is most likely RFAP synthase. The inhibitors do not adversely affect the growth of pure cultures of the bacteria (acetogens) that play a beneficial role in the rumen. Inhibitors added to dense ruminal fluid cultures (artificial rumena) halt methanogenesis; however, they do not inhibit volatile fatty acid (VFA) production and, in some cases, VFA levels are slightly elevated in the methanogenesis-inhibited cultures. We suggest that inhibiting methanopterin biosynthesis could be considered in strategies to decrease anthropogenic methane emissions, which could have an environmental benefit since methane is a potent greenhouse gas.


Sequential intravenous allogeneic mesenchymal stromal cells as a potential treatment for thromboangiitis obliterans (Buerger's disease).
Thromboangiitis obliterans (TAO), also known as Buerger's Disease, is an occlusive vasculitis linked with high morbidity and amputation risk. To date, TAO is deemed incurable due to the lack of a definitive treatment. The immune system and inflammation are proposed to play a central role in TAO pathogenesis. Due to their immunomodulatory effects, mesenchymal stromal cells (MSCs) are the subject of intense research for the treatment of a wide range of immune-mediated diseases. Thus far, local intramuscular injections of autologous or allogeneic MSCs have shown promising results in TAO. However, sequential intravenous allogeneic MSC administration has not yet been explored, which we hypothesized could exert a systemic anti-inflammatory effect in the vasculature and modulate the immune response. Here, we report the first case of a TAO patient at amputation risk treated with four sequential intravenous infusions of bone marrow-derived allogeneic MSCs from a healthy donor. Following administration, there was significant regression of foot skin ulcers and improvements in rest pain, Walking Impairment Questionnaire scores, and quality of life. Sixteen months after the infusion, the patient had not required any further amputations. This report highlights the potential of sequential allogeneic MSC infusions as an effective treatment for TAO, warranting further studies to compare this approach with the more conventionally used intramuscular MSC administration and other cell-based therapies.


Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort.
Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented. LITESPARK-001 is an ongoing open-label study with a 3 + 3 dose-escalation design followed by an expansion phase. Patients with ccRCC enrolled at 7 sites received belzutifan 120 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The data cutoff date was July 15, 2021. The primary end point was identifying the maximum tolerated dose and/or the recommended phase II dose. Secondary end points included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by investigator assessment and safety. Median follow-up was 41.2 months (range, 38.2-47.7). Patients received a median of 3 (range, 1-9) prior systemic therapies. Of 55 patients, 14 (25 %) achieved an objective response. Median DOR was not reached (range, 3.1 + to 38.0 + months). Adverse events (AEs) attributed to study treatment by investigator assessment were reported in 53 patients (96 %). 22 patients (40 %) had grade 3 treatment-related AEs; the most common were anemia (n = 13; 24 %) and hypoxia (n = 7; 13 %). No grade 4 or 5 treatment-related AEs occurred. After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety. gov. NCT02974738.


Infection with feline leukemia virus associated with induction of humoral response to a normal cell protein.
Selected populations of cats that were naturally exposed to the feline leukemia virus (FeLV) were found to have humoral antibodies to a normal cell protein designated NCP105. Earlier studies revealed that cats exposed to FeLV often had serum antibodies to the feline oncornavirus-associated cell membrane (FOCMA) as well as to a feline sarcoma virus (FeSV) -specific transforming protein designated gag-fes. Cats with no history of exposure to FeLV or FeSV lacked antibodies to all three antigens: NCP105, FOCMA, and gag-fes. Following exposure to FeLV, cats develop antibodies to either NCP105 or to gag-fes and FOCMA, but not to both groups of antigens. NCP105 is present in both normal and transformed cells from a wide variety of species. It lacks peptide homology with gag-fes and it is not a phosphoprotein. The presence of antibodies to NCP105 in cats exposed to FeLV but not in unexposed cats suggests that FeLV may activate the NCP105 gene or increase the relative immunogenicity of this protein in vivo.


[Extent of endemic yaws in Upper Volta in 1981].
This yaws investigation has been realized in the South West of Upper-Volta, in 1981, in areas around Gaoua, Niangoloko, N'Dorola; this investigation concerns 15 villages, chosen at random, and a sample of 1540 persons older than 4 years. The clinical prevalence (infectious cases) is 0.6%; the higher prevalence is observed around Gaoua (1.5%). Infectious contagious lesions are found especially in the 5-14 years old group. This investigation shows a low prevalence (under 5%) of active yaws. The serological prevalence (Kline-test) is 5.8% and we observe also around Gaoua the highest prevalence (8%). Periodical screening surveys of the population, during years 1952-1957, had shown a low prevalence of yaws, with a medium prevalence of yaws around Gaoua. Yaws treatment campaigns had been realized from 1957 to 1960 in South-West of Upper-Volta with very good results (prevalence: 0.06% - 1960). Now, in 1981, we note a resurgence of endemic foci, especially around Gaoua, from where the infection is spreading again, this, threatening the gains made by previous mass treatment campaigns. Taking in account the present result, it is necessary to treat contagious cases and contact sick persons (selective mass treatment or S.M.T., recommended in areas of low prevalence, by the WHO scientific group on treponemal infections).


Quantitative polymerase chain reaction for transforming growth factor-beta applied to a field study of fish health in Chesapeake Bay tributaries.
Fish morbidity and mortality events in Chesapeake Bay tributaries have aroused concern over the health of this important aquatic ecosystem. We applied a recently described method for quantifying mRNA of an immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), by reverse transcription quantitative-competitive polymerase chain reaction to a field study of fish health in the Chesapeake Basin, and compared the results to those of a traditional cellular immunoassay macrophage bactericidal activity. We selected the white perch (Morone americana) as the sentinel fish species because of its abundance at all of the collection sites. White perch were sampled from Chesapeake Bay tributaries in June, August, and October 1998. Splenic mononuclear cell TGF-beta mRNA levels increased and anterior kidney macrophage bactericidal activity decreased, particularly in eastern shore tributaries, from June to August and October. The results of the two assays correlated inversely (Kendall's [Tau] b = -0.600; p = 0.0102). The results indicated both temporal and spatial modulation of white perch immune systems in the Chesapeake Basin, and demonstrated the utility of quantitative PCR for TGF-beta as a molecular biomarker for field assessment of teleost fish immune status.


Development of a Cadaveric Multiport Model of Posterior Circulation Aneurysm Clipping for Neurosurgery and Otolaryngology Residents.
Posterior circulation aneurysms are difficult to treat with the current methods of coiling and clipping. To address limitations in training, we developed a cadaveric model to train learners on endoscopic clipping of posterior circulation aneurysms. An endoscopic transclival approach (ETA) and a transorbital precaruncular approach (TOPA) to successfully access and clip aneurysms of the posterior circulation are described. The model has flexibility in that a colored silicone compound can be injected into the cadaveric vessels for the purpose of training learners on vascular anatomy. The other option is that the model could be connected to a vascular perfusion pump allowing real-time appreciation of a pulsatile or ruptured aneurysm. This cadaveric model is the first of its kind for training of endoscopic clipping of posterior circulation aneurysms. Learners will develop proficiency in endoscopic skills, appropriate dissection, and appreciation for relative anatomy while developing an algorithm that can be employed in a real operative arena. Going forward, various clinical scenarios can be developed to enhance the realism, allow learners from different specialties to work together, and emphasize the importance of teamwork and effective communication.


Esophageal Atresia: Improved Outcome in High-Risk Groups Revisited.
Objectives Improved survival in infants with esophageal atresia (EA) with a birth weight < 1,500 g or a major cardiac anomaly has been reported when compared with the original Spitz classification proposed in 1994. Aim We reviewed outcome data for infants born over the last decade in our institution to update previously reported survival statistics. Materials and Methods The records of all neonates (n = 200) with a diagnosis of EA managed in a single institution between 2001 and 2011 were reviewed and compared with data from the original Spitz study and the subsequent reported cohort from the same institution. Data were obtained on birth weight, presence of a major cardiac anomaly, and survival. Differences in survival were compared using the Yates-corrected chi-square test. Local ethical study approval was obtained. Results Infants born over the last decade had a comparable overall survival rate of 93% (186/200) versus 92.6% (174/188) in the previously reported cohort (1993-2004). We demonstrate an improved survival as compared to the Spitz cohort (87.6%, 326 /372, p = 0.06) and a statistically significant improvement in survival in Group II (p = 0.01). Within this group, 12/51 neonates had a birth weight < 1,500 g and 39/51 had major cardiac anomalies. Of interest, of the nine deaths in Group II, eight were in the subgroup with major cardiac anomalies. Conclusion The survival of neonates in Group II has significantly improved. Mortalities within this group were predominantly in the subgroup with major cardiac anomalies suggesting birth weight is of less significance than in previous years reflecting recent advances in neonatal care. We propose an updated prognostic classification that makes a distinction between cardiac and low-birth-weight infants.


"Debye-Scherrer Ellipses" from 3D fullerene polymers: An anisotropic pressure memory signature
High-pressure studies on fullerenes have previously shown the existence of one- and two-dimensional (2D) polymerized C60 structures. Synchrotron radiation measurements, performed on C60 samples quenched from 13 gigapascals and 820 kelvin, yield unambiguous proof for the existence of a three-dimensional (3D) polymerized C60 derivative. Moreover, unusual ellipsoidal Debye-Scherrer diffraction patterns are observed, which shows that the giant anisotropic deformation induced by the nonhydrostatic compression is retained in the quenched samples. The multiple bonding possibilities of the highly symmetrical C60 allow the retention (down to ambient pressure) of the deformation, a phenomenon reported previously only under high pressure.


A comparison of collagen and PTFE patch repair in a rabbit model of congenital diaphragmatic hernia.
The use of prosthetic material in severe cases of congenital diaphragmatic hernia is complicated by infection, bowel adhesion, and patch dehiscence. We hypothesized that a bioprosthetic collagen patch would reduce these complications and be remodeled into autogenous tissue over a short period of time. Thirty-two New Zealand White rabbits had two 2 x 2-cm left diaphragmatic defects created. One of these defects was repaired with a collagen bioprosthetic patch (n = 20) and the other with a polytetrafluoroethylene (PTFE) patch (n = 20). Members of a control group (n = 12) had their defects closed primarily. The animals were then placed in either a 6- or 12-week survival cohort. At necrosectomy the repairs were assessed histologically, graded for adhesion formation, and tensiometrically tested. The PTFE patch was noted to have a significantly higher average adhesion grade than the collagen patch. The tensile strength of the two repair methods was statistically equivalent at both time intervals. On histologic examination the collagen patches were surrounded by an increased number of macrophages and fibroblasts. The PTFE patch exhibited no neovascularization or fibroblast deposition at the periphery, but had a much greater surrounding inflammatory response. Thus, there was evidence of early remodeling of the collagen with no increase in the amount of adhesions or loss of strength when compared to the PTFE, while the PTFE patches exhibited a more severe grade of adhesions.


Two distinct actin waves correlated with turns-and-runs of crawling microglia.
Freely crawling cells are often viewed as randomly moving Brownian particles but they generally exhibit some directional persistence. This property is often related to their zigzag motile behaviors that can be described as a noisy but temporally structured sequence of "runs" and "turns." However, its underlying biophysical mechanism is largely unexplored. Here, we carefully investigate the collective actin wave dynamics associated with the zigzag-crawling movements of microglia (as primary brain immune cells) employing a number of different quantitative imaging modalities including synthetic aperture microscopy and optical diffraction tomography, as well as conventional fluorescence imaging and scanning electron microscopy. Interestingly, we find that microglia exhibit two distinct types of actin waves working at two quite different time scales and locations, and they seem to serve different purposes. One type of actin waves is fast "peripheral ruffles" arising spontaneously with an oscillating period of about 6 seconds at some portion of the leading edge of crawling microglia, where the vigorously biased peripheral ruffles seem to set the direction of a new turn (in 2-D free space). When the cell turning events are inhibited with a physical confinement (in 1-D track), the peripheral ruffles still exist at the leading edge with no bias but showing phase coherence in the cell crawling direction. The other type is "dorsal actin waves" which also exhibits an oscillatory behavior but with a much longer period of around 2 minutes compared to the fast "peripheral ruffles". Dorsal actin waves (whether the cell turning events are inhibited or not) initiate in the lamellipodium just behind the leading edge, travelling down toward the core region of the cell and disappear. Such dorsal wave propagations seem to be correlated with migration of the cell. Thus, we may view the dorsal actin waves are connected with the "run" stage of cell body, whereas the fast ruffles at the leading front are involved in the "turn" stage.


Chidamide tablets: HDAC inhibition to treat lymphoma.
Chidamide is the first oral subtype-selective histone deacetylase inhibitor (HDACI) approved in China as well as the first HDACI of the benzamide class approved for the treatment of relapsed and refractory peripheral T-cell lymphoma (PTCL). This review addresses detailed information regarding chidamide, including the mechanism of action, preclinical pharmacology, pharmacokinetics and metabolism, clinical studies and application, safety, drug interactions and ongoing clinical trials. Although twice-weekly chidamide monotherapy has been recommended based on the evidence from preclinical and clinical studies with tolerable toxicities, its clinical efficacy could be further increased by combination with multidrug chemotherapy or chemo-free regimens. Further investigations into the mechanism of chidamide will facilitate the identification of optimal combined therapy approaches and suitable treatment populations. This review will contribute to a comprehensive understanding and better use of chidamide in clinical practice.


Prevalence of oral and systemic manifestations in pediatric HIV cohorts with and without drug therapy.
The prevalence of orofacial and systemic manifestations and their association with drug therapy in pediatric HIV patients is scarce in the literature. The aim of the study was to determine the prevalence of oro-facial and systemic manifestations in HIV sero-positive children with and without highly active antiretroviral therapy (HAART). The study population consisted of 100 pediatric HIV patients (n=47 on HAART and n=53 not on HAART). The majority of the children (n=56) had at least one or more oro-facial manifestation associated with HIV. Oral candidiasis was the most common oral finding present in the HAART (14/33) and non-HAART groups (19/33). Recurrent aphthous ulcers was the only significant oral finding, present more in the HAART group. The percentage of children with upper respiratory tract infection was also more in the HAART group. The other lesions which were found to be significant were seborrheic dermatitis, pulmonary tuberculosis and otitis media. There was no significant difference in the participants' oral findings based on CD4 counts in the HAART and non- HAART groups. The prevalence of oral and systemic manifestations is a persistent feature associated with pediatric HIV, though of moderate intensity in those using HAART and may vary according to individual immune status.


Double-blind trial of recombinant gamma-interferon versus placebo in the treatment of rheumatoid arthritis. 1989.
One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.


Mitochondrial genetic polymorphisms and pancreatic cancer risk.
The role of genes that influence the risk of developing pancreatic cancer (PC) has not been well studied. The mitochondrion, conventionally thought to be an organelle specific to energy metabolism, is in fact multifunctional and has been implicated in many diseases, including cancer. To evaluate whether single nucleotide polymorphisms in mitochondrial DNA (mtSNP) are associated with increased risk of PC, we screened Caucasian cases diagnosed or seen at the Mayo Clinic with primary pancreatic adenocarcinoma (n = 955), and healthy clinic-based Caucasian controls (n = 1,102). A total of 24 mtSNPs, including 10 of the most common tagSNPs, 7 non-tagSNPs in the coding region, and 7 common SNPs in the regulatory region were genotyped. For analysis, these samples were grouped into two phases, the "testing" set (474 cases and 615 controls), and the "validation" set (481 cases and 487 controls). In the testing set, one mtSNP (SNP11719) suggested an association in single SNP analysis, with an odds ratio of 1.34 (95% confidence intervals, 1.05-1.72; P = 0.020), but did not remain statistically significant after correction for multiple testing. In the validation set, none of the 24 variants indicated any association with PC. For haplogroup analysis, 10 core SNPs that form common haplogroups in Caucasians (1719, 4580, 7028, 8251, 9055, 10398, 12308, 13368, 13708, and 16391) were evaluated. No significant associations with PC were identified either by analyzing the two sets separately or combined (combined global P = 0.17). Overall, these results do not support a significant involvement of mitochondrial DNA variation in the risk of developing PC. Investigation of other mitochondrial genetic variations (i.e., nuclear-encoded mitochondrial proteins) would be necessary to elucidate any role of mitochondrial DNA variation in PC.