Bone marrow-derived cells contribute to vascular endothelial growth factor-induced angiogenesis in the adult mouse brain by supplying matrix metalloproteinase-9.
Our previous studies have shown that bone marrow-derived cells (BMDCs) home to a brain angiogenic focus. The angiogenic response to vascular endothelial growth factor (VEGF) stimulation is reduced in matrix metalloproteinase-9 (MMP-9) knockout mice. We hypothesized that BMDCs contribute to VEGF-induced angiogenesis by supplying MMP-9. Bone marrow (BM) transplantation was conducted using MMP-9 knockout (MMP-9 KO) or wild-type (WT) mice as both donors and recipients. Adeno-associated viral vectors expressing VEGF or LacZ were injected into the striatum 4 weeks after BM transplantation. Circulating white blood cells (WBCs), microvessel density, number of BMDCs, and MMP-9 activity around the injection site were analyzed. Two weeks after vector injection, circulating WBCs increased in WT mice but not in MMP-9 KO mice. VEGF overexpression increased microvessel density by 38% in WT mice 4 weeks after vector injection (P=0.0001). After transplantation of MMP-9 KO BM to WT mice, microvessel density only increased 18% after VEGF stimulation (P=0.037), with MMP-9 activity reduced to 35% of the level of WT mice (P<0.01). There was minimal angiogenic response in MMP-9 KO mice with MMP-9 KO BM (P=0.28). Transplantation of WT BM to MMP-9 KO mice restored brain angiogenic response to 92% of the WT level, ie, a 30% increase of microvessel density with VEGF overexpression (P=0.0006); MMP-9 activity was similar to that in WT mice. BM-derived MMP-9 plays an important role in BM cell mobilization and focal angiogenesis in the brain in response to VEGF stimulation.


Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era.
The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.


Oral fungal colonization and oral candidiasis in renal transplant patients: the relationship to Miswak use.
The aim of this study was to determine and compare the prevalence of oral candidal colonization and oral candidiasis in a group of medically stable renal transplant patients (RTPs) and age and sex-matched healthy control (HC) subjects. The oral cavities of 58 RTPs and 52 HC subjects were clinically examined for the presence of oral candidiasis. Oral fungal colonization was determined by using the concentrated oral rinse technique. Prevalence of oral fungal colonization was not significantly higher in RTPs than in HC subjects (74.1% vs 59.6%, respectively; P =.1), but the density of growth was significantly higher in RTPs (P <.0017). Oral candidiasis was diagnosed in 15.5% of RTPs but in none of HC subjects (P =.002). RTPs who used a chewing stick (Miswak: Salvadora persica ) for oral hygiene had a significantly lower prevalence of oral candidiasis (P =.04) compared with other RTPs. RTPs are at high risk of developing oral candidiasis. More clinical investigations are needed to determine the antimycotic effect of Miswak. Regular oral screening is recommended for RTPs.


Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus.
8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed. A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non-high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed. ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population. http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.


Post- and Pre-Radiolabeling Assays for anti Thymidine Cyclobutane Dimers as Intrinsic Photoprobes of Various Types of G-Quadruplexes, Reverse Hoogsteen Hairpins, and Other Non-B DNA Structures.
G-quadruplexes are thought to play an important role in gene regulation and telomere maintenance, but developing probes for their presence and location is challenging due to their transitory and highly dynamic nature. The majority of probes for G-quadruplexes have relied on antibody or small-molecule binding agents, many of which can also alter the dynamics and relative populations of G-quadruplexes. Recently, it was discovered that ultraviolet B (UVB) irradiation of human telomeric DNA and various G-quadruplex forming sequences found in human promoters, as well as reverse Hoogsteen hairpins, produces a unique class of non-adjacent anti cyclobutane pyrimidine dimers (CPDs). Therefore, one can envision using a pulse of UVB light to irreversibly trap these non-B DNA structures via anti CPD formation without perturbing their dynamics, after which the anti CPDs can be identified and mapped. As a first step toward this goal, we report radioactive post- and pre-labeling assays for the detection of non-adjacent CPDs and illustrate their use in detecting trans,anti T=(T) CPD formation in a human telomeric DNA sequence. Both assays make use of snake venom phosphodiesterase (SVP) to degrade the trans,anti T=(T) CPD-containing DNA to the tetranucleotide pTT=(pTT) corresponding to CPD formation between the underlined T's of two separate dinucleotides while degrading the adjacent syn TT CPDs to the trinucleotide pGT=T. In the post-labeling assay, calf intestinal phosphodiesterase is used to dephosphorylate the tetranucleotides, which are then rephosphorylated with kinase and [32P]-ATP to produce radiolabeled mono- and diphosphorylated tetranucleotides. The tetranucleotides are confirmed to be non-adjacent CPDs by 254 nm photoreversion to the dinucleotide p*TT. In the pre-labeling assay, radiolabeled phosphates are introduced into non-adjacent CPD-forming sites by ligation prior to irradiation, thereby eliminating the dephosphorylation and rephosphorylation steps. The assays are also demonstrated to detect the stereoisomeric cis,anti T=(T) CPD.


Intraflagellar Transport and Ciliary Dynamics.
Cilia and flagella are microtubule-based organelles whose assembly requires a motile process, known as intraflagellar transport (IFT), to bring tubulin and other components to the distal tip of the growing structure. The IFT system uses a multiprotein complex with components that appear to be specialized for the transport of different sets of cargo proteins. The mechanisms by which cargo is selected for ciliary import and transport by IFT remain an area of active research. The complex dynamics of cilia and flagella are under constant regulation to ensure proper length control, and this regulation appears to involve regulation at the stage of IFT injection into the flagellum, as well as regulation of flagellar disassembly and, possibly, of cargo binding. Cilia and flagella thus represent a convenient model system to study how multiple motile and signaling pathways cooperate to control the assembly and dynamics of a complex cellular structure.


Cross-sectional study of randomly selected 18-year-old students showed that body mass index was only associated with sleep duration in girls.
This study investigated the associations, by sex, between sleep and adiposity, dietary habits, cardiorespiratory fitness and metabolic risk in 18-year-old students. We carried out a cross-sectional study of 199 randomly chosen, healthy 18-year-old students (53% girls) in Iceland's capital region. The data collection took place in the winter months of 2012 to 2015. The anthropometric measurements were body mass index, waist circumference and body fat percentage. Sleep duration and dietary habits were self-reported. Cardiorespiratory fitness was measured on a stationary bicycle. A subsample of 152 participants gave blood samples. A quarter of the adolescents failed to reach the minimum recommended sleep duration of seven hours per night on weekdays. In girls, the average sleep score was associated with body mass index and waist circumference, after adjusting for cardiorespiratory fitness and unhealthy eating scores. In boys, the average sleep score was not associated with anthropometric measurements, but cardiorespiratory fitness was an independent predictor (p < 0.001). No associations were found between average sleep scores and metabolic profiles in either sex. Sleep duration and adiposity only appeared to be associated in girls and were independent of cardiorespiratory fitness and unhealthy eating. Sleep duration was not related to metabolic risk.


Relationships of exercise with frailty, depression, and cognitive function in older women.
The purpose of the present study was to provide basic data to identify which types of exercise promote health of older adults. To this end, this study investigated how exercise affects frailty, depression, and cognitive functions in older adults. Frailty, depression, and cognitive function assessed in the exercise participants, 164 older adult women. Results revealed that participants' frailty and depression varied according to exercise participation time and frequency. In particular, dancing was more effective than other types of exercise in reducing frailty and depression. Exercise duration and frequency did not influence cognitive function, but results indicated that table tennis exerted a greater influence on cognitive function than other types of exercise did. In addition, cognitive function differed according to the degree of frailty participants displayed.


Reconstructive procedure after distal gastrectomy to prevent remnant gastritis.
Gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II) after distal gastrectomy is associated with duodenogastric reflux and remnant gastritis. This study sought to determine which reconstructive procedure is least likely to cause remnant gastritis and to determine the correlation between duodenogastric reflux and remnant gastritis. Sixty patients who underwent curative distal gastrectomy for gastric cancer were classified into three groups by reconstructive procedure: group A, Roux-Y (n=18); group B, Billroth I (n=25); group C, Billroth II (n=17). Intragastric bile reflux was monitored using the Bilitec 2000 14 days after surgery, and endoscopy was performed and a patient questionnaire was completed 12 weeks after surgery. Bile reflux occurred in 23.9%, 40.4%, and 73.4% of the time (p<0.001), and remnant gastritis developed in 33%, 76%, and 100% of patients (p<0.001), in groups A, B, and C, respectively. Helicobacter pylori infection did not correlate with remnant gastritis (p=0.57). Symptoms following Roux-Y reconstruction were comparable to those following Billroth I and II reconstructions. Roux-Y reconstruction following distal gastrectomy is superior to Billroth I and II reconstruction in preventing remnant gastritis because it reduces duodenogastric reflux.


Onset of initial planar instability with surface-tension anisotropy during directional solidification.
A simple model is presented to describe the variation of the onset of the initial planar instability with surface tension anisotropy during directional solidification. The effect of surface-tension anisotropy on the incubation time and the initial average wavelength of planar instability are predicted by the simple model quantitatively, which are also verified by phase field simulation. Investigation results reveal that surface-tension anisotropy is one of important factors in the dynamic process of planar instability. The contribution of surface-tension anisotropy to the tilting modulation is also analyzed by comparing the results from the present simple model with those from phase field simulation.


Reconstruction and computation of microscale biovolumes using geographical information systems: potential difficulties.
Biofilms are bacterial colonies enveloped in a matrix of extracellular polymeric secretions. Confocal scanning laser microscopy has been used in conjunction with different image analysis techniques to investigate the structure of biofilms. A major goal is to reconstitute the three-dimensional structure of biofilms, and compute or estimate the biovolumes. Our previous research focused on the utilization of remote sensing techniques and Geographical Information Systems for quantitative analyses of confocal images. The present study investigates potential problems in microbial imaging, and uses two approaches, the program COMSTAT and a Geographical Information Systems-based method, to reconstitute three-dimensional structures and estimate biovolumes. Volumes of thirty fluorescent polymeric microspheres with a known diameter were estimated and used as a ground truth, to statistically compare both methods. In a next step, the two approaches were used to estimate the biovolume of a section through a Pseudomonas aeruginosa biofilm. Difficulties were encountered in image acquisition due to the optical properties of the microbeads. Our results indicate that the Geographical Information Systems approach produced results consistent with the existing COMSTAT approach, and close to theoretical values, despite many problems inherent to each phase of this process. Also, the image classification process encountered several limitations. It is suggested that the unique constraints of the microscopic world may generate additional problems, especially related to image classification.


[Living donor liver transplantation of the right liver lobe between adults].
Adult living donor liver transplantation has been established in an increasing number of transplant centres during the last few years. Donor safety and risks are important criteria influencing the further development. We report our experience with 43 adult-to-adult right lobe living donor liver transplantations. 43 patients (mean age: 49,8 +/- 16,0 years; f:m = 14:29) with end-stage liver disease received a right lobe liver graft from an adult living donor (mean age: 42,4 +/- 13,4 years; f:m = 27:16) between December 1999 and December 2001. An approval by the local ethics committee was obtained prior to the start of the programme and each donation. None of the donors experienced fatal or long-term complications. The rate of surgical complications in donors (biliary leakage, bleeding) was 9 %. Actuarial recipient survival was 93 % after three months and 88 % after one year. Five patients had to be re-transplanted. Thus the actuarial 1-year graft survival was 79 %. Biliary complications occurred in 14 % of all recipients. According to our experience, living donor liver transplantation of the right hepatic lobe is a safe and effective procedure. Especially for patients in acute and chronic liver failure, who otherwise would have died on the waiting list, this approach offers a life-saving option.


[Characterization of the alpha adrenoreceptors in the vascular bed of the isolated rat kidney].
The vasoconstrictive effect of alpha-adrenoceptor agonists was studied on isolated perfused kidney from normal Wistar rats. Methoxamine (ED50 = 1.61 +/- 0.16 X 10(-6) M; m +/- SEM), phenylephrine (2.33 +/- 0.16 X 10(-6) M) and alpha-methylnoradrenaline (1.60 +/- 0.40 X 10(-6) M) acted as full agonists. Dopamine (9.5 +/- 1.08 X 10(-5) M) had a partial agonistic effect. Clonidine and B-HT 920 were inactive up to the concentration of 10(-4) M. Prazosin, but not yohimbine (10(-6) M) antagonized the response to phenylephrine (pA2 = 8.48 +/- 0.12) and to alpha-methylnoradrenaline (8.02 +/- 0.10). Our results suggest that the postsynaptic alpha-adrenoceptors which when stimulated increases vascular resistance of isolated rat kidney, belong exclusively to the alpha 1-subtype.


Implementation of a pharmacist-led transitional care clinic.
To describe a pharmacist-led transitional care clinic (TCC) for high-risk patients who were recently hospitalized or seen in the emergency department (ED). The Memphis Veterans Affairs Medical Center (VAMC) established a pharmacist-led face-to-face and telephone follow-up TCC to improve posthospitalization follow-up care through medication optimization and disease state management, particularly for veterans with high-risk disease states such as chronic obstructive pulmonary disease (COPD) and heart failure (HF). The clinic's clinical pharmacy specialists (CPSs) ordered diagnostic and laboratory tests, performed physical assessments, and consulted other providers and specialty services in addition to performing medication reconciliation, compliance assessment, and evaluation of adverse drug events. TCC patients were typically seen within 2 weeks of discharge and subsequently referred back to their primary care provider or a specialty care provider for continued management. A retrospective review of 2016 TCC data found that 7.8% of patients seen in the TCC were readmitted within 30 days of discharge; readmission rates for COPD and HF were reduced to 13% and 10%, respectively, compared to hospital-wide readmission rates of 17% and 24%. A separate observational analysis found that 30-day readmissions for COPD and HF were reduced in TCC patients, with pharmacists documenting an average of 6.2 interventions and 3.3 medication-related problems per patient. To reduce clinic appointment no-shows, the CPSs worked with inpatient providers and schedulers to emphasize to patients the importance of clinic attendance; also, TCC services were expanded to include telehealth appointments to increase access for rural and/or homebound patients. A pharmacist-led TCC effectively reduced readmissions and prevented medication-related problems for high-risk patients who were hospitalized or seen in the ED.


Long-term alteration of daily melatonin, 6-sulfatoxymelatonin, cortisol, and temperature profiles in burn patients: a preliminary report.
Melatonin, which shows a robust nycthemeral rhythm, plays the role of an endogenous synchronizer, able to stabilize and reinforce circadian rhythms and maintain their mutual phase relationships. Additionally, melatonin is a potent antioxidant and displays immunological properties. Because free radical generation, immune dysfunction, and sleep and metabolic disorders are involved in the short- and long-term pathophysiology of the burn syndrome, we undertook the study of daily urine melatonin, 6-sulfatoxymelatonin (aMT6s, the main hepatic melatonin metabolite), and cortisol variations plus temperature profiles in burn patients using a non-invasive protocol. Eight patients (6 males, 2 females) were studied on three occasions after admission to the intensive care unit (early session: days 1 to 3; intermediate session: day 10; late session: days 20 to 30). Melatonin, aMT6s, and free cortisol levels were determined in urine samples collected at 4 h intervals over a continuous 24 h span. Core temperature was recorded daily. Controls consisted of healthy subjects in the same age range. Cosinor analysis of the data provided an evaluation of mesor, amplitude, and acrophase of circadian rhythms. Also, we calculated day (D), night (N), and 24 h hormone excretions, N/D ratio for melatonin and aMT6s, and D/N ratio for cortisol. These data were analyzed using Kruskal-Wallis test followed by multiple comparisons. Cosinor analysis did not detect a circadian rhythm in melatonin, aMT6s, or cortisol in any of the three sessions. D melatonin excretion displayed a major increase, resulting in a decreased N/D melatonin ratio, and the melatonin mesor (24 h mean) was increased in the early session, compared with controls. For aMT6s, only the early N/D ratio was decreased, and the mesor of the intermediate session increased. These results were not the consequence of hepatic and/or kidney alteration, as the patients' hepatic and renal parameters were in the normal range. The D and N melatonin/aMT6s ratios of controls and patients were similar, and the aMT6s profiles were superimposed on the melatonin ones, mainly during the day. The D, N, and 24 h cortisol values were increased in all sessions, except for the D level of the early session. The consistently increased mesors in the three sessions provided confirmation. The core temperature profiles were abnormal in all three sessions, mainly during the night, although there was a tendency toward normalization with time. The individual mesors were consistently increased compared with controls. Globally, the abnormalities we report could participate in the pathophysiology of short- and long-term alterations observed in burn syndrome, especially disturbances of sleep, metabolism, and immune function.


Lycopus lucidus Turcz. ex Benth. Attenuates free fatty acid-induced steatosis in HepG2 cells and non-alcoholic fatty liver disease in high-fat diet-induced obese mice.
Non-alcoholic fatty liver disease (NAFLD) is closely related to metabolic diseases such as obesity and insulin resistance. We studied whether an ethanol extract of Lycopus lucidus Turcz. ex Benth (LLE) exhibited effects on lipid metabolism in NAFLD. An in vitro modelwas established by treatment of HepG2 cells with a 1 mM free fatty acid (FFA) mixture (oleic acid/palmitic acid, 2:1). C57BL/6 mice were fed a high-fat diet (HFD; 60 kcal% fat) for 14 weeks to induce obesity and were treated with or without LLE (100 or 200 mg/kg daily by oral gavage). HepG2 cells were exposed to 1 mM FFA, with or without LLE (250 - 1000 mg/ml). Intracellular lipid contents were measured by Oil Red O staining and a Nile Red assay. The body weight, relative liver weight, hepatic lipids, triglycerides (TGs), and total cholesterol (TC) were measured in the mice. Serum alanine aminotransferase (ALT), TG, TC, glucose, insulin, leptin, and tumor necrosis factor-alpha (TNF-α) levels were determined by biochemical or enzyme-linked immunosorbent assays. Histologic analysis was performed in the liver. Western blotting and quantitative real-time polymerase chain reaction were used to analyze the expression of key enzymes of hepatic lipid metabolism. LLE significantly decreased the intracellular lipid accumulation in FFA-treated HepG2 cells. LLE not only remarkably decreased the expression of lipogenesis genes but also increased β-oxidation in FFA-induced HepG2 cells. In the in vivo study, LLE treatment significantly decreased the body weight, relative liver weight, serum ALT, TC, and low-density lipoprotein cholesterol, as well as the serum glucose, insulin, leptin, and TNF-α levels in HFD-fed mice. The hepatic TG and TC contents were significantly reduced in the LLE-treated groups. Western blot analysis showed that the expression of sterol-regulatory element-binding protein 1 decreased, while that of phosphorylated AMP-activated protein kinase and peroxisome proliferator-activated receptor α increased in the LLE-treated mice. These results suggest that LLE may exert protective effects against NAFLD-related obesity and metabolic disease.


Immunologic mechanism in contact allergy--a review.
The last decade saw rapid advances in the understanding of the immunology of contact allergy, a cutaneous delayed hypersensitivity reaction. Of great importance was the recognition of the role of epidermal Langerhans cells as antigen-presenting cells to T lymphocytes. The necessity of an intact lymphatic system to mount contact allergy was demonstrated. The identification of lymphokines, mediators and modulators of inflammatory response in contact allergy, enable us to understand the histological and clinical manifestation of allergic contact dermatitis. Based on the discovery of the immunologic pathways of contact allergy successful attempts have been achieved to prevent and treat allergic contact dermatitis by blocking or modifying its pathways. This paper reviews recent development in the immunologic mechanism of contact allergy.


Augmented Reality in Scientific Publications-Taking the Visualization of 3D Structures to the Next Level.
The examination of three-dimensional structural models in scientific publications allows the reader to validate or invalidate conclusions drawn by the authors. However, either due to a (temporary) lack of access to proper visualization software or a lack of proficiency, this information is not necessarily available to every reader. As the digital revolution is quickly progressing, technologies have become widely available that overcome the limitations and offer to all the opportunity to appreciate models not only in 2D, but also in 3D. Additionally, mobile devices such as smartphones and tablets allow access to this information almost anywhere, at any time. Since access to such information has only recently become standard practice, we want to outline straightforward ways to incorporate 3D models in augmented reality into scientific publications, books, posters, and presentations and suggest that this should become general practice.


In vitro exploration of ACAT contributions to lipid droplet formation during adipogenesis.
As adipose tissue is the major cholesterol storage organ and most of the intracellular cholesterol is distributed to lipid droplets (LDs), cholesterol homeostasis may have a role in the regulation of adipocyte size and function. ACATs catalyze the formation of cholesteryl ester (CE) from free cholesterol to modulate the cholesterol balance. Despite the well-documented role of ACATs in hypercholesterolemia, their role in LD development during adipogenesis remains elusive. Here, we identify ACATs as regulators of de novo lipogenesis and LD formation in murine 3T3-L1 adipocytes. Pharmacological inhibition of ACAT activity suppressed intracellular cholesterol and CE levels, and reduced expression of genes involved in cholesterol uptake and efflux. ACAT inhibition resulted in decreased de novo lipogenesis, as demonstrated by reduced maturation of SREBP1 and SREBP1-downstream lipogenic gene expression. Consistent with this observation, knockdown of either ACAT isoform reduced total adipocyte lipid content by approximately 40%. These results demonstrate that ACATs are required for storage ability of lipids and cholesterol in adipocytes.


Identification of the core motif of the BRCA2 C-terminal RAD51-binding domain by comparing canine and human BRCA2.
Mammary tumors are the most common tumors in women and non-spayed female dogs. One of the reasons for mammary tumors is mutations of the tumor suppressor gene, BRCA2. BRCA2 participates in homologous recombination repair by interacting with the RAD51 recombinase. BRCA2 has two RAD51-binding domains, consisting of BRC repeats and the C-terminal RAD51-binding domain, respectively. Although several studies have addressed the function of the C-terminal RAD51-binding domain of human BRCA2, the amino acid sequences required for the RAD51-interaction activity remain unclear. In this study, the C-terminal RAD51-binding domains of canine and human BRCA2 were compared; the canine domain displayed a weaker interaction with RAD51. This difference was attributed to the C-terminal portion of the domain via a comparison between canine and human domains. Furthermore, peptides shorter than those previously reported displayed RAD51-interacting activity, and a core motif of this domain consisting of 25 amino acids was identified. Since a mutation (S3323N) was reported in the core motif of this domain, the effect of this mutation was evaluated. The mutant exhibited similar RAD51-binding activity as that of the wild-type protein, suggesting that the mutation was functionally neutral. These data suggested that the C-terminal portion of the BRCA2 C-terminal RAD51-binding domain influenced its RAD51-interaction activity, and a minimum core motif of 25 amino acids was identified in this domain. These data may help clarify BRCA2 function, as well as the tumorigenic effects of BRCA2 mutation.


Clonidine induced endothelium-dependent tonic contraction in circular muscle of the rat hepatic portal vein.
Clonidine, an alpha2-agonist, has been shown to be useful in the treatment of hepatic portal hypertension in cirrhosis. The mechanism has been attributed to a clonidine-induced decrease in sympathetic activity. While clonidine has been shown to stimulate the alpha2-adrenoceptors of blood vessels, there is limited knowledge of the effects of clonidine on the circular muscle of the hepatic portal vein which regulates its blood flow. To investigate clonidine-induced contraction of the circular muscle of the hepatic portal vein and to clarify the possible role of the endothelium in the contraction, we examined the effects of clonidine on the isometric contraction of endothelium-intact and -removed ring preparations of the rat hepatic portal vein. In endothelium-intact preparations, clonidine caused a concentration-dependent increase in the amplitude of contractions. Inhibition of NO synthesis with Nomega-nitro-L-arginine (L-NNA) elevated the resting tone, and increased the amplitude of the clonidine-induced contractions. Inhibition of cyclooxygenase by diclofenac did not change the amplitude of the clonidine-induced contractions observed both in the presence and absence of L-NNA. Application of a single concentration of clonidine induced a clear increase in amplitude of both twitch and tonic contractions. Twitch and tonic contractions induced by clonidine were inhibited by yohimbine. When the endothelium was damaged by sodium deoxycholate, tonic contractions induced by clonidine were completely suppressed, whereas the increase in twitch contractions was not influenced by chemical damage of the endothelium. Neither SKF-96365, a nonselective cation channel blocker, nor superoxide dismutase, a free radical scavenger, in the presence of catalase, changed the tonic contraction induced by clonidine. These results indicate that stimulation of alpha2-adrenoceptors enhanced twitch contractions and induced tonic contractions in the circular muscle of the rat hepatic portal vein, especially in the absence of NO. The latter, but not the former, occurs through an endothelium-dependent pathway.


Relationship between pulmonary function and exercise capacity in individuals with spinal cord injury.
The aim of this study was to determine whether the relationship between impaired pulmonary function and level of spinal cord injury would relate to lower maximal ventilation during exercise (Vemax) and hence reduced aerobic capacity. Pulmonary function and maximal aerobic capacity (V˙O2max) were assessed as measured by maximal oxygen uptake in 20 men with complete spinal cord injury (C5-T11). Static and dynamic lung volumes (forced vital capacity, forced expiratory volume in 1 sec, and maximum voluntary ventilation) were measured by spirometry. V˙O2max and Vemax were measured during a graded maximal exercise test on an arm crank ergometer. Level of injury was inversely correlated with measures of pulmonary function, Vemax and V˙O2max. On the basis of the correlations, the authors constructed a path analysis to test whether level of injury indirectly (via pulmonary function and/or Vemax) or directly reduced V˙O2max. Akaike information criteria indicated that the strongest effect of level of injury on V˙O2max was via reduced Vemax. Respiratory capacity does influence exercise capacity in the population with spinal cord injury and may play an important role in delimiting aerobic exercise capacity.


Roles of endothelin ETA and ETB receptors in the pathogenesis of monocrotaline-induced pulmonary hypertension.
The functional roles of endothelin ETA and ETB receptors in the development of monocrotaline (MCT)-induced pulmonary hypertension were investigated using MCT-treated rats in the absence or presence of a daily administration of A-192621, a selective ETB receptor antagonist, ABT-627, a selective ETA receptor antagonist, or a combination of both drugs. Four weeks after the injection of saline or MCT (60 mg/kg, s.c.), cardiac hypertrophy, right ventricular systolic pressure and morphologic changes of pulmonary arteries were evaluated. Compared with the control animals, MCT produced marked pulmonary hypertension associated with increases in right ventricular pressure and hypertrophy, and pulmonary arterial medial thickening. These MCT-induced alterations were markedly suppressed by daily treatment with ABT-627 for 4 weeks (10 mg/kg/d, twice daily), whereas treatment with A-192621 significantly aggravated the above MCT-induced pathologic changes. The blockade of both receptor subtypes by a combination of A-192621 and ABT-627 also significantly improved the MCT-induced pathologic changes, to the same extent as with ABT-627 administration. Thus, an exaggerated response to MCT during ETB receptor blockade also seems to be mediated by ETA receptor activation, thereby suggesting that ETA receptor-mediated action is exclusively contributive to the pathogenesis of MCT-induced pulmonary hypertension, although we cannot rule out a protective role of ETB receptor-mediated action.


Infertile Couples' Needs after Unsuccessful Fertility Treatment: a Qualitative Study.
Introduction: Infertility is a major medical issue. Investigations and treatment of infertility are the beginning of a complex, time-consuming and stressful process for couples that may fail well. The present study explored the needs of infertile couples following treatment failure with Assisted Reproductive Technologies (ARTs). Methods: A descriptive qualitative study was conducted in an Iranian infertility center, in the Northeast of the country between April 2016 and June 2017. The researchers recruited 29 individuals including 9 couples, 9 women and two men with primary infertility through purposive sampling. The data were collected using semi-structured interviews and analyzed iteratively, using conventional content analysis with MAXQDA software. Results: The main concepts obtained from the data were classified into one theme titled: ""The need for support"" and four main categories along with their subcategories, and included the need for psychological support, the need for more useful information, the need for social support and the need to access to supplementary services. Conclusion: The findings show that following treatment failure, the infertile patients' expressed needs and preferences were not met. Identifying and meeting their needs may help the infertile couples to deal with ARTs failure and to reach a decision about future treatment.


Polycystin-1 is required for insulin-like growth factor 1-induced cardiomyocyte hypertrophy.
Cardiac hypertrophy is the result of responses to various physiological or pathological stimuli. Recently, we showed that polycystin-1 participates in cardiomyocyte hypertrophy elicited by pressure overload and mechanical stress. Interestingly, polycystin-1 knockdown does not affect phenylephrine-induced cardiomyocyte hypertrophy, suggesting that the effects of polycystin-1 are stimulus-dependent. In this study, we aimed to identify the role of polycystin-1 in insulin-like growth factor-1 (IGF-1) signaling in cardiomyocytes. Polycystin-1 knockdown completely blunted IGF-1-induced cardiomyocyte hypertrophy. We then investigated the molecular mechanism underlying this result. We found that polycystin-1 silencing impaired the activation of the IGF-1 receptor, Akt, and ERK1/2 elicited by IGF-1. Remarkably, IGF-1-induced IGF-1 receptor, Akt, and ERK1/2 phosphorylations were restored when protein tyrosine phosphatase 1B was inhibited, suggesting that polycystin-1 knockdown deregulates this phosphatase in cardiomyocytes. Moreover, protein tyrosine phosphatase 1B inhibition also restored IGF-1-dependent cardiomyocyte hypertrophy in polycystin-1-deficient cells. Our findings provide the first evidence that polycystin-1 regulates IGF-1-induced cardiomyocyte hypertrophy through a mechanism involving protein tyrosine phosphatase 1B.


Assessment of PD treatment delivered by 125I-Iothalamate plasma disappearance.
The calculation of treatment delivered to PD patients requires the collection of PD effluent, plasma and urine samples. 125I-Iothalamate plasma disappearance, which eliminates the need for PD effluent collections, was tested as an alternate method to measure the weekly PD treatment delivered. Two protocols were designed. In protocol A, a 35 microCi dose of 125I-Iothalamate was injected in three subjects and allowed to equilibrate. A plasma sample was taken and patients returned on both of the following two days with timed labeled effluent bags and a 24-hour urine collection for each day. The timed PD effluent and 24-hour urine collections were measured for 125I-Iothalamate, urea and creatinine concentrations. 125I-Iothalamate and urea clearances were strongly correlated for both PD (R2 = 0.76, n = 24) and renal (R2 = 0.92, n = 6) clearances. In protocol B, thirteen subjects were given a 35 microCi injection of 125I-Iothalamate. A blood sample was taken one hour post injection and a second blood sample taken on day five. Kt/V were calculated from the 125I-Iothalamate plasma disappearance curve and compared to weekly Kt/V values extrapolated from one day's collections (Traditional Method). The comparison of Kt/V values found by 125I-Iothalamate Method vs. the "Traditional Method" yielded R2 = 0.79, n = 13. In conclusion, the plasma disappearance of 125I-Iothalamate is an alternate method of determining weekly Kt/V, over an extended period of time, which eliminates the need for PD effluent collections.


Gastric Signet-Ring-Cell Adenocarcinoma with Delayed Retroperitoneal Metastasis and Fibrosis.
Gastric signet-ring-cell adenocarcinoma (SRCC) is a rare disease entity, often characterized by early age of the onset and sometimes attributable to heritable genetic mutations. Overall prognosis is usually poor due to diagnosis at late stages. There are a handful of case reports that describe patient presentation with retroperitoneal fibrosis secondary to malignancy from a concurrent gastric SRCC found on the workup. No information exists on timing from primary tumor development to retroperitoneal disease. Further, there is speculation that gastric SRCC may have an indolent phase prior to symptomatic disease, but its natural history is essentially entirely unknown. In this case report, we describe a 39-year-old male with an incidentally discovered gastric SRCC who then underwent multimodality treatment with curative intent. No evidence of recurrence was documented on interval surveillance scans for 4.5 years, at which point, he rapidly developed a large retroperitoneal mass that was biopsied for metastatic disease. He succumbed to his pathology within 6 months. This presentation suggests that gastric SRCC could have both a relatively long indolent phase and an unpredictable propensity for explosive metastatic progression. Tumor biology factors that affect this balance are not understood.


Spontaneous splenic rupture: an unusual presentation of CML.
A 47-year-old man presented with sudden onset of severe, generalised abdominal pain and collapse. He also had a 4-month history of lethargy and weight loss. On examination he was shocked with a distended tender abdomen. He had haemoglobin of 3.8 g/dl and a white cell count count of 280.3×10(9)/l with predominance of neutrophils. Arterial gases showed mixed metabolic-respiratory acidosis. A CT scan of abdomen showed active extravasation in splenic bed. In view of probable hyperviscosity syndrome, it was decided to attempt an angiographic embolisation. This was successfully carried out but 4 h later, he developed abdominal compartment syndrome and underwent a laparotomy and splenectomy. Subsequently, bone marrow aspirates were taken which showed granulocytic hyperplasia. Cytogenetic studies confirmed the presence of Philadelphia Chromosome and he was started on Imatinib. It is now 5 months since diagnosis and he has achieved complete haematological and cytogenetic response.


Small-scale-structure of the interstellar medium probed through diffuse band observations.
The carriers of the diffuse interstellar band spectrum represent an important baryonic component of the interstellar medium (ISM) and it is expected that their identification will contribute significantly to the understanding of the chemistry and physics of interstellar clouds. It is widely held that the carriers are linked to the presence of dust grains on account of the good correlation of their strengths with interstellar reddening, so they offer an important potential route to improving our understanding of the composition and chemistry of grains and grain surfaces. In addition to the challenge of making the spectral assignments, an important current question concerns the spatial distribution and physical state of interstellar material, with recent observational atomic and molecular line absorption studies suggesting that diffuse clouds are more 'clumpy' than previously thought. We describe here high signal-to-noise optical observations made at the Anglo-Australian Telescope using UCLES that were undertaken to investigate the spatial distribution of diffuse band carriers. We describe the first detection of 'small-scale-structure' in the diffuse band carrier distribution in the ISM, and comment on the possibilities that these data hold for contributing to the solution of the diffuse band problem and our understanding of the nature of small-scale-structure in the diffuse ISM.


Pervasive Chromatin-RNA Binding Protein Interactions Enable RNA-Based Regulation of Transcription.
Increasing evidence suggests that transcriptional control and chromatin activities at large involve regulatory RNAs, which likely enlist specific RNA-binding proteins (RBPs). Although multiple RBPs have been implicated in transcription control, it has remained unclear how extensively RBPs directly act on chromatin. We embarked on a large-scale RBP ChIP-seq analysis, revealing widespread RBP presence in active chromatin regions in the human genome. Like transcription factors (TFs), RBPs also show strong preference for hotspots in the genome, particularly gene promoters, where their association is frequently linked to transcriptional output. Unsupervised clustering reveals extensive co-association between TFs and RBPs, as exemplified by YY1, a known RNA-dependent TF, and RBM25, an RBP involved in splicing regulation. Remarkably, RBM25 depletion attenuates all YY1-dependent activities, including chromatin binding, DNA looping, and transcription. We propose that various RBPs may enhance network interaction through harnessing regulatory RNAs to control transcription.


Nicolau syndrome associated with fluphenazine depot: A case report.
Nicolau syndrome is a rare condition characterized by severe pain at the site of injection, leading to ulceration and necrosis of the local tissues. Its presentation is usually acute. Nicolau syndrome is commonly seen in patients after intramuscular, intra-articular, or subcutaneous injections of non-steroidal anti-inflammatory drugs, antiepileptics, antipsychotics, antibiotics, antihistamines, and corticosteroids. Immediate diagnosis and management of this syndrome are of great importance. We herein report a rare presentation of Nicolau syndrome in a 36-year-old married male who suffered from paranoid schizophrenia for the past 3 years. The patient presented with dull pain, mild swelling, and necrotic ulceration over the injection site after receiving intramuscular fluphenazine. The patient underwent wound debridement and was given prophylactic antibiotics. Despite a wide range of therapeutic options for the management of Nicolau syndrome described in the literature, there exist limited guidelines for its management.


[Rhabdomyosarcoma of the bladder].
Two cases of rhabdomyosarcoma of the bladder are reported. These tumours mainly occur in male children. They may arise in any part of the bladder and usually cause dysuria, lower urinary tract obstruction and a palpable suprapubic mass. The clinical, radiological and cystoscopic findings are typical. The histology may vary from a myxomatous appearance to a clear rhabdomyosarcomatous lesion. Early radical surgery, combined with radiotherapy and cystostatic agents is the treatment of choice.


Zyxin inhibits the epithelial-mesenchymal transition process in gastric cancer by upregulating SIRT1.
Tumor development relies on the stemness of cancer stem cells, which is regulated by environmental cues. Previous studies have shown that zyxin can inhibit the expression of genes for embryonic stem cell status. In the present study, the expression levels of zyxin protein in cancer tissues and adjacent noncancerous tissues from 73 gastric cancer patients with different clinical stages were analyzed by Western blot. We showed that the relative expression levels of zyxin in gastric cancer tissues (cancer tissues/adjacent tissues) were significantly downregulated in advanced clinical stages. Overexpression of zyxin inhibited the stemness and epithelial-mesenchymal transition (EMT) processes in gastric cancer cells. Zyxin also inhibited the proliferation, migration, and invasion but increased the sensitivity of cancer cells to drugs. Overexpression of zyxin in MKN45 cells inhibited tumor growth in nude mice. We show that the interactions between zyxin and SIRT1 led to the upregulation of SIRT1, reduced acetylation levels of histone H3 K9 and K23, decreased transcription levels of SNAI 1/2, and inhibition of the EMT process. This study demonstrated that zyxin negatively regulates the progression of gastric cancer by inhibiting the stemness of cancer stem cells and EMT. Our findings shed new light on the pathogenesis of gastric cancer.


Experimental epileptology before 1900.
The available English and other major Western European language literature was reviewed to assess the stage of development of experimental epileptology prior to the end of the 19th Century. The relevant investigations had been carried out in animals of various species employing a number of methods of evoking convulsive seizures, mainly mechanical, electrical or chemical stimulation or surgical removal of parts of the cerebral cortex. The studies had produced some conflicting data but (i) allowed the development of a number of reasonably satisfactory experimental models of convulsive epileptic seizures (ii) confirmed that such epileptic seizures arose from the cerebral cortex, and (iii) suggested that for local onset epileptic seizures to become generalised tonic-clonic ones, the opposite motor cortex and probably a brain stem, possibly pontine, centre needed to be involved. No generally acceptable animal model of chronic epilepsy had been developed, and the non-motor manifestations of epileptic seizures were still largely unexplored experimentally. Nevertheless, the pre-1900 investigations not only laid the foundations for the 20th Century expansion of experimental studies on epileptogenesis but also advanced the understanding of epileptic seizure production.


Pharmaceutical care in community pharmacies: practice and research in Estonia.
To describe practice and research related to pharmaceutical care in Estonia following the country's restoration of independence from Russia in 1991. The transition from a Soviet to a free market economy has impacted the healthcare and pharmacy systems in Estonia. Following independence, ownership of community pharmacies was transferred from the State government to individual pharmacists. However, pharmacy ownership is no longer restricted to pharmacists and recent years have seen the emergence of large pharmacy chains. The number of community pharmacies in Estonia increased from 270 in 1992 to 523 in 2007. In addition to dispensing, Estonian pharmacies retain a focus on compounding of extemporaneous products and supply of herbal medications. Research into pharmaceutical care has addressed topics including pharmaceutical policy and the quality of pharmacy services provided at community pharmacies. There has been limited pressure to date from the governmental institutions and patient organizations to introduce extended pharmaceutical services. However, the trend toward providing health services in primary care will create greater responsibilities and new opportunities for community pharmacists. Recent inclusion of clinical pharmacy and interprofessional learning in the undergraduate pharmacy curriculum will help ensure ongoing development of the profession and high-quality pharmacy services in the future. Pharmaceutical care services in Estonian community pharmacies have become more patient-oriented over the past 17 years. However, community pharmacies continue to retain a focus on traditional roles.


Critical evaluation of deep neural networks for wrist fracture detection.
Wrist Fracture is the most common type of fracture with a high incidence rate. Conventional radiography (i.e. X-ray imaging) is used for wrist fracture detection routinely, but occasionally fracture delineation poses issues and an additional confirmation by computed tomography (CT) is needed for diagnosis. Recent advances in the field of Deep Learning (DL), a subfield of Artificial Intelligence (AI), have shown that wrist fracture detection can be automated using Convolutional Neural Networks. However, previous studies did not pay close attention to the difficult cases which can only be confirmed via CT imaging. In this study, we have developed and analyzed a state-of-the-art DL-based pipeline for wrist (distal radius) fracture detection-DeepWrist, and evaluated it against one general population test set, and one challenging test set comprising only cases requiring confirmation by CT. Our results reveal that a typical state-of-the-art approach, such as DeepWrist, while having a near-perfect performance on the general independent test set, has a substantially lower performance on the challenging test set-average precision of 0.99 (0.99-0.99) versus 0.64 (0.46-0.83), respectively. Similarly, the area under the ROC curve was of 0.99 (0.98-0.99) versus 0.84 (0.72-0.93), respectively. Our findings highlight the importance of a meticulous analysis of DL-based models before clinical use, and unearth the need for more challenging settings for testing medical AI systems.


An implantable composite scaffold for amplified chemodynamic therapy and tissue regeneration.
Tissue regeneration and tumor cell killing after surgical resection are the two keys to achieving effective tumor therapy. In this study, an implantable system with combined functions of tumor therapy and tissue repair was constructed. Tannic acid (TA)/Fe3+ nanoparticles with Fenton catalytic activity were loaded with GSH inhibitor BSO drug (BTF), and acted as the therapeutic factor to realize amplified chemodynamic tumor treatment. Bioactive glass (BG) fibers loaded with vascular endothelial growth factor (VEGF) were used as the drug carrier matrix with tissue repair function (BGV). Then the BGV@BTF composite fibers were obtained by anchoring BTF nanoparticles on the surface of BGV fibers. Under tumorous acidic conditions, BTF nanoparticles can be released from the composite fibers, and taken up by tumor cells. Facilitated by BSO with the GSH suppression effect and TA with Fe3+ reducing properties, BTF nanoparticles can realize high oxidative stress in tumor cells and subsequent cell death. In addition, BG fibers and VEGF can both promote tissue regeneration and accelerate postoperative wound healing. The simultaneous suppression of tumor growth and promotion of tissue repair in this work is inspiring in the field of postoperative tumor treatment and recovery.


Evaluation of antimicrobial and antimalarial activities of crude extract, fractions and 4-nerolidylcathecol from the aerial parts of Piper umbellata L. (Piperaceae).
Presently, natural products, such as Piper umbellata L. (Piperaceae), have been evaluated as sources of antimicrobial agents with efficacies against microorganisms. The in vitro antimicrobial activity was performed by broth micro-dilution susceptibility assay, according to the protocols of the National Committee for Clinical Laboratory Standards, and described the antibacterial and antifungal activities of crude ethanolic extract and fractions obtained by partitions sequentially among water-methanol, methylene chloride and ethyl acetate, as well as the major constituent, 4-nerolidylcatechol from the aerial parts of P. umbellata L. Amphotericin B and ciprofloxacin were used as controls. Among the microorganism cultures, hydromethanol fraction demonstrated the pre-eminent antifungal activity. 4-Nerolidylcathecol was the only tested plant component that exhibited activity against all the selected microorganisms, suggesting its great potential as a source for the development of new drugs. In order to estimate the antimalarial activity of P. umbellata L., a micro-dilution method protocol, parasite lactate dehydrogenase assay, with a Plasmodium falciparum Sierra Leone (D6) clone was utilised. The antimalarial agent artemisinin was used as control. 4-Nerolidylcathecol exhibited the best antimalarial activity; however, it was not significant when compared with control. These in vitro results do not justify the use of P. umbellata L. in malaria patients. However, there is a possibility of 4-nerolidylcathecol, after biotransformation, exhibiting a significant antimalarial activity in in vivo assays. However, 4-nerolidylcathecol demonstrated to possess a broad antimicrobial activity which is, in fact, a promising source for the development of new therapeutic agents.


[Antihyperlipidemic effect of iodine egg: Search for the screening method and active ingredients].
A screening method for the hypolipidemic effect of iodine egg and its active fractions have been investigated with Wistar strain male rats fed on a cholesterol-rich diet. The animals were kept on the cholesterol-rich diet for 5 days, and then iodine egg was fed to them in addition to the above diet for 10 more days. The present method was the most adequate for screening the hypolipidemic effect. Iodine egg yolk was fractionated into the following 3 fractions by Folch's method: Protein ( IEY -P), water-soluble ( IEY -A) and lipid ( IEY -L) fractions. The hypolipidemic effect of these fractions was determined with the screening method. The marked hypolipidemic effect was induced by the IEY -L fraction. The serum total cholesterol level in rats that received the fraction was 57% as compared with that of the ch group (fed on the cholesterol-rich diet). The other groups showed no such effect. Serum thyroid hormone levels were not affected by the IEY -L fraction which was found to be the active hypolipidemic fraction of iodine egg. The thyroid gland did not seem to participate directly in such a hypolipidemic effect.


[Smarter Medicine in General Internal Medicine in Hospitals: Where are we now?]
Smarter Medicine in General Internal Medicine in Hospitals: Where are we now? Abstract. In accordance to the "Choosing Wisely" initiative in the United States, Switzerland has launched the "Smarter Medicine" movement in 2014 with the aim to tackle overdiagnosis and overtreatment. A "Smarter Medicine" Top Five List has been developed for Hospital Medicine, pointing out diagnostic tests and treatments with an unfavorable risk-benefit ratio. The five recommendations include: 1) do not order repetitive blood tests or x-rays without specific clinical questions, 2) avoid urinary catheters for the sole purpose of convenience or monitoring urine output in non-critically ill patients, 3) transfuse only the minimum number of red blood cell units necessary, 4) promote the mobilization of hospitalized older patients, and 5) do not prescribe benzodiazepines or other sedative agents to treat insomnia or agitation in older patients. The following article discusses the rationale for the "Smarter Medicine" recommendations for Hospitalists and provides an overview on various interventions implemented in Switzerland and elsewhere aimed at enforcing these recommendations.


The use of reception checks in client pretherapy orientation research.
The psychotherapy research literature abounds with evidence of the problems of premature termination and unsatisfactory outcome, especially among low-SES clients. In attempting to enhance the success rate of therapeutic services, some researchers have instituted pretherapy orientation procedures that convey information to clients with regard to the goals and processes of therapy. Although research in this area has continued for two decades, the efficacy of such procedures has not been established firmly. Even when orientations have demonstrable positive effects, the processes through which these results are achieved usually remain unknown. In order to gain an understanding of these mechanisms, researchers must employ measures to assess directly the immediate effects of the orientation. In a recent study, the authors developed a questionnaire to determine whether clients had attended to and understood a pretherapy videotape presentation and whether they recalled the material 1 month later. The results obtained on this measure facilitated the interpretation of the overall research findings.


Prevalence of Self-Reported Anosmia and Ageusia in Elderly Patients Who Had Been Previously Hospitalized by SARS-CoV-2: The LONG-COVID-EXP Multicenter Study.
We explored two different graph methods for visualizing the prevalence of self-reported post-COVID anosmia and ageusia in a large sample of individuals who had been previously hospitalized in five different hospitals. A cohort of 1266 previously hospitalized COVID-19 survivors participated. Participants were assessed at hospitalization (T0) and at three different follow-up periods: 8.4 (T1), 13.2 (T2), and 18.3 (T3) months after hospital discharge. They were asked about the presence of self-reported anosmia and ageusia that they attributed to infection. Anosmia was defined as a self-perceived feeling of complete loss of smell. Ageusia was defined as a self-perceived feeling of complete loss of taste. Data about hospitalization were recorded from medical records. The results revealed that the prevalence of anosmia decreased from 8.29% (n = 105) at hospitalization (T0), to 4.47% (n = 56) at T1, to 3.27% (n = 41) at T2, and 3.35% (n = 42) at T3. Similarly, the prevalence of ageusia was 7.10% (n = 89) at the onset of SARS-CoV-2 infection (T0), but decreased to 3.03% (n = 38) at T1, to 1.99% (n = 25) at T2, and 1.36% (n = 17) at T3. The Sankey plots showed that only 10 (0.8%) and 11 (0.88%) patients exhibited anosmia and ageusia throughout all the follow-ups. The exponential curves revealed a progressive decrease in prevalence, demonstrating that self-reported anosmia and ageusia improved in the years following hospitalization. The female sex (OR4.254, 95% CI 1.184-15.294) and sufferers of asthma (OR7.086, 95% CI 1.359-36.936) were factors associated with the development of anosmia at T2, whereas internal care unit admission was a protective factor (OR0.891, 95% CI 0.819-0.970) for developing anosmia at T2. The use of a graphical method, such as a Sankey plot, shows that post-COVID self-reported anosmia and ageusia exhibit fluctuations during the first years after SARS-CoV-2 infection. Additionally, self-reported anosmia and ageusia also show a decrease in prevalence during the first years after infection, as expressed by exponential bar plots. The female sex was associated with the development of post-COVID anosmia, but not ageusia, in our cohort of elderly patients previously hospitalized due to COVID-19.


Fluid management in extensive liposuction: A retrospective review of 83 consecutive patients.
Tumescent anesthesia makes it feasible to perform liposuction in an office setting. There are often patients who desire extensive liposuction on approximately 30% of total body surface area, which means the potential of fluid overload. In this study, the charts of 83 patients undergoing extensive liposuction were retrospectively reviewed. The intra-operative fluid ratio was 1.66 for the extensive liposuction. There were no episodes of pulmonary edema, congestive heart failure exacerbation, or other major complications. The average urine output in the operating room, the recovery room, and while on the floors was 1.35, 2.3, and 1.4 mL/kg/hour respectively. Intravenous (IV) fluid administration during operation was minimized to approximately 300 to 500 mL. The total volume of IV injection was also reduced to less than 1500 mL when the patient was in the recovery room and on the hospital floor. Our fluid management strategy in extensive liposuction reflects minimal risk of volume overload. Foley catheters are not applied and patients could resume oral intake in usual, so they can discharge after 6 hours of recovery room stay in our daily practice.


[Intraoperative digital cholangiography during laparoscopic cholecystectomy interventions].
In the last years, laparoscopic cholecystectomy has become the method of choice in the surgical treatment of gallbladder stones. Recently, the same laparoscopic approach has been used to remove choledochus stones. This surgical procedure needs the accurate intraoperative study of the biliary tree with diagnostic imaging modalities to better define the anatomy of the biliary ducts and the possible presence of choledochus stones. To this purpose, transcutaneous and endolaparoscopic US with dedicated probes and intraoperative cholangiography can be performed. In this study, we performed 30 laparoscopic cholecystectomies during which all the patients were submitted to intraoperative cholangiography with a digital fluoroscopic unit. The maneuvers for catheter insertion in the cystic duct and the examination as a whole took 3 to 5 minutes. Intraoperative cholangiography demonstrated choledochus stones in 3 patients, while preoperative US detected them in 2 patients only. In 8 cases the dynamic study, carried out with digital image acquisition, allowed to refer the biliary duct filling defects to artifacts caused by the presence of air bubbles. In conclusion, intraoperative cholangiography, also during endolaparoscopic cholecystectomy, plays a major role in the surgical assessment of the biliary tree. When the procedure was performed with a digital fluoroscopic unit, its diagnostic accuracy was higher and the images on the TV monitor were better visualized.


Schizoaffective disorders.
Schizoaffective disorders should be divided by polarity. Much of the data on schizoaffective mania indicate that most cases are very similar in symptomatology, course, family history, and response to treatment to bipolar affective disorder patients. They may be the most severe episodic affective disorder patients. A few are probably excited schizophrenics. The data on the schizoaffective depressed patients are far more confusing. No clear data emerge from these studies, except when using biological markers of sleep and dexamethasone suppression on these patients. Future work must be concentrated on these patients.


Polydimethylsiloxane versus polytetrafluoroethylene for vocal fold medialization: histologic evaluation in a rabbit model.
The objective is to study the tissue reaction of the paralyzed vocal cord in response to the injection of particulate plastics in a rabbit model. Forty-five New Zealand rabbits with surgical vocal-fold paralysis were used in the study. Histologic reactions of the larynx and the regional lymph nodes were analyzed by a single blinded pathologist at 6 weeks and 6 months after a vocal-cord injection of Teflon or of silicone elastomer. Macroscopic studies of the liver, lungs, spleen, kidney, and brain were performed. The histological study showed a greater proportion of chronic granulomatous inflammation in animals injected with silicone than in those injected with Teflon. The immunohistochemical study showed a higher degree of phagocytosis of Teflon particles than of the silicone particles. The silicone group presented a more severe fibrous reaction than the Teflon group, but the difference was not significant. No migration particles were found. It is concluded that silicone, having a greater viscosity than Teflon because of the size of its particles, induces more fibrosis and a larger proportion of foreign giant cells in the host. Due to this histological reaction, silicone particles present greater anchorage and stability.


Multistep phosphorylation by oncogenic kinases enhances the degradation of the NF2 tumor suppressor merlin.
Mutations in the Neurofibromatosis 2 gene (NF2) predispose to tumors of the nervous system, mainly schwannomas and meningiomas. The NF2 gene encodes for the tumor suppressor protein merlin (moesin-ezrin-radixin-like protein), which functions as a linker between the plasma membrane and the cytoskeleton. Carboxyterminal phosphorylation affects merlin activity, but many open questions on the regulation of merlin function still remain. The phosphoinositide 3-kinase/Akt pathway is activated in human vestibular schwannoma, suggesting a role for Akt-dependent merlin regulation in the formation of these tumors. In this study, we identify merlin serine 10 as a novel substrate for Akt phosphorylation. We demonstrate that this N-terminal phosphorylation directs merlin for proteasome-mediated degradation and affects merlin binding to the E3 ligase component DCAF1. Our data indicate that sequential phosphorylation of merlin C- and N-terminus by different oncogenic kinases targets merlin for degradation and thus downregulates its activity. On the basis of these findings, we propose a model for a posttranslational mechanism of merlin inactivation.


Leber's hereditary optic neuropathy mitochondrial DNA mutations at nucleotides 11778 and 3460 in multiple sclerosis.
Leber's hereditary optic neuropathy (LHON) can be difficult to distinguish from optic neuritis seen in multiple sclerosis (MS). About half of the LHON patients harbor a mutation at nucleotide (nt) 11778 in the mitochondrial (mt) DNA. In addition, mutations at nt-3460 and nt-14484 have been associated with LHON. An association of LHON and MS has been suspected for decades, and, recently, the LHON nt-11778 and nt-3460 mtDNA mutations have been found in several patients with MS or MS-like disease. We attempted to determine which MS patients should be evaluated further for LHON mutations. We screened 103 clinically definite MS patients (age range from 18 to 72 years, 27 men and 76 women) for the LHON nt-11778 and nt-3460 mtDNA mutations. Neither mutation was identified in the patients. Our findings confirm previous reports which found that both LHON mutations are rare in unselected MS patients. The reports to date suggest that MS patients with peripapillary teleangiectasia typical of LHON, with relatives harboring LHON or with early severe bilateral optic neuropathy, particularly if female, should be further evaluated for LHON mutations.


Self-Assembly of Charged Nanoparticles by an Autocatalytic Reaction Front.
In this work we present that aggregation of charged and pH sensitive nanoparticles can be spatiotemporally controlled by an autonomous way using the chlorite-tetrathionate autocatalytic front, where the front regulates the electrostatic interaction between nanoparticles due to protonation of the capping (carboxylate-terminated) ligand. We found that the aggregation and sedimentation of nanoparticles in liquid phase with the effect of reversible binding of the autocatalyst (H(+)) play important roles in changing the front stability (mixing length) and the velocity of the front in both cases when the fronts propagate upward and downward. Calculation of interparticle interactions (electrostatic and van der Waals) with the measurement of front velocity revealed that the aggregation process occurs fast (within a few seconds) at the front position.


Propagation characteristics of pulverized coal and gas two-phase flow during an outburst.
Coal and gas outbursts are dynamic failures that can involve the ejection of thousands tons of pulverized coal, as well as considerable volumes of gas, into a limited working space within a short period. The two-phase flow of gas and pulverized coal that occurs during an outburst can lead to fatalities and destroy underground equipment. This article examines the interaction mechanism between pulverized coal and gas flow. Based on the role of gas expansion energy in the development stage of outbursts, a numerical simulation method is proposed for investigating the propagation characteristics of the two-phase flow. This simulation method was verified by a shock tube experiment involving pulverized coal and gas flow. The experimental and simulated results both demonstrate that the instantaneous ejection of pulverized coal and gas flow can form outburst shock waves. These are attenuated along the propagation direction, and the volume fraction of pulverized coal in the two-phase flow has significant influence on attenuation of the outburst shock wave. As a whole, pulverized coal flow has a negative impact on gas flow, which makes a great loss of large amounts of initial energy, blocking the propagation of gas flow. According to comparison of numerical results for different roadway types, the attenuation effect of T-type roadways is best. In the propagation of shock wave, reflection and diffraction of shock wave interact through the complex roadway types.


A hybrid of mPEG-b-PCL and G1-PEA dendrimer for enhancing delivery of antibiotics.
The development of novel materials is essential for the efficient delivery of drugs. Therefore, the aim of the study was to synthesize a linear polymer dendrimer hybrid star polymer (3-mPEA) comprising of a generation one poly (ester-amine) dendrimer (G1-PEA) and a diblock copolymer of methoxy poly (ethylene glycol)-b-poly(ε-caprolactone) (mPEG-b-PCL) for formulation of nanovesicles for efficient drug delivery. The synthesized star polymer was characterized by FTIR, 1H and 13C NMR, HRMS, GPC and its biosafety was confirmed by MTT assays. Thereafter it was evaluated as a nanovesicle forming polymer. Vancomycin loaded nanovesicles were characterized using in vitro, molecular dynamics (MD) simulations and in vivo techniques. MTT assays confirmed the nontoxic nature of the synthesized polymer, the cell viability was 77.23 to 118.6%. The nanovesicles were prepared with size, polydispersity index and zeta potential of 52.48 ± 2.6 nm, 0.103 ± 0.047, -7.3 ± 1.3 mV respectively, with the encapsulation efficiency being 76.49 ± 2.4%. MD simulations showed spontaneous self-aggregation of the dendritic star polymer and the interaction energy between the two monomers was -146.07 ± 4.92, Van der Waals interactions playing major role for the aggregates stability. Human serum albumin (HSA) binding studies with Microscale Thermophoresis (MST) showed that the 3-mPEA did not have any binding affinity to the HSA, which showed potential for long systemic circulation. The vancomycin (VCM) release from the drug loaded nanovesicles was found to be slower than bare VCM, with an 65.8% release over a period of 48 h. The in vitro antibacterial test revealed that the drug loaded nanovesicles had 8- and 16-fold lower minimum inhibitory concentration (MIC) against methicillin sensitive Staphylococcus aureus and methicillin-resistant S. aureus strains (MRSA) compared to free drug. The flow cytometry study showed 3.9-fold more dead cells of MRSA in the population when samples were treated with the drug loaded nanovesicles than the bare VCM at concentration 0.488 μg/mL. An in vivo skin infection mice model showed a 20-fold reduction in the MRSA load in the drug loaded nanovesicles treated groups compared to bare VCM. These findings confirmed the potential of 3-mPEA as a promising biocompatible effective nanocarrier for antibiotic delivery.


Combined Intervention of Physical Activity, Aerobic Exercise, and Cognitive Exercise Intervention to Prevent Cognitive Decline for Patients with Mild Cognitive Impairment: A Randomized Controlled Clinical Study.
This study aimed to investigate the association between a dual-task intervention program and cognitive and physical functions. In a randomized controlled trial, we enrolled 49 individuals with MCI. The MCI diagnosis was based on medical evaluations through a clinical interview conducted by a dementia specialist. Cognitive assessments were performed by neuropsychologists according to standardized methods, including the MMSE and modified Alzheimer's disease Assessment Scale-Cognitive Subscale (ADAS-Cog), both at baseline and at 3 months follow-up. The program comprised physical activity and behavior modification, aerobic exercise, and a cognitive and exercise combined intervention program. Analysis of the subjects for group-time interactions revealed that the exercise group exhibited a significantly improved ADAS-Cog, working memory, and executive function. Total physical activity levels were associated with improvements in working memory function and the modified ADAS-Cog score, and the associations were stronger for daily moderate intensity activity than for daily step count. The 24-week combined intervention improved cognitive function and physical function in patients with MCI relative to controls. Encouraging participants to perform an additional 10 min of moderate physical activity under supervision, during ongoing intervention, may be more beneficial to prevent cognitive decline and improve exercise adherence.


Postural influence on intracranial and cerebral perfusion pressure in ambulatory neurosurgical patients.
We evaluated postural effects on intracranial pressure (ICP) and cerebral perfusion pressure [CPP: mean arterial pressure (MAP) - ICP] in neurosurgical patients undergoing 24-h ICP monitoring as part of their diagnostic workup. We identified nine patients (5 women, age 44 ± 20 yr; means ± SD), who were "as normal as possible," i.e., without indication for neurosurgical intervention (e.g., focal lesions, global edema, abnormalities in ICP-profile, or cerebrospinal fluid dynamics). ICP (tip-transducer probe; Raumedic) in the brain parenchyma (n = 7) or in the lateral ventricles (n = 2) and cardiovascular variables (Nexfin) were determined from 20° head-down tilt to standing up. Compared with the supine position, ICP increased during 10° and 20° of head-down tilt (from 9.4 ± 3.8 to 14.3 ± 4.7 and 19 ± 4.7 mmHg; P < 0.001). Conversely, 10° and 20° head-up tilt reduced ICP to 4.8 ± 3.6 and 1.3 ± 3.6 mmHg and ICP reached -2.4 ± 4.2 mmHg in the standing position (P < 0.05). Concordant changes in MAP maintained CPP at 77 ± 7 mmHg regardless of body position (P = 0.95). During head-down tilt, the increase in ICP corresponded to a hydrostatic pressure gradient with reference just below the heart, likely reflecting the venous hydrostatic indifference point. When upright, the decrease in ICP was attenuated, corresponding to formation of a separate hydrostatic gradient with reference to the base of the skull, likely reflecting the site of venous collapse. ICP therefore seems to be governed by pressure in the draining veins and collapse of neck veins may protect the brain from being exposed to a large negative pressure when upright. Despite positional changes in ICP, MAP keeps CPP tightly regulated.


A Universal Upconversion Sensing Platform for the Sensitive Detection of Tumour-Related ncRNA through an Exo III-Assisted Cycling Amplification Strategy.
Here, a sensitive and universal noncoding RNA (ncRNA) upconversion sensing nanoplatform is developed. Gold nanoparticles bearing one hairpin DNA (Hp) molecule are conjugated to the linker DNA modified NaYF4 :Yb, Er@NaYF4 upconversion nanoparticles by DNA hybridization, leading to quenching of the upconversion emission through fluorescence resonance energy transfer. A signal DNA (SDNA) sequence is designed to open Hp, recovering the upconversion emission. To achieve universality and high sensitivity of the nanoprobe, an exonuclease III (Exo III)-assisted cycling amplification strategy is introduced. A multifunctional hairpin DNA (mHp) containing ncRNA recognition sequence and SDNA sequence is designed to recognize ncRNA and trigger Exo III as a biocatalyst to stepwise disintegrate itself, releasing both ncRNA and SDNA. The released ncRNA can be reused to release more SDNA, which greatly improves the sensing sensitivity. By changing the recognition portion of mHp, various ncRNA can be detected. The sensitive detection of both homeobox (HOX) transcript antisense RNA segment and miR-21 is achieved with this novel strategy, even in human serum, indicating the universality and sensitivity of the proposed strategy. Additionally, the expression level of miR-21 in human breast cancer cell (MCF-7) lysate is successfully measured, suggesting its potential in clinical diagnosis.


Canine heartworms in coyotes in Illinois.
Canine heartworm (Dirofilaria immitis) disease affects wild canids and may be a factor impacting the health and population dynamics of coyotes (Canis latrans). Coyotes may serve also as a potential reservoir for transmission of these parasites to domestic dogs. We investigated 920 coyotes harvested by hunters and trappers throughout Illinois (USA) from 1995-1997. The objectives of the study were to: 1) survey the regional prevalence and intensity of heartworms in coyotes in Illinois, 2) determine whether heartworm intensity correlates with physical condition, particularly body weight and winter fat levels, and 3) evaluate the relationship between heartworm infections and the reproductive success of females. Prevalence of heartworms statewide was 16.0%. Prevalence was significantly higher in males (17.7%) than in females (14.1%; P = 0.04) and was higher in the older age-classes (P < 0.0001). The regional prevalence of heartworms increased from northern to southern Illinois. Intensity ranged from 1 to 111 with a mean of 8.7 (SD = 13.2) worms. Intensities did not differ significantly between sexes (P = 0.53) or among age-classes (P = 0.84). Most infected coyotes had low intensity infections, 78.2% carried < 12 heartworms, 11.6% had 12-24 worms, and 10.2% were infected with > 24 worms. Body weights were not correlated with the presence of heartworms, nor were levels of kidney fat and marrow fat. However, reproductive success was lower in infected females. The percent of yearling females that bred was lower among infected females, as was the number of offspring produced by adults > or = 3.5 yr old. Our study demonstrates that heavy infections adversely affect fur quality and reduce fecundity of some females, but these effects are small and few coyotes (4.1%) had enough worms to trigger them. Coyote populations have increased in Illinois during the past 20 yr, but prevalence and intensity of heartworm disease appears to have changed little in that period. We conclude that heartworm disease is only a minor factor influencing coyote population dynamics in Illinois.


Oriented Built-in Electric Field Introduced by Surface Gradient Diffusion Doping for Enhanced Photocatalytic H2 Evolution in CdS Nanorods.
Element doping has been extensively attempted to develop visible-light-driven photocatalysts, which introduces impurity levels and enhances light absorption. However, the dopants can also become recombination centers for photogenerated electrons and holes. To address the recombination challenge, we report a gradient phosphorus-doped CdS (CdS-P) homojunction nanostructure, creating an oriented built-in electric-field for efficient extraction of carriers from inside to surface of the photocatalyst. The apparent quantum efficiency (AQY) based on the cocatalyst-free photocatalyst is up to 8.2% at 420 nm while the H2 evolution rate boosts to 194.3 μmol·h-1·mg-1, which is 58.3 times higher than that of pristine CdS. This concept of oriented built-in electric field introduced by surface gradient diffusion doping should provide a new approach to design other types of semiconductor photocatalysts for efficient solar-to-chemical conversion.


Comparative study of quantum Otto and Carnot engines powered by a spin working substance.
Quantum Otto and Carnot engines have recently been receiving attention due to their ability to achieve high efficiencies and powers based on the laws of quantum mechanics. This paper discusses the theory, progress, and possible applications of quantum Otto and Carnot engines, such as energy production, cooling, and nanoscale technologies. In particular, we investigate a two-spin Heisenberg system that works as a substance in quantum Otto and Carnot cycles while exposed to an external magnetic field with both Dzyaloshinsky-Moriya and dipole-dipole interactions. The four stages of engine cycles are subject to analysis with respect to the heat exchanges that occur between the hot and cold reservoirs, alongside the work done during each stage. The operating conditions of the heat engine, refrigerator, thermal accelerator, and heater are all achieved. Moreover, our results demonstrate that the laws of thermodynamics are strictly upheld and the Carnot cycle produces more useful work than that of the Otto cycle.


Antigen presenting cells in the skin of a patient with hair loss and systemic lupus erythematosus.
Hair loss is one of the most striking clinical features of active systemic lupus erythematosus (SLE), however, very few studies have investigated the immunological features of this process. We describe a 33 years old female who presented with scalp hair loss and arthralgias. Physical examination revealed erythematous plaques on the nose and scalp, with bitemporal hair loss. Scalp biopsies revealed epidermal hyperkeratosis, with a mild interface infiltrate of lymphocytes and histiocytes and a superficial and deep, perivascular and periadnexal infiltrate of mostly CD4 positive cells. Antibodies to HAM 56, CD68, CD1a, S-100, mast cell tryptase and c-kit/CD117 were strongly positive around the hair follicles, and in the adjacent sebaceous glands. We present the first report showing a significant presence of several antigen presenting cells around the hair follicular units in a patient with alopecia in active SLE. Today, antigen presenting cells and dendritic cells (DC) are modeled as the master regulators of human immunity. One aspect that has become clearly appreciated is the great diversity of DC subtypes, each with considerable functional differences. Thus, we suggest that APC and DCs are equipped with Pattern Recognition Receptors (PRRs) to some hair follicular unit antigens; that these innate sensors recognize conserved molecular patterns on self- tissue, and play a significant role in the pathophysiology of alopecia in SLE patients.


Thyrotrope expression and thyroid hormone inhibition map to different regions of the mouse glycoprotein hormone alpha-subunit gene promoter.
The alpha-subunit gene of the glycoprotein hormones is normally expressed in pituitary thyrotropes and gonadotropes and in placental cells. Thus, this gene must contain elements that mediate expression and hormonal responses in different cell types. The localization of DNA regions important for expression and regulation of the alpha-subunit gene in thyrotrope cells has not previously been reported. In these studies luciferase expression constructs containing 1700 basepairs of 5' flanking DNA derived from the mouse alpha-subunit gene were introduced by electroporation into freshly dispersed cells from TSH-producing mouse pituitary tumors (TtT 97). This promoter functioned with greater efficiency in thyrotropes than in nonthyrotrope pituitary GH4 cells and L-cell fibroblasts. Primer extension confirmed that transcription from the alpha-subunit constructs initiated at the same site as the endogenous gene. Studies using 5' truncations showed a progressive loss of alpha-subunit promoter activity in thyrotropes between -480 and -120, with regions upstream of -254 contributing substantially to expression in thyrotrope cells. Thyroid hormone inhibited alpha-subunit promoter activity in a dose-dependent fashion, although in vivo treatment of tumors with thyroid hormone before transfection was necessary to achieve maximal inhibition. Thyroid hormone inhibition of alpha-subunit promoter activity also occurred in GH4 cells, but no effect was observed in L-cells. Studies using 5' truncations localized a region responsible for thyroid hormone inhibition between -62 and +43, encompassing the TATA sequence and the transcriptional initiation site. When this region was compared to the thyroid hormone inhibitory regions of the alpha-subunit genes from other species and the mouse TSH beta-subunit gene, a 6-basepair motif, 5' (G/A)GTG(G/A)G 3', emerged as a possible consensus sequence for a thyroid hormone inhibitory element.


Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.
We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single-cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.


The relationship between resting energy expenditure and weight loss in benign and malignant disease.
The relationship between cancer, weight loss, and resting energy expenditure (REE) has been investigated in 136 patients using indirect calorimetry. Ninety-one patients had gastric, colorectal, or nonsmall cell bronchial neoplasm, seven patients had other malignancies, and 38 patients had nonmalignant illness. Four groups were studied: weight stable cancer patients (CWS: N = 56), weight losing cancer patients (CWL: N = 42), weight stable patients with nonmalignant illness (NCWS: N = 22), and weight losing patients with nonmalignant illness (NCWL: N = 16). In each group REE correlated significantly with body weight, metabolic body size, and lean body mass (LBM: estimated from total body water measurements). The closest correlation was between REE and lean body mass, with the slope of the CWL regression line differing significantly from that of the CWS (p less than 0.05) and NCWS (p less than 0.02) groups. However, there was no difference in REE expressed as kcal/kg LBM/d between the groups. The slopes of the regressions between REE and LBM were almost identical when all cancer patients were compared with all patients with nonmalignant illness. However, when all weight stable patients were compared with all weight losing patients, there was a highly significant difference between the slopes of the regressions (p less than 0.005). This indicates that the weight losing state rather than the presence or absence of cancer is responsible for an alteration in the relationship between REE and LBM. There were no differences in REE between the different tumor types. It is concluded that REE is not elevated in patients with gastric, colorectal, or nonsmall cell bronchial cancer. Elevation of REE contributes very little to the etiology of cancer cachexia.


Effectiveness and Adverse Effects of Risperidone in Children with Autism Spectrum Disorder in a Naturalistic Clinical Setting at a University Hospital in Oman.
This study aimed at examining the effectiveness of treating children with autism spectrum disorder (ASD) who present with irritability, aggression, and disruptive behavior at the Sultan Qaboos University Hospital (SQUH) in Muscat, Oman, with risperidone, and to note any sex-based differences among this cohort. This was a retrospective study conducted at the Department of Behavioral Medicine at SQUH over two years from January 2017 to December 2018. This study included all children aged 3 to 18 years attending the Child and Adolescent Mental Health Service (CAMHS) outpatient clinic with a diagnosis of ASD, based on the DSM-5 criteria, and comorbid disruptive behavior, who had been prescribed risperidone. This study identified 95 ASD patients (72 males). Male patients' BMI score after 12 months of risperidone treatment showed an increase by 0.62 (1.57 SD; P=0.001); however, there was no significant change among female patients. Somnolence was noted in 69.6% of female patients as compared to 34.7% of males (P=0.003). Among those with a family history of ASD, 5 out of 17 patients had treatment success (29.4%), whereas 70 out of 78 patients (90.0%) who did not have a similar history had successful treatment. In conclusion, low-dose risperidone monotherapy is effective and well tolerated among some children with ASD who present with disruptive behavior in a naturalistic clinical setting. However, we found that some of the side effects, such as weight gain and somnolence, were concerning.


Use of cryopreserved donor corneal tissues first time in India for therapeutic penetrating keratoplasty during COVID-19 pandemic - A case series.
Coronavirus disease (COVID-19) pandemic caused restricted eye retrieval leading to acute scarcity of donor corneas. Nine patients with perforated corneas needed urgent donor tissues where we used 10 cryopreserved corneal tissues for therapeutic penetrating keratoplasty (TPK). Repeat TPK was done in one eye for recurrence of infection. The anatomical integrity of the eyeball was maintained in seven eyes, while two eyes were lost to phthisis. Thus, cryopreserved corneas can be taken into consideration for TPK when other donor tissues are not available.


A study of experimental hypersplenism.
Methyl cellulose syndrome induced by repeated i. p. injections of methyl cellulose (MC) was followed in experimental rats. Following application of 2--4 MC injections early haematological changes are observed including increased values of reticulocytes, development of serum aggregation factor having anti-erythrocyte antibody nature and altered filtrability of non-washed erythrocytes. Later alterations developing with further MC injections (8-32) are characterized by expressive splenic enlargement, by decrease in erythrocyte and platelet values and by additional increase in number of reticulocytes. The cause of anaemia is pooling and sequestration of erythrocytes in the spleen and haemodilution from hypervolaemia blood plasma. The decreased platelet amount is the result of reduced survival time of platelets due to their increased sequestration in the spleen. Haematological changes are normalized after splenectomy. This picture resembles to a great extent human hypersplenism.


[Role of pharmacists during serious natural disasters: report from Ishinomaki, the disaster-struck city].
On August 31, 2011, five months after the Great East Japan Earthquake, Miyagi prefecture reported 9357 dead and 2288 missing citizens, whereas Ishinomaki reported 4753 dead and 1302 missing citizens. A total of 12 pharmacists in Miyagi prefecture had lost their lives. Many medical institutions at the time were rendered out of service due to damage. Ishinomaki Red Cross had to serve as headquarters of disaster medicine management for the area. The government of Miyagi and Miyagi Pharmacist Association signed a contract regarding the provision of medical and/or other related tasks. Nevertheless, the contract was not fully applied given the impact of the tsunami, which caused chaos in telecommunication, traffic, and even the functions of the government. Given the nature of the disaster, medical teams equipped only with emergency equipment could not offer appropriate response to the needs of patients with chronicle diseases. "Personal medicine logbook" and pharmacists were keys to relief works during the disaster. Pharmacists played a critical role not only for self-medication by distributing over the counter (OTC) drugs, but also in hygiene management of the shelter. Apart from the establishment of an adoptive management system for large-scale natural disasters, a coordinated system for disaster medical assistance team (DMAT), Japanese Red Cross (JRC), Self-Defense Force (SDF), and other relief work organizations was imperative.


Ventilatory response of healthy Nigerians and Europeans to carbon dioxide.
Ventilatory response to carbon dioxide was measured by the rebreathing technique in 32 Nigerians and 20 Europeans resident in Lagos. Although the Europeans had larger physical characteristics and lung volumes than Nigerians, the responses to carbon dioxide were similar. The range of ventilatory response was 0,55 to 4,2 and 0,7 to 3,7 1/min/mm Hg for Nigerians and Europeans respectively. These results show that Nigerians are as sensitive to carbon dioxide as their European counterparts.


Antifreeze proteins enable plants to survive in freezing conditions.
Overwintering plants secrete antifreeze proteins (AFPs) to provide freezing tolerance. These proteins bind to and inhibit the growth of ice crystals that are formed in the apoplast during subzero temperatures. Antifreeze activity has been detected in more than 60 plants and AFPs have been purified from 15 of these, including gymnosperms, dicots and monocots. Biochemical characterization of plant antifreeze activity, as determined by the high ice recrystallization inhibition (IRI) activities and low thermal hysteresis (TH) of AFPs, showed that their main function is inhibition of ice crystal growth rather than the lowering of freezing temperatures. However, recent studies showed that antifreeze activity with higher TH also exists in plants. Calcium and hormones like ethylene and jasmonic acid have been shown to regulate plant antifreeze activity. Recent studies have shown that plant AFPs bind to both prism planes and basal planes of ice crystals by means of two flat ice binding sites. Plant AFPs have been postulated to evolve from the OsLRR-PSR gene nearly 36 million years ago. In this review, we present the current scenario of plant AFP research in order to understand the possible potential of plant AFPs in generation of freezing-tolerant crops.


The role of putrescine in the regulation of proteins and fatty acids of thylakoid membranes under salt stress.
Polyamines can alleviate the inhibitory effects of salinity on plant growth by regulating photosynthetic efficiency. However, little information is available to explain the specific mechanisms underlying the contribution of polyamines to salt tolerance of the photosynthetic apparatus. Here, we investigated the role of putrescine (Put) on the photosynthetic apparatus of cucumber seedlings under salt stress. We found that NaCl stress resulted in severe ion toxicity and oxidative stress in cucumber chloroplasts. In addition, salinity caused a significant increase in the saturated fatty acid contents of thylakoid membranes. Put altered unsaturated fatty acid content, thereby alleviating the disintegration of thylakoid grana lamellae and reducing the number of plastoglobuli in thylakoid membranes. BN-PAGE revealed Put up-regulated the expression of ATP synthase, CP47, D1, Qb, and psbA proteins and down-regulated CP24, D2, and LHCII type III in NaCl-stressed thylakoid membranes. qRT-PCR analysis of gene expression was used to compare transcript and protein accumulation among 10 candidate proteins. For five of these proteins, induced transcript accumulation was consistent with the pattern of induced protein accumulation. Our results suggest that Put regulates protein expression at transcriptional and translational levels by increasing endogenous polyamines levels in thylakoid membranes, which may stabilise photosynthetic apparatus under salt stress.


Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons.
A tonic inhibitory conductance mediated by GABA(A) receptors that supplements the phasic inhibition produced by IPSCs has been identified in the hippocampus and cerebellum. It is presently unknown whether tonic and phasic inhibitions are mediated by GABA(A) receptors with different subunit assemblies. Here we demonstrate that a low concentration (200 nm) of the highly specific competitive GABA(A) antagonist SR95531 (gabazine) reduces phasic inhibition in hippocampal granule cells by 71% but has no effect on tonic inhibition, whereas a high concentration (10 microm) of the antagonist blocked both conductances. These findings are consistent with tonic and phasic conductances being mediated by different GABA(A) receptor subtypes with different affinities for GABA.