How common is depression in patients with polymyalgia rheumatica?
Depression is common in inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus and negatively impacts on outcomes. Given the long-term nature of polymyalgia rheumatica (PMR) and its glucocorticoid treatment, these patients may be at an increased risk of depression, although few studies exist to date. This study aimed to investigate the prevalence of, and factors associated with, depression in PMR patients. Prevalent PMR patients (with a first diagnostic code for PMR in the last 3 years) were mailed a postal questionnaire (n = 704) examining PMR symptoms, glucocorticoid use and patient reported comorbidities. Depressive symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8), with a score of ≥10 defined as current depressive symptoms. Logistic regression was used to examine association between demographics, comorbidity and current depressive symptoms. Five hundred fifty (78%) patients responded, of which 365 (66%) were female, with a mean (SD) age of 74.1 years (8.4). The prevalence of current depressive symptoms was 15% (n = 81) and was significantly associated with female gender: OR 1.87 (95%CI 1.08-3.22), current PMR symptoms: OR 2.1 (1.11-3.97), self-reported acid reflux: OR 1.75 (1.05-2.93) and diabetes: OR 2.86 (1.6-5.09). Older patients were less likely to report current depressive symptoms (OR 0.35 (0.13-0.9) for those >80 years versus those aged 50-59 years). Depressive symptoms are common in patients with PMR patients, especially younger patients and those with comorbidities. Clinicians should consider screening these patients for depressive symptoms and managing them appropriately, as untreated depression may negatively impact on health-related outcomes and quality of life.


Banxia Xiexin decoction: A review on phytochemical, pharmacological, clinical and pharmacokinetic investigations.
Banxia Xiexin decoction (BXD), a famous traditional Chinese prescription constituted by Pinelliae Rhizoma, Zingiberis Rhizoma, Scutellariae Radix, Coptidis Rhizoma, Ginseng Radix et Rhizoma, Jujubae Fructus and Glycyrrhizae Radix et Rhizoma Praeparata Cum Mell, has notable characteristics of acrid-opening, bitter down-bearing and sweet-tonification, interfering with tumors, gastrointestinal diseases, central nervous system diseases and much more. Based on the wide clinical applications, current investigations of BXD focused on several aspects: chemical analysis to explore the underlying substrates responsible for the therapeutic effects; basic studies on pharmacological actions of the whole prescription or of those representative ingredients to demonstrate the intriguing molecular targets for specific pathological processes; pharmacokinetic feature studies of single or all components of BXD to reveal the chemical basis and synergistic actions contributing to the pharmacological and clinically therapeutic effects. In this review, we summarized the main achievements of phytochemical, pharmacological, clinical and pharmacokinetic profiles of BXD and its herbal or pharmacologically active chemicals, as well as discussions of our understanding which further reveals the significance of BXD clinically.


Cryptococcus neoformans and Streptococcus pneumoniae co-infection in post-traumatic meningitis in a patient with unknown HIV status.
Meningitis is a serious disease associated with considerable morbidity and mortality. Mixed meningeal infections due to bacteria and fungi are exceptionally rare. Here we report a case of meningeal co-infection with cryptococcus neoformans and streptococcus pneumoniae in a patient with unknown human immunodeficiency virus status. Because of the rarity of such cases, stringent screening of every cerebrospinal fluid specimen to exclude the presence of multiple pathogens is imperative. Assessment of patients for immunodeficiencies in case of isolation of an opportunistic organism like cryptococcus is also needed.


Prognostic Role of Measurement of Renal Resistive Index in Systemic Sclerosis.
The spectrum of vascular involvement in systemic sclerosis (SSc) includes digital ulcers, gangrene, Raynaud's phenomenon, renovascular disease, and pulmonary hypertension (PH). Recognition of markers of subclinical vascular disease in SSc is an area of active research, but such studies are limited. This study assesses the role of measurement of the renal resistive index (RRI) as an early marker of renal and systemic vasculopathy. It is a step forward towards examining the possibility of a "unified vascular phenotype' in SSc. In this single-centre prospective study, RRI was calculated for SSc patients >18 years age. Elevated RRI (>0.7) was correlated with renal function (eGFR and proteinuria) and systemic vasculopathy manifestations like digital ulcers, digital infarcts, and PH. A total of 73 patients with mean (SD) age 41.8(10.9) years were included. Mean (SD) RRI in the right and left renal artery was 0.65(0.08) and 0.66(0.07), respectively. 16 (21.9%) patients had elevated RRI (>0.7). A strong negative correlation was noted between elevated RRI and eGFR (r= -0.96, p=0.03). The percentage of patients with overt proteinuria was higher in the group with elevated RRI (20% versus 7%) (p=0.16). Similarly, digital ulcers (56% vs 33%) and digital pitting (50% vs 35%.) were numerically higher in the group with raised RRI, although statistical significance was not reached because of small numbers (p=0.09 and 0.28, respectively). No correlation of RRI with PH was identified. RRI correlates well with asymptomatic renal dysfunction and holds promise in the assessment of systemic vasculopathy. However, validation in studies with a larger sample size is needed.


Aural Rehabilitation for Older Adults with Hearing Loss: Impacts on Quality of Life-A Systematic Review of Randomized Controlled Trials.
Few systematic reviews have been conducted regarding aural rehabilitation for adults with hearing loss, with none specifically targeting the older adult population. With prevalence rates of hearing loss being highest in older adults, examining the effects of aural rehabilitation on this population is warranted. To evaluate the effects of aural rehabilitation on quality of life in an older adult population presenting with hearing loss. Studies with adults presenting with hearing loss, ≥50 yr of age, with or without hearing aids, receiving interventions such as auditory training, speech-reading, communication strategies training, speech tracking, counseling, or a combination of approaches, and measuring outcomes related to quality of life, in an individual or group format, with or without significant others and with no limitations as to year of publication. Searches in six databases, as well as results from hand-searching, gray literature, and cross-referencing of articles, yielded 386 articles. Of the 145 assessed as full-text articles for eligibility, 8 studies met inclusion criteria. A component-based risk of bias assessment, as recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. No effect sizes were found in group interventions measuring outcomes related to quality of life, such as mental and emotional functions, environmental factors, participation restrictions, and activity limitations. An intervention effect regarding participation was found for a self-administered home training program, but an effect size was unavailable. Small-to-medium effect sizes were found in one of two individual communication training programs, for which outcomes related to quality of life, such as emotional functions, activities, participation, and environmental factors were measured. The results of the component-based risk of bias assessment indicated that the quality of reporting was poor, thus compromising the internal validity of included primary studies. Our results indicate that the combined body of evidence in support of aural rehabilitation for older adults with hearing loss is not sufficient to draw any firm conclusions. We identify a need for more rigorous research to guide clinical decision-making.


Platicon microcomb generation using laser self-injection locking.
The past decade has witnessed major advances in the development and system-level applications of photonic integrated microcombs, that are coherent, broadband optical frequency combs with repetition rates in the millimeter-wave to terahertz domain. Most of these advances are based on harnessing of dissipative Kerr solitons (DKS) in microresonators with anomalous group velocity dispersion (GVD). However, microcombs can also be generated with normal GVD using localized structures that are referred to as dark pulses, switching waves or platicons. Compared with DKS microcombs that require specific designs and fabrication techniques for dispersion engineering, platicon microcombs can be readily built using CMOS-compatible platforms such as thin-film (i.e., thickness below 300 nm) silicon nitride with normal GVD. Here, we use laser self-injection locking to demonstrate a fully integrated platicon microcomb operating at a microwave K-band repetition rate. A distributed feedback (DFB) laser edge-coupled to a Si3N4 chip is self-injection-locked to a high-Q ( > 107) microresonator with high confinement waveguides, and directly excites platicons without sophisticated active control. We demonstrate multi-platicon states and switching, perform optical feedback phase study and characterize the phase noise of the K-band platicon repetition rate and the pump laser. Laser self-injection-locked platicons could facilitate the wide adoption of microcombs as a building block in photonic integrated circuits via commercial foundry service.


Can there be a moral obligation to participate in biomedical research?
In clinical medicine, the moral obligation to care for the individual patient is absolute. Patient care means at least and by negative terms to minimize any risk of treatment. In this context, the question arises about the compatibility of clinical ethics and human biomedical research ethics. Or conversely, is there a common ground between the two? At the opposite end of the field between clinical ethics and biomedical research ethics is the proposal of an obligation to participate in biomedical research, which is argued for on the basis of biomedical knowledge being a public good available to the community as a whole. While patient accrual during a clinical investigation would certainly be facilitated by obligatory research participation, and the data obtained would be-at first sight-more representative for the population studied, the still feasible refusal to participate would be stigmatizing and as such detrimental for the patient-physician relation. This essay seeks to provide a reply to the titled question by focusing on aspects such as individual vs common medical claims, shared grounds between the two and an important document of medical research ethics, that is the Nuremberg code.


Mortality in systemic sclerosis.
Systemic sclerosis is a rare and potentially devastating connective tissue disease. It is highly heterogeneous in terms of clinical presentation, extent and severity of organ involvement, immunologic abnormalities, and clinical course. Although clinical outcomes appear to have improved in recent years, the disease continues to cause substantial excess mortality. In this review, we have systematically collected the published studies addressing the mortality burden in patients with scleroderma in comparison with the general population, as well as studies exploring the most important potential predictors of mortality. Results of these studies are presented and discussed, with emphasis on methodological limitations. Suggestions are made for the design, conduct, and reporting of further research on these themes.


Newcastle disease virus Malaysian strain AF2240 induces apoptosis in MCF-7 human breast carcinoma cells at an early stage of the virus life cycle.
Newcastle disease virus (NDV) AF2240 Malaysian strain is a very virulent avian virus. NDV strain AF2240 was previously demonstrated to induce apoptosis in human breast carcinoma MCF-7 cells. However, at which stage of the NDV life cycle apoptosis is induced and whether NDV replication and protein synthesis are involved in apoptosis induction have yet to be determined. In the present study, we investigated the time course of NDV strain AF2240 nucleoprotein (NP) gene expression and the early apoptotic signs in the form of activation of caspase-8 and mitochondrial transition pore opening. In addition, the induction of apoptosis by both ultraviolet-inactivated and cycloheximide-treated NDV-infected MCF-7 cells were examined. Our findings showed that NDV strain AF2240 induced apoptosis at 1 h post-infection (pi) through activation of mitochondrial transition pore opening and at 2 h through activation of caspase-8, while the NP gene was expressed at 6 h pi. The induced apoptosis was independent of both virus replication and protein synthesis. In conclusion, NDV strain AF2240 induces apoptosis at an early stage of its life cycle, possibly during virus binding or fusion with the cell membrane. The mitochondrial-related pathway may be the central activator in NDV strain AF2240-induced apoptosis.


The fatigued anesthesiologist: A threat to patient safety?
Universally, anesthesiologists are expected to be knowledgeable, astutely responding to clinical challenges while maintaining a prolonged vigilance for administration of safe anesthesia and critical care. A fatigued anesthesiologist is the consequence of cumulative acuity, manifesting as decreased motor and cognitive powers. This results in impaired judgement, late and inadequate responses to clinical changes, poor communication and inadequate record keeping. With rising expectations and increased medico-legal claims, anesthesiologists work round the clock to provide efficient and timely services, but are the "sleep provider" in a sleep debt them self? Is it the right time to promptly address these issues so that we prevent silent perpetuation of problems pertinent to anesthesiologist's health and the profession. The implications of sleep debt on patient safety are profound and preventive strategies are quintessential. Anesthesiology governing bodies must ensure requisite laws to prevent the adverse outcomes of sleep debt before patient care is compromised.


[Impact of Socioeconomic Risk Exposure on Maternal Sensitivity, Stress and Family Functionality].
Impact of Socioeconomic Risk Exposure on Maternal Sensitivity, Stress and Family Functionality Parental stress exposure can influence the parent-child relationship, child development and child wellbeing in negative ways. The aim of this study was to investigate the impact of socio-economic risk exposure on the quality of the mother-child-interaction and family functionality. A sample of 294 mother-infant dyads at psychosocial risk was compared with a lower-risk, middle-class sample of 125 mother-infant-dyads in regard to maternal sensitivity/child's cooperation (CARE-Index), maternal stress (PSI-SF) and family functionality (FB-K). Lower levels of maternal sensitivity/child's cooperation and by trend also of the family functionality were found among the mothers from the at-risk sample in comparison to the low-risk sample. The level of maternal stress was similar in both samples. The results underpin the negative effects of a socio-economic risk exposure on the mother-child relationship. An early, sensitivity-focused family support could be encouraged to counteract the negative effects of early socioeconomic stress.


Giant pulmonary artery aneurysm with right ventricular outflow tract obstruction.
Aneurysm of the main pulmonary artery is rare. Its natural history is not well understood and there are no clear guidelines regarding its optimal treatment. We present a case of a huge saccular aneurysm of the main pulmonary artery which was associated with infundibular and valvular pulmonary stenosis. It was repaired using a pericardial patch with concomitant pulmonary valvotomy and infundibular resection. Postoperative recovery was uneventful and the patient is doing well. Follow-up echocardiogram revealed good repair.


Novel hybrid QSPR-GPR approach for modeling of carbon dioxide capture using deep eutectic solvents.
In recent years, deep eutectic solvents (DESs) have garnered considerable attention for their potential in carbon capture and utilization processes. Predicting the carbon dioxide (CO2) solubility in DES is crucial for optimizing these solvent systems and advancing their application in sustainable technologies. In this study, we presented an evolving hybrid Quantitative Structure-Property Relationship and Gaussian Process Regression (QSPR-GPR) model that enables accurate predictions of CO2 solubility in various DESs. The QSPR-GPR model combined the strengths of both approaches, leveraging molecular descriptors and structural features of DES components to establish a robust and adaptable predictive framework. Through a systematic evolution process, we iteratively refined the model, enhancing its performance and generalization capacity. By incorporating experimental CO2 solubility data in varied DES compositions and temperatures, we trained the model to capture the intricate solubility behaviour precisely. The analytical capability of the evolving hybrid model was validated against an extensive dataset of experimental CO2 solubility values, demonstrating its superiority over individual QSPR and GPR models. The model achieves high accuracy, capturing the complex interactions between CO2 and DES components under varying thermodynamic conditions. The versatility of the evolving hybrid model was highlighted by its ability to accommodate new experimental data and adapt to different DES compositions and temperatures. The proposed QSPR-GPR model presented a powerful tool for predicting CO2 solubility in DES, providing valuable insights for designing and optimizing solvent systems in carbon capture technologies. The model's remarkable performance enhances our understanding of CO2 solubility mechanisms and contributes to sustainable solutions for mitigating greenhouse gas emissions. As research in DESs progresses, the evolving hybrid QSPR-GPR model offers a versatile and accurate means for predicting CO2 solubility, supporting advancements in carbon capture and utilization processes towards a greener and more sustainable future.


Global poplar root and leaf transcriptomes reveal links between growth and stress responses under nitrogen starvation and excess.
Nitrogen (N) starvation and excess have distinct effects on N uptake and metabolism in poplars, but the global transcriptomic changes underlying morphological and physiological acclimation to altered N availability are unknown. We found that N starvation stimulated the fine root length and surface area by 54 and 49%, respectively, decreased the net photosynthetic rate by 15% and reduced the concentrations of NH4+, NO3(-) and total free amino acids in the roots and leaves of Populus simonii Carr. in comparison with normal N supply, whereas N excess had the opposite effect in most cases. Global transcriptome analysis of roots and leaves elucidated the specific molecular responses to N starvation and excess. Under N starvation and excess, gene ontology (GO) terms related to ion transport and response to auxin stimulus were enriched in roots, whereas the GO term for response to abscisic acid stimulus was overrepresented in leaves. Common GO terms for all N treatments in roots and leaves were related to development, N metabolism, response to stress and hormone stimulus. Approximately 30-40% of the differentially expressed genes formed a transcriptomic regulatory network under each condition. These results suggest that global transcriptomic reprogramming plays a key role in the morphological and physiological acclimation of poplar roots and leaves to N starvation and excess.


The protective effect of Epimedii Folium and Curculiginis Rhizoma on Alzheimer's disease by the inhibitions of NF-κB/MAPK pathway and NLRP3 inflammasome.
The purpose of the current study was to explore the effects of the water extracts of Epimedii Folium and Curculiginis Rhizoma (EX) on Aβ-induced Alzheimer's disease. Aβ1-42 was stereotaxically injected bilaterally into the dorsal hippocampus, and then the rats were orally received EX at the doses of 2 g/kg and 6 g/kg for 30 days. Behavior was monitored through Morris water maze test. The neuroprotective effect of EX were examined with methods of histochemistry and biochemistry. EX reduced the contents of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) in hippocampus and cortex. EX also reduced the levels of malondialdehyde (MDA) and increased superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GSH-Px) in the serum. Immunohistochemical analysis demonstrated that EX inhibited the expressions of NLRP3. In addition, we further confirmed that EX suppressed the expression of the NLRP3 inflammasome. EX inhibited the phosphorylations MAPKs, nuclear factor κB (NF-κB), myeloid differentiation factor 88(MyD88), cathepsin B. In conclusion, these results suggest that EX may be a potential agent for treating Alzheimer's disease.


Photon Recycling in Semiconductor Thin Films and Devices.
Photon recycling (PR) plays an important role in the study of semiconductor materials and impacts the properties of their optoelectronic applications. However, PR has not been investigated comprehensively and it has not been demonstrated experimentally in many different kinds of semiconductor materials and devices. In this review paper, first, the authors introduce the background of PR and describe how this phenomenon was originally identified in semiconductors. Then, the theory and modelling of PR is reviewed and some of the important parameters that are used to quantify PR are highlighted. Next, a variety of the methods used to achieve and characterize PR in materials and devices are discussed. Examples of how the performance parameters of different types of optoelectronic devices are affected by PR are described. Finally, a summary of the roles of PR in semiconductor materials and devices and an outlook on how PR can be used to solve existing problems and challenges in the field of optoelectronics are provided. From this review, it is apparent that PR can have a positive impact on optoelectronic device performance, and that further in-depth theoretical and experimental studies are needed to rigorously demonstrate the advantages and importance of PR.


Upregulation of Na+/Ca2+ exchanger contributes to the enhanced Ca2+ entry in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.
A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) in pulmonary artery smooth muscle cells (PASMC) is a trigger for pulmonary vasoconstriction and a stimulus for PASMC proliferation and migration. Multiple mechanisms are involved in regulating [Ca(2+)](cyt) in human PASMC. The resting [Ca(2+)](cyt) and Ca(2+) entry are both increased in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH), which is believed to be a critical mechanism for sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in these patients. Here we report that protein expression of NCX1, an NCX family member of Na(+)/Ca(2+) exchanger proteins is upregulated in PASMC from IPAH patients compared with PASMC from normal subjects and patients with other cardiopulmonary diseases. The Na(+)/Ca(2+) exchanger operates in a forward (Ca(2+) exit) and reverse (Ca(2+) entry) mode. By activating the reverse mode of Na(+)/Ca(2+) exchange, removal of extracellular Na(+) caused a rapid increase in [Ca(2+)](cyt), which was significantly enhanced in IPAH PASMC compared with normal PASMC. Furthermore, passive depletion of intracellular Ca(2+) stores using cyclopiazonic acid (10 microM) not only caused a rise in [Ca(2+)](cyt) due to Ca(2+) influx through store-operated Ca(2+) channels but also mediated a rise in [Ca(2+)](cyt) via the reverse mode of Na(+)/Ca(2+) exchange. The upregulated NCX1 in IPAH PASMC led to an enhanced Ca(2+) entry via the reverse mode of Na(+)/Ca(2+) exchange, but did not accelerate Ca(2+) extrusion via the forward mode of Na(+)/Ca(2+) exchange. These observations indicate that the upregulated NCX1 and enhanced Ca(2+) entry via the reverse mode of Na(+)/Ca(2+) exchange are an additional mechanism responsible for the elevated [Ca(2+)](cyt) in PASMC from IPAH patients.


Advance Directives in Some Western European Countries: A Legal and Ethical Comparison between Spain, France, England, and Germany.
We have studied national laws on advance directives in various Western European countries: Romance-speaking countries (Italy, France, Portugal, and Spain), English-speaking countries (Ireland and the United Kingdom), and German-speaking countries (Austria, Germany, and Switzerland). We distinguish two potentially complementary types of advance medical declaration: the 'living will' and the nomination of a legal proxy. After examining the similarities and differences between countries, we analyse in detail the legislation of four countries (Spain, France, England, and Germany), since the other countries in this survey have similar legal principles and/or a similar political approach. In conclusion, we note that in all the countries examined, advance directives have been seen as an instrument to enable the patient's right to self-determination. Notwithstanding, in Romance-speaking countries, the involvement of physicians in the end-of-life process and risks arising from the execution of advance directives were also considered.


Broadly neutralizing antiviral antibodies.
A fascinating aspect of viral evolution relates to the ability of viruses to escape the adaptive immune response. The widely held view has been that the great variability of viral glycoproteins would be an absolute obstacle to the development of antibody-based therapies or vaccines that could confer broad and long-lasting protection. In the past five years, new approaches have been developed to interrogate human memory B cells and plasma cells with high efficiency and to isolate several broadly neutralizing antiviral antibodies against highly variable pathogens such as HIV-1 and influenza virus. These antibodies not only provide new tools for prophylaxis and therapy for viral diseases but also identify conserved epitopes that may be used to design new vaccines capable of conferring broader protection.


Designing learning activities.
In the fifth part of this series on teaching skills, Dai Hall suggests some ways of organising your material when imparting information or when organising a discussion.


Human tolerability and pharmacodynamic study of Tisacid tablet in duodenal ulcer patients. A prospective, randomized, self-controlled clinicopharmacological study.
A randomized, prospective, crossing-over clinico-pharmacological study was conducted on the tolerability by humans, of TISACID (Al-Mg-hydroxy-carbonate), a new antacid of up-to-date composition produced in Hungary. Even a relatively high dose of the preparation is tolerated by the human organism. During a 6-week continuous treatment neither subjective nor objective side-effects were observed. The tablet is immediately decomposed in the gastric juice, a considerable portion of it will permanently stick to the mucosa of the stomach and duodenum. Depending on the dose, it rapidly and permanently reduces the acidity of the gastric content and increases serum gastrin concentration only moderately and for a short time. Administered together with cimetidine, it promotes healing of duodenal ulcer and the cessation of complaints. It does not increase the aluminium and magnesium concentrations of the plasma not even on prolonged administration, and clinical symptoms and laboratory changes characterizing the phosphate depletion syndrome do not develop either. Based on the results, authors consider Tisacid a beneficial preparation as regards both effectivity and tolerability.


Target volume dose and clinical outcome in radiotherapy for primary marginal zone lymphoma of the ocular adnexa.
The aim of the present study was to determine the optimal dose and optimal target volume for marginal zone lymphoma of the ocular adnexa. Between January, 2008 and December, 2013, 40 patients with histologically proven primary marginal zone lymphoma of the ocular adnexa who underwent radiotherapy at the Tokyo Medical University were evaluated. The prescribed dose was 30 Gy in 15 fractions to the iso-center. Doses to the gross tumor volume (GTV), conjunctiva, bulbus oculi, retina and retrobulbar space were investigated, and the association between dose-volume factors and clinical outcome was analyzed. The overall and local progression-free survival rates at 3 and 5 years were 100% during a median observation period of 32 months. Two patients relapsed in the contralateral ocular adnexa. The progression-free survival rates at 3 and 5 years were 100 and 93.3%, respectively. The mean dose was 2.0 and 1.9 Gy for targets receiving 95% of the GTV dose (D95). The minimum dose was 0.9-2.0 Gy (median, 1.8 Gy). Thus, primary marginal zone lymphoma of the ocular adnexa favorably responded to lower doses of radiation, compared with prescribed doses to the iso-center. A radiation dose of 27 Gy in 15 fractions at D95 of GTV appeared to be optimal.


In vivo trafficking and immunostimulatory potential of an intranasally-administered primary dendritic cell-based vaccine.
Coccidioidomycosis or Valley fever is caused by a highly virulent fungal pathogen: Coccidioides posadasii or immitis. Vaccine development against Coccidioides is of contemporary interest because a large number of relapses and clinical failures are reported with antifungal agents. An efficient Th1 response engenders protection. Thus, we have focused on developing a dendritic cell (DC)-based vaccine for coccidioidomycosis. In this study, we investigated the immunostimulatory characteristics of an intranasal primary DC-vaccine in BALB/c mouse strain that is most susceptible to coccidioidomycosis. The DCs were transfected nonvirally with Coccidioides-Ag2/PRA-cDNA. Expression of DC-markers, Ag2/PRA and cytokines were studied by flow cytometry, dot-immunoblotting and cytometric bead array methods, respectively. The T cell activation was studied by assessing the upregulation of activation markers in a DC-T cell co-culture assay. For trafficking, the DCs were co-transfected with a plasmid DNA encoding HSV1 thymidine kinase (TK) and administered intranasally into syngeneic mice. The trafficking and homing of TK-expressing DCs were monitored with positron emission tomography (PET) using 18F-FIAU probe. Based on the PET-probe accumulation in vaccinated mice, selected tissues were studied for antigen-specific response and T cell phenotypes using ELISPOT and flow cytometry, respectively. We found that the primary DCs transfected with Coccidioides-Ag2/PRA-cDNA were of immature immunophenotype, expressed Ag2/PRA and activated naïve T cells. In PET images and subsequent biodistribution, intranasally-administered DCs were found to migrate in blood, lung and thymus; lymphocytes showed generation of T effector memory cell population (T(EM)) and IFN-γ release. In conclusion, our results demonstrate that the intranasally-administered primary DC vaccine is capable of inducing Ag2/PRA-specific T cell response. Unique approaches utilized in our study represent an attractive and novel means of producing and evaluating an autologous DC-based vaccine.


Fiberoptic hemodynamic spectroscopy reveals abnormal cerebrovascular reactivity in a freely moving mouse model of Alzheimer's disease.
Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and damaged cerebral vasculature. Cerebrovascular dysfunction could play an important role in this disease. However, the mechanism underlying a vascular contribution in AD is still unclear. Cerebrovascular reactivity (CVR) is a critical mechanism that maintains cerebral blood flow and brain homeostasis. Most current methods to analyze CVR require anesthesia which is known to hamper the investigation of molecular mechanisms underlying CVR. We therefore combined spectroscopy, spectral analysis software, and an implantable device to measure cerebral blood volume fraction (CBVF) and oxygen saturation (SO2) in unanesthetized, freely-moving mice. Then, we analyzed basal CBVF and SO2, and CVR of 5-month-old C57BL/6 mice during hypercapnia as well as during basic behavior such as grooming, walking and running. Moreover, we analyzed the CVR of freely-moving AD mice and their wildtype (WT) littermates during hypercapnia and could find impaired CVR in AD mice compared to WT littermates. Our results suggest that this optomechanical approach to reproducibly getting light into the brain enabled us to successfully measure CVR in unanesthetized freely-moving mice and to find impaired CVR in a mouse model of AD.


Relationship between iron-catalysed lipid peroxidation potential and human sperm function.
The relationship between lipid peroxidation and the functional competence of human spermatozoa has been investigated in a cohort of 31 infertility patients. Lipid peroxidation was assessed using a sensitive fluorometric assay for the generation of malondialdehyde in response to the presence of a ferrous ion promoter. Sperm function was evaluated by monitoring the movement characteristics of these cells and their capacity for sperm-oocyte fusion. Each sample was separated into high- and low-density sperm populations on discontinuous, two-step (40%:80%), Percoll gradients prior to analysis. The way in which individual ejaculates fractionated on these gradients was highly positively correlated (P < 0.001) with the lipoperoxidation status of the spermatozoa; the greater the potential for malondialdehyde generation, the higher the proportion of cells entering the low density region of the gradients. The lipoperoxidation potential of the freshly prepared spermatozoa was also highly predictive (P = 0.0001) of their capacity for movement at 3 and 24 h and their ability to exhibit sperm-oocyte fusion in response to the ionophore A23187. The potential for malondialdehyde generation in the 40% and 80% Percoll fractions was positively associated with midpiece abnormalities in the spermatozoa. These results emphasize the importance of lipid peroxidation in the pathophysiology of male infertility and suggest a mechanism by which such damage might arise.


Therapeutic developments for SARS-CoV-2 infection-Molecular mechanisms of action of antivirals and strategies for mitigating resistance in emerging variants in clinical practice.
This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19.


Diurnal Variation in Trigeminal Pain Sensitivity in Mice.
Management of time and circadian disruption is an extremely important factor in basic research on pain and analgesia. Although pain is known to vary throughout the day, the mechanism underlying this circadian variation remains largely unknown. In this study, we hypothesized that the process of pain transmission to the central nervous system (after receiving nociceptive stimuli from outside the body) would show day-night differences. Ten-week-old male mice were kept under a strict 12/12-h light/dark cycle for at least 10 days. Formalin was then injected into the second branch region of the trigeminal nerve and the duration of pain-related behaviors (PRBs) was assessed. Immunohistochemical staining was then performed, and the c-Fos-immunopositive cells in the trigeminal spinal tract subnucleus caudalis (Sp5C) were counted. The results showed that the duration of PRBs was longer and the number of c-Fos immunopositive cells in the Sp5C was higher at nighttime than during the day. In addition, the trigeminal ganglia (TG) were extracted from the mice and examined by quantitative real-time PCR to evaluate the daytime and nighttime expression of nociceptive receptors. The results showed that the mRNA expression of transient receptor potential ankyrin 1 in the TG was significantly higher at night than during the day. These results suggest that pain in the trigeminal nerve region is more intense at nighttime, when rodents are active, than during the daytime, partly due to differences in nociceptor expression.


Central neurotransmitter effects of organotin compounds: trials, tribulations and observations.
Administration of trimethyltin (TMT) or triethyltin (TET) compounds to rats during postnatal development has known behavioral and neuropathological consequences. By measuring the concentrations of dopamine, norepinephrine, homovanillic acid, dihydroxyphenylacetic acid, gamma-aminobutyric acid, acetylcholine, and choline in different brain areas of TMT and TET-treated animals, an attempt was made to correlate these functional deficits with changes in CNS neurotransmitter alterations in vivo. TET had no effect on any of the substances measured whereas TMT significantly decreased gamma-aminobutyric acid and dopamine levels, but only in hippocampus and striatum, respectively. All other neurotransmitter substances measured were not affected. These findings illustrate the complexity inherent in attempting to use neurochemical techniques alone as an index of toxicity in the absence of specific defined hypotheses.


The first case of Staphylococcus aureus ST398 causing bacteremia in an immunocompromised patient in Greece.
We describe a case of catheter-related bloodstream infection, in a patient with colon cancer, caused by a methicillin-sensitive Staphylococcus aureus strain, nontypeable by pulsed field gel electrophoresis of SmaI macrorestriction fragment analysis, belonging to ST398. The patient recovered after daptomycin therapy. This is the first report that documents the emergence of ST398 in Greece.


Now Or Never: "Public Health Issues Requiring Urgent Attention".
Pakistan is a developing country and most of its population is based in rural areas. Over the last two decades' significant changes have occurred in the health system in an attempt to improve the health care in general with a particular emphasis in the health of people living in rural areas. Despite these efforts, significant development and planning is required to improve the health of nation. Undoubtedly ministry of health has taken practical steps in tacking some serious health issues such as polio. However, the fact remains that there are a number of public health issues which if not addressed on an urgent basis, there is a great danger that the implications would be huge with unbearable consequences. Among various issues, only those are discussed here which are in a dire need of attention of government, ministry of health, department of public health, disaster management authorities, health education authorities, health institutions and health professionals.


Evaluation of hydrate-screening methods.
The purpose of this work is to evaluate the effectiveness and reliability of several common hydrate-screening techniques, and to provide guidelines for designing hydrate-screening programs for new drug candidates. Ten hydrate-forming compounds were selected as model compounds and six hydrate-screening approaches were applied to these compounds in an effort to generate their hydrate forms. The results prove that no screening approach is universally effective in finding hydrates for small organic compounds. Rather, a combination of different methods should be used to improve screening reliability. Among the approaches tested, the dynamic water vapor sorption/desorption isotherm (DVI) method and storage under high humidity (HH) yielded 60-70% success ratios, the lowest among all techniques studied. The risk of false negatives arises in particular for nonhygroscopic compounds. On the other hand, both slurry in water (Slurry) and temperature cycling of aqueous suspension (TCS) showed high success rates (90%) with some exceptions. The mixed solvent systems (MSS) procedure also achieved high success rates (90%), and was found to be more suitable for water-insoluble compounds. For water-soluble compounds, MSS may not be the best approach because recrystallization is difficult in solutions with high water activity. Finally, vapor diffusion (VD) yielded a reasonably high success ratio in finding hydrates (80%). However, this method suffers from experimental difficulty and unreliable results for either highly water-soluble or water-insoluble compounds. This study indicates that a reliable hydrate-screening strategy should take into consideration the solubility and hygroscopicity of the compounds studied. A combination of the Slurry or TCS method with the MSS procedure could provide a screening strategy with reasonable reliability.


Towards Langmuir-Blodgett films of magnetically interesting materials: solution equilibria in amphiphilic iron(II) complexes of a triazole-containing ligand.
As a first step towards amphiphilic spin crossover (SCO) systems where the hydrophobic part of the system is introduced by a non-coordinating anion (i.e. where no modification of the ligands to introduce hydrophobic substituents is required), [Fe(II)(OH(2))(2)(C(16)SO(3))(2)] and [Co(II)(OH(2))(2)(C(16)SO(3))(2)] have been prepared and reacted with the triazole-containing ligands adpt and pldpt (C(16)SO(3) = hexadecanesulfonate anion, adpt = 4-amino-3,5-bis(2-pyridyl)-1,2,4-triazole, pldpt = 4-pyrrolyl-3,5-bis(2-pyridyl)-1,2,4-triazole). In the solid state, two HS complexes of the form [Fe(II)(Rdpt)(2)(C(16)SO(3))(2)] and two of the form [Co(II)(Rdpt)(2)(CH(3)OH)(2)](C(16)SO(3))(2) are obtained, even when a six-fold excess of ligand is used (Rdpt = adpt or pldpt). In solution, the cobalt complexes remain in this form as evidenced by colour, Visible/NIR and IR spectroscopy. For the iron complexes, there is an equilibrium in solution between the neutral high-spin form of the complex [Fe(II)(Rdpt)(2)(C(16)SO(3))(2)] and the dicationic low-spin tris form [Fe(II)(Rdpt)(3)](C(16)SO(3))(2). Polar solvents favour the dicationic form, while less polar solvents favour the neutral form (as evidenced by solution colour and solution IR spectroscopy). Visible/NIR spectroscopy and Evans' method NMR spectroscopy show the equilibrium can be shifted towards the [Fe(II)(Rdpt)(3)](C(16)SO(3))(2) form by adding additional ligand to the solution. The X-ray crystal structures of [Fe(II)(adpt)(2)(C(16)SO(3))(2)] and [Co(II)(adpt)(2)(CH(3)OH)(2)](C(16)SO(3))(2).1.33CH(3)OH are presented. [Fe(II)(adpt)(2)(C(16)SO(3))(2)] has a 2D bilayer structure with alternating layers of polar Fe(adpt)(2) centres, and hydrophobic alkyl chains. The complex cations in [Co(II)(adpt)(2)(CH(3)OH)(2)](C(16)SO(3))(2).1.33CH(3)OH form 1-D columns in the solid state. The capacity of the amphiphilic complexes [Fe(II)(pldpt)(2)(C(16)SO(3))(2)] and [Fe(II)(adpt)(2)(C(16)SO(3))(2)] to self-assemble has been probed at the air-water interface using Langmuir techniques. The pertinent pressure-area isotherms reveal only a low tendency of the complexes to form films.


Autologous marrow transplantation for patients with chronic myelogenous leukemia (CML) in blast crisis.
Even patients with chronic myelogenous leukemia (CML) in blast crisis were treated with chemotherapy, followed by infusion of autologous bone marrow that had been collected during the chronic phase of the disease and cryopreserved at -198 degrees C. The mean age of the nine females and two males in this study was 34 years with an average duration of the chronic phase of the disease of 5.5 years. Seven out of the 11 patients had a splenectomy prior to intensive chemotherapy. The median survival of the first four patients who received 6-thioguanine, cytosine arabinoside, daunorubicin (TAD) chemotherapy was 2.6 weeks and no patient reachieved the chronic phase of CML. The second group of seven patients received more intensive chemotherapy (MAdHAT), which included melphalan 30 mg/m2 days 1, 2, and 3; Adriamycin 50 mg/m2 intravenously (iv) day 1, hydroxyurea 1500 mg/m2 by mouth for 5-7 days, cytosine arabinoside 100 mg/m2 continuous infusion for 5-7 days, and VM-26 100 mg/m2 iv on day 3. Six out of these seven patients reachieved chronic phase CML after bone marrow reinfusion. The median survival was 29.9 weeks for all patients and 33 weeks for the six patients who reachieved chronic phase CML. All patients subsequently died of recurrent blast crisis. There was no correlation between the time of bone marrow storage and the duration of subsequent chronic phase CML. These studies have shown that autologous bone marrow transplantation after high-dose chemotherapy can result in bone marrow engraftment with reestablishment of chronic phase CML, and prolongation of survival.


Identification with sport teams as a function of the search for certainty.
Based on ideas from subjective uncertainty reduction theory, we examined the extent to which individuals hold similar sport team preferences to their family and friends. We also assessed the extent to which perceived sport importance and personal need for structure are influential in the development of team identification. Australian high school students aged 15.5+/-1.0 years (mean+/-s) completed questionnaires containing the Personal Need for Structure Scale, the Relational-Interdependent Self-Construal scale, a Team Identification Scale, and items assessing perceptions of sport importance and team preferences. As expected, correlations indicated that preferences for sport teams were significantly related to the preferences of family and friends. Separate analyses of variance confirmed the remaining hypotheses. More specifically, individuals who perceived that sport was important identified with the team more than individuals who perceived sport to be less important. Also, individuals high in personal need for structure scored higher in cognitive/affective team identification than those low in this need. Individuals with differing needs for structure did not differ in their scores on other dimensions of team identification. The results support the notion that cognitive/emotional attachments to sport teams are influenced by perceptions of the importance of sport and by needs for subjective structure. It is possible that other psychological motives, such as the desire for self-esteem, facilitate the development of evaluative dimensions of team identification.


Tumor DNA Index and α-Fetoprotein Level Define Outcome following Liver Transplantation for Advanced Hepatocellular Carcinoma.
Patients with hepatocellular carcinoma (HCC) beyond the Milan criteria are expected to have inferior outcome after liver transplantation (LT) and are therefore currently not considered for LT in many countries. The purpose of this study was to identify predictive factors for overall survival following LT for HCC that may support the Milan criteria in the selection of appropriate transplant candidates. Clinicopathological data on 364 patients with HCC who underwent LT between 1989 and 2010 were retrospectively evaluated. Predictors of overall survival in the entire cohort as well as in subsets of patients within (n = 214) and beyond (n = 150) the Milan criteria were analyzed. Multivariate analysis in the entire cohort identified DNA index >1.5 (p < 0.0001), α-fetoprotein level (AFP) >200 ng/ml (p = 0.005), and HCC beyond the Milan criteria (p = 0.002) to be associated with worse overall survival. In patients within the Milan criteria (median survival: 170 months), DNA index >1.5 (p < 0.0001) was the only predictor of worse overall survival in multivariate analysis. In patients beyond the Milan criteria (median survival: 44 months), DNA index >1.5, AFP >200 ng/ml, microvascular invasion, patient age >60 years, and DNA index >1.5 concomitant with AFP >200 ng/ml were associated with worse overall survival in univariate analysis. Multivariate analysis identified DNA index >1.5 concomitant with AFP >200 ng/ml (p < 0.0001) as the only independent predictor of worse overall survival. Consequently, patients beyond the Milan criteria with a combined favorable DNA index ≤1.5 and AFP ≤200 ng/ml had a median survival (147 months) comparable to that of patients within the Milan criteria. DNA index and AFP level predict overall survival following LT in patients with advanced HCC beyond the Milan criteria. A combined assessment of these markers during the evaluation of transplant candidates can contribute to the selection of patients with HCC who may benefit from LT independently of their tumor burden.


Controlled agitation during hybridization: surface acoustic waves are shaking up microarray technology.
Microarray hybridization experiments are mostly based on quite small sample volumes being confined between the microarray itself and a cover slip or lifter slip on top of the narrow fluid layer. Under such conditions, the system is governed by the rules of microfluidics, i.e., by the regime of small Reynold's numbers. Here, diffusion is the only source for moving sample molecules toward their target spots. However, for a typical macromolecule such as that used in microarray hybridization experiments, the diffusion constant is very small. Hence, because they are driven by diffusion only, traveling over typical distances on a microarray may take them a very long time. Additionally, the slow time constants associated with the diffusion limit lead to pronounced depletion effects, which strongly influence the dynamics of a hybridization assay. In this report, we describe a novel technique to overcome the diffusion limit in microarray hybridization experiments. Surface acoustic waves on a piezoelectric substrate are coupled with the sample fluid on a microarray, where they act as a highly efficient agitation source. We demonstrate that the diffusion limit can be overcome in this fashion, leading to a remarkable increase in signal intensity and homogeneity in fluorescence-labeled microarray assays.


Comparative diagnostic criteria for melancholia and endogenous depression.
Five scales were evaluated for the diagnosis of melancholia or endogenous depression. Of 21 total items, none appeared in all five scales, but four items occurred in four of the scales: autonomy of mood, prevasive anhedonia, psychomotor change, and guilt. Vegetative changes were represented inconsistently, with anorexia and weight loss in three scales, as was distinct quality of mood. Thereafter, item agreement between the scales fell off. Scale performance was tested in 50 depressive patients. Major differences were found in frequency of melancholia and scale orientation toward inpatients and outpatients. A number of old controversies remain dormant in these scales. Unresolved are the relationship between melancholia and severity of depression; the relevance of precipitating events, previous depressive episodes, type of onset, and adequacy of personality; and whether to classify by category or continuum. The merits of statistically and consensually derived scales also need to be evaluated.


New aspects on reperfusion injury to liver--impact of organ harvest.
The aetiology of primary graft non-function and dysfunction is unknown but most likely involves Kupffer cell-dependent reperfusion injury; however, reasons for transplant failure are complex and involve organ retrieval, preservation and transplantation. Important factors include the donor's condition, cold and warm ischaemic times, operative complications in the recipient, the immune status of the recipient and surgical experience. The donor operation and surgical technique also have an effect on outcome after transplantation. This is important, since surgical organ manipulation of the liver during harvest cannot be prevented completely with standard procedures. This is especially true during organ harvest for living-donor liver transplantation and split-liver transplantation in general. Most recently, an experimental setting has conclusively demonstrated that gentle in situ organ manipulation by touching, retracting and moving liver lobes gently during harvest dramatically reduces survival after transplantation via Kupffer cell-dependent mechanisms. These mechanisms involve disturbances of hepatic microcirculation, a hypermetabolic state of the liver, hypoxia and almost complete denudation of endothelial lining cells. Glycine, a non-essential, non-toxic amino acid, which prevents activation of Kupffer cells, prevented all effects of harvest-related injury to the liver when given before transplantation. Based on these data, intravenous glycine has been administered to patients before reperfusion of their liver transplant. Both serum transaminases and the rate of primary non-function have been dramatically reduced, compared with historic controls. These preliminary clinical results with glycine before reperfusion are promising for further improvement of the overall outcome after liver transplantation.


Conserved small non-coding RNAs that belong to the sigmaE regulon: role in down-regulation of outer membrane proteins.
Enteric bacteria respond to misfolded proteins by activating the transcription of "heat shock" genes. These genes are arranged in two major regulons controlled by the alternative sigma factors sigmaH and sigmaE. The two transcription factors coordinate the stress response in different cellular compartments; the sigmaH regulon is induced by stress in the cytoplasm whereas the sigmaE regulon is activated by stress signals in the cell envelope. In Escherichia coli sigmaE plays a central role in maintaining cell envelope integrity both under stress conditions and during normal growth. Previous work established that sigmaE is essential for viability of the bacterium and up-regulates expression of approximately 100 protein-encoding genes that influences nearly every aspect of the cell envelope. Moreover, the expression of several outer membrane proteins is down-regulated upon sigmaE activation. Here, we show that two Hfq-binding small RNAs, MicA and RybB, are under positive control of sigmaE. Transient induction of RybB resulted in decreased levels of the mRNAs encoding OmpC and OmpW. sigmaE -mediated regulation of ompC and ompW expression was abolished in strains lacking RybB or Hfq. Recently MicA was shown to act in destabilizing the ompA transcript when rapidly grown cells entered the stationary phase of growth. Also, the alternative sigma factor down-regulates this message in a small non-coding RNA-dependent fashion. These findings add the sigmaE regulon to the growing list of stress induced regulatory circuits that include small regulatory RNAs and provide insight in a homeostatic loop that prevent a build-up of unassembled outer membrane proteins in the envelope.


Functional expression of a single-chain antibody to ErbB-2 in plants and cell-free systems.
Aberrant signaling by ErbB-2 (HER 2, Neu), a member of the human Epidermal Growth Factor (EGF) receptor family, is associated with an aggressive clinical behaviour of carcinomas, particularly breast tumors. Antibodies targeting the ErbB-2 pathway are a preferred therapeutic option for patients with advanced breast cancer, but a worldwide deficit in the manufacturing capacities of mammalian cell bioreactors is foreseen. Herein, we describe a multi-platform approach for the production of recombinant Single chain Fragments of antibody variable regions (ScFvs) to ErbB-2 that involves their functional expression in (a) bacteria, (b) transient as well as stable transgenic tobacco plants, and (c) a newly developed cell-free transcription-translation system. An ScFv (ScFv800E6) was selected by cloning immunoglobulin sequences from murine hybridomas, and was expressed and fully functional in all the expression platforms, thereby representing the first ScFv to ErbB-2 produced in hosts other than bacteria and yeast. ScFv800E6 was optimized with respect to redox synthesis conditions. Different tags were introduced flanking the ScFv800E6 backbone, with and without spacer arms, including a novel Strep II tag that outperforms conventional streptavidin-based detection systems. ScFv800E6 was resistant to standard chemical radiolabeling procedures (i.e. Chloramine T), displayed a binding ability extremely similar to that of the parental monovalent Fab' fragment, as well as a flow cytometry performance and an equilibrium binding affinity (Ka approximately 2 x 10(8) M(-1)) only slightly lower than those of the parental bivalent antibody, suggesting that its binding site is conserved as compared to that of the parental antibody molecule. ScFv800E6 was found to be compatible with routine reagents for immunohistochemical staining. ScFv800E6 is a useful reagent for in vitro biochemical and immunodiagnostic applications in oncology, and a candidate for future in vivo studies.


Cell and region specificity of Aryl hydrocarbon Receptor (AhR) system in the testis and the epididymis.
Aryl hydrocarbon receptor (AhR) plays multiple important functions in adaptive responses. Exposure to AhR ligands may produce an altered metabolic activity controlled by the AhR pathways, and consequently affect drug/toxin responses, hormonal status and cellular homeostasis. This research revealed species-, cell- and region-specific pattern of the AhR system expression in the rat and human testis and epididymis, complementing the existing knowledge, especially within the epididymal segments. The study showed that AhR level in the rat and human epididymis is higher than in the testis. The downregulation of AhR expression after TCDD treatment was revealed in the spermatogenic cells at different stages and the epididymal epithelial cells, but not in the Sertoli and Leydig cells. Hence, this basic research provides information about the AhR function in the testis and epididymis, which may provide an insight into deleterious effects of drugs, hormones and environmental pollutants on male fertility.


Ni and Cu-catalyzed one pot synthesis of unsymmetrical 1,3-di(hetero)aryl-1H-indazoles from hydrazine, o-chloro (hetero)benzophenones, and (hetero)aryl bromides.
The nickel-catalyzed cyclization of in situ generated ortho-chlorobenzophenone hydrazone derivatives, to afford 3-(hetero)aryl-1H-indazoles, is documented for the first time. The product 1H-indazoles can be transformed subsequently in a one-pot procedure into 1,3-di(hetero)aryl-1H-indazoles via copper-catalyzed N-arylation with (hetero)aryl bromides.


Scrub typhus associated with multiorgan failure: a case report.
The spectrum of clinical severity for scrub typhus ranges from inapparent, mild, to severe or fatal. The pathologic changes are focal or disseminated multiorgan vasculitis of the small blood vessels, a fact that helps explain the great diversity of clinical manifestations that can be encountered. We reported a case of scrub typhus with unusual and serious multiorgan involvement, including tubulointerstitial nephritis (TIN) with acute renal failure (ARF), interstitial pneumonitis with adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), liver function impairment, upper gastrointestinal bleeding, prolonged hyperamylasaemia and hyperlipasaemia. Chloramphenicol administration rapidly altered the clinical course, but with sequelae of renal impairment and prolonged hyperamylasaemia and hyperlipasaemia for 10 months.


Arterial blood pressure response to transient arousals from NREM sleep in nonapneic snorers with sleep fragmentation.
To assess the hemodynamic effects of graded arousals during nonrapid eye movement (NREM) sleep in patients with partial upper airway obstruction during sleep without obstructive sleep apnea/hypopnea, overnight beat-to-beat BP was recorded in six patients. At the end of each nonapneic obstructive event, EEG responses were graded as follows: grade 2, grade 1, and grade 0 were defined as increased high-frequency EEG lasting >15 s, 3 to 15 s, and no EEG arousals according to the American Sleep Disorders Association, respectively. The following were observed during grade 0, 1, and 2 EEG patterns (mean+/-SD): systolic pressure increased by 7.1+/-1.5, 11.7+/-1.9, and 14.2+/-3.4 (p<0.005), respectively; diastolic pressure increased by 4.6+/-0.6, 6.7+/-1.7, and 9.4+/-3.0 (p<0.005), respectively; heart rate increased by 2.9+/-0.4, 3.9+/-2.2, and 8.6+/-4.6 (p<0.005), respectively. We conclude that nonapneic-nonhypopneic obstructive events are followed by arterial systemic pressure increases whose magnitude varies with the grade of the arousal.


Gold decorated porous biosilica nanodevices for advanced medicine.
Diatomite is a fossil material made of amorphous porous silica. In this work, polyethylene glycol (PEG)-modified diatomite NPs (PEG-DNPs) are decorated with gold NPs (AuNPs) by one-pot liquid-phase synthesis. Nanocomplexes (PEG-DNPs@AuNPs), with an average size of about 450 nm, are characterized by dynamic light scattering, electron microscopy, nitrogen adsorption/desorption analysis, UV-vis and photoluminescence spectroscopies. Preliminary studies on the use of the nanocomplex in nanomedicine are also presented. Tests performed incubating PEG-DNPs@AuNPs in physiological conditions reveal a good stability of material. Cellular uptake of labeled PEG-DNPs@AuNPs is investigated by confocal microscopy after incubation with human cervix epithelioid carcinoma (HeLa) cells up to 48 h: an efficient cytoplasmic localization is observed. In vitro cytotoxicity of nanocomplexes with a concentration up to 400 μg ml-1 for 72 h is also evaluated. The results suggest the use of PEG-DNPs@AuNPs as advanced nanodevices adding imaging features to the nanocomplexes, due to AuNPs as contrast agent.


Uterine myxoid leiomyosarcoma with an underlying haematological disorder--case report and review of literature.
Uterine myxoid leiomyosarcoma is an exceptionally unusual variant of leiomyosarcoma with only 34 cases having been reported in the literature. The authors describe a case of myxoid leiomyosaroma with an underlying haematological profile that has not been described previously. A 38-year-old Caucasian woman with a known uterine fibroid discovered during pregnancy presented to the emergency department with heavy per vaginal bleeding. On examination, she had a large abdominal mass. She had a haemoglobin level of 5.2, platelets of 16 and a low white cell count. She received multiple blood and platelet transfusions, despite which her haemoglobin and platelet count levels remained low. She underwent two bone marrow biopsies, which were inconclusive. She underwent laparotomy for abdominal hysterectomy, bilateral salphingo-oohphorectomy, omentectomy and appendicectomy. Histological examination showed uterine myxoid leiomyosarcoma (International Federation of Gynaecology and Obstetrics stage IIIA). Her haematological profile improved significantly following surgical resection of the tumour, reappearing with the recurrence of the disease. The authors hence, consider that pancytopaenia in this patient was a manifestation of paraneoplastic syndrome.


The Mycobacterium tuberculosis Clp gene regulator is required for in vitro reactivation from hypoxia-induced dormancy.
Mycobacterium tuberculosis (Mtb) is the leading cause of death from an infectious disease worldwide and is the causative agent of tuberculosis (Chao, M. C., and Rubin, E. J. (2010) Annu. Rev. Microbiol. 64, 293-311). Throughout infection, Mtb encounters a variety of host pressures. Thus, responding to these host stresses via the induction of multiple regulatory networks is needed for survival within the host. The Clp protease gene regulator, Rv2745c (clgR), is induced in response to environmental stress conditions, implicating its potential role in Mtb pathogenesis. Transcriptional activation of genes downstream of Rv2745c occurs in a condition-dependent manner. Our isogenic Mtb:ΔRv2745c mutant expresses a significantly different phenotype upon reaeration conditions. Transcriptional analysis revealed differential gene expression profiles relative to wild-type Mtb. Rv2745c is strongly induced in response to hypoxic and reaeration conditions, implicating a role of Rv2745c in vivo during both establishment of infection and reactivation. We found dysregulation of downstream genes within both the σ(H)/σ(E) regulon as well as the dosR regulon in the isogenic mutant, Mtb:ΔRv2745c. Upon hypoxic and reaeration conditions, Clp protease induction occurred within wild-type Mtb, indicating that activation of clgR, which subsequently leads to Clp protease induction, is crucial for degradation of misfolded proteins and ultimately survival of Mtb upon specific stress conditions. Our data indicate the diverse response of Rv2745c, σ(H) and σ(E) in response to a variety of stress conditions. Activation of Rv2745c in response to various stress conditions leads to differential activation of downstream genes, indicating the diverse role of Rv2745c and its importance for Mtb survival in vivo.


A systematic review of the engagement with social media-delivered interventions for improving health outcomes among sexual and gender minorities.
Sexual and gender minority (SGM) persons face a number of physical and mental health disparities closely linked to discrimination, social stigma, and victimization. Despite the acceptability and increasing number of digital health interventions focused on improving health outcomes among SGM people, there is a lack of reviews summarizing whether and how researchers assess engagement with social media-delivered health interventions for this group. The objective of this systematic review was to synthesize and critique the evidence on evaluation of engagement with social media-delivered interventions for improving health outcomes among SGM persons. We conducted a literature search for studies published between January 2003 and June 2020 using 4 electronic databases. Articles were included if they were peer-reviewed, in English language, assessed engagement with a social media-delivered health intervention for improving health outcomes among sexual and gender minorities. A minimum of two authors independently extracted data from each study using an a priori developed abstraction form. We assessed quality of data reporting using the CONSORT extension for pilot and feasibility studies and CONSORT statement parallel group randomized trials. We included 18 articles in the review; 15 were feasibility studies and 3 were efficacy or effectiveness randomized trials. The quality of data reporting varied considerably. The vast majority of articles focused on improving HIV-related outcomes among men who have sex with men. Only three studies recruited cisgender women and/or transgender persons. We found heterogeneity in how engagement was defined and assessed. Intervention usage from social media data was the most frequently used engagement measure. In addition to the heterogeneity in defining and assessing engagement, we found that the focus of assessment was often on measures of intervention usage only. More purposeful recruitment is needed to learn about whether, how, and why different SGM groups engage with social media-interventions. This leaves significant room for future research to expand evaluation criteria for cognitive and emotional aspects of intervention engagement in order to develop effective and tailored social media-delivered interventions for SGM people. Our findings also support the need for developing and testing social media-delivered interventions that focus on improving mental health and outcomes related to chronic health conditions among SGM persons.


Translesional synthesis on DNA templates containing a single abasic site. A mechanistic study of the "A rule".
Site-specifically modified oligodeoxynucleotides containing a single natural abasic site or a chemically synthesized (tetrahydrofuran or deoxyribitol) model abasic site were used as templates for primer extension reactions catalyzed by the Klenow fragment of Escherichia coli DNA polymerase I or by calf thymus DNA polymerase alpha. Analysis of the fully extended products of these reactions indicated that both polymerases preferentially incorporate dAMP opposite the natural abasic site and tetrahydrofuran, while DNA templates containing the ring-opened deoxyribitol moiety block translesional synthesis, promoting sequence context-dependent deletions. The frequency of nucleotide insertion opposite the three types of abasic sites follows the order dAMP > dGMP > dCMP > dTMP. The frequency of chain extension was highest when dAMP was positioned opposite a natural abasic site. The frequency of translesional synthesis past abasic sites follows the order tetrahydrofuran > deoxyribose > deoxyribitol. The Klenow fragment promotes blunt end addition of dAMP; this reaction was much less efficient than insertion of dAMP opposite an abasic site. We conclude that the miscoding potential of a natural abasic site in vitro closely resembles that of its tetrahydrofuran analog. Ring-opened abasic sites favor deletions. Studies with polymerase alpha in vitro predict preferential incorporation of dAMP at abasic sites in mammalian cells.


Construction of a mini-RNA replicon in Escherichia coli.
How the ribonucleic acid (RNA) world transited to the deoxyribonucleic acid (DNA) world has remained controversial in evolutionary biology. At a certain time point in the transition from the RNA world to the DNA world, 'RNA replicons', in which RNAs produce proteins to replicate their coding RNA, and 'DNA replicons', in which DNAs produce RNA to synthesize proteins that replicate their coding DNA, can be assumed to coexist. The coexistent state of RNA replicons and DNA replicons is desired for experimental approaches to determine how the DNA world overtook the RNA world. We constructed a mini-RNA replicon in Escherichia coli. This mini-RNA replicon encoded the β subunit, one of the subunits of the Qβ replicase derived from the positive-sense single-stranded Qβ RNA phage and is replicated by the replicase in E. coli. To maintain the mini-RNA replicon persistently in E. coli cells, we employed a system of α complementation of LacZ that was dependent on the Qβ replicase, allowing the cells carrying the RNA replicon to grow in the lactose minimal medium selectively. The coexistent state of the mini-RNA replicon and DNA replicon (E. coli genome) was successively synthesized. The coexistent state can be used as a starting system to experimentally demonstrate the transition from the RNA-protein world to the DNA world, which will contribute to progress in the research field of the origin of life.


Sleep Duration and Adiposity in Early Childhood: Evidence for Bidirectional Associations from the Born in Bradford Study.
To examine independent associations of sleep duration with total and abdominal adiposity, and the bidirectionality of these associations, in a young biethnic sample of children from a disadvantaged location. Child sleep duration (h/day) was parent-reported by questionnaire and indices of total (body weight, body mass index, percent body fat (%BF), sum of skinfolds) and abdominal adiposity (waist circumference) were measured using standard anthropometric procedures at approximately 12, 18, 24, and 36 months of age in 1,338 children (58% South Asian; 42% White). Mixed effects models were used to quantify independent associations (expressed as standardised β-coefficients (95% confidence interval (CI)) of sleep duration with adiposity indices using data from all four time-points. Factors considered for adjustment in models included basic demographics, pregnancy and birth characteristics, and lifestyle behaviours. With the exception of the sum of skinfolds, sleep duration was inversely and independently associated with indices of total and abdominal adiposity in South Asian children. For example, one standard deviation (SD) higher sleep duration was associated with reduced %BF by -0.029 (95% CI: -0.053, -0.0043) SDs. Higher adiposity was also independently associated with shorter sleep duration in South Asian children (for example, %BF: β = -0.10 (-0.16, -0.028) SDs). There were no significant associations in White children. Associations between sleep duration and adiposity are bidirectional and independent among South Asian children from a disadvantaged location. The results highlight the importance of considering adiposity as both a determinant of decreased sleep and a potential consequence.


Outcomes of pulmonary endarterectomy surgery.
Chronic thromboembolic pulmonary hypertension has emerged as one of the leading causes of severe pulmonary hypertension. This disease is estimated to occur in approximately 1 to 5% of all patients who have previously developed an acute pulmonary embolism, although the true prevalence is suspected to be much higher. Chronic thromboembolic pulmonary hypertension is characterized by intraluminal thrombus organization, fibrous stenosis, and vascular remodeling of pulmonary vessels. Pulmonary endarterectomy is an operation that is considered curative for thromboembolic pulmonary hypertension and is therefore superior to transplantation for this condition. This article focuses on the surgical outcomes of patients undergoing pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension and discusses the currently known factors that affect survival after this operation.


Efficacy of mouth opening exercises in treating trismus after maxillectomy.
Patients with maxillary tumor often suffer from trismus after maxillectomy, which could turn out to be a permanent sequela without proper intervention. In this study, the efficacy of mouth opening exercises in preventing and treating trismus was observed in patients with maxillary tumor early after their operations. At the same time, radiotherapy as an influencing factor for the mouth opening exercises was evaluated. In this study, 22 patients with maxillary oncology began their mouth opening exercises at an early stage (1-2 weeks) after maxillectomy. They were divided into two groups based on the principle of voluntariness: 11 patients in group 1 chose TheraBites as their instruments of mouth opening exercises, and the other 11 in group 2 chose stacked tongue depressors to help their exercises. All participants were trained to exercise 3-5 times a day, 30-40 oscillations at one time, with a 2-second pause at their maximum possible mouth open position. The maximal interincisor distances (MID) of patients were measured and recorded by a single investigator every week after the beginning of the mouth opening exercises. Medical information and the responses of patients were also recorded. Initial and final MIDs were calculated by SPSS 13.0. The changes of the mouth aperture every week during exercises in both groups were described in figures, and there were statistical increases in the final MIDs compared with the initial ones. However, no significant differences were achieved between groups 1 and 2 (P > 0.05). Radiotherapy seemed to have no negative impact on the mouth opening results during the exercises. Physical mouth opening exercises should be executed early after maxillectomy for the prevention and treatment of trismus, especially for those who had radiotherapy as part of antitumor treatments.


Aspartate taxis mutants of the Escherichia coli tar chemoreceptor.
The Tar protein of Escherichia coli belongs to a family of methyl-accepting inner membrane proteins that mediate chemotactic responses to a variety of compounds. These transmembrane signalers monitor the chemical environment by means of specific ligand-binding sites arrayed on the periplasmic side of the membrane, and in turn control cytoplasmic signals that modulate the flagellar rotational machinery. The periplasmic receptor domain of Tar senses two quite different chemoeffectors, aspartate and maltose. Aspartate is detected through direct binding to Tar molecules, whereas maltose is detected indirectly when complexed with the periplasmic maltose-binding protein. Saturating levels of either aspartate or maltose do not block behavioral responses to the other compound, indicating that the detection sites for these two attractants are not identical. We initiated structure-function studies of these chemoreceptor sites by isolating tar mutants which eliminate aspartate or maltose taxis, while retaining the ability to respond to the other chemoeffector. Mutants with greatly reduced aspartate taxis are described and characterized in this report. When present in single copy in the chromosome, these tar mutations generally eliminated chemotactic responses to aspartate and structurally related compounds, such as glutamate and methionine. Residual responses to these compounds were shifted to higher concentrations, indicating a reduced affinity of the aspartate-binding site in the mutant receptors. Maltose responses in the mutants ranged from 10 to 80% of normal, but had no detectable threshold shifts, indicating that these receptor alterations may have little effect on maltose detection sensitivity. The mutational changes in 17 mutants were determined by DNA sequence analysis. Each mutant exhibited a single amino acid replacement at residue 64, 69, or 73 in the Tar molecule. The wild-type Tar transducer contains arginines at all three of these positions, implying that electrostatic forces may play an important role in aspartate detection.


Carbapenemase-Producing Aeromonas veronii Disseminated in the Environment of an Equine Specialty Hospital.
The emergence of bacterial resistance to carbapenem antibiotics is an urgent public health threat. Carbapenem drugs are a last resort treatment option for life-threatening infections. The frequent use of broad-spectrum antibiotics to treat hospitalized patients provides significant selection pressure favoring the emergence and dissemination of resistant organisms, including carbapenem-resistant Enterobacteriaceae (CRE). CREs have been reported in animal populations, but only rarely in horses. Our objective was to determine the prevalence of CRE in the environment of a referral equine specialty hospital. Environmental samples were collected on seven different sampling dates. Four clonal carbapenemase-producing Aeromonas veronii were recovered from 315 sampled surfaces (1.3%). All four isolates harbored the carbapenemase-producing, metallo-β-lactamase gene blacphA, although corresponding minimum inhibitory concentrations were within the susceptible range for imipenem and meropenem. All had an identical multilocus sequence type with a previously unreported allelic profile and contained multiple plasmids. To our knowledge, this recovery of blacphA-harboring A. veronii is the first report of carbapenemase-producing bacteria in the environment of an equine veterinary hospital. However, the low recovery rate suggests that environmental contamination is uncommon. Appropriate hospital cleaning and disinfection protocols are necessary to maintain a low risk of contamination for patients and personnel.


Study on the Microstructure of the New Paste of Recycled Aggregate Self-Compacting Concrete.
Previous literature indicates a decrease in the mechanical properties of various concrete types that contain recycled aggregates (RA), due to their porosity and to their interface of transition zone (ITZ). However, other components of the RA concrete microstructure have not yet been explored, such as the modification of the new paste (NP) with respect to a reference concrete. This paper deals with the microstructure of the new paste of self-compacting concrete (SCC) for different levels of RA. The water to binder ratio (w/b) was kept constant for all concrete mixtures, and equal to 0.5. The SCC mixtures were prepared with percentages of coarse RA of 0%, 30%, 50% and 100%. Mercury intrusion porosimetry test (MIP) and scanning electron microscope (SEM) observations were conducted on the new paste of each concrete. The results indicated that the porosity of the new paste presents a significant variation for replacement percentages of 50% and 100% with respect to NP0 and NP30. However, RA contributed to the refinement of the pore structure of the new paste. The amount of macrospores the diameter of which is in the 50-10,000 nm range was reduced to 20% for NP50 and NP100, while it was about 30% for NP0 and NP30, attributed to the water released by RA. Compressive strength loss for SCC50 and SCC100 concretes are both influenced by porosity of RA, and by the NP porosity. The latter is similar for these two concretes with the 26% increase compared to a reference concrete.


Combinatorial selection and edited combinatorial selection of phosphorothioate aptamers targeting human nuclear factor-kappaB RelA/p50 and RelA/RelA.
Nuclear factor-kappaB (NF-kappaB) transcription factors are important in regulating the immune response and play critical roles in the pathogenesis of chronic inflammatory diseases and a variety of human cancers. Agents that target specific NF-kappaB dimers may serve as therapeutic agents for the prevention of pathogenic immune responses. We have selected monothiophosphate-modified aptamers, or "thioaptamers", to the NF-kappaB p50/RelA heterodimer using combinatorial selection techniques. We also utilized a "double sieve" or editing approach for the generation of thioaptamers with enhanced selectivity to the RelA/RelA homodimer. The thioaptamers from these selections and our previous selections on the p50/p50 and RelA/RelA homodimers all had unique sequences and bound tightly to the recombinant NF-kappaB dimers against which they were selected. The selected thioaptamers also appear to maintain their selectivity and specificity among other cellular proteins, because they have the ability to bind NF-kappaB proteins within nuclear extracts from lipopolysaccharide (LPS)-induced macrophages and B cells.


From vice to madness: the semantics of naturalistic and personalistic understandings in Trinidadian local medicine.
Whilst the common analytical distinction between 'naturalistic' and 'personalistic' paradigms of medical knowledge has some immediate heuristic value and may indeed closely resemble the explicit schema elaborated by informants, interpretation of the semantics of bush medicine and madness in Creole Trinidad suggests that the two types of knowledge are not incompatible, nor mutually exclusive, nor distinct. The vices of ganja and rum use may be interpreted within the hot-cold classification of bush medicine but, like other vices and like the more 'intrapersonal' categories of pressure, grinding, studiation and tabanka, they may be understood as leading to madness. A common idiom of opposition and catharsis unites them, providing a higher level of analytical generality manifest in a range of local social institutions, and one rooted in post-colonial Afro-Caribbean experience and ideology.


Cutaneous infection due to a rough variant of Mycobacterium marinum.
Spreading lesions clinically resembling lymphangitic sporotrichosis developed on the right arm and chest of a 60-year-old man with chronic lymphocytic leukemia. Acid-fast bacilli were seen in exudates from lesions and in biopsies, and were cultured from them. The isolant grew initially as a yellowish-orange scotochromogen on Lowenstein-Jensen medium at room temperature and at 35 C., but failed to grow at 37 C. It failed to grow on 7-H-10 medium. On repeated subculturing over a 2-year period it gradually converted to a photochromogen. Histologically, there was ulceration with extensive acute and chronic inflammation with fibrosis. Organisms occurred intracellularly as dense, compact, cigar-like packets resembling lepara bacilli. The appeared to have a predilection for the nucleus. The patient was anergic to PPD S, B, Y and G, and lacked antibodies to BCG phosphoglycolipids. The mycobacteriosis was alleviated by combined INH and ethambutol therapy. The isolant was identified as a rough variant of Mycobacterium marinum. It may have been transmitted by an insect vector.


Electrophysiological evidence for facilitatory control of oxytocin neurones by oxytocin during suckling in the rat.
Antidromically identified paraventricular neurones were recorded simultaneously with intramammary pressure in urethane (1.2 g/kg) anaesthetized rats during suckling. The correlation of the firing pattern of these neurones with milk ejection enabled distinction between oxytocin and vasopressin neurones. Oxytocin neurones displayed a short (2-6 s) characteristic high-frequency burst of spikes. This activation probably occurred simultaneously in all oxytocin neurones 12-18 s before milk ejection and was regular in both frequency and amplitude (total number of spikes). The role of neurohypophysial peptides and analogues in the control of these characteristics was studied. Injecting 10 pg, 100 pg and 1 ng of oxytocin into the 3rd ventricle increased background activity of slow-firing oxytocin neurones (less than 3 spikes/s) and had a strong dose-dependent facilitatory effect on the milk ejection reflex, increasing both the amplitude and frequency of neurosecretory bursts. No effect was observed on non-neurosecretory neurones. Such injection also triggered the milk ejection reflex when it had not appeared an hour after suckling began. Oxytocin did not itself induce neurosecretory activation, which only appeared if the young rats were sucking. Injecting oxytocin into the lateral ventricle was less effective than into the 3rd ventricle. No effect was observed after injection into the venous blood or into the 4th ventricle, which suggested that oxytocin acts in the hypothalamus. Injecting mesotocin or isotocin into the 3rd ventricle had a facilitatory effect similar to that of oxytocin but vasopressin, vasotocin, MIF I (pro-leu-gly-NH2, terminal triplet oxytocin) or bovine neurophysins I and II did not modify neurosecretory activation or the milk ejection pattern. Injecting an oxytocin antagonist, ([1(beta-mercapto-beta, beta cyclopentamethylene propionic acid), 8-ornithine] vasotocin, d(CH2)5OVT) into the 3rd ventricle decreased milk ejection frequency and considerably delayed the reappearance of the first milk ejection. This resulted from a decrease in both frequency and amplitude of neurosecretory bursts, which were too small to induce detectable oxytocin release. Moreover, d(CH2)5OVT suppressed the facilitatory effect of exogenous oxytocin. Under normal conditions, endogenous oxytocin seemed to be involved in the control of neurosecretory activation. Injecting 1 ng oxytocin or 1 or 10 ng vasopressin into the 3rd ventricle did not modify the firing pattern of vasopressin neurones whether activated by hyperosmotic stimulation (1 ml NaCl, 9% solution (w/v) I.P.) or not.(ABSTRACT TRUNCATED AT 400 WORDS)


Synthesis of complement by guinea pig bronchoalveolar macrophages. Effect of acute and chronic infection with Pseudomonas aeruginosa.
In order to assess the potential role of local production of complement in pulmonary host defenses against bacterial infection, this aspect of bronchoalveolar macrophage function was studied in guinea pigs challenged with Pseudomonas aeruginosa in an acute and chronic infection model. Acute infection resulted in an increase in bronchoalveolar macrophage cell number and an increase in synthesis and secretion rates for the second (C2) and fourth (C4) complement components per macrophage. Manipulation of the airway without introduction of Pseudomonas also increased synthesis of both C2 and C4 when studied 60 h after control solutions were administered. Pseudomonas aeruginosa delivered in agar beads to induce chronic inflammation resulted in specific stimulation of C2 and C4 synthesis at 2 wk and to a lesser extent at 4 wk postchallenge. This increase in local complement synthesis by bronchoalveolar macrophages, in addition to enhancing the local inflammatory response, may serve to facilitate recruitment of intravascular cellular and humoral mediators of host defense against bacterial infection.


Incorporating biological information in sparse principal component analysis with application to genomic data.
Sparse principal component analysis (PCA) is a popular tool for dimensionality reduction, pattern recognition, and visualization of high dimensional data. It has been recognized that complex biological mechanisms occur through concerted relationships of multiple genes working in networks that are often represented by graphs. Recent work has shown that incorporating such biological information improves feature selection and prediction performance in regression analysis, but there has been limited work on extending this approach to PCA. In this article, we propose two new sparse PCA methods called Fused and Grouped sparse PCA that enable incorporation of prior biological information in variable selection. Our simulation studies suggest that, compared to existing sparse PCA methods, the proposed methods achieve higher sensitivity and specificity when the graph structure is correctly specified, and are fairly robust to misspecified graph structures. Application to a glioblastoma gene expression dataset identified pathways that are suggested in the literature to be related with glioblastoma. The proposed sparse PCA methods Fused and Grouped sparse PCA can effectively incorporate prior biological information in variable selection, leading to improved feature selection and more interpretable principal component loadings and potentially providing insights on molecular underpinnings of complex diseases.


Inhibition of established rat fibrosarcoma growth by the glucose antagonist 2-deoxy-D-glucose.
Sarcoma cells exhibit higher rates of glycolysis than normal tissues and may be dependent on glucose utilization for growth. Accordingly, we tested the ability of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) to inhibit the growth of an established methylcholanthrene-induced rat fibrosarcoma in three groups of F344 rats with increasing subcutaneous inoculations of tumor (2 X 10(6) cells, 1 X 10(7) cells, and 1 mm tumor fragments). Rats were randomized to receive 2-DG or saline solution at doses of 0.75 gm/kg, 1.5 gm/kg, or 1.75 gm/kg, beginning 3 days after tumor implantation and continuing for 10 days. Tumors were removed and weighed on day 14. We measured tissue [14C]-2-DG levels in tumor, brain, liver, and muscle after intraperitoneal injection of radiolabeled 2-DG. In these same tissues we determined the activity of glucose-6-phosphatase (G-6-Pase), an enzyme which dephosphorylates the intracellular glycolytic inhibitor 2-DG-6-phosphate, thus reversing the antitumor effect of 2-DG. All groups treated with 2-DG had a significant reduction in tumor weight of 50% to 70% when compared with saline solution-treated controls. Toxicity was substantial at the highest dose of 2-DG, but minimal toxicity was noted at intermediate and low doses. Tumor had the greatest uptake of [14C]-2-DG, with low levels of G-6-Pase leading to prolonged retention and highest tissue levels of radiolabeled 2-DG. Use of 2-DG inhibits established sarcoma growth because it is rapidly transported into tumors, cannot be metabolized after phosphorylation, and is dephosphorylated and released slowly from tumor cells. Rat sarcoma growth is dependent on glucose utilization and can be effectively inhibited by glucose antagonism.


Accurate empathy of romantic partners increases pain ratings but promotes recovery.
Perceived empathy is a commonly used strategy to cope with pain and is crucial for maintaining intimacy in dyadic relationships. This study used the cold pressor test to investigate how perceived empathy and relationship type interact with the subjective perception of pain and objective measures of recovery time, using heart rate as an index. One hundred and ninety participants were recruited, including 49 friend dyads and 46 romantic partner dyads. Perceived empathy was manipulated by adopting three levels as the experimental conditions: high, accurate, and low. In the subjective perception stage, the results showed a significant interaction of relationship type and empathy with pain reporting, indicating that romantic partners reported more pain than friends under the accurate empathy condition. There were no differences between the two groups in the high and low perceived empathy conditions. In the self-recovery stage, the results showed that romantic partners had less pain tolerance than friends in all three perceived empathy conditions. On the other hand, romantic partners recovered faster than friends under the accurate empathy condition, but not under the high and low perceived empathy conditions. These results suggest that perceived accurate empathy is necessary for romantic relationships when coping with pain. The findings deepen our understanding of the mechanism of perceived empathy, and the ways in which it modulates psychological and physiological responses in a social context.


Predictive value of cytokine gene polymorphisms for the development of end-stage renal disease.
Cytokines play a crucial role in different immunopathological conditions. Cytokine secretion is reported to be determined by polymorphisms in the cytokine genes. Since TNF-alfa and IL-10 are involved in regulation of inflammation, and TGF-beta 1 can induce fibrosis and renal insufficiency - dominant features of end-stage renal disease (ESRD), we explored the hypothesis that polymorphisms of these cytokine genes may be possible genetic susceptibility factors for the progression of renal failure. We studied the IL-10 (-1082), TNF-alfa (-308), TGF-beta 1 (codon 10;25) gene single nucleotide polymorphisms in 118 healthy donors and 103 patients with ESRD (44 hemodialysis patients with diabetic nephropathy and 59 hemodialysis patients with glomerulonephritis) using PCR-SSP. Significant associations of ESRD with the TGF-beta 1 (codon 10) TT (odds ratio [OR] = 5.31; 95% confidence interval [95% CI], 3.77-7.02; p<0.001) and IL-10 (-1082) GG (OR=2.35; 95% CI, 1.67-3.15; p<0.01) genotypes were found. Statistical analysis of genotype frequencies made separately for the underlying renal disease (diabetes or glomerulo-nephritis) revealed the same linkage trend: TGF-beta 1 (codon 10) TT and IL-10 (-1082) GG were associated with type 2 diabetic nephropathy (p<0.001 and p<0.05, respectively) and chronic glomerulonephritis (p<0.001 and p<0.01, respectively). No significant differences in the TNF-alfa , TGF-beta 1 (codon 25) genotype distribution between healthy controls and patients with diabetic nephropathy- or glomerulonephritis-associated ESRD were detected. Carriage of the TGF-beta 1 (codon 10) TT and IL-10 (-1082) GG genotypes may increase susceptibility to ESRD in German patients with type 2 diabetes or glomerulonephritis.