SmgGDS displays differential binding and exchange activity towards different Ras isoforms.
Ras family GTPases play central roles in a wide variety of biological responses, including cell proliferation, differentiation, and oncogenic transformation. We searched for novel guanine nucleotide exchange factors of HRas and isolated small G-protein dissociation stimulator (smgGDS), a guanine nucleotide exchange factor known to act on numerous Ras and Rho family GTPases. SmgGDS specifically interacts with both dominant negative and nucleotide free forms of H and NRas, but not with the corresponding oncogenic forms. An effector domain mutant of HRas, HRasN17G37, selectively lost the ability to bind smgGDS. However, smgGDS does not catalyze guanine nucleotide exchange on either H or NRas in vitro. In contrast, substrates of smgGDS, such as KRas, Rac1, and RhoA, bind to smgGDS in both active and inactive forms which requires the presence of poly-basic residues in the C-termini of the GTPases. Our data suggest that the C-terminal poly-basic region of small GTPases is important for both binding and nucleotide exchange by smgGDS. Furthermore, these data underscore the idea that mammalian Ras isoforms are not functionally equivalent.


Imipramine and EEG sleep in children with depressive symptoms.
Depression in children is currently an area of considerable controversy, as is the use of potent psychopharmacologic agents in children. Since EEG sleep techniques have proven to be useful in understanding the mechanisms of depression in adults and in predicting their response to antidepressants, a pilot study employing these techniques was undertaken in a population of hospitalized children. The EEG sleep of 12 children with significant depressive symptomatology was first examined after a two-week drug-free period and again approximately three weeks later when an optimum dose of imipramine had been maintained for at least 7 -- 10 days. Changes in sleep continuity, as reflected in increased wakefulness and a decreased sleep efficiency, as well as an increase in Stage 2 and a decrease in Stage 4 sleep, were observed throughout the entire sample. REM suppression was also noted, but tended to be most pronounced in those children who improved on imipramine.


Evidence from ESR studies for [Co(eta-C2H4)3] produced at 77 K in a rotating cryostat.
Co atoms were reacted with ethene at 77 K and the paramagnetic products studied by electron spin resonance (ESR) at X- and K-bands. The ESR spectra of the major product at both frequencies showed eight cobalt multiplets (ICo=7/2) indicating a mono-cobalt complex. The spectra have orthorhombic g and cobalt hyperfine tensors and were simulated by the parameters; g1=2.284, g2=2.0027, g3=2.1527; A1<-25 MHz, A2=-109 MHz, A3=-198 MHz. Proton and 13C (1% natural abundance) hyperfine couplings were lower than the line widths (<2 MHz) indicating less than 0.5 spin transfer to the ethene ligands. We assigned the spectrum to a Jahn-Teller-distorted planar trigonal mono-cobalt tris-ethene [Co(eta-C2H4)3] complex in C2v symmetry. The SOMO is either a 3dx2-y2 (2a1) orbital in a T-geometry or a 3dxy (b1) orbital in a Y-geometry but there is only a spin density, a2, of 0.30 in these d orbitals. The spin deficiency of 0.70 is attributed to two factors; spin transfer from the Co to ethene pi/pi* orbitals and a 4p orbital contribution, b2, to the SOMO. Calculations of a2 and b2 have been made at three levels of spin transfer, theta. At theta=0.00a2 is 0.23 and b2 is 0.78, at theta=0.25a2 is 0.25 and b2 is 0.52 and at theta=0.50a2 is 0.28 and b2 is 0.23. The other possible assignment to a mono-cobalt bis-ethene complex [Co(eta-C2H4)2] cannot be discounted from the ESR data alone but is considered unlikely on other grounds. The complex is stable up to approximately 220 K indicating a barrier to decomposition of approximately 50 kJ Mol-1


The significance of ANXA7 expression and its correlation with poor cellular differentiation and enhanced metastatic potential of gastric cancer.
Annexin-A7 (ANXA7) exhibits biological and genetic properties expected of a tumor suppressor gene and may play a role in cancer progression. However, the ANXA7 expression in different histological subtypes of gastric adenocarcinomas and its correlation with invasive potentials has not been elucidated. Immunohistochemical staining of ANXA7 for 84 primary gastric adenocarcinomas was performed, and data was correlated with clinicopathological parameters of patients. The ANXA7 expression was well correlated with the grade of differentiation of primary tumors. Its expression was detected in 100% (8/8), 64.9% (24/37), 66.7% (2/3), 31.9% (13/31), 0% (0/3), and 0% (0/2) of well-differentiated tubular, moderately-differentiated tubular, papillary, poorly differentiated, signet-ring cell, and mucinous adenocarcinoma, respectively. According to the Lauren's classification, the ANXA7 expression was higher in intestinal type than in diffuse type tumor (71.9% vs. 6.1%, P = 0.003). The loss of expression of ANXA7 expression was significantly related to distant metastasis (P = 0.04). However, there were no significant associations between the ANXA7 expression and survival of cancer patients (P = 0.159). A striking correlation between ANXA7 expression and cell differentiation of gastric cancer was observed. The loss of expression of ANXA7 is associated with distant metastasis.


Sensitivity of selected drug biotransformation enzymes to dietary protein levels in adult F344 male rats.
Adult male Fischer 344 rats were fed inadequate, adequate, and excessive quantities of dietary protein (8, 12, and 22%, respectively) for a period of 14 days. An increase in dietary protein did not increase liver weight but resulted in an increase in cytochrome P-450 content and 7-ethoxycoumarin O-deethylase activity. No significant difference in glutathione S-transferase activity was observed at the three protein levels. The in vivo hepatotoxicity of bromobenzene increased with an elevation in dietary protein intake from 12 to 22%. These data from mature rats follow trends similar to findings we have reported previously with juvenile rats.


Scaphotrapeziotrapezoid joint loading during key pinch grip before and after trapeziometacarpal arthroplasty: a cadaver study.
In a previous cadaver study, we directly measured the load acting on the trapeziometacarpal joint for increasingly greater key pinch forces. We noted that the joint load ranges from 2 kg to 4 kg during progressively greater key pinch from 0.5 kg to 1.5 kg. Using the same experimental approach, the aim of the current study was to measure and compare the load acting on the scaphotrapeziotrapezoid joint for the same levels of isometric key pinch force, and how it changes after trapeziometacarpal arthroplasty. We performed a cadaver study using 7 fresh-frozen, unembalmed adult forearms and hands (2 right and 5 left). Thumb pinch was simulated by loading the main actuator tendons involved in the key pinch grip (i.e., adductor pollicis, flexor pollicis longus, extensor pollicis longus, extensor pollicis brevis and abductor pollicis longus tendons). Measurements were made inside the joint using a force-sensing resistor sensor (Tekscan® FlexiForce™ force sensor). Before the trapeziometacarpal joint surgery, median load values recorded in the scaphotrapeziotrapezoid joint were 1.2 kg (IQR, 1.0-1.4), 1.6 kg (IQR, 1.6-2.5) and 2.4 kg (IQR, 2.3-3.4) during 0.5 kg, 1 kg and 1.5 kg key pinch, respectively. After the trapeziometacarpal arthroplasty, median joint contact forces did not change significantly relative to the original configuration. Our findings indicate that the loads measured in the scaphotrapeziotrapezoid joint during a simple key pinch are in fact lower than those measured inside the trapeziometacarpal joint. After trapeziometacarpal arthroplasty, the values are similar with no increase in load, suggesting that clinically asymptomatic scaphotrapeziotrapezoid radiographic involvement may not be a contraindication to arthroplasty.


Protective effect of sucralfate against aspirin-induced damage to the human gastric mucosa.
Sucralfate, an agent that heals peptic ulcers in humans, has been shown to reduce aspirin-induced gastric mucosal damage in experimental animals. It has been suggested that the protective effect of sucralfate is due to stimulation of local prostaglandin production. The purpose of this study was to establish whether sucralfate was capable of reducing aspirin-induced gastric damage in humans. The effect of 1 g of sucralfate or identical placebo was studied in random order in eight healthy subjects. To determine if the effect of sucralfate was related to local prostaglandin synthesis, a second series of studies was performed in which prostaglandin production was inhibited with indomethacin 50 mg given orally eight hours before sucralfate. In each subject, all studies were performed at least one week apart. Following an overnight fast, upper gastrointestinal endoscopy was performed, with sucralfate or placebo given orally 30 minutes before ingestion of 1,200 mg of soluble aspirin in 50 ml of water. Both endoscopist and subject were unaware of the test agent. Ninety minutes after aspirin ingestion, endoscopy was again performed and gastric mucosal lesions were counted and graded to derive an erosion score. Results are expressed as mean +/- SEM. Aspirin produced endoscopic changes (score of 2.75 +/- 0.49) that were significantly (p less than 0.05) inhibited by sucralfate (score of 1.13 +/- 0.44). The protective effect of sucralfate was abolished by pretreatment with indomethacin (scores of 2.88 +/- 0.55 and 1.88 +/- 0.40, respectively). These results demonstrate that sucralfate significantly protects the human gastric mucosa against the acute damaging effects of aspirin. This effect is abolished by indomethacin, suggesting that the protective action of sucralfate on the gastric mucosa of humans may be related to stimulation of endogenous prostaglandins.


A rare case of swyer-james macleod syndrome and a new clinical presentation, acquired lobar emphysema.
Swyer-James Macleod syndrome is a radiologic entity characterized by hyperlucency of one or more lobes or of the entire lung, decreased number and diameter of ipsilateral peripheral pulmonary vessels, and difficult visibility of the arterial network and unobstructed bronchial system. A 21-year-old male was admitted to our clinic on the observation of left hemithoracic hyperinflation on chest radiography. Preoperative evaluation revealed an increase of ventilation to the left lower lobe and the deletion of peripheral vascular structures. Scintigraphy revealed a perfusion defect in the left lower lobe. In this patient with congenital left upper lobe hypoplasia and Swyer-James Macleod syndrome in the lower half of the lower lobe, I present the coexistence of these two rare clinical entities and "acquired lobar emphysema."


[Our surgical heritage: the tragic destiny of the surgeon. Eugen Alexander Pólya (1876-1944)].
Eugen Pólya was an outstanding hungarian surgeon of the first half of this century, a man of international reputation. Already in 1913 on the basis of animal experiments he realised the necessity of conservative treatment in acute pancreatitis. He and Reichel (Germany) share the fame of the introduction of a modified GE in partial resection of the stomach (B-II-type). In 1944 Pólya was killed by hungarian fascists for racial and political reasons. Nobody knows where his corpse was buried.


Administering esomeprazole subcutaneously via a syringe driver in the palliative demographic: A case series.
Proton pump inhibitors are potent suppressors of gastric acid secretion, and are commonly prescribed in palliative medicine. Despite multiple relevant indications in patients at the end-of-life, their use is often precluded as oral and intravenous administration is frequently inappropriate or not possible. Limited anecdotal evidence suggests proton pump inhibitors may be administered subcutaneously. Our objective was to investigate the tolerability and effectiveness of the administration of esomeprazole as a continuous subcutaneous infusion over 24 h via a syringe driver. Case series (n = 7) design assessing sequential patients admitted to a specialist inpatient centre for palliative care, who required parenteral proton pump inhibitor therapy. Four patients reported complete resolution of dyspeptic and reflux symptoms post commencement of esomeprazole. Two patients developed upper gastrointestinal bleeding, which via observation of vomitus and stools, resolved with the initiation of esomeprazole. A single patient, deemed high risk of gastrointestinal bleeding, was commenced on esomeprazole and no bleeding events occurred. Esomeprazole when administered via a syringe driver over 24 h appears well tolerated and effective for the symptomatic management of dyspepsia and treatment of gastrointestinal bleeding. Overall, this series adds to the limited evidence base for using subcutaneous proton pump inhibitors in the palliative demographic.


Reproductive interference between three parapatric species of reptile tick.
Reproductive interference between three species of reptile tick, Aponomma hydrosauri, Amblyomma albolimbatum and Amb. limbatum was investigated. Adults of two species attach together on the same lizard hosts in narrow overlap zones at parapatric boundaries between species, providing opportunities for interference. The possibility of reproductive interference was suggested because of similarities in the sexual communication systems.Three forms of interference were found in laboratory experiments. Firstly male movement to search for sexually receptive females was inhibited when females of two species were present on the same host, probably because of signal interference. Secondly, a nonspecific, short range attractant pheromone led males into non-conspecific courtship attempts which reduced the time for conspecific courtships. Thirdly Amb. albolimbatum males physically blocked the genitalia of female Ap. hydrosauri after unsuccessful non-conspecific courtship attempts. Field data showed this behaviour was common in both Amblyomma species after conspecific matings. Reproductive interference would reduce the fitness of each species in sympatry, and may contribute to the maintenance of the narrow parapatric boundaries.


Synthesis and biological evaluation of 1-azabicyclo-[3.2.1]octanes: new dopamine transporter inhibitors.
The synthesis and biological activity of a series of 6-substituted 1-azabicyclo[3.2.1]octanes are described. 1-Azabicyclo[3.2.1]octanes represent a new class of compounds that exhibit monoamine transporter inhibitory activity highly dependent on the overall topology and the absolute stereochemistry of the molecule.


Changes in the level of spontaneous DNA damage in whole blood leukocytes during storage.
We evaluated structural damage to DNA (%TDNA) in blood leukocytes from healthy donors of different age at different periods (0-6 days) of blood storage at 4-8°C. It was found that the basal level of DNA damage increased and intracellular antioxidant level decreased during storage. Mean %TDNA was 6.8±3.3% in the fresh blood and 19.2±8.1% after 5-day storage. The experiments with exposure to reactive oxygen species induced by irradiation suggest that depletion of low-molecular-weight endogenous antioxidants occurs as soon as after 5-h storage. Our results suggest that storage time should be taken into account when assessing the basal and induced levels of leukocyte DNA damage by the comet assay.


Bacterial scleral abscesses after retinal buckling operations. Pathogenesis, management, and laboratory investigations.
Between 1971 and 1985, 28 patients were treated for a scleral abscess after a scleral buckle procedure. Twenty-six of the patients had the original surgery performed between those years during which a total of 4480 buckling procedures were performed. Therefore, the incidence of scleral abscess after buckling procedures was 0.58% (26/4480). All 28 patients had excessive pain, conjunctival chemosis and proptosis, a creamy white area of retina on the buckle, and a variable amount of vitreous inflammation. Seventeen of these patients had an especially severe scleral abscess with inflammatory vitreous opacification, which precluded visualization of the retinal vessels or allowed at most a hazy view of the optic nervehead or the scleral buckle. A review of these 17 severely involved patients showed that, in most cases (13 of 17), the vitreous inflammation was sterile. Therefore, most patients can be managed simply with immediate removal of the buckle along with topical and systemic antibiotics. A laboratory investigation showed that a cell-free millipore filtrate of Staphylococcus aureus culture in trypticase soy broth caused prominent but self-limited inflammation when injected intravitreally. Therefore, bacterial toxins or secretions could be the cause of the prominent vitreous inflammation in most patients with scleral abscesses. In another experiment, sponge exoplants, which had been soaked in a highly concentrated culture of S. aureus, were sutured episclerally in rabbits. A scleral abscess developed in 19 of 23 rabbit eyes with these infective sponges. Progressive scleral abscesses, which closely resembled those seen in humans, developed in 14 of the 23 eyes.(ABSTRACT TRUNCATED AT 250 WORDS)


Appendicitis presenting as a swollen thigh.
A case of acute appendicitis presenting as an abscess in the thigh with associated gas is described. The tracking of the pus down the psoas muscle is stressed, and its association with the psoas sign is noted.


Recommendations for working from home during the COVID-19 pandemic (and beyond).
There is a growing trend around the globe for having more people working from home, particularly in the current COVID-19 pandemic. Although it is widely implemented in a number of countries and types of companies, it has shown to have multiple challenges. In this article, we provide several recommendations on how to work from home, incorporating information from several publications. The suggestions are: create routines, be organized, have an adequate home office, enhance your productivity, be responsible, avoid extreme multitasking, facilitate communication and networking, be balanced, use available computer programs and platforms, be creative with remote teaching, explore options for remote research and learn from the challenges. These recommendations would help students, professors and researchers around the globe during the current COVID-19 pandemic, and beyond.


Maturation-related adaptations in running speed in response to sprint training in youth soccer players.
This study investigated the effects of a previously recommended dose of sprint training (ST) in young male soccer players of differing maturity status. Quasi-experimental design. Male soccer players from two professional academies were divided into Pre-PHV (Training: n=12; Control: n=13) and Mid-PHV (Training: n=7; Control=10) groups. The training groups completed 16 sprints of 20m with 90s recovery, once per week for 8weeks. Between-group effect sizes (ES) were substantially larger in Pre-PHV (10m [1.54, CI: 0.74-2.23]; 20m [1.49, CI: 0.75-2.23]; 5-10-5 [0.92, CI: 0.23-1.61]) than in Mid-PHV (10m [-0.00, CI: -0.81 to 0.81]; 20m [-0.12, CI: -0.93 to 0.69]; 5-10-5 [-0.41, CI: -1.22 to 0.41]). Within-group effects demonstrated a similar, though less accentuated, trend which revealed ST to be effective in both Pre-PHV (10m [0.44, CI: -0.24 to 1.12]; 20m [0.45, CI: -0.23 to 1.13]; 5-10-5 [0.69, CI: 0.00-1.38]) and Mid-PHV (10m [0.51, CI: -0.38 to 1.40]; 20m [0.33, CI: -0.56 to 1.21]; 5-10-5 [0.43, CI: -0.46 to 1.32]). ST, in the amount of 16 sprints over 20m with a 90s rest, may be more effective in Pre-PHV youths than in Mid-PHV youths.


Lean oncology: a new model for oncologists.
The history of the term Lean is relatively recent and originates from the Toyota Production System (TPS). The term "Lean" means "thin", which refers to a mental process, operational, productive, no-frills, quick but not hasty, consequential to the previous event. The Lean process flows seamlessly into the result, eliminates unnecessary complications to the effect, prevents unnecessary equipment processes. The idea is to 'do more with less', like using the (few) available resources in the most productive way possible, through the elimination of all types of waste that inevitably accompanies every stage of a production process. Lean management is primarily a management philosophy, a system of values and behaviors that goes beyond the mere application of the instrument and that, once internalized, will form the nucleus of the corporate culture. "Lean Oncology" is a term coined to identify a methodology of care and treatment to cancer patients, consisting on process simplification, streamlining of the organizational and routes of drug treatment, detection and elimination of waste. Its main objective is the centrality of the patient.


Effects of intestinally absorbed thymidine on tritiated thymidine utilization.
Experimental evidence presented suggests that [3H]TdR can be rapidly and efficiently transported from the intestine to the systemic circulation. This pathway for thymidine transport may be physiologically important since administration of cold thymidine in the drinking water enhances the utilization of a parenterally injected dose of [3H]TdR in several body tissues of the mouse.


An In Vitro Study on the Efficacy of Mycotoxin Sequestering Agents for Aflatoxin B1, Deoxynivalenol, and Zearalenone.
The objective of this study was to determine the efficacy of mycotoxin sequestering agents for aflatoxin B1 (AFB1), deoxynivalenol (DON), and zearalenone (ZEA) using an in vitro method. The twelve toxin sequestering agents tested were seven bentonite products (bentonite A, B, C, D, E, F, and G), two aluminosilicate products (aluminosilicate A and B), a heulandite product, an activated charcoal product, and a yeast cell wall product. A two-step in vitro procedure was employed to mimic the conditions of temperature, pH, and digestive enzymes in the stomach and small intestine of pigs. All mycotoxin sequestering agents tested were able to bind to AFB1 with a high efficacy (>92%). The DON sequestering rate of activated charcoal (99.1%) was greater (p < 0.05) than that of other products. The ZEA sequestering rate of bentonite F (97.0%), aluminosilicate A (99.6%), and activated charcoal (100.0%) was the greatest (p < 0.05) among the tested mycotoxin sequestering agents. Overall, most mycotoxin sequestering agents had the ability to bind to AFB1, but most products, except activated charcoal, failed to sequester DON and ZEA.


Recovery of ischaemic injured porcine ileum: evidence for a contributory role of COX-1 and COX-2.
We have previously shown that the non-selective cyclooxygenase (COX) inhibitor indomethacin retards recovery of intestinal barrier function in ischaemic injured porcine ileum. However, the relative role of COX-1 and COX-2 elaborated prostaglandins in this process is unclear. To assess the role of COX-1 and COX-2 elaborated prostaglandins in the recovery of intestinal barrier function by evaluating the effects of selective COX-1 and COX-2 inhibitors on mucosal recovery and eicosanoid production. Porcine ileal mucosa subjected to 45 minutes of ischaemia was mounted in Ussing chambers, and transepithelial electrical resistance was used as an indicator of mucosal recovery. Prostaglandins E1 and E2 (PGE) and 6-keto-PGF1alpha (the stable metabolite of prostaglandin I2 (PGI2)) were measured using ELISA. Thromboxane B2 (TXB2, the stable metabolite of TXA2) was measured as a likely indicator of COX-1 activity. Ischaemic injured tissues recovered to control levels of resistance within three hours whereas tissues treated with indomethacin (5x10(-6) M) failed to fully recover, associated with inhibition of eicosanoid production. Injured tissues treated with the selective COX-1 inhibitor SC-560 (5x10(-6) M) or the COX-2 inhibitor NS-398 (5x10(-6) M) recovered to control levels of resistance within three hours, associated with significant elevations of PGE and 6-keto-PGF1alpha compared with untreated tissues. However, SC-560 significantly inhibited TXB2 production whereas NS-398 had no effect on this eicosanoid, indicating differential actions of these inhibitors related to their COX selectivity. The results suggest that recovery of resistance is triggered by PGE and PGI2, which may be elaborated by either COX-1 or COX-2.


Intracellular localisation of a subunit of human DNA polymerase alpha affecting primase activity recognised by monoclonal antibody (HDR-854-E4) and its application to distinction between proliferative and non-proliferative lesions.
We have successfully established one murine hybridoma that secretes a monoclonal antibody specific for the 77,000 subunit of human DNA polymerase alpha. The results of immunochemical studies, using HDR-854-E4 monoclonal antibody (MAb) and immunoperoxidase detection methods, demonstrate intranuclear and intracytoplasmic localisation of the subunit in all the human culture cell lines tested. The immunoperoxidase reaction product exhibits a diffuse pattern of distribution within the cytoplasm and nucleoplasm, but nucleoli are clearly negative. In cultured cell lines, HeLa and KATO III, more than 95% of the cells are positive, suggesting that the subunit antigens persist throughout the mitotic cycle. No subunit antigen was recognised in resting mononuclear cells (MNC). Immuno-electron microscopic examination of HeLa cells confirms and extends these observations. We have further examined the expression level of the subunit antigen in various normal and cancerous tissues. Strong reaction was observed in proliferating normal and cancer cells such as cancer cells from the gastrointestinal (GI) tract, thyroid, malignant lymphoma, breast, cells in the germinal centres of lymph nodes, epithelial cells in the GI tract and nephrogenic zones in fetal kidney. Finally, we utilised this antibody as a diagnostic tool in biopsies of the thyroid and GI tract. Thyroid cancer was stained positively with this antibody, while follicular adenoma was not. Gastric cancer was stained strongly and adenomatous polyp and hyperplastic polyp were stained moderately. This antibody is not only specific and powerful for application of a novel approach to the complex biochemical mechanisms of mammalian DNA replication, but also useful for distinction between proliferative and non-proliferative lesions.


Monitoring regional anaesthesia.
Monitoring patients under regional anaesthesia is more challenging than patients under general anaesthesia but it has been somewhat neglected in anaesthesia literature. The fundamental differences are that during regional anaesthesia. 1. The patient is often awake. 2. Respiration is more difficult to measure. 3. Autonomic changes influence information obtained by pulse oximetry. 4. Monitoring personnel are at a greater risk of vigilance decrement. A review of reported complications during regional anaesthesia enabled conclusions to be reached regarding monitoring policies in an institution. These include particular reference to spontaneous respiration and cerebral function. The need for an appropriately skilled person monitoring the patient in the operating room at all times is emphasized, as is the necessity for education appropriate for the skills they may have to exercise even on rare occasions. Specific instruction in vigilance decrement avoidance should be part of that curriculum.


Current advances in microbial-based cancer therapies.
Microbes have an immense metabolic capability and can adapt to a wide variety of environments; as a result, they share complicated relationships with cancer. The goal of microbial-based cancer therapy is to treat patients with cancers that are not easily treatable, by using tumor-specific infectious microorganisms. Nevertheless, a number of difficulties have been encountered as a result of the harmful effects of chemotherapy, radiotherapy, and alternative cancer therapies, such as the toxicity to non-cancerous cells, the inability of medicines to penetrate deep tumor tissue, and the ongoing problem of rising drug resistance in tumor cells. Due to these difficulties, there is now a larger need for designing alternative strategies that are more effective and selective when targeting tumor cells. The fight against cancer has advanced significantly owing to cancer immunotherapy. The researchers have greatly benefited from their understanding of tumor-invading immune cells as well as the immune responses that are specifically targeted against cancer. Application of bacterial and viral cancer therapeutics offers promising potential to be employed as cancer treatments among immunotherapies. As a novel therapeutic strategy, microbial targeting of tumors has been created to address the persisting hurdles of cancer treatment. This review outlines the mechanisms by which both bacteria and viruses target and inhibit the proliferation of tumor cells. Their ongoing clinical trials and possible modifications that can be made in the future have also been addressed in the following sections. These microbial-based cancer medicines have the ability to suppress cancer that builds up and multiplies in the tumor microenvironment and triggers antitumor immune responses, in contrast to other cancer medications.


OSO paradigm--A rapid behavioral screening method for acute psychosocial stress reactivity in mice.
Chronic psychosocial stress is an important environmental risk factor for the development of psychiatric diseases. However, studying the impact of chronic psychosocial stress in mice is time consuming and thus not optimally suited to 'screen' increasing numbers of genetically manipulated mouse models for psychiatric endophenotypes. Moreover, many studies focus on restraint stress, a strong physical stressor with limited relevance for psychiatric disorders. Here, we describe a simple and a rapid method based on the resident-intruder paradigm to examine acute effects of mild psychosocial stress in mice. The OSO paradigm (open field--social defeat--open field) compares behavioral consequences on locomotor activity, anxiety and curiosity before and after exposure to acute social defeat stress. We first evaluated OSO in male C57Bl/6 wildtype mice where a single episode of social defeat reduced locomotor activity, increased anxiety and diminished exploratory behavior. Subsequently, we applied the OSO paradigm to mouse models of two schizophrenia (SZ) risk genes. Transgenic mice with neuronal overexpression of Neuregulin-1 (Nrg1) type III showed increased risk-taking behavior after acute stress exposure suggesting that NRG1 dysfunction is associated with altered affective behavior. In contrast, Tcf4 transgenic mice displayed a normal stress response which is in line with the postulated predominant contribution of TCF4 to cognitive deficits of SZ. In conclusion, the OSO paradigm allows for rapid screening of selected psychosocial stress-induced behavioral endophenotypes in mouse models of psychiatric diseases.


Gene variants of the SLC2A5 gene encoding GLUT5, the major fructose transporter, do not contribute to clinical presentation of acquired fructose malabsorption.
While role of ALDOB-related gene variants for hereditary fructose intolerance is well established, contribution of gene variants for acquired fructose malabsorption (e.g. SLC2A5, GLUT5) is not well understood. Patients referred to fructose breath test were further selected to identify those having acquired fructose malabsorption. Molecular analysis of genomic DNA included (I) exclusion of 3 main ALDOB gene variants causing hereditary fructose intolerance and (II) sequencing analysis of SLC2A5 gene comprising complete coding region, at least 20 bp of adjacent intronic regions and 700 bp of proximal promoter. Among 494 patients, 35 individuals with acquired fructose malabsorption were identified based on pathological fructose-breath test and normal lactose-breath test. Thirty four of them (97%) had negative tissue anti-transglutaminase and/or deamidated gliadin antibodies in their medical records. Molecular analysis of SLC2A5 gene of all 35 subjects identified 5 frequent and 5 singular gene variants mostly in noncoding regions (promoter and intron). Allele frequencies of gene variants were similar to those reported in public databases strongly implying that none of them was associated with acquired fructose malabsorption. Gene variants of coding exons, adjacent intronic regions and proximal promoter region of SLC2A5 gene are unlikely to contribute to genetic predisposition of acquired fructose malabsorption.


Residual information processing in the neglected visual half-field.
A patient with neglect of visual half-field without hemianopia performed "same/different" interfield comparisons and named stimuli presented either unilaterally or bilaterally in the visual half-fields. With unilateral presentation he could name all stimuli in both fields, whereas with simultaneous bilateral stimulation his performance decreased to about 50% correct naming of left visual field (LVF) stimuli. This performance was not improved by cueing for the presence of LVF stimuli. Interfield comparisons were 100% correct in all conditions. It is concluded that inattention for the left hemispace in patients with visual neglect occurs whenever information in the right hemi-space attracts attention or must be consciously processed. Simple "same/different" judgements are presumably performed on a pre-attentional level and are not affected by neglect.


Perspectives on HIV Self-Testing Among Key and Affected Populations in Kenya.
Kenya's Key and Affected Populations (KAP) - men who have sex with men (MSM), female sex workers, people who inject drugs (PWID), and young women aged 18-24 - often experience stigma and discrimination in Kenyan health care settings due to their identity and/or behaviors, which can deter facility-based testing for HIV. Kenya has promoted self-testing as a means to reach these communities. To identify KAP perspectives on self-testing and place our findings within Kenya's human rights and legal context. We conducted 4 focus group discussions (FGD) and 16 in-depth interviews (IDI). One FGD was conducted with each of the following communities: MSM, female sex workers, PWID, and young women aged 18-24. 1-4 IDI were conducted with each KAP community, and 1-3 IDI were conducted with health professionals working on HIV care in each study site. The semi-structured question guideline included one question soliciting opinions on self-testing. KAP support self-testing in concept, however prevailing concerns among participants included access to pre- and post-test counseling services, as well as risk for harms (self-inflicted and otherwise) that might result from a positive result. Kenya should ensure that human rights are promoted and respected through implementing rights-based policies and practices for HIV self-testing, including pre- and post-test counseling.


[The role of the adenohypophysis in connection with changes in the thyroid caused by old age (author's transl)].
The findings indicate that changes caused by old age in the mechanism of the TSH action on the thyroid occur in the phases which are connected with the storage of adenosine triphosphate. That leads one to assume that changes caused by old age in the thyroid responsiveness to the action of TSH are probably conditioned by the following phenomena: 1. the decrease in the receptors "pro tropes" hormone and/or the disturbance of the correlations between TSH and the receptor 2. disturbance of the activity of the adenylocyclase 3. the phospho-diesterase activation.


The rate of sputum smear-positive tuberculosis after treatment default in a high-burden setting: a retrospective cohort study.
High rates of recurrent tuberculosis after successful treatment have been reported from different high burden settings in Sub-Saharan Africa. However, little is known about the rate of smear-positive tuberculosis after treatment default. In particular, it is not known whether or not treatment defaulters continue to be or become again smear-positive and thus pose a potential for transmission of infection to others. To investigate, in a high tuberculosis burden setting, the rate of re-treatment for smear-positive tuberculosis among cases defaulting from standardized treatment compared to successfully treated cases. Retrospective cohort study among smear-positive tuberculosis cases treated between 1996 and 2008 in two urban communities in Cape Town, South Africa. Episodes of re-treatment for smear-positive tuberculosis were ascertained via probabilistic record linkage. Survival analysis and Poisson regression were used to compare the rate of smear-positive tuberculosis after treatment default to that after successful treatment. A total of 2,136 smear-positive tuberculosis cases were included in the study. After treatment default, the rate of re-treatment for smear-positive tuberculosis was 6.86 (95% confidence interval [CI]: 5.59-8.41) per 100 person-years compared to 2.09 (95% CI: 1.81-2.41) after cure (adjusted Hazard Ratio [aHR]: 3.97; 95% CI: 3.00-5.26). Among defaulters, the rate was inversely associated with treatment duration and sputum conversion prior to defaulting. Smear grade at start of the index treatment episode (Smear3+: aHR 1.61; 95%CI 1.11-2.33) was independently associated with smear-positive tuberculosis re-treatment, regardless of treatment outcome. In this high-burden setting, there is a high rate of subsequent smear-positive tuberculosis after treatment default. Treatment defaulters are therefore likely to contribute to the pool of infectious source cases in the community. Our findings underscore the importance of preventing treatment default, as a means of successful tuberculosis control in high-burden settings.


Microvascular reconstruction in the vessel depleted neck - A systematic review.
Surgical therapy is the gold standard in head and neck cancer treatment, whereas adjuvant radiation and chemotherapy may be indicated in advanced cases. Frequently, neck dissections, former flap anastomoses and irradiated tissue leave a neck depleted of recipient vessels. If further surgery becomes inevitable the surgeon is faced with a heavily pretreated surgical field asking for highly reliable solutions for microsurgical reconstruction. From September 2017 until October 2017, a standardised review on the literature of the databases PubMed, Cochrane Library and Web of Science was performed. The primary research led to 1.614 articles, an evaluation by comprehensive content resulted in 26 suitable articles. Overall, 325 patient cases were included in the study. 112 postsurgical complications were noted (34.5%) and 12 deaths were reported (3.7%). The most common flaps harvested were the anterolateral-thigh flap (n = 85, 25.8%), the radial forearm flap (n = 78, 23.7%) and the flaps from the trunk (n = 31, 9.4%). The arteries most frequently used for anastomosis were the internal mammary artery (n = 81; 28%), the transverse cervical artery (n = 46; 15.9%) and the superficial temporal artery (n = 43; 14.9%). The cephalic vein (n = 84; 25.9%), the internal mammary vein (n = 79; 24.4%) and the superficial temporal vein (n = 50; 15.4%) were the most successfully applied veins.


Detection of spatial fluctuations of non-point source fecal pollution in coral reef surrounding waters in southwestern Puerto Rico using PCR-based assays.
Human fecal contamination of coral reefs is a major cause of concern. Conventional methods used to monitor microbial water quality cannot be used to discriminate between different fecal pollution sources. Fecal coliforms, enterococci, and human-specific Bacteroides (HF183, HF134), general Bacteroides-Prevotella (GB32), and Clostridium coccoides group (CP) 16S rDNA PCR assays were used to test for the presence of non-point source fecal contamination across the southwestern Puerto Rico shelf. Inshore waters were highly turbid, consistently receiving fecal pollution from variable sources, and showing the highest frequency of positive molecular marker signals. Signals were also detected at offshore waters in compliance with existing microbiological quality regulations. Phylogenetic analysis showed that most isolates were of human fecal origin. The geographic extent of non-point source fecal pollution was large and impacted extensive coral reef systems. This could have deleterious long-term impacts on public health, local fisheries and in tourism potential if not adequately addressed.


CDK5RAP3 Deficiency Restrains Liver Regeneration after Partial Hepatectomy Triggering Endoplasmic Reticulum Stress.
CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) plays a crucial role in mammalian liver development and hepatic function by controlling hepatocyte proliferation and differentiation, glucose and lipid metabolism, UFMylation, and endoplasmic reticulum homeostasis. However, the role of CDK5RAP3 in liver regeneration remains unknown. A liver-specific Cdk5rap3 knockout (CKO) mouse model was used to study the function of CDK5RAP3 during liver regeneration induced by standard two-thirds partial hepatectomy (PHx). Twenty-four hours after PHx, the liver-to-body weight ratio was markedly higher in CKO mice than in wild-type mice. However, this ratio did not increase significantly and gradually over time after PHx in CKO mice. Hepatocyte proliferation was significantly delayed in CKO mice compared with wild-type mice. Meanwhile, CDK5RAP3 deficiency increased lipid accumulation, impaired glycogen synthesis, and lowered blood glucose levels after PHx. Critically, the absence of CDK5RAP3 seemed to promote an inflammatory response and induce apoptosis at a late stage of liver regeneration. In addition, CDK5RAP3 deficiency disrupted UFMylation homeostasis and aggravated endoplasmic reticulum stress in hepatocytes after PHx. Taken together, these data suggest that CDK5RAP3 enhances liver regeneration, at least partially via controlling cell cycle and glucose and lipid metabolism.


Forest-to-pasture conversion influences on soil organic carbon dynamics in a tropical deciduous forest.
On a global basis, nearly 42% of tropical land area is classified as tropical deciduous forest (TDF) (Murphy and Lugo 1986). Currently, this ecosystem has very high deforestation rates; and its conversion to cattle pasture may result in losses of soil organic matter, decreases in soil fertility, and increases in CO2 flux to the atmosphere. The soil organic matter turnover rate in a TDF after pasture conversion was estimated in Mexico by determining natural abundances of13C. Changes in these values would be induced by vegetation changes from the C3 (forest) to the C4 (pasture) photosynthetic pathway. The rate of loss of remnant forest-soil organic matter (fSOM) was 2.9 t ha-1 year-1 in 7-year-old pasture and decreased to 0.66 t ha-1 year-1 by year 11. For up to 3 years, net fSOM level increased in pastures; this increment can be attributed to decomposition of remnant forest roots. The sand-associated SOM fraction was the most and the silt-associated fraction the least depleted. TDF conversion to pasture results in extremely high rates of loss of remnant fSOM that are higher than any reported for any tropical forest.


Patient dose evaluation by means of DICOM images for a direct radiography system.
The purpose of this work was to evaluate the statistical distribution of patient dose for different examinations by using the data stored in a DICOM image archive of a direct digital radiography system. An automatic procedure to extract dose data and exposure parameters from the image archives was implemented. During a 4.5-month period, 8,292 images were collected. Exposure parameters and the air kerma area product (P (KA)) stored in the image DICOM header were examined for each image. The entrance surface air kerma (K (a,e)), a quantity comparable to the current diagnostic reference levels (DRL), was estimated considering the P (KA) and the geometric parameters of each examination. P (KA) and K (a,e ) distributions showed highly variable values. The obtained K (a,e ) values were substantially lower than the DRL. DRL were more than six times the mean value of K (a,e ) distribution for the abdomen anteroposterior (AP) and lumbar spine lateral (LAT) projections, whereas the ratio was equal to 2.7 for posteroanterior (PA) chest examinations. The method adopted proved to be effective for characterising the dose of each examination by means of the statistical analysis of the dose quantities over extensive samples. The dose values obtained and the comparison with the DRL showed that this radiographic device allows substantial dose savings compared with estimations made for nondigital or for phosphor-based systems.


Generation of Acute Hind Limb Ischemia in NOD/SCID Mice and Treatment with Nanofiber-Expanded CD34+ Hematopoietic Stem Cells.
Critical limb ischemia (CLI) is primarily associated with a high risk of major amputation, cardiovascular events, and death. The current therapy involves direct endovascular intervention and is associated with long-term recurrence. However, patients with significant comorbidities are not eligible for this therapy. Hind limb ischemia model via femoral artery excision has commonly been used to determine therapeutic potential and for investigating cellular and molecular mechanisms. This protocol describes the ischemic model development in NOD/SCID mice and the use of human umbilical cord blood-derived and nanofiber scaffold-expanded CD34+ stem cells to investigate the efficacy of regenerative therapy.


Study of Abl1 tyrosine kinase inhibitors by liquid chromatography-electrospray ionization-mass spectrometry.
A method to study Abl1 tyrosine kinase inhibitors (TKIs) by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) was developed and validated. Chromatographic separation was achieved on a Symmetry(®) C-18 column using a gradient. The detection was performed by selected ion monitoring (SIM) mode via positive ESI interface. The limit of quantification (LOQ) was 40.8 nM for p-Abltide [product, KKGEAIpYAAPFA-NH2] and 26.7 nM for Abltide (substrate, KKGEAIYAAPFA-NH2). The residual plot of linearity calibration curve indicated a good fit with a linear model. Intra- and inter-day precision was less than 10% and accuracy was from -6.93% to +0.15%. Matrix effect was not significant in this method. The validated method was applied to an Abl1 TKIs study. Imatinib mesylate (IM) and dasatinib were used to evaluate this method and the IC50 values were 202.1 nM and 925.1 pM, respectively. Two natural products (-)- epigallocatechingallate (EGCG) and caffeic acid were tested with this model. The IC50 value of EGCG was found at 64.03 nM and caffeic acid showed fluctuant inhibitory activity from 26% to 55% in the concentration range from 1 nM to 1mM. The IC50 value of a dimethylpyrrole hydroxylbenzoic acid derivative (MPB) was 1.915 μM.


Perspectives for genetic engineering of poplars for enhanced phytoremediation abilities.
Phytoremediation potential has been widely accepted as highly stable and dynamic approach for reducing eco-toxic pollutants. Earlier reports endorse remediation abilities both in herbaceous plants as well as woody trees. Poplars are dominant trees to the ecosystem structure and functioning in riparian forests of North America Rivers and also to other part of the world. Understanding of the fact that how genetic variation in primary producer structures communities, affects species distribution, and alters ecosystem-level processes, attention was paid to investigate the perspectives of genetic modification in poplar. The present review article furnishes documented evidences for genetic engineering of Populus tree for enhanced phytoremediation abilities. The versatility of poplar as a consequence of its distinct traits, rapid growth rates, extensive root system, high perennial biomass production, and immense industrial value, bring it in the forefront of phytoremediation. Furthermore, remediative capabilities of Populus can be significantly increased by introducing cross-kingdom, non-resident genes encoding desirable traits. Available genome sequence database of Populus contribute to the determination of gene functions together with elucidating phytoremediation linked metabolic pathways. Adequate understanding of functional genomics in merger with physiology and genetics of poplar offers distinct advantage in identifying and upgrading phytoremediation potential of this model forest tree species for human welfare.


Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling.
Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.


Dental anxiety and psychological functioning in children: its relationship with behaviour during treatment.
In this study the relationship between the levels of dental anxiety, psychological functioning and earlier experience with dental injections are examined and the possible influence of these factors on children's behaviour before and during a local anaesthesia injection. A total of 128 children (4-11 years) were included. The level of dental anxiety and the psychological functioning were measured using the 'Children's Fear Survey Schedule' (CFSS-DS) and the 'Strengths and Difficulties Questionnaire' (SDQ). Based on video recordings the anxiety behaviour was scored on the Venham-scale. There was a positive correlation between levels of dental anxiety, psychological functioning and anxiety behaviour before and during the dental injection. In particular children with emotional problems or peer problems tended to show more anxiety behaviour before the injection and children with emotional or hyperactivity problems tend to show more anxiety behaviour during the injection. Furthermore, the younger children (below 6 years of age), with previous dental experience in the past 6 months, tended to display more anxiety behaviour both before and during the injection than children without or with experience from longer ago. The level of dental anxiety and psychological functioning and recent previous dental experience are important factors in determining which child is likely to display more anxiety and uncooperative behaviour during treatment and therefore potentially need more attention to be able to cope well with dental treatment.


Expiratory airflow at 7-8 years of age in children born extremely low birthweight from 14 years before to 14 years after the introduction of exogenous surfactant.
It is unclear if expiratory airflow in survivors born extremely low birth weight (ELBW; 500-999 g) has improved after the introduction of exogenous surfactant into clinical practice in 1991. The primary aim of this study was to describe the changes in airflow at 7-8 years of age of survivors born ELBW in five discrete cohorts from 14 years before to 14 years after the introduction of exogenous surfactant into clinical practice. The cohorts comprised consecutive survivors born ELBW in 1977-82 and 1985-87 at the Royal Women's Hospital, Melbourne, and in 1991-92, 1997 and 2005 in the state of Victoria, Australia. Survival rates to 2-years of age for infants born ELBW in the state of Victoria rose from approximately 1-in-4 to 3-in-4 over the time of this study. Expiratory airflow measurements at 7-8 years included the forced expired volume in 1 s (FEV1), converted to z-scores for age, height, sex, and race. There were 596 ELBW participants with expiratory flow data, 280 (47%) of whom had bronchopulmonary dysplasia (BPD). Overall, there was little change in zFEV1 over the 28-year period (mean change per year; 0.003, 95% CI -0.010, 0.015, P = 0.67). There was, however, evidence of an interaction between BPD and year; zFEV1 in those who had BPD fell over time (mean change per year -0.019, 95% CI -0.037, -0.009, P = 0.035), whereas zFEV1 improved in those who did not have BPD (mean change per year 0.021, 95% CI 0.006, 0.037, P = 0.007). Contrary to recent evidence, expiratory airflow of children born ELBW has not improved with the introduction of surfactant, and may be deteriorating in those who had BPD. National Health and Medical Research Council (Australia); Victorian Government's Operational Infrastructure Support Program.


IgD cross-linking induces gene expression profiling changes and enhances apoptosis in chronic lymphocytic leukemia cells.
Gene profile and functional changes upon IgD cross-linking were evaluated in chronic lymphocytic leukemia (CLL). Microarrays highlighted responsiveness to IgD in all cases, independently of clinico-biological characteristics. Stimulated samples exhibited the down-regulation of transcripts of B-cell receptor signaling and cell-adhesion at 24h and the up-modulation of differentiation and apoptosis genes at 48 h. A significant increase in apoptosis upon ligation was also documented. Furthermore, comparison between IgD and IgM stimulation displayed a differential transcriptional/functional response. In conclusion, CLL respond to IgD displaying expression changes and cell-death enhancement, indicating the apoptosis induction via-IgD as an alternative approach for CLL management.


In the Italian population sexual dimorphism affects pre-natal thyroid migration but not biochemical severity of gland ectopia and pre-natal bone maturation.
The aim of the present study was to retrospectively re-evaluate a population of selected infants with congenital hypothyroidism (CH), in order to investigate whether sexual dimorphism affects: a) CH etiology; b) its biochemical severity at the time of screening and recall; c) patients' biochemical response to replacement treatment during the 1st yr of life; d) their bone maturation (BM) at birth; e) their psychomotor status at 1 yr. This retrospective study covers 192 infants (116 females) with persistent CH who were selected from a larger population of CH patients identified during a 10-yr period (1990-1999) by the screening programs of 5 northern, central, and southern regions of Italy. Thirty boys (39.5%) and 66 girls (56.9%) were found to have ectopia, whereas the remaining 46 boys and 50 girls exhibited the other causes of CH. When compared with the prevalence of the remaining causes that of ectopia was significantly higher in girls than in boys (66/116 vs 30/76; chi2=5.57, p<0.025), and sex ratio in ectopia was significantly different also compared with the orthotopic gland group only (66/84 vs 30/51; chi2=6.02, p<0.025). No differences between males and females were detected in the groups with either athyreosis or orthotopic gland. In no groups were there differences between sexes for gestational age, birth auxological data, percentage of newborns with bone retardation or developmental quotient at 1 yr. Thyroid tests at birth, age at TSH normalization and average thyroid tests under L-T4 treatment during the 1st yr did not differ between sexes in any of the groups. a) in the Italian population sexual dimorphism affects pre-natal thyroid migration but neither biochemical severity of ectopia, nor pre-natal bone maturation and psychomotor development; b) girls with CH do not require higher doses of initial therapy in order to achieve TSH normalization; c) future developmental and molecular studies on ectopia etiology in CH need to take into account the effect of sexual dimorphism.


Delayed splenic hematoma rupture.
The diagnosis of splenic hematoma can be clinically challenging. A case of delayed rupture of an atraumatic splenic hematoma is described, illustrating how unusual the presentation of this entity can be.


Conventions of Courtship: Gender and Race Differences in the Significance of Dating Rituals.
Dating rituals include dating-courtship methods that are regularly enacted. We explored gender and race differences in the relative importance placed on certain symbolic activities previously identified by the dating literature as constituting such rituals. Using information collected from a racially diverse sample of college students (N = 680), we find that some traditional gender differences persist, but that these are also cross-cut by racial contrasts. Men, overall, place more emphasis on gifting, as well as sexual activity. Gender differences, however, are significantly greater among African Americans as compared to Whites in our sample. African American respondents are also significantly more likely than White respondents to associate meeting the family with a more serious dating relationship. Our findings highlight the need for greater efforts to uncover and account for racial differences in dating, relationships, and courtship.


Tubercular panophthalmitis in a patient with human immunodeficiency virus infection: Proven clinicopathologically and by molecular diagnostic tests.
Ocular tuberculosis (OTB) in patients with human immunodeficiency virus (HIV) commonly presents as choroidal tubercles or granuloma. We report a rare presentation of OTB with hypopyon granulomatous uveitis in a patient with HIV on highly active antiretroviral therapy (HAART). Aqueous humor polymerase chain reaction (PCR) was positive for Mycobacterium tuberculosis (MTB). Antitubercular therapy (ATT) was initiated despite which it progressed to scleral abscess and panophthalmitis. Enucleation with ball implantation was done. Histopathology revealed caseating granuloma with numerous acid-fast bacilli (AFB) and real-time PCR showed increased copies of MTB genome. After a full course of ATT, he had stable ocular and systemic condition at final follow-up.


A framework for the radiologic diagnosis of skeletal dysplasias and syndromes as revealed by molecular genetics.
This article simplifies the radiologic diagnosis of skeletal dysplasia by first presenting an ordered approach for analysis of standard radiographs done for skeletal dysplasias. With that foundation, a more detailed discussion of three separate families of skeletal disorders follows. Similarities among dysplasia group members are discussed to provide a certain connectedness among dysplasias. The paper also elucidates the scientific basis behind the radiographic findings so that previously purely descriptive terms have the weight of understanding behind them.


Five-year follow-up study of a controlled clinical trial using light mobilization and an informative approach to low back pain.
A controlled clinical trial. To examine the long-term effect of an informative approach to low back pain. In management and prevention of low back pain, back school based on an ergonomic approach have played in important role. The effect of such informative interventions is not clear. A 5-year follow-up study was done on patients included in a previous study. The outcome was measured by return to work or still on sick leave. The patients were allocated to an intervention group (n = 245) and a control group (n = 244). Only the intervention group was called in for examination and intervention and answered a battery of tests for psychological and health factors. The intervention apart from the clinical examination consisted of education in an "mini back school." The program was based on a new medical model for low back pain. Forty-seven (19%) of the patients in the intervention group, compared with 84 patients (34%) in the control group, were still on sick leave after 5 years (P < 0.001). There were fewer recurrences of sick leave (P < 0.03) in the intervention group than in the control group. Based on Internal Health Locus of Control, number of children, and income, 75% were correctly classified as nonreturners in the intervention group. This study indicates that subchronic low back pain may be managed successfully with an approach that includes clinical examination combined with information for patients about the nature of the problem, provided in a manner designed to reduce fear and give them reason to resume light activity.


Impact of preoperative hemodynamic support on early outcome in patients assisted with paracorporeal Thoratec ventricular assist device.
Mechanical circulatory support has become a well-established procedure for some patients with cardiogenic shock. However, patient selection and timing of implantation remains critical. This retrospective study was undertaken to identify preoperative predictors of survival in ICU of patients requiring mechanical circulatory support. Between 1996 and 2006, 71 patients (61 men, 10 women, aged 41.6+/-12.2 years) with primary cardiogenic shock were assisted using the paracorporeal Thoratec VAD. Twenty-seven (38%) patients needed preoperative mechanical ventilation. Preoperative IV hemodynamic drug support included dobutamine in 63 (89%), vasopressors (adrenaline, noradrenaline or dopamine > or =5 microg/kg min) in 47 (66%), and intraaortic balloon counter-pulsation in 22 (31%) patients. Mean preoperative blood creatinine and total bilirubin levels were 162.2+/-72.4 micromol/l and 36.4+/-53.9 micromol/l, respectively. Fifty-six (79%) patients required biventricular and 15 (21%) left ventricular support. Patients were assisted for a mean duration of 73.1+/-93.6 days (extremes, 1-480 days). Twenty-five patients (35%) died while on support. Among these, 18 patients (25%) never recovered sufficiently to allow dismissal from ICU, and died after a mean of 15.4+/-14.3 days. Logistic regression identified preoperative IV adrenaline as sole predictor for ICU death (OR, 5.48; 95% CI, 1.45-20.7, p=0.012). The need for preoperative IV adrenaline therapy appeared to be the sole independent risk factor for death in ICU in patients assisted with the Thoratec paracorporeal VAD. This suggests that, besides hemodynamic and metabolic consequences of cardiogenic shock, preoperative activation of the inflammatory cascade could influence the prognosis of patients undergoing mechanical circulatory support.


New haplotype for the Glu104Asp mutation in triose-phosphate isomerase deficiency and prenatal diagnosis in a Spanish family.
First-trimester prenatal diagnosis was undertaken by chorionic villus DNA analysis in a Spanish family with the inherited Glu104Asp triose-phosphate isomerase deficiency. The fetus was heterozygous for the mutation and therefore predicted to be clinically unaffected. To investigate the evolutionary origin of this mutation, studies were conducted on the intragenic 2262A/G polymorphism and the CD4 pentameric tandem repeat marker. A different haplotype was found to the one previously described, suggesting a different origin of the Spanish mutation.


X-linked retinoschisis: About a case.
X-linked retinoschisis (XLR) is a cause of retinal degeneration that affects males at an early age. X-linked disorders classically affect only males. We present the case of a 10-year-old female with the full spectrum of the pathology. BCVA 0.7 OU. Optical coherence tomography (OCT) showed bilateral foveal alteration with cystic appearance. The genetic study identified the variant c.644A>T (p.Glu215Gly) in the RS1 gene in homozygosis, associated with retinoschisis with X-linked recessive mode of inheritance. XLR is a condition that has a great variety in the severity of the disease and there is no correlation between the latter and the progression of the pathology. The disease has been described in a limited number of females mainly in families with high degree of consanguinity.


Fodder beet is a reservoir of drought tolerance alleles for sugar beet breeding.
Drought leads to serious yield losses and followed by increasing food prices. Thereby, drought tolerance is one of most important, pivotal issues for plant breeding and is determined by the very complex genetic architecture, which involves a lot of genes engaged in many cell processes. Within genomes of currently cultivated sugar beet forms, the number of favourable allelic variants is limited. However, there is a potential to identify genes related to drought tolerance deposited in genomes of wild or fodder relatives. Therefore, the goal of our study, was to identify the source of allelic variants involved in drought tolerance using a large spectrum of sugar or fodder beets and their wild relatives for analyses. Based on the drought tolerance index, calculated for morphophysiological traits, it was demonstrated that some of selected fodder beets showed the highest level of drought tolerance. The most drought tolerant fodder beet genotype did not show differences in the level of expression of genes engaged in osmoprotection and the antioxidative system, between control and drought condition, compared to sugar and wild beets. The genetic distance between selected beet forms was broad and ranged from 18 to 87%, however the most drought tolerant sugar, fodder and wild beets showed high genetic similarity and formed the common clade. Based on obtained results we propose that an adequate broad source of genes related to drought tolerance occurs in fodder beets, the crossing with which is easier, less time-consuming and more cost-effective than with wild forms of beets.


Cytogenetic study in spermatocytes of mice and Chinese hamsters after treatment with isoniazid (INH).
Meiotic chromosomes of spermatocytes from INH-treated male mice and Chinese hamsters were analysed for chromosome aberrations in diakinesis-metaphase I and metaphase II. The experiments were performed in two laboratories while a third laboratory participated in the chromosome evaluation. No enhancement of chromosome aberrations could be observed after acute treatment of early primary spermatocytes or chronic treatment of spermatogonia with INH.


C9orf72 in myeloid cells suppresses STING-induced inflammation.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation1-3. Expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells4-6. Here we show in mice that loss of C9orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of C9orf72. Dendritic cells isolated from C9orf72-/- mice show marked early activation of the type I interferon response, and C9orf72-/- myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in C9orf72-/- myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in C9orf72-/- immune cells as well as splenomegaly and inflammation in C9orf72-/- mice. Moreover, mice lacking one or both copies of C9orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.


Effects of Combined Action of Neutron and Proton Radiation on the Pool of Breast Cancer Stem Cells and Expression of Stemness Genes In Vitro.
Radiation response of cancer stem cells was studied in two breast cancer cell lines: luminal A (MCF-7) and triple negative (MDA-MB-231) subtypes. The relative number of CD44+CD24-/low cancer stem cells of the MCF-7 line increased by 1.7 times under the influence of γ-irradiation at a dose of 4 Gy (p=0.047 in comparison with the control). However, no significant changes were found in the relative number of cancer stem cells and the expression level of OCT4, NANOG, and SOX2 genes after neutron, proton beam irradiation or their combined action at a total equieffective dose of 4 Gy in comparison with the control in both cell lines. The absolute number of cancer stem cells decreased under the influence of neutron or proton radiation in comparison with the control (p<0.05 for both cell lines). At the same time, the effects of sequential exposures to neutron and proton radiation on the size of the cancer stem cell pool depended on the molecular subtype of cancer cells. Additive interaction was observed for MCF-7 line and antagonistic one for MDA-MB-231 line (coefficients of synergism were 0.96 and 0.45, respectively).


Thyroid function tests in ageing and their relation to associated nonthyroidal disease.
Thyroid function tests of 179 euthyroid geriatric inpatients (83 +/- 6 yr) unaffected by acute diseases or malnutrition were investigated and compared with those of 76 ambulatory healthy younger subjects (42 +/- 13 yr). Elderly population was divided in three groups, respectively: group G I (n = 37, 65-78 yr), group G II (n = 64, 79-85 yr) and group G III (n = 78, over 85 yr). Severity-of-illness index of the patients was evaluated at entry in the study protocol. While total thyroxine (TT4), free triiodothyronine (FT3) and TSH levels remained unchanged, circulating total triiodothyronine (TT3) was significantly lower (113 +/- 32 vs 150 +/- 31 ng/dl, p less than 0.05) and free thyroxine (FT4) was significantly higher (12.4 +/- 2.7 vs 10.3 +/- 2.3 pg/ml, p less than 0.05) in aged people. Furthermore, TT3 decreased significantly from 130 +/- 36 in G I to 110 +/- 33 in G II and to 108 +/- 25 in G III (p less than 0.01), and FT4 increased progressively although not significantly in the same groups. A close correlation was found between TT3 and severity index in male observations only (r = -0.43, p less than 0.01), as well as between FT4 and severity index in both sexes (r = 0.51, p less than 0.001 for men, r = 0.21, p less than 0.01 for women). These data suggest that thyroid function tests have to be cautiously interpreted in a geriatric population, particularly in relation to the severity of the clinical state, and reference values should be determined for TT3 and FT4 in the ageing process.


New thiophene-derived α-aminophosphonic acids: Synthesis under microwave irradiations, antioxidant and antifungal activities, DFT investigations and SARS-CoV-2 main protease inhibition.
Four new α-aminophosphonic acids containing thiophene ring have been synthesized using simple, neat and catalyst-free conditions, more convenient and eco-friendly method under microwave irradiations. The structures of the title molecules have been confirmed by UV-Vis, FT-IR, 1H NMR, 13C NMR and 31P NMR. Moreover, their antioxidant activity was evaluated using DPPH, ABTS and phenantroline methods; the obtained results indicate that the title molecules exhibit excellent activity better than standards BHT and BHA. Also, the synthesized compounds show a good antifungal activity against two fungi, Fusarium oxysporum and Alternaria alternata. In addition, molecular, electronic properties, stability and reactivity of the synthesized products were studied by the density functional theory (DFT). Furthermore, molecular docking investigations of the studied α-aminophosphonic acids showed a good inhibition of SARS-CoV-2 main protease (Mpro).


Lux C, D and E genes of the Vibrio fischeri luminescence operon code for the reductase, transferase, and synthetase enzymes involved in aldehyde biosynthesis.
The lux C, D, and E genes of the Vibrio fischeri luminescence operon code for three polypeptides of 54, 33, and 42 kDa, respectively, which are required for synthesis of the aldehyde substrate for the luminescent reaction. These polypeptides have been identified in V. fischeri and V. harveyi as well as in recombinant E. coli harboring the cloned genes by specific acylation with [3H]fatty acid, showing that they are components of a fatty acid reductase system with reductase, synthetase and transferase activities. By using glycerol in the assay and/or extraction buffer and decreasing the reducing agent, the levels of the acylation of the 54 and 42 kDa polypeptides have been greatly increased. As a consequence, it was possible to demonstrate that the 54 kDa polypeptide coded by the lux C gene has reductase activity. In a subclone missing the lux E gene, the 42 kDa polypeptide was missing and the 54 kDa polypeptide could not be acylated in vitro with tetradecanoic acid (+ATP) and only to a low level in vivo indicating that the synthetase enzyme, responsible for fatty acid activation, is coded by the lux E gene. In vitro acylation with tetradecanoyl CoA of the 33 kDa polypeptide coupled with the specific cleavage of acyl-ACP only in E. coli extracts transformed with DNA containing the lux D gene, demonstrated that the lux D gene coded for the transferase enzyme.


Tetanus toxin-[2,3-3H]propionamid. Synthesis, specific activity, immunoreactivity, toxicity and ascent into the spinal cord.
Tetanus toxin was tritiated with various amounts of N-succinimidyl-[2,3-3H]propionate. A tenfold molar excess of reagent over toxin was used for the introduction of about 5 nmol of [2,3-3H]propionate into 1 nmol of toxin, corresponding to a specific activity of about 48 MBq/mg protein. The labelling procedure did not change significantly the immunoreactivity of tetanus toxin, but reduced the toxicity in mice from 12 ng/kg to 16 ng/kg. Tetanus toxin-[2,3-3H]propionamid was carried through the peripheral nerves into the spinal cord. It could be used instead of 125I-labelled toxin for the detection of anti-tetanus toxin antibodies with a detection limit of 0.25 mU/ml of serum.


Phosphorylated tau interactome in the human Alzheimer's disease brain.
Accumulation of phosphorylated tau is a key pathological feature of Alzheimer's disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer's disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer's disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer's disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer's disease.


Embryotoxicity of silver nanomaterials (Ag NM300k) in the soil invertebrate Enchytraeus crypticus - Functional assay detects Ca channels shutdown.
Despite that silver (Ag) is among the most studied nanomaterials (NM) in environmental species and Ag's embryotoxicity is well known, there are no studies on Ag NMs embryotoxicity in soil invertebrates. Previous Full Life Cycle (FLC) studies in Enchytraeus crypticus, a standard soil invertebrate, showed that Ag materials decreased hatching success, which was confirmed to be a hatching delay effect for silver nitrate (AgNO3) and mortality for Ag NM300K. In the present study, we aimed to investigate if the impact of Ag takes place during the embryonic development, using histology and immunohistochemistry. E. crypticus cocoons were exposed to a range of concentrations of Ag NM300K (0-10-20-60-115 mg Ag/kg) and AgNO3 (0-20-45-60-96 mg Ag/kg) in LUFA 2.2 soil, in an embryotoxicity test, being sampled at days 1, 2, 3 and 6 (3, 4, 5 and 7 days after cocoon laying). Measured endpoints included the number of embryonic structures, expression of transferrin receptor (TfR) and L type calcium channels (LTCC) through histological and immunohistochemistry analysis, respectively. Results confirmed that Ag materials affected the embryonic development, specifically at the blastula stage (day 3). The expression and localization of TfR in E. crypticus was shown in the teloblasts cells, although this transcytosis mechanism was not activated. Ag affected calcium (Ca) metabolism during embryonic development: for AgNO3, LTCC was initially activated, compensating the impact, for Ag NM300K, LTCC was not activated, hence no Ca balance, with irreversible consequences, i.e. terminated embryonic development. An Adverse Outcome Pathway was drafted, integrating the mechanisms here discovered with previous knowledge.


Hemostasis in Skull Base Surgery.
Having absolute hemostasis is crucial in skull base surgery, because bleeding decreases visualization and increases the risk of postoperative complications. Achieving hemostasis starts from the preoperative evaluation. A thorough clinical history and routine tests guide the surgeon to minimize bleeding risk preoperatively, and comprehensive study of preoperative images helps the surgeon to predict bleeding risk and to consider preoperative embolization in suitable cases. Many hemostatic agents are available to control intraoperative bleeding; understanding of their indications and properties is crucial to achieve hemostasis. Whether endoscopic or transcranial approach, microsurgical techniques to avoid and control bleeding are the same.


Osmoregulatory capacity and the ability to use marine food sources in two coastal songbirds (Cinclodes: Furnariidae) along a latitudinal gradient.
Cinclodes nigrofumosus and C. oustaleti are two closely related songbirds that inhabit the northern Chilean coast during the austral fall and winter. This stretch spans a dramatic north to south latitudinal gradient in rainfall and temperature. Whereas C. nigrofumosus lives exclusively on coastal environments, C. oustaleti shifts seasonally from coastal environments to inland freshwater ones. We used the delta13C of these two species' tissues to investigate whether the reliance on marine versus terrestrial sources varied from the hyper-arid north to the wet south. We also investigated latitudinal variation in the renal traits that mediate how these birds cope with dehydration and a salty marine diet. Both species increased the incorporation of terrestrial carbon, as measured by delta13C, as terrestrial productivity increased southwards. However, C. nigrofumosus had consistently more positive (i.e. more marine) and less variable delta13C values than C. oustaleti. The osmoregulatory traits of both species varied with latitude as well. Urine osmolality decreased from extremely high values in the north to moderate values in the south, while C. nigrofumosus produced more concentrated urine than C. oustaleti. In both species, the proportion of kidney devoted to medullary tissue decreased from north to south, and kidney size increased significantly with latitude. Cinclodes nigrofumosus had larger kidneys with larger proportions of medullary tissue than C. oustaleti. C. nigrofumosus and C. oustaleti are terrestrial organisms subsidized by a rich marine environment where it is adjacent to an unproductive terrestrial. Variation in the reliance on marine food sources seems to be accompanied by adjustments in the osmoregulatory mechanisms used by these birds to cope with salt and dehydration.


Metabolic Cooperation among Commensal Bacteria Supports Drosophila Juvenile Growth under Nutritional Stress.
The gut microbiota shapes animal growth trajectory in stressful nutritional environments, but the molecular mechanisms behind such physiological benefits remain poorly understood. The gut microbiota is mostly composed of bacteria, which construct metabolic networks among themselves and with the host. Until now, how the metabolic activities of the microbiota contribute to host juvenile growth remains unknown. Here, using Drosophila as a host model, we report that two of its major bacterial partners, Lactobacillus plantarum and Acetobacter pomorum, engage in a beneficial metabolic dialogue that boosts host juvenile growth despite nutritional stress. We pinpoint that lactate, produced by L. plantarum, is utilized by A. pomorum as an additional carbon source, and A. pomorum provides essential amino acids and vitamins to L. plantarum. Such bacterial cross-feeding provisions a set of anabolic metabolites to the host, which may foster host systemic growth despite poor nutrition.


Close-kin mark-recapture informs critically endangered terrestrial mammal status.
Reliable information on population size is fundamental to the management of threatened species. For wild species, mark-recapture methods are a cornerstone of abundance estimation. Here, we show the first application of the close-kin mark-recapture (CKMR) method to a terrestrial species of high conservation value; the Christmas Island flying-fox (CIFF). The CIFF is the island's last remaining native terrestrial mammal and was recently listed as critically endangered. CKMR is a powerful tool for estimating the demographic parameters central to CIFF management and circumvents the complications arising from the species' cryptic nature, mobility, and difficult-to-survey habitat. To this end, we used genetic data from 450 CIFFs captured between 2015 and 2019 to detect kin pairs. We implemented a novel CKMR model that estimates sex-specific abundance, trend, and mortality and accommodates observations from the kin-pair distribution of male reproductive skew and mate persistence. CKMR estimated CIFF total adult female abundance to be approximately 2050 individuals (95% CI (950, 4300)). We showed that on average only 23% of the adult male population contributed to annual reproduction and strong evidence for between-year mate fidelity, an observation not previously quantified for a Pteropus species in the wild. Critically, our population estimates provide the most robust understanding of the status of this critically endangered population, informing immediate and future conservation initiatives.


Antiretroviral therapy abrogates association between arginase activity and HIV disease severity.
Arginase-induced L-arginine deprivation is emerging as a key mechanism for the downregulation of immune responses. We hypothesised that arginase activity increases with disease severity in HIV-seropositive patients. Our results show that peripheral blood mononuclear cells (PBMCs) from 23 HIV-seropositive patients with low CD4(+) T cell counts (≤350 cells/μl) expressed significantly more arginase compared with 21 patients with high CD4(+) T cell counts. Furthermore, we found a significant association between the two principal prognostic markers used to monitor HIV disease (CD4(+) T cell count and plasma viral load) and PBMC arginase activity in antiretroviral therapy naïve patients but not in patients undergoing therapy.


Incidence of meningeal involvement by rhabdomyosarcoma of the head and neck in children: a report of the Intergroup Rhabdomyosarcoma Study (IRS).
141 patients with embryonal rhabdomyosarcoma (RMS) of the head and neck are reviewed. 57/141 had lesions of para-meningeal sites. 20/57 (35%) developed evidence of direct meningeal extension. 18/20 (90%) died of this complication. Radiation portals and doses were limited in 42% and 32%, respectively. All patients had chemotherapy for 6 weeks prior to radiation. The significance of the adequacy of radiation factors and the timing of chemotherapy are reviewed. Recommendations for managing these patients include earlier use of radiation and increased coverage of adjacent meninges by radiation including total craniospinal axis radiation when brain meningeal involvement exists.


Mechanisms of CNS injury in behavioral dysfunction.
Advances in the neurosciences have led to a greater understanding of the anatomical, biochemical, and molecular loci involved in injury to, and adaptation of, the central nervous system. Recent research has permitted the elucidation of the mechanisms for some neurotoxicants whose actions have been studied for decades, as in the example of the pyrethroid insecticides. In contrast, the mechanism of the neurotoxicity of the organophosphate insecticides and nerve gases has been known for many years, but our understanding of the many resulting sequelae has been markedly increased by recent discoveries. Two examples illustrate the strengths and weaknesses of such methods in predicting neurotoxicity. Studies of the parkinsonian-like toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (a by-product of synthesis of illicit opiates) exemplify the best application of current methods in neurotoxicology. It has been shown that the expression of MPTP toxicity requires both metabolism of MPTP to the proximal toxicant 1-methyl-4-phenylpyridinium (MPP+) and active uptake into central dopamine neurons. The discovery of binding sites of MPP+ in these cells has clarified how dopamine neurons are destroyed, thereby causing neurological signs. This illustrates two key concepts: first, the bioconversion of compounds to proximal toxicants is often ignored, and second, these events are unlikely to be detectable by in vitro studies that focus on a few biochemical endpoints. Another useful example was that of erythrosin (FD&C Red No. 3), in which numerous in vitro studies suggested that this food color was a potential neurotoxicant. However, this was shown to be an artifact of the ability of this color to disrupt biomembranes at high in vitro concentrations, and this idea was supported by negative data from both behavioral and clinical studies. Thus, the plethora of possible molecular and biochemical targets in the central nervous system (receptors, second messenger events, transmitter-modulator synthesis, storage and release, membrane maintenance, etc.) preclude the likelihood of developing a single test or a battery of neurochemical or biochemical tests that will be able to screen for neurotoxicants randomly or efficiently. Use of in vitro methods is likely to detect both false positives and negatives. While the availability of theoretical or phenomenological data provides the best start to the application of available biochemical and molecular techniques, predictions of neurotoxicity best can come from theoretical comparison of the structure of suspect compounds (and hypothesized metabolites) with known target sites in the CNS.(ABSTRACT TRUNCATED AT 400 WORDS)


Validity and reliability of Turkish version of the Brief Pain Inventory-Short Form for patients with chronic nonmalignant pain.
The aim of this study was to evaluate the validity and reliability of the Turkish version of the Brief Pain Inventory-Short Form for patients with chronic nonmalignant pain. An analytical design was used. A total of 192 patients were included in the study. A demographic questionnaire and the Brief Pain Inventory-Short Form were used to collect data. Content validity was assessed by experts and construct validity was tested using exploratory factor analysis. Reliability analyses estimated the internal consistency and test-retest reliability. Cronbach's alpha and the item-total correlations were calculated for the subscales to examine internal consistency. Exploratory factor analysis yielded 2 factors: pain severity and pain interference, which accounted for 68.81% of the total variance. The coefficient alpha of both subscales demonstrated good internal consistency. The item-total correlations of the scale ranged between 0.56 and 0.87. The test-retest reliability was r=0.774 for pain severity and r=0.808 for pain interference (p=0.001). The Turkish version of the Brief Pain Inventory-Short Form is a valid and reliable instrument to assess chronic nonmalignant pain.


MicroRNA-361-5p acts as a biomarker for carotid artery stenosis and promotes vascular smooth muscle cell proliferation and migration.
Vascular smooth muscle cells (VSMCs) dysfunction participates in carotid artery stenosis (CAS). The study aimed to examine the expression pattern of miR-361-5p in CAS patients, and explore its role in VSMCs proliferation and migration. qRT-PCR was performed for the detection of miR-361-5p in serum samples of 150 CAS cases and 150 healthy people. Multiple logistic regression analysis and receiver operating characteristic (ROC) curve was accomplished to detect diagnostic value via SPSS 21.0 statistical software. Cell function of VSMCs was evaluated. Target association was predicted through bioinformatic analysis and confirmed via luciferase activity. Serum miR-361-5p was enhanced in CAS cases and was positively correlated with CAS degree. Logistic regression analysis determined the independent influence of miR-361-5p in CAS, and ROC curve demonstrated its diagnostic value with AUC of 0.892. miR-361-5p promoted VSMCs proliferation and migration, but the influence was counteracted by TIMP4. MiR-361-5p is a promising biomarker for CAS, and can be used as a potential target for early diagnosis and treatment of CAS. MiR-361-5p can promote VSMCs proliferation and migration via targeting TIMP4.


Chronic endometritis and positive Mycoplasma cultures: is there a correlation?
This study was undertaken to assess the impact of mycoplasma strains (Mycoplasma hominis or Ureaplasma urealyticum) on the development of chronic endometritis. Fifty-eight patients with acute pelvic infection were enrolled in this prospective cohort study. Endometrial cultures and biopsies were obtained on admission and 5-7 and 21-28 days after completion of treatment. Of 148 samples, 40 were positive for mycoplasma strains (group A) and 58 were positive for mycoplasma with other pathogens (group B). Twenty-seven samples were positive for other pathogens only (group C). Chronic endometritis was seen in 7 (17.5%), 30 (51.7%), and 10 (37%) in group A, B, and C patients, respectively. The presence of mycoplasma strains in the endometrial cavity was not found to be associated with an increased incidence of chronic endometritis.


Clinical biochemistry of peroxisomal disorders.
Peroxisomes have been shown to participate in a variety of pathological processes. Peroxisomal anomalities are central features of Zellweger's cerebro-hepato-renal syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease and several other genetic metabolic disorders (pseudo-Zellweger syndrome, Leber congenital amaurosis, cerebrotendinous xanthomatosis, rhizomelic chondrodysplasia punctata). In disorders with general loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease) an accumulation of very long-chain fatty acids and pathological bile acids are found. Patients have a defective synthesis of plasmalogens and show increased excretion of dicarboxylic acids of medium chain length and of pipecolic acid in the urine. These anomalities which are due to the lack of peroxisomal enzymes, supply the basis for clinical laboratory tests. The study of these peroxisomal disorders has presented valuable information on the normal function of peroxisomes.


Interactions Among Brain-Derived Neurotrophic Factor and Neuroimmune Pathways Are Key Components of the Major Psychiatric Disorders.
The purpose of this review is to summarize the current knowledge regarding the reciprocal associations between brain-derived neurotrophic factor (BDNF) and immune-inflammatory pathways and how these links may explain the involvement of this neurotrophin in the immune pathophysiology of mood disorders and schizophrenia. Toward this end, we delineated the protein-protein interaction (PPI) network centered around BDNF and searched PubMed, Scopus, Google Scholar, and Science Direct for papers dealing with the involvement of BDNF in the major psychosis, neurodevelopment, neuronal functions, and immune-inflammatory and related pathways. The PPI network was built based on the significant interactions of BDNF with neurotrophic (NTRK2, NTF4, and NGFR), immune (cytokines, STAT3, TRAF6), and cell-cell junction (CTNNB, CDH1) DEPs (differentially expressed proteins). Enrichment analysis shows that the most significant terms associated with this PPI network are the tyrosine kinase receptor (TRKR) and Src homology region two domain-containing phosphatase-2 (SHP2) pathways, tyrosine kinase receptor signaling pathways, positive regulation of kinase and transferase activity, cytokine signaling, and negative regulation of the immune response. The participation of BDNF in the immune response and its interactions with neuroprotective and cell-cell adhesion DEPs is probably a conserved regulatory process which protects against the many detrimental effects of immune activation and hyperinflammation including neurotoxicity. Lowered BDNF levels in mood disorders and schizophrenia (a) are associated with disruptions in neurotrophic signaling and activated immune-inflammatory pathways leading to neurotoxicity and (b) may interact with the reduced expression of other DEPs (CTNNB1, CDH1, or DISC1) leading to multiple aberrations in synapse and axonal functions.


Spatial patterns and spatially-varying factors associated with childhood acute respiratory infection: data from Ethiopian demographic and health surveys (2005, 2011, and 2016).
In Ethiopia, acute respiratory infections (ARIs) are a leading cause of morbidity and mortality among children under five years. Geographically linked data analysis using nationally representative data is crucial to map spatial patterns of ARIs and identify spatially-varying factors of ARI. Therefore, this study aimed to investigate spatial patterns and spatially-varying factors of ARI in Ethiopia. Secondary data from the Ethiopian Demographic Health Survey (EDHS) of 2005, 2011, and 2016 were used. Kuldorff's spatial scan statistic using the Bernoulli model was used to identify spatial clusters with high or low ARI. Hot spot analysis was conducted using Getis-OrdGi statistics. Eigenvector spatial filtering regression model was carried out to identify spatial predictors of ARI. Acute respiratory infection spatially clustered in 2011 and 2016 surveys year (Moran's I:-0.011621-0.334486). The magnitude of ARI decreased from 12.6% (95%, CI: 0.113-0.138) in 2005 to 6.6% (95% CI: 0.055-0.077) in 2016. Across the three surveys, clusters with a high prevalence of ARI were observed in the North part of Ethiopia. The spatial regression analysis revealed that the spatial patterns of ARI was significantly associated with using biomass fuel for cooking and children not initiating breastfeeding within 1-hour of birth. This correlation is strong in the Northern and some areas in the Western part of the country. Overall there has been a considerable decrease in ARI, but this decline in ARI varied in some regions and districts between surveys. Biomass fuel and early initiation of breastfeeding were independent predictors of ARI. There is a need to prioritize children living in regions and districts with high ARI.


Urinary and gastrointestinal malakoplakia in a 12-year-old girl.
Malakoplakia is a rare chronic inflammatory disease that was originally described in the urinary bladder but can involve many other organs and soft tissues. It is believed to be caused by an alteration in the bacterial phagocytic system. Clinically, it is described as single or multiple tumors that can appear in any part of the body. Histologically, the presence of Michaelis-Gutmann bodies is pathognomonic. Malakoplakia in children is rare. Few pediatric cases in the urinary tract, kidney, or gastrointestinal tract have been published. We present a case of urinary and gastrointestinal malakoplakia in a 12-year-old girl.