Autoantibodies to thrombopoietin and the thrombopoietin receptor in patients with immune thrombocytopenia.
Autoantibodies to thrombopoietin (TPO, also termed THPO) or the TPO receptor (cMpl, also termed MPL) could play a pathological role in immune thrombocytopenia (ITP). In this study, we tested for autoantibodies against TPO, cMpl, or the TPO/cMpl complex in ITP and other thrombocytopenic disorders. Using an inhibition step with excess TPO in fluid-phase to improve binding specificity, the prevalence of anti-TPO autoantibodies was: active ITP: 9/32 (28%); remission ITP: 0/14 (0%); non-immune thrombocytopenias: 1/10 (10%); and healthy controls: 1/11 (9%). Similarly, using an inhibition step with excess cMpl, the prevalence of specific anti-cMpl autoantibodies was: active ITP: 7/32 (22%); remission ITP: 1/14 (7%); non-immune thrombocytopenias: 3/10 (30%); and healthy controls: 0/11 (0%). Two active ITP patients had autoantibodies against the TPO/cMpl complex, but not against TPO or cMpl alone. Anti-TPO or anti-cMpl autoantibodies were found in 44% of ITP patients, and in 40% of patients with other thrombocytopenic disorders. These autoantibodies did not correlate with ITP disease severity or number of ITP treatments received; however, in this cohort, 3 patients failed to respond to TPO receptor agonist medications, and of those, 2 had anti-TPO autoantibodies. This suggests that anti-TPO and anti-cMpl autoantibodies are associated with thrombocytopenia, and may be clinically relevant in a subset of ITP patients.


[Cilioretinal arteries under fundus fluorescein angiography].
Cilioretinal arteries were found in 825 (40.2%) of 2,050 eyes with fundus fluorescein angiography records. Among 195 cases in which all retinal arteries were demonstrated satisfactorily, the cilioretinal arteries were 1-6 in number, supplying 1-4 quadrants of the fundus, while in 102 cases (52.3%) they did not supply the macular area as conventionally believed. Besides, in another group of 129 eyes in which cilioretinal arteries were recognized with the ophthalmoscope, those in 28 eyes (21.7%) were disproved by angiography. Therefore, angiography should be the only means to confirm clinically diagnosed cilioretinal arteries.


Efficacy and Safety of Epilepsy Surgery for Older Adult Patients with Refractory Epilepsy.
The population of elderly patients with epilepsy has been growing rapidly and the chances of referring older patients with refractory epilepsy for surgical options could be increasing. In general, epilepsy surgery at higher ages has been less likely to be performed, because little is known regarding the risks and benefits in elderly patients. We, therefore, investigated surgical outcomes and comorbidities in a population ≥50 years old who underwent epilepsy surgery. Patients ≥50 years old who underwent epilepsy surgery were identified from the database of our epilepsy center for the period from 2009 to 2017. Surgical complications and seizure outcome were reviewed, and seizure outcomes were evaluated using the International League Against Epilepsy (ILAE) surgery outcome scale. The mean age of 32 patients at the time of surgery was 56.1±5.1 years. The mean duration of epilepsy was 23.4±18.5 years and mean follow-up was 2.7±2.0 years. As of the most recent visit, 56.3% of patients remained completely seizure-free (ILAE Class I). The surgery-related complication rate was 11.5%, comprising permanent deficits in 3.8% and transient deficits in 7.7%. These results suggest that epilepsy surgery may represent a valuable approach in selected adult patients.


Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.
There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119-30. ©2017 AACR.


National survey of notifications of tuberculosis in England and Wales in 1983. Medical Research Council Tuberculosis and Chest Diseases Unit.
In a survey of all notifications of tuberculosis in England and Wales for the first six months of 1983 56% of the 3002 newly notified patients who had not been treated before were of white and 37% were of Indian subcontinent (Indian, Pakistani, or Bangladeshi) ethnic origin, findings similar to those of a survey in 1978-9. In the four and a quarter years between the surveys the number of patients notified had declined by 26%, the decline being 28% among those of white and 23% among those of Indian subcontinent ethnic origin. The white patients were on average older than the patients of Indian subcontinent ethnic origin, and a higher proportion of them had respiratory disease (82% compared with 66%). The pulmonary lesions were on average larger and more often bacteriologically positive in the white patients. There were considerable differences between the ethnic groups in the estimated yearly rates of notifications per 100 000 population in England in 1983. The highest rates occurred in the Indian (178) and the Pakistani and Bangladeshi (169) populations and were roughly 25 times the rate in the white population (6 X 9). In the Indian subcontinent ethnic groups the highest rates occurred among those who had arrived in the United Kingdom within the previous five years.


SOCS1 regulates type I/type II NKT cell balance by regulating IFNgamma signaling.
Suppressor of cytokine signaling-1 (SOCS1) has been shown to be an essential negative regulator of cytokine responses, including those of IFNγ, IL-2, IL-4 and IL-7. SOCS1 deficiency resulted in hyperactivation not only of T cells in general but also of NKT cells specifically. Consistent with previous reports, T- and NKT-cell-specific deletion of Socs1 in mice resulted in enhanced sensitivity to ConA-induced hepatitis. Compared with wild-type (WT) NKT cells, SOCS1-deficient NKT cells produced larger quantities of IFNγ in response to ConA and proliferated faster in response to IL-2 and IL-15. To our surprise, however, SOCS1-deficient NKT cells did not respond to the synthetic glycolipid ligand alpha-galactosylceramide (α-GalCer), though they did respond to sulfatide. α-GalCer-CD1d-tetramer-positive type I NKT [invariant NKT (iNKT)] cells were marginally detected in the periphery of SOCS1-conditional knockout (cKO) mice, suggesting that most of the SOCS1-deficient NKT cells at the periphery were type II NKT cells. Consistently, invariant Vα14 expression was much lower in SOCS1-deficient NKT cells than in WT NKT cells, indicating that iNKT cell homeostasis was abnormal in SOCS1-cKO mice. This reduction in iNKT cells was not observed in mice of an IFNγ-deficient background. These results suggest that SOCS1 is an important regulator of the balance between type I and type II NKT cells at the periphery.


A novel candidate region for ALS on chromosome 14q11.2.
Sequence variations with biologic effect in ALS have been identified in the gene for vascular endothelial growth factor (VEGF). The gene for a related protein, angiogenin, lies on chromosome 14q11.2. Analysis of the angiogenin (ANG) gene in the authors' population has demonstrated a significant allelic association with the rs11701 single nucleotide polymorphism (SNP) and identified a novel mutation in two individuals with sporadic ALS that potentially inhibits angiogenin function. These observations propose a candidate region for ALS on chromosome 14q11.2 and suggest that other genes with similar function to VEGF may be important in the pathogenesis of ALS.


[Evaluation of the corneal epithelium kinetics using cell proliferation markers].
In order to maintain its clear and uniform structure, the corneal epithelium needs constant equilibrium between production (division) and desquamation of its epithelial cells. The author aimed to evaluate the cell kinetics of corneal epithelium of rabbits in three situations (control, hypoproliferation and hyperproliferation) using BrdU, Ki-67/MIB-1 and AgNORs proliferation markers. Fifteen white female rabbits had their eyes randomly divided into three groups (A, B and. C). Group A included eyes submitted to phosphate buffer saline instillation (total 10 eyes); group B, instillation of phosphate buffer saline after removing a 10 mm central area of the corneal epithelium (total 10 eyes) and group C, instillation of 5-fluorouracil in normal epithelium (total 10 eyes). The results of the mean number and standard deviation of the marked cells using BrdU in groups A, B e C were, respectively, 7.17 +/- 0.74; 35.00 +/- 3.01 e 0.22 +/- 0.1 marked cells per 100 basal cells. Differences among groups were statistically significant. The mean number and standard deviation of the labelled cells using Ki-67 were 7.55 +/- 1.22 in group A; 35.55 +/- 3.84 in group B and 0.34 +/- 0.14 in group C. Differences among groups were statistically significant. The mean area and standard deviation of NORs in group A were 1.92 +/- 0.24, in group B, 3.61 +/- 0.27 and in group C, 1.71 +/- 0.26. The markers BrdU, Ki-67 and AgNOR showed a positive correlation with statistical significance among the cellular proliferation situations studied (control, hypoproliferation and hyperproliferation); the AgNOR did not show statistically significant differences among the control and hypoproliferation situations and there was more agreement in the results among markers BrdU and Ki-67 in three cell proliferation situations.


Marine n-3 fatty acids alter the proteomic response to methylmercury in Atlantic salmon kidney (ASK) cells.
Fish based diets have been linked to the amelioration of methylmercury (MeHg) induced symptoms in several epidemiological studies, particularly due to their contents of marine n-3 fatty acids. It has been suggested that n-3 fatty acids may mask the detrimental effects of MeHg due to their beneficial effect on the same biological functions which are negatively affected by MeHg. However, in vitro studies have implied that there may be direct interactions between the marine n-3 FAs and MeHg, which ameliorates MeHg toxicity through interactions at a biological level. To understand how marine n-3 FAs and MeHg interact in fish as a biological system, we wanted to investigate molecular interaction in a fish cell system. Atlantic salmon kidney (ASK) cells were pre-incubated with the marine n-3 FAs docosahexaenoic acid (22:6n-3, DHA) and eicosapentaenoic acid (20:5n-3, EPA) before exposing them to MeHg. Modulating effects of the marine FAs on MeHg toxicity were subsequently assessed using the exploratory technique of proteomics, in a factorial design. Thirty-four differentially regulated proteins were identified. From these; twenty-seven were shown to be differentially regulated by MeHg, twelve were regulated by the fatty acids, and another eight showed interaction effects between MeHg and the FAs. Several of the proteins were concomitantly affected by MeHg- and FA-main effects, as well as interaction effects. Functional annotations and pathway analysis of the proteins revealed that marine n-3 FAs and MeHg concurrently affected the abundance of protein markers relating to such molecular mechanisms as: cell signaling, calcium homeostasis, structural integrity, apoptosis, and energy metabolism. In conclusion, both marine n-3 FAs and MeHg can differentially affect the abundances of the same proteins, indicating modulating effects of EPA and DHA on MeHg metabolism, and possibly on its toxicity.


Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression.
Developmental exposure to chlorpyrifos (CPF) causes persistent changes in serotonergic (5HT) systems. We administered 1 mg/kg/day CPF to rats on postnatal days 1-4, a regimen below the threshold for systemic toxicity. When tested in adulthood, CPF-exposed animals showed abnormalities in behavioral tests that involve 5HT mechanisms. In the elevated plus maze, males treated with CPF spent more time in the open arms, an effect seen with 5HT deficiencies in animal models of depression. Similarly, in an anhedonia test, the CPF-exposed group showed a decreased preference for chocolate milk versus water. Developmental CPF exposure also has lasting effects on cognitive function. We replicated our earlier finding that developmental CPF exposure ablates the normal sex differences in 16-arm radial maze learning and memory: during acquisition training, control male rats typically perform more accurately than do control females, but CPF treatment eliminated this normal sex difference. Females exposed to CPF showed a reduction in working and reference memory errors down to the rate of control males. Conversely, CPF-exposed males exhibited an increase in working and reference memory errors. After radial-arm acquisition training, we assessed the role of 5HT by challenging the animals with the 5HT2 receptor antagonist ketanserin. Ketanserin did not affect performance in controls but elicited dose-dependent increases in working and reference memory errors in the CPF group, indicating an abnormal dependence on 5HT systems. Our results indicate that neonatal CPF exposures, classically thought to be subtoxic, produce lasting changes in 5HT-related behaviors that resemble animal models of depression.


Treatment of T cell lymphoma in dogs.
Overall, canine lymphoma remains one of the most chemotherapy-responsive cancers in the dog. In addition to the stage and the substage of disease, T cell phenotype is the most consistently important prognostic factor. T cell lymphoma (TCL) in dogs is a heterogeneous disease; dogs with a separate entity of indolent TCL can have a considerably better prognosis than dogs with other forms of lymphoma, and indolent TCL may not always require immediate treatment. In contrast, high-grade TCL is an aggressive disease, and when treated with CHOP-based protocols, dogs with this high-grade TCL have a complete remission rate as low as 40 per cent, relapse earlier and have shorter survival time than dogs with a comparable stage, high-grade B cell lymphoma. This review describes the different disease entities that comprise canine TCL, discusses prognosis for each and treatment options that appear to give the best outcomes.


Qualitative development and content validation of the "SPART" model; a focused ethnography study of observable diagnostic and therapeutic activities in the emergency medical services care process.
Clinical reasoning is a crucial task within the Emergency Medical Services (EMS) care process. Both contextual and cognitive factors make the task susceptible to errors. Understanding the EMS care process' structure could help identify and address issues that interfere with clinical reasoning. The EMS care process is complex and only basically described. In this research, we aimed to define the different phases of the process and develop an overarching model that can help detect and correct potential error sources, improve clinical reasoning and optimize patient care. We conducted a focused ethnography study utilizing non-participant video observations of real-life EMS deployments combined with thematic analysis of peer interviews. After an initial qualitative analysis of 7 video observations, we formulated a tentative conceptual model of the EMS care process. To test and refine this model, we carried out a qualitative, thematic analysis of 28 video-recorded cases. We validated the resulting model by evaluating its recognizability with a peer content analysis utilizing semi-structured interviews. Based on real-life observations, we were able to define and validate a model covering the distinct phases of an EMS deployment. We have introduced the acronym "SPART" to describe ten different phases: Start, Situation, Prologue, Presentation, Anamnesis, Assessment, Reasoning, Resolution, Treatment, and Transfer. The "SPART" model describes the EMS care process and helps to understand it. We expect it to facilitate identifying and addressing factors that influence both the care process and the clinical reasoning task embedded in this process.


[Topical characteristics of the organization of the strio-cortical tract in the brain of the dog].
The study was carried out by the method of axo-terminal regeneration with impregnation of frontal sections of the brain with the Laidlaw liquid. It was shown that following a lesion of the dorsal and ventral area of the caudate nucleus in the dog's cerebral cortex correspondingly different amount of degenerating terminations of strio-cortical fibres could be revealed. These bonds were mainly directed into the VI and V layers of the cortex, namely into the frontal, precoronary, postcoronary, orbital and insular areas.


Undergraduate dental education in Nigeria: perceptions of dental students and recent dental graduates.
Students' perception of their education is a subject that has received very little attention by those providing dental school education. This is more so in the Nigerian environment, where limited research has been carried out in dental education, particularly with respect to the students' perspectives on the quality of training received. Thus, the aim of this study was to determine the perceptions of dental students and recent dental graduates in Nigeria on their level of satisfaction with the quality of academic and clinical training received in their respective dental schools and the challenges faced in receiving this training. This was a cross-sectional descriptive study carried out amongst 271 dental students and recent dental graduates from eight dental schools in the country. Ethical approval for the study was obtained from the Institutional Review Board of the Lagos University Teaching Hospital (LUTH). Data collection was via self-administered questionnaires. Statistical analysis was carried out using SPSS 17. The final study sample was made up of 239 students, with a mean age of 24.57 (2.21) years. The two dental specialties in which the least level of satisfaction was recorded with regard to the quality of academic training received were Conservative Dentistry and Orthodontics, while for clinical training they were Conservative Dentistry and Oral Biology/Pathology. The three most common factors which were adversely affecting the quality of clinical training received were, poor electricity supply, insufficient dental chairs and quality of training received. Dental students and recent graduates of Nigerian Dental schools are not satisfied with the quality of undergraduate training received in some dental specialties at their respective dental schools.


Why mothers choose to enrol their children in malaria clinical studies and the involvement of relatives in decision making: evidence from Malawi.
This study was aimed at researching the reasons why mothers enrol their children in malaria clinical research and how family members or relatives are involved in the decision-making process. Issues related to informed consent were also a particular focus of this study. A total of 81 participants took part in 8 focus group discussions. Thirty-nine participants were recruited from Blantyre, an urban setting, and forty-two participants were from Chikwawa, a rural setting. All the participants were mothers whose children had participated or were participating in the Intermittent Prevention Therapy post-discharge (IPTpd) Malaria Research. A majority of the participants reported that they chose to participate in the IPTpd research as a way of accessing better quality medical care. They also decided to enrol their children in order to benefit from the material and monetary incentives that were being given to participants for their participation. Most participants reported that they made the enrollment decisions on their own. They informed their family members/marital partners about their enrollment decisions after they had given their consent. A few made their enrollment decisions after consulting their family members. There was also a sense of trust in health workers who asked the potential participants to join the IPTpd research. Most participants decide to take part in malaria research because of better medical treatment. Partners and relatives play a very small role in the decision-making process of participants in malaria clinical research. Research participants'have a sense of trust in health workers who enrol them in clinical research.


Effect of Cannabidiol and Δ9-Tetrahydrocannabinol on Driving Performance: A Randomized Clinical Trial.
Cannabis use has been associated with increased crash risk, but the effect of cannabidiol (CBD) on driving is unclear. To determine the driving impairment caused by vaporized cannabis containing Δ9-tetrahydrocannabinol (THC) and CBD. A double-blind, within-participants, randomized clinical trial was conducted at the Faculty of Psychology and Neuroscience at Maastricht University in the Netherlands between May 20, 2019, and March 27, 2020. Participants (N = 26) were healthy occasional users of cannabis. Participants vaporized THC-dominant, CBD-dominant, THC/CBD-equivalent, and placebo cannabis. THC and CBD doses were 13.75 mg. Order of conditions was randomized and balanced. The primary end point was standard deviation of lateral position (SDLP; a measure of lane weaving) during 100 km, on-road driving tests that commenced at 40 minutes and 240 minutes after cannabis consumption. At a calibrated blood alcohol concentration (BAC) of 0.02%, SDLP was increased relative to placebo by 1.12 cm, and at a calibrated BAC of 0.05%, SDLP was increased relative to placebo by 2.4 cm. Among 26 randomized participants (mean [SD] age, 23.2 [2.6] years; 16 women), 22 (85%) completed all 8 driving tests. At 40 to 100 minutes following consumption, the SDLP was 18.21 cm with CBD-dominant cannabis, 20.59 cm with THC-dominant cannabis, 21.09 cm with THC/CBD-equivalent cannabis, and 18.28 cm with placebo cannabis. SDLP was significantly increased by THC-dominant cannabis (+2.33 cm [95% CI, 0.80 to 3.86]; P < .001) and THC/CBD-equivalent cannabis (+2.83 cm [95% CI, 1.28 to 4.39]; P < .001) but not CBD-dominant cannabis (-0.05 cm [95% CI, -1.49 to 1.39]; P > .99), relative to placebo. At 240 to 300 minutes following consumption, the SDLP was 19.03 cm with CBD-dominant cannabis, 19.88 cm with THC-dominant cannabis, 20.59 cm with THC/CBD-equivalent cannabis, and 19.37 cm with placebo cannabis. The SDLP did not differ significantly in the CBD (-0.34 cm [95% CI, -1.77 to 1.10]; P > .99), THC (0.51 cm [95% CI, -1.01 to 2.02]; P > .99) or THC/CBD (1.22 cm [95% CI, -0.29 to 2.72]; P = .20) conditions, relative to placebo. Out of 188 test drives, 16 (8.5%) were terminated due to safety concerns. In a crossover clinical trial that assessed driving performance during on-road driving tests, the SDLP following vaporized THC-dominant and THC/CBD-equivalent cannabis compared with placebo was significantly greater at 40 to 100 minutes but not 240 to 300 minutes after vaporization; there were no significant differences between CBD-dominant cannabis and placebo. However, the effect size for CBD-dominant cannabis may not have excluded clinically important impairment, and the doses tested may not represent common usage. EU Clinical Trials Register: 2018-003945-40.


[Abscess in the right flank--a late complication of laparoscopic cholecystectomy].
Laparoscopic cholecystectomy (LC) is the treatment of choice in cases of symptomatic gallstones. A 74-year-old female presented with a spontaneously perforated abscess in her right flank and passage through it of gallstones. Four years previously during LC the gallbladder perforated and 10-15 stones were lost intraperitoneally. In case of perforation of the gallbladder during LC it is essential to reduce loss of and remove all gallstones. In case of abdominal symptoms postoperatively, an intra-abdominal abscess must be suspected.


[Structural peculiarities of the SCP2 plasmid of Streptomyces coelicolor A3(2)].
Structural peculiarities of SCP2 plasmid isolated from different derivatives of Streptomyces coelicolor A3(2) were studied. By means of heteroduplexing 800 b.p. DNA insertion in SCP2 plasmid of S18-1 derivative was detected. The position of this insertion was localised on the SCP2 restriction map. A transposon-like structure with similar characteristics was detected and localised in different variants of SCP2 plasmid. This 600 bp DNA region is flanked by 20 bp inverted repeats and has the single EcoRI cleavage site. It is noted that the stretching of single-strand DNA circles of SCP2 plasmid was significantly less than that of single-strand DNA circles of pBR322 and PAS3; Tn9 plasmids. This may likely depend on the GC content of different plasmids.


'Covering doctors' standing in for unavailable colleagues: What is the legal position?
Covering doctors are those who stand in for colleagues when the latter are unable to deal with their patients. Covering doctors who begin to issue telephonic instructions to nurses or other healthcare practitioners regarding the treatment of the patients they are covering are in the same position as any other doctors treating patients. They cannot argue that the patients they are covering only become their patients once an emergency or crisis occurs or when they see the patients for the first time, and that prior to that their function is merely to monitor the patient's progress. They also cannot rely on telephone instructions for long periods of time when the patient's health may be in danger, without seeing the patient. However, if covering doctors are found to be negligent they can still escape liability if the plaintiff cannot prove a causal link between their negligence and the harm that resulted 'beyond a reasonable doubt'.


Reduction in Blood Culture Contamination Through Use of Initial Specimen Diversion Device.
Blood culture contamination is a clinically significant problem that results in patient harm and excess cost. In a prospective, controlled trial at an academic center Emergency Department, a device that diverts and sequesters the initial 1.5-2 mL portion of blood (which presumably carries contaminating skin cells and microbes) was tested against standard phlebotomy procedures in patients requiring blood cultures due to clinical suspicion of serious infection. In sum, 971 subjects granted informed consent and were enrolled resulting in 904 nonduplicative subjects with 1808 blood cultures. Blood culture contamination was significantly reduced through use of the initial specimen diversion device™ (ISDD) compared to standard procedure: (2/904 [0.22%] ISDD vs 16/904 [1.78%] standard practice, P = .001). Sensitivity was not compromised: true bacteremia was noted in 65/904 (7.2%) ISDD vs 69/904 (7.6%) standard procedure, P = .41. No needlestick injuries or potential bloodborne pathogen exposures were reported. The monthly rate of blood culture contamination for all nurse-drawn and phlebotomist-drawn blood cultures was modeled using Poisson regression to compare the 12-month intervention period to the 6 month before and after periods. Phlebotomists (used the ISDD) experienced a significant decrease in blood culture contamination while the nurses (did not use the ISDD) did not. In sum, 73% of phlebotomists completed a post-study anonymous survey and widespread user satisfaction was noted. Use of the ISDD was associated with a significant decrease in blood culture contamination in patients undergoing blood cultures in an Emergency Department setting. NCT02102087.


Volatile fatty acids: their production, absorption, utilization, and roles in human health.
The evidence shows that microbial fermentation of carbohydrates and endogenous substrates occurs in the large intestine of humans and that VFA represent a major endproduct. The large number of bacterial species, the complex nature of their interactions, and the endproducts of their fermentation processes are all likely to have significance in human health. Fermentation in the human intestine resembles rumen fermentation with respect to the metabolic pathways involved in anaerobic degradation of organic matter and in the concentrations of VFA endproducts. Thus, rumen bacteria are useful for understanding the dynamics and potential interactions of human intestinal bacteria. Current research is directed towards examining fermentation processes in animals, such as the pig and some species of monkey, since these animals most closely resemble the human. From such animal studies the metabolic activities of VFA and the processes by which they are produced and absorbed can be more clearly investigated and understood. The effects of diet on the microflora and on the metabolic pathways leading to the generation of VFA are under investigation. Modification of diet seems the most likely way of modifying the extent to which VFA are produced and absorbed by the human. As methodologies and protocols for evaluating human intestinal fermentation in vivo are revised and made more sensitive, the significance of fermentation will become more clearly understood. However, it appears that VFA make a physiologically significant contribution to the health of the colonic mucosa, and to the energy supply of the host. The magnitude of these effects is probably influenced by diet.


Anti-Scl-70 antibodies in autoimmune hypothyroidism.
The relationship between autoimmune thyroiditis and systemic sclerosis is controversial. Data exist on the presence of thyroid autoantibodies in patients with systemic sclerosis but, as far as we could ascertain, anti-Scl-70 antibodies, which are highly specific for systemic sclerosis, have not been investigated in autoimmune hypothyroidism. This study compares the presence of anti-Scl-70 in females with autoimmune hypothyroidism (n = 24) and in healthy age-matched female controls (n = 26). Free thyroxine levels were similar in both groups. Thyroid stimulating hormone (TSH), antithyroid peroxidase (anti-TPO), antithyroglobulin (anti-Tg) and index values for anti-Scl-70 levels were significantly higher in patients with autoimmune hypothyroidism compared with controls, although the anti-Scl-70 test was negative in both groups. Anti-TPO, anti-Tg and TSH significantly correlated with anti-Scl-70. In conclusion, autoimmune hypothyroidism seems to be associated with a higher index level of anti-Scl-70, yet a negative anti-Scl-70 antibody test. This suggests that autoimmune hypothyroidism might have common aetiological factors with systemic sclerosis.


Is the efficiency of mammalian (mouse) skeletal muscle temperature dependent?
Myosin crossbridges in muscle convert chemical energy into mechanical energy. Reported values for crossbridge efficiency in human muscles are high compared to values measured in vitro using muscles of other mammalian species. Most in vitro muscle experiments have been performed at temperatures lower than mammalian physiological temperature, raising the possibility that human efficiency values are higher than those of isolated preparations because efficiency is temperature dependent. The aim of this study was to determine the effect of temperature on the efficiency of isolated mammalian (mouse) muscle. Measurements were made of the power output and heat production of bundles of muscle fibres from the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles during isovelocity shortening. Mechanical efficiency was defined as the ratio of power output to rate of enthalpy output, where rate of enthalpy output was the sum of the power output and rate of heat output. Experiments were performed at 20, 25 and 30◦C. Maximum efficiency of EDL muscles was independent of temperature; the highest value was 0.31}0.01 (n =5) at 30◦C. Maximum efficiency of soleus preparations was slightly but significantly higher at 25 and 30◦C than at 20◦C; the maximum mean value was 0.48±0.02 (n =7) at 25◦C. It was concluded that maximum mechanical efficiency of isolated mouse muscle was little affected by temperature between 20 and 30◦C and that it is unlikely that differences in temperature account for the relatively high efficiency of human muscle in vivo compared to isolated mammalian muscles.


Hydrogen impurity effects. A(5)Tt(3)Z intermetallic compounds between A = Ca, Sr, Ba, Eu, Yb and Tt = Sn, Pb with Cr(5)B(3)-like structures that are stabilized by hydride or fluoride (Z).
The binary systems Ca-Sn, Ba-Sn, Eu-Sn, Yb-Sn, Sr-Pb, Ba-Pb, and Eu-Pb do not contain Cr(5)B(3)-like A(5)Tt(3) phases when care is taken to exclude hydrogen from the reactions (Tt = tetrel, Si-Pb). All form ternary A(5)Tt(3)H(x)() phases (x < or = 1) with "stuffed" Cr(5)B(3)-like structures instead, and all of those tested, Ca-Sn, Ba-Sn, Sr-Pb, and Ba-Pb, also yield the isostructural A(5)Tt(3)F. The structures and compositions of Ca(5)Sn(3)H(x), Ca(5)Sn(3)F(0.89), Eu(5)Sn(3)H(x), and Sr(5)Pb(3)F have been refined from single-crystal X-ray diffraction data and of Ca(5)Sn(3)D from powder neutron data. The interstitial H, F atoms are bound in a tetrahedral (A(2+))(4) cavity in a Cr(5)B(3)-type metal atom structure. Nine previous reports of binary "Ba(5)Sn(3)", "Yb(5)Sn(3)", "Sr(5)Pb(3)", and "Ba(5)Pb(3)" compounds were wrong and presumably concerned the hydrides. The new ternary phases are generally Pauli-paramagnetic, evidently with pi electrons from the characteristic tetrelide dimers in this structure type at least partially delocalized into the conduction band. The Sn-Sn bonds appear correspondingly shortened on oxidation. Other new phases reported are CaSn (CrB type), Yb(5)Sn(4)H(x) (Sm(5)Ge(4)), YbSn ( approximately TlTe), Ba(5)Pb(3) ( approximately W(5)Si(3)), and Yb(31)Pb(20) (Ca(31)Sn(20)).


Cytogenetics in the management of B-cell acute lymphoblastic leukemia: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).
Cytogenetic analysis is mandatory at initial assessment of B-cell acute lymphoblastic leukemia (B-ALL) due to its diagnostic and prognostic value. Results from chromosome banding analysis and complementary FISH are taken into account in therapeutic protocols and further completed by other techniques (RT-PCR, SNP-array, MLPA, NGS, OGM). Indeed, new genomic entities have been identified by NGS, mostly RNA sequencing, such as Ph-like ALL that can benefit from targeted therapy. Here, we have attempted to establish cytogenetic guidelines by reviewing the most recent published data including the novel 5th World Health Organization and International Consensus Classifications. We also focused on newly described cytogenomic entities and indicate alternative diagnostic tools such as NGS technology, as its importance is vastly increasing in the diagnostic setting.


Recent advances in head and neck surgical oncology.
In recent years, the field of head and neck oncology has witnessed a remarkable transformation with unprecedented advances that have revolutionized the management of complex tumors in this region. As an intricate subspecialty within oncology, head and neck surgical procedures demand detailed knowledge of the complex anatomy meticulous precision in surgical technique, and expertise to preserve vital functions while ensuring optimal oncological outcomes. With the relentless pursuit of improved patient outcomes, the integration of innovative technologies has significantly enhanced the surgical armamentarium. Robotics, endoscopic platforms, and image-guided navigation have revolutionized the surgical approach, enabling precise tumor resection and sparing healthy tissues. Furthermore, the application of advanced imaging modalities and molecular biomarker profiling has opened new avenues for personalized treatment strategies. From targeted therapies and immunotherapies to adaptive radiation techniques, clinicians are now equipped with an array of tailored options, ushering in a new era of personalized care for patients with head and neck malignancies. This article delves into the unfolding narratives of clinical triumphs, exploring the transformative potential of emerging therapies and the collaborative efforts propelling head and neck surgical oncology toward a future of hope and healing.


Synthesis of Novel α-Trifluoroanisole Derivatives Containing Phenylpyridine Moieties with Herbicidal Activity.
To find novel herbicidal compounds with high activity and broad spectrum, a series of phenylpyridine moiety-containing α-trifluoroanisole derivatives were designed, synthesized, and identified via nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Greenhouse-based herbicidal activity assays revealed that compound 7a exhibited > 80% inhibitory activity against Abutilon theophrasti, Amaranthus retroflexus, Eclipta prostrate, Digitaria sanguinalis, and Setaria viridis at a dose of 37.5 g a.i./hm2, which was better than fomesafen. Compound 7a further exhibited excellent herbicidal activity against Abutilon theophrasti and Amaranthus retroflexus in this greenhouse setting, with respective median effective dose (ED50) values of 13.32 and 5.48 g a.i./hm2, both of which were slightly superior to fomesafen (ED50 = 36.39, 10.09 g a.i./hm2). The respective half-maximal inhibitory concentration (IC50) for compound 7a and fomesafen when used to inhibit the Nicotiana tabacum protoporphyrinogen oxidase (NtPPO) enzyme, were 9.4 and 110.5 nM. The docking result of compound 7a indicated that the introduction of 3-chloro-5-trifluoromethylpyridine and the trifluoromethoxy group was beneficial to the formation of stable interactions between these compounds and NtPPO. This work demonstrated that compound 7a could be further optimized as a PPO herbicide candidate to control various weeds.


A novel mitochondrial DEAD box protein (Mrh4) required for maintenance of mtDNA in Saccharomyces cerevisiae.
In a screen of nuclear genes that assist splicing of mitochondrial localized group II introns in yeast we isolated low-copy number suppressors of splicing and respiratory-deficient point mutants of intron aI5gamma, the last intron of the gene encoding cytochrome c oxidase subunit I. One of the genes found contains the open reading frame (ORF) YGL064c that has previously been proposed to encode a putative RNA helicase of the DEAD box family. Deletion of the ORF gives rise to 100% cytoplasmic petites, indicating that the protein plays an essential role in the mitochondrial RNA metabolism. Overexpression of YGL064c-GFP fusions clearly revealed a mitochondrial localization of the protein. The gene encodes the fourth putative RNA helicase of Saccharomyces cerevisiae implicated in a mitochondrial function and was therefore termed MRH4 (for mitochondrial RNA helicase).


Iterative reconstruction for quantitative computed tomography analysis of emphysema: consistent results using different tube currents.
To assess the advantages of iterative reconstruction for quantitative computed tomography (CT) analysis of pulmonary emphysema. Twenty-two patients with pulmonary emphysema underwent chest CT imaging using identical scanners with three different tube currents: 240, 120, and 60 mA. Scan data were converted to CT images using Adaptive Iterative Dose Reduction using Three Dimensional Processing (AIDR3D) and a conventional filtered-back projection mode. Thus, six scans with and without AIDR3D were generated per patient. All other scanning and reconstruction settings were fixed. The percent low attenuation area (LAA%; < -950 Hounsfield units) and the lung density 15th percentile were automatically measured using a commercial workstation. Comparisons of LAA% and 15th percentile results between scans with and without using AIDR3D were made by Wilcoxon signed-rank tests. Associations between body weight and measurement errors among these scans were evaluated by Spearman rank correlation analysis. Overall, scan series without AIDR3D had higher LAA% and lower 15th percentile values than those with AIDR3D at each tube current (P<0.0001). For scan series without AIDR3D, lower tube currents resulted in higher LAA% values and lower 15th percentiles. The extent of emphysema was significantly different between each pair among scans when not using AIDR3D (LAA%, P<0.0001; 15th percentile, P<0.01), but was not significantly different between each pair among scans when using AIDR3D. On scans without using AIDR3D, measurement errors between different tube current settings were significantly correlated with patients' body weights (P<0.05), whereas these errors between scans when using AIDR3D were insignificantly or minimally correlated with body weight. The extent of emphysema was more consistent across different tube currents when CT scans were converted to CT images using AIDR3D than using a conventional filtered-back projection method.


Species boundaries and nomenclature of Rhizopus arrhizus (syn. R. oryzae).
Rhizopus arrhizus (Mucorales, Mucoromycotina) is the prevalent opportunist worldwide among the mucoralean species causing human infections. On the other hand the species has been used since ancient times to ferment African and Asian traditional foods and condiments based on ground soybeans. As producer of organic acids and hydrolytic enzymes it is widely applied in food industry and biotechnology. Using a set of 82 strains we studied phylogenetic and biological species boundaries within Rhizopus arrhizus s.l. to test the taxonomic status of R. delemar that was recently separated from R. arrhizus. Sequence analyses based on the internal transcribed spacer region, the gene of the largest subunit of the RNA polymerase II, a part of the actin gene, and the translation elongation factor 1-α as well as amplified fragment length polymorphism analysis were performed. Phenotypic characters such as enzyme profiles and growth kinetics were examined and the mating behavior was tested. Molecular analyses supported the existence of two phylogenetic species. However, the results of the mating test suggest that the mating barrier is still not complete. No physiological, ecological or epidemiological distinction could be found beside the difference in the production of organic acids. Consequently the status of varieties is proposed for the two phylogenetic species. Because the description of the first described R. arrhizus is considered to be conclusive we recommend the use of Rhizopus arrhizus var. arrhizus and var. delemar.


Teleradiology for remote consultation using iPad improves the use of health system human resources for paediatric fractures: prospective controlled study in a tertiary care hospital in Italy.
The growing cost of health care and lack of specialised staff have set e-Health high on the European political agenda. In a prospective study we evaluated the effect of providing images for remote consultation through an iPad on the number of in-hospital orthopaedic consultations for children with bone fractures. Children from 0 to 18 years diagnosed with a bone fracture by the radiologist during the hours when an orthopaedic service is provided only on-call were eligible for enrollment. Cases were enrolled prospectively during September and October 2013. A standard approach (verbal information only, no X-Ray provided remotely) was compared to an experimental approach (standard approach plus the provision of X-ray for remote consultation through an iPad). The primary outcome was the number of orthopaedic in-hospital consultations that occurred. Other outcomes included: immediate activation of other services; time needed for decision-making; technical difficulties; quality of images and diagnostic confidence (on a likert scale of 1 to 10). Forty-two children were enrolled in the study. Number of in-hospital consultancies dropped from 32/42 (76.1%) when no X-ray was provided to 16/42 (38%) when the X-rays was provided (p < 0.001). With remote X-ray consultation in 14/42 (33.3%) cases services such as surgery and plaster room could be immediately activated, compared to no service activated without teleradiology (p < 0.001). Average time for decision making was 23.4 ± 21.8 minutes with remote X-ray consultation, compared to 56.2 ± 16.1 when the X-ray was not provided (p < 0.001). The comparison between images on the iPad and on the standard system for X- Ray visualisation resulted in a non statistically significant difference in the quality of images (average score 9.89 ± 0.37 vs 9.91 ± 0.30; p = 0.79), and in non statistically significant difference in diagnostic confidence (average score 9.91 ± 0.32 vs 9.92 ± 0.31; p = 0.88). Remote X-ray consultation through Aycan OsiriX PRO and iPad should be considered as a means for reducing the need of in-hospital orthopaedic consultation during on-call times, and potentially decrease the cost of care for the health system. In the future, alternative systems less expensive than Aycan OsiriX PRO should be further developed and tested.


Knowledge and practices toward COVID-19 among healthcare students: A cross-sectional study at the University of Zambia.
The COVID-19 pandemic led to the disruption of physical classes for university students globally, as large gatherings fuelled the transmission of the virus. In the efforts to mitigate its transmission and return to normality, prevention measures, including vaccination, have been encouraged. Therefore, it is critical to understand the knowledge and practices of students regarding COVID-19. This study assessed the knowledge and practices toward COVID-19 among healthcare students at the University of Zambia. This questionnaire-based cross-sectional study was carried out from August 2021 to October 2021 among 478 healthcare students (pharmacy, physiotherapy, nursing, biomedical, medicine, and radiography). We used a previously validated questionnaire to measure knowledge and practice. The predictors of knowledge and practices were assessed using logistic regression with robust estimation of standard errors. Statistical analysis was conducted using Stata/BE version 17.0. Of the 478 respondents, 243 (50.8%) were females. A larger proportion, 175 (36.6%) were in Pharmacy training, and 156 (32.6%) were in their fifth year of study. The overall mean knowledge score of the participants was 87.9 (SD = 16.1), being higher at 89.6 (SD = 14.3) among medical students and the lowest at 86.7 (SD = 17.1) among Pharmacy students, although this was statistically non-significant (p = 0.488). The overall mean practice score was 60.0 (SD = 24.7), being significantly higher at 63.5 (23.4) among nursing, physiotherapy and environmental students compared to other students (p = 0.048). In multivariable analysis, the participant training program was non-significantly associated with knowledge and practice toward COVID-19. However, increased age (AOR = 1.09, 95% CI: 1.01-1.117) and residing in urban areas (AOR = 1.79, 95% CI: 1.07-3.01) than in rural areas were associated with higher odds of good practice toward COVID-19. The healthcare students generally showed good knowledge levels and poor practices toward COVID-19. Further, there was no evidence of a difference in knowledge of COVID-19 among healthcare students. These findings suggest the need for implementation strategies to be centered on improving the practices of students toward COVID-19.


[TESTING THE PROTECTIVE PROPERTIES OF ARGON DURING SUBACUTE EXPOSURE TO HYPOXIC HYPOXIA].
Previously it has been shown that argon has a stimulating effect on biological processes including, specifically, strong protective properties during exposure to acute (1-4 hrs.) hypoxic hypoxia. Experiments with animals under hypoxia gradually growing over 3 to 7 days may give insight into mechanisms of the argon protective action. Purpose of the work was to explore character and severity of developing disorders, to attempt their prognosis and to test potentiality of argon as a protector from the effects of subacute hypoxic exposure. In two series of experiments Wistar male rats were housed in pressure chambers with different rates of O2 reduction without argon and with argon in concentration of 32-38%. Oxygen reduction from 20.9 to 9.0% in 3 days led to the death of 50% animals. Oxygen reduction to 12.0% in 7 days and one day in low-oxygen atmosphere was harmless for animals. Argon in air makes the response to hypoxia almost twice as sharp on virtually every level (red blood system, physiological, morphological and biochemical shifts) validating the concept that argon acts as a stimulator. In context of the most critical processes of adaptation to hypoxia--activation of blood formation and lipid metabolism--this sharpening of the response results in depletion of body resources and instigates irreversible shifts.


Antihyperalgesic, Antiallodynic, and Antinociceptive Effects of Cebranopadol, a Novel Potent Nociceptin/Orphanin FQ and Opioid Receptor Agonist, after Peripheral and Central Administration in Rodent Models of Neuropathic Pain.
Cebranopadol is a novel and highly potent analgesic acting via nociceptin/orphanin FQ peptide (NOP) and opioid receptors. Since NOP and opioid receptors are expressed in the central nervous system as well as in the periphery, this study addressed the question of where cebranopadol exerts its effects in animal models of chronic neuropathic pain. Mechanical hypersensitivity in streptozotocin (STZ)-treated diabetic rats, cold allodynia in the chronic constriction injury (CCI) model in rats, and heat hyperalgesia and nociception in STZ-treated diabetic and control mice was determined after intraplantar (i.pl.), intracerebroventricular (i.c.v.), or intrathecal (i.th.) administration. In STZ-treated rats, cebranopadol (i.pl.) reduced mechanical hypersensitivity in the ipsilateral paw, but had no effect at the contralateral paw. In CCI rats, cebranopadol (i.pl.) showed antiallodynic activity at the ipsilateral paw. After administration to the contralateral paw, cebranopadol also showed ipsilateral antiallodynic activity, but with reduced potency and delayed onset. In diabetic mice, cebranopadol i.th. and i.c.v. decreased heat hyperalgesia with full efficacy and similar potency for both routes. Cebranopadol also produced significant antinociception in nondiabetic controls. Thus, cebranopadol exerts potent and efficacious antihyperalgesic, antiallodynic, and antinociceptive effects after local/peripheral, spinal, and supraspinal administration. The contralateral effects after i.pl. administration were likely due to systemic redistribution. After central administration of cebranopadol, antihyperalgesic efficacy is reached at doses that are not yet antinociceptive. This study shows that cebranopadol is effective after peripheral as well as central administration in nociceptive and chronic neuropathic pain. Thus, it may be well-suited for the treatment of chronic pain conditions with a neuropathic component.


Novel synthesized triazole derivatives as effective corrosion inhibitors for carbon steel in 1M HCl solution: experimental and computational studies.
This article outlines the synthesis of two derivatives of 4-amino-5-hydrazineyl-4H-1,2,4-triazole-3-thiol for the prevention of carbon steel corrosion in 1M HCl solution. These derivatives are (Z)-3-(1-(2-(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)hydrazono)ethyl)-2H-chromen-2-one (TZ1) and 5-(2-(9H-fluoren-9-ylidene)hydrazineyl)-4-amino-4H-1,2,4-triazole-3-thiol (TZ2). Weight loss, electrochemical experiments, surface examinations, and theoretical computation are used to evaluate the effectiveness of the two compounds to be used as corrosion inhibitors. Weight loss and electrochemical studies demonstrate that these derivatives reduce the corrosion rate of carbon steel. To examine the morphology and constitution of the carbon steel surface submerged in HCl solution as well as after adding inhibitors, surface examination tests are performed. Analysis of the test solution via UV-visible spectroscopy is employed to check the possibility of complex formation between inhibitor molecules and Fe2+ ions released during the corrosion process. In order to explore their biological activity, the antibacterial activity was investigated against (E. coli and Bacillus subtilis). Finally, theoretical confirmation of the experimental findings is provided by quantum chemical (DFT) and Monte Carlo (MC) simulation studies. More adsorption sites are present in the derivatives of 4-amino-5-hydrazineyl-4H-1,2,4-triazole-3-thiol, which offer a novel perspective for developing new classes of corrosion inhibitors with substantial protective efficacy, especially at high temperatures.


The nature and origin of intraocular metallic foreign bodies appearing after phacoemulsification.
In order to evaluate the nature and origin of metallic foreign bodies embedded in the iris after uneventful phacoemulsification, we aimed to produce metallic fragments by applying ultrasound power with the same phaco machine and handpiece in an experimental model in vitro. In a glass bottle, we used linear phaco power of 100% continuously for 5 min first with a new phaco tip and then with a used tip. Afterwards, the fluid in the bottle was filtered through a Millipore filter. The remains on the filter were studied by scanning electron microscopy (SEM) and microprobe. Small particles remained on the filter which was used for the new tip. Microprobe microanalysis showed that these particles were mainly titanium, the same as the phaco tip. SEM of both the new and the used tips showed small fragments on the exterior surface and lumen. Intraocular metallic foreign bodies after phacoemulsification are likely to be shaken loose from the phaco tip. Although it is mostly agreed that these fragments are well tolerated, their overall effect remains to be evaluated in the long term.


Some features of binaural input to single neurons in physiologically defined area AI of cat cerebral cortex.
1. In the ectosylvian cortex of 24 barbiturate-anesthetized cats, area AI was identified by its frequency organization and the responses to tonal stimuli of single neurons in that field were examined using sealed stimulating systems incorporating calibrated probe microphone assemblies. 2. The responsiveness to monaural and binaural best-frequency stimuli was examined quantitatively for 282 single units in AI. One hundred thirty-nine cells (49%) were excited by independent stimulation of only one ear and were classified as EO cells. In general, the effective monaural excitatory input was derived from the contralateral ear. One hundred ten (39%) neurons were excited by independent stimulation of each ear and were classified as EE units. For these neurons, the contralateral responses were generally stronger, shorter in latency, and lower in threshold than were their ipsilateral responses. Thirty-three cells (12%) gave weak or no responses to monaural stimuli but responded securely to binaural stimuli. These cells were classified as predominantly binaural (PB). 3. Binaural interactions were examined by comparison of the response to binaural, equally intense stimuli to the stronger monaural response. Among EO cells suppression was the most common form of interaction, while for EE cells summation was the more common. Less than 8% of cells were found to be monaural. 4. In electrode penetrations radial to the cortex surface, cells received their stronger or sole monaural excitatory input from a common ear, generally the contralateral. Within such penetrations, however, cells commonly differed with regard to the nature of their input from the other ear and/or in their binaural interactions. 5. Comparison of these data with data previously reported for subcortical auditory nuclei revealed that AI preserves many of the stimulus specificity characteristics of the lower nuclei. The reasons for the preservation of these characteristics at the cortex and the implications of the present data for the binaural column hypothesis are discussed.


Update on otitis media - prevention and treatment.
Acute otitis media and otitis media with effusion are common childhood disorders, a source of significant morbidity, and a leading cause of antibiotic prescription in primary health care. Although effective treatments are available, some shortcomings remain, and thus better treatments would be welcome. Recent discoveries within the field of otitis media research relating to its etiology and pathogenesis have led to further investigation aimed at developing novel treatments. This article provides a review of the latest evidence relating to the understanding of acute otitis media and otitis media with effusion, current treatment strategies, their limitations, new areas of research, and novel strategies for treatment.


The effects of major burn related pathophysiological changes on the pharmacokinetics and pharmacodynamics of drug use: An appraisal utilizing antibiotics.
Patients suffering major burn injury represent a unique population of critically ill patients. Widespread skin and tissue damage causes release of systemic inflammatory mediators that promote endothelial leak, extravascular fluid shifts, and cardiovascular derangement. This phase is characterized by relative intra-vascular hypovolaemia and poor peripheral perfusion. Large volume intravenous fluid resuscitation is generally required. The patients' clinical course is then typically complicated by ongoing inflammation, protein catabolism, and marked haemodynamic perturbation. At all times, drug distribution, metabolism, and elimination are grossly distorted. For hydrophilic agents, changes in volume of distribution and clearance are marked, resulting in potentially sub-optimal drug exposure. In the case of antibiotics, this may then promote treatment failure, or the development of bacterial drug resistance. As such, empirical dose selection and pharmaceutical development must consider these features, with the application of strategies that attempt to counter the unique pharmacokinetic changes encountered in this setting.


A review of the evolving landscape between the consumer Internet and men's health.
Internet adoption continues to increase as broadband access and mobile connectivity penetrate developing global markets. Alongside increasing adoption, the Internet continues to evolve and usher in new modes of user interaction. Social media and search engines have facilitated the emergence of the participatory web, in which users are able to contribute content, form online communities, and disseminate information. This participatory web is reshaping the patient-physician relationship as patients are able to search for medical information, directly engage with healthcare practitioners through social media, and make therapeutic decisions via online marketplaces. The ability for patients to self-diagnose and self-treat is highly relevant to andrology, given that men have a baseline reluctance to visit healthcare providers. Furthermore, men's health issues such as erectile dysfunction and male infertility are stigmatized, with men turning to the Internet for guidance. The focus of this review is to survey the academic literature that evaluates the quality of online content for four common men's health conditions: hypogonadism, male infertility, erectile dysfunction, and Peyronie's disease.


Fever in travellers returning from the tropics.
The increase in international travel, the growing presence of arbovirus vectors in our country, and notifications of haemorrhagic fever such as the current outbreak of Ebola in D.R. Congo and the cases of Crimea-Congo haemorrhagic fever in our country have again cast the spotlight on tropical diseases Isolating suspected cases of highly contagious and lethal diseases must be a priority (Haemorrhagic fever, MERS-CoV). Assessing the patient, taking a careful medical history based on epidemiological aspects of the area of origin, activities they have carried out, their length of stay in the area and the onset of symptoms, will eventually help us, if not to make a definitive diagnosis, at least to exclude diseases that pose a threat to these patients. Malaria should be ruled out because of its frequency, without forgetting other common causes of fever familiar to emergency doctors.


Ceftazidime in the treatment of Pseudomonas infections in intensive-care patients.
The present study was designed to define the clinical activity and pharmacokinetics of ceftazidime in Pseudomonas sp. infections. The intensive care patients included in this study were hospitalized for at least 2 weeks and have frequently received antibiotic treatment which contributed with poor host resistance to the infections with highly resistant Pseudomonas strains. Sixteen adult patients entered the study. Their age ranged from 18 to 70 years. Ceftazidime was administered in a dose of 2 g three times daily by a constant infusion over 20-30 min. Frequent clinical assessment multiple cultures and determination of renal, hepatic and bacteriological functions were performed. Bacterial cultures were obtained prior to the beginning of therapy and every 2-3 days thereafter with a follow-up period of about 1-2 weeks. Pharmacokinetics in the blood were performed. Measurements of ceftazidime were made by using HPLC. Mean peak serum concentration of ceftazidime was 58.5 micrograms/ml after administration of 2.0 g of ceftazidime and eight hours after dosing the mean plasma concentration was about 5 micrograms/ml. No accumulation of ceftazidime could be observed during the treatment period. Mean plasma half-life was 2.1 hours at the beginning and 2.2 hours at the end of therapy. The mean apparent volume distribution was 0.35 l/kg. No severe adverse effects were reported throughout the study. Ceftazidime may be effectively used as single antiinfective agent in various conditions and higher plasma concentrations are an important predictor of bacteriological and clinical response in pulmonary infections caused by Pseudomonas species.


Requirement of the Saccharomyces cerevisiae APN1 gene for the repair of mitochondrial DNA alkylation damage.
The Saccharomyces cerevisiae APN1 gene that participates in base excision repair has been localized both in the nucleus and the mitochondria. APN1 deficient cells (apn1 Delta) show increased mutation frequencies in mitochondrial DNA (mtDNA) suggesting that APN1 is also important for mtDNA stability. To understand APN1-dependent mtDNA repair processes we studied the formation and repair of mtDNA lesions in cells exposed to methyl methanesulfonate (MMS). We show that MMS induces mtDNA damage in a dose-dependent fashion and that deletion of the APN1 gene enhances the susceptibility of mtDNA to MMS. Repair kinetic experiments demonstrate that in wild-type cells (WT) it takes 4 hr to repair the damage induced by 0.1% MMS, whereas in the apn1 Delta strain there is a lag in mtDNA repair that results in significant differences in the repair capacity between the two yeast strains. Analysis of lesions in nuclear DNA (nDNA) after treatment with 0.1% MMS shows a significant difference in the amount of nDNA lesions between WT and apn1 Delta cells. Interestingly, comparisons between nDNA and mtDNA damage show that nDNA is more sensitive to the effects of MMS treatment. However, both strains are able to repair the nDNA lesions, contrary to mtDNA repair, which is compromised in the apn1 Delta mutant strain. Therefore, although nDNA is more sensitive than mtDNA to the effects of MMS, deletion of APN1 has a stronger phenotype in mtDNA repair than in nDNA. These results highlight the prominent role of APN1 in the repair of environmentally induced mtDNA damage.


Retrephination keratoplasty for high astigmatism after penetrating keratoplasty.
We report preliminary results of a new procedure for correcting high astigmatism after penetrating keratoplasty. The procedure entails full-thickness trephination along the original donor-recipient junction with careful suturing in a combined interrupted and running fashion. Four eyes of four patients with severe astigmatism and myopia after penetrating keratoplasty underwent the procedure. High preoperative cylinder ranging from 4.50 to 16.00 D (mean 9.00 D) was reduced to 0.50 to 3.50 D (mean 1.90 D) at the last examination (between 3 to 6 months). Spherical equivalent myopia ranging from -2.00 to -10.25 D (mean -4.90 D) was essentially unchanged at plano to -9.00 D (-4.70 D) at the last examination. Overall, there was a mean refractive cylinder reduction of 7.10 D (79%). Retrephination after penetrating keratoplasty appears to be an acceptable alternative for correcting high astigmatism, and had only a small effect on the level of myopia.


[Experimental validation of a procedure for modulated perfusion of thiopental].
The pharmacokinetics of sodium thiopental was studied in 9 normal dogs of various ages by the usual bolus method. Data were fittable by a two compartment open model in 8, three compartments were needed in one. Constant-rate infusions, as used in cerebral resuscitation, were performed in 6 of them. As expected, constant blood levels could not be obtained during the distribution phase which lasted about 6 hours. From the individual pharmacokinetic constants, the time equation of infusion rate intended to exactly compensate for distribution was calculated. The resulting "modulated infusions" succeeded in reducing the blood level trough from 50% to 20%. After the end of infusions, the decrease of plasma levels exhibited a non linear pattern which had not been noticeable in the elimination phase after boluses. Such unknown non linearity may lead to systematic errors when calculating pharmacokinetic parameters: this could explain why a complete correction was not obtained with modulated infusions. A better parametrization method in the case of non-linear elimination is under study.


Conjunctivitis in children. A refresher survey of diagnosis and contemporary treatment.
The management of acute conjunctivitis need not be confusing. In the newborn period the common etiologic agents are chemical, TRIC, and bacterial. The latter two causes are effectively treated with sulfacetamide ophthalmic preparations. Dacryostenosis should be suspected in any child with recurrent conjunctivitis in the first six months of life. With older children the major causes can be classified as viral, allergic, foreign bodies, and bacterial. Bacterial conjunctivitis almost always responds to sulfacetamide ophthalmic preparations.


The effect of simvastatin treatment on behavioral parameters, cognitive performance, and hippocampal morphology in rats fed a standard or a high-fat diet.
The aim of this study was to examine the effect of simvastatin (SMV), a 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor, in rats fed with a standard or a high-fat diet (HFD) throughout the prenatal and the postnatal periods. The emotional status of the animals was evaluated by elevated plus-maze and modified forced swimming tests, whereas cognitive performance was assessed by a Morris water maze task. Morphological changes in the hippocampus were examined by design-based stereology. HFD exposure significantly increased blood serum triglycerides without altering cholesterol levels relative to the controls. After four weeks of oral SMV (5 mg/kg) administration, serum triglycerides reverted to the control level. SMV caused significant anxiolytic, antidepressant-like, and nootropic effects in animals fed the standard diet. In the HFD group, enhanced anxiety and depression, and reduced cognitive performances of animals were reversed by SMV treatment. Although a total volume estimation of the hippocampal subfields indicated no significant change among the groups, the total number of pyramidal neurons decreased significantly in animals fed the HFD; following SMV treatment, this detrimental effect was reversed. In conclusion, chronic SMV administration has significant therapeutic potential for the treatment of affective and cognitive disorders with or without altering the serum lipid profiles.


Gene regulation by structured mRNA elements.
The precise temporal and spatial coordination of gene activity, based on the integration of internal and external signals, is crucial for the accurate functioning of all biological processes. Although the basic principles of gene expression were established some 60 years ago, recent research has revealed a surprising complexity in the control of gene activity. Many of these gene regulatory mechanisms occur at the level of the mRNA, including sophisticated gene control tasks mediated by structured mRNA elements. We now know that mRNA folds can serve as highly specific receptors for various types of molecules, as exemplified by metabolite-binding riboswitches, and interfere with pro- and eukaryotic gene expression at the level of transcription, translation, and RNA processing. Gene regulation by structured mRNA elements comprises versatile strategies including self-cleaving ribozymes, RNA-folding-mediated occlusion or presentation of cis-regulatory sequences, and sequestration of trans-acting factors including other RNAs and proteins.


Characterization of novel MSX1 variants causally associated with non-syndromic oligodontia in Chinese families.
MSX1 (OMIM #142983) is crucial to normal dental development, and variants in MSX1 are associated with dental anomalies. The objective of this study was to characterize the pathogenicity of novel MSX1 variants in Chinese families with non-syndromic oligodontia (NSO). Genomic DNA was extracted from individuals representing 35 families with non-syndromic oligodontia and was analyzed by Sanger sequencing and whole-exome sequencing. Pathogenic variants were screened via analyses involving PolyPhen-2, Sorting-Intolerant from Tolerant, and MutationTaster, and conservative analysis of variants. Patterns of MSX1-related NSO were analyzed. MSX1 structural changes suggested functional consequences in vitro. Three previously unreported MSX1 heterozygous variants were identified: one insertion variant (c.576_577insTAG; p.Gln193*) and two missense variants (c. 871T>C; p.Tyr291His and c. 644A>C; p.Gln215Pro). Immunofluorescence analysis revealed abnormal subcellular localization of the p.Gln193* MSX1 variant. In addition, we found that these MSX1 variants likely lead to the loss of second premolars. Three novel MSX1 variants were identified in Chinese Han families with NSO, expanding the MSX1 variant spectrum and presenting a genetic origin for the pathogenesis detected in patients and their families.


A novel cold-inducible zinc finger protein from soybean, SCOF-1, enhances cold tolerance in transgenic plants.
Cold stress on plants induces changes in the transcription of cold response genes. A cDNA clone encoding C2H2-type zinc finger protein, SCOF-1, was isolated from soybean. The transcription of SCOF-1 is specifically induced by low temperature and abscisic acid (ABA) but not by dehydration or high salinity. Constitutive overexpression of SCOF-1 induced cold-regulated (COR) gene expression and enhanced cold tolerance of non-acclimated transgenic Arabidopsis and tobacco plants. SCOF-1 localized to the nucleus but did not bind directly to either C-repeat/dehydration (CRT/DRE) or ABA responsive element (ABRE), cis-acting DNA regulatory elements present in COR gene promoters. However, SCOF-1 greatly enhanced the DNA binding activity of SGBF-1, a soybean G-box binding bZIP transcription factor, to ABRE in vitro. SCOF-1 also interacted with SGBF-1 in a yeast two-hybrid system. The SGBF-1 transactivated the beta-glucuronidase reporter gene driven by the ABRE element in Arabidopsis leaf protoplasts. Furthermore, the SCOF-1 enhanced ABRE-dependent gene expression mediated by SGBF-1. These results suggest that SCOF-1 may function as a positive regulator of COR gene expression mediated by ABRE via protein-protein interaction, which in turn enhances cold tolerance of plants.


Occupational health characteristics of women on dairy farms in Pennsylvania.
Women play a significant role in Pennsylvania production agriculture, thereby exposing themselves to occupational health risks. The goal of this cross-sectional study was to assess the incidence of health conditions with a possible zoonotic origin in this underserved population. A written survey was sent to a stratified, random sample of dairy farms in Pennsylvania (n = 3709) using a modified version of the Dillman method. In addition to demographic data, the survey was used to collect information on the occurrence of zoonotic diseases, gastrointestinal illnesses, respiratory problems, dermatoses, and women's reproductive health issues. Of the 624 respondents, 10.4% (n = 65) reported that they had contracted a disease from an animal. Interestingly, only 9 respondents indicated that they had suffered from foodborne illnesses in the past year including salmonellosis (n = 1), campylobacteriosis (n = 1), and gastroenteritis due to Escherichia coli (n = 1). A risk factor associated with difficulty breathing was the lack of use of a breathing mask, whereas ventilation in the free stall area appeared to offer a protective effect. Difficulty breathing was reported by 9.8% (n = 61) of the respondents. Risk factors associated with skin disorders included raising fruits and/or vegetables, raising swine, and not wearing gloves when milking. The findings of the study suggest that many of the illnesses and conditions could have been acquired by working with dairy animals and their environment. Based on the findings of this study, additional investigations on the causes and prevention of these illnesses are warranted.


Differential effect of motor cortex stimulation on unit activities in the ventral posterior lateral thalamus in cats.
Although motor cortex stimulation (MCS) is being increasingly used to treat chronic refractory neuropathic pain in humans, its mechanisms of action remain elusive. Studies in animals have suggested the involvement of subcortical structures, in particular, the thalamus. Most of these studies have been performed in rats, a species presenting significant differences in thalamic anatomy and function relative to primates, in particular, a very limited number of thalamic GABA interneurons. The aim of this study was to investigate the effects of MCS on single-unit activities of the thalamic ventral posterior lateral (VPL) nucleus in cats, which contains substantial numbers of GABA interneurons. Spontaneous and evoked activities of VPL units were studied before and after MCS. Motor cortex stimulation induced significant depression of the wide-dynamic-range (WDR) cells' firing rate, concomitant with activity enhancement of nonnociceptive (NN) units. More than half of WDR cells showed a significant decrease in the firing rate, while a similar proportion of NN units exhibited the opposite after-effect. Maximal firing attenuation of WDR cells occurred when the MCS location matched somatotopically their receptive field. Repetition of MCS runs led to an accentuation of WDR depression. After peripheral stimulation, evoked activity in each cell showed MCS effects similar to those observed in spontaneous activity. These data demonstrate a selective top-down inhibition by MCS of nonspecific nociceptive (WDR) cells, enhanced by somatotopic concordance and stimulation repetition, in parallel to facilitation of NN cells. These 2 outcomes may play a role in the complex analgesic effect of MCS observed in neuropathic pain conditions.


Change in the use of and attitude to peak flow measurement among general practitioners in Northern Ireland between 1989 and 1994.
In 1994 we repeated a study first performed in 1989 to assess the change in general practitioners' use of and attitudes to peak flow measurement. Of 232 general practitioners surveyed, 199 (86%) and 192 (83%) responded in 1989 and 1994 respectively. The percentage who reported having patients using domiciliary peak flow monitoring rose form 58.3 (95% confidence limits 51.4 to 65.2)% to 97.9 (95.9 to 99.9)%. The percentage who reported 'usually' using peak flow measurements for the diagnosis and management of asthma rose from 81.9 (76.5 to 87.3)% to 93.2 (89.6 to 96.8)% and from 83.3 (78.1 to 88.5)% to 95.8 (92.9 to 98.7)% respectively. An unchanged proportion took peak flow meters on house calls. General practitioners have become more aware of the potential of peak flow measurements but are still unlikely to have a meter available to assess patients seen at home. They are therefore likely to be ill-equipped to manage acute exacerbations of asthma in this setting.


Comparison of Plasma Ionization- and Secondary Electrospray Ionization- High-resolution Mass Spectrometry for Real-time Breath Analysis.
Real-time breath analysis by high-resolution mass spectrometry (HRMS) is a promising method to noninvasively retrieve relevant biochemical information. In this work, we conducted a head-to-head comparison of two ionization techniques: Secondary electrospray ionization (SESI) and plasma ionization (PI), for the analysis of exhaled breath. Two commercially available SESI and PI sources were coupled to the same HRMS device to analyze breath of two healthy individuals in a longitudinal study. We analyzed 58 breath specimens in both platforms, leading to 2,209 and 2,296 features detected by SESI-HRMS and by PI-HRMS, respectively. 60% of all the mass spectral features were detected in both platforms. However, remarkable differences were noted in terms of the signal-to-noise ratio (S/N), whereby the median (interquartile range, IQR) S/N ratio for SESI-HRMS was 115 (IQR = 408), whereas for PI-HRMS it was 5 (IQR = 5). Differences in the mass spectral profiles for the same samples make the inter-comparability of both techniques problematic. Overall, we conclude that both techniques are excellent for real-time breath analysis because of the very rich mass spectral fingerprints. However, further work is needed to fully understand the exact metabolic insights one can gather using each of these platforms.


The 7-phenyl benzoxaborole series is active against Mycobacterium tuberculosis.
We identified a series of novel 7-phenyl benzoxaborole compounds with activity against Mycobacterium tuberculosis. Compounds had a range of activity with inhibitory concentrations (IC90) as low as 5.1 μM and no cytotoxicity against eukaryotic cells (IC50 > 50 μM). Compounds were active against intracellular mycobacteria cultured in THP-1 macrophages. We isolated and characterized resistant mutants with mutations in NADH dehydrogenase (Ndh) or the regulatory protein Mce3R. Mutations suggest that Ndh may be the target of this series.


Plutonium hazard in respirable dust on the surface of soil.
Plutonium-239 in the fine particulate soil fraction of surface dust is subject to suspension by air currents and is a potential health hazard to humans who may inhale it. This respirable particulate fraction is defined as particles less than or equal to 5 micrometers. The respirable fraction of surface dust was separated by ultrasonic dispersion and a standard water-sedimentation procedure. Plutonium concentration in this fraction of off-site soils located downwind from the Rocky Flats Nuclear Weapons Plant (Jefferson County, Colorado) were as much as 380 times the background concentration. It is prposed that this method of evaluation defines more precisely the potential health hazard from the respirable fraction of plutonium-contaminated soils.


Survival of 16-celled and morula stage rabbit embryos frozen to -196 degrees C,.
Preimplantation stage (16-celled and morula) rabbit embryos were successfully frozen to -196 degrees C. The cooling rate (from a room temperature to 0 degrees C), the presence of the mucin layer surrounding embryos, the ice-seeding treatment and the thawing procedure were examined to determine their effects on the survival of the frozen embryos of Japanese white, New Zealand white and Dutch-Belted rabbits. A high proportion (51%; 16-celled, 69%; morula) of Dutch-Belted rabbit embryos developed in vitro, when they were frozen to -196 degrees C, applying the ice-seeding at -4 degrees C in the presence of 12.5% DMSO, after being cooled to 0 degrees C at the rate of 7-9 degrees C/min, and were diluted by a stepwise addition of 4 different strength PBS on thawing. The highest rate of in vitro development (81%; Japanese white, 75%; New Zealand white, 82%; Dutch Belted embryos) was obtained when the morula stage embryos were frozen to -196 degrees C applying seeding at -4 degrees C after being cooled to 0 degrees C at the rate of 1 degrees C/2.5 min and were diluted, on thawing, by stepwise addition of 6, 3 and 1% DMSO solution and a culture medium. No great difference was found in the survival rate between the embryos covered with the mucin layer and those which had not the coat. All the embryos frozen without applying seeding treatment failed to develop in vitro after being thawed and diluted. Nine out of 27 does each of which received 6 reimplantations of the embryos frozen-thawed became pregnant and were found to be carrying 37 normal fetuses on the 12th day of pregnancy.


Robo signaling regulates the production of cranial neural crest cells.
Slit/Robo signaling plays an important role in the guidance of developing neurons in developing embryos. However, it remains obscure whether and how Slit/Robo signaling is involved in the production of cranial neural crest cells. In this study, we examined Robo1 deficient mice to reveal developmental defects of mouse cranial frontal and parietal bones, which are derivatives of cranial neural crest cells. Therefore, we determined the production of HNK1+ cranial neural crest cells in early chick embryo development after knock-down (KD) of Robo1 expression. Detection of markers for pre-migratory and migratory neural crest cells, PAX7 and AP-2α, showed that production of both was affected by Robo1 KD. In addition, we found that the transcription factor slug is responsible for the aberrant delamination/EMT of cranial neural crest cells induced by Robo1 KD, which also led to elevated expression of E- and N-Cadherin. N-Cadherin expression was enhanced when blocking FGF signaling with dominant-negative FGFR1 in half of the neural tube. Taken together, we show that Slit/Robo signaling influences the delamination/EMT of cranial neural crest cells, which is required for cranial bone development.


Synergistic and Additive Effects of Menadione in Combination with Antibiotics on Multidrug-Resistant Staphylococcus aureus: Insights from Structure-Function Analysis of Naphthoquinones.
Antimicrobial resistance (AMR) interferes with the effective treatment of infections and increases the risk of microbial spread and infection-related illness and death. The synergistic activities of combinations of antimicrobial compounds offer satisfactory approaches to some extent. Structurally diverse naphthoquinones (NQs) including menadione (-CH3 group at C2) exhibit substantial antimicrobial activities against multidrug-resistant (MDR) pathogens. We explored the combinations of menadione with antibiotic ciprofloxacin or ampicillin against Staphylococcus aureus and its biofilms. We found an additive (0.5<FICI ≤ ${ \le }$ 1.0) and synergistic (FICI≤0.5) effect of menadione with ciprofloxacin and ampicillin, respectively. High reactive oxygen species (ROS) activity and inhibition of biofilm formation (>90 %) were also observed. However, preformed biofilms were not affected. Dent formation was also evident in S. aureus treated with the test compounds. The structure-function relationship (SFR) of NQs was used to determine and predict their activity pattern against pathogens. Analysis of 10 structurally distinct NQs revealed that the compounds with -Cl, -Br, -CH3 , or -OH groups displayed the lowest MICs (32-256 μg/mL). Furthermore, 1,4-NQs possessing a halogen or -CH3 moiety showed elevated ROS activity, whereas molecules with an -OH group affected cell integrity. Improved activity of antimicrobial combinations and SFR approaches are significant in antimicrobial therapies.


Outcomes of out-of-hospital cardiac arrest by public location in the public-access defibrillation era.
The strategy to place public-access automated external defibrillators (AEDs) has not yet been established in real settings. This, prospective, population-based observational study in Osaka, Japan, included consecutive out-of-hospital cardiac arrest (OHCA) patients with resuscitation attempts during 7 years, from January 2005 through December 2011. The trends in the proportion of public-access AED use and 1-month survival with neurologically favorable outcome were evaluated by location. Factors associated with neurologically favorable outcome (defined as cerebral performance category 1 or 2) after ventricular fibrillation were also assessed using multiple logistic regression analysis. A total of 9453 bystander-witnessed OHCAs of cardiac origin were documented and 894 (9.5%) of them occurred at public places. The proportion of public-access AED use significantly increased from 0.0% (0/20) in 2005 to 41.2% (7/17) in 2011 at railway stations and from 0.0% (0/7) to 56.5% (13/23) at sports facilities. Mean time from collapse to shock was 5.0 minutes among those who received shocks with public-access AEDs. The proportion of neurologically favorable outcome was 28.0% (33/118) at railway stations, 51.6% (48/93) at sports facilities, 23.3% (20/86) in public buildings, and 41.9% (13/31) in schools. In multivariate analysis, early defibrillation, irrespective of bystander or emergency medical service (EMS) personnel, was significantly associated with neurologically favorable outcome (adjusted odds ratio for 1-minute increment, 0.89; 95% confidence interval, 0.87 to 0.92). This large, population-based OHCA registry demonstrated that earlier shock, irrespective the shock provider (bystander or EMS personnel), contributed to improving outcome, and a public-access defibrillation program was successfully implemented so that shocks with public-access AEDs were delivered to over 40% of bystander-witnessed OHCAs and time to shock was shortened in some kinds of public places.


Conformational changes and flexibility in T-cell receptor recognition of peptide-MHC complexes.
A necessary feature of the immune system, TCR (T-cell receptor) cross-reactivity has been implicated in numerous autoimmune pathologies and is an underlying cause of transplant rejection. Early studies of the interactions of alphabeta TCRs (T-cell receptors) with their peptide-MHC ligands suggested that conformational plasticity in the TCR CDR (complementarity determining region) loops is a dominant contributor to T-cell cross-reactivity. Since these initial studies, the database of TCRs whose structures have been solved both bound and free is now large enough to permit general conclusions to be drawn about the extent of TCR plasticity and the types and locations of motion that occur. In the present paper, we review the conformational differences between free and bound TCRs, quantifying the structural changes that occur and discussing their possible roles in specificity and cross-reactivity. We show that, rather than undergoing major structural alterations or 'folding' upon binding, the majority of TCR CDR loops shift by relatively small amounts. The structural changes that do occur are dominated by hinge-bending motions, with loop remodelling usually occurring near loop apexes. As predicted from previous studies, the largest changes are in the hypervariable CDR3alpha and CDR3beta loops, although in some cases the germline-encoded CDR1alpha and CDR2alpha loops shift in magnitudes that approximate those of the CDR3 loops. Intriguingly, the smallest shifts are in the germline-encoded loops of the beta-chain, consistent with recent suggestions that the TCR beta domain may drive ligand recognition.


The prognostic significance of obsessive-compulsive symptoms in schizophrenia.
Obsessive-compulsive symptomatology has been described in schizophrenia for more than 60 years, but its clinical significance has yet to be explored systematically. This report details the clinical characteristics and long-term course of a group of 21 schizophrenic patients with prominent obsessive-compulsive symptoms from the Chestnut Lodge Follow-Up Study. While this group differed on admission only minimally from schizophrenic patients without obsessive-compulsive symptoms, their long-term outcome in the areas of social relations, employment, psychopathology, and global functioning was significantly, and almost uniformly, poorer. Persistent obsessive-compulsive symptoms thus appear to be a powerful predictor of poor prognosis in schizophrenia.


Laparoscopic-assisted right lobe donor hepatectomy.
The major impediment to a wider application of living donor hepatectomy, particularly of the right lobe, is its associated morbidity. The recent interest in a minimally invasive approach to liver surgery has raised the possibility of applying these techniques to living donor right lobectomy. Herein, we report the first case of a laparoscopic, hand-assisted living donor right hepatic lobectomy. We describe the technical aspects of the procedure, and discuss the rationale for considering this option. We propose that the procedure, as described, did not increase the operative risks of the procedure; instead, it decreased potential morbidity. We caution that this procedure should only be considered for select donors, and that only surgical teams familiar with both living donor hepatectomy and laparoscopic liver surgery should entertain this possibility.


Functional and metabolic studies of polymorphonuclear leukocytes in the congenital Pelger-Huet anomaly.
Polymorphonuclear leukocytes (PMNL) from two individuals with congenital Pelger-Huet anomaly (PHA) were examined to determine whether functional or metabolic defects accompanied the known morphological abnormality. No abnormalities of the PHA cells, as compared to normal control cells, were found when tested for quantitative leukocyte enzyme activities, nitroblue tetrazolium reduction, hexose monophosphate shunt activity, superoxide production, generation of chemiluminescence, or iodination. The PHA cells, as compared to normal PMNL, demonstrated normal chemotaxis and random migration, as well as bactericidal activity.


Specific Physical Training in Elite Male Team Handball.
Wagner, H, Gierlinger, M, Adzamija, N, Ajayi, S, Bacharach, DW, and von Duvillard, SP. Specific physical training in elite male team handball. J Strength Cond Res 31(11): 3083-3093, 2017-Specific physical training in elite team handball is essential for optimal player's performance; however, scientific knowledge is generally based on temporary training studies with subelite athletes. Therefore, the aim of the study was to analyze the effects of specific physical training in an elite male handball team over the entire season. Twelve players of a male handball team from the First Austrian Handball League conducted a 1-year specific physical training program in addition to their normal (team handball techniques and tactics) weekly training. Performance was measured with 5 general and 4 specific tests as well as game statistics during competition. Repeated measures analysis of variances and paired sample t-test were used to analyze differences in performance during training. We found a significant increase in oxygen uptake, offense time, defense time, fast break time, and jump height in the specific tests. Game performance statistics revealed a lower throwing percentage in the hosting team (59%) compared with the rival teams (63%). Our results indicated that specific endurance and agility are an acceptable modality in elite male team handball. However, performance in competition is strongly influenced by specific techniques and tactics. We recommend to strength and conditioning professionals that they tailor strength and power training, coordination and endurance as specific as possible, using free weights, agility exercises that include change in direction and jumps as well as short (10-15 seconds) high-intensity intervals.


[Acute delirium, probably precipitated by clarithromycin].
Clarithromycin is a relatively new antibiotic with many applications. Its frequent use explains why side-effects previously reported seldom now become clear. Two patients, a man aged 74 and a woman aged 56 years, developed delirium after treatment with clarithromycin as part of eradication treatment of Helicobacter pylori, presumably as a result of an ideosyncratic reaction to the clarithromycin. Preclinical and clinical investigations did not reveal side effects on the central nervous system. By now the appearance of a delirium presumably related to the use of clarithromycin has been described in several patients. Furthermore some patients had a positive rechallenge. Finally, 17 reports on psychiatric side effects, of which 7 were delirium, after the use of clarithromycin reached the Netherlands Pharmacovigilance Foundation (Lareb). This combination of facts makes a causal relationship probable.


[The effect of lithium oxybutyrate on the circadian rhythms of the activity and body temperature of rats maintained under different light regimens].
The chronobiological properties of lithium hydroxybutrate were studied in the open field test at the preventive administration of the drug to rats (7 days, 10 mg/kg daily subcutaneously) kept under natural photoperiod of the summer and winter solstice and CT 12:12. It was found that lithium hydroxybutrate can preserve, reveal the lost rhythms and synchronize the available circadian and infradian rhythms of the activity and body temperature of the rats. The degree and direction of this effect depend on the initial rhythmostasis, the time of the drug administration and the regimen of illumination under which the animals are kept.


Pain treatment in gynaecological cancer.
Women suffering from gynaecological malignancies are highly represented in patients with cancer pain: 19.3% of tumour related deaths in females are caused by breast carcinoma, 7.1% by carcinoma of the uterus, 6.7% by ovarian carcinoma and 2.3% by other malignant gynaecological tumours. These tumours may give rise to severe pain due to osseous metastases, nerve or plexus infiltration, soft tissue infiltration and (in the case of ovarian carcinoma) obstruction of the gastrointestinal tract. The experience represented in the literature and our own experience demonstrate that there are very effective measurements of symptom control in cancer pain. Based on the results of a specialized cancer pain control clinic at the University of Düsseldorf, Germany, recommendations will be given for the treatment of cancer pain. The use of nonsteroidal anti-inflammatory drugs, weak and strong acting opioids and co-analgesics in relation to the different sites of metastases as well as neurosurgical and anaesthetic manoeuvres are the subject of the presentation. Furthermore an overview of the psycho-social care of cancer patients by the social worker and the priest will be given.


Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure.
To determine the frequency of mitochondrial DNA depletion syndrome (MDS) in infants with cholestasis and liver failure and to further clarify the clinical, biochemical, radiologic, histopathologic, and molecular features associated with MDS due to deoxyguanosine kinase (DGUOK) and MPV17 gene mutations. We studied 20 infants with suspected hepatocerebral MDS referred to our tertiary care center between 2007 and 2013. Genomic DNA was isolated from blood leukocytes, liver, and/or skeletal muscle samples by standard methods. Mitochondrial DNA copy number relative to nuclear DNA levels was determined in muscle and/or liver DNA using real-time quantitative polymerase chain reaction and compared with age-matched controls. Nuclear candidate genes, including polymerase γ, MPV17, and DGUOK were sequenced using standard analyses. We identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure referred to our center during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11 cases where tissue was available. Seven patients had mutations in the MPV17 gene (3 novel mutations), 4 patients had DGUOK mutations (of which 2 were novel mutations). Mutations in the MPV17 and DGUOK genes are present in a significant percentage of infants with liver failure and are associated with poor prognosis.