N-Acetyl cysteine does not improve repeated intense endurance cycling performance of well-trained cyclists.
To evaluate the effect of antioxidant supplementation on intense endurance exercise performance and the physiologic exercise response acutely and in early recovery. Well-trained cyclists (n = 11, peak VO2: 69 ± 7 ml/min/kg) completed two identical standardized 20-min warm-up periods (WU-1 and WU-2) prior to two performance tests (PT) with a duration of ~ 4 min representing a qualifying (PT-1) and final race (PT-2) on the same day separated by 90 min. Subjects were supplemented orally with placebo (PLA) and N-acetyl cysteine (NAC; 20 mg/kg) before exercise in a double-blinded crossover design. Mean power during PT-1 did not differ (P = 0.39) between PLA (400 ± 44 W) and NAC (401 ± 44 W) as was the case during PT-2 with similar performance (P = 0.74) between PLA (401 ± 43 W) and NAC (400 ± 42 W). Subjective "readiness" was lowered by prior exhaustive exercise from PT-1 to PT-2 (P = 0.012) in both PLA and NAC. Plasma total antioxidant capacity was not affected by supplementation and prior exhaustive exercise (respective main effects: P = 0.83 and P = 0.19) which also was observed for peak VO2 at ~ 5 L/min (P = 0.84 and P = 0.30). In WU-1 and WU-2, both cycling economy at ~ 20% (P = 0.10 and P = 0.21) and plasma potassium at ~ 5 mmol/L (P = 0.46 and P = 0.26) were unaffected by supplementation and prior exercise. Athletes executing maximal efforts of a ~ 4-min duration twice daily, as seen in track cycling, appear to gain no benefit from oral NAC supplementation on acute and subsequent performance following short-term recovery. Moreover, well-trained cyclists exhibit rapid recovery from a single bout of intense endurance cycling.


Temozolomide-induced desquamative skin rash in a patient with metastatic melanoma.
Temozolomide is an oral alkylating agent used in the treatment of metastatic melanoma. Commonly reported adverse effects of the drug include nausea and vomiting, constipation, headache, and fatigue, as well as myelosuppression, which may be dose limiting. Few reports have described dermatologic adverse effects such as rash and pruritus, and, to our knowledge, none have discussed the seriousness or extensiveness of the rash. We describe a 37-year-old woman who was receiving temozolomide for treatment of metastatic melanoma. After 6 weeks of therapy, the patient developed an unexplained fever. The drug was discontinued, and the fever resolved within 2 days. Temozolomide was restarted 2 months later; the patient again developed a fever. This time the fever was accompanied by a diffuse erythematous skin rash that progressed to an extensive, full-body, desquamative skin rash. The rash was treated with moisturizing cream along with intravenous and topical corticosteroids and antibiotics. Due to the severity of the rash, temozolomide was permanently discontinued. Even after its discontinuation, the patient experienced the rash on a long-term basis, with periodic exacerbations. However, none were as severe as the first rash. The patient's metastatic disease remained stable for the next 2 years. According to the Naranjo adverse drug reaction probability scale, the likelihood that temozolomide was responsible for the adverse drug reaction of fever was probable (score of 6). Clinicians should be aware that an erythematous and exfoliative rash may be induced by temozolomide, and be familiar with the pharmacologic and supportive measures necessary for its treatment.


[HLA immunogenetic markers in predicting therapeutic resistance in paranoid schizophrenia].
A study was made of the incidence of HLA histocompatibility antigens of A, B and C loci in 100 male patients suffering from paranoid continuous schizophrenia associated with hallucinatory paranoid symptomatology during the formation in them of therapeutic resistance. In accordance with the clinico-pathogenetic philosophy, 2 groups of resistant patients were formed: an "endogenous" one (because of rapid progression) and a "pharmacogenous" one (secondary, formed by the mechanisms of "adaptation" to neuroleptics). In addition, a group of "nonresistant" patients (a reference one) was also distinguished. The data were compared to those obtained in normal subjects (50 men) and to those derived within the distinguished groups, employing mathematic computation of the risk coefficient. It has been shown that in contrast to the group of normal subjects, the general group of patients suffering from paranoid schizophrenia manifested the accumulation of the HLA antigens A2, A9, W7 and B15. The accumulation of the HLA antigens A2 and A11 was characteristic of the patients suffering from "endogenous" resistance, which distinguished those patients from normal subjects, from "nonresistant" patients and those with "pharmacogenous" resistance. The HLA phenotype A2,11 can be regarded as a potential marker of progression (risk grades 9.8). Besides, it has been demonstrated that the HLA antigens B7 may attest to risk of tolerance to psychopharmacotherapy and formation of "pharmacogenous" resistance (risk grades 4.3).


Evidence of survival bias in the association between APOE-Є4 and age of ischemic stroke onset.
Large genome-wide association studies (GWAS) employing case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing age at onset (AAO) of ischemic stroke. Analyses were conducted in a Discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value < 1×10 -5 in a sex-combined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for association of AAO with rs429358, an exonic variant in APOE that encodes for the APOE-є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29 years earlier stroke AOO (meta p-value = 2.48×10 -11 ). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decline in mortality among APOE-є4 carriers and have no association to stroke AAO per se. Using a simulation study, we found that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a two-fold increase on mortality risk would lead to an observed effect of AAO that is comparable to what we found. In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.


Phenotypes and protein-epitope phenotypic variation among fresh isolates of Trichomonas vaginalis.
Fresh isolates of Trichomonas vaginalis were examined for reactions to a panel of five monoclonal antibodies (MAbs). Four MAbs (C20A3, DM126, DM116, and C55) were to distinct surface immunogens and one MAb (L64) was to a cytoplasmic component. The fresh isolates were evaluated by indirect immunofluorescence (IF), immunoblotting, and radioimmunoprecipitation. IF assay with C20A3 MAb gave isolates which were homogeneous nonstaining (negative [Neg] phenotype) and isolates which were heterogeneous staining and nonstaining (positive [Pos] and Neg phenotype, respectively) organisms. Immunoblotting and radioimmunoprecipitation assays revealed that surface phenotypic heterogeneity among isolates with C20A3 MAb was due to the presence or absence of the immunogen from the parasite surface. IF assay with DM126 MAb also gave Pos and Neg phenotypes among parasites of some isolates. All of the isolates were always Neg phenotype with DM116 and C55 MAbs. The occurrence of Neg phenotype organisms with DM126, DM116, and C55 was due to epitope inaccessibility to their respective MAbs and not to the absence of the immunogen from trichomonal membranes. All isolates possessed the cytoplasmic protein recognized by L64 MAb. Paired isolates (taken 5 to 6 days apart) from 24 women were also studied. Four of the 24 paired isolates (16%) had different phenotype distributions at the two timepoints for C20A3. Fresh isolates also underwent phenotypic variation during in vitro growth and multiplication, as determined with C20A3. Also, 7 of the 24 paired isolates demonstrated dramatic changes in the accessibility of DM126 MAb to epitope binding. Lastly, 55 (90%) of 60 serum samples from patients with trichomoniasis evaluated in this study possessed antibody to the C20A3 reactive molecule. The data show that the fresh T. vaginalis isolates were predominantly Neg phenotype and confirm the occurrence of protein and epitope phenotypic variation for major immunogens among fresh isolates of the pathogenic human trichomonads.


Effect of sludge age on population dynamics and acetate utilization kinetics under aerobic conditions.
The study addressed acetate utilization by an acclimated mixed microbial culture under different growth conditions. It explored changes in the composition of the microbial community and variable process kinetics induced by different culture history. Sequencing batch reactors were operated at steady-state at different sludge ages of two and ten days. Microbial population structure was determined using high-throughput sequencing of 16S rRNA genes. Parallel batch experiments were conducted with acclimated biomass for respirometric analyses. A lower sludge age sustained a different community, which also reflected as variable kinetics for microbial growth and biopolymer storage. The maximum growth rate was observed to change from 3.9/d to 8.5/d and the substrate storage rate from 3.5/d to 5.9/d when the sludge age was decreased from 10 d to 2.0 d. Results challenge the basic definition of heterotrophic biomass in activated sludge models, at least by means of variable kinetics under different growth conditions.


Vascular endothelial growth factor level as a prognostic determinant of small cell lung cancer in Japanese patients.
To clarify the clinical significance of vascular endothelial growth factor (VEGF) in Japanese patients with small cell lung cancer (SCLC). We measured serum VEGF levels using an enzyme-linked immunosorbent assay in 45 patients with SCLC before treatment and in 38 patients with benign pulmonary disease and in 32 healthy subjects (71 non-malignant subjects). VEGF immunostaining was performed in tissue biopsies obtained from 23 SCLC patients during bronchoscopic examination. Median serum VEGF level was 332 pg/ml in patients with SCLC and 160 pg/ml in non-malignant subjects, respectively. The 95% cut-off level to exclude non-malignant subjects was 500 pg/ml. An elevated VEGF level (>500 pg/ml) was found more frequently in patients with extensive disease of SCLC than in those with the limited disease (p<0.01). A significant positive correlation was found between the serum VEGF level and platelet count in SCLC patients (r=0.389; p=0.0083). Serum VEGF level also correlated with serum lactate dehydrogenase in SCLC patients (r=0.381; p=0.0098). However, it did not correlate with serum neuron-specific enolase and pro-gastrin-releasing peptide level. Patients with the elevated VEGF levels had significantly shorter progression-free time than those with the normal VEGF levels (p<0.05). Patients with the elevated VEGF levels had a significantly shorter overall survival time than those with the normal VEGF levels in univariate survival analysis (p<0.05). Further, the elevated VEGF level remained as a significant determinant of poor survival in multivariate analysis (p<0.01). Serum VEGF level was significantly higher in patients with positive VEGF protein immunoreactivity in tumor tissue in SCLC. Elevated serum VEGF levels were associated with poor outcome in SCLC.


Aural localization of silent objects by active human biosonar: neural representations of virtual echo-acoustic space.
Some blind humans have developed the remarkable ability to detect and localize objects through the auditory analysis of self-generated tongue clicks. These echolocation experts show a corresponding increase in 'visual' cortex activity when listening to echo-acoustic sounds. Echolocation in real-life settings involves multiple reflections as well as active sound production, neither of which has been systematically addressed. We developed a virtualization technique that allows participants to actively perform such biosonar tasks in virtual echo-acoustic space during magnetic resonance imaging (MRI). Tongue clicks, emitted in the MRI scanner, are picked up by a microphone, convolved in real time with the binaural impulse responses of a virtual space, and presented via headphones as virtual echoes. In this manner, we investigated the brain activity during active echo-acoustic localization tasks. Our data show that, in blind echolocation experts, activations in the calcarine cortex are dramatically enhanced when a single reflector is introduced into otherwise anechoic virtual space. A pattern-classification analysis revealed that, in the blind, calcarine cortex activation patterns could discriminate left-side from right-side reflectors. This was found in both blind experts, but the effect was significant for only one of them. In sighted controls, 'visual' cortex activations were insignificant, but activation patterns in the planum temporale were sufficient to discriminate left-side from right-side reflectors. Our data suggest that blind and echolocation-trained, sighted subjects may recruit different neural substrates for the same active-echolocation task.


Biochemical, Nutritional, and Clinical Parameters of Vitamin B12 Deficiency in Infants: A Systematic Review and Analysis of 292 Cases Published between 1962 and 2022.
Pooled data from published reports on infants with clinically diagnosed vitamin B12 (B12) deficiency were analyzed with the purpose of describing the presentation, diagnostic approaches, and risk factors for the condition to inform prevention strategies. An electronic (PubMed database) and manual literature search following the PRISMA approach was conducted (preregistration with the Open Science Framework, accessed on 15 February 2023). Data were described and analyzed using correlation analyses, Chi-square tests, ANOVAs, and regression analyses, and 102 publications (292 cases) were analyzed. The mean age at first symptoms (anemia, various neurological symptoms) was four months; the mean time to diagnosis was 2.6 months. Maternal B12 at diagnosis, exclusive breastfeeding, and a maternal diet low in B12 predicted infant B12, methylmalonic acid, and total homocysteine. Infant B12 deficiency is still not easily diagnosed. Methylmalonic acid and total homocysteine are useful diagnostic parameters in addition to B12 levels. Since maternal B12 status predicts infant B12 status, it would probably be advantageous to target women in early pregnancy or even preconceptionally to prevent infant B12 deficiency, rather than to rely on newborn screening that often does not reliably identify high-risk children.


Home-based pulmonary rehabilitation in chronic obstructive pulmonary disease patients.
Home-based pulmonary rehabilitation programs have been proposed as an alternative to hospital-based programs for patients with chronic obstructive pulmonary disease (COPD). We undertook a systematic review of randomized studies on home-based pulmonary rehabilitation in patients with COPD which report health-related quality of life and/or exercise capacity, in order to assess the benefits of this intervention. From 888 identified references, 12 met the inclusion criteria. Overall, the methodological quality of the studies was average to poor. Eight studies compared home-based rehabilitation to standard care, three compared home-based rehabilitation to hospital-based programs and one included both comparisons. Most of the studies showed improvement in health-related quality of life (statistically and clinically significant) and exercise capacity following home-based rehabilitation as compared with standard care (no pulmonary rehabilitation). Studies that compared home-based pulmonary rehabilitation with hospital-based outpatient programs have not been able to show statistically and clinically significant differences for health-related quality of life and exercise capacity. Adverse events, usually mild, were reported in only two studies. Self-monitored, home-based rehabilitation may be an alternative to outpatient rehabilitation. These findings can help expand the recognition, application and accessibility of pulmonary rehabilitation for patients with COPD.


Non-operative treatment of the torn anterior cruciate ligament.
The purpose of this study was to assess and describe the status of twenty-four patients with a diagnosed tear of the anterior cruciate ligament who participated in a non-operative program of rehabilitation emphasizing strengthening of the hamstrings. The knees were evaluated by testing stability, strength, and range of motion; by roentgenographic examination; and by the patient's level of participation in sports. The patient's uninjured knee was used for comparison. The results showed a high incidence of anterior instability, but no significant differences in degenerative changes or range of motion. All patients returned to some sports participation, with fourteen (59 per cent) returning to their full preinjury level of participation. Higher levels of sports participation were found in the patients whose hamstrings strength was equal to or more than their quadriceps strength.


The influence of folic acid, vitamins B(2) and B(6) supplementation on feed intake, body and organs weight, and liver fatty acids composition of rats subjected to 3 months moderate protein deprivation.
This study was conducted to determine the effect of a 3-month dietary protein restriction - protein provided 9% of energy (20% in control group). In this dietary restriction folic acid, vitamins B(2) and B(6) were delivered in amount three times above the standard level. It was observed that animals fed a protein restricted (PR) diet weighed about 5% less than animals consuming adequate diet, but the difference was not statistically significant. Enrichment of PR diet with vitamin B or folic acid caused tendency to further suppression of weight gain, and in case of vitamin B(6) these differences were statistically significant. However, such body weight (BW) suppression was not observed when all studied vitamins were used together. Significant reductions in relative liver weight (vitamin B(2) addition), the heart (folic acid) and the lungs (vitamin B(6)) were observed. The PR diet, when all vitamins were added together, caused a decrease in weights of the lungs, heart and liver scaled to BW of rats, simultaneously with a significant increase in testis weight. Feed intake and feed conversion ratio were higher in animals given PR diet without a significant influence of vitamin supplementation (except vitamin B(6) causing further increase in feed conversion ratio). Hepatic fatty acids composition of rats was not affected by protein restriction, as well as by single vitamin supplementation. However, dietary supplementation of all examined vitamins together caused a decrease in monounsaturated fatty acids followed by an increase in polyunsaturated fatty acids participation in total fatty acids pool. It seems that enrichment of PR diet with a mixture of folic acid, vitamins B(2) and B(6) resulted in a partial reverse of growth suppression and reduction in testis size in rats.


Triploidy in 40 human spontaneous abortuses: assessment of phenotype in embryos.
Forty human spontaneous abortuses were identified as triploid, 34 by karyotype and 6 by DNA measurement. Of the 40, 26 were embryos of 5 to 7 weeks' developmental age, 6 were intact empty sacs, 4 were early growth-disorganized embryos, and 4 were fetuses. In an attempt to determine the extent to which embryonic phenotype reveals triploid karyotype, the phenotypes of the 26 triploid embryos were compared with those of the 40 embryos of known nontriploid karyotype identified in larger study of consecutive spontaneous abortuses. Each embryo was scored for presence or absence of each of 4 abnormal phenotypic features: retarded limb development, facial dysplasia, subectodermal hemorrhage, and cystic chorionic villi. Whereas this combination of features was found in a few abortuses with normal or trisomic karyotype, it was both common and most frequent with triploidy. Approximately half (12 of 22) of the triploid embryos had at least 3 of the features. Conversely, among assessable embryos of known karyotype, four fifths (12 of 15) of those with at least 3 of the 4 abnormal features were triploid. Thus, while not definitive, such phenotypic information can be used with caution in counseling for subsequent pregnancies.


The current managements of pancreatic diabetes in Japan.
Pancreatic diabetes is secondary diabetes followed by progressions of pancreatic exocrine diseases, such as chronic pancreatitis, pancreatic neoplasm and post-pancreatectomy. Because of destruction and reduction of the pancreatic endocrine and exocrine functional compartments, patients with pancreatic diabetes frequently show malnutrition from maldigestion and malabsorption by insufficiencies in pancreatic digestive enzymes, and show unstable glycemic control and prolonged hypoglycemia by insufficiencies in synthesis and secretion of insulin and glucagon. Epidemiological studies have suggested that the incidence and development of pancreatic diabetes in patients with chronic pancreatitis (CP) depends on several risk factors, such as alcohol intake, the presence of pancreatic calcification and the long-term duration of CP. The clinical management of pancreatic diabetes is divided into two parts: one is the supplementation of pancreatic digestive enzymes and the other is the achievement of appropriate glycemic control. The appropriate and sufficient pancreatic exocrine replacement therapy is important for the maintenance of better nutrient conditions for patients with pancreatic diabetes. Furthermore, the intensive insulin therapy combined with short- or ultra-short-acting insulin and long-acting insulin glargine can be achieved for stable glycemic control and reduction of severe frequent hypoglycemia in patients with pancreatic diabetes. These current advanced management techniques against insufficiencies of pancreatic exocrine endocrine functions are beneficial for improving and maintaining the quality of life in patients with pancreatic diabetes.


A mini review of nanosuspensions development.
Nanosuspension drug delivery has obtained great success in the preparation of insoluble drugs. The nanosuspension technology can confer a series of special characteristics to the drugs, such as the enhanced dissolution rate and saturation solubility. This mini review first described the differences between the nanocrystals and nanosuspensions. Next, the product techniques, the stable measures, the special features, and the routes of administration of the nanosuspensions were reviewed and compared. Finally, some existing shortcomings of the nanosuspensions were mentioned and the perspectives of the nanosuspensions were also made.


[Neuro-orthopedic problems in the area of the elbow joint].
Neuromuscular impairment of elbow function directly affects the activities of daily living as well as the ability to work in many patients. A series of typical pathophysiological syndromes occur in the region of the elbow as immediate or late results of local trauma or more distant injuries to the brain, cervical cord, cervicobrachial plexus, or peripheral nerves. The operative management is determined by the pathophysiology of the lesions and the anatomical relationship between the muscles and the neurovascular structures at the elbow. These syndromes and their treatment are reviewed.


Evaluation of topical ophthalmic ganciclovir gel for the treatment of dogs with experimentally induced ocular canine herpesvirus-1 infection.
OBJECTIVE To determine the in vitro half maximal effective concentration (EC50) of ganciclovir for canine herpesvirus-1 (CHV-1) and to evaluate the efficacy of ganciclovir ophthalmic gel in dogs with experimentally induced ocular CHV-1 infection. ANIMALS 10 specific pathogen-free adult Beagles. PROCEDURES Cytotoxicity and EC50 of ganciclovir for CHV-1 were determined during in vitro experiments. During an in vivo experiment, dogs with experimentally induced ocular CHV-1 infections received 1 drop of 0.15% ganciclovir (ganciclovir group; n = 5) or artificial tear (control group; 5) ophthalmic gel in both eyes 5 times daily for 7 days, then 3 times daily for 7 days. For each dog, ophthalmic and confocal microscopic examinations were performed at predetermined times to determine severity of ocular disease and inflammation. Conjunctival swab specimens were collected at predetermined times for PCR assay analysis to determine CHV-1 shedding. RESULTS No in vitro cytotoxic effects were observed for ganciclovir concentrations ≤ 500μM. The EC50 of ganciclovir for CHV-1 was 37.7μM. No adverse effects associated with ganciclovir were observed during the in vivo experiment. Mean ocular disease and inflammation scores for the ganciclovir group were significantly lower than those for the control group. Mean duration of CHV-1 shedding for the ganciclovir group (0.4 days) was significantly shorter than that for the control group (6.2 days). CONCLUSIONS AND CLINICAL RELEVANCE Topical administration of 0.15% ganciclovir ophthalmic gel was well tolerated and effective in decreasing clinical disease scores, ocular tissue inflammation, and duration of viral shedding in dogs with experimentally induced ocular CHV-1 infection.


Fertility-Related Wishes and Concerns of Adolescent Cancer Patients and Their Parents.
Purpose: Within a multicenter European study, we explored fertility-related wishes, concerns, and decision-making of adolescent cancer patients and their parents. Patients and Methods: Patients and parents were each asked to complete a fertility-related questionnaire 3 months after initial diagnosis. In total, 113 of 142 (79.6%) eligible patients participated; 53.1% were male and the median age was 16 years (range 13-20 years). The questionnaire was completed by 111 parents. Univariate analyses were conducted using nonparametric methods with alpha = 5%. For multivariate analyses, binary logistic regression was conducted. Results: Both patients (86.1%) and parents (96.3%) indicated a strong desire for biological parenthood for themselves/their children. Female patients (odds ratio [OR] = 3.70; confidence interval [CI]: 1.43-9.50) and parents (OR = 2.70; CI: 1.21-6.00) were more likely to report a high fear of cancer recurrence. Patients who estimated their risk for fertility impairment being high were more likely to be concerned about their fertility (OR = 5.69; CI: 1.41-22.98). Parents who received fertility preservation information were more likely to recommend its use to their children (OR = 5.50; CI: 1.07-28.40), whereas parents of female patients were less likely to do so (OR = 0.13; CI: 0.03-0.61). Conclusions: The prospect of fertility following cancer treatment is important for adolescent cancer patients and their parents, yet it is associated with many concerns. Counseling regarding fertility preservation can be more effective when the individual needs of patients and their parents are taken into consideration.


Thermal Sensation After the 10-km Open-Water Swimming in Cool Water Depends on the Skin's Thermal Sensitivity Rather Than Core Temperature.
To assess the core temperature fluctuations during 10-km open-water swimming (OWS) in cool water and the relationship between thermal sensation (TS) after 10-km OWS, core temperature, and local skin thermal sensitivity. Nine highly trained OWS swimmers (4 female; age 22 [3] y) completed a single 10-km trial in cool water (22.3 °C) wearing swimsuits for OWS. During the trial, core temperature was continuously recorded via ingestible temperature sensors, and TS after trial was also measured. Then, local skin warm/cool sensitivity was measured in the forearm. All swimmers completed the 10-km OWS. Mean swimming speed for males and females were 1.39 (1.37-1.42 m/s) and 1.33 m/s (1.29-1.38 m/s), respectively. Core temperature increased in 8 out of 9 swimmers during 10-km OWS (P = .047), with an average increase of 0.8 °C. TS after 10-km OWS varied among swimmers. There were no correlations between post-OWS TS and post-OWS core temperature (P = .9333), whereas there was a negative correlation between post-OWS TS and local skin cool sensitivity (P = .0056). These results suggest that core temperature in elite swimmers might not decrease during 10-km OWS in the cool water temperature of official OWS. In addition, individual differences in TS after 10-km OWS may be related to skin cool sensitivity rather than core temperature.


Pupil constriction can alter the accuracy of dark room provocative test.
Primary angle-closure glaucoma (PACG) is a major cause of visual morbidity in East Asia. Dark-room provocative test (DRPT) has been used to determine which narrow angles have the risk to develop angle closure. However, the accuracy of DRPT might be altered because that after emerging from the dark room, the configuration of the angle is affected by the light of the slit-lamp and the appositionally closed angle reopens. The aim of this study was to examine the pupillary diameter in different light conditions and use it as a parameter to assess the accuracy of dark-room provocative test. Patients with suspected primary angle-closure glaucoma undergoing DRPT were recruited. The anterior chamber angle was examined by anterior segment optical coherence tomography under the following conditions: (1) in standard room illumination; (2) after short-term dark-adaptation and (3) after DRPT. Mean values of pupil size and numbers of appositionally closed angle under different conditions were compared. A total of 47 eyes of 47 patients were analyzed. The pupil size after DRPT was smaller than that after short-term dark-adaptation (P < 0.001) and smaller than that in standard room illumination (P = 0.026). The numbers of appositionally closed angles after short-term dark-adaptation were significantly larger than those after DRPT (P < 0.001). There was no significant difference between the numbers of appositionally closed angles in standard room illumination and after DRPT (P = 0.157). Constriction of pupil size immediately after prolonged dark room provocative test may lead to change in the angle configuration, which may lead to false negative results. We suggest a modified protocol of recording intraocular pressure immediately after DRPT and performing gonioscopy following short-term dark adaptation to improve the accuracy of angle closure assessment.


Microbial Biomanufacturing Using Chemically Synthesized Non-Natural Sugars as the Substrate.
The bioproduction of valuable materials using biomass sugars is attracting attention as an environmentally friendly technology. However, its ability to fulfil the enormous demand to produce fuels and chemical products is limited. With a view towards the future development of a novel bioproduction process that addresses these concerns, this study investigated the feasibility of bioproduction of valuable substances using Corynebacterium glutamicum (C. glutamicum) with a chemically synthesized non-natural sugar solution. Cells were grown using the synthesized sugar solution as the sole carbon source and they produced lactate under oxygen-limited conditions. It was also found that some of the sugars produced by the series of chemical reactions inhibited cell growth since prior removal of these sugars increased the cell growth rate. The results obtained in this study indicate that chemically synthesized sugars have the potential to resolve the concerns regarding future biomass sugar supply in microbial biomanufacturing.


Perceptions of students in different phases of medical education of educational environment: ankara university faculty of medicine.
The present study was undertaken to identify the perceptions of students about their educational environment in a newly restructured curriculum. The Turkish version of the DREEM questionnaire (total score: 200) was used to diagnose the strengths and weaknesses of the curriculum which is known to be a major determinant of educational environment. Five hundred fifty three students (years 1, 3, 5) voluntarily replied to the questionnaire. The mean DREEM score was found to be 117.63 (58.8%). The mean scores for the whole DREEM questionnaire and the five essential domains were found to be significantly different in different phases of medical education. The scores were found to be highest (123.65) for year 3 students and lowest (109.39) for year 5 students. The results are the first data of a curriculum reform obtained from the students about the educational environment and give important feedback to curriculum planners and change managers of the faculty for necessary improvement.


Fibrous testing papers for fluorescence trace sensing and photodynamic destruction of antibiotic-resistant bacteria.
The increasing prevalence of antibiotic-resistant bacteria needs rapid identification and efficient destruction routes. This study proposes testing paper derived from electrospun fibrous mats and aggregation-induced emission (AIE) probes for trace sensing and simultaneous destruction of antibiotic-resistant E. coli. Aptamers are conjugated on fibers for selective capture of E. coli, and the capture capability can be regenerated via rinsing with salt solution. Hydroxyl tetraphenylethene (TPE) is linked with two cephalosporin molecules to construct TPE-Cep probes, and the fluorescence emission is turned on specifically in the presence of β-lactamase, which is a critical marker for screening resistant bacteria. Fibrous mats are lit up only in the presence of antibiotic-resistant bacteria, and the fluorescence intensity changes could be statistically fitted into an equation for quantitative analysis. Fibrous strips display apparent color changes from blue to green for a visual readout of bacterial levels, and the limit of detection (LOD) is much lower than those of previous paper substrates. In addition, the TPE-Cep probes could produce reactive oxygen species (ROS) under room light illumination to kill the captured bacteria. Thus, the integration of aptamer-grafted electrospun fibers and functional AIE probes provides potential for selective capture, trace imaging and photodynamic destruction of antibiotic-resistant bacteria.


Effects of gradual exposure to carbon dioxide gas on the blood pressure status of workers in coal mines of Kerman province, Iran.
The present study was conducted to investigate the probable changes in blood pressure of workers in coal mines. In this study 91 workers, who worked in forwarding, preparation and exploitation units of coal mines and were in direct contact with carbon dioxide gas (from fireworks), have been selected as the case group, and 70 workers, who did not have direct contact with this gas, from other units were selected as the control group by simple random sampling method. The inclusion criteria were over 10 years of work experience and the age range of 30 to 45 years. The blood pressure values and their classification were determined based on the Seventh Report of the Joint National Committee on Prevention of Hypertension. Statistical analysis was performed using t-test. The results of this study showed that mean systolic and diastolic blood pressures in the case group were significantly lower than the control group (P < 0.001). The mean diastolic blood pressure of workers in coal mines is less than other people due to the CO2 gas. A greater control of the existing gas in mines by relevant factors is required. Necessary medical care and support measures should also be considered.


Testing Positive and Disclosing in Pregnancy: A Phenomenological Study of the Experiences of Adolescents and Young Women in Maseru, Lesotho.
The routine antenatal screening through the prevention of mother to child transmission of HIV (PMTCT) services results in pregnancy being often the point at which an HIV diagnosis is made. Disclosure to partners presents particular complexities during pregnancy. However, research on the pattern and experiences of disclosure in pregnancy is limited in Lesotho, despite the high prevalence of HIV among pregnant women. The aim of this study was to explore and describe the disclosure experiences of adolescent girls and young women (AGYW) after receiving a positive HIV test result during pregnancy. Methods. Descriptive phenomenology using semistructured in-depth interview was used to collect data from AGYM sampled purposively from PMTCT sites located in urban areas of Maseru, Lesotho. Data analysis was inductive and followed the thematic approach. Findings. There were 15 AGYW involved in this study with the mean age of 20 years. Fourteen reported being pregnant with their first child and perceived HIV testing in antenatal care as compulsory. Ten AGYM disclosed their HIV status in the immediate posttesting period to protect their partners from HIV infection. The narratives revealed that the AGYM hoped that after disclosing, the partner would be tested for HIV. Furthermore, the AGYM disclosed because they wanted freedom to take their medication. Their experience of disclosure was relief, as they did not have to hide their HIV status. The AGYM reported being supported to adhere to medication and clinic attendance by their partners who also provided emotional support to them to deal with being HIV positive and pregnant. Conclusion. The AGYM recounted an overall positive experience of disclosure to their partners who agreed to test for HIV and adopted safe sex practices. This has positive implications for the PMTCT programme and the involvement of men in reproductive health. Therefore, there is need to integrate disclosure and partner testing interventions in the cascade of services in PMTCT programmes.


Progressive vision loss. A rare manifestation of familial cavernous angiomas.
We studied four generations of a family in which the index case had progressive loss of vision secondary to a cavernous angioma of the optic nerve and chiasm. Magnetic resonance imaging of the brain revealed multiple, asymptomatic intracerebral cavernous angiomas. Brain magnetic resonance imaging scans of the family members revealed multiple cavernous angiomas in the brother and paternal grandfather, but none in the father or his siblings. Autopsy reports of the paternal great grandfather noted multiple cavernous angiomas in the brain and abdominal viscera. We believe our patient to be the sixth reported case in which a cavernous angioma involved the optic chiasm and optic nerve. Magnetic resonance imaging is a sensitive and specific method of detecting cavernous angiomas. Cavernous angiomas have an autosomal dominant pattern of inheritance with variable penetrance. Surgical intervention in patients with symptomatic cavernous angiomas depends on the location and size of the lesion and associated surgical risks.


Role of Surface Termination in Atomic Layer Deposition of Silicon Nitride.
There is an urgent need to deposit uniform, high-quality, conformal SiN(x) thin films at a low-temperature. Conforming to these constraints, we recently developed a plasma enhanced atomic layer deposition (ALD) process with bis(tertiary-butyl-amino)silane (BTBAS) as the silicon precursor. However, deposition of high quality SiNx thin films at reasonable growth rates occurs only when N2 plasma is used as the coreactant; strongly reduced growth rates are observed when other coreactants like NH3 plasma, or N2-H2 plasma are used. Experiments reported in this Letter reveal that NH(x)- or H- containing plasmas suppress film deposition by terminating reactive surface sites with H and NH(x) groups and inhibiting precursor adsorption. To understand the role of these surface groups on precursor adsorption, we carried out first-principles calculations of precursor adsorption on the β-Si3N4(0001) surface with different surface terminations. They show that adsorption of the precursor is strong on surfaces with undercoordinated surface sites. In contrast, on surfaces with H, NH2 groups, or both, steric hindrance leads to weak precursor adsorption. Experimental and first-principles results together show that using an N2 plasma to generate reactive undercoordinated surface sites allows strong adsorption of the silicon precursor and, hence, is key to successful deposition of silicon nitride by ALD.


The solution phase interaction between apolipoprotein(a) and plasminogen inhibits the binding of plasminogen to a plasmin-modified fibrinogen surface.
In the present study, we assessed the binding of recombinant forms of apolipoprotein(a) [r-apo(a)] to plasminogen. Apo(a)-plasminogen interactions were demonstrated to be lysine-dependent, as they were abolished by the addition of epsilon-aminocaproic acid. Binding of r-apo(a) and plasma-derived Lp(a) to Glu-plasminogen was assessed in solution using a mutant form of recombinant plasminogen [Plg(S741C)] labeled at the active site with 5'-(iodoacetamido)fluorescein. High-affinity binding of apo(a) to plasminogen was observed with the 17-kringle r-apo(a) (Kd = 20.1 +/- 3.3 nM) as well as with plasma-derived Lp(a) (Kd = 5.58 +/- 0.08 nM). Binding studies using various truncated and mutant forms of r-apo(a) demonstrated that sequences within apo(a) kringle IV types 2-9 and the strong lysine binding site (LBS) in apo(a) kringle IV type 10 are not required for high-affinity binding to plasminogen. In all cases, the binding stoichiometry for the apo(a)-plasminogen interaction was determined to be 1:1. Binding data obtained using a 17-kringle r-apo(a) derivative lacking the protease-like domain (17KDeltaP; Kd = 3158 +/- 138 nM) indicate that sequences within the protease-like domain of apo(a) mediate its interaction with LBS in plasminogen. We determined that r-apo(a) and plasminogen bind to distinct sites on plasmin-modified fibrinogen with the concentration of plasminogen binding sites exceeding the concentration of r-apo(a) sites by a factor of 10. Furthermore, r-apo(a) is capable of inhibiting the binding of plasminogen to plasmin-modified fibrinogen surfaces, an effect which we show is attributable to the formation of a solution phase apo(a)/plasminogen complex which exhibits a greatly reduced affinity for plasminogen binding sites on plasmin-modified fibrinogen. The results of this study provide new insights into the mechanism by which apo(a) and Lp(a) may inhibit fibrinolysis, thus contributing to the atherothrombotic risk associated with this lipoprotein.


Clinical application of a soft denture liner: a case report.
Patients with thin, nonresilient mucosa, poor ridge morphology, chronic xerostomia, and acquired or congenital defects are candidates for soft denture liners. Soft denture liners may be placed during fabrication of the new denture or during relining of the existing dentures. Soft mandibular denture liners are ideal for senior patients with resorbed mandibular ridges who need replacement of existing dentures to correct excessively closed vertical dimension of occlusion and for patients who have maxillary complete dentures and mandibular natural teeth, severe loss of maxillary ridge, and clenching habits. Soft denture liners should be used only when needed because of their short service life. However, for those patients who cannot tolerate hard denture bases, soft liners are an appropriate alternative treatment.


Ergonomic assessment of enhanced protection under body armour combat shirt neck collars.
Combat neck injury due to explosively propelled fragments is a significant cause of mortality and long-term morbidity in UK soldiers deployed on current operations. Reinforcing the collar of the existing under body armour combat shirt (UBACS) has been suggested as a potential method for reducing the incidence of combat neck injury. 20 soldiers serving in Afghanistan objectively compared three designs of enhanced protection UBACS (EP-UBACS) using 10 representative military tasks against a baseline of a standard UBACS. Each EP-UBACS design was trialled using three constituent materials: two layers of para-aramid felt, one layer of ultra high molecule weight polyethylene (UHMWPE) felt or two layers of a silk fabric. Subjective assessment of these nine configurations in terms of comfort, heat dissipation and overall acceptability were compared with the standard UBACS using a χ² test. All military tasks could be performed with all nine configurations of EP-UBACS. Although silk was the most comfortable material, it was not functionally practical in any of the three designs. Crossover collars incorporating UHMWPE or para-aramid were the only two of the nine configurations to demonstrate similar user acceptability to a standard UBACS. The EP-UBACS has the potential to provide neck protection without reducing performance incorporating materials analogous to either of the felts assessed in this study. The collar should provide stand-off from the skin to improve heat dissipation and comfort, which can be maximised by changing the current UBACS collar shape to one that crosses over at the front. Should a zip be desired, it should be moved to one side of the midline to reduce rubbing on the chin and be covered with ballistic protective material. Additional semi-circles of silk beneath the collar at the front and back would improve protection without affecting comfort.


Helminth parasites of the endangered hooded grebe, Podiceps gallardoi, from Patagonia Argentina, with the description of two new digenean species.
In March 2011, a predator killed 33 hooded grebes, Podiceps gallardoi Rumboll (Podicipedidae), a critically endangered species, in a nesting colony at El Cervecero Lake, Santa Cruz Province, Argentina. The viscera of ten birds were examined for helminths. Two new species of Trematoda were recovered from the intestines. The plagiorchid Plagiorchis patagonensis n. sp. is mainly characterized by the larger size of the oral sucker relative to the ventral sucker, and by the distribution of the vitellarium in two lateral fields, confluent between the caecal bifurcation and the ventral sucker. The echinostomatid Euparyphium tobianum n. sp. is mainly characterized by possessing a head collar with 37-39 spines (4 angle spines on each ventral lappet, 4 lateral spines in a single row on each side, and 21-23 dorsal spines in a double row). An unidentified cestode, a tetramerid nematode and a notocotylid trematode were also recovered from the birds. This is the first record of helminths parasitizing the hooded grebe.


What's in a grade? Academic success and political orientation.
Expanding the literature on person-environment fit, the authors argue that political orientation is an important factor in shaping academic success in college. Based on social dominance theory, it was expected that academic disciplines that are more likely to provide students with future access to social and economic power tend to favor individuals who hold attitudes that strengthen the existing societal order. In a longitudinal sample of undergraduate students at a major American university (n=3,890), the authors demonstrated that student grades in these disciplines, but not in other disciplines, are positively related to a precollege measure of conservatism. This association between conservatism is consistent over time and subgroups, thus implicating higher education in the reproduction of social hierarchy. The discussion examines the causal processes underlying the relationship between political orientation and academic success in college.


A human septin octamer complex sensitive to membrane curvature drives membrane deformation with a specific mesh-like organization.
Septins are cytoskeletal proteins interacting with the inner plasma membrane and other cytoskeletal partners. Being key in membrane remodeling processes, they often localize at specific micrometric curvatures. To analyze the behavior of human septins at the membrane and decouple their role from other partners, we used a combination of bottom-up in vitro methods. We assayed their ultrastructural organization, their curvature sensitivity, as well as their role in membrane reshaping. On membranes, human septins organize into a two-layered mesh of orthogonal filaments, instead of generating parallel sheets of filaments observed for budding yeast septins. This peculiar mesh organization is sensitive to micrometric curvature and drives membrane reshaping as well. The observed membrane deformations together with the filamentous organization are recapitulated in a coarse-grained computed simulation to understand their mechanisms. Our results highlight the specific organization and behavior of animal septins at the membrane as opposed to those of fungal proteins.


Opioid peptide receptors and membrane biology.
The opioid peptides, beta-endorphin and the enkephalins, exhibit binding to brain tissue that is stereospecific, of high affinity, and saturable; from comparisons of the pharmacological potencies of a number of alkaloids with their abilities to displace peptide binding, it is concluded that peptide binding is probably relevant to pharmacological response for beta-endorphin, but not necessarily for enkephalins. The results of structure-activity studies indicate that both the (1-5) and a C-terminal sequence of the beta-endorphin molecule are necessary for both binding and pharmacological response, while pentapeptide conformation is related to enkephalin binding and pharmacological potency. The binding of opioid peptides possesses a brain regional distribution similar to that of alkaloids, with greatest enrichment in the striate, somewhat lesser amounts in the hypothalamus, thalamus, and amygdala, and least in the cortex and cerebellum; physiochemical properties, including inhibition by Na+, GTP, and by pretreatment of brain tissue with sulfhydryl reagents and proteolytic and lipolytic enzymes, are also similar to those of alkaloids. Other evidence, however, indicates that enkephalins and alkaloids bind to different sites: (1) differences in the abilities of enkephalins and alkaloids to displace labeled enkephalin and labeled alkaloid binding; (2) differences in relative pharmacological potencies of alkaloids and enkephalins in different systems; (3) small but significant differences in brain regional distribution and in certain physicochemical properties; and (4) selective protection of inhibition by irreversible reagents. This evidence, together with other data implicating both proteins and lipids in binding, has led us to propose a model of the beta-endorphin receptor in which the peptide binds to both an enkephalin site, located on a protein, and an alkaloid site, located on a lipid. Binding of enkephalins and beta-endorphin is related to a number of membrane-associated processes that are similarly affected by alkaloid binding, including changes in activity of adenylate cyclase and protein kinase, and in lipid metabolism and calcium ion disposition; some or all of these factors are presumably involved in the mediation of acute and chronic pharmacological effects. All of this work should be greatly aided by isolation of functionally active binding material, and recent work suggests that this breakthrough is finally possible.


Empowering processes and outcomes of participation in online support groups for patients with breast cancer, arthritis, or fibromyalgia.
Ever since the rise of online support groups it has been presumed that there is an empowering effect from patients' participating in these groups, despite a lack of evidence to back up this assumption. In this study we explored if, and in which ways, patients feel empowered by participation. Additionally, we studied which empowering and disempowering processes occur as a result of taking part in these groups. To accomplish this aim, we interviewed 32 participants of online support groups. This analysis revealed the following empowering processes: exchanging information, encountering emotional support, finding recognition, sharing experiences, helping others, and amusement. Disempowering processes were mentioned far less often. Empowering outcomes mentioned were being better informed; feeling confident in the relationship with their physician, their treatment, and their social environment; improved acceptance of the disease; increased optimism and control; enhanced self-esteem and social well-being; and collective action. This article demonstrates that participation in online support groups can make a valuable contribution to the emergence of empowered patients.


[Genetics and some characterization of C6 deficiency in rabbits (author's transl)].
C6 deficient rabbits were found in a breed of Angora rabbits reared in Japan. The genetic studies confirmed that this complement deficiency was transmitted as an autosomal recessive trait. Alloimmunization of the deficient rabbits with normal rabbit serum produced a specific antibody to C6 component. This antiserum cross-reacted against human, cattle, sheep, goat, pig, dog, guinea pig and mouse serum, but not to horse, hamster and chicken serum. The C6 levels in the sera of Angora rabbits, measured by the single radial immunodiffusion method using the alloantiserum, were distributed in three distinct group; normal, about half of normal and null level. The C6 level in the sera of F1 rabbits (C6+/-), crosses between C6 deficient Angora rabbit (C6-/-) and New Zealand White rabbit (C6+/+), was about half of normal level. These results suggested that the level of C6 in the sera was under the dosage effect of C6 deficient gene.


Aripiprazole and Risperidone for Treatment of Methamphetamine-Associated Psychosis in Chinese Patients.
We evaluated tolerability and efficacy of aripiprazole and risperidone for treatment of methamphetamine (METH) associated psychotic symptoms in China. Patients with acute METH-associated psychotic symptoms (N=42) and with Positive and Negative Syndrome Scale (PANSS) total score between 60 and 120 were randomized to aripiprazole (initial dose 5-10mg per day followed by flexible doses 5-15 mg per day) or risperidone (initial dose 2-4 mg per day followed by flexible doses 4-6 mg per day) from day 3 to 25 of inpatient hospital stay. Outcome measures included PANSS and Clinical Global Impressions-Severity of Illness scale (CGI-S), METH craving Visual Analogue Scale (VAS), Simpson Angus Scale (SAS), Barnes Assessments Akathasia Rating Scale (BARS), and self-reported adverse effects evaluated during treatment. Retention was evaluated using Kaplan-Meier survival analysis and the MIXED models procedure was used to compare the groups on measures of psychotic and extra-pyramidal symptoms. Patients in both aripiprazole and risperidone groups showed statistically significant reductions in psychotic symptomatology from baseline during treatment (p<0.001) with no statistically significant differences between the treatment groups (p=0.73 and p=0.15, respectively). Risperidone-treated patients reported significantly greater METH craving reductions (p<0.001). Overall, 71% of patients completed the entire study, but the aripiprazole group had a significantly lower retention than the risperidone group (p=0.007), primarily due to medication related adverse effects. Aripiprazole-treated patients also had significantly more akathisia (p=0.03) and agitation (p=0.02) than risperidone-treated patients. Patients in both groups who tolerated their medications and completed the entire study achieved comparable reductions of psychotic symptoms.


[Hemolysins of Listeria monocytogenes demonstrable by activation with 2-mercaptoethanol].
Jones and Seeliger with the endorsement of the International Committee on Systematic Bacteriology, Subcommittee on the Taxonomy of Listeria, are considering to replace L. monocytogenes ATCC 15313 as prototype strain of species because of the lack of hemolytic activity in conventional agar blood media. We demonstrate in this work that ATCC 15313 strain is able to induce hemolysis in conventional media under microaerophilic conditions and also has a definite hemolytic activity when supernatants of a 24 hs growth in brain heart infusion plus 0.5% dextrose were activated with 2-mercaptoethanol (Table 3). Thirteen strains previously identified as L. monocytogenes were studied. Nine of them are compatible with the identification of L. monocytogenes, all show hemolytic activity under microaerophilic conditions, ATCC 15313 does nos show hemolysis on surface test but induces hemolysis, as other nine strains do, when activated by 2-mercaptoethanol. It is interesting to reinforce the need to perform all the different test to analyze hemolytic activity as a basis for presumptive L. monocytogenes identification. The absence of demonstrable hemolysis using all proposed test is an important factor to be taken into account for Listeria identification.


Do we get better at picking our battles? Age group differences in descriptions of behavioral reactions to interpersonal tensions.
Individuals of various ages may react in different ways when they are upset with their social partners. This study examines age group differences in descriptions of behavioral reactions to interpersonal tensions. Participants ages 13 to 99 (84 men, 100 women) described interpersonal tensions that occurred with close and problematic social network members. Descriptions were coded with Rusbult's typology of conflict strategies (voice, loyalty, neglect, exit). Multilevel models revealed that older adults were more likely to report loyalty strategies (e.g., doing nothing) while younger people were more likely to report exit (e.g., yelling) strategies in response to interpersonal problems. These age differences were not accounted for by intensity of distress, relationship quality, contact frequency, or type of social partner. It appears that individuals are better able to regulate their behavioral responses to interpersonal problems as they age.


Doyne Memorial Lecture, 1977. The superior oblique tendon.
New concepts concerning the anatomy of the tissues surrounding the superior oblique tendon are presented. A safe visual approach to the tendon after its penetration through Tenon's capsule is described. The various surgical procedures and techniques developed to weaken the overacting superior oblique muscles associated with A pattern and the taut superior oblique muscle found in Brown's syndrome are reviewed.


Toll-like receptor 4 mediates the development of fatigue in the murine Lewis Lung Carcinoma model independently of activation of macrophages and microglia.
Cancer-related fatigue at the time of tumor diagnosis is commonly attributed to inflammation associated with the disease process. However, we have previously demonstrated that running wheel deficits occur well before increased expression of proinflammatory cytokines in the liver and brain in a murine model of human papilloma virus-related head and neck cancer (mEER). Further, we have demonstrated that genetic deletion of type I interleukin-1 receptor and MyD88 has no effect. In the current investigation we sought to test the generality of this finding by assessing whether there is a role for toll-like receptor (TLR) 4-dependent inflammation in the fatigue-like behavior observed in mice with Lewis Lung Carcinoma (LLC) or mEER tumors. Genetic deletion of TLR4 attenuated tumor-induced elevations in liver pro-inflammatory cytokine expression in both models. However, it only abrogated wheel running deficits in LLC tumor bearing mice. To determine whether TLR4 signaling in the LLC model involves innate immune cells, mice were treated with the colony stimulating factor (CSF)-1 receptor antagonist PLX-5622 before and throughout tumor development to deplete microglia and peripheral macrophages. Administration of PLX-5622 had no protective effect on wheel running deficits in either mEER or LLC tumor models despite effective depletion of microglia and a down regulation of peripheral proinflammatory cytokine expression. These results indicate that the TLR4 signaling that mediates fatigue-like behavior in LLC mice is not dependent upon microglial or peripheral macrophage activation. Based on the literature and our data demonstrating attenuation of ubiquitin proteasome pathway activation in the gastrocnemius muscle of Tlr4-/- mice implanted with LLC cells, we interpret our current findings as indication that skeletal muscle TLR4 signaling may be involved. These results are important in that they add to the evidence that tumor-induced fatigue develops independently from classical neuroinflammation.


Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients.
Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non-invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2-6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively cool had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules.


"Non-infectious" syndromes associated with infectious agents.
Over the past two decades there has been numerous new associations between chronic diseases traditionally considered non-infectious with infectious agents. This list of diseases include peptic ulcer, coronary heart disease, neuropsychiatric disorders, haematological disorders and malignancies. These associations have been made possible through improvements in diagnostic tests based on molecular biology techniques. The discovery of these associations is important as it opens up exciting opportunities for the prevention and treatment of many diseases hitherto considered incurable.


Ketanserin versus alpha-methyldopa in the treatment of hypertension during pregnancy: a preliminary report.
The antihypertensive efficacy of acute treatment with the serotonin receptor antagonist, ketanserin, in women with preeclampsia has been recently documented. The purpose of this study was to determine the safety and efficacy of chronic ketanserin treatment in a group of 20 hypertensive pregnant women: 10 received daily oral doses of ketanserin (20-80 mg), and 10 were treated with oral alpha-methyldopa (500-2000 mg). This study includes (a) patients with a sustained elevation of systolic blood pressure higher than 159 mm Hg and/or diastolic blood pressure higher than 99 mm Hg at bed rest, and (b) hypertensive patients with systolic blood pressure higher than 140 mm Hg or diastolic blood pressure higher than 90 mm Hg with superimposed symptoms such as headaches, stomach aches, and neurological disturbances. A significant and comparable decrease in blood pressure was noted in both groups, in relation with pretreatment levels; no adverse affects were observed in mother or fetus from the ketanserin and alpha-methyldopa groups.


Pterostilbene as a potential novel telomerase inhibitor: molecular docking studies and its in vitro evaluation.
Pterostilbene is a naturally occurring dimethyl ether analog of resveratrol identified in several plant species. Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. Molecular docking studies were performed on pterostilbene with the crystal structure of telomerase (3DU6). Pterostilbene was evaluated for its in vitro cytotoxicity in breast (MCF7) and lung cancer (NCI H-460) cell lines, antimitotic activity in green grams and telomerase activity. Curcumin was used as a standard. Docking results indicated good interaction between pterostilbene and the active site of telomerase and the docked energy of pterostilbene was -7.10 kcal/mol. Pterostilbene showed strong inhibitory effect on in vitro telomerase activity and cell growth in both the cell lines tested in a dose dependent manner. Cancer cells treated with 80 µM pterostilbene exhibited significant telomerase inhibition, after 72 hours (MCF-7 and NCI H-460; 81.52% and 74.69% reduction, respectively, compared to control). The IC50 of pterostilbene for anti-proliferative activity in MCF7 and NCI H-460 cell lines were found to be 30.0 and 47.2 µM, respectively. The best antimitotic activity was obtained with 80 μM of pterostilbene (100% reduction in water imbibition). All the above results were comparable to that of curcumin. The drug-related properties of pterostilbene were calculated using Molinspiration, Osiris Property Explorer and ACD/Chemsketch softwares. Pterostilbene obeyed Lipinski's Rule of Five indicating its therapeutic potential in humans. It was found that the telomerase inhibitory activity exhibited by pterostilbene was dependent of the cell viability and has the potential to be a new drug candidate against breast and lung cancers.


Sleep characteristics in children with growth hormone deficiency.
Growth hormone (GH) is preferentially secreted during slow wave sleep and the interactions between human sleep and the somatotropic system are well documented, although only few studies have investigated the sleep EEG in children with GH deficiency (GHD). The aim of this study was to evaluate the sleep structure of children with dysregulation of the GH/insulin-like growth factor axis. Laboratory polysomnographic sleep recordings were obtained from 10 GHD children and 20 normal healthy age-matched children. The classical sleep parameters were evaluated together with sleep microstructure, by means of the cyclic alternating pattern (CAP), in GHD patients and compared to the control group. GHD children showed a significant decrease in total sleep time, sleep efficiency, movement time and in non-rapid eye movement sleep stage 2. Although some indicators of sleep fragmentation were increased in GHD children, we found a general decrease in EEG arousability represented by a significant global decrease in the CAP rate, involving all CAP A phase subtypes. The analysis of sleep microstructure by means of CAP, in children with GHD, showed a reduction of transient EEG amplitude oscillations. Further studies are needed in order to better clarify whether GH therapy is able to modify sleep microstructure in GHD children, and the relationships between sleep microstructure, hormonal secretion and neurocognitive function in these patients.


Precision design of stable genetic circuits carried in highly-insulated E. coli genomic landing pads.
Genetic circuits have many applications, from guiding living therapeutics to ordering process in a bioreactor, but to be useful they have to be genetically stable and not hinder the host. Encoding circuits in the genome reduces burden, but this decreases performance and can interfere with native transcription. We have designed genomic landing pads in Escherichia coli at high-expression sites, flanked by ultrastrong double terminators. DNA payloads >8 kb are targeted to the landing pads using phage integrases. One landing pad is dedicated to carrying a sensor array, and two are used to carry genetic circuits. NOT/NOR gates based on repressors are optimized for the genome and characterized in the landing pads. These data are used, in conjunction with design automation software (Cello 2.0), to design circuits that perform quantitatively as predicted. These circuits require fourfold less RNA polymerase than when carried on a plasmid and are stable for weeks in a recA+ strain without selection. This approach enables the design of synthetic regulatory networks to guide cells in environments or for applications where plasmid use is infeasible.


Representations of self and other in the narratives of neglected, physically abused, and sexually abused preschoolers.
The MacArthur Story Stem Battery was used to examine maternal and self-representations in neglected, physically abused, sexually abused, and nonmaltreated comparison preschool children. The narratives of maltreated children contained more negative maternal representations and more negative self-representations than did the narratives of nonmaltreated children. Maltreated children also were more controlling with and less responsive to the examiner. In examining the differential impact of maltreatment subtype differences on maternal and self-representations, physically abused children evidenced the most negative maternal representations; they also had more negative self-representations than nonmaltreated children. Sexually abused children manifested more positive self-representations than neglected children. Despite these differences in the nature of maternal and self-representations, physically and sexually abused children both were more controlling and less responsive to the examiner. The investigation adds to the corpus of knowledge regarding disturbances in the self-system functioning of maltreated children and provides support for relations between representational models of self and other and the self-organizing function that these models exert on children's lives.


Social stress and atherosclerosis in normocholesterolemic monkeys.
Socially stressed adult male cynomolgus monkeys (Macaca fascicularis) fed a low fat, low cholesterol diet developed more extensive coronary artery atherosclerosis than unstressed controls. Groups did not differ in serum lipids, blood pressure, serum glucose, or ponderosity. These results suggest that psychosocial factors may influence atherogenesis in the absence of elevated serum lipids. Psychosocial factors thus may help explain the presence of coronary artery disease (occasionally severe) in people with low or normal serum lipids and normal values for the other "traditional" risk factors.


Retinotopic organization of early visual spatial attention effects as revealed by PET and ERPs.
Cerebral blood flow PET scans and high-density event-related potentials (ERPs) were recorded (separate sessions) while subjects viewed rapidly-presented, lower-visual-field, bilateral stimuli. Active attention to a designated side of the stimuli (relative to passive-viewing conditions) resulted in an enhanced ERP positivity (P1 effect) from 80-150 msec over occipital scalp areas contralateral to the direction of attention. In PET scans, active attention vs. passive showed strong activation in the contralateral dorsal occipital cortex, thus following the retinotopic organization of the early extrastriate visual sensory areas, with some weaker activation in the contralateral fusiform. Dipole modeling seeded by the dorsal occipital PET foci yielded an excellent fit for the P1 attention effect. In contrast, dipoles constrained to the fusiform foci fit the P1 effect poorly, and, when the location constraints were released, moved upward to the dorsal occipital locations during iterative dipole fitting. These results argue that the early ERP P1 attention effects for lower-visual-field stimuli arise mainly from these dorsal occipital areas and thus also follow the retinotopic organization of the visual sensory input pathways. These combined PET/ERP data therefore provide strong evidence that sustained visual spatial attention results in a preset, top-down biasing of the early sensory input channels in a retinotopically organized way.


The acid-secreting parietal cell as an endocrine source of Sonic Hedgehog during gastric repair.
Sonic Hedgehog (Shh) has been shown to regulate wound healing in various tissues. Despite its known function in tissue regeneration, the role of Shh secreted from the gastric epithelium during tissue repair in the stomach remains unknown. Here we tested the hypothesis that Shh secreted from the acid-secreting parietal cell is a fundamental circulating factor that drives gastric repair. A mouse model expressing a parietal cell-specific deletion of Shh (PC-ShhKO) was generated using animals bearing loxP sites flanking exon 2 of the Shh gene (Shh(flx/flx)) and mice expressing a Cre transgene under the control of the H(+),K(+)-ATPase β-subunit promoter. Shh(flx/flx), the H(+),K(+)-ATPase β-subunit promoter, and C57BL/6 mice served as controls. Ulcers were induced via acetic acid injury. At 1, 2, 3, 4, 5, and 7 days after the ulcer induction, gastric tissue and blood samples were collected. Parabiosis experiments were used to establish the effect of circulating Shh on ulcer repair. Control mice exhibited an increased expression of Shh in the gastric tissue and plasma that correlated with the repair of injury within 7 days after surgery. PC-ShhKO mice showed a loss of ulcer repair and reduced Shh tissue and plasma concentrations. In a parabiosis experiment whereby a control mouse was paired with a PC-ShhKO littermate and both animals subjected to gastric injury, a significant increase in the circulating Shh was measured in both parabionts. Elevated circulating Shh concentrations correlated with the repair of gastric ulcers in the PC-ShhKO parabionts. Therefore, the acid-secreting parietal cell within the stomach acts as an endocrine source of Shh during repair.


[Colorectal carcinoma. Multifactorial analysis of prognostic factors following curative resection].
Cox regression analysis was used in the study of 151 cases of surgically treated colorrectal carcinoma. A "curative" resection was performed in all of them. Clinical data from medical records, histology, biochemical determinations, and intraoperative findings were assessed. Four of the studied variables were significantly related to tumor recurrence: Dukes stage, tumor spread, histological variety and preoperative CEA level. Age, sex, tumor location, surgical technique, lymphocytes in the peripheral blood, preoperative levels of acute phase reactants and hepatic enzymes did not provide information about the final outcome of these patients. An index of prognosis was statistically obtained in order to identify a high risk of recurrence group of patients, who may benefit from adjuvant therapy.


Self-Management Support with Yoga on Psychological Health and Quality of Life for Breast Cancer Survivors.
The purpose of this study was to identify whether the improvement of self-management support (SMS) combined with yoga can improve anxiety, depression, stress, and quality of life in female breast cancer survivors. The SMS combined with yoga group and control group (yoga only) were comprised of 21 and 20 participants, respectively. The SMS with yoga and yoga programs were provided to each group for 8 weeks. Data obtained from self-report questionnaires included details of anxiety, depression, stress, and quality of life. The levels of anxiety, depression, and stress significantly decreased in both the SMS with yoga and control groups (p < 0.05). Moreover, the quality of life improved significantly in the SMS with yoga group (p < 0.001). Among the five quality-of-life domains (physical, social/family, emotional and functional well-being, and breast cancer subscale), social/family well-being in the SMS with yoga group was significantly higher than that in the yoga-only group (p = 0.011). Conclusions: The results show that yoga is a beneficial activity for the psychological health of breast cancer survivors. Our findings suggest that SMS strategies can improve quality of life.


Assessing the utility of conserving evolutionary history.
It is often claimed that conserving evolutionary history is more efficient than species-based approaches for capturing the attributes of biodiversity that benefit people. This claim underpins academic analyses and recommendations about the distribution and prioritization of species and areas for conservation, but evolutionary history is rarely considered in practical conservation activities. One impediment to implementation is that arguments related to the human-centric benefits of evolutionary history are often vague and the underlying mechanisms poorly explored. Herein we identify the arguments linking the prioritization of evolutionary history with benefits to people, and for each we explicate the purported mechanism, and evaluate its theoretical and empirical support. We find that, even after 25 years of academic research, the strength of evidence linking evolutionary history to human benefits is still fragile. Most - but not all - arguments rely on the assumption that evolutionary history is a useful surrogate for phenotypic diversity. This surrogacy relationship in turn underlies additional arguments, particularly that, by capturing more phenotypic diversity, evolutionary history will preserve greater ecosystem functioning, capture more of the natural variety that humans prefer, and allow the maintenance of future benefits to humans. A surrogate relationship between evolutionary history and phenotypic diversity appears reasonable given theoretical and empirical results, but the strength of this relationship varies greatly. To the extent that evolutionary history captures unmeasured phenotypic diversity, maximizing the representation of evolutionary history should capture variation in species characteristics that are otherwise unknown, supporting some of the existing arguments. However, there is great variation in the strength and availability of evidence for benefits associated with protecting phenotypic diversity. There are many studies finding positive biodiversity-ecosystem functioning relationships, but little work exists on the maintenance of future benefits or the degree to which humans prefer sets of species with high phenotypic diversity or evolutionary history. Although several arguments link the protection of evolutionary history directly with the reduction of extinction rates, and with the production of relatively greater future biodiversity via increased adaptation or diversification, there are few direct tests. Several of these putative benefits have mismatches between the relevant spatial scales for conservation actions and the spatial scales at which benefits to humans are realized. It will be important for future work to fill in some of these gaps through direct tests of the arguments we define here.


[Biopathology of fibrosing alveolitis].
Fibrosis is a condition where the functional tissue of an organ has been replaced by mesenchymal cells and their extracellular matrix. The process is frequent and may be regarded as univocal and independent of aetiology. An initial tissue damage is responsible for an inflammatory reaction which modulates and controls tissue repair with accumulation of mesenchymal cells, an accumulation which results from their migration and replication under the influence of chemotactic and/or mitogenic mediators (cytokines). Fibrosis occurs as an accentuation of this physiological process and may be understood as a healing process that has succeeded beyond normal expectation. Studies of idiopathic pulmonary fibrosis have improved our understanding of the physiopathology of pulmonary fibrosis. Alveolitis sets in response to an initial injury of undetermined nature, and from then on lymphocytes, neutrophils and macrophages intervene in the pathological process: (1) lymphocytes contribute to the perpetuation of the process by local production of immune complexes and coactivation of other inflammatory cells; (2) neutrophils and, to a lesser extent, eosinophils worsen the initial tissue injury by producing proteases and oxydants; (3) finally, macrophages control the local accumulation of mesenchymal cells by producing chemotactic and growth factors and by modulating the secretion by these cells of extracellular matrix.


Twenty-year protocol liver biopsies: Invasive but useful for the management of liver recipients.
Most liver transplant centres have discontinued the practice of protocol liver biopsies (LB), mainly because of the perceived lack of therapeutic benefit. This study aimed to examine the usefulness of 20-year LBs. Ten, 15, and 20-year protocol LBs from 147 patients surviving for >20 years were reviewed. Twenty-year biopsy findings were correlated with clinical data. Twenty-year-biopsy patients (N=91) and 20-year-non-biopsy patients (N=56) were similar in terms of transplant data, adverse events, and liver function tests (LFTs). Twenty-year LBs revealed a 90% prevalence of abnormalities, among which viral chronic hepatitis (VCH) was the most common (46%). Between 15 and 20 years, hepatic structural abnormalities were the only disorder to increase (p=0.008). An individual progression of abnormalities occurred in 56% of patients. At 20 years, the negative and positive predictive values (PV) of LFTs with respect to histological abnormalities were 95% and 18%, respectively; in VCH, Fibrotest and transient elastography displayed poor discriminative ability for fibrosis (80% and 81% discordance, respectively), but were satisfactory regarding significant fibrosis (negative PV of 77.7% and 80%, respectively). A decrease in immunosuppression was less frequent (14/91 vs. 20/56, p=0.008) while an increase was more common (15/91 vs. 2/56, p=0.017) in 20-year-biopsy patients than in non-biopsy patients. Antiviral therapy was administered in seven of the 20-year biopsy patients, but in none of the non-biopsy patients (p=0.04). Twenty-year LBs provided important histological information on graft function that was available to a limited degree from LFTs and non-invasive markers. They exerted an impact on immunosuppressive and antiviral therapies.


Adsorption of small mono- and poly-alcohols on rutile TiO2: a density functional theory study.
We have studied by means of density functional theory including dispersion contributions, the interaction of small chain alcohols with up to four carbons and three hydroxyl groups on the TiO2(110) rutile surface with different reduction degrees. Adsorption takes place through an acid-base interaction that can lead to both molecular and dissociated species. The latter are energetically preferred. Bulk reduction does not apport significant change neither in the structure nor in the adsorption energies, because the electrons are delocalized to a great extent. If vacancies are present at the surface these are the best adsorption sites for primary and secondary monoalcohols. Tertiary or poly-alcohols prefer the Ticus channels, but the reasons for the site preference are different. In the case of bulky alcohols, steric hindrance is the main adsorption-controlling factor, while templating effects of the basic (oxygen) sites on the surface are the key parameters to understand the adsorption of poly-alcohols. Vicinal polyalcohols behave even in a more complex way, for that they prefer the vacancy position only when dissociated, otherwise they stay in the Ticus channel. Our results warn about the use of small surrogates to investigate the chemistry of large alcohols as the adsorption patterns are not only quantitatively but also qualitatively wrong.


Biomechanical analysis of the three-dimensional foot structure during gait: a basic tool for clinical applications.
A novel three-dimensional numerical model of the foot, incorporating, for the first time in the literature, realistic geometric and material properties of both skeletal and soft tissue components of the foot, was developed for biomechanical analysis of its structural behavior during gait. A system of experimental methods, integrating the optical Contact Pressure Display (CPD) method for plantar pressure measurements and a Digital Radiographic Fluoroscopy (DRF) instrument for acquisition of skeletal motion during gait, was also developed in this study and subsequently used to build the foot model and validate its predictions. Using a Finite Element solver, the stress distribution within the foot structure was obtained and regions of elevated stresses for six subphases of the stance (initial-contact, heel-strike, midstance, forefoot-contact, push-off, and toe-off) were located. For each of these subphases, the model was adapted according to the corresponding fluoroscopic data, skeletal dynamics, and active muscle force loading. Validation of the stress state was achieved by comparing model predictions of contact stress distribution with respective CPD measurements. The presently developed measurement and numerical analysis tools open new approaches for clinical applications, from simulation of the development mechanisms of common foot disorders to pre- and post-interventional evaluation of their treatment.


Long-Term Temporal Trends of Polychlorinated Biphenyls and Their Controlling Sources in China.
Polychlorinated biphenyls (PCBs) are industrial organic contaminants identified as persistent, bioaccumulative, toxic (PBT), and subject to long-range transport (LRT) with global scale significance. This study focuses on a reconstruction and prediction for China of long-term emission trends of intentionally and unintentionally produced (UP) ∑7PCBs (UP-PCBs, from the manufacture of steel, cement and sinter iron) and their re-emissions from secondary sources (e.g., soils and vegetation) using a dynamic fate model (BETR-Global). Contemporary emission estimates combined with predictions from the multimedia fate model suggest that primary sources still dominate, although unintentional sources are predicted to become a main contributor from 2035 for PCB-28. Imported e-waste is predicted to play an increasing role until 2020-2030 on a national scale due to the decline of intentionally produced (IP) emissions. Hypothetical emission scenarios suggest that China could become a potential source to neighboring regions with a net output of ∼0.4 t year-1 by around 2050. However, future emission scenarios and hence model results will be dictated by the efficiency of control measures.


Relationship of traditional and nontraditional cardiovascular risk factors to coronary artery calcium in type 2 diabetes.
We evaluated correlates of coronary atherosclerosis, measured by coronary artery calcium, in a racially diverse group of male and female subjects with type 2 diabetes. Age, systolic blood pressure, sex, and race/ethnicity were significant determinants of coronary artery calcium. Among lipoproteins, cholesterol level contained in a particle excluded from direct measures of LDL and HDL cholesterol (designated triglyceride-rich lipoprotein cholesterol) was most strongly linked to coronary artery calcium. Neither inflammatory markers nor metabolic factors correlated with coronary artery calcium in models adjusted for age and sex, but measures of adipose distribution did. Waist-to-hip ratio and the ratio of visceral to total abdominal tissue were positively associated with coronary artery calcium. In fully adjusted multivariate models, the relationship of adiposity measures to coronary artery calcium was no longer significant after inclusion of apolipoprotein B or triglyceride-rich lipoprotein cholesterol. Traditional risk factors and race/ethnicity remain important correlates of coronary artery calcium in a cohort at elevated risk of cardiovascular disease because of type 2 diabetes. Adiposity measures are significantly associated with coronary artery calcium score, but their importance may be largely explained by apolipoprotein B or triglyceride-rich lipoprotein cholesterol.


Early diet in preterm infants and later cognition: 10-year follow-up of a randomized controlled trial.
Achieving adequate nutrition in preterm infants is challenging. The post-discharge period may be critical for influencing growth and cognitive outcomes. We studied the effects of post-discharge nutrition on childhood cognition. Preterm-born children were randomized at ~36 weeks corrected age (CGA) to either preterm formula (PTF) or term formula (TF) until 6 months, or PTF until 40 weeks CGA, then TF until 6 months (crossover group). Childhood cognition was assessed using the short form Wechsler Intelligence Scale for Children III, allowing computation of full-scale intelligence quotient (FSIQ) and four-factor index scores; verbal comprehension, freedom from distractibility (FDI), perceptual organization (POI), and processing speed (PSI). Ninety-two children were recruited (mean 10.1 years). FSIQ did not differ by group. PTF-fed children had 10-point higher PSI (p = 0.03) compared to crossover. Faster weight gain from term to 12 weeks CGA was associated with 5-point higher FSIQ (p = 0.02) and four-point higher POI (p = 0.04). Infant head growth was positively associated with FSIQ (+3.8 points, p = 0.04) and FDI (+6 points, p = 0.003). While there is no long-term impact of post-discharge macronutrient enrichment on childhood cognition, greater weight and head growth in specific epochs is associated with better outcomes. Further studies are needed to determine optimal early diet in preterm infants. Achieving adequate nutrient intakes in preterm infants before and after hospital discharge is challenging. Nutrient intakes prior to discharge affect later cognitive and metabolic outcomes. Follow-up of a randomized controlled trial shows no cognitive benefit in later childhood from a more nutrient-dense formula compared to standard formula after hospital discharge. Growth in the first year of life is strongly correlated with childhood cognition and emphasizes the importance of nutrition in early life.


Fingolimod effect on brain volume loss independently contributes to its effect on disability.
Brain volume loss occurs in patients with relapsing-remitting MS. Fingolimod reduced brain volume loss in three phase 3 studies. To evaluate whether the effect of fingolimod on disability progression was mediated by its effects on MRI lesions, relapses or brain volume loss, and the extent of this effect. Patients (992/1272; 78%) from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study were analyzed. Month-24 percentage brain volume change, month-12 MRI-active lesions and relapse were assessed. The Prentice criteria were used to test surrogate marker validity. The proportion of treatment effect on disability progression explained by each marker was calculated. Two-year disability progression was associated with active T2 lesions (OR = 1.24; p = 0.001) and more relapses during year 1 (OR = 2.90; p < 0.001) and lower percentage brain volume change over two years (OR = 0.78; p < 0.001). Treatment effect on active T2 lesions, relapses and percentage brain volume change explained 46%, 60% and 23% of the fingolimod effect on disability. Multivariate analysis showed the number of relapses during year 1 (OR = 2.62; p < 0.001) and yearly percentage brain volume change over two years (OR = 0.85; p = 0.009) were independent predictors of disability progression, together explaining 73% of fingolimod effect on disability. The treatment effect on relapses and, to a lesser extent, brain volume loss were both predictors of treatment effect on disability; combining these predictors better explained the effect on disability than either factor alone.


Identification and functional recording of the recurrent nerve by electrical stimulation during neck surgery.
A method for identification and functional recording of the recurrent nerve during neck operations is described. The basic principle implicates electrical stimulation of the recurrent nerve causing adduction of the vocal cord registered by means of a balloon placed between the vocal cords. Three different recording methods have been tested in animal experiments and during 26 neck operations on patients. The most simple method employed is recommended as a routine procedure, likely to reduce surgical damage to the recurrent nerve.


The diagnostic yield of histologic examination of seborrheic keratoses.
To examine the diagnostic yield in submitting clinically diagnosed seborrheic keratoses for routine microscopic examination. Retrospective examination of preoperative and postoperative diagnoses based on information provided by the clinician on the laboratory worksheet and the subsequent histopathologic diagnosis. A regional nonhospital-based dermatopathology laboratory with specimens submitted by physicians (dermatologists and nondermatologists) practicing in a 4-state midwestern region of the United States. A total of 5592 cutaneous pathology reports were reviewed. Specimens submitted with a preoperative clinical diagnosis of seborrheic keratosis, with or without a modifier, were examined. A comparison group with the clinical diagnosis of melanocytic nevus was reviewed. Preoperative clinical diagnoses were compared with the microscopic diagnoses. Of 577 specimens clinically diagnosed and submitted as seborrheic keratoses, 37 (6.4%) were histologically diagnosed as malignant tumors. The rate of malignant tumors increased when clinical information suggested findings beyond the classic clinical presentation, such as irritation, or when a malignant tumor was considered in the differential diagnosis. Two lesions that histologically proved to be melanomas were in this group. Comparison of the seborrheic keratosis group with the nevus group showed that seborrheic keratoses were more likely to be malignant tumors than were melanocytic nevi. Clinically diagnosed seborrheic keratoses submitted by dermatologists were more likely than clinically diagnosed melanocytic nevi to be melanomas. Our data suggest that there were differences in the rate of malignant tumors between dermatologists and nondermatologists and that clinically diagnosed, surgically removed seborrheic keratoses are more likely than clinically diagnosed, surgically removed melanocytic nevi to be malignant tumors.


Non-lethal sampling method for the analysis of white muscle fatty acid profiles in European sea bass (Dicentrarchus labrax).
This study presents a novel non-lethal sampling method for assessing fatty acid (FA) composition in juvenile European sea bass (Dicentrarchus labrax) using subcutaneous white muscle biopsies. This research aimed to evaluate the suitability of the biopsy for FA analysis using two lipid extraction protocols and comparing them to a lethal routine method. The results showed that a mass of fresh tissue as low as 1.4 mg provided good quality FA chromatograms for both reserve and membrane lipids. Although the biopsy method displayed high variability in terms of FA quantity among intra-individual replicates, it showed good FA profile repeatability in both reserve and membrane lipids. The study highlights the potential of this non-lethal approach for studying FA dynamics in fish, with its application being particularly promising for ecological and experimental studies. However, careful biopsy implementation is recommended to account for potential lipid droplet and lipid distribution variability within the tissue.


Leptospirosis: twelve Turkish patients with the Weil syndrome.
Twelve cases of leptospirosis followed by the Infectious Diseases Clinic of the Cukurova University Medical School, Adana, Turkey, between January 1994 and November 1995 are reported. Included are their clinical manifestation, laboratory findings and serotype. Nine men and three women with an average age of 40.4 years were studied. Symptoms, clinical manifestations, laboratory findings and treatment of the disease are evaluated. All of the patients had fever and chills and the following symptoms: nausea and vomiting (91.6%), lower back pain and myalgia (58.3%), headache (50%), epistaxis (16.6%) and confusion (25%). The predominant clinical findings were jaundice (91.6%), hepatomegaly (41.6%), dyspnea (25%), conjunctival suffusion (33%), and nuchal rigidity (33%). Diagnosis was based on dark-field examination of the blood, cerebrospinal fluid and urine specimens. Also, microscopic agglutination tests (MAT) were carried out for serodiagnosis. MAT showed L. interrogans serovar icterohaemorrhagiae in 11 cases and L. interrogans serovar grippomosocova in one case. There was cross reaction with L. biflexa patoc in all cases. Agglutinations were tested in the same specimens twice and confirmed in the Microbiology Laboratory of the Etlik Veterinary Research Institute in Ankara. All cases were treated with penicillin and doxycycline. In the end; 83.3% of the patients were cured and 16.6% died due to hepatorenal failure.