Future temperature and salinity do not exert selection pressure on cyst germination of a toxic phytoplankton species.
Environmental conditions regulate the germination of phytoplankton resting stages. While some factors lead to synchronous germination, others stimulate germination of only a small fraction of the resting stages. This suggests that habitat filters may act on the germination level and thus affect selection of blooming strains. Benthic "seed banks" of the toxic dinoflagellate Alexandrium ostenfeldii from the Baltic Sea are genetically and phenotypically diverse, indicating a high potential for adaptation by selection on standing genetic variation. Here, we experimentally tested the role of climate-related salinity and temperature as selection filters during germination and subsequent establishment of A. ostenfeldii strains. A representative resting cyst population was isolated from sediment samples, and germination and reciprocal transplantation experiments were carried out, including four treatments: Average present day germination conditions and three potential future conditions: high temperature, low salinity, and high temperature in combination with low salinity. We found that the final germination success of A. ostenfeldii resting cysts was unaffected by temperature and salinity in the range tested. A high germination success of more than 80% in all treatments indicates that strains are not selected by temperature and salinity during germination, but selection becomes more important shortly after germination, in the vegetative stage of the life cycle. Moreover, strains were not adapted to germination conditions. Instead, highly plastic responses occurred after transplantation and significantly higher growth rates were observed at higher temperature. High variability of strain-specific responses has probably masked the overall effect of the treatments, highlighting the importance of testing the effect of environmental factors on many strains. It is likely that A. ostenfeldii populations can persist in the future, because suitable strains, which are able to germinate and grow well at potential future climate conditions, are part of the highly diverse cyst population. This article has earned an Open Data Badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. The data is available at https://doi.org/10.5061/dryad.c8c83nr.


Visual function and cortical organization in carriers of blue cone monochromacy.
Carriers of blue cone monochromacy have fewer cone photoreceptors than normal. Here we examine how this disruption at the level of the retina affects visual function and cortical organization in these individuals. Visual resolution and contrast sensitivity was measured at the preferred retinal locus of fixation and visual resolution was tested at two eccentric locations (2.5° and 8°) with spectacle correction only. Adaptive optics corrected resolution acuity and cone spacing were simultaneously measured at several locations within the central fovea with adaptive optics scanning laser ophthalmoscopy (AOSLO). Fixation stability was assessed by extracting eye motion data from AOSLO videos. Retinotopic mapping using fMRI was carried out to estimate the area of early cortical regions, including that of the foveal confluence. Without adaptive optics correction, BCM carriers appeared to have normal visual function, with normal contrast sensitivity and visual resolution, but with AO-correction, visual resolution was significantly worse than normal. This resolution deficit is not explained by cone loss alone and is suggestive of an associated loss of retinal ganglion cells. However, despite evidence suggesting a reduction in the number of retinal ganglion cells, retinotopic mapping showed no reduction in the cortical area of the foveal confluence. These results suggest that ganglion cell density may not govern the foveal overrepresentation in the cortex. We propose that it is not the number of afferents, but rather the content of the information relayed to the cortex from the retina across the visual field that governs cortical magnification, as under normal viewing conditions this information is similar in both BCM carriers and normal controls.


Phenotypic variation of a Thr704Met mutation in skeletal sodium channel gene in a family with paralysis periodica paramyotonica.
Patients with paralysis periodica paramyotonica exhibit a clinical syndrome with characteristics of both hyperkalaemic periodic paralysis and paramyotonia congenita. In several types of periodic paralysis associated with hyperkalaemia, mutations in the skeletal muscle sodium channel (SCN4A) gene have been previously reported. Phenotypic variations of mutations in SCN4A, however, have not been described yet. The present study aimed to evaluate genetic variations in a family with clinical and electrophysiological characteristics of paralysis periodica paramyotonia. Seven members of a family affected with symptoms of paralysis periodica paramyotonia were studied by electrophysiological and genetic analyses. There were increased serum potassium concentrations in four members during paralytic attacks induced by hyperkalaemic periodic paralysis provocation tests. Short exercise tests before and after cold immersion were carried out in four patients to distinguish electrophysiological characteristics of hyperkalaemic periodic paralysis and paramyotonia. Sequencing analyses of SCN4A were performed on one patient and a normal control to identify polymorphisms. Restriction fragment length polymorphism (RFLP) analysis was then performed at the identified polymorphic sites. Electrophysiological studies showed both exercise sensitivity and temperature sensitivity. Compound motor action potential (CMAP) amplitudes were decreased (7.3%-28.6%) after short exercise tests. The CMAP amplitudes were even more severely decreased (21.7%-56.5%) in short exercise tests after cold exposure. Three polymorphic sites, Gln371Glu, Thr704Met, and Aspl376Asn were identified in SCN4A. RFLP analyses showed that all affected patients carried the Thr704Met mutation, whereas unaffected family members and a normal control did not. Phenotypic variation of the Thr704Met mutation, which was previously reported in patients with hyperkalaemic periodic paralysis, is described in a family affected with paralysis periodica paramyotonia.


Conditional knockout of the androgen receptor in gonadotropes reveals crucial roles for androgen in gonadotropin synthesis and surge in female mice.
Polycystic ovary syndrome is the major cause of infertility in reproductive aged women. Polycystic ovary syndrome is associated with high circulating levels of androgens and impaired metabolic function. The goal of this study was to understand how androgen signaling via the androgen receptor (AR) affects reproductive function. We knocked out the AR gene specifically in pituitary gonadotropes (PitARKO) to explore the role of androgen on the development of reproductive function in female mice. There was no difference in the age of puberty between control and PitARKO littermates, which was assessed by the ages of vaginal opening and first estrus. Cyclicity and fertility were also studied, and there was no significant difference between control and PitARKO mice. We observed a significant decrease in basal FSH serum and mRNA levels with no corresponding change in LH serum and mRNA levels. Although the numbers of litters born to control and PitARKO females were the same, the litter size was significantly smaller for PitARKO mice. The LH and FSH responses to ovariectomy was altered with reduced LH/FSH hormone and mRNA levels in PitARKO females. This reduction may be due to reduced expression of activin A/B and gnrhr. The preovulatory surge levels of LH and FSH were dramatically lower in PitARKO mice. The number of corpora lutea was decreased whereas the number of antral follicles was similar between control and PitARKO mice. Overall the pituitary AR contributes to the elaboration of the LH surge and normal reproductive function by regulating LH/FSH expression and secretion.


Biostatistics Faculty and NIH Awards at U.S. Medical Schools.
Statistical principles and methods are critical to the success of biomedical and translational research. However, it is difficult to track and evaluate the monetary value of a biostatistician to a medical school (SoM). Limited published data on this topic is available, especially comparing across SoMs. Using National Institutes of Health (NIH) awards and American Association of Medical Colleges (AAMC) faculty counts data (2010-2013), together with online information on biostatistics faculty from 119 institutions across the country, we demonstrated that the number of biostatistics faculty was significantly positively associated with the amount of NIH awards, both as a school total and on a per faculty basis, across various sizes of U.S. SoMs. Biostatisticians, as a profession, need to be proactive in communicating and advocating the value of their work and their unique contribution to the long-term success of a biomedical research enterprise.


A probabilistic analysis of a simplified biogeography-based optimization algorithm.
Biogeography-based optimization (BBO) is a population-based evolutionary algorithm (EA) that is based on the mathematics of biogeography. Biogeography is the study of the geographical distribution of biological organisms. We present a simplified version of BBO and perform an approximate analysis of the BBO population using probability theory. Our analysis provides approximate values for the expected number of generations before the population's best solution improves, and the expected amount of improvement. These expected values are functions of the population size. We quantify three behaviors as the population size increases: first, we see that the best solution in the initial randomly generated population improves; second, we see that the expected number of generations before improvement increases; and third, we see that the expected amount of improvement decreases.


The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin.
Skin cancer, the most common cancer in the general population, is strongly associated with exposure to the ultraviolet component of sunlight. To investigate the relationship between DNA damage processing and skin tumour development, we determined the POLH status of a cohort of skin cancer patients. The human POLH gene encodes DNA polymerase eta (poleta), which normally carries out accurate translesion synthesis past the major UV-induced photoproduct, the dithymine cyclobutane dimer. In the absence of active poleta in xeroderma pigmentosum variant (XPV) patients, mutations accumulate at sites of UV-induced DNA damage, providing the initiating step in skin carcinogenesis. Forty patients diagnosed with skin cancer were genotyped for polymorphisms in the POLH protein-coding sequence, using glycosylase-mediated polymorphism detection (GMPD) and direct DNA sequencing of POLH PCR products derived from white blood cell genomic DNA. All individuals carried the wild-type POLH sequence. No POLH mutations were identified in genomic DNA from skin tumours derived from 15 of these patients. As determined by RT-PCR, POLH mRNA was expressed in all normal and skin tumour tissue examined. Poleta protein was also detectable by Western blotting, in two matched normal and skin tumour extracts. An alternatively spliced form of POLH mRNA, lacking exon 2, was more readily detected in skin tissue than in white blood cells from the same patient. Real-time PCR was used to quantify POLH expression in matched normal and skin tumour-derived mRNA from a series of patients diagnosed with either basal or squamous cell carcinoma. Compared to matched normal skin tissue from the same patient, 1 of 7 SCC, and 4 of 10 BCC tumours examined showed at least a 2-fold reduction in POLH expression, while 1 of 7 SCC, and 3 of 10 BCC tumours showed at least a 2-fold increase in POLH expression. Differences in gene expression, rather than sequence changes may be the main mechanism by which POLH status varies between normal and skin tumours in the population under investigation. Knowledge of the POLH status in skin tumours could contribute to an understanding of the role of this gene in the development of the most common cancer in the general population.


Prevalence of sleep apnea in morbidly obese patients who presented for weight loss surgery evaluation: more evidence for routine screening for obstructive sleep apnea before weight loss surgery.
The incidence of obstructive sleep apnea has been underestimated in morbidly obese patients who present for evaluation for weight loss surgery. This retrospective study shows that the incidence of obstructive sleep apnea in this patient population is greater than 70 per cent and increases in incidence as the body mass index increases. Obstructive sleep apnea (OSA) is a common comorbidity in obese patients who present for evaluation for gastric bypass surgery. The incidence of sleep apnea in obese patients has been reported to be as high as 40 per cent. A retrospective review of our prospectively collected database was performed. All patients being evaluated for weight loss surgery for obesity were screened preoperatively for OSA using a sleep study. The overall incidence of sleep apnea in our patients was 78 per cent (227 of 290). All 227 were diagnosed by formal sleep study. There were 63 (22%) males and 227 (78%) females. The mean age was 43 years (range, 17-75 years). The mean body mass index (BMI) was 52 kg/m2 (range, 31-94 kg/m2). The prevalence of OSA in the severely obese group (BMI 35-39.9 kg/m2) was 71 per cent. For the morbidly obese group (BMI 40-40.9 kg/m2), the prevalence was 74 per cent and for the superobese group (BMI 50-59.9 kg/m2) 77 per cent. Those with a BMI 60 kg/m2 or greater, the prevalence of OSA rose to 95 per cent. The incidence of sleep apnea in patients presenting for weight loss surgery was greater than 70 per cent in our study. Patients presenting for weight loss surgery should undergo a formal sleep study to diagnose OSA before bariatric surgery.


The yield of UGIE: a study of a ten-year period in the 'Zaanstreek'.
Study of the occurrence of abnormalities in the oesophagus, stomach and duodenum, and of changes in specific diagnoses. All consecutive upper gastrointestinal endoscopies (UGIEs) carried out in a period of ten years were included. In ten years 14,927 diagnostic UGIEs were performed (7335 men (49%) and 7592 women (51%)). These procedures were done at the request of the general practitioner in 4995 (33%) cases. A steady yearly increase in the number of open-access UGIEs was noted. Each year a mean of 796 abnormalities was seen in the oesophagus, a mean of 437 in the stomach, and of 162 in the duodenum. The presence of hiatal hernia and reflux oesophagitis significantly increased in the ten years (p < 0.001). The numbers of Barrett's oesophagus and oesophageal cancer remained constant. Gastritis showed a gradual increase (p < 0.001), while the number of gastric ulcers found per year decreased significantly in the ten-year period (p < 0.001). Gastric malignancy remained constant. Presence of duodenal ulcers and bulbitis significantly decreased (p = 0.01 and p = 0.06, respectively). The number of UGIEs carried out at the request of the general practitioner has significantly increased. Peptic ulcer disease shows a significant decrease, while reflux disease increases.


Qualitative proteomic comparison of metabolic and CM-like protein fractions in old and modern wheat Italian genotypes by a shotgun approach.
The close relationship between diet and health is generally recognized and the growing wellness and consciousness, especially in developed countries, have led to increasing interest for old wheat genotypes, based on perceived health benefits. Although nutritional comparison between old and modern wheat varieties is still controversial, it is generally accepted that old wheat genotypes remained unchanged over the last hundred years. By contrast, modern wheat genotypes are derived by modification of old wheats during the so-called "Green-Revolution" in the second half of the 20th century focusing on obtaining properties in terms of higher grain yield. The present work reports the first comprehensive proteomic profiling and qualitative comparison at the molecular level of metabolic and Chloroform-Methanol (CM)-like protein fractions extracted from mature kernels of two old Sicilian durum wheat landraces, Russello and Timilia Reste Bianche, and Simeto, an improved durum wheat variety widespread in Italy and other Mediterranean countries and chosen as representative of the most widely commercial cultivars. The results obtained reveal that metabolic and CM-like protein fractions of old and modern genotypes present remarkably high similarity with only minor differences. This leads to the conclusion that from a food and nutritional perspective there is a substantial equivalence of the protein composition of the old and modern cultivars. Data are available via ProteomeXchange with identifier PXD014449. BIOLOGICAL SIGNIFICANCE: In recent years consumers have shown growing interest in the old wheat genotypes, which are generally perceived more "natural" and healthier than modern ones. However, comparison of nutritional value for modern and old wheat varieties is still controversial suggesting further studies. In particular proteome analysis of old and modern wheat genotypes is currently ongoing with particular focus on gluten proteins, whereas the metabolic protein fraction has not yet been investigated. In the present study, we conducted a comprehensive proteomic profile and qualitative comparison at the molecular level of metabolic and Chloroform-Methanol (CM)-like protein fractions of the old Sicilian landraces Russello and Timilia Reste Bianche and the modern cultivar Simeto by applying a shotgun approach. The results reveal that the metabolic and CM-like protein fractions of old and modern genotypes are remarkably similar with only minor differences, leading to the conclusion that from a food and nutritional perspective there is a substantial equivalence of these cultivars. These results may contribute to improved understanding of the relationship between protein profiles of old wheat genotypes and their potential benefits for human consumption.


Racial and Ethnic Differences in Initiation and Discontinuation of Antidementia Drugs by Medicare Beneficiaries.
To examine racial and ethnic differences in initiation and time to discontinuation of antidementia medication in Medicare beneficiaries. Retrospective cohort study. Secondary analysis of 2009-10 enrollment, claims, and Part D prescription data for a 10% national sample of U.S. Medicare fee-for-service beneficiaries. Beneficiaries aged 65 and older with Alzheimer's disease or related dementia (ADRD) before 2009 and no fills for antidementia medications in the first half of 2009 (N = 84,043). Initiation was defined as having one or more fills for antidementia medication in the second half of 2009 and discontinuation as a gap in coverage of 30 days or more during the year after initiation. The Andersen Behavioral Model was used to guide covariate selection. Overall, 3,481 (4.1%) of previous nonusers initiated antidementia medication in the second half of 2009. Of those initiating one drug class (acetylcholinesterase inhibitors (AChEIs) or memantine), 9% later added the other class, and 2% switched classes. Of initiators, 23% discontinued within 1 month, and 62% discontinued within 1 year. Hispanic beneficiaries were more likely than white beneficiaries to initiate (adjusted odds ratio = 1.25, 95% confidence interval (CI) = 1.10-1.41). Black and white beneficiaries did not differ in likelihood of initiation. Hispanic (adjusted hazard ratio (aHR) = 1.56, 95% CI = 1.34-1.82) and black (aHR = 1.25, 95% CI = 1.08-1.44) beneficiaries discontinued at a faster rate than white beneficiaries. Initiation of antidementia medications was no different in black and white beneficiaries and more likely in Hispanic beneficiaries; black and Hispanic beneficiaries discontinued at a faster rate. More research into reasons explaining these differences is needed.


Controlled cord traction for the third stage of labour.
Active management of the third stage of labour (AMTSL) consists of a group of interventions, including administration of a prophylactic uterotonic (at at or after delivery of the baby), baby, cord clamping and cutting, controlled cord traction (CCT) to deliver the placenta, and uterine massage. Recent recommendations are to delay cord clamping until the caregiver is ready to initiate CCT. The package of AMTSL reduces the risk of postpartum haemorrhage, (PPH), as does one component, routine use of uterotonics. The contribution, if any, of CCT needs to be quantified, as it is uncomfortable, and women may prefer a 'hands-off' approach. In addition its implementation has resource implications in terms of training of healthcare providers. To evaluate the effects of controlled cord traction during the third stage of labour, either with or without conventional active management. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (29 January 2014), PubMed (1966 to 29 January 2014), and reference lists of retrieved studies. Randomised controlled trials comparing planned CCT versus no planned CCT in women giving birth vaginally. Two authors assessed trial quality and extracted data using a standard data extraction form. We included three methodologically sound trials with data on 199, 4058 and 23,616 women respectively. Blinding was not possible, but bias could be limited by the fact that blood loss was measured objectively.There was no difference in the risk of blood loss ≥ 1000 mL (three trials, 27,454 women; risk ratio (RR) 0.91, 95% confidence interval (CI) 0.77 to 1.08). Manual removal of the placenta was reduced with CCT (two trials, 27,665 women; RR 0.69, 95% CI 0.57 to 0.83). In the World Health Organization (WHO) trial the reduction in manual removal occurred mainly in sites where ergometrine was used routinely in the third stage of labour. The non-prespecified analysis excluding sites routinely using ergometrine for management of the third stage of labour found no difference in the risk of manual removal of the placenta in the WHO trial (one trial, 23,010 women; RR 1.03, 95% CI 0.73 to 1.46). The policy of restricting the third stage of labour to 30 minutes (4057 women; RR 0.69, 95% CI 0.53 to 0.90) may have had an effect in the French study.Among the secondary outcomes, there were reductions in blood loss ≥ 500 mL (three trials, 27,454 women; RR 0.93, 95% CI 0.88 to 0.99), mean blood loss (two trials, 27,255 women; mean difference (MD) -10.85 mL, 95% CI -16.73 to -4.98), and duration of the third stage of labour (two trials, 27,360 women; standardised MD -0.57, -0.59 to -0.54). There were no clear differences in use of additional uterotonics (three trials, 27,829 women; average RR 0.95, 95% CI 0.88 to 1.02), blood transfusion, maternal death/severe morbidity, operative procedures nor maternal satisfaction. Maternal pain (non-prespecified) was reduced in one trial (3760 women; RR 0.78, 95% CI 0.61 to 0.99).The following secondary outcomes were not reported upon in any of the trials: retained placenta for more than 60 minutes or as defined by trial author; maternal haemoglobin less than 9 g/dL at 24 to 48 hours post-delivery or blood transfusion; organ failure; intensive care unit admission; caregiver satisfaction; cost-effectiveness; evacuation of retained products; or infection. CCT has the advantage of reducing the risk of manual removal of the placenta in some circumstances, and evidence suggests that CCT can be routinely offered during the third stage of labour, provided the birth attendant has the necessary skills. CCT should remain a core competence of skilled birth attendants. However, the limited benefits of CCT in terms of severe PPH would not justify the major investment which would be needed to provide training in CCT skills for birth attendants who do not have formal training. Women who prefer a less interventional approach to management of the third stage of labour can be reassured that when a uterotonic agent is used, routine use of CCT can be omitted from the 'active management' package without increased risk of severe PPH, but that the risk of manual removal of the placenta may be increased.Research gaps include the use of CCT in the absence of a uterotonic, and the place of uterine massage in the management of the third stage of labour.


A phase II randomized study of vinorelbine alone or with cisplatin against chemo-naïve inoperable non-small cell lung cancer in the elderly.
Our aim here was to determine whether or not the addition of cisplatin into vinorelbine (V) treatment is an appropriate regimen for physically fit chemo-naïve non-small cell lung cancer (NSCLC) patients aged 70 or older. Patients were randomized into vinorelbine (V) or vinorelbine plus cisplatin (VP) treatment arms. Treatment consisted of vinorelbine 25 mg/m(2) intravenous infusion (i.v.) on days 1 and 8 every 3 weeks (V arm), or vinorelbine 22.5 mg/m(2) i.v. on days 1 and 8 plus cisplatin 50 mg/m(2) i.v. on day 1 every 3 weeks (VP arm). Sixty-five patients were enrolled from May 2005 to December 2006, including 31 who received V treatment and 34 who received VP treatment. Objective response rates were 16.1% in V and 32.4% in VP (p=0.009). Control rates were 51.6% in V and 82.4% in VP (p=0.008). Myelosuppression was more common and severe in the VP arm. Any grade of anemia and neutropenia was significantly higher in the VP arm (p=0.001 and 0.009, respectively). Fatigue sensation was more common and severe in the VP arm (p=0.032). Median time to disease progression was 3.1 months in the V arm and 5.2 months in the VP arm (p=0.0303). The 1-year survival rate was 50.9% in the V arm and 47.2% in the VP arm. Adding cisplatin to vinorelbine treatment is feasible in elderly patients, and has a better response rate and longer median time to disease progression. However, both statistically significantly higher toxicity and no survival advantage for the combination treatment was observed.


Pseudomonas osteomyelitis of the proximal humerus after arthroscopic rotator cuff repair.
A 59-year-old male patient was operated arthroscopically due to a rotator cuff tear. An early postoperative Pseudomonas aeruginosa infection was treated with early arthroscopic debridement and antibiotic therapy. The patient was lost to follow-up and presented to our clinic with Pseudomonas aeruginosa osteomyelitis after two years. Debridement was again performed and antibiotic-impregnated cement beads were filled into the cavity and taken out 6 weeks postoperatively. No findings of infection were observed at the patient's 2nd year follow-up. To our knowledge, this is the first case of Pseudomonas aeruginosa osteomyelitis of the shoulder after arthroscopic rotator cuff repair.


Evaluation of live avian-human reassortant influenza A H3N2 and H1N1 virus vaccines in seronegative adult volunteers.
An avian-human reassortant influenza A virus deriving its genes coding for the hemagglutinin and neuraminidase from the human influenza A/Washington/897/80 (H3N2) virus and its six "internal" genes from the avian influenza A/Mallard/NY/6750/78 (H2N2) virus (i.e., a six-gene reassortant) was previously shown to be safe, infectious, nontransmissible, and immunogenic as a live virus vaccine in adult humans. Two additional six-gene avian-human reassortant influenza viruses derived from the mating of wild-type human influenza A/California/10/78 (H1N1) and A/Korea/1/82 (H3N2) viruses with the avian influenza A/Mallard/NY/78 virus were evaluated in seronegative (hemagglutination inhibition titer, less than or equal to 1:8) adult volunteers for safety, infectivity, and immunogenicity to determine whether human influenza A viruses can be reproducibly attenuated by the transfer of the six internal genes of the avian influenza A/Mallard/NY/78 virus. The 50% human infectious dose was 10(4.9) 50% tissue culture infectious doses for the H1N1 reassortant virus and 10(5.4) 50% tissue culture infectious doses for the H3N2 reassortant virus. Both reassortants were satisfactorily attenuated with only 5% (H1N1) and 2% (H3N2) of infected vaccines receiving less than 400 50% human infectious doses developing illness. Consistent with this level of attenuation, the magnitude of viral shedding after inoculation was reduced 100-fold (H1N1) to 10,000-fold (H3N2) compared with that produced by wild-type virus. The duration of virus shedding by vaccines was one-third that of controls receiving wild-type virus. At 40 to 100 50% human infectious doses, virus-specific immune responses were seen in 77 to 93% of volunteers. When vaccinees who has received 10(7.5) 50% tissue culture infectious doses of the H3N2 vaccine were experimentally challenged with a homologous wild-type human virus only 2 of 19 (11%) vaccinees became ill compared with 7 of 14 (50%) unvaccinated seronegative controls ( P < 0.025; protective efficacy, 79%). Thus, three different virulent human influenza A viruses have been satisfactorily attenuated by the acquisition of the six internal genes of the avian influenza A/Mallard/NY/78 virus. The observation that this donor virus can reproducibly attenuate human influenza A viruses indicates that avian-human influenza A reassortants should be further studied as potential live influenza A virus vaccines.


Are "social drugs" (tobacco, coffee and chocolate) related to the bipolar spectrum?
Across all ages and cultures, mankind has always used substances in order to induce pleasurable sensations or desirable psychophysical states. These substances, notably caffeine, tobacco, alcohol and chocolate, can be labeled 'social drugs'. We analyzed the social drug habits of 562 patients suffering from mood disorders, according to DSM-IV-R criteria (major depressive episode, recurrent depression, bipolar type I and II disorders and depression not otherwise specified). The sample was also divided into bipolar and non-bipolar according to Hypomania Check-list 32 (HCL-32), which proposes a broader concept of hypomania and soft bipolarity, comprising the spectrum of bipolar disorders proper, along with other, "softer" expressions of bipolarity intermediate between bipolar disorder and normality. Using HCL-32 criteria, but DSM-IV-R criteria, a link was confirmed between bipolar spectrum and substance use including social drugs such as tobacco and coffee. Observational correlational study. This study is in support of earlier theoretical formulations within the framework of the Pisa-San Diego collaboration.


Risk-based learning games improve long-term retention of information among school pupils.
Risk heightens motivation and, if used appropriately, may have the potential to improve engagement in the classroom. We have developed a risk-based learning game for school pupils in order to test whether such learning games can improve later recall of information. The study was performed during a series of public engagement workshops delivered by undergraduate students. Undergraduate neuroscience students delivered 90-minute science workshops to 9-10 year old school pupils (n = 448) that were divided into 'Risk', 'No risk' and 'Control' classes. 'Risk' classes received periodic multiple-choice questions (MCQs) during the workshops which required small teams of pupils to assign tokens to the answer(s) they believed to be correct. Tokens assigned to the correct answer were returned to the group and an equal number given back as a prize; tokens assigned to incorrect answers were lost. Participation was incentivised by the promise of a brain-related prize to the team with the most tokens at the end of the workshop. 'No risk' classes received MCQs without the risk component whilst the 'Control' classes received no MCQs. When presented with a neuroscience quiz based on workshop content at the end of the workshop, pupils in the 'Risk' classes exhibited significantly greater recall of information one week later. Quiz scores were higher than scores from the day of the workshop which suggested pupils may have discussed the workshop content outside of the classroom, thereby increasing knowledge over and above what was learned during the workshop. This is supported by feedback from pupils in 'Risk' classes which indicated that 'Risk' workshops were more interesting than 'No risk' and 'Control' workshops. These data suggest that there is a role for risk in the classroom but further investigations are required to elucidate the causal mechanisms of improved retention of information.


[Prodigiozan modulation of the specific activity of antidepressants].
The experiments carried out on mongrel male mice showed that bacterial lipopolysaccharide Prodigiozan inhibit the activity of P-450-dependent monooxygenases of the liver, thus changing the activity of antidepressants--amitriptyline and imipraminum. The data on biological activity were tested in "tail suspension" test. Prodigiozan exhibited no central effect. Changes in biotransformation processes after single administration of both drugs resulted in the delay and prolongation of the effect. Prodigiozan prevents the induction of microsomal enzymes caused by antidepressants. Amitriptyline do not affect the immunostimulating action of prodigiozan, whereas imipraminum inhibited prodigiozan activity.


FCN-A mediates the inflammatory response and the macrophage polarization in Aspergillus fumigatus keratitis of mice by activating the MAPK signaling pathway.
Fungal keratitis (FK) is a severe corneal disease that may cause vision loss. Previous studies indicate that the innate immune response produces the most effective anti-Aspergillus immune resistance. Ficolin-A (FCN-A), a soluble pattern-recognition receptor (PRR) family plays an important role in the innate immunity. In this study, we aimed to study the role of FCN-A in the A. fumigatus infected cornea. Here for the first time, we reported that the expression of FCN-A increases after A. fumigatus infection in the cornea of mice. Then, our results showed that the down-regulation of FCN-A reduced the inflammatory response of the cornea infected mice and decreased the expression of the TNF-a, p-p38, p-JNK. We also found that FCN-A can affect the recruitment of macrophages in the cornea of mice with A. fumigatus keratitis. In the mouse model of A. fumigatus keratitis and the A. fumigatus stimulation of RAW 264.7 cells, knocking down of FCN-A expression promoted the macrophage polarization toward M2. Furthermore, we observed that both the p38 and JNK inhibitors pretreatment decreased the proportion of M1/M2 in RAW 264.7 cells. Taken together, our data provide evidence that FCN-A participated in the inflammatory response of A. fumigatus keratitis in mice. Moreover, FCN-A mediates the inflammatory response and the polarization of the macrophages by activating the MAPK signaling pathway in A. fumigatus keratitis.


Opportunistic deep cutaneous mycoses in solid organ transplant recipients.
Invasive fungal infections are a major cause of morbidity and mortality among organ transplant recipients, despite many progresses concerning diagnosis, preventions and treatment. Risk factors for invasive fungal infections in transplanted recipients include type and severity of immunosuppression, especially in life-saving organs as lung or liver, older age at transplantation, and technical complexity of surgery, living in endemic areas or exposure to a contaminated environment. Superficial fungal infections are caused by Candida, Dermatophytes, and Malassezia. In invasive mycoses, skin lesions may occur as a consequence of the systemic dissemination of invasive mycoses, or after direct inoculation in the skin. Aspergillosis, cryptococcosis, Zygomycoses, dark mould infections, fusariosis and infections attributable to Scedosporium and Pseudallescheria species are the most common etiological agents. Cutaneous manifestations of fungal infection are not specific, and a high degree of suspicion is required, and prompt biopsy for histology and culture is needed. Therapy with lyposomal amphotericin B and new triazoles are effective.


Long-Term Follow-Up in Active Transcutaneous Bone Conduction Implants.
To evaluate long-term outcomes of active transcutaneous bone conduction implants (atBCIs) regarding safety, hearing, and quality of life. A clinical study with retrospective medical record analysis combined with prospective audiometry and quality of life questionnaires. Three secondary to tertiary care hospitals. All subjects operated with an atBCI in three regions in Sweden were asked for informed consent. Indications for atBCI were single-sided deafness (SSD) and conductive or mixed hearing loss (CMHL). Evaluation of atBCI. Pure tone and speech audiometry and Glasgow Benefit Inventory (GBI). Thirty-three subjects were included and 29 completed all parts. The total follow-up time was 124.1 subject-years. Nineteen subjects had CMHL and in this group, pure tone averages (PTA4) were 56.6 dB HL unaided and 29.6 dB HL aided, comparable with a functional gain of 26.0 dB. Effective gain (EG) was -12.7 dB. With bilateral hearing, Word Recognition Scores (WRS) in noise were 36.5% unaided and 59.1% aided. Fourteen subjects had SSD or asymmetric hearing loss (AHL) and in this group, PTA4 were >100 dB HL unaided and 32.1 dB HL aided with the contralateral ear blocked. EG was -9.1 dB. With bilateral hearing, WRSs were 53.2% unaided and 67.9% aided. The means of the total GBI scores were 31.7 for CMHL and 23.6 for SSD/AHL. Few complications occurred during the study. The atBCI is concluded to provide a safe and effective long-term hearing rehabilitation.


Anti-inflammatory and anti-oxidant role of ursolic acid in cerulein-induced acute pancreatitis in rats.
Ursolic acid (UA) is found in many plants, and has been reported to have anti-protease, antioxidant, anti-inflammatory, antimicrobial, nephroprotective, hepatoprotective, and cardioprotective effects. The purpose of this study was to investigate the effects of ursolic acid in cerulein-induced acute pancreatitis (AP). Thirty-two Wistar albino rats were randomly assigned to 4 equal groups: Sham, acute pancreatitis, treatment, and ursolic acid group. Serum amylase levels in the AP and treatment groups were significantly higher than in the others (p < 0.05). In addition, serum IL-1β, IL-6, and TNF-α levels were significantly higher in the AP group in comparison with the treatment group. Although pancreatic tissue total oxidant activity in the AP and treatment groups was similar, pancreatic tissue total antioxidant capacity was significantly higher in the treatment group than in the AP group. Damage to the pancreas and remote organs in AP was observed to be reduced by UA. In addition, oxidative stress was observed to be decreased by the effect of UA.


Optical imaging through scattering media via magnetically modulated fluorescence.
A weak (< 1000 G) magnetic field can influence photochemical processes through its effect on electron spin dynamics in a photogenerated radical pair. In a solution of pyrene and dimethylaniline this effect manifests as magnetic field-dependent exciplex fluorescence. Here we describe magnetofluorescence imaging (MFI). A localized magnetic null defines a fluorescence detection volume, which is scanned through a sample to create an image. MFI forms an image without lenses and in the presence of arbitrarily strong optical scattering. The resolution of MFI is in principle not limited by optical diffraction, although the present implementation is far from the diffraction limit.


Effects of a glucose meal on human pulmonary function at 1600-m and 4300-m altitudes.
The effects of a high-glucose meal on pulmonary function were observed in seven healthy males at medium (1,600 m) and high (4,300 m) altitude. Thirty minutes after the ingestion of 410 kcal (109.9 g cerelose) of glucose, peak serum glucose values were noted with a subsequent decrease over 3 h to below fasting levels at both elevations. At the same time, triglyceride levels continued to decline from 104.2 to 83.3 mg at 1,600 m and 103.7 to 80.5 mg/100 ml at 4,300 m, with differences being significant after 2 h. Both V-E and V-T increased in response to translocation to altitude; however, only V-T increased by 10.9% and 13.3% at 0.5 h for 1,600 m and 4,300 m, respectively. The V-o-2 increased during glucose elevation at 4300 m, while P-A-O2 remained essentially unchanged except for differences associated with translocation to altitude. A 13.9% increase was noted in D-L-CO followign glucose ingestion at 4,300 m along with a decreased triglyceride levels. The elevated D-L-CO values suggest an increase in gas exchange at the alveolar-capillary (A-c) level following the ingestion of a glucose meal for individuals transported to high altitude.


Effect of Conventional Lifestyle Interventions on Type 2 Diabetes Incidence by Glucose-Defined Prediabetes Phenotype: An Individual Participant Data Meta-analysis of Randomized Controlled Trials.
To examine whether the effect of conventional lifestyle interventions on type 2 diabetes incidence differs by glucose-defined prediabetes phenotype. We searched multiple databases until 1 April 2023 for randomized controlled trials that recruited people with isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), and impaired fasting glucose plus impaired glucose tolerance (IFG+IGT). Individual participant data were pooled from relevant trials and analyzed through random-effects models with use of the within-trial interactions approach. Four trials with 2,794 participants (mean age 53.0 years, 60.7% men) were included: 1,240 (44.4%), 796 (28.5%), and 758 (27.1%) had i-IFG, i-IGT, and IFG+IGT, respectively. After a median of 2.5 years, the pooled hazard ratio for diabetes incidence in i-IFG was 0.97 (95% CI 0.66, 1.44), i-IGT 0.65 (0.44, 0.96), and IFG+IGT 0.51 (0.38, 0.68; Pinteraction = 0.01). Conventional lifestyle interventions reduced diabetes incidence in people with IGT (with or without IFG) but not in those with i-IFG.


Joint diseases and matrix metalloproteinases: a role for MMP-13.
The role of matrix metalloproteinases in disease has been investigated over the last two decades. A focus on this family of proteases is particularly emphasized in two major arthritides in humans, osteoarthritis and rheumatoid arthritis. Early work described the presence of multiple MMP family members in the joint of the disease state and recent advances in the development of new knockout mice and disease models have allowed investigators to directly test the role of the MMP proteases in arthritis. MMP-13 is expressed by chondrocytes and synovial cells in human OA and RA and is thought to play a critical role in cartilage destruction. The recent development of an MMP-13 knockout mouse has documented the important role for this enzyme in cartilage formation and further studies under disease conditions promise to reveal the function of this enzyme in disease pathology. This review describes a body of research that supports the development of novel selective MMP-13 inhibitors with the hope of developing these compounds in clinical trials for the treatment of arthritis.


The pattern of early cleavage of the marsupial frog Gastrotheca riobambae.
Comparison of early development of the marsupial frog Gastrotheca riobambae with Xenopus laevis suggests that the cleavage pattern of Xenopus and the tight coupling of events at the midblastula transition are features of the accelerated development of small amphibian eggs with aquatic reproduction, rather than generalized features of amphibian development. The large eggs of the marsupial frog Gastrotheca riobambae not only display an atypical holoblastic pattern of cleavage and a very slow rate of development, but the events of the midblastula transition are uncoupled, suggesting that amphibians may have a diversity of developmental patterns. Early cleavage of the egg, which measures about 3 mm in diameter, occurs mostly by meridional and vertical furrows. The first cleavage cycle takes about 16 to 20 h and about four days may be required to reach the midblastula stage. Cleavage becomes asynchronous at about the third cleavage cycle evidenced by the formation of cleavage furrows. However, during cleavage (up to 342-cells), the majority of the nuclei divide synchronously and only 15 to 40% of the nuclei of a given embryo have a different cleavage schedule. At the 8-cell stage, nucleoli become visible (approximately 24 h after amplexus), signaling that transcription of rRNA has started at this early stage. Cell motility was detected in three- to four-day old embryos and seems to be associated with changes in cell shape and with expansion of the blastocoel at this stage.


[Clinico-epidemiologic characteristics of a contingent of chronic schizophrenic patients of the "new type"].
Using clinico-epidemiological research methods, the authors have studied 260 schizophrenic patients in whom the disease was first manifested in the period when wide-scale combined rehabilitation programmes were under way. It has been demonstrated that the incidence of chronic schizophrenia shows no tendency to decrease despite the use of modern rehabilitation methods. Chronicity itself has become more variable in its manifestations; thus the population of "chronics" is mostly made up of young people. An analysis of the time-course of invalidization of schizophrenic patients in the first four years of the disease has indicated a clear-cut peak at the second year after the manifestation of the process. The findings obtained made it possible to describe a number of parameters of functioning of "chronic patients of a new type". It has been shown that these patients are young and characterized by a comparatively short duration of the disease, frequent rehospitalization, marked manifestations of social disadaptation in the presence of externally normal behaviour due to rapid incapsulation of the current symptomatology, formally intact familial ties and a high frequency of abnormal behavioural manifestations.


Decorating graphene nanosheets with electron accepting pyridyl-phthalocyanines.
We describe herein the preparation of novel exfoliated graphene-phthalocyanine nanohybrids, and the investigation of their photophysical properties. Pyridyl-phthalocyanines (Pcs) are presented as novel electron accepting building blocks of variable strengths with great potential for the exfoliation of graphite via their immobilization onto the basal plane of graphene in dimethylformamide (DMF) affording single layered and turbostratic graphene based . were fully characterized (AFM, TEM, Raman, steady-state and pump probe transient absorption spectroscopy) and were studied in terms of electron donor-acceptor interactions in the ground and excited states. In this context, electron transfer upon photoexcitation from graphene to the electron accepting Pcs with dynamics, for example, in of <1 and 330 ± 50 ps for charge separation and charge recombination, respectively, was corroborated in a series of steady-state and time-resolved spectroscopy experiments.


Molecular Serotyping and Antibiotic Resistance Profile of Group B Streptococcus Strains Isolated from Iranian Pregnant Women with Urinary Tract Infection.
Group B Streptococcus (GBS) can cause serious infections in neonates and pregnant women. GBS may cause urinary tract infections (UTIs). However, molecular epidemiology of such infections is rarely reported. The present study aimed to determine drug resistance patterns and molecular serotyping of GBS isolates in a population of pregnant Iranian women with UTIs. A cross-sectional study was conducted during the first half of 2021 in the Department of Biology, East Tehran Branch, Islamic Azad University (Tehran, Iran). Sixty GBS strains isolated from the urine and placenta samples of pregnant women with UTIs were evaluated. The women were aged 19-46 years old at 35 to 37 weeks of gestation. The molecular serotype of GBS isolates was determined using a multiplex polymerase chain reaction, and the disc diffusion method was used to determine the antibiotic susceptibility pattern of isolates for different antibiotics. The association of the GBS serotype with the phenotype of antibiotic resistance was statistically analyzed using SPSS software (version 22.0) with a Chi square test and Cramer's V test. P<0.05 was considered statistically significant. GBS capsular serotype II was most prevalent (66.7%) followed by serotypes Ib (21.7%), Ia (3.3%), and III (1.7%). The prevalence of non-typeable isolates was significantly low (6.6%). Of the 60 GBS isolates, 18.3% were resistant to penicillin, 81.6% to ampicillin, 23.3% to clindamycin, and 30% to vancomycin; indicating the need for treatment alternatives. Region-specific information on antibiotic resistance and molecular characteristics of GBS is essential for epidemiological investigations, effective treatment, and vaccine development.


Executive function performance and change in aging is predicted by apolipoprotein E, intensified by catechol-O-methyltransferase and brain-derived neurotrophic factor, and moderated by age and lifestyle.
Recent studies have reported several genetic, health, and aging interaction effects in predicting cognitive performance and change. We used an accelerated longitudinal design to examine interactions among genetic, lifestyle, and aging for executive function (EF) in non-demented older adults (n = 634; age range = 53-95 years). The polymorphisms were apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). We tested (1) independent and additive effects of APOE, COMT, and BDNF and (2) APOE effect modification for COMT + BDNF, on EF performance and 9-year change as separated by age and lifestyle activities. First, APOE ε4+ carriers had poorer EF performance and steeper 9-year decline. Second, APOE ε4+ carriers with (1) BDNF Met/Met genotype and (2) increasing allelic risk in the COMT + BDNF risk panel had poorer EF performance; these effects were moderated by lifestyle activities (composite of everyday social, physical, and cognitive activities). Examining APOE effect modification for COMT + BDNF risk panel effects with other moderating factors may help identify complex neurobiological and genetic underpinnings of polygenic phenotypes such as EF in aging.


Birth-cohort trends in rates of major depressive disorder among relatives of patients with affective disorder.
As part of the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression Clinical Study, 2,289 relatives of 523 probands with affective disorder were interviewed with the Schedule for Affective Disorders and Schizophrenia and diagnosed for major depressive disorder by the Research Diagnostic Criteria. Data were analyzed using life-table and survival methods. The findings suggest a progressive increase in rates of depression in successive birth cohorts through the 20th century and an earlier age at onset of depression in each birth cohort. A predominance of female depressives was found in all birth cohorts but the magnitude of female-male differences fluctuated over the decades. The existence of these trends is reported to stimulate further research. These findings are discussed in terms of possible gene-environment interactions. However, no conclusive causal inferences can be drawn pending further investigation.


[Industrially produced eubiotics as materials for isolation and study of DNA].
The optimum and available methods for the isolation of DNA from bacteria, used as the basis of the industrial manufacture of eubiotics (colibacterin, lactobacterin, biobactone) have been developed. The proposed approach makes it possible to isolate DNA, suitable for genosystematic studies under laboratory conditions, directly from producer strains.


Use of history science methods in exposure assessment for occupational health studies.
To show the power of history science methods for exposure assessment in occupational health studies, using the dry cleaning industry in Denmark around 1970 as the example. Exposure data and other information on exposure status were searched for in unconventional data sources such as the Danish National Archives, the Danish Royal Library, archives of Statistics Denmark, the National Institute of Occupational Health, Denmark, and the Danish Labor Inspection Agency. Individual census forms were retrieved from the Danish National Archives. It was estimated that in total 3267 persons worked in the dry cleaning industry in Denmark in 1970. They typically worked in small shops with an average size of 3.5 persons. Of these, 2645 persons were considered exposed to solvents as they were dry cleaners or worked very close to the dry cleaning process, while 622 persons were office workers, drivers, etc in shops with 10 or more persons. It was estimated that tetrachloroethylene constituted 85% of the dry cleaning solvent used, and that a shop would normally have two machines using 4.6 tons of tetrachloroethylene annually. The history science methods, including retrieval of material from the Danish National Archives and a thorough search in the Royal Library for publications on dry cleaning, turned out to be a very fruitful approach for collection of exposure data on dry cleaning work in Denmark. The history science methods proved to be a useful supplement to the exposure assessment methods normally applied in epidemiological studies.


Morphometry of axon cytoskeleton at internodal regions of rat sciatic nerve during aging.
Nerve endings undergo a lifespan morphofunctional modulation which is reported to be markedly impaired with aging. Neurone structural remodelling is in charge of processes occurring in the nerve cell soma, however the axonal transportation of organelles and molecules by cytoskeletal elements plays a very important role in the morphological rearrangements taking place at peripheral compartments. To assess the involvement of axonal ultrastructure in the reported age-related decline of slow axoplasm flow mechanisms, we carried out a morphometric study of axon cytoskeleton in aging. Female Wistar rats (3, 12 and 30 months of age) were anesthetized and perfused with saline followed by a fixation solution (glutaraldehyde 5% + formalin 2% in 0.1 cacodylate buffer pH 7.4). The excised sciatic nerves were processed according to conventional electron microsopic procedures. Axons sectioned perpendicularly to their longitudinal axis at the internodal region (mean axoplasm area: 18.25-26.5 microm(2)) were sampled by a systematic random procedure. The overall number of neurofilaments (No.Nfs) and microtubules (No.Mts) per total axoplasm area analysed, the numeric density (number/microm(2) of axoplasm area) of neurofilaments (NaNfs) and microtubules (NaMts), the myelin thickness, the number of myelin lamellae and the R proportion [No. Nfs/(No.Nfs + No.Mts)] were the parameters measured by computer-assisted semiautomatic methods. No.Nfs, NaNfs, myelin thickness and the number of myelin lamellae did not change between 12 and 30 months of age, while a significant increase of these parameters was found in a comparison with younger rats. No.Mts and NaMts were significantly increased at 12 vs. 3 as well as at 30 vs. 12 months of age, respectively. R proportion did not show any difference due to age. The present findings support that the dynamic condition of the axonal cytoskeleton appears to be preserved at a high extent in aging. Thus, the intra-axonal defective spacing of cytoskeletal elements (e.g. neurofilaments), rather than their number, is proposed to contribute to the decline of the slow axonal transport of organelles and molecules reported in aging.


Mechanism of Dyspnea during Exercise in Children with Corrected Congenital Heart Disease.
This study will evaluate cardiorespiratory and peripheral muscle function and their relationship with subjective dyspnea threshold after the surgical correction of congenital heart disease in children. Thirteen children with surgically repaired congenital heart disease were recruited. Each participant performed an incremental exercise test on a cycle ergometer until exhaustion. Gas exchanges were continuously sampled to measure the maximal aerobic parameters and ventilatory thresholds. The functional capacity of the subjects was assessed with a 6 min walk test. At the end of the exercise test, isokinetic Cybex Norm was used to evaluate the strength and endurance of the knee extensor muscle in the leg. Dyspnea was subjectively scored with a visual analog scale during the last 15 s of each exercise step. Oxygen consumption measured at the dyspnea score/VO2 relationship located at the dyspnea threshold, at which dyspnea suddenly increased. Results: The maximal and submaximal values of the parameters describing the exercise and the peripheral muscular performances were: VO2 Peak: 33.8 ± 8.9 mL·min-1·kg-1; HR: 174 ± 9 b·min-1; VEmax: 65.68 ± 15.9 L·min-1; P max: 117 ± 27 W; maximal voluntary isometric force MVIF: 120.8 ± 41.9 N/m; and time to exhaustion Tlim: 53 ± 21 s. Oxygen consumption measured at the dyspnea threshold was related to VO2 Peak (R2 = 0.74; p < 0.01), Tlim (R2 = 0.78; p < 0.01), and the distance achieved during the 6MWT (R2 = 0.57; p < 0.05). Compared to the theoretical maximal values for the power output, VO2, and HR, the surgical correction did not repair the exercise performance. After the surgical correction of congenital heart disease, exercise performance was impeded by alterations of the cardiorespiratory function and peripheral local factors. A subjective evaluation of the dyspnea threshold is a reliable criterion that allows the prediction of exercise capacity in subjects suffering from congenital heart disease.


Zika virus and pregnant women: A psychological approach.
Zika virus presents risk of physical harm to pregnant women, but the fear of infection is also affecting women around the world. There is a gap in the research on Zika virus in the areas involving the impact on the psychosocial well-being of pregnant women. Therefore, this study is aimed at the investigation of the psychosocial adjustment of pregnant women to the risks of Zika virus infection during pregnancy. We investigated 14 pregnant women who were classified in three different groups: six in the first trimester, five in the second trimester and three in the third trimester, aged from 28 to 40 years (33.43 ± 3.76 years). Content analysis was used to interpret data. Our results show that the psychosocial adjustment of participants was significantly negative and included five aspects: (1) negative feelings, (2) changes in family planning, (3) adopting new customs (avoiding places of risk, use of specific clothes and use of repellent), (4) changed attitudes regarding body image and (5) feeling of external demand regarding prevention. The fear of Zika virus infection and all its associated risks have a negative biopsychosocial impact on the pregnant women in this study.


The interplay of friendship networks and social networking sites: longitudinal analysis of selection and influence effects on adolescent smoking and alcohol use.
We examined the coevolution of adolescent friendships and peer influences with respect to their risk behaviors and social networking site use. Investigators of the Social Network Study collected longitudinal data during fall 2010 and spring 2011 from 10th-grade students in 5 Southern California high schools (n = 1434). We used meta-analyses of stochastic actor-based models to estimate changes in friendship ties and risk behaviors and the effects of Facebook and MySpace use. Significant shifts in adolescent smoking and drinking occurred despite little change in overall prevalence rates. Students with higher levels of alcohol use were more likely to send and receive friendship nominations and become friends with other drinkers. They were also more likely to increase alcohol use if their friends drank more. Adolescents selected friends with similar Facebook and MySpace use habits. Exposure to friends' risky online pictures increased smoking behaviors but had no significant effects on alcohol use. Our findings support a greater focus on friendship selection mechanisms in school-based alcohol use interventions. Social media platforms may help identify at-risk adolescent groups and foster positive norms about risk behaviors.


Activation of hepatic stellate cells after phagocytosis of lymphocytes: A novel pathway of fibrogenesis.
Increased CD8-T lymphocytes and reduced natural killer (NK) cells contribute to hepatic fibrosis. We have characterized pathways regulating the interactions of human hepatic stellate cells (HSCs) with specific lymphocyte subsets in vivo and in vitro. Fluorescence-activated cell sorting (FACS) was used to characterize human peripheral blood lymphocytes (PBLs) and intrahepatic lymphocytes (IHLs) obtained from healthy controls and from patients with either hepatitis B virus (HBV) or hepatitis C virus (HCV) with advanced fibrosis. Liver sections were analyzed by immunohistochemistry and confocal microscopy. To investigate in vitro interactions, PBLs from healthy controls or patients with HCV cirrhosis were co-cultured with an immortalized human HSC line (LX2 cells) or with primary HSCs. Significant alterations in lymphocyte distribution were identified in IHLs but not PBLs. The hepatic CD4/CD8 ratio and NK cells were significantly reduced in HBV/HCV patients. Expression of alpha-smooth muscle actin and infiltration of CD4, CD8, and NK cells were readily apparent in liver sections from patients with cirrhosis but not in healthy controls. Lymphocytes from each subset were in proximity to HSCs primarily within the periportal regions, and some were directly attached or engulfed. In culture, HSC activation was stimulated by HCV-derived CD8-subsets but attenuated by NK cells. Confocal microscopy identified lymphocyte phagocytosis within HSCs that was completely prevented by blocking intracellular adhesion molecule 1 (ICAM-1) and integrin molecules, or by irradiation of HSCs. LX2 knockdown of either Cdc42 or Rac1 [members of the Rho-guanosine triphosphatase (GTPase) family] prevented both phagocytosis and the activation of HSC by HCV-derived lymphocytes. The CD4/CD8 ratio and NK cells are significantly decreased in livers with advanced human fibrosis. Moreover, disease-associated but not healthy lymphocytes are engulfed by cultured HSCs, which is mediated by the Rac1 and Cdc42 pathways. Ingestion of lymphocytes by HSCs in hepatic fibrosis is a novel and potentially important pathway regulating the impact of lymphocytes on the course of hepatic fibrosis.


Molecular epidemiology of African trypanosomiasis: the contributions of David George Godfrey OBE to the biochemical characterization of trypanosomes.
The accurate identification of the causative organisms of disease is fundamental to the study of epidemiology. Hence molecular tools are now widely used to detect and distinguish pathogens, and have greatly improved our understanding of epidemiology. David Godfrey pioneered the use of molecular markers in the epidemiology of African trypanosomiasis, thus enabling the light of reliable evidence to shine on this previously problematic and controversial subject area. From the early 1970's David's group employed first isoenzyme electrophoresis and subsequently DNA-based characterization methods to aid identification of typanosomes collected from a range of endemic countries across Africa. These investigations had a major impact on our understanding of the zoonotic nature of human trypanosomiasis in Africa and of the genetic diversity of African trypanosomes.


Application of ARID1A to murine formalin-fixed paraffin embedded tissue using immunohistochemistry.
ARID1A is a known suppressor of tumour formation and the Human Protein Atlas antibody HPA005456 has been demonstrated in previous literature to stain tumour tissue by immunohistochemistry (IHC) in formalin-fixed paraffin embedded human tissue and human cell lines. This article details the validation of this antibody for immunohistochemistry of formalin-fixed paraffin embedded murine tissue using a Leica BondMax immunostainer. Using Western blot and IHC on murine wild-type and knockout tissue we have demonstrated that this antibody to ARID1A correctly stains murine tissue by immunohistochemistry.


Line of duty firefighter fatalities: an evolving trend over time.
Between 1990 and 2012, 2775 firefighters were killed in the line of duty. Myocardial infarction (MI) was responsible for approximately 40% of these mortalities, followed by mechanical trauma, asphyxiation, and burns. Protective gear, safety awareness, medical care, and the age of the workforce have evolved since 1990, possibly affecting the nature of mortality during this 22-year time period. The purpose of this study is to determine whether the causes of firefighter mortality have changed over time to allow a targeted focus in prevention efforts. The U.S. Fire Administration fatality database was queried for all-cause on-duty mortality between 1990 to 2000 and 2002 to 2012. The year 2001 was excluded due to inability to eliminate the 347 deaths that occurred on September 11. Data collected included age range at the time of fatality (exact age not included in report), type of duty (on-scene fire, responding, training, and returning), incident type (structure fire, motor vehicle crash, etc), and nature of fatality (MI, trauma, asphyxiation, cerebrovascular accident [CVA], and burns). Data were compared between the two time periods with a χ test. Between 1990 and 2000, 1140 firefighters sustained a fatal injury while on duty, and 1174 were killed during 2002 to 2012. MI has increased from 43% to 46.5% of deaths (P = .012) between the 2 decades. CVA has increased from 1.6% to 3.7% of deaths (P = .002). Asphyxiation has decreased from 12.1% to 7.9% (P = .003) and burns have decreased from 7.7% to 3.9% (P = .0004). Electrocution is down from 1.8% to 0.5% (P = .004). Death from trauma was unchanged (27.8 to 29.6%, P = .12). The percentage of fatalities of firefighters over age 40 years has increased from 52% to 65% (P = .0001). Fatality by sex was constant at 3% female. Fatalities during training have increased from 7.3% to 11.2% of deaths (P = .00001). The nature of firefighter mortality has evolved over time. In the current decade, line-of-duty mortality is more likely to occur during training. Mortality from burns, asphyxiation, and electrocution has decreased; but death from MI and CVA has increased, particularly in older firefighters. Outreach and education should be targeted toward vehicle safety, welfare during training, and cardiovascular disease prevention in the firefighter population.


Antimicrobial allergy 'labels' drive inappropriate antimicrobial prescribing: lessons for stewardship.
The presence of antimicrobial allergy designations ('labels') often substantially reduces prescribing options for affected patients, but the frequency, accuracy and impacts of such labels are unknown. The National Antimicrobial Prescribing Survey (NAPS) is an annual de-identified point prevalence audit of Australian inpatient antimicrobial prescribing using standardized definitions of guideline compliance, appropriateness and indications. Data were extracted for 2 years (2013-14) and compared for patients with an antimicrobial allergy label (AAL) and with no AAL (NAAL). Among 21 031 patients receiving antimicrobials (33 421 prescriptions), an AAL was recorded in 18%, with inappropriate antimicrobial use significantly higher in the AAL group versus the NAAL group (OR 1.12, 95% CI 1.05-1.22, P < 0.002). Patterns of antimicrobial use were significantly influenced by AAL, with lower β-lactam use (AAL versus NAAL; OR 0.47, 95% CI 0.43-0.50, P < 0.001) and higher quinolone (OR 2.07, 95% CI 1.83-2.34, P < 0.0001), glycopeptide (OR 1.59, 95% CI 1.38-1.83, P < 0.0001) and carbapenem (OR 1.74, 95% CI 1.43-2.13, P < 0.0001) use. In particular, among immunocompromised patients, AAL was associated with increased rates of inappropriate antimicrobial use (OR 1.68, 95% CI 1.21-2.30, P = 0.003), as well as increased use of quinolones (OR 1.88, 95% CI 1.16-3.03, P = 0.02) and glycopeptides (OR 1.82, 95% CI 1.17-2.84, P = 0.01). AALs are common and appear to be associated with higher rates of inappropriate prescribing and increased use of broad-spectrum antimicrobials. Improved accuracy in defining AALs is likely to be important for effective antimicrobial stewardship (AMS), with efforts to 'de-label' inappropriate AAL patients a worthwhile feature of future AMS initiatives.


The Biogenetic Origin of the Biologically Active Naematolin of Hypholoma Species Involves an Unusual Sesquiterpene Synthase.
Naematolin is a biologically active sesquiterpene produced by Hypholoma species. Low titres and complex structure constrain the exploitation of this secondary metabolite. Here, we de novo sequenced the H. fasciculare genome to identify a candidate biosynthetic gene cluster for production of naematolin. Using Aspergillus oryzae as a heterologous host for gene expression, the activity of several sesquiterpene synthases were investigated, highlighting one atypical sesquiterpene synthase apparently capable of catalysing the 1,11 and subsequent 2,10 ring closures, which primes the synthesis of the distinctive structure of caryophyllene derivatives. Co-expression of the cyclase with an FAD oxidase adjacent within the gene cluster generated four oxidised caryophyllene-based sesquiterpenes: 5β,6α,8β-trihydroxycariolan, 5β,8β-dihydroxycariolan along with two previously unknown caryophyllene derivatives 2 and 3. This represents the first steps towards heterologous production of such basidiomycete-derived caryophyllene-based sesquiterpenes, opening a venue for potential novel antimicrobials via combinatorial biosynthesis.


Cellulose-degrading bacteria associated with the invasive woodwasp Sirex noctilio.
Sirex noctilio is an invasive wood-feeding wasp that threatens the world's commercial and natural pine forests. Successful tree colonization by this insect is contingent on the decline of host defenses and the ability to utilize the woody substrate as a source of energy. We explored its potential association with bacterial symbionts that may assist in nutrient acquisition via plant biomass deconstruction using growth assays, culture-dependent and -independent analysis of bacterial frequency of association and whole-genome analysis. We identified Streptomyces and γ-Proteobacteria that were each associated with 94% and 88% of wasps, respectively. Streptomyces isolates grew on all three cellulose substrates tested and across a range of pH 5.6 to 9. On the basis of whole-genome sequencing, three Streptomyces isolates have some of the highest proportions of genes predicted to encode for carbohydrate-active enzymes (CAZyme) of sequenced Actinobacteria. γ-Proteobacteria isolates grew on a cellulose derivative and a structurally diverse substrate, ammonia fiber explosion-treated corn stover, but not on microcrystalline cellulose. Analysis of the genome of a Pantoea isolate detected genes putatively encoding for CAZymes, the majority predicted to be active on hemicellulose and more simple sugars. We propose that a consortium of microorganisms, including the described bacteria and the fungal symbiont Amylostereum areolatum, has complementary functions for degrading woody substrates and that such degradation may assist in nutrient acquisition by S. noctilio, thus contributing to its ability to be established in forested habitats worldwide.


Induction of neutralizing antibodies and mucosal IgA through intranasal immunization with the receptor binding domain of SARS-CoV-2 spike protein fused with the type IIb E. coli heat-labile enterotoxin A subunit.
The outbreak of SARS-CoV-2 infections had led to the COVID-19 pandemic which has a significant impact on global public health and the economy. The spike (S) protein of SARS-CoV-2 contains the receptor binding domain (RBD) which binds to human angiotensin-converting enzyme 2 receptor. Numerous RBD-based vaccines have been developed and recently focused on the induction of neutralizing antibodies against the immune evasive Omicron BQ.1.1 and XBB.1.5 subvariants. In this preclinical study, we reported the use of a direct fusion of the type IIb Escherichia coli heat-labile enterotoxin A subunit with SARS CoV-2 RBD protein (RBD-LTA) as an intranasal vaccine candidate. The results showed that intranasal immunization with the RBD-LTA fusion protein in BALB/c mice elicited potent neutralizing antibodies against the Wuhan-Hu-1 and several SARS-CoV-2 variants as well as the production of IgA antibodies in bronchoalveolar lavage fluids (BALFs). Furthermore, the heterologous RBD representing the same strains used in the bivalent mRNA vaccine were used as a second-dose RBD-LTA/RBD protein booster after bivalent mRNA vaccination. The results showed that the neutralizing antibody titers elicited by the intranasal bivalent RBD-LTA/RBD protein booster were similar to the intramuscular bivalent mRNA booster, but the RBD-specific IgA titers in sera and BALFs significantly increased. Overall, this preclinical study suggests that the RBD-LTA fusion protein could be a promising candidate as a mucosal booster COVID-19 vaccine.


Impact of fluoxetine on liver damage in rats.
Fluoxetine (Flux) is a fluorine-containing drug that selectively inhibits serotonin reuptake. It is widely prescribed as a treatment for depression disorders. Hepatic side effects have been reported during Flux therapy. These reports led us to investigate the involvement of oxidative stress mechanisms in liver injury caused by Flux. It has been shown that exposure to fluoride (F(-)) induces excessive production of free radicals and affects the antioxidant defense system. Based on this knowledge, we examined the F(-) concentration in serum and urine during administration of Flux. In our study, the effects of one month of Flux treatment on lipid and protein peroxidation, the concentration of uric acid in the liver and the activity of transaminases and transferases in the serum were investigated in rats. Eighteen adult male Wistar rats were divided into three equal groups of six animals each: (I) controls who drank tap water and received 1 ml of tap water intragastrically; (II) animals that received 8 mg Flux/kg bw/day intragastrically; and (III) animals that received 24 mg Flux/kg bw/day intragastrically. Flux treatment increased of the levels of carbonyl groups, thiobarbituric acid reactive species (TBARS) and the uric acid content in the liver. The activities of alanine transaminase (ALT), aspartate transaminase (AST) and glutathione-S transferase (GST) increased in the serum of the treated groups. The Flux levels in the plasma of the treated rats increased significantly in a dose-dependent manner. We observed no changes in the concentration of fluoride in either the serum or the urine of treated rats compared to the control group. In conclusion, our study indicates that Flux induces liver damage and mediates free radical reactions. Our data also indicate that Flux does not release F(-) during metabolism and does not affect physiological levels of F(-) in the serum or urine.


Mast cells as "tunable" effector and immunoregulatory cells: recent advances.
This review focuses on recent progress in our understanding of how mast cells can contribute to the initiation, development, expression, and regulation of acquired immune responses, both those associated with IgE and those that are apparently expressed independently of this class of Ig. We emphasize findings derived from in vivo studies in mice, particularly those employing genetic approaches to influence mast cell numbers and/or to alter or delete components of pathways that can regulate mast cell development, signaling, or function. We advance the hypothesis that mast cells not only can function as proinflammatory effector cells and drivers of tissue remodeling in established acquired immune responses, but also may contribute to the initiation and regulation of such responses. That is, we propose that mast cells can also function as immunoregulatory cells. Finally, we show that the notion that mast cells have primarily two functional configurations, off (or resting) or on (or activated for extensive mediator release), markedly oversimplifies reality. Instead, we propose that mast cells are "tunable," by both genetic and environmental factors, such that, depending on the circumstances, the cell can be positioned phenotypically to express a wide spectrum of variation in the types, kinetics, and/or magnitude of its secretory functions.


Fecal transplantation as a treatment for Clostridium difficile infection in patients with ulcerative colitis.
Clostridium difficile (CD) infection is currently the most frequent etiology of nosocomial diarrhea. Besides, its incidence is progressively increasing in ambulatory patients. Inflammatory bowel disease (IBD) is a risk factor of CD infection itself, but also due to the regular immunosuppressive treatment used in these patients. At the present time, fecal transplantation (FT) is a safe and cost-effective alternative if the previous antibiotic treatments have failed. Similar outcomes between patients with IBD and general population have been reported. We present a case of a patient with ulcerative colitis and recurrent CD infection successfully treated with FT.


Multi-octave tunable RF signal generation based on a dual-polarization fiber grating laser.
A simple technique has been proposed and demonstrated to generate radio-frequency (RF) signal based on a fiber grating laser with multi-octave tunablity. The laser is fabricated by inscribing a wavelength-matched Bragg grating pair in a short section of low-birefringence Er/Yb co-doped fiber. A RF signal can be obtained by beating the two-polarization mode output with its frequency determined by the birefringence within the cavity. By slicing the laser cavity into two sections and then aligning them with a rotated angle, the output beat frequency can be continuously tuned in a multi-octave frequency range as shown in the experiment from 2.05 GHz down to 289 MHz, as a result of the induced change in optical length for each polarization mode. The present technique has the advantages including simple scheme and large tuning range, and the ability of tuning could be further improved by use of active fibers with higher birefringence.


Hepatitis C virus risk behaviors within the partnerships of young injecting drug users.
Young injection drug users (IDU) are at high risk for hepatitis C virus (HCV). We sought to determine whether perceiving one's injecting partner to be HCV positive was associated with decreased odds of engaging in receptive needle/syringe sharing (RNS) or ancillary equipment sharing (AES) with that partner. Cross sectional study. 2003 to 2007 in San Francisco. 212 young (under age 30) IDU who were HCV antibody negative reported on 492 injecting partnerships. Self-reported RNS and AES within injecting partnerships. RNS and AES (in the absence of RNS) occurred in 23% and 64% of injecting partnerships in the prior month. The odds of engaging in RNS were significantly lower for relationships in which the participant reported that his/her partner was HCV positive (odds ratio [OR] 0.49; 95% confidence interval [CI] 0.25-0.95). This association was attenuated when adjusted for reusing one's own needle/syringe (adjusted OR 0.57; 95% CI 0.28-1.15). The odds of engaging in AES were lower for participants who did not know the HCV status of their partner, only among non-sexual partnerships (OR 0.47; 95% CI 0.29-0.76). Because perceiving one's partner to be HCV positive was associated with decreased RNS, increased HCV testing and partner disclosure may be warranted. AES was common and was decreased only among non-sexual partnerships in which the HCV status of the partner was not known. This suggests that interventions to reduce AES in young IDU must be widespread.


Temperature dependence of the kinetic isotope effects in thymidylate synthase. A theoretical study.
In recent years, the temperature dependence of primary kinetic isotope effects (KIE) has been used as indicator for the physical nature of enzyme-catalyzed H-transfer reactions. An interactive study where experimental data and calculations examine the same chemical transformation is a critical means to interpret more properly temperature dependence of KIEs. Here, the rate-limiting step of the thymidylate synthase-catalyzed reaction has been studied by means of hybrid quantum mechanics/molecular mechanics (QM/MM) simulations in the theoretical framework of the ensemble-averaged variational transition-state theory with multidimensional tunneling (EA-VTST/MT) combined with Grote-Hynes theory. The KIEs were calculated across the same temperature range examined experimentally, revealing a temperature independent behavior, in agreement with experimental findings. The calculations show that the H-transfer proceeds with ∼91% by tunneling in the case of protium and ∼80% when the transferred protium is replaced by tritium. Dynamic recrossing coefficients are almost invariant with temperature and in all cases far from unity, showing significant coupling between protein motions and the reaction coordinate. In particular, the relative movement of a conserved arginine (Arg166 in Escherichia coli ) promotes the departure of a conserved cysteine (Cys146 in E. coli ) from the dUMP by polarizing the thioether bond thus facilitating this bond breaking that takes place concomitantly with the hydride transfer. These promoting vibrations of the enzyme, which represent some of the dimensions of the real reaction coordinate, would limit the search through configurational space to efficiently find those decreasing both barrier height and width, thereby enhancing the probability of H-transfer by either tunneling (through barrier) or classical (over-the-barrier) mechanisms. In other words, the thermal fluctuations that are coupled to the reaction coordinate, together with transition-state geometries and tunneling, are the same in different bath temperatures (within the limited experimental range examined). All these terms contribute to the observed temperature independent KIEs in thymidylate synthase.


Urban land use limits regional bumble bee gene flow.
Potential declines in native pollinator communities and increased reliance on pollinator-dependent crops have raised concerns about native pollinator conservation and dispersal across human-altered landscapes. Bumble bees are one of the most effective native pollinators and are often the first to be extirpated in human-altered habitats, yet little is known about how bumble bees move across fine spatial scales and what landscapes promote or limit their gene flow. In this study, we examine regional genetic differentiation and fine-scale relatedness patterns of the yellow-faced bumble bee, Bombus vosnesenskii, to investigate how current and historic habitat composition impact gene flow. We conducted our study across a landscape mosaic of natural, agricultural and urban/suburban habitats, and we show that B. vosnesenskii exhibits low but significant levels of differentiation across the study system (F(ST) = 0.019, D(est) = 0.049). Most importantly, we reveal significant relationships between pairwise F(ST) and resistance models created from contemporary land use maps. Specifically, B. vosnesenskii gene flow is most limited by commercial, industrial and transportation-related impervious cover. Finally, our fine-scale analysis reveals significant but declining relatedness between individuals at the 1-9 km spatial scale, most likely due to local queen dispersal. Overall, our results indicate that B. vosnesenskii exhibits considerable local dispersal and that regional gene flow is significantly limited by impervious cover associated with urbanization.


Violent children: bridging development, intervention, and public policy.
Childhood violence is a major public health and social policy concern in the United States. Scientists and policymakers alike have increasingly turned their attention to the causes of childhood violence and the extent to which its course can be modified through well-planned preventive interventions. However, it is not apparent that policymakers draw upon basic research findings in formulating their priorities and policies, nor is it apparent that developmental scientists incorporate policy considerations and prevention findings into their research frameworks and designs. The goal of this special issue on violent children is to begin to bridge the gaps among basic developmental science, prevention science, and public policy.


First-trimester fetal growth restriction and the occurrence of miscarriage in rural Bangladesh: A prospective cohort study.
Fetal growth restriction in early pregnancy increases the risk of adverse pregnancy outcome, which has a significant social and psychological impact on women. There is limited information related to community-based study to evaluate early indicators related to miscarriage. The aim of this study is to examine the relationship between fetal growth restriction, measured by ultrasound crown-rump length (CRL), and subsequent occurrence of miscarriage in pregnant women in rural Bangladesh. The study was conducted within the Maternal and Infant Nutrition Interventions Trial in Matlab (MINIMat study), Bangladesh. A total of 4436 pregnant women were enrolled in the study when they were at less than 14 gestational weeks. The expected CRL was determined based on an established growth curve of gestational age and CRL, and deviation from this curve of CRL was expressed as a z-score. After identifying related covariates, the multiple Poisson regression model was used to determine the independent contribution from the CRL to miscarriage. A total of 3058 singleton pregnant women were included in analyses, with 92 miscarriages and 2966 continued pregnancies. The occurrence of miscarriages was significantly higher in the smaller categories of CRL z-score after adjustments for maternal age, parity, early pregnancy BMI, gestational age at CRL measurement and socioeconomic status (adjusted relative risk [95% confidence interval]: 1.03 [1.02-1.05] for less than -2 z-score). In a rural Bangladesh population, smaller than expected CRL for the gestational age was related to subsequent miscarriage. Ultrasound biometry information together with careful clinical assessment should provide much needed attention and care for pregnant women.


Near-fatal poisoning after ricin injection.
To report a near-fatal poisoning after intentional injection of ricin from a castor bean (Ricinus communis) extract. A 21 year-old man self-injected ∼3 mL of a castor bean extract intramuscularly and subcutaneously in the left antecubital fossa. Upon admission to our ED (1 h post-exposure; day 1, D1) he was awake and alert, but complained of mild local pain and showed slight local edema and erythema. He evolved to refractory shock (∼24 h post-exposure) that required the administration of a large volume of fluids and high doses of norepinephrine and vasopressin, mainly from D2 to D4. During this period, he developed clinical and laboratory features compatible with systemic inflammatory response syndrome, multiple organ dysfunction, capillary leak syndrome, rhabdomyolysis, necrotizing fasciitis and possible compartment syndrome. The patient underwent forearm fasciotomy on D4 and there was progressive improvement of the hemodynamic status from D7 onwards. Wound management involved several debridements, broad-spectrum antibiotics and two skin grafts. Major laboratory findings within 12 days post-exposure revealed hypoalbuminemia, proteinuria, thrombocytopenia, leukocytosis and increases in cytokines (IL-6, IL-10 and TNF-α), troponin and creatine kinase. Ricin A-chain (ELISA) was detected in serum up to D3 (peak at 24 h post-exposure), with ∼79% being excreted in the urine within 64 h post-exposure. Ricinine was detected in serum and urine by LC-MS up to D5. A ricin A-chain concentration of 246 µg/mL was found in the seed extract, corresponding to the injection of ∼738 µg of ricin A-chain (∼10.5 µg/kg). The patient was discharged on D71, with limited range of motion and function of the left forearm and hand. Ricin injection resulted in a near-fatal poisoning that evolved with septic shock-like syndrome, multiple organ dysfunction and necrotizing fasciitis, all of which were successfully treated with supportive care.


Control of the ductus arteriosus.
In the fetus the major function of the ductus arteriosus is to divert flow away from the lungs toward the placenta, therby avoiding unnecessary circulation through the lungs and reducing the work load of the heart. Constriction of the ductus arteriosus is produced by several mechanisms that may interact with one another in producing normal postnatal closure of the ductus arteriosus. The major mechanism is the constrictor effect of an increased O2 environment. This may directly affect the ductus arteriosus muscle or may work through the release of an intermediary substance. Other vasoactive substance circulating in the blood after birth may also play some role in constriction of the ductus arteriosus. There are major species differences in the degree and type of response to the various stimuli and the exact mechanisms ultimately responsible for closure are not yet fully understood.


Reconciling certification and intact forest landscape conservation.
In 2014, the Forest Stewardship Council (FSC) added a new criterion to its principles that requires protection of intact forest landscapes (IFLs). An IFL is an extensive area of forest that lacks roads and other signs of human activity as detected through remote sensing. In the Congo basin, our analysis of road networks in formally approved concessionary logging areas revealed greater loss of IFL in certified than in noncertified concessions. In areas of informal (i.e., nonregulated) extraction, road networks are known to be less detectable by remote sensing. Under the current definition of IFL, companies certified under FSC standards are likely to be penalized relative to the noncertified as well as the informal logging sector on account of their planned road networks, despite an otherwise better standard of forest management. This could ultimately undermine certification and its wider adoption, with implications for the future of sustainable forest management.


A Framework for Latino Nursing Leadership.
There is an urgent need for Latino leaders in nursing, yet little has been written about Latino leaders and leadership. Leadership comes with challenges and opportunities in particular for Latino nurses who contend with specific cultural imperatives and obstacles. In this article, I review the current healthcare environment and propose a framework for Latino nursing leadership within the context of current challenges and opportunities and my personal experience in nursing. This framework is meant to serve as a guide for the development of Latino nurses who will improve the health and well-being of those in the most vulnerable communities by utilizing their cultural strengths and professional skills to deliver quality and compassionate care.


Differences in heart rate profile during exercise among subjects with subclinical thyroid disease.
Clinical thyroid disease is associated with changes in the cardiovascular system, including changes in heart rate during exercise. However, data on the relation between subclinical thyroid disease (SCTD) and heart rate during exercise are limited. We investigated 3799 apparently healthy subjects who were evaluated in the Institute for Preventive Medicine at the Sheba Medical Center. All subjects answered standard health questionnaires; were examined by a physician; completed routine blood tests including thyrotropin, free triiodothyronine, and free thyroxine levels; and underwent a treadmill exercise according to the Bruce protocol. Subjects with known thyroid disease or those who were taking thyroid-related drugs were excluded from the analysis. Heart rate profile was compared between patients with subclinical hypothyroidism (SCHypoT), patients with normal thyroid function, and patients with subclinical hyperthyroidism (SCHyperT) using propensity score matching. Seventy patients had SCHyperT and 273 had SCHypoT. Compared with age- and sex-matched normal subjects, SCHyperT subjects had a higher resting heart rate (83±17 vs. 76±12 beats per minute [bpm], p=0.006), a significantly higher recovery heart rate (94±12 vs. 90±12 bpm, p=0.045), and a significantly lower heart rate reserve (80±20 vs. 87±18 bpm, p=0.006). Subjects with SCHypoT showed a trend toward a lower resting heart rate (75±13 vs. 77±15 bpm, p=0.09) and had a significantly lower recovery heart rate (88±12 vs. 90±13 bpm, p=0.035). There was no significant difference in exercise duration or blood pressure between subjects with SCTD and their matched normal controls. Subjects with SCTD have a significantly different heart rate profile during rest, exercise, and recovery.


AIDS and the eye.
The AIDS pandemic has finally emerged from the big cities to the small towns of this country, as patients with this disease are returning home to spend their last months and days in the care of their families. No physician will be spared from caring for patients with AIDS. This multisystem disease crosses the boundaries of primary and specialty medicine, and with its various manifestations, presents to virtually all health care professionals. This infection has an enormous impact on our society: economically, socially, and medically. The seriousness of this condition is reflected in the medical school curriculum at the University of Pittsburgh. AIDS education begins the first day of the first year for our medical students.


Cellular proteases involved in the pathogenicity of enveloped animal viruses, human immunodeficiency virus, influenza virus A and Sendai virus.
In enveloped viruses, post-translational proteolytic activation is a critical step for the fusion activity and thus for the infectivity of the virus. In addition to the membrane receptors for the viruses, proteolytic activation is indispensable for effective virus spread in the infected host and it is a prime determinant for pathogenicity. Here we described the host cellular processing proteases, tryptase Clara and tryptase TL2, which proteolytically activate the infectivity of influenza A and Sendai viruses in the respiratory tract and HIV-1 in human CD4+ T cells, respectively. A novel trypsin-like protease, designated tryptase Clara, was purified from rat lung. The enzyme is localized in Clara cells of the bronchial epithelium and is secreted into the airway lumen. The enzyme specifically recognizes the consensus cleavage motif Gln(Glu)-X-Arg of influenza A and Sendai viruses and proteolytically activates the envelope fusion glycoproteins of the progeny viruses extracellularly in the airway lumen. Human mucus protease inhibitor and pulmonary surfactant in airway fluid inhibited the proteolytic activation of these viruses and also suppressed multiple cycles of viral replication in vitro. These results suggest that an imbalance between the amount of tryptase Clara and that of endogenous inhibitors in airway fluid is a prime determinant for pneumopathogenicity of the viruses. Therefore supplementing an endogenous inhibitor at therapeutic doses may protect against virus infection. In HIV-1 infection, binding of the gp120 envelope glycoprotein to the CD4 receptor is not sufficient in itself to allow virus entry, and an additional component(s) in the membrane is required for cell infection as a cofactor. We isolated a serine protease named tryptase TL2, in the membrane of CD4+ lymphocytes, which specifically binds to the V3 loop of HIV-1 gp120 as a cofactor. After binding, tryptase TL2 proteolytically processed gp120 into two protein species of 70 and 50 kDa and the cleavage was suppressed by a neutralizing antibody against the V3 loop. The amino acids that constitute the cleavage sites in the V3 loop of almost all HIV isolates are variable, but they are restricted to those which are susceptible to chymotryptic and/or tryptic enzyme. The multi-substrate specificity of tryptase TL2, which has tryptic and chymotryptic specificities, may correspond tot he variability of the V3 loop. The selective cleavage of the V3 loop by tryptase TL2 may lead to a conformational change of gp120, resulting in the dissociation of gp120 from gp41, exposing the fusogenic domain of the transmembrane protein gp41 following virus-host cell fusion.


Health outcomes associated with use of hormonal contraception: breast cancer.
To review recent literature on health outcomes associated with use of hormonal contraception with a focus on breast cancer. A large cohort study documented an increased risk of breast cancer among hormonal contraceptive users compared to those who had never used hormonal contraception. The overall relative risk of breast cancer among current or recent users was 1.2 [95% confidence interval (CI), 1.14-1.26]. Overall, this translates into one additional case of breast cancer for every 7690 users of hormonal contraception. Recent publications have also documented a decrease in risk for endometrial, ovarian, and colorectal cancers among hormonal contraceptive users. Based on these data, it is estimated that a third of endometrial and ovarian cancers and a fifth of colorectal cancers were prevented with combined oral contraceptive use. Several factors must be taken into consideration regarding the risk of breast cancer associated with hormonal contraceptive use. Contraceptive benefits related to preventing unintended pregnancy are protective against associated maternal morbidity and mortality. Noncontraceptive benefits of protecting against other types of cancers must also be considered. Overall, breast cancer risk is low among hormonal contraceptive users and women should be counseled accordingly.