Formulation of a minimal nutritional medium for enhanced lipid productivity in Chlorella sp. and Botryococcus sp. using response surface methodology.
Chlorella sp. MCC 7 and Botryococcus sp. MCC 31 were investigated to enable large-scale biodiesel production from minimal constituents in the growth medium. Response surface methodology (RSM) was used to maximise the biomass productivity and lipid yield using only nitrogen (N), phosphorus (P) and potassium (K) as urea, single super phosphate and muriate of potash. The optimum values were 0.42 g/L nitrogen; 0.14 g/L phosphorus and 0.22 g/L potassium for Chlorella sp.; and 0.46 g/L; 0.14 g/L and 0.25 g/L for Botryococcus sp. Lipid yield of 42% for Chlorella sp. and 52% in Botryococcus sp. was observed. An enhancement in lipid yield by approximately 55% for Chlorella sp. and 73% for Botryococcus sp. was registered as compared to original nutrient medium. Fourier transform infrared (FTIR) analysis of extracted lipids revealed characteristic bands for triglycerides. This study provided utilisation of a practicable nutrient recipe in the form of N, P, K input for enhanced lipid yield from the selected microalgal strains.


Increased labor induction and women presenting with decreased or altered fetal movements - a population-based survey.
Women's awareness of fetal movements is important as perception of decreased fetal movements can be a sign of a compromised fetus. We aimed to study rate of labor induction in relation to number of times women seek care due to decreased or altered fetal movements during their pregnancy compared to women not seeking such care. Further, we investigated the indication of induction. A prospective population-based cohort study including all obstetric clinics in Stockholm, Sweden. Questionnaires were distributed to women who sought care due to decreased or altered fetal movements ≥ 28 week's gestation in 2014, women for whom an examination did not indicate a compromised fetus that required induction of labor or cesarean section when they sought care. Women who gave birth at ≥ 28 weeks' gestation in 2014 in Stockholm comprises the reference group. Labor was induced more often among the 2683 women who had sought care due to decreased or altered fetal movements (RR 1.4, 95% CI 1.3-1.5). In women who presented with decreased or altered fetal movements induction of labor occurred more frequently for fetal indication than those with induction of labor and no prior fetal movement presentation (RR 1.6, 95% CI 1.4-1.8). The rate of induction increased with number of times a woman sought care, RR 1.3 for single presentation to 3.2 for five or more. We studied women seeking care for decreased or altered fetal movements and for whom pregnancy was not terminated with induction or caesarean section. Subsequent (median 20 days), induction of labor and induction for fetal indications were more frequent in this group compared to the group of women with no fetal movement presentations. Among women seeking care for altered or decreased fetal movements, the likelihood of induction of labor increased with frequency of presentation.


Combat duty in Iraq and Afghanistan, mental health problems and barriers to care.
The current combat operations in Iraq and Afghanistan have involved US military personnel in major ground combat and hazardous security duty. Studies are needed to systematically assess the mental health of members of the armed services who have participated in these operations and to inform policy with regard to the optimal delivery of mental health care to returning veterans. We studied members of 4 US combat infantry units (3 Army units and a Marine Corps unit) using an anonymous survey that was administered to the subjects either before their deployment to Iraq (n=2530) or 3 to 4 months after their return from combat duty in Iraq or Afghanistan (n=3671). The outcomes included major depression, generalized anxiety, and posttraumatic stress disorder (PTSD), which were evaluated on the basis of standardized, self-administered screening instruments. Exposure to combat was significantly greater among those who were deployed to Iraq than among those deployed to Afghanistan. The percentage of study subjects whose responses met the screening criteria for major depression, generalized anxiety, or PTSD was significantly higher after duty in Iraq (15.6% to 17.1%) than after duty in Afghanistan (11.2%) or before deployment to Iraq (9.3%); the largest difference was in the rate of PTSD. Of those whose responses were positive for a mental disorder, only 23% to 40% sought mental health care. Those whose responses were positive for a mental disorder were twice as likely as those whose responses were negative to report concern about possible stigmatization and other barriers to seeking mental health care. This study provides an initial look at the mental health of members of the Army and the Marine Corps who were involved in combat operations in Iraq and Afghanistan. Our findings indicate that among the study groups there was a significant risk of mental health problems and that the subjects reported important barriers to receiving mental health services, particularly the perception of stigma among those most in need of such care. The recent military operations in Iraq and Afghanistan, which have involved the first sustained ground combat undertaken by the United States since the war in Vietnam, raise important questions about the effect of the experience on the mental health of members of the military services who have been deployed there. Research conducted after other military conflicts has shown that deployment stressors and exposure to combat result in considerable risks of mental health problems, including posttraumatic stress disorder, major depression, substance abuse, impairment in social functioning and in the ability to work, and the increased use of healthcare services. One study that was conducted just before the military operations in Iraq and Afghanistan began found that at least 6% of all US military service members on active duty receive treatment for a mental disorder each year. Given the ongoing military operations in Iraq and Afghanistan, mental disorders are likely to remain an important healthcare concern among those serving there. Many gaps exist in the understanding of the full psychosocial effect of combat. The all-volunteer force deployed to Iraq and Afghanistan and the type of warfare conducted in these regions are very different from those involved in past wars, differences that highlight the need for studies of members of the armed services who are involved in the current operations. Most studies that have examined the effects of combat on mental health were conducted among veterans years after their military service had ended. A problem in the methods of such studies is the long recall period after exposure to combat. Very few studies have examined a broad range of mental health outcomes near to the time of subjects' deployment. Little of the existing research is useful in guiding policy with regard to how best to promote access to and the delivery of mental health care to members of the armed services. Although screening for mental health problems is now routine both before and after deployment and is encouraged in primary care settings, we are not aware of any studies that have assessed the use of mental health care, the perceived need for such care, and the perceived barriers to treatment among members of the military services before or after combat deployment. We studied the prevalence of mental health problems among members of the US armed services who were recruited from comparable combat units before or after their deployment to Iraq or Afghanistan. We identified the proportion of service members with mental health concerns who were not receiving care and the barriers they perceived to accessing and receiving such care.


The many meanings of care in clinical research.
The conduct of clinical research often involves two distinguishable sets of relationships: the researcher-subject relationship, and the clinician-patient relationship. Some scholars argue that being a patient in a clinical care setting and a subject in a research study are so different that anything that would promote in subjects the view that they are in clinician-patient relationships is exploitative and deceptive. This paper presents findings intended to initiate a more empirically-based discussion of this issue. Using data from 82 in-depth interviews with physician-investigators, nurse-study coordinators and patient-subjects in early phase clinical trials, we find that research personnel are likely to be seen, and to see themselves, as clinical caregivers. We also find evidence that while researchers and subjects often tend to view care and research as conflicting activities, both parties tend to see research as a way of caring for patients. We found no relationship, however, between subjects' perception of care-giving by researchers and the tendency to misunderstand that they are in a research study. Because research, by necessity and inclination, is unlikely ever to be 'care-free', we recommend that the ethical debate surrounding the danger of confusing research with treatment take into account the kinds of care described by respondents.


Sample size estimates for well-powered cross-sectional cortical thickness studies.
Cortical thickness mapping is a widely used method for the analysis of neuroanatomical differences between subject groups. We applied power analysis methods over a range of image processing parameters to derive a model that allows researchers to calculate the number of subjects required to ensure a well-powered cross-sectional cortical thickness study. 0.9-mm isotropic T1 -weighted 3D MPRAGE MRI scans from 98 controls (53 females, age 29.1 ± 9.7 years) were processed using Freesurfer 5.0. Power analyses were carried out using vertex-wise variance estimates from the coregistered cortical thickness maps, systematically varying processing parameters. A genetic programming approach was used to derive a model describing the relationship between sample size and processing parameters. The model was validated on four Alzheimer's Disease Neuroimaging Initiative control datasets (mean 126.5 subjects/site, age 76.6 ± 5.0 years). Approximately 50 subjects per group are required to detect a 0.25-mm thickness difference; less than 10 subjects per group are required for differences of 1 mm (two-sided test, 10 mm smoothing, α = 0.05). Sample size estimates were heterogeneous over the cortical surface. The model yielded sample size predictions within 2-6% of that determined experimentally using independent data from four other datasets. Fitting parameters of the model to data from each site reduced the estimation error to less than 2%. The derived model provides a simple tool for researchers to calculate how many subjects should be included in a well-powered cortical thickness analysis.


In vitro and in vivo evaluation of cephalosporins for the treatment of Lyme disease.
Lyme disease accounts for >90% of all vector-borne disease cases in the United States and affect ~300,000 persons annually in North America. Though traditional tetracycline antibiotic therapy is generally prescribed for Lyme disease, still 10%-20% of patients treated with current antibiotic therapy still show lingering symptoms. In order to identify new drugs, we have evaluated four cephalosporins as a therapeutic alternative to commonly used antibiotics for the treatment of Lyme disease by using microdilution techniques like minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). We have determined the MIC and MBC of four drugs for three Borrelia burgdorferi s.s strains namely CA8, JLB31 and NP40. The binding studies were performed using in silico analysis. The MIC order of the four drugs tested is cefoxitin (1.25 µM/mL) > cefamandole (2.5 µM/mL), > cefuroxime (5 µM/mL) > cefapirin (10 µM/mL). Among the drugs that are tested in this study using in vivo C3H/HeN mouse model, cefoxitin effectively kills B. burgdorferi. The in silico analysis revealed that all four cephalosporins studied binds effectively to B. burgdorferi proteins, SecA subunit penicillin-binding protein (PBP) and Outer surface protein E (OspE). Based on the data obtained, cefoxitin has shown high efficacy killing B. burgdorferi at concentration of 1.25 µM/mL. In addition to it, cefoxitin cleared B. burgdorferi infection in C3H/HeN mice model at 20 mg/kg.


CBCT of a Moving Sample From X-Rays and Multiple Videos.
In this paper, we consider dense volumetric modeling of moving samples such as body parts. Most dense modeling methods consider samples observed with a moving X-ray device and cannot easily handle moving samples. We propose instead a novel method to observe shape motion from a fixed X-ray device and to build dense in-depth attenuation information. This yields a low-cost, low-dose 3-D imaging solution, taking benefit of equipment widely available in clinical environments. Our first innovation is to combine a video-based surface motion capture system with a single low-cost/low-dose fixed planar X-ray device, in order to retrieve the sample motion and attenuation information with minimal radiation exposure. Our second innovation is to rely on Bayesian inference to solve for a dense attenuation volume given planar radioscopic images of a moving sample. This approach enables multiple sources of noise to be considered and takes advantage of very limited prior information to solve an otherwise ill-posed problem. Results show that the proposed strategy is able to reconstruct dense volumetric attenuation models from a very limited number of radiographic views over time on synthetic and in-situ data.


3D Printing as a Promising Tool in Personalized Medicine.
Personalized medicine has the potential to revolutionize the healthcare sector, its goal being to tailor medication to a particular individual by taking into consideration the physiology, drug response, and genetic profile of that individual. There are many technologies emerging to cause this paradigm shift from the conventional "one size fits all" to personalized medicine, the major one being three-dimensional (3D) printing. 3D printing involves the establishment of a three-dimensional object, in a layer upon layer manner using various computer software. 3D printing can be used to construct a wide variety of pharmaceutical dosage forms varying in shape, release profile, and drug combination. The major technological platforms of 3D printing researched on in the pharmaceutical sector include inkjet printing, binder jetting, fused filament fabrication, selective laser sintering, stereolithography, and pressure-assisted microsyringe. A possible future application of this technology could be in a clinical setting, where prescriptions could be dispensed based on individual needs. This manuscript points out the various 3D printing technologies and their applications in research for fabricating pharmaceutical products, along with their pros and cons. It also presents its potential in personalized medicine by individualizing the dose, release profiles, and incorporating multiple drugs in a polypill. An insight on how it tends to various populations is also provided. An approach of how it can be used in a clinical setting is also highlighted. Also, various challenges faced are pointed out, which must be overcome for the success of this technology in personalized medicine.


Closure versus non-closure of the peritoneum at caesarean section: short- and long-term outcomes.
Caesarean section is a very common surgical procedure worldwide. Suturing the peritoneal layers at caesarean section may or may not confer benefit, hence the need to evaluate whether this step should be omitted or routinely performed. The objective of this review was to assess the effects of non-closure as an alternative to closure of the peritoneum at caesarean section on intraoperative and immediate- and long-term postoperative outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 November 2013). Randomised controlled trials comparing leaving the visceral or parietal peritoneum, or both, unsutured at caesarean section with a technique which involves suturing the peritoneum in women undergoing elective or emergency caesarean section. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked it for accuracy. A total of 29 trials were included in this review and 21 trials (17,276 women) provided data that could be included in an analysis. The quality of the trials was variable. 1. Non-closure of visceral and parietal peritoneum versus closure of both parietal layersSixteen trials involving 15,480 women, were included and analysed, when both parietal peritoneum was left unclosed versus when both peritoneal surfaces were closed. Postoperative adhesion formation was assessed in only four trials with 282 women, and no difference was found between groups (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.76 to 1.29). There was significant reduction in the operative time (mean difference (MD) -5.81 minutes, 95% CI -7.68 to -3.93). The duration of hospital stay in a total of 13 trials involving 14,906 women, was also reduced (MD -0.26, 95% CI -0.47 to -0.05) days. In a trial involving 112 women, reduced chronic pelvic pain was found in the peritoneal non-closure group. 2. Non-closure of visceral peritoneum only versus closure of both peritoneal surfacesThree trials involving 889 women were analysed. There was an increase in adhesion formation (two trials involving 157 women, RR 2.49, 95% CI 1.49 to 4.16) which was limited to one trial with high risk of bias.There was reduction in operative time, postoperative days in hospital and wound infection. There was no significant reduction in postoperative pyrexia. 3. Non-closure of parietal peritoneum only versus closure of both peritoneal layersThe two identified trials involved 573 women. Neither study reported on postoperative adhesion formation. There was reduction in operative time and postoperative pain with no difference in the incidence of postoperative pyrexia, endometritis, postoperative duration of hospital stay and wound infection. In only one study, postoperative day one wound pain assessed by the numerical rating scale, (MD -1.60, 95% CI -1.97 to -1.23) and chronic abdominal pain d by the visual analogue score (MD -1.10, 95% CI -1.39 to -0.81) was reduced in the non-closure group. 4. Non-closure versus closure of visceral peritoneum when parietal peritoneum is closed.There was reduction in all the major urinary symptoms of frequency, urgency and stress incontinence when the visceral peritoneum is left unsutured. There was a reduction in operative time across all the subgroups. There was also a reduction in the period of hospitalisation post-caesarean section except in the subgroup where parietal peritoneum only was not sutured where there was no difference in the period of hospitalisation. The evidence on adhesion formation was limited and inconsistent. There is currently insufficient evidence of benefit to justify the additional time and use of suture material necessary for peritoneal closure. More robust evidence on long-term pain, adhesion formation and infertility is needed.


Care as an Alternative to Euthanasia? Reconceptualizing Veterinary Palliative and End-of-life Care.
Palliative care is routinely offered to humans in the United Kingdom, while euthanasia remains illegal. The converse is true for nonhuman animals (henceforth animals). Indeed, euthanasia is widely accepted as the appropriate course of action for "suffering" animals, and for those whose behaviors or suspected ill health are thought to pose a threat to others. This article details examples of nonhuman death at a multi-faith ashram whose members vehemently oppose all forms of killing on religious grounds. Through exploring their efforts in palliative care for animals, and their emphasis on natural death as a means of respecting the sanctity of life, the practical, emotional, and theoretical viability of caring for, instead of killing, other animals at the ends of their lives is considered. In the process, normative distinctions between different categories of animals, (including humans), and different approaches to end of life care (palliative care, euthanasia, natural death) are called into question. Indeed, paying mindful attention to the diverse ways in which individual animals are cared for as they die reveals the potential violence inherent in both palliative care leading to natural death, and euthanasia, blurring perceptions of good and bad death in both veterinary and human medicine.


Improved sensitivity to cerebral white matter abnormalities in Alzheimer's disease with spherical deconvolution based tractography.
Diffusion tensor imaging (DTI) based fiber tractography (FT) is the most popular approach for investigating white matter tracts in vivo, despite its inability to reconstruct fiber pathways in regions with "crossing fibers." Recently, constrained spherical deconvolution (CSD) has been developed to mitigate the adverse effects of "crossing fibers" on DTI based FT. Notwithstanding the methodological benefit, the clinical relevance of CSD based FT for the assessment of white matter abnormalities remains unclear. In this work, we evaluated the applicability of a hybrid framework, in which CSD based FT is combined with conventional DTI metrics to assess white matter abnormalities in 25 patients with early Alzheimer's disease. Both CSD and DTI based FT were used to reconstruct two white matter tracts: one with regions of "crossing fibers," i.e., the superior longitudinal fasciculus (SLF) and one which contains only one fiber orientation, i.e. the midsagittal section of the corpus callosum (CC). The DTI metrics, fractional anisotropy (FA) and mean diffusivity (MD), obtained from these tracts were related to memory function. Our results show that in the tract with "crossing fibers" the relation between FA/MD and memory was stronger with CSD than with DTI based FT. By contrast, in the fiber bundle where one fiber population predominates, the relation between FA/MD and memory was comparable between both tractography methods. Importantly, these associations were most pronounced after adjustment for the planar diffusion coefficient, a measure reflecting the degree of fiber organization complexity. These findings indicate that compared to conventionally applied DTI based FT, CSD based FT combined with DTI metrics can increase the sensitivity to detect functionally significant white matter abnormalities in tracts with complex white matter architecture.


CRNF, a molluscan neurotrophic factor that interacts with the p75 neurotrophin receptor.
A 13.1-kilodalton protein, cysteine-rich neurotrophic factor (CRNF), was purified from the mollusk Lymnaea stagnalis by use of a binding assay on the p75 neurotrophin receptor. CRNF bound to p75 with nanomolar affinity but was not similar in sequence to neurotrophins or any other known gene product. CRNF messenger RNA expression was highest in adult foot subepithelial cells; in the central nervous system, expression was regulated by lesion. The factor evoked neurite outgrowth and modulated calcium currents in pedal motor neurons. Thus, CRNF may be involved in target-derived trophic support for motor neurons and could represent the prototype of another family of p75 ligands.


Exploratory investigation of obesity risk and prevention in Chinese Americans.
To examine the beliefs and attitudes related to obesity risk and its prevention in Chinese Americans via in-depth, qualitative interviews using the guiding tenets of Health Belief Model, Theory of Planned Behavior, and social ecological models. A qualitative study using tenets of the Health Belief Model, the Theory of Planned Behavior, and social ecological models. The New York City metropolitan area. Forty young Chinese American adults (24 females; 16 males) were interviewed. Obesity risk and prevention. Common themes were identified, coded, and compared using NVivo computer software. Poor dietary habits and sedentary lifestyles were seen as major weight gain contributors. Obesity was seen predominantly as a non-Asian phenomenon, although 60% of the participants felt susceptible to obesity. Physical and social environmental factors were the overriding themes generated as to the causes of weight gain among young adult Chinese Americans. Physical factors included the powerful effect of media-generated advertisements and a plethora of inexpensive fast and convenience foods emphasizing large portion sizes of low nutrient density. The social environment encourages the consumption of large quantities of these foods. Traditional Chinese cuisine was seen as providing more healthful alternatives, but increasing acculturation to American lifestyle results in less traditional food consumption. Some traditional Chinese beliefs regarding the desirability of a slightly heavy physique can encourage overeating. Nutrition educators need to be public policy advocates for environments providing tasty, low cost, healthful foods. Young adult Chinese Americans seek knowledge and skills for making convenient healthful food selections in the midst of a culture that advocates and provides an abundance of unhealthy choices.


Morphological Evolution of Tetrachlorinated Perylene Bisimides with Lengthy Alkyl Substituent Polycrystalline Thin Films during Reversible Phase Transitions.
The phase behavior and related morphological evolution of thin films of lengthy alkyl substituted core-tetrachlorinated perylene bisimide (C18-4ClPBI), a large π-conjugated molecule, have been studied. It is found that the C18-4ClPBI can exist in two different crystalline phases depending on temperature, which transform reversibly in heating and cooling processes. The X-ray diffraction results demonstrate that the two crystalline forms of C18-4ClPBI exhibit a similar packing geometry but with different unit cell dimensions. It is confirmed that the low-temperature phase is packed more compactly than its high-temperature counterpart. During high-temperature to low-temperature crystalline phase transition, nonbirefringent protrusions were observed, which disassembled in the reverse crystalline phase transition process during heating. The exact formation mechanism of the protrusions is not clear at the moment. Nevertheless, their influence on the transfer characteristics of the polycrystalline C18-4ClPBI thin film has been clearly illustrated.


Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials.
Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C(FX)) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.


Impact of hospital teaching status on survival from ruptured abdominal aortic aneurysm repair.
Controversy exists over the optimal hospital type to which high-risk surgical patients should be referred for operative management. While high volume centers have been traditionally advocated, recent evidence suggests teaching hospitals may have better outcomes for high-risk patients. We investigated whether mortality outcomes of patients undergoing surgery for ruptured abdominal aortic aneurysm (rAAA) were different between teaching hospitals and non-teaching hospitals, independent of hospital operative volume. A retrospective review of the Nationwide Inpatient Sample dataset (1998-2004) was performed to identify open and endovascular (EVAR) repair for rAAA. Hospitals were stratified by teaching status, including teaching hospitals (TH) with any type of residency training program, those with general surgery training programs (GSTH) and those with vascular surgery training programs (VSTH). The association of hospital teaching status with in-hospital mortality for open AAA repair and EVAR was assessed via multi-level multivariable logistic regression, controlling for patient demographics, comorbidities, and hospital operative volume. Of 6636 open AAA repairs for rAAA, the overall perioperative mortality was 42%. Mortality was significantly lower at TH than non-TH (39.3% vs 44.5%; P < .05). Mortality was also lower at GSTH (38.7%) and VSTH (34.3%). After adjusting for hospital operative volume, patient demographics, and comorbidities, we found a 25% decrease in likelihood of in-hospital death at VSTH vs non-VSTH (odds ratio 0.75; 95% confidence interval 0.60-0.94; P < .05). In-hospital mortality is significantly reduced for patients undergoing open AAA repair for rAAA at teaching hospitals and hospitals with vascular surgery training programs, independent of volume. These results suggest that in addition to factors associated with teaching hospitals in general, the type of specialty training within teaching institutions is a critical factor which may influence outcomes, specifically for patients with rAAA.


Different distribution of breast ductal carcinoma in situ, ductal carcinoma in situ with microinvasion, and invasion breast cancer.
Breast ductal cancer in situ (DCIS) can recur or progress to invasive ductal cancer (IDC), and the interim stage include DCIS with microinvasion (DCIS-Mi). In this article, we attempt to study the study the differences of clinicopathological features, imaging data, and immunohistochemical-based subtypes among DCIS, DCIS-Mi, and IDC. In this retrospective study, we attempt to compare the clinicopathological features, immunohistochemical results and imaging data of 866 patients (included 73 DCIS, 72 DCIS-Mi, and 721 IDC). Patients with DCIS and DCIS-Mi were younger than those with IDC (P = 0.007). DCIS and DCIS-Mi often happened in premenopausal women while IDC was opposite (P <0.001). The incidence of IDC with node-positive was significantly higher than it in DCIS and DCIS-Mi (P <0.001). We also observed that the Her2-positive was more often found in patients with pure DCIS compared to those with DCIS-Mi and DCIS-I (P <0.001). There was a significant difference between the four subgroups (Luminal-A, Luminal-B, ERBB2+, Basal-like) from DCIS, DCIS-Mi, and IDC (P <0.001). Basal-like patients were fewer than other subgroups in DCIS, DCIS-Mi, and IDC. The incidence of the first performance of ultrasound (catheter winded and nodular mass) and mammography (nodular mass) had significantly difference among patients with DCIS, DCIS-Mi, and IDC (P <0.001). Different clinicopathological, immunohistochemical, and imaging features among DCIS, DCIS-Mi, and IDC indicate that they are distinct entities. A larger sample size is needed for further study.


Toll-like Receptor 4 Signaling and Downstream Neutrophilic Inflammation Mediate Endotoxemia-Enhanced Blood-Labyrinth Barrier Trafficking.
Both toll-like receptor 4 (TLR4) and downstream neutrophil activity are required for endotoxemia-enhanced blood-labyrinth barrier (BLB) trafficking. Aminoglycoside and cisplatin are valuable clinical therapies; however, these drugs often cause life-long hearing loss. Endotoxemia enhances the ototoxicity of aminoglycosides and cisplatin in a TLR4 dependent mechanism for which downstream proinflammatory signaling orchestrates effector immune cells including neutrophils. Neutrophil-mediated vascular injury (NMVI) can enhance molecular trafficking across endothelial barriers and may contribute to endotoxemia-enhanced drug-induced ototoxicity. Lipopolysaccharide (LPS) hypo-responsive TLR4-KO mice and congenitally neutropenic granulocyte colony-stimulating factor (GCSF) GCSF-KO mice were studied to investigate the relative contributions of TLR4 signaling and downstream neutrophil activity to endotoxemia-enhanced BLB trafficking. C57Bl/6 wild-type mice were used as a positive control. Mice were treated with LPS and 24 hours later cochleae were analyzed for gene transcription of innate inflammatory cytokine/chemokine signaling molecules, neutrophil recruitment, and vascular trafficking of the paracellular tracer biocytin-TMR. Cochlear transcription of innate proinflammatory cytokines/chemokines was increased in endotoxemic C57Bl/6 and GCSF-KO, but not in TLR4-KO mice. More neutrophils were recruited to endotoxemic C57Bl/6 cochleae compared with both TLR4 and GCSF-KO cochleae. Endotoxemia enhanced BLB trafficking of biocytin-TMR in endotoxemic C57Bl/6 cochleae and this was attenuated in both TLR4 and GCSF-KO mice. Together these results suggest that TLR4-mediated innate immunity cytokine/chemokine signaling alone is not sufficient for endotoxemia-enhanced trafficking of biocytin-TMR and that downstream neutrophil activity is required to enhance BLB trafficking. Clinically, targeting neutrophilic inflammation could protect hearing during aminoglycoside, cisplatin, or other ototoxic drug therapies.


Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group.
To evaluate the efficacy of a 10-mg dose of midodrine 3 times per day in improving blood pressure (BP) and ameliorating symptoms of orthostatic hypotension in patients with neurogenic orthostatic hypotension. Midodrine hydrochloride, an alpha-agonist, could improve orthostatic BP by increasing vasomotor and venomotor tone. A total of 171 patients with orthostatic hypotension participated in a multicenter, randomized, placebo-controlled study. They were randomized to a 10-mg dose of midodrine or placebo 3 times per day in a 6-week study, comprising single-blind run-in (at week 1) and washout at weeks 5 and 6, with an intervening double-blind period (weeks 2 to 4). Twenty-five centers, with most patients evaluated in referral centers. The primary end points were improvement in standing systolic BP, symptoms of lightheadedness, and a global symptom relief score (by the investigator and patient separately). Nine patients were not evaluable because of noncompliance or taking concomitant vasoactive medications (3 in the midodrine group, 6 in the placebo group). In the evaluable patients, midodrine resulted in improvements in standing systolic BP at all time points (P<.001 at visits 2, 3, 4, and 5), in reported symptoms by the end of the second week of treatment (P=.001), and in the global symptom relief score rated by both the patient (P=.03) and the investigator (P<.001). There was no effect by center, severity of orthostatic hypotension, use of fludrocortisone or compression garments, or diagnosis. The main adverse effects were those of pilomotor reactions, urinary retention, and supine hypertension. Midodrine is efficacious and safe in the treatment of neurogenic orthostatic hypotension.


Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes.
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.


Assessment of serum level of corticotropin-releasing factor in primary nocturnal enuresis.
Primary nocturnal enuresis is one of the sleep related phenomena characterized by disruption in the relationship between arousal and urination. Corticotropin-releasing factor (CRF) is a neurohormone released from the paraventricular nucleus of the hypothalamus into the median eminence to elicit release of adrenocorticotrophin from the anterior pituitary. It may act to modulate autonomic function and behavior in concert with the endocrine effects. Conflicting animal studies about the role of CRF in micturition, either facilitating or inhibiting, have been raised. It was suggested to be a novel target for treatment of urinary disorders based on the finding that manipulation of CRF in the pontine micturition circuit could affect urodynamic function. The aim was to throw light on the possible role of CRF in primary monosymptomatic nocturnal enuresis by assessing its serum level. Twenty-nine children aged 8-14 years complaining of primary monosymptomatic nocturnal enuresis and 16 age- and sex-matched healthy children with good toilet control day and night were recruited to the study. History taking, clinical examination, and assessment of serum CRF levels in the morning and evening (9 a.m. and 9 p.m.) were carried out for all patients and controls. A positive family history of enuresis was detected in 82.8% of enuretic patients. Serum levels of CRF (both morning and evening) were significantly lower in patients than in controls. Several animal studies suggested that CRF in descending projections from Barrington's nucleus to the lumbosacral parasympathetic neurons is inhibitory to micturition, which supports our results and the assumption that reduction of the evening serum CRF level could have a role in the occurrence of primary monosymptomatic nocturnal enuresis. No significant difference was found between morning and evening CRF serum levels in either cases or controls, which negates our assumption of having a rhythmic pattern of release (figure). No correlations with age were found. According to their history, all our enuretic patients were deep sleepers. Deep sleep and difficult arousal were found to have a major role in primary monosymptomatic nocturnal enuresis. It was proposed that CRF function may allow arousal to occur before micturition to facilitate preparative behaviors. A lower CRF level may explain deep-sleep pattern in children with enuresis. CRF was deficient in our enuretic children, which may draw attention to the possible pathophysiological implications in primary nocturnal enuresis (either at the level of loss of inhibitory effect on micturition or lack of arousal in response to bladder distension). Further proof studies are recommended.


An international survey of current physiotherapy practice in diagnosis and knowledge translation of greater trochanteric pain syndrome (GTPS).
To evaluate how physiotherapists across three countries (Australia, New Zealand (NZ) and Ireland) diagnose greater trochanteric pain syndrome (GTPS) using clinical tests and imaging findings, and how physiotherapists update their knowledge regarding GTPS. Cross-sectional observational study of physiotherapists. An online survey was distributed to registered physiotherapists in Australia, NZ and Ireland. Ordinal and nominal data were analysed using frequency counts or mean ranks; medians and interquartile ranges were calculated for numerical data. Comparisons between the three countries were made using Chi-squared analyses for nominal/ordinal data and Kruskal Wallis tests for numerical data. Statistical significance was set at p < 0.05. Valid responses were received from 361 physiotherapists; 61% were female and 79.8% worked in private practice. Most respondents were very confident in diagnosing GTPS (67.9%) and incorporated a range of symptoms and tests, including validated tests, in their diagnosis. However, many physiotherapists were not commonly using some available validated diagnostic tests (e.g. FABER and FADER-R). Approximately 30% of physiotherapists used imaging to inform assessment, with ultrasound being most preferred. Physiotherapists rated hands-on experience as most valuable for updating their knowledge of GTPS, followed by courses. While most clinicians appear to be using current evidence in their assessment of patients with GTPS, a proportion use suboptimal methods and/or a limited range of diagnostic tests, suggesting that despite their confidence in diagnosis, further knowledge translation may be required. Future research should determine the best methods of facilitating knowledge acquisition and translation of research into practice.


Estrogen-astrocyte interactions: implications for neuroprotection.
Recent work has suggested that the ovarian steroid 17beta-estradiol, at physiological concentrations, may exert protective effects in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and acute ischemic stroke. While physiological concentrations of estrogen have consistently been shown to be protective in vivo, direct protection upon purified neurons is controversial, with many investigators unable to show a direct protection in highly purified primary neuronal cultures. These findings suggest that while direct protection may occur in some instances, an alternative or parallel pathway for protection may exist which could involve another cell type in the brain. A hypothetical indirect protective mechanism is proposed whereby physiological levels of estrogen stimulate the release of astrocyte-derived neuroprotective factors, which aid in the protection of neurons from cell death. This hypothesis is attractive as it provides a potential mechanism for protection of estrogen receptor (ER)-negative neurons through an astrocyte intermediate. It is envisioned that the indirect pathway could act in concert with the direct pathway to achieve a more widespread global protection of both ER+ and ER- neurons. We hypothesize that targeted deletion of estrogen receptors in astrocytes will significantly attenuate the neuroprotective effects of estrogen. If true, the hypothesis would significantly advance our understanding of endocrine-glia-neuron interactions. It may also help explain, at least in part, the reported beneficial effects of estrogen in neurodegenerative disorders. Finally, it also sets the stage for potential extension of the hypothetical mechanism to other important estrogen actions in the brain such as neurotropism, neurosecretion, and synaptic plasticity.


Apathy and cortical atrophy in Alzheimer's disease.
Apathy has been reported as the most prevalent behavioural symptom experienced in Alzheimer's disease (AD), associated with greater functional decline and caregiver distress. The aim of the current study was to investigate structural correlates of apathy in AD using magnetic resonance imaging (MRI) regional volume and regional cortical thickness measures. Semi-structured interviews were conducted with 111 AD patients and their caregivers as part of the European multi-centre study AddNeuroMed. Apathy was measured using the apathy domain of the Neuropsychiatric Inventory (NPI). All AD patients were scanned using a 1.5T MRI scanner and the images analysed using an automated analysis pipeline. We found apathy to be the most prevalent neuropsychiatric symptom occurring in 57% of patients. Apathetic patients had significantly greater cortical thinning in left caudal anterior cingulate cortex (ACC) and left lateral orbitofrontal cortex (OFC), as well as left superior and ventrolateral frontal regions, than those without apathy symptoms. Apathy is mediated by frontocortical structures but this is specific to the left hemisphere at least for patients in the mild to moderate stages of AD.


Reactive oxygen species mediate oridonin-induced apoptosis through DNA damage response and activation of JNK pathway in diffuse large B cell lymphoma.
This study investigated the cytotoxic effect of oridonin (ORI), a diterpenoid isolated from Rabdosia rubescens, in human diffuse large B cell lymphoma (DLBCL) in vitro and in vivo and the potential molecular mechanisms for ORI-induced cell apoptosis. ORI treatment caused reactive oxygen species (ROS)-mediated oxidative DNA damage response (DDR) and the c-Jun N-terminal kinase (JNK) pathway activation, leading to an induction of intrinsic apoptosis. ROS abolition blocked ORI-induced apoptosis and attenuated the expression of phospho-histone H2AX and phospho-JNK, indicating that ROS-mediated DNA damage and JNK pathway activation were involved in ORI-induced apoptosis. The systemic administration of ORI suppressed the growth of human DLBCL xenografts without showing significant toxicity. These findings suggest that ORI may have promising therapeutic application in DLBCL.


Cryopreservation and storage of embryogenic callus cultures of several Citrus species and cultivars.
Nucellus-derived embryogenic callus cultures of Salustiana sweet orange were subjected to cryoconservation assays. Cryoprotection with 10%(vol/vol) dimethylsulfoxide, freezing by slow cooling and thawing by fast warming was suitable to recover viable growing cultures and whole plants through embryogenesis. Evaluation of liquid phase R 1 and solid phase R 2 cooling rates using a programmable freezing unit indicated that 100% of embryogenic cultures survived when frozen using a range of cooling rates (R 1 not above 0.5°C min-1 and R 2 not above 1°C min 1) and thawed by fast warming. Storage up to 2 years in liquid nitrogen did not affect the growth of the cryopreserved cultures and the recovery of whole plants. Cultures of four cultivars of sweet orange (C. sinensis Osb.), three cultivars of grapefruit (C. paradisi Macf.), and one cultivar each of lemon [C. limon (L.) Burm. f.], Cleopatra mandarin (C. reshni Hort. ex Tan.), sour orange (C. aurantium L.) and Mexican lime [C. aurantifolia (Christm.) Swing.] have been successfully cryopreserved. Problems using a viability assessment using fluorescein diacetate staining are discussed.


The effect on immunity of long-term intensive training in elite swimmers.
The impact of long-term training on systemic and mucosal immunity was assessed prospectively in a cohort of elite swimmers over a 7-month training season in preparation for national championships. The results indicated significant suppression (P < 0.05) of serum IgA, IgG and IgM and salivary IgA concentration in athletes associated with long-term training at an intensive level. There was also a trend towards lower IgG2 subclass levels in serum in athletes compared with controls (P = 0.07). There were no significant changes in numbers or percentages of B or T cell subsets, but there was a significant fall in natural killer (NK) cell numbers and percentages in athletes over the training season (P < 0.05). After individual training sessions there was a significant decrease in salivary IgA levels for athletes compared with controls (P = 0.002). In athletes there was a downward trend in salivary IgA levels over the 7-month training period in both the pre-exercise (P = 0.06) and post-exercise samples (P = 0.04). There were no significant trends in salivary IgG levels over the study period in either athletes or controls. The only significant change in salivary IgM levels was an increase in detection rate in the pre-competition phase in athletes (P = 0.03). The study suggests that training of elite athletes at an intensive level over both short- and long-time frames suppresses both systemic and mucosal immunity. Protracted immune suppression linked with prolonged training may determine susceptibility to infection, particularly at times of major competitions.


Field-induced slow relaxation of magnetization in a pentacoordinate Co(II) compound [Co(phen)(DMSO)Cl2].
The static and dynamic magnetic properties of a pentacoordinate [Co(phen)(DMSO)Cl2] compound (phen = 1,10'-phenanthroline, DMSO = dimethyl sulfoxide) were thoroughly studied by experimental (SQUID magnetometry and HF-EPR spectroscopy) and theoretical methods (DFT and CASSCF calculations). It has been found from temperature/field-dependent magnetization measurements that the studied compound possesses a large and negative magnetic anisotropy (D = -17(1) cm(-1)) with large rhombicity (E/D = 0.24(5)), and these experimental results are in agreement with ab initio calculations (D = -17.7 cm(-1), E/D = 0.31). Interdoublet resonances were not observed in the HF-EPR measurements, but the large rhombicity was confirmed (DEPR = -17.7 cm(-1) (fixed from CASSCF calculations), E/DEPR = 0.33). A frequency dependent out-of-phase susceptibility signal was observed only in a non-zero static magnetic field (B = 0.1 T) and the following parameters of slow-relaxation of magnetisation were derived from the experimental data: either the energy of spin reversal barrier, Ueff = 10.4 K, and the relaxation time, τ0 = 5.69 × 10(-9) s using the Debye model, or Ueff = 21.4-40.3 K and τ0 = 0.248-58.3 × 10(-9) based on a simplified model.


Trazodone influence on rat sera beta-endorphins level.
Some 25 years ago it was found that parts of CNS could produce strong analgesic response on little morphine quantities. Later studies proved the existence for dozen of morphine-like substances, called opioids, which are normally produced in the brain. The most important are endorphins, met- and leu-encephalin and dinorphin produced both in hypothalamus and pituitary gland. The aim of our study was to found whether and how strong produce of beta-endorphins is to be expected when psychotropic drugs are used. Trazodon as antidepressant was used, and RIA technique for quantification of sera beta-endorphins. The results showed significant difference in rat sera beta-endorphins between certain days of drug application. These studies showed that beta-endorphins could be of great importance, used as markers for evaluation of patient treatment and eventual abuse of psychotropic drugs.


Health insurance and health at age 65: implications for medical care spending on new Medicare beneficiaries.
To investigate the consequences of endogeneity bias on the estimated effect of having health insurance on health at age 63 or 64, just before most people qualify for Medicare, and to simulate the implications for total and public insurance (Medicare and Medicaid) spending on newly enrolled beneficiaries in their first years of Medicare coverage. The longitudinal Health and Retirement Survey of people who were 55-61 years old in 1992, followed through biannual surveys to age 63-64 or until 2000 (whichever came first), and those who were 66-70 years olds from the Medicare Current Beneficiary Surveys, 1992-1998. Instrumental variable (IV) estimation of a simultaneous equation model of insurance choice and health at age 63-64 as a function of baseline health and sociodemographic characteristics in 1992 and endogenous insurance coverage over the observation period. Continuous insurance coverage is associated with significantly fewer deaths prior to age 65 and, among those who survive, a significant upward shift in the distribution of health states from fair and poor health with disabilities to good to excellent health. Treating insurance coverage as endogenous increases the magnitude of the estimated effect of having insurance on improved health prior to age 65. The medical spending simulations suggest that if the near-elderly had continuous insurance coverage, average annual medical spending per capita for new Medicare beneficiaries in their first few years of coverage would be slightly lower because of the improvement in health status. In addition, total Medicare and Medicaid spending for new beneficiaries over their first few years of coverage would be about the same or slightly lower, even though more people survive to age 65. Extending insurance coverage to all Americans between the ages of 55 and 64 would improve health (increase survival and shift people from good-fair-poor health to excellent-very good health) at age 65, and possibly reduce total short-term spending by Medicare and Medicaid for newly eligible Medicare beneficiaries, even though more people would enter the program because of increased survival.


Pharmacological MRI responses of raclopride in rats: The relationship with D2 receptor occupancy and cataleptic behavior.
Pharmacological magnetic resonance imaging (phMRI) allows the visualization of brain pharmacological effects of drugs using functional MRI (fMRI). phMRI can help us facilitate central nervous system (CNS) drug development. However, there have been few studies demonstrating the dose relationship of the fMRI response induced by CNS drugs to underlying target engagement or behavioral efficacy. To clarify these relationships, we examined receptor occupancy measurements using positron emission tomography (PET) (n = 3~5), fMRI (n = 5~8) and a cataleptic behavior (n = 6) with raclopride, a dopamine D2 receptor antagonist (8, 20, and 200 μg/kg) on Wistar rats. Dopamine D2 receptor occupancy was increased dose dependently by raclopride (41.8 ± 2.7%, 8 μg/kg; 64.9 ± 2.8%, 20 μg/kg; 83.1 ± 3.0%, 200 μg/kg). phMRI study revealed significant positive responses to raclopride at 200 μg/kg specifically in the striatum and nucleus accumbens, related to dopaminergic system. Slight fMRI responses were observed at 20 μg/kg in some areas corresponding to the striatum and nucleus accumbens. There were no noticeable fMRI responses at 8 μg/kg raclopride administration. Raclopride at 200 μg/kg significantly increased the cataleptic score, although, at 8 and 20 μg/kg, raclopride had no significant effects. These findings showed that raclopride-induced fMRI responses were observed at doses inducing cataleptic behavior and high D2 receptor occupancy, suggesting that phMRI can be useful for dose selection in clinical trial as an evaluation method of brain activity, which reflects behavioral responses induced by target engagements.


Follow-up and family study of anxious depression.
The failure of the concept of anxious depression to find its way into DSM-III-R led the authors to conclude that a further report on the occurrence of anxiety symptoms in depressed subjects is indicated. The subjects were 327 consecutively evaluated inpatients and outpatients with primary unipolar depressive disorder at five university medical centers participating in the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression--Clinical Studies. The authors restricted their sample selection to patients with primary depressive disorder so that patients with other preexisting psychiatric disorders, especially anxiety disorders, would not contaminate the symptom picture, family studies, or follow-up. The examined six anxiety symptoms and derived a new anxiety summary score to show the effect of anxiety in depression on family data and 5-year outcome. Depressed subjects with higher ratings for anxiety took longer to recover. There was also a significant relationship between anxiety in depressed probands and the risk for primary unipolar depressive disorder, but not anxiety disorders or alcoholism, among 832 blindly interviewed first-degree relatives. These data confirm the usefulness of subdividing depressed patients according to anxiety symptoms: psychic and somatic symptoms of anxiety, taken together, significantly predict family illness and course. The data also emphasize the wisdom of requiring that generalized anxiety disorder not be diagnosed in the presence of a mood disorder. Clearly, symptoms of anxiety coexist with depression and need to be recognized for the effective treatment of the underlying depressive disorder.


The aerodynamic effects of wing rotation and a revised quasi-steady model of flapping flight.
We used a dynamically scaled model insect to measure the rotational forces produced by a flapping insect wing. A steadily translating wing was rotated at a range of constant angular velocities, and the resulting aerodynamic forces were measured using a sensor attached to the base of the wing. These instantaneous forces were compared with quasi-steady estimates based on translational force coefficients. Because translational and rotational velocities were constant, the wing inertia was negligible, and any difference between measured forces and estimates based on translational force coefficients could be attributed to the aerodynamic effects of wing rotation. By factoring out the geometry and kinematics of the wings from the rotational forces, we determined rotational force coefficients for a range of angular velocities and different axes of rotation. The measured coefficients were compared with a mathematical model developed for two-dimensional motions in inviscid fluids, which we adapted to the three-dimensional case using blade element theory. As predicted by theory, the rotational coefficient varied linearly with the position of the rotational axis for all angular velocities measured. The coefficient also, however, varied with angular velocity, in contrast to theoretical predictions. Using the measured rotational coefficients, we modified a standard quasi-steady model of insect flight to include rotational forces, translational forces and the added mass inertia. The revised model predicts the time course of force generation for several different patterns of flapping kinematics more accurately than a model based solely on translational force coefficients. By subtracting the improved quasi-steady estimates from the measured forces, we isolated the aerodynamic forces due to wake capture.


Organotypic culture as a research and preclinical model to study uterine leiomyomas.
Organotypic cultures of tissue slices have been successfully established in lung, prostate, colon, gastric and breast cancer among other malignancies, but until now an ex vivo model based on tissue slices has not been established for uterine leiomyoma. In the present study, we describe a method for culturing tumour slides onto an alginate scaffold. Morphological integrity of tissue slices was maintained for up to 7 days of culture, with cells expressing desmin, estrogen and progesterone receptors. Driver mutations were present in the ex vivo slices at all-time points analyzed. Cultivated tumour slices responded to ovarian hormones stimulation upregulating the expression of genes involved in leiomyoma pathogenesis. This tissue model preserves extracellular matrix, cellular diversity and genetic background simulating more in-vivo-like situations. As a novelty, this platform allows encapsulation of microspheres containing drugs that can be tested on the ex vivo tumour slices. After optimizing drug release rates, microspheres would then be directly tested in animal models through local injection.


Persistent infection with high-risk human papilloma viruses: cohort study, Mérida, Venezuela.
Cervical lesions have been associated with infection by high-risk human papilloma virus (high-risk HPV). In 409 women aged >15 years high-risk HPV lesions were identified. In a cohort of this population persistent infection was compared with cytological, colposcopic, and histological lesions. Cervical scrapes were taken and DNA was isolated. HPV was detected by PCR in the E6/E7 region. Genotyping was performed by PCR nested multiple E6/E7. HPV was detected in a 37.40% (153/409), high-risk HPV in 86% (153/178), HPV18 46.64% (83/178), HPV16 34.28% (61/178). Among these 53.93% (96/178) were multiple infections, and HPV18/16 (30/96) was the most frequent 31.25%. The cytology showed changes in 15% of positive patients. A 49.67% in women positive for HPV infection showed abnormalities in the colposcopic study, a relationship that turned out to be statistically significant ( p < 0.0019 test χ(2)). Among all 85% of the women were younger than 45 years of age. Fifty-seven patients were evaluated 15 months after the base study, with initial prevalence of morbidity 49.12% (28/57) and at the end 10.53% (6/57), showing in 89.29% (25/28) negative for HR-HPV infection, 10.34% (3/28) showed persistence of infection, 17.54% (10/57) presented cytological alterations, with 80% of positivity for HPV, and a regression of 100% (10/10) of the previously identified lesions. With colposcopy, 50% (14/28) presented alterations related to HPV, of these 85.71% (12/14) showed regression of such an alteration. The cumulative incidence for HPV was 10.34% (3/29). The incidence rate was 4.23% (3/71), which is equal to 4.23 new cases of HPV infection per 100 people, per year of follow-up. In conclusion, the present work shows a high frequency of infection by high-risk HPV, with predominance of HPV18 and 16 and in general for multiple infections. Colposcopy was better predictor than the Pap smear for infection. The follow-up study revealed a low percentage of persistent infection, and a high frequency of negativity for viral infection, high regression of cytological and colposcopic lesions, a low cumulative and incidence rate similar to that reported by other Latin American countries and higher than the European countries.


Functional Effect of the Mutations Similar to the Cleavage during Platelet Activation at Integrin β3 Cytoplasmic Tail when Expressed in Mouse Platelets.
Previous studies in Chinese hamster ovary cells showed that truncational mutations of β3 at sites of F754 and Y759 mimicking calpain cleavage regulate integrin signaling. The roles of the sequence from F754 to C-terminus and the conservative N756ITY759 motif in platelet function have yet to be elaborated. Mice expressing β3 with F754 and Y759 truncations, or NITY deletion (β3-ΔTNITYRGT, β3-ΔRGT, or β3-ΔNITY) were established through transplanting the homozygous β3-deficient mouse bone marrow cells infected by the GFP tagged MSCV MigR1 retroviral vector encoding different β3 mutants into lethally radiated wild-type mice. The platelets were harvested for soluble fibrinogen binding and platelet spreading on immobilized fibrinogen. Platelet adhesion on fibrinogen- and collagen-coated surface under flow was also tested to assess the ability of the platelets to resist hydrodynamic drag forces. Data showed a drastic inhibition of the β3-ΔTNITYRGT platelets to bind soluble fibrinogen and spread on immobilized fibrinogen in contrast to a partially impaired fibrinogen binding and an almost unaffected spreading exhibited in the β3-ΔNITY platelets. Behaviors of the β3-ΔRGT platelets were consistent with the previous observations in the β3-ΔRGT knock-in platelets. The adhesion impairment of platelets with the β3 mutants under flow was in different orders of magnitude shown as: β3-ΔTNITYRGT>β3-ΔRGT>β3-ΔNITY to fibrinogen-coated surface, and β3-ΔTNITYRGT>β3-ΔNITY>β3-ΔRGT to collagen-coated surface. To evaluate the interaction of the β3 mutants with signaling molecules, GST pull-down and immunofluorescent assays were performed. Results showed that β3-ΔRGT interacted with kindlin but not c-Src, β3-ΔNITY interacted with c-Src but not kindlin, while β3-ΔTNITYRGT did not interact with both proteins. This study provided evidence in platelets at both static and flow conditions that the calpain cleavage-related sequences of integrin β3, i.e. T755NITYRGT762, R760GT762, and N756ITY759 participate in bidirectional, outside-in, and inside-out signaling, respectively and the association of c-Src or kindlin with β3 integrin may regulate these processes.


Outcomes of Allogeneic Stem Cell Transplant for Elderly Patients with Hematologic Malignancies.
Reduced-intensity conditioning (RIC) regimens, improved HLA matching, and better supportive care allow allogeneic stem cell transplant (alloSCT) to be offered to older patients. Only a small percentage of eligible patients between ages 65 and 74 years actually undergo alloSCT, and comprehensive outcome data from the aging population are still lacking. We examined the outcome of older patients who underwent alloSCT using melphalan-based RIC for hematologic malignancies at our institution. We identified 125 patients older than 65 years (median, 69; range, 66 to 77) who underwent matched related donor, matched unrelated donor, or combined haploidentical/umbilical cord alloSCT between 2012 through November, 2017. Among them, 52 (41.6%) and 70 (56%) had, respectively, intermediate and high/very high Center for International Blood and Marrow Transplant Research (CIBMTR) disease risk index (DRI). One hundred six patients (85%) received fludarabine/melphalan-based RIC regimen with either antithymocyte globulin (ATG) or alemtuzumab. The median time to neutrophil engraftment was 13 days (range, 8 to 37) and platelet engraftment 17 days (range, 9 to 169). The cumulative incidence of nonrelapse mortality was 11.5% at 100 days and 30.1% and 34.8% at 1 and 2 years, respectively. The cumulative incidence of relapse was 35% and 40% at 1 and 2 years. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) at day 100 and 6 months was 29.5% and 34.5%, and chronic GVHD at 6, 12, and 24 months was 2.5%, 5.2%, and 6.3%, respectively. With a median follow-up of 32 months, the 1-, 2-, and 3-year progression-free survival (PFS) was 34.6%, 24.4%, and 16.5%, respectively. The graft GVHD-free survival was 24.6%, 16.1%, and 9.3%, respectively. The 1-, 2-, and 3-year overall survival (OS) was 44.5%, 30.7%, and 26.5%, respectively. In multivariable analysis, low albumin was predictive of poor PFS and OS and high hematopoietic cell transplantation-specific comorbidity index, and CIBMTR DRI was predictive of worse graft GVHD-free survival. Among long-term survivors the median Karnofsky performance status was 80. Older patients, even when referred with advanced disease, can benefit from melphalan-based alloSCT with HLA-matched or alternative donor sources without discernible impact of donor source on outcome. Using alemtuzumab- or ATG-based in vivo T cell depletion, the incidence of chronic GVHD is extremely low. Performance status in survivors is excellent. Better predictors for outcome in this patient population need to be identified.


RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer.
Right-sided colorectal cancer (RCRC) demonstrates worse survival outcome compared with left-sided CRC (LCRC). Recently, the importance of RNF43 mutation and BRAF V600E mutation has been reported in the serrated neoplasia pathway, which is one of the precancerous lesions in RCRC. It was hypothesized that the clinical significance of RNF43 mutation differs according to primary tumor sidedness. To test this hypothesis, the clinicopathological characteristics and survival outcome of patients with RNF43 mutation in RCRC and LCRC were investigated. Stage I-IV CRC patients (n=201) were analyzed. Genetic alterations including RNF43 using a 415-gene panel were investigated. Clinicopathological characteristics between RNF43 wild-type and RNF43 mutant-type were analyzed. Moreover, RNF43 mutant-type was classified according to primary tumor sidedness, i.e., right-sided RNF43 mutant-type or left-sided RNF43 mutant-type, and the clinicopathological characteristics between the two groups were compared. RNF43 mutational prevalence, spectrum and frequency between our cohort and TCGA samples were compared. RNF43 mutation was observed in 27 out of 201 patients (13%). Multivariate analysis revealed that age (≥65), absence of venous invasion, and BRAF V600E mutation were independently associated with RNF43 mutation. Among the 27 patients with RNF43 mutation, 12 patients were right-sided RNF43 mutant-type and 15 left-sided RNF43 mutant-type. Right-sided RNF43 mutant-type was significantly associated with histopathological grade 3, presence of lymphatic invasion, APC wild, BRAF V600E mutation, microsatellite instability-high (MSI-H), and RNF43 nonsense/frameshift mutation compared with left-sided RNF43 mutant-type. Similarly, RNF43 nonsense/frameshift mutations were more frequently observed in RCRC compared with LCRC in the TCGA cohort (P=0.042). Right-sided RNF43 mutant-type exhibited significantly worse overall survival than RNF43 wild-type and left-sided RNF43 mutant-type (P=0.001 and P=0.023, respectively) in stage IV disease. RNF43 mutation may be a distinct molecular subtype which is associated with aggressive tumor biology along with BRAF V600E mutation in RCRC.


Functional imaging of an alcohol-Implicit Association Test (IAT).
This research assessed activation in neural substrates involved in implicit associative processes through functional magnetic resonance imaging of an alcohol-Implicit Association Test (IAT) focused on positive outcomes of alcohol use. Comparisons involved 17 heavy and 19 light drinkers, ranging in age from 18 to 22, during compatible and incompatible association task trials. Behaviorally, a significant IAT effect was found with heavy drinkers showing stronger positive implicit associations toward alcohol use than light drinkers. Imaging data revealed heavy drinkers showed greater activity during compatible trials relative to incompatible trials in the left putamen and insula while no significant difference in activity between conditions was found in the light drinkers. Light drinkers showed significantly more activity in the left orbital frontal cortex during both compatible and incompatible trials than heavy drinkers, and the dorsolateral prefrontal cortex was engaged more in both light and heavy drinkers during incompatible trials relative to compatible trials. Further, within-group analyses showed significant amygdala activity along with the putamen and insula among heavy drinkers during compatible trials relative to incompatible trials. These results are consistent with a dual process framework of appetitive behaviors proposing that (1) implicit associations underlying habit are mediated through neural circuitry dependent on the striatum, and (2) controlled behaviors are mediated through neural circuitry more dependent on the prefrontal cortex. This is the first study to evaluate the neural mechanisms elicited by an alcohol-IAT, providing an additional step toward increasing understanding of associative habit processes and their regulatory influence over addictive behaviors.


Renal collecting duct carcinoma with extensive coagulative necrosis mimicking anemic infarct: report of a case and the literature review.
Collecting duct carcinoma (CDC) with a mass of coagulative necrosis is very rare. We report here a case of CDC with extensive geographic coagulative necrosis mimicking anemic infarct with tumor cells embedded around the necrotic foci in a 73-years-old man. Histopathological examination showed that tumor nests near the necrotic foci were arranged as angulated tubules, tubulopapillary and glandular structures. Neoplastic cells had moderate to abundant eosinophilic cytoplasm and large hyperchromatic nuclei with prominent nucleoli as Fuhrman nuclear grade 3 or 4. The tumor cells were positive for pan-Cytokeratin, Vimentin, E-cadherin, CD10, and CK7, confirming the diagnosis as CDC. The patient is still alive 6 months later from nephrectomy, a long time following up is needed to learn the prognosis. Conclusively, morphology from different portions of the lesion, immunohistochemical stain and the combination analysis of the radiological features is essential to make a precise pathological diagnosis of CDC. And CDC should also be distinguished from clear cell renal cell carcinoma, renal medullary carcinoma, urothelial carcinoma with glandular differentiation, renal neuroendocrine tumor, renal epithelioid angiomyolipoma, renal pigmented paraganglioma and renal mesenchymal chondrosarcoma etc. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1264270525975030.


Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors.
Wnt5a is a non-canonical signaling Wnt that has been implicated in tumor suppression. We previously showed that loss of Wnt5a in MMTV-PyVmT tumors resulted in a switch in tumor phenotype resulting in tumors with increased basal phenotype and high Wnt/β-catenin signaling. The object of this study was to test the hypothesis that Wnt5a can act to inhibit tumors formed by activation of Wnt/β-catenin signaling. To this end, we characterized tumor and non-tumor mammary tissue from MMTV-Wnt1 and double transgenic MMTV-Wnt1;MMTV-Wnt5a mice. Wnt5a containing mice demonstrated fewer tumors with increased latency when compared to MMTV-Wnt1 controls. Expression of markers for basal-like tumors was down-regulated in the tumors that formed in the presence of Wnt5a indicating a phenotypic switch. Reduced canonical Wnt signaling was detected in double transgenic tumors as a decrease in active β-catenin protein and a decrease in Axin2 mRNA transcript levels. In non-tumor tissues, over-expression of Wnt5a in MMTV-Wnt1 mammary glands resulted in attenuation of phenotypes normally observed in MMTV-Wnt1 glands including hyperbranching and increased progenitor and basal cell populations. Even though Wnt5a could antagonize Wnt/β-catenin signaling in primary mammary epithelial cells in culture, reduced Wnt/β-catenin signaling was not detected in non-tumor MMTV-Wnt1;Wnt5a tissue in vivo. The data demonstrate that Wnt5a suppresses tumor formation and promotes a phenotypic shift in MMTV-Wnt1 tumors.


The effect of atrial natriuretic peptide infusion on intestinal injury in septic shock.
The aim of this study is to assess the effect of atrial natriuretic peptide (ANP) on intestinal ischemia-reperfusion injury in septic shock. A prospective randomized controlled, observer-blinded study was carried out in surgical Intensive Care Unit (ICU), University Hospital. Forty adult patients in septic shock were randomly divided into two groups, control group (Group C) received normal saline and ANP group (Group A) patients received ANP in the form of 1.5 mg vial added to 250 ml solvent in plastic bag (1 ml = 6 micg) given at 2 mcg/kg intravenous bolus over 1 min followed by 0.01 mcg/kg/min for 24 h. The primary outcome measurements were blood marker of intestinal hypoperfusion in form of intestinal fatty acid binding protein (I-FABP), malondialdehyde (MDA), myloperoxidase enzyme activity (MPO), protein carbonyl (PC), and glutathione peroxidase activity (GPA) measured before start of ANP infusion, 6 h, 12 h, and 24 h after start of infusion. The secondary outcome measurements were the duration of noradrenaline infusion, duration of ICU stay, hospital mortality rate, and complications related to ANP. In comparison with Group C, Group A showed a significant decrease (P < 0.05) in serum level of MPO, MDA, PC, and I-FABP, with a significant increase (P < 0.05) in serum level of GPA, 6 h, 12 h, and 24 h after the start of ANP infusion. There was significant decrease (P < 0.05) in mean duration of noradrenaline infusion, the length of ICU stay and mortality rate in Group A in comparison with Group C. In Group A, seven patients had mean arterial blood pressure < 65 mmHg but respond to volume resuscitation, three patients serum sodium was 125-130 mmol/L. In cases of septic shock, concomitant administration of ANP with noradrenaline may have a protective effect against intestinal injury through a decrease in the level of intestinal hypoperfusion owing to its anti-inflammatory and antioxidant effect.


Gamma knife radiosurgery for local recurrence of glioblastoma.
Local recurrence of glioblastoma is observed in most patients after standard oncologic treatment (surgery, chemotherapy and radiotherapy). Stereotactic radiosurgery with the Leksell Gamma Knife (SRS with LGK) was used to treat recurrent tumors in selected cases, and retrospective analysis of treatment outcome was performed. Altogether 126 patients were treated for glioblastoma at our center from 1992-2014. Sixty-nine patients (55%) were male and 57 (45%) female, with a median age of 56 years (range 17-80 years). Prior to LGK radiosurgery, 123 (98%) underwent surgery, 126 (100%) radiotherapy and 116 (92%) chemotherapy. The median Karnofsky score before LGK radiosurgery was 90% (range 50-100), and the median time from GBM diagnosis to LGK radiosurgery was 12 months (range 1-96 months). The median tumor volume was 3.75 cm3 (range 0.04-37.10 cm3). LGK radiosurgery was performed in a single fraction with a median minimal tumor dose of 12 Gy (range 10-25 Gy) on a median 50% (range 40-86%) isodose line. Two and more LGK radiosurgeries were performed in 19 (15%) cases, a median interval of 9.6 months (range 2-45 months) from the initial LGK radiosurgery. The median prescribed dose in these patients was 12.6 Gy (range 10-15 Gy), and the median volume 5.8 cm3 (range 0.1-13.7 cm3). The median survival from GBM diagnosis was 20 months (range 6-237 months). The median survival after LGK radiosurgery was 7 months (range 1-223 months). The one year survival after LGK radiosurgery was 27%, 2 years 8%, and more than 3 years 4%. Tumor regression on MR images was observed in 17% of patients at a median interval of 7 months. The median interval to tumor progression on MR images after LGK treatment was 8.5 months. No treatment-related radionecrosis with expansive behaviour was detected after radiosurgery. We show that LGK radiosurgery is a safe palliative treatment modality in patients with recurrent GBM.


Complementary process to response bias in the centromedian nucleus of the thalamus.
Activity in several areas of the human brain and the monkey brain increases when a subject anticipates events associated with a reward, implicating a role for bias of decision and action. However, in real life, events do not always appear as expected, and we must choose an undesirable action. More than half of the neurons in the monkey centromedian (CM) thalamus were selectively activated when a small-reward action was required but a large-reward option was anticipated. Electrical stimulation of the CM after a large-reward action request substituted a brisk performance with a sluggish performance. These results suggest involvement of the CM in a mechanism complementary to decision and action bias.


Determinants of the in vivo folding of the prion protein. A bipartite function of helix 1 in folding and aggregation.
Misfolding of the mammalian prion protein (PrP) is implicated in the pathogenesis of prion diseases. We analyzed wild type PrP in comparison with different PrP mutants and identified determinants of the in vivo folding pathway of PrP. The complete N terminus of PrP including the putative transmembrane domain and the first beta-strand could be deleted without interfering with PrP maturation. Helix 1, however, turned out to be a major determinant of PrP folding. Disruption of helix 1 prevented attachment of the glycosylphosphatidylinositol (GPI) anchor and the formation of complex N-linked glycans; instead, a high mannose PrP glycoform was secreted into the cell culture supernatant. In the absence of a C-terminal membrane anchor, however, helix 1 induced the formation of unglycosylated and partially protease-resistant PrP aggregates. Moreover, we could show that the C-terminal GPI anchor signal sequence, independent of its role in GPI anchor attachment, mediates core glycosylation of nascent PrP. Interestingly, conversion of high mannose glycans to complex type glycans only occurred when PrP was membrane-anchored. Our study indicates a bipartite function of helix 1 in the maturation and aggregation of PrP and emphasizes a critical role of a membrane anchor in the formation of complex glycosylated PrP.


Fluctuations in number of Cercospora beticola conidia in relationship to environment and disease severity in sugar beet.
Cercospora leaf spot, caused by Cercospora beticola, is the most damaging foliar disease of sugar beet in Minnesota (MN) and North Dakota (ND). Research was conducted to characterize the temporal progression of aerial concentration of C. beticola conidia in association with the environment and disease severity in sugar beet. In 2003 and 2004, volumetric spore traps were placed within inoculated sugar beet plots to determine daily dispersal of conidia at Breckenridge, MN, and St. Thomas, ND. Plots were rated weekly for disease severity. At both locations, conidia were first collected in early July 2003 and late June in 2004. Peaks of conidia per cubic meter of air were observed with maxima in late August 2003 and in early September 2004 at both locations. Peaks of airborne conidium concentration were significantly correlated with the average temperature of daily hours when relative humidity was greater than 87%. Weekly mean hourly conidia per cubic meter of air was significantly (P < 0.01) associated with disease severity during both years and across locations. This study showed that C. beticola conidial numbers may be used to estimate potential disease severity that, with further research, could be incorporated in a disease forecasting model to rationalize Cercospora leaf spot management.


Understanding rice adaptation to varying agro-ecosystems: trait interactions and quantitative trait loci.
Interaction and genetic control for traits influencing the adaptation of the rice crop to varying environments was studied in a mapping population derived from parents (Moroberekan and Swarna) contrasting for drought tolerance, yield potential, lodging resistance, and adaptation to dry direct seeding. A BC2F3-derived mapping population for traits related to these four trait groups was phenotyped to understand the interactions among traits and to map and align QTLs using composite interval mapping (CIM). The study also aimed to identify QTLs for the four trait groups as composite traits using multivariate least square interval mapping (MLSIM) to further understand the genetic control of these traits. Significant correlations between drought- and yield-related traits at seedling and reproductive stages respectively with traits for adaptation to dry direct-seeded conditions were observed. CIM and MLSIM methods were applied to identify QTLs for univariate and composite traits. QTL clusters showing alignment of QTLs for several traits within and across trait groups were detected at chromosomes 3, 4, and 7 through CIM. The largest number of QTLs related to traits belonging to all four trait groups were identified on chromosome 3 close to the qDTY 3.2 locus. These included QTLs for traits such as bleeding rate, shoot biomass, stem strength, and spikelet fertility. Multivariate QTLs were identified at loci supported by univariate QTLs such as on chromosomes 3 and 4 as well as at distinctly different loci on chromosome 8 which were undetected through CIM. Rice requires better adaptation across a wide range of environments and cultivation practices to adjust to climate change. Understanding the genetics and trade-offs related to each of these environments and cultivation practices thus becomes highly important to develop varieties with stability of yield across them. This study provides a wider picture of the genetics and physiology of adaptation of rice to wide range of environments. With a complete understanding of the processes and relationships between traits and trait groups, marker-assisted breeding can be used more efficiently to develop plant types that can combine all or most of the beneficial traits and show high stability across environments, ecosystems, and cultivation practices.


Latitudinal distribution of prokaryotic picoplankton populations in the Atlantic Ocean.
Members of the prokaryotic picoplankton are the main drivers of the biogeochemical cycles over large areas of the world's oceans. In order to ascertain changes in picoplankton composition in the euphotic and twilight zones at an ocean basin scale we determined the distribution of 11 marine bacterial and archaeal phyla in three different water layers along a transect across the Atlantic Ocean from South Africa (32.9 degrees S) to the UK (46.4 degrees N) during boreal spring. Depth profiles down to 500 m at 65 stations were analysed by catalysed reporter deposition fluorescence in situ hybridization (CARD-FISH) and automated epifluorescence microscopy. There was no obvious overall difference in microbial community composition between the surface water layer and the deep chlorophyll maximum (DCM) layer. There were, however, significant differences between the two photic water layers and the mesopelagic zone. SAR11 (35 +/- 9%) and Prochlorococcus (12 +/- 8%) together dominated the surface waters, whereas SAR11 and Crenarchaeota of the marine group I formed equal proportions of the picoplankton community below the DCM (both approximately 15%). However, due to their small cell sizes Crenarchaeota contributed distinctly less to total microbial biomass than SAR11 in this mesopelagic water layer. Bacteria from the uncultured Chloroflexi-related clade SAR202 occurred preferentially below the DCM (4-6%). Distinct latitudinal distribution patterns were found both in the photic zone and in the mesopelagic waters: in the photic zone, SAR11 was more abundant in the Northern Atlantic Ocean (up to 45%) than in the Southern Atlantic gyre (approximately 25%), the biomass of Prochlorococcus peaked in the tropical Atlantic Ocean, and Bacteroidetes and Gammaproteobacteria bloomed in the nutrient-rich northern temperate waters and in the Benguela upwelling. In mesopelagic waters, higher proportions of SAR202 were present in both central gyre regions, whereas Crenarchaeota were clearly more abundant in the upwelling regions and in higher latitudes. Other phylogenetic groups such as the Planctomycetes, marine group II Euryarchaeota and the uncultured clades SAR406, SAR324 and SAR86 rarely exceeded more than 5% of relative abundance.


Lack of the t(2;5) or other mutations resulting in expression of anaplastic lymphoma kinase catalytic domain in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin's disease.
The t(2;5) (p23;q35) chromosomal translocation has been found in a high proportion of lymph node-based CD30+ large cell lymphomas of T-cell lineage. This translocation is believed to result in the expression of a fusion protein containing the catalytic domain of anaplastic lymphoma kinase (ALK) under the control of the promoter for nucleophosmin, a nucleolar phosphoprotein. Expression of ALK activity, which does not normally occur in lymphocytes, is postulated to be involved in the pathogenesis of lymphomas bearing the t(2;5) translocation. Several primary cutaneous lymphoproliferative disorders and Hodgkin's disease are also known to contain CD30+ large lymphoid cells. To determine the role of the t(2;5) translocation in these diseases, we developed a DNA-based polymerase chain reaction (PCR)/Southern blot assay to detect this translocation at the genomic level in lymphomatoid papulosis (14 cases), primary cutaneous CD30+ large cell lymphoma of T-lineage (10 cases) and Hodgkin's disease (13 cases). Two cases of pityriasis lichenoides were also studied. The t(2;5) translocation was not present in any of these specimens. To determine if some other somatic mutation might have resulted in inappropriate expression of ALK catalytic domain, we devised an RNA-based reverse transcriptase-PCR assay to detect transcripts encoded by this ALK region. None were found in the six additional cases of lymphomatoid papulosis that were studied. In aggregate, these results strongly suggest that inappropriate expression of ALK is not involved in the pathogenesis of these CD30+ lymphoproliferative disorders, and that lymph node-based CD30+ large cell lymphoma is a disease that is biologically distinct from skin-based CD30+ lymphoproliferative disorders and Hodgkin's disease. Using methods developed for this report, we also cloned and sequenced the t(2;5) genomic junctional sequences present in the SUP-M2 and SU-DHL-1 cell lines. These intron sequences will be useful for mapping t(2;5) breakpoint clusters.


Effects of a commercial broiler enrichment programme with or without natural light on behaviour and other welfare indicators.
Commercial broiler production systems based on market initiatives to improve animal welfare beyond minimum legal requirements have emerged in several European countries. A common factor in the 'higher welfare' indoor systems is the application of environmental enrichment, with or without natural light, to promote locomotor activity and natural behaviours of the broiler chickens. In the current study, we evaluated the effects of a commercial enrichment programme for fast-growing indoor-housed broiler chickens, with or without natural light entering the broiler house. Enrichment materials were selected in relation to perceived minimal hygiene risk and ease of cleaning in between production cycles. Selected enrichments were a combination of wood shavings bales (1.5 bale/1000 chickens), round metal perches (2.7 m/1000 chickens) and metal chains as pecking objects (1/1000 chickens). Three treatments were studied: control (C) without enrichment and natural light, enriched (E) with enrichments as previously defined but without natural light and enriched plus natural light (EL) with enrichments as previously defined and natural light entrance. The experiment was carried out during five subsequent production cycles on one commercial broiler farm with three identical houses. EL could only be assigned to the middle house that was equipped with roof windows (light entrance area: 3% of floor space). C and E were in the two outer houses (alternated in between production cycles). Behaviour was observed during daytime at days 25 and 39 of age by scan sampling. Lameness, footpad dermatitis, hock burn, cleanliness and injuries were scored at the same ages, in addition to the response of the chickens to a novel object. Results showed that the treatments only affected broiler behaviour. E flocks showed significantly more resting as compared with EL and C. EL flocks showed significantly more walking, exploration and foraging behaviour as compared with E and C. Thus, broiler activity was highest in the EL treatment and lowest in the E treatment, with the C treatment in between. No treatment effects were found on the other welfare indicators and only a few tendencies for treatment effects were found for the novel object test, with E birds tending to be more reluctant to approach the object as compared with EL and C birds. We concluded that providing environmental enrichment and natural light-stimulated activity and natural behaviours in broiler chickens, whereas providing enrichment only seemed to have the opposite effect as compared with control flocks without enrichment.


Surgery for gliomas involving the left inferior parietal lobule: new insights into the functional anatomy provided by stimulation mapping in awake patients.
Surgery in the left dominant inferior parietal lobule (IPL) is challenging because of a high density of somatosensory and language structures, both in the cortex and white matter. In the present study, on the basis of the results provided by direct cerebral stimulation in awake patients, the authors revisit the anatomofunctional aspects of surgery within the left IPL. Fourteen consecutive patients underwent awake craniotomy for a glioma involving the left IPL. Intraoperative motor, sensory, and language mapping was performed before and during the tumor removal, at both the cortical and subcortical levels, to optimize the extent of resection, which was determined based on functional boundaries. Anatomofunctional correlations were performed by combining the results of intraoperative mapping and those provided by pre- and postoperative MR imaging. At the cortical level, the primary somatosensory area (retrocentral gyrus) limited the resection anteriorly in all cases, at least partially. Less frequently, speech arrest or articulatory problems were observed within the parietal operculum (4 cases). The lateral limit was determined by language sites that were variably distributed. Anomia was the most frequent response (9 cases) at the posterior third of the superior (and/or middle) temporal gyrus. Posteriorly, less reproducible reorganized language sites were seldom observed in the posterior portion of the angular gyrus (2 cases). At the subcortical level, in addition to somatosensory responses due to stimulation of the thalamocortical pathways, articulatory disturbances were induced by stimulation of white matter in the anterior and lateral part of the surgical cavity (11 cases). This tract anatomically corresponds to the horizontal portion of the lateral segment of the superior longitudinal fascicle (SLF III). Deeper and superiorly, phonemic paraphasia was the main language disturbance (12 cases), elicited by stimulation of the posterosuperior portion of the arcuate fascicle. All these eloquent structures were surgically preserved. Despite slight cognitive disorders (working memory, writing, or calculation) in 6 cases, no patient retained a severe or a moderate postoperative deficit (except one with right hemianopia [mean follow-up 41.8 months]). Resection was total or near total in 9 patients and partial in 3 cases. To the authors' knowledge, this is the first series dedicated to the surgery of gliomas involving the left IPL. Interestingly, a certain degree of interindividual variability was observed in the distribution of the cortical maps, especially for language. Therefore, it is suggested that no rigid pattern of resection can be considered within the left IPL, and that surgery in this region should be performed in awake patients to adapt the tumor removal to individual functional limits. Nonetheless, several landmarks have been regularly identified, especially at the subcortical levels (SLF III and arcuate fascicle); a better knowledge of these functional tracts could be helpful to optimize functional outcomes.


Constructing a FRET-based molecular chemodosimeter for cysteine over homocysteine and glutathione by naphthalimide and phenazine derivatives.
A molecular chemodosimeter , with a naphthalimide fluorophore connected to a newly designed phenazine energy acceptor, for the selective detection of cysteine was effectively synthesized. featured efficient intramolecular fluorescence resonance energy transfer (FRET) based on spectral overlap between the emission of naphthalimide and the absorption of phenazine. A cystamine chain with a S-S bond was applied to play the role of recognition moiety and the linker part. The specific reaction between the biological thiols and gave rise to an obvious fluorescence intensity enhancement at 540 nm, which is induced by cleavage of the disulfide bond followed by elimination of the FRET effect. High sensitivity and selectivity for cysteine over homocysteine and glutathione were also achieved. In addition, upon excitation at 400 nm, a relatively weak NIR emission provided an internal standard making a promising ratiometric sensor for cellular detection of cysteine.


Clinical-therapeutic management of thoracoscopy in pleural effusion: a groundbreaking technique in the twenty-first century.
The aim of this study was to investigate the effectiveness of thoracoscopy in the diagnosis of non-affiliated pleural effusions (PE). A five-year prospective study including data from 110 patients that were clinically diagnosed as benign (14.5%), malign (34.5%) and non-affiliated (50.9%). PE in patents without oncology disease and negative biopsy or cytology were considered as benign. Malignant diagnosis was established according to a pleural biopsy, compatible cytology and/or clinical features. Remaining cases were considered as non-affiliated. Thoracoscopy was done under local anaesthesia and sedation. Thoracoscopy confirmed previous clinical diagnosis of benignity and malignity. Regarding non-affiliated patients, 30.35% were diagnosed after thoracoscopy as unspecific pleuritis, 17.86% mesothelioma and 1.79% pleural tuberculosis (TBC). The other 48.21% of patients reported as non-affiliated were diagnosed with pleural carcinoma. Statistical analysis did not reveal differences between frequencies analysed. Our results indicate that thoracoscopy is a cost-effective and reliable technique for obtaining histological diagnosis in PE and also allows a directed pleurodesis if indicated.