Bile acid metabolism in cirrhosis. VIII. Quantitative evaluation of bile acid synthesis from [7 beta-3H]7 alpha-hydroxycholesterol and [G-3H]26-hydroxycholesterol.
In order to evaluate more definitively the observed aberrations in the synthesis of cholic and chenodeoxycholic acids in patients with advanced cirrhosis, two bile acid biosynthesis pathways were examined by determining the efficiency of conversion of [3H]7 alpha-hydroxycholesterol and [3H] 26-hydroxycholesterol to primary bile acids. Bile acid kinetics were determined by administration of [14C]cholic and [14C]chenodeoxycholic acids. Cholic acid synthesis in cirrhotic patients was markedly depressed (170 vs. 927 mumoles per day)( while chenodeoxycholic acid synthesis was reduced to a much lesser degree (227 vs. 550 mumoles per day). The administration of [3H]7 alpha-hydroxycholesterol allowed for an evaluation of the major pathway of bile acid synthesis via the 7 alpha-hydroxylation of cholesterol. This compound was efficiently incorporated into primary bile acids by the two normal subjects (88 and 100%) and two cirrhotic patients (77 and 91%). However, the recovery of the label in cholic acid was slightly less in cirrhotic patients than in normal subjects. [3H]26-hydroxycholesterol was administered to ascertain the contribution of the 26-hydroxylation pathway to bile acid synthesis. All study subjects showed poor conversion (9 to 22%) of this intermediate into bile acids. The results of this study suggest that a major block in the bile acid synthesis pathway in cirrhosis is at the level of 7 alpha-hydroxylation of cholesterol (impairment of 7 alpha-hydroxylase) and /or in the feedback triggering mechanism regulating bile acid synthesis. The data also suggest that the 26-hydroxylation pathway in normal subjects and patients with cirrhosis is a minor contributor to synthesis of the primary bile acids. Therefore, the relative sparing of chenodeoxycholic acid synthesis observed in cirrhotic patients is not due to preferential synthesis of this bile acid via the 26-hydroxylation pathway.


The 30-year experience-A meta-analysis of randomised and high-quality non-randomised studies of hyperthermic intraperitoneal chemotherapy in the treatment of gastric cancer.
Hyperthermic intraperitoneal chemotherapy (HIPEC) has been used within various multimodality strategies for the prevention and treatment of gastric cancer peritoneal carcinomatosis. To systematically evaluate the role of HIPEC in gastric cancer and clarify its effectiveness at different stages of peritoneal disease progression. Medline and Embase databases between January 1, 1985 and June 1, 2016. Randomised control trials and high-quality non-randomised control trials selected on a validated tool (methodological index for non-randomised studies) comparing HIPEC and standard oncological management for the treatment of advanced stage gastric cancer with and without peritoneal carcinomatosis were considered. A random-effects network meta-analysis. The primary outcomes were overall survival and disease recurrence. Secondary outcomes were overall complications, type of complications, and sites of recurrence. A total of 11 RCTs and 21 non-randomised control trials (2520 patients) were included. For patients without the presence of peritoneal carcinomatosis (PC), the overall survival rates between the HIPEC and control groups at 3 or 5 years resulted in favour of the HIPEC group (risk ratio [RR] = 0.82, P = 0.01). No difference in the 3-year overall survival (RR = 0.99, P = 0.85) in but a prolonged median survival of 4 months in favour of the HIPEC group (WMD = 4.04, P < 0.001) was seen in patients with PC. HIPEC was associated with significantly higher risk of complications for both patients with PC (RR = 2.15, P < 0.01) and without (RR = 2.17, P < 0.01). This increased risk in the HIPEC group was related to systemic drugs toxicity. Anastomotic leakage rates were found to be similar between groups. Our study demonstrates a survival advantage of the use of HIPEC as a prophylactic strategy and suggests that patients whose disease burden is limited to positive cytology and limited nodal involvement may benefit the most from HIPEC. For patients with extensive carcinomatosis, the completeness of cytoreductive surgery is a critical prognostic factor for survival. Future RCTs should better define patient selection criteria.


Thrombolysis-related intracranial hemorrhage: a radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.
Intracranial hemorrhage (ICH) is a serious complication of thrombolytic therapy. We systematically reviewed the radiographic features of 244 cases of symptomatic ICH complicating thrombolysis for acute myocardial infarction in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, correlated these observations with clinical data, and speculated on hemorrhage pathogenesis. CT scans from 244 patients suffering symptomatic ICH were systematically reviewed for selected radiographic features, including ICH type, location, hematoma characteristics, mass effect features, hydrocephalus, and preexisting lesions. Hematoma volume was estimated by computer-assisted volumetric analysis. Data from this analysis were correlated with clinical data including hypertension, anticoagulation, age, thrombolytic regimen, and ICH timing. Most hemorrhages were large (median [25th, 75th percentile] volume, 72 mL [39, 118]), solitary (66%), lobar (77%), confluent (80%), and intraparenchymal (82%) with a blood/fluid level (82%) and little edema (median [25th, 75th percentile] volume, 9 mL [5, 16]). Hydrocephalus (P<.001), any one mass effect feature (P<.001), intraventricular hemorrhage (P=.022), mottled hematoma appearance (P=.050), and hematoma blood/fluid level (P<.001) were associated with higher hemorrhage volume in the radiographic analysis, as were older age (P=.005), treatment with combined streptokinase and tissue plasminogen activator (P=.034), and hemorrhage onset 8 to 13 hours after treatment (P=.008) in the clinical analysis. Subdural hemorrhage was a high-volume subgroup whose risk increased with antecedent trauma (P=.026) or syncope (P=.006). Deep intraparenchymal hemorrhage was associated with hypertension (P=.016), and multifocal ICH occurred significantly earlier after treatment (P=.002). Although the majority of postthrombolytic ICH are large, solitary, and supratentorial, the spectrum is diverse. Features of mass effect reflected the large volumes, and hematoma characteristics of mottling and blood/fluid levels were frequent. Thrombolysis-related coagulopathy and age appear to be the most important identifiable factors in the genesis of postthrombolytic ICH, but the hemorrhage subtype seen may reflect an interaction with other factors such as hypertension, ICH timing, antecedent head trauma, and syncope.


'I'm fine!': Assertions of lack of support need among patients with chronic obstructive pulmonary disease: A mixed-methods study.
To understand how people with Chronic Obstructive Pulmonary Disease (COPD) disavow their support needs and the impact on care. Two stage mixed-method design. Stage 1 involved sub-analyses of data from a mixed-method population-based longitudinal study exploring the needs of patients with advanced COPD. Using adapted criteria from mental health research, we identified 21 patients who disavowed their needs from the 235 patient cohort. Qualitative interview transcripts and self-report measures were analysed to compare these patients with the remaining cohort. In stage 2 focus groups (n = 2) with primary healthcare practitioners (n = 9) explored the implications of Stage 1 findings. Patients who disavowed their support needs described non-compliance with symptom management and avoidance of future care planning (qualitative data). Analysis of self-report measures of mental and physical health found this group reported fewer needs than the remaining sample yet wanted more GP contact. The link between risk factors and healthcare professional involvement present in the rest of the sample was missing for these patients. Focus group data suggested practitioners found these patients challenging. This study identified patients with COPD who disavow their support needs, but who also desire more GP contact. GPs report finding these patients challenging to engage.


L-Citrulline acts as potential hypothermic agent to afford thermotolerance in chicks.
Recently we demonstrated that L-citrulline (L-Cit) causes hypothermia in chicks. However, the question of how L-Cit mediates hypothermia remained elusive. Thus, the objective of this study was to examine some possible factors in the process of L-Cit-mediated hypothermia and to confirm whether L-Cit can also afford thermotolerance in young chicks. Chicks were subjected to oral administration of L-Cit along with intraperitoneal injection of a nitric oxide synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester HCl (L-NAME), to examine the involvement of NO in the process of hypothermia. Food intake and plasma metabolites were also analyzed after oral administration of L-Cit in chicks. To examine thermotolerance, chicks were orally administered with a single dose of L-Cit (15mmol/10ml/kg body weight) or the same dose twice within a short interval of 1h (dual oral administration) before the exposure to high ambient temperature (35 ± 1°C) for 180min. Although the rectal temperature was reduced following administration of L-Cit, L-NAME caused a greater reduction. L-NAME reduced total NO2 and NO3 (NOx) in plasma, which confirmed its inhibitory effect on NO. A single oral administration of L-Cit mediated a persistent state of hypothermia for the 300min of the study without affecting food intake. It was further found that plasma glucose was significantly lower in L-Cit-treated chicks. Dual oral administration of L-Cit, but not a single oral administration, afforded thermotolerance without a significant change in plasma NOx in chicks. In conclusion, our results suggest that L-Cit-mediated hypothermia and thermotolerance may not be involved in NO production. L-Cit-mediated thermotolerance further suggests that L-Cit may serve as an important nutritional supplement that could help in coping with summer heat.


Plant invasion and speciation along elevational gradients on the oceanic island La Palma, Canary Islands.
Ecosystems that provide environmental opportunities but are poor in species and functional richness generally support speciation as well as invasion processes. These processes are expected not to be equally effective along elevational gradients due to specific ecological, spatial, and anthropogenic filters, thus controlling the dispersal and establishment of species. Here, we investigate speciation and invasion processes along elevational gradients. We assess the vascular plant species richness as well as the number and percentage of endemic species and non-native species systematically along three elevational gradients covering large parts of the climatic range of La Palma, Canary Islands. Species richness was negatively correlated with elevation, while the percentage of Canary endemic species showed a positive relationship. However, the percentage of Canary-Madeira endemics did not show a relationship with elevation. Non-native species richness (indicating invasion) peaked at 500 m elevation and showed a consistent decline until about 1,200 m elevation. Above that limit, no non-native species were present in the studied elevational gradients. Ecological, anthropogenic, and spatial filters control richness, diversification, and invasion with elevation. With increase in elevation, richness decreases due to species-area relationships. Ecological limitations of native ruderal species related to anthropogenic pressure are in line with the absence of non-native species from high elevations indicating directional ecological filtering. Increase in ecological isolation with elevation drives diversification and thus increased percentages of Canary endemics. The best preserved eastern transect, including mature laurel forests, is an exception. The high percentage of Canary-Madeira endemics indicates the cloud forest's environmental uniqueness-and thus ecological isolation-beyond the Macaronesian islands.


The research environment in family practice.
Both the place of family practice in academic medicine and the intellectual underpinning of the specialty itself are thought by many to depend on the development of successful research programs in academic departments of family medicine. Yet many believe less research than desired is being done in such departments, even by faculty trained in research. To gain additional information on this important subject, a survey was conducted of the departmental research experiences of 42 graduates of the several Robert Wood Johnson Foundation Family Practice Academic Fellowship Programs who had had the opportunity for at least one year of faculty experience. The responses indicate that the majority of such graduates spend 20 percent or less of their time in research, that most perceive administrative duties as interfering with research, that a minority have budgeted research time, and few have departmental research funds. Despite these obstacles, those who do research publish with surprising frequency, about one paper per fellow per year. Several ways are presented to improve the research environment in departments of family practice and to lead to even more productive, secure research activities of these and other family practice faculty.


Mechanisms of immune privilege in the eye and hair follicle.
It has been recognized for over a century that the eye is endowed with remarkable properties that permit the long-term survival of foreign tumor and tissue grafts that are normally rejected at extraocular sites. This ocular immune privilege was originally attributed to a putative sequestration of antigens in the eye as a result of the conspicuous absence of intraocular lymphatic drainage channels. In the last 30 years, a sizeable body of information indicates that ocular immune privilege is a product of multiple anatomical, physiological, and immunoregulatory processes. Ocular tissues and fluids express a wide variety of anti-inflammatory and immunosuppressive molecules, including CD95L (FasL), transforming growth factor-beta, macrophage migration inhibitory factor, alpha-melanocyte-stimulating hormone, calcitonin gene-related peptide, somatostatin, and complement regulatory proteins. Moreover, antigens entering the anterior chamber of the eye evoke a unique form of immune deviation that culminates in the antigen-specific suppression of TH1 immune responses. Finally, the intraocular milieu contains both cell membrane and soluble factors that inhibit both the adaptive and innate immune systems. The hair follicle is also recognized for its immune privilege. Like the anterior chamber of the eye, it produces anti-inflammatory and immunosuppressive cytokines, such as transforming growth factor-beta and adrenocorticotrophic hormone. The cells of the hair follicle display limited expression of class Ia MHC molecules and, like cells that line the anterior chamber of the eye, are protected against CD8+ cytotoxic T lymphocyte attack. Gaining a better understanding of the immune privilege of the hair follicle may provide insights into the regulation and pathogenesis of immune-mediated diseases of the skin.


Security and Privacy in a DACS.
The management of electronic health records (EHR), in general, and clinical documents, in particular, is becoming a key issue in the daily work of Healthcare Organizations (HO). The need for providing secure and private access to, and storage for, clinical documents together with the need for HO to interoperate, raises a number of issues difficult to solve. Many systems are in place to manage EHR and documents. Some of these Healthcare Information Systems (HIS) follow standards in their document structure and communications protocols, but many do not. In fact, they are mostly proprietary and do not interoperate. Our proposal to solve the current situation is the use of a DACS (Document Archiving and Communication System) for providing security, privacy and standardized access to clinical documents.


Introduction to in vivo 31P magnetic resonance spectroscopy of (human) skeletal muscle.
31P magnetic resonance spectroscopy (MRS) offers a unique non-invasive window on energy metabolism in skeletal muscle, with possibilities for longitudinal studies and of obtaining important bioenergetic data continuously and with sufficient time resolution during muscle exercise. The present paper provides an introductory overview of the current status of in vivo 31P MRS of skeletal muscle, focusing on human applications, but with some illustrative examples from studies on transgenic mice. Topics which are described in the present paper are the information content of the 31P magnetic resonance spectrum of skeletal muscle, some practical issues in the performance of this MRS methodology, related muscle biochemistry and the validity of interpreting results in terms of biochemical processes, the possibility of investigating reaction kinetics in vivo and some indications for fibre-type heterogeneity as seen in spectra obtained during exercise.


Effects of ethosuximide and tetramethylsuccinimide on cultured cortical neurons.
In cultured cortical neurons, ethosuximide (ESM) had unexpected actions for an antiepileptic drug; it slightly diminished the effects of inhibitory neurotransmitters, GABA, and glycine. ESM had no direct membrane effects, did not change action potential characteristics or alter spontaneous activity, and did not reverse the effects of convulsants that are GABA antagonists. The structurally related convulsant tetramethylsuccinimide (TMSM) reduced the amplitude of GABA-mediated inhibitory postsynaptic potentials and antagonized responses to applied GABA, effects not reversed by ESM. The convulsant effects of TMSM include a blockade of postsynaptic GABA actions, but the antiepileptic effects of ESM are not due to an enhancement of GABA-mediated inhibition.


Enhancing the Antimicrobial Properties of Peptides through Cell-Penetrating Peptide Conjugation: A Comprehensive Assessment.
Combining antimicrobial peptides (AMPs) with cell-penetrating peptides (CPPs) has shown promise in boosting antimicrobial potency, especially against Gram-negative bacteria. We examined the CPP-AMP interaction with distinct bacterial types based on cell wall differences. Our investigation focused on AMPs incorporating penetratin CPP and dihybrid peptides containing both cell-penetrating TAT protein fragments from the human immunodeficiency virus and Antennapedia peptide (Antp). Assessment of the peptides TAT-AMP, AMP-Antp, and TAT-AMP-Antp revealed their potential against Gram-positive strains (Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), and Bacillus cereus). Peptides TAT-AMP and AMP-Antp using an amyloidogenic AMP from S1 ribosomal protein Thermus thermophilus, at concentrations ranging from 3 to 12 μM, exhibited enhanced antimicrobial activity against B. cereus. TAT-AMP and TAT-AMP-Antp, using an amyloidogenic AMP from the S1 ribosomal protein Pseudomonas aeruginosa, at a concentration of 12 µM, demonstrated potent antimicrobial activity against S. aureus and MRSA. Notably, the TAT-AMP, at a concentration of 12 µM, effectively inhibited Escherichia coli (E. coli) growth and displayed antimicrobial effects similar to gentamicin after 15 h of incubation. Peptide characteristics determined antimicrobial activity against diverse strains. The study highlights the intricate relationship between peptide properties and antimicrobial potential. Mechanisms of AMP action are closely tied to bacterial cell wall attributes. Peptides with the TAT fragment exhibited enhanced antimicrobial activity against S. aureus, MRSA, and P. aeruginosa. Peptides containing only the Antp fragment displayed lower activity. None of the investigated peptides demonstrated cytotoxic or cytostatic effects on either BT-474 cells or human skin fibroblasts. In conclusion, CPP-AMPs offer promise against various bacterial strains, offering insights for targeted antimicrobial development.


Winter runoff losses of phosphorus from paddy soils in the Taihu Lake Region of South China.
A winter wheat field plot experiment was conducted on two types of paddy soils, from November, 2000 to June, 2001 to assess P losses to its surrounding watercourses by runoff in the Taihu Lake Region. Commercial NPK compound fertilizer and single superphosphate fertilizer were applied to furnish 0, 20, 80, and 160 kg P ha(-1). The experiments consisted of six replicates of each treatment in Changshu site and four replicates in Anzhen site, with a plot size of 5x6 m2 in a randomized block design. Results revealed that the average concentration of dissolved P (DP), particulate P (PP), and total P (TP) in runoff water during the winter season was 0.13, 0.90 and 1.04 mg P l(-1) respectively, from P20 plots in Anzhen site. While it was 0.67, 1.08 and 1.75 mg P l(-1) respectively, from P20 plots in Changshu site. The seasonal TP load (mass loss) from P20 plot ranged from a low of 290.88 g P ha(-1)season(-1) to a high of 483.54 g P ha(-1)season(-1), with a mean of 382.29 g P ha(-1)season(-1) in Anzhen, but from 444.92 to 752.21 g P ha(-1)season(-1), with a mean of 539.13 g P ha(-1)season(-1) in Changshu. Both in Anzhen and Changshu PP represented a major portion of the TP lost in runoff, the average PP/TP was about more than 80% in P0 and P20 plot, but it was decreased with the increase of P rate. The average seasonal P loads (DP, PP, and TP) in Changshu were greater than in Anzhen although runoff volume in Anzhen (45 mm season(-1)) was more than in Changshu (36 mm season(-1)). This was probably associated with the differences of soil physical and chemical properties between the two sites. Phosphate fertilizer rate significantly affected P concentrations and P loads by runoff. Both the mean concentrations and the average seasonal P loads from the P80 plots were lower than from the P160 plots, but obviously higher than from the P20 and P0 plots. There was no significant difference found between the P20 plots and the P0 plots both in Anzhen and Changshu sites. It indicated that P loads by runoff would be greatly increased in 5-10 years due to the accumulation of soil P if 20 kg P ha(-1) applied each wheat season in this area.


Posttraumatic use of dental implants immediately after tooth extraction: clinical study.
Root fracture is a combined injury of cementum, dentin, and pulp. Many of these traumas remain untreated, mistreated, or overtreated. It leads to a more complicated treatment in case of tooth loss. Many different treatment procedures, with a very changeable success rate, have been proposed for years to treat teeth with root fractures. The objective of the following clinical studies was to evaluate the clinical effectiveness of implants placed in fresh extraction sites to treat teeth with horizontal root fracture. The study group included 25 patients (15 men and 10 women) between the ages of 20 and 65 years. After an initial examination and a treatment planning, all of the patients underwent periodontal treatment, which was deemed necessary to favor wound healing. All the 25 teeth were extracted because of horizontal root fracture located at the level of the middle third. The second-stage surgery was performed 6 months after the initial procedure. The following clinical parameters, presence or absence of mobility, presence or absence of pain, and presence or absence of suppuration, were evaluated in each patient at 6 and 12 months after implant placement. Radiographs were taken using the standard method to evaluate the marginal bone loss. The healing period was uneventful for all patients. All implants had osseointegrated. After 12 months, patients were asymptomatic and showed no signs of infection or bleeding when probed. On the basis of this study, implants placed right after tooth extraction are a valid treatment procedure, which induces predictable results as treatment of fractured teeth.


JAM-A functions as a female microglial tumor suppressor in glioblastoma.
Glioblastoma (GBM) is the most aggressive primary brain tumor and has a dismal prognosis. Previously, we identified that junctional adhesion molecule A (JAM-A), a cell adhesion molecule, is highly elevated in human GBM cancer stem cells and predicts poor patient prognosis. While JAM-A is also highly expressed in other cells in the tumor microenvironment, specifically microglia and macrophages, how JAM-A expression in these cells affects tumor growth has yet to be determined. The goal of this study was to understand the role of microenvironmental JAM-A in mediating GBM growth. Male and female wild-type (WT) and JAM-A-deficient mice were transplanted intracranially with the syngeneic glioma cell lines GL261 and SB28 and were assessed for differences in survival and microglial activation in tumors and in vitro. RNA-sequencing was performed to identify differentially regulated genes among all genotypes, and differences were validated in vitro and in vivo. We found that JAM-A-deficient female mice succumbed to GBM more quickly compared with WT females and JAM-A-deficient and male WT mice. Analysis of microglia in the tumors revealed that female JAM-A-deficient microglia were more activated, and RNA-sequencing identified elevated expression of Fizz1 and Ifi202b specifically in JAM-A-deficient female microglia. Our findings suggest that JAM-A functions to suppress pathogenic microglial activation in the female tumor microenvironment, highlighting an emerging role for sex differences in the GBM microenvironment and suggesting that sex differences extend beyond previously reported tumor cell-intrinsic differences.


A national survey of medical education fellowships.
The purpose of our study was to determine the prevalence, focus, time commitment, graduation requirements and programme evaluation methods of medical education fellowships throughout the United States. Medical education fellowships are defined as a single cohort of medical teaching faculty who participate in an extended faculty development programme. A 26-item online questionnaire was distributed to all US medical schools (n=127) in 2005 and 2006. The questionnaire asked each school if it had a medical education fellowship and the characteristics of the fellowship programme. Almost half (n=55) of the participating schools (n=120, response rate 94.5 %) reported having fellowships. Duration (10-584 hours) and length (<1 month-48 months) varied; most focused on teaching skills, scholarly dissemination and curriculum design, and required the completion of a scholarly project. A majority collected participant satisfaction; few used other programme evaluation strategies. The number of medical education fellowships increased rapidly during the 1990s and 2000s. Across the US, programmes are similar in participant characteristics and curricular focus but unique in completion requirements. Fellowships collect limited programme evaluation data, indicating a need for better outcome data. These results provide benchmark data for those implementing or revising existing medical education fellowships.


Effects of Breathing-Based Meditation on Earthquake-Affected Health Professionals.
On March 11, 2013, the Great East Japan Earthquake (magnitude 9) hit the northern part of Japan (Tohoku), killing more than 15 000 people and leaving long-lasting scars, including psychological damage among evacuees, some of whom were health professionals. Little is known about meditation efficacy on disaster-affected health professionals. The present study investigated the effects of breathing-based meditation on seminar participants who were health professionals who had survived the earthquake. This study employed a mixed methods approach, using both survey data and handwritten qualitative data. Quantitative results of pre- and postmeditation practice indicated that all mood scales (anger, confusion, depression, fatigue, strain, and vigor) were significantly improved (N = 17). Qualitative results revealed several common themes (emancipation from chronic and bodily senses; holistic sense: transcending mind-body; re-turning an axis in life through reflection, self-control, and/or gratitude; meditation into mundane, everyday life; and coming out of pain in the aftermath of the earthquake) that had emerged as expressions of participant meditation experiences. Following the 45-minute meditation session, the present study participants reported improvements in all psychological states (anger, confusion, depression, fatigue, strain, and vigor) in the quantitative portion, which indicated efficacy of the meditation. Our analysis of the qualitative portion revealed what and how participants felt during meditating.


Association of plasma micronutrient levels and urinary isoprostane with risk of lung cancer: the multiethnic cohort study.
Although smoking is the primary risk factor for lung cancer, there is evidence to suggest that fruit and vegetable intake are important cofactors. The present case-control study, nested within the Multiethnic Cohort Study, examined the associations of biomarkers of fruit and vegetable intake (individual plasma micronutrient levels), serum selenium, and a urinary biomarker for total lipid peroxidation with lung cancer risk. Two hundred seven incident cases were matched to 414 controls on age, sex, ethnicity, study location (Hawaii or California), smoking status, date/time of collection, and hours of fasting. We measured prediagnositic circulating levels of individual tocopherols and carotenoids, retinol, and serum selenium, and urinary 15-isoprostane F(2t). Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI). For men, strong reductions in risk were seen with increasing tertiles of each plasma carotenoid, with the ORs for the third tertile, compared with the first tertile, ranging from 0.24 to 0.45 (P(trends), 0.002-0.04). No associations were found among women for carotenoids or among either sex for tocopherols, selenium, and retinol. A doubling in risk was seen for men in the second and third tertiles, compared with the first tertile of urinary 15-isoprostane F(2t) (OR, 2.31; 95% CI, 1.02-5.25; and OR, 2.16; 95% CI, 0.98-4.78). This study supports the previously observed association between circulating carotenoids and lung cancer risk in men, and adds to the limited literature regarding urinary 15-isoprostane F(2t) as a marker of cancer risk. Future research examining the possible relationship between isoprostanes and lung cancer is warranted.


Function after amputation, arthrodesis, or arthroplasty for tumors about the knee.
We studied the function of twenty-two patients who had had a malignant skeletal tumor adjacent to the knee. An above-the-knee amputation was done in seven; a resection arthrodesis, in nine; and a replacement arthroplasty, in six. The patients all walked at a similar speed (sixty-one to sixty-six meters per minute), which is slower than normal (eighty meters per minute). They all walked with comparable efficiency at three velocities: the mean consumption of oxygen was 0.210 milliliter per kilogram of body weight per meter at free velocity, 0.215 milliliter per kilogram of body weight per meter when they walked 25 per cent faster, and 0.211 to 0.240 milliliter per kilogram of body weight per meter when they walked 50 per cent faster. The three groups of patients and a normal control group consumed oxygen at similar rates. The patients who had had an amputation were very active, and they were the least worried about damaging the affected limb, but they had difficulty walking on steep, rough, or slippery surfaces. The patients who had had an arthrodesis had a more stable limb and performed the most demanding physical work and recreational activities, but they had difficulty sitting. The patients who had had an arthroplasty led sedentary lives and were the most protective of the limb, but they were the least self-conscious about the limb.


Updated systematic review of the effects of exercise on understudied health outcomes in cancer survivors.
The American College of Sports Medicine provided guidelines for exercise prescriptions in cancer survivors for specific cancer- and treatment-related health outcomes. However, there was insufficient evidence to generate exercise prescriptions for 10 health outcomes of cancer treatment. We sought to update the state of evidence. We conducted a systematic review of these 10 understudied health outcomes (bone health, sleep, cardiovascular function, chemotherapy-induced peripheral neuropathy (CIPN), cognitive function, falls and balance, nausea, pain, sexual function, and treatment tolerance) and provided an update of evidence. While the evidence base for each outcome has increased, there remains insufficient evidence to generate exercise prescriptions. Common limitations observed across outcomes included: variability in type and quality of outcome measurement tools, variability in definitions of the health outcomes, a lack of phase III trials, and a majority of trials investigating breast or prostate cancer survivors only. We identified progress in the field of exercise oncology for several understudied cancer- and treatment-related health outcomes. However, we were not able to generate exercise prescriptions due to continued insufficient evidence base. More work is needed to prescribe exercise as medicine for these understudied health outcomes, and our review highlights several strategies to aid in research acceleration within these areas of exercise oncology.


Slum clearance, privatization and residualization: the practices and politics of council housing in mid-twentieth-century England.
This article contributes to a growing literature on working-class suburbanization by arguing that both the residualization and privatization of council housing need to be properly historicized. This case study of housing policy in the borough of Brighton demonstrates that council house sales between the 1950s and 1970s were important in the residualization of inter-war estates well before the 'right to buy' legislation of the 1980s. Concerns about excessively affluent tenants can also be traced to the inter-war period, although it was not until the late 1950s that local Conservatives sought to push affluent council tenants into owner occupation via capping incomes and encouraging council house sales. The article shows that slum clearance had long been central to the local council's provision of municipal housing and that apart from two short periods following the First and Second World Wars, council housing was conceived of primarily as a residual tenure by those in control of policy implementation. It further demonstrates that slum clearance between the 1920s and 1960s altered the social constituency for council housing and, combined with selective privatization, specific allocation policies and disinvestment, led to the stigmatization of certain inter-war estates. The article suggests that further case studies are needed in order to test the wider applicability of these arguments during the middle years of the twentieth century.


Therapeutic measures for prevention of allergic rhinitis/asthma development.
The development of asthma and allergic disease involves not only genetic factors but environmental influences as well. Preventative measures many involve changes in breastfeeding, diet, environmental exposure, medications, and vaccination methods. Breastfeeding is recommended during the first 4-6 months of life. Probiotics should be consumed by mothers during pregnancy and breast-feeding. Solid foods should not be introduced to high-risk infants until four months of age. Consumption of dairy products should be delayed until 1 year, eggs until 2 years, and peanuts, nuts, and fish until 3 years of age. Exposure to tobacco smoke should be avoided by the expectant mother and by the child after birth. Ample evidence suggests that dust-mite avoidance should be performed. Diets rich in antioxidants and omega-3 fatty acids should be encouraged. No current recommended changes in vaccination practices have been proposed. Because allergy and asthma is a multifactorial process with both complex genetic and environmental components, it is mlikely that a single intervention will have a significant impact on their prevalence.


Suicide among gay and lesbian adolescents and young adults: a review of the literature.
This paper explores the issue of suicide among gay and lesbian adolescents and young adults, as well as provides information to guide clinicians in working effectively with this population. The theoretical perspectives on homosexual identity development by Troiden, Cass, and Lewis are discussed in connection with Durkheim's Suicide Theory and various theoretical risk factors, as well as implications for social work practice. This paper is intended to be utilized as a tool during the assessment phase of treatment with an adolescent or young adult who may be questioning his or her sexuality.


Age estimation of captive Asian elephants (Elephas maximus) based on DNA methylation: An exploratory analysis using methylation-sensitive high-resolution melting (MS-HRM).
Age is an important parameter for bettering the understanding of biodemographic trends-development, survival, reproduction and environmental effects-critical for conservation. However, current age estimation methods are challenging to apply to many species, and no standardised technique has been adopted yet. This study examined the potential use of methylation-sensitive high-resolution melting (MS-HRM), a labour-, time-, and cost-effective method to estimate chronological age from DNA methylation in Asian elephants (Elephas maximus). The objective of this study was to investigate the accuracy and validation of MS-HRM use for age determination in long-lived species, such as Asian elephants. The average lifespan of Asian elephants is between 50-70 years but some have been known to survive for more than 80 years. DNA was extracted from 53 blood samples of captive Asian elephants across 11 zoos in Japan, with known ages ranging from a few months to 65 years. Methylation rates of two candidate age-related epigenetic genes, RALYL and TET2, were significantly correlated with chronological age. Finally, we established a linear, unisex age estimation model with a mean absolute error (MAE) of 7.36 years. This exploratory study suggests an avenue to further explore MS-HRM as an alternative method to estimate the chronological age of Asian elephants.


Topiramate Protects Pericytes from Glucotoxicity: Role for Mitochondrial CA VA in Cerebromicrovascular Disease in Diabetes.
Hyperglycemia in diabetes mellitus causes oxidative stress and pericyte depletion from the microvasculature of the brain thus leading to the Blood-Brain Barrier (BBB) disruption. The compromised BBB exposes the brain to circulating substances, resulting in neurotoxicity and neuronal cell death. The decline in pericyte numbers in diabetic mouse brain and pericyte apoptosis in high glucose cultures are caused by excess superoxide produced during enhanced respiration (mitochondrial oxidative metabolism of glucose). Superoxide is precursor to all Reactive Oxygen Species (ROS) which, in turn, cause oxidative stress. The rate of respiration and thus the ROS production is regulated by mitochondrial carbonic anhydrases (mCA) VA and VB, the two isoforms expressed in the mitochondria. Inhibition of both mCA: decreases the oxidative stress and restores the pericyte numbers in diabetic brain; and reduces high glucose-induced respiration, ROS, oxidative stress, and apoptosis in cultured brain pericytes. However, the individual role of the two isoforms has not been established. To investigate the contribution of mCA VA in ROS production and apoptosis, a mCA VA overexpressing brain pericyte cell line was engineered. These cells were exposed to high glucose and analyzed for the changes in ROS and apoptosis. Overexpression of mCA VA significantly increased pericyte ROS and apoptosis. Inhibition of mCA VA with topiramate prevented increases both in glucose-induced ROS and pericyte death. These results demonstrate, for the first time, that mCA VA regulates the rate of pericyte respiration. These findings identify mCA VA as a novel and specific therapeutic target to protect the cerebromicrovascular bed in diabetes.


Histone regulatory (hir) mutations suppress delta insertion alleles in Saccharomyces cerevisiae.
Changes in histone gene dosage as well as mutations within some histone genes suppress delta insertion mutations in the HIS4 and LYS2 loci of Saccharomyces cerevisiae by altering the site of transcription initiation. We have found that three histone regulatory (hir) mutations, identified by their effects on the regulation of histone gene expression, suppress the same insertion mutations. In addition, we have examined whether any previously identified spt (suppressor of Ty) mutations might suppress the delta insertion alleles because of effects on histone gene regulation. Our results demonstrate that mutations in the histone genes SPT11/HTA1 and SPT12/HTB1 and in three other SPT genes, SPT1, SPT10 and SPT21, confer Hir- phenotypes. The spt1 mutation was found to be an allele of HIR2 while the spt10 and spt21 mutations are not in any of the known HIR genes.


Galanin suppresses proliferation of human U251 and T98G glioma cells via its subtype 1 receptor.
Galanin is a neuropeptide with a widespread distribution throughout the nervous and endocrine systems, and recent studies have shown an anti-proliferative effect of galanin on several types of tumors. However, whether and how galanin and its receptors are involved in the regulation of cell proliferation in glioma cells remains unclear. In this study, the roles of galanin and its subtype 1 receptor (GAL1) in the proliferation of human U251 and T98G glioma cells were investigated. We found that galanin significantly suppressed the proliferation of U251 and T98G cells as well as tumor growth in nude mice. However, galanin did not exert apoptotic or cytotoxic effects on these two cell lines. In addition, we showed that galanin decreased the proliferation of U251 and T98G cells via its GAL1 receptor. Finally, we found that the GAL1 receptor was involved in the suppressive effects of galanin by activating ERK1/2.


Asymptomatic diabetes in childhood and adolescence. A review.
An account is given of the present conception of asymptomatic (chemical) diabetes in the pediatric age group, which also has been named MODY (maturity-onset type of diabetes of young people). Long-term studies show that about 10% will eventually decompensate to overt diabetes. In contrast to classical juvenile-onset type of diabetes the inheritance of MODY seems to be autosomal dominant in many cases. Some authors have suggested that insulin resistance exists in non-obese patients with asymptomatic diabetes, but this view is not supported by observations of the author. Obese patients should reduce their body fat, but other therapeutic approaches are difficult to evaluate because of the normal fluctuation of the disease. There is no general agreement in the literature concerning the value of insulin treatment. The author supports the view that insulin treatment should be started in the late stages of chemical diabetes just before symptomatic disease emerges. In the long run this approach may ameliorate the condition due to the preservation of some beta-cell function for long periods. An unsettled question is whether early insulin treatment in asymptomatic diabetes will delay diabetic vascular complications.


Kinetics of helix-handedness inversion: folding and unfolding in aromatic amide oligomers.
A series of helically folded oligoamides of 8-amino-2-quinoline carboxylic acid possessing 6, 7, 8, 9, 10 or 16 units are prepared following convergent synthetic schemes. The right-handed (P) and the left-handed (M) helical conformers of these oligomers undergo an exchange slow enough to allow their chromatographic separation on a chiral stationary phase. Thus, the M conformer is isolated for each of these oligomers and its slow racemization in hexane/CHCl(3) solutions is monitored at various temperatures using chiral HPLC. The kinetics of racemization at different temperatures in hexane/CHCl(3) (75:25 vol/vol) are fitted to a first order kinetic model to yield the kinetic constant and the Gibbs energy of activation for oligomers having 6, 7, 8, 9, 10 or 16 quinoline units. This energy gives the first quantitative measure of the exceptional stability of the helical conformers of an aromatic amide foldamer with respect to its partly unfolded conformations that occur between an M helix and a P helix. The trend of the Gibbs energy as a function of oligomer length suggests that helix-handedness inversion does not require a complete unfolding of a helical strand and may instead occur through the propagation of a local unfolding separating two segments of opposite handedness.


Interaction of cholecystokinin (CCK-33) and its C-terminal fragments: CCK-8 and CCK-4 with alpha- and beta-adrenoceptor agonists and antagonists in the cardiovascular system of rats. Part A.
The goal of the present study was to examine the interaction of cholecystokinin (CCK-33) and its fragments: C-terminal octapeptide (CCK-8) and C-terminal tetrapeptide (CCK-4) with alpha- and beta-adrenoceptor agonists and antagonists. The effect of this interaction on arterial blood pressure and function of isolated heart was studied in rats. The results indicate that: 1) CCK-33 enhances the influence of catecholamines: noradrenaline and isoprenaline, mainly on the function of isolated heart. This peptide does not change cardiovascular effects of alpha-adrenoceptor antagonist--phentolamine. CCK-33 diminishes the influence of propranolol on the function of isolated heart. The hypotensive effect of beta-adrenoceptor antagonist is not affected by CCK-33. 2) CCK-8 does not alter cardiovascular effects of noradrenaline and isoprenaline. The peptide diminishes the hypotensive effect of phentolamine and reverses the hypotensive effect of propranolol. CCK-8 enhances the influence of propranolol and does not change the influence of phentolamine on the function of isolated heart. CCK-8 enhances bradycardia evoked by propranolol. 3) CCK-4 does not change the influence of noradrenaline and isoprenaline on arterial blood pressure and diminishes the hypotensive effect of phentolamine and propranolol. The peptide does not change cardiac effects of noradrenaline and diminishes the effects of isoprenaline, phentolamine and propranolol. On the basis of the present study, we concluded that CCK-33 and its fragments CCK-8 and CCK-4 modify the cardiovascular action of alpha- and beta-adrenoceptor agonists and antagonists. We suggest that effects we have observed correlate with the activation of the CCK-A receptors (CCK-33, CCK-8) or CCK-B receptors (CCK-4). CCK-related peptides may increase or reduce the effects of catecholamines indirectly through activation of alpha-adrenoceptors. We can not exclude direct action of the peptides on the heart.


Caries prevalence of children and adolescents in Bosnia and Herzegovina.
The aim of this study was to present epidemiological parameters of caries prevalence in children and adolescents in index age groups on a national and regional level in Bosnia and Herzegovina (BH). The study was conducted during 2004 year for children aged 6 and 12, and during 2007 for adolescents aged 15. An oral health survey was performed on a total number of 1,240 children and adolescents in line with World Health Organization methodology and criteria. Results for caries prevalence and treatment needs were presented and discussed in this paper. Mean dmft (decay, missing, filled teeth for primary dentition) for children aged six was 6.7 (SD±3.9) in that the decayed teeth constituted the major part of the index (88.8%), followed by extracted teeth (8.9%) and a small percentage of filled teeth (2.3%). In 12-year-olds DMFT (Decay, Missing, Filled Teeth for permanent dentition) was 4.2 (SD±2.9), Significant Caries index (SiC) was 7.7 (SD±2.9), the decayed teeth constituted the major part of the index (45.4%), followed by 42.1% of FT and 12.5% of extracted teeth. Among 15-year-olds the DMFT was 7.6 (SD±4.1), SiC was 9.2 (SD±1.2), and filled teeth constituted the major part of the index. The present study provides some evidence of relatively high caries prevalence and severity in comparison with Western European countries. It is necessary to devote more attention to the oral health of children and adolescents. Community based oral health promotion, preventive programs and preventive oriented public dental health care services should be made available and accessible to all children in Bosnia and Herzegovina.


Urinary nickel and prolactin in workers exposed to urban stressors.
The aim of our study is to verify whether the exposure to low Ni doses in urban air may have some effects on the prolactin values of outdoor workers exposed to urban pollutants. 334 workers have been included in the study and divided on the basis of gender, job, age, length of service and smoking habits. Each worker underwent urinary Ni and prolactin sampling. The t-test for independent samples, the Mann-Whitney U test for two mode variables (gender, smoking habit), the univariate ANOVA test and the Kruskal Wallis test for the variables in more than two modes (age, length of service and job duties) were performed on the total sample. Pearson's correlation coefficient (p two-tailed) among the parameters was evaluated both in the total sample and after the stratification by gender, smoking habit and job. Multiple linear regression was performed after taking account of the major confounding factors on the total sample and on the subcategories. The statistical tests showed a significant correlation between urinary Ni and prolactin both in the total sample and in the subcategories. We believe that the occupational exposure to low doses of Ni present in urban pollution may influence the prolactin values in exposed workers.


Large scale RNAi reveals the requirement of nuclear envelope breakdown for nuclear import of human papillomaviruses.
A two-step, high-throughput RNAi silencing screen was used to identify host cell factors required during human papillomavirus type 16 (HPV16) infection. Analysis of validated hits implicated a cluster of mitotic genes and revealed a previously undetermined mechanism for import of the viral DNA (vDNA) into the nucleus. In interphase cells, viruses were endocytosed, routed to the perinuclear area, and uncoated, but the vDNA failed to be imported into the nucleus. Upon nuclear envelope perforation in interphase cells HPV16 infection occured. During mitosis, the vDNA and L2 associated with host cell chromatin on the metaphase plate. Hence, we propose that HPV16 requires nuclear envelope breakdown during mitosis for access of the vDNA to the nucleoplasm. The results accentuate the value of genes found by RNAi screens for investigation of viral infections. The list of cell functions required during HPV16 infection will, moreover, provide a resource for future virus-host cell interaction studies.


Gene transfer into marrow repopulating cells: comparison between amphotropic and gibbon ape leukemia virus pseudotyped retroviral vectors in a competitive repopulation assay in baboons.
Many diseases might be treated by gene therapy targeted to the hematopoietic system, but low rates of gene transfer achieved in humans and large animals have limited the application of this technique. We have developed a competitive hematopoietic repopulation assay in baboons to evaluate methods for improving gene transfer and have used this method to compare gene transfer rates for retroviral vectors having an envelope protein (pseudotype) from amphotropic murine retrovirus with similar vectors having an envelope protein derived from gibbon ape leukemia virus (GALV). We hypothesized that vectors with a GALV pseudotype might perform better based on our previous work with cultured human hematopoietic cells. CD34(+) marrow cells from each of four untreated baboons were divided into two equal portions that were cocultivated for 48 hours with packaging cells producing equivalent titers of either amphotropic or GALV pseudotyped vectors containing the neo gene. The vectors contained small sequence differences to allow differentiation of cells genetically marked by the different vectors. Nonadherent and adherent cells from the cultures were infused into animals after they received a myeloablative dose of total body irradiation. Polymerase chain reaction (PCR) analysis for neo gene-specific sequences in colony-forming unit-granulocyte-macrophage from cell populations used for transplant showed gene transfer rates of 2.7%, 7.1%, <15%, and 3.9% with the amphotropic vectors and 7.1%, 11.3%, <15%, and 26.4% with the GALV pseudotyped vector. PCR analysis of peripheral blood and marrow cells after engraftment showed the neo gene to be present in all four animals analyzed at levels between 0.1% and 5%. Overall gene transfer efficiency was higher with the GALVpseudotyped vector than with the amphotropic vectors. Southern blot analysis in one animal confirmed a gene transfer efficiency of between 1% and 5%. The higher gene transfer efficiency with the GALV-pseudotyped vector correlated with higher levels of GALV receptor RNA compared with the amphotropic receptor in CD34(+) hematopoietic cells. These results show that GALV-pseudotyped vectors are capable of transducing baboon marrow repopulating cells and may allow more efficient gene transfer rates for human gene therapy directed at hematopoietic cells. In addition, our data show considerable differences in gene transfer efficiency between individual baboons, suggesting that a competitive repopulation assay will be critical for evaluation of methods designed to improve gene transfer into hematopoietic stem cells.


Executive dysfunction in substance dependent individuals during drug use and abstinence: an examination of the behavioral, cognitive and emotional correlates of addiction.
Increasing evidence indicates that substance-dependent individuals (SDI) are impaired in executive control tasks relying on different systems within the prefrontal cortex (PFC). Three different functional systems have been described: the dorsolateral prefrontal cortex (DLPC), orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC) circuits. Dysfunction within each PFC system is associated with different behavioral, cognitive, and emotional abnormalities. Few studies have conducted an exhaustive examination of all these different factors in SDI. In this study, SDI (including alcohol, cocaine, and methamphetamine polysubstance users, n=35) were compared with healthy controls (n=36) on a series of behavioral (Frontal Systems Behaviour Scale, FrSBe), cognitive (N-back, Go-No Go, and Wisconsin Card Sorting Tasks), and emotional (International Affective Picture System, IAPS) tasks, each of which was thought to tax a different component of these PFC functional systems. SDI showed greater behavioral problems in the apathy, disinhibition, and executive dysfunction subscales of the FrSBe. Behavioral deficits were significantly associated with several real-life domains in which SDI typically have problems. SDI also showed poorer performance on cognitive tests of working memory, response inhibition and mental flexibility, and abnormal processing of affective images from the IAPS. Cognitive, behavioral, and emotional measures were moderately correlated.


A role for neuropeptide Y in rat iridial arterioles.
A role for neuropeptide Y (NPY) in neurotransmission in rat iridial arterioles has been investigated. Reverse transcription-polymerase chain reaction analysis has demonstrated mRNA expression for both Y1 and Y2 receptors in the superior cervical ganglion and iris. The Y1 agonist [Leu31,Pro34]NPY caused a dose-dependent constriction of iris arterioles (50% effective concentration of 10(-8) M), but, at low concentrations (10(-9) and 10(-10) M), it failed to potentiate either submaximal responses to norepinephrine (10(-6) M) or submaximal, noradrenergic responses to nerve stimulation. In contrast, 10(-7) M [Leu31,Pro34]NPY potentiated submaximal, noradrenergic responses to nerve stimulation (10 Hz, < or = 1 s) and to a concentration of norepinephrine (10(-7) M) which produced only small contractions. The Y1 antagonist 1229U91 blocked contractions induced by [Leu31,Pro34]NPY. Stimulation of the nerves for longer periods (10 or 20 Hz; 5, 30, or 60 s) revealed a component of the response which was reduced by 1229U91. This component was not apparent after brief stimuli (10 Hz, < or = 1 s), even when opposing receptor pathways were blocked. The Y2 agonist N-acetyl-[Leu28,Leu31]NPY24-36 had little effect on arterioles preconstricted with either high potassium or an alpha 2-adrenoceptor agonist, or on nerve-mediated contractions. Results suggest that NPY, released from sympathetic nerves during long-duration, high-frequency stimulation, activates Y1 receptors on iris arterioles to produce vasoconstriction and to potentiate responses to low concentrations of norepinephrine.


Further studies on mefloquine and praziquantel alone or interaction of both drugs against Schistosoma japonicum in vitro.
The aim of the present study is to further understand and analyze the interaction of mefloquine with praziquantel against adult Schistosoma japonicum in vitro. Mice infected with S. japonicum cercariae for 35-37 days were sacrificed, and adult schistosomes were collected by perfusion. Schistosomes were placed to each of 12 wells of a Falcon plate and maintained in RPMI 1640 supplemented by 10% calf serum. For determination of 50% and 95% lethal concentration (LC50 and LC95) of the two drugs in vitro, schistosomes were exposed to mefloquine at concentrations of 1, 2, 3, 4, 5, 6, 7, and 10 μg/mL or praziquantel at concentrations of 0.001, 0.01, 0.05, 0.1, 0.2, 0.5, 1, 10, and 30 μg/mL. The plate was incubated at 37°C in 95% air + 5% CO₂ for 72 h. According to the half-life of oral mefloquine and praziquantel in mice, mefloquine combined with praziquantel simultaneously, mefloquine administered within 1 h after praziquantel and praziquantel administered within 17 h after mefloquine were used to evaluate the effect of mefloquine in combination with praziquantel against S. japonicum in vitro. The results showed that the LC50 and LC95 of mefloquine calculated by the Bliss method were 6.17 μg/mL (95% confidence limits, 5.84-6.517 μg/mL) and 8.703 μg/mL (95% confidence limits, 7.632-9.797 μg/mL), respectively. As to praziquantel, no worm death was seen when schistosomes were exposed to praziquantel at concentrations of 0.005-0.2 μg/mL for 72 h. While in the worms exposed to praziquantel 1, 10, and 30 μg/mL, strong spasmodic contractions of the worm body and vesiculation along the worm surface were observed, but 48-75% of the schistosomes survived the exposure in 72-h incubation. Meanwhile, the number of dead worms that emerged in each group was not proportion to the increasing concentrations. Therefore, it is not appropriate to calculate the LC50 and LC95 of praziquantel. For evaluation of the interaction with the two drugs, praziquantel 0.1 or 0.2 μg/mL, which may induce moderate or strong spasmodic contractions of the worm body and vesiculation along the worm surface, was combined with mefloquine 5, 6, or 7 μg/mL. It was found that when mefloquine combined with praziquantel simultaneously or administered 1 h after addition of praziquantel, the spasmodic contraction of the male worm body was antagonized by mefloquine in various degrees according to the concentrations of mefloquine used. Meanwhile, praziquantel-induced weakened motor activity could be reversed by mefloquine. In female worms, morphological alterations and stimulated motor activity induced by mefloquine still developed. Interestingly, using these two regimens to combine mefloquine with praziquantel resulted in no impact or a decrease in worm mortality. On the other hand, praziquantel 0.2 μg/mL administered within 17 h after mefloquine 5 or 6 μg/mL promoted the damage to the tegument of the worms, which led to enhance the worm mortality compared with that of worms exposed to mefloquine alone. The results indicate that in vitro higher concentrations of praziquantel administered within 17 h after mefloquine may increase the effect against adult schistosomes, while praziquantel combined with mefloquine simultaneously or administered 1 h before addition of mefloquine exhibits no impact or decrease in the effect against schistosomes.


Transcriptional profiles of leukocyte populations provide a tool for interpreting gene expression patterns associated with high fat diet in mice.
Microarray experiments in mice have shown that high fat diet can lead to elevated expression of genes that are disproportionately associated with immune functions. These effects of high fat (atherogenic) diet may be due to infiltration of tissues by leukocytes in coordination with inflammatory processes. The Novartis strain-diet-sex microarray database (GSE10493) was used to evaluate the hepatic effects of high fat diet (4 weeks) in 12 mouse strains and both genders. We develop and apply an algorithm that identifies "signature transcripts" for many different leukocyte populations (e.g., T cells, B cells, macrophages) and uses this information to derive an in silico "inflammation profile". Inflammation profiles highlighted monocytes, macrophages and dendritic cells as key drivers of gene expression patterns associated with high fat diet in liver. In some strains (e.g., NZB/BINJ, B6), we estimate that 50-60% of transcripts elevated by high fat diet might be due to hepatic infiltration by these cell types. Interestingly, DBA mice appeared to exhibit resistance to localized hepatic inflammation associated with atherogenic diet. A common characteristic of infiltrating cell populations was elevated expression of genes encoding components of the toll-like receptor signaling pathway (e.g., Irf5 and Myd88). High fat diet promotes infiltration of hepatic tissue by leukocytes, leading to elevated expression of immune-associated transcripts. The intensity of this effect is genetically controlled and sensitive to both strain and gender. The algorithm developed in this paper provides a framework for computational analysis of tissue remodeling processes and can be usefully applied to any in vivo setting in which inflammatory processes play a prominent role.


Metachronous, colitis-associated rectal cancer that developed after sporadic adenocarcinoma in an adenoma in a patient with longstanding Crohn's disease: a case report.
Colorectal cancer associated with Crohn's disease (CD) is increasing in proportion to the number of patients with CD in Japan. There are two subtypes of colorectal cancer with CD: sporadic cancer and colitis-associated cancer. Early diagnosis of colitis-associated cancer is sometimes difficult; when colorectal cancer is found in patients with CD, both colitis-associated cancer and sporadic cancer should be kept in mind. Here, we describe a case of metachronous, colitis-associated rectal cancer that developed after the complete resection of an adenoma that became a sporadic adenocarcinoma in a patient with longstanding CD. To the best of our knowledge, this is the first report of colitis-associated cancer in a patient with CD after removal of a sporadic cancer. We describe a 51-year old man with CD who had difficulty in defecation. A rectal polyp was detected and a transanal resection of the polyp was performed. A histopathological examination showed an adenoma with sporadic adenocarcinoma. After three years, a follow-up colonoscopy revealed a reddish, elevated lesion in the patient's rectum. A colonoscopic biopsy showed a signet ring cell carcinoma. We performed an abdominoperineal resection of the rectum and a bilateral pelvic lymph node dissection. A histopathological examination revealed a mucinous adenocarcinoma with signet ring cell carcinoma and lymph node metastasis. The patient received adjuvant chemotherapy with oral uracil 224 mg combined with tegafur 100 mg plus leucovorin. No signs of recurrence were noted at a follow-up 18 months after the third surgery and 60 months after the second surgery.


Genome Editing in Stem Cells for Disease Therapeutics.
Programmable nucleases including zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindrome repeats (CRISPR)/CRISPR-associated protein have tremendous potential biological and therapeutic applications as novel genome editing tools. These nucleases enable precise modification of the gene of interest by disruption, insertion, or correction. The application of genome editing technology to pluripotent stem cells or hematopoietic stem cells has the potential to remarkably advance the contribution of this technology to life sciences. Specifically, disease models can be generated and effective therapeutics can be developed with great efficiency and speed. Here we review the characteristics and mechanisms of each programmable nuclease. In addition, we review the applications of these nucleases to stem cells for disease therapies and summarize key studies of interest.


Active Usage of Mobile Health Applications: Cross-sectional Study.
Mobile health applications are being increasingly used for people's health management. The different uses of mobile health applications lead to different health outcomes. Although active usage of mobile health applications is shown to be linked to the effectiveness of mobile health services, the factors that influence people's active usage of mobile health applications are not well studied. This paper aims to examine the antecedents of active usage of mobile health applications. Grounded on the 3-factor theory, we proposed 10 attributes of mobile health applications that influence the active usage of mobile health applications through consumers' satisfaction and dissatisfaction. We classified these 10 attributes into 3 categories (ie, excitement attributes, performance attributes, and basic attributes). Using the survey method, 494 valid responses were collected and analyzed using structural equation modeling. Our analysis results revealed that both consumer satisfaction (β=0.351, t=6.299, P<.001) and dissatisfaction (β=-0.251, t=5.119, P<.001) significantly influenced active usage. With regard to the effect of attributes, excitement attributes (β=0.525, t=12.861, P<.001) and performance attributes (β=0.297, t=6.508, P<.001) positively influenced consumer satisfaction, while performance attributes (β=-0.231, t=3.729, P<.001) and basic attributes (β=-0.412, t=7.132, P<.001) negatively influenced consumer dissatisfaction. The results of the analysis confirmed our proposed hypotheses. Our study provides a novel perspective to study the active usage of mobile health applications. By categorizing the attributes of mobile health applications into 3 categories, the differential effects of different attributes can be tested. Meanwhile, consumer satisfaction and dissatisfaction are confirmed to be independent from each other.


Photoassociative production and trapping of ultracold KRb molecules.
We have produced ultracold heteronuclear KRb molecules by the process of photoassociation in a two-species magneto-optical trap. Following decay of the photoassociated KRb*, the molecules are detected using two-photon ionization and time-of-flight mass spectroscopy of KRb+. A portion of the metastable triplet molecules thus formed are magnetically trapped. Photoassociative spectra down to 91 cm(-1) below the K(4s)+Rb(5p(1/2)) asymptote have been obtained. We have made assignments to all eight of the attractive Hund's case (c) KRb* potential curves in this spectral region.


A Prader-Willi locus lncRNA cloud modulates diurnal genes and energy expenditure.
Prader-Willi syndrome (PWS), a genetic disorder of obesity, intellectual disability and sleep abnormalities, is caused by loss of non-coding RNAs on paternal chromosome 15q11-q13. The imprinted minimal PWS locus encompasses a long non-coding RNA (lncRNA) transcript processed into multiple SNORD116 small nucleolar RNAs and the spliced exons of the host gene, 116HG. However, both the molecular function and the disease relevance of the spliced lncRNA 116HG are unknown. Here, we show that 116HG forms a subnuclear RNA cloud that co-purifies with the transcriptional activator RBBP5 and active metabolic genes, remains tethered to the site of its transcription and increases in size in post-natal neurons and during sleep. Snord116del mice lacking 116HG exhibited increased energy expenditure corresponding to the dysregulation of diurnally expressed Mtor and circadian genes Clock, Cry1 and Per2. These combined genomic and metabolic analyses demonstrate that 116HG regulates the diurnal energy expenditure of the brain. These novel molecular insights into the energy imbalance in PWS should lead to improved therapies and understanding of lncRNA roles in complex neurodevelopmental and metabolic disorders.


Heterotopic ossification around the elbow following burns in children: results after excision.
Major burn injuries close to joints alter the function of the musculoskeletal system through tissue loss and limitation of joint motion. In children with involvement of the hand, wrist, and forearm, restriction of elbow motion secondary to heterotopic ossification following a burn injury severely limits the function of the upper extremity. The purpose of this study was to review elbow function following excision of heterotopic ossification around the elbow in children. Eight children (ten elbows) from a population of 3245 consecutive patients who were admitted to our pediatric burn center were found to have severe heterotopic ossification of the elbow, leading to an inability to reach the mouth for feeding and the head and the perineum for self-care. Excision of the heterotopic ossification was undertaken if the patient had this limitation of function and if movement was restricted to a total arc of motion of <50 degrees. Pain was not an indication for the operation. The procedure was performed at an average of 17.3 months following the injury. Seven children (nine elbows) were available for follow-up at an average of fifty-six months after surgery. All nine elbows had an improved arc of motion (an average increase of 57 degrees ). Following excision, heterotopic ossification did not recur. All children were able to reach the face and the perineum following the operation. Excision of heterotopic ossification around the elbow following a burn injury in children can improve the arc of motion and improve the function of the extremity. A relatively simple operative and postoperative regimen can achieve satisfactory results.


Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis.
Chronic pancreatitis (CP) is a precancerous condition associated with pancreatic ductal adenocarcinoma (PDAC), but its evolutionary mechanism is unclear. Pancreatic stellate cells (PSCs) are closely related to the occurrence and development of CP and PDAC, but it is not clear whether PSCs play a key role in this "inflammation-cancer transition". Our research found that co-culture with activated PSCs promoted the proliferation, migration and invasion of normal pancreatic duct epithelial cells and pancreatic cancer cells. At the same time, activated PSCs had a significant effect on the expression of the glycolysis markers (pyruvate kinase M2, lactate dehydrogenase A, glucose transporter 1, hexokinase-II and monocarboxylate transporter 4; PKM2, LDHA, GLUT1, HK2 and MCT4) in normal pancreatic duct epithelial cells and pancreatic cancer cells and increased lactic acid production and glucose consumption in these two cells. In vivo experiments showed that the expression of the glycolysis markers in pancreatic duct epithelial cells and the marker protein (α-SMA) of activated PSCs in the pancreatic duct peripancreatic interstitium were higher in pancreatic cancer tissues and chronic pancreatitis tissues than in normal pancreatic tissues in both animals and humans. In addition, analysis of human tissue specimens showed that there is a correlation between the expression of glycolysis markers and α-SMA. These findings indicate that activated PSCs play an important role in the development and progression of chronic pancreatitis into pancreatic cancer by regulating and promoting aerobic glycolysis. Our research provides a new theoretical basis for further understanding the mechanism of CP malignancy and the selection of targets for reversing CP malignancy.


When calculators lie: A demonstration of uncritical calculator usage among college students and factors that improve performance.
Calculators are often unnecessary to solve routine problems, though they are convenient for offloading cognitively effortful processes. However, errors can arise if incorrect procedures are used or when users fail to monitor the output for keystroke mistakes. To investigate the conditions under which people's attention are captured by errant calculator outputs (i.e., from incorrectly chosen procedures or keystroke errors), we programmed an onscreen calculator to "lie" by changing the answers displayed on certain problems. We measured suspicion by tracking whether users explicitly reported suspicion, overrode calculator "lies", or re-checked their calculations after a "lie" was presented. In Study 1, we manipulated the concreteness of problem presentation and calculator delay between subjects to test how these affect suspicion towards "lies" (15% added to answers). We found that numeracy had no effect on whether people opted-in or out of using the calculator but did predict whether they would become suspicious. Very few people showed suspicion overall, however. For study 2, we increased the "lies" to 120% on certain answers and included questions with "conceptual lies" shown (e.g., a negative sign that should have been positive). We again found that numeracy had no effect on calculator usage, but, along with concrete formatting, did predict suspicion behavior. This was found regardless of "lie" type. For study 3, we reproduced these effects after offering students an incentive for good performance, which did raise their accuracy across the math problems overall but did not increase suspicion behavior. We conclude that framing problems within a concrete domain and being higher in numeracy increases the likelihood of spotting errant calculator outputs, regardless of incentive.


Strange behavior of a passive scalar in a linear velocity field.
Damping (or growth) rates of a typical realization, mean-field and high-order correlation functions of a passive scalar (e.g., a number density of particles) advected by a linear velocity fields are estimated. It is shown that all statistical moments higher than the first moment and a typical realization of a passive scalar without an external pumping decay for both laminar and random incompressible linear velocity fields. Strong compressibility of a laminar linear velocity field can result in a growth of a typical realization and the high-order moments of a passive scalar. It is demonstrated that for a laminar compressible linear velocity field the flux of particles from the infinity does not vanish and the total number of particles is not conserved. For a random compressible linear velocity field a typical realization decays whereas the high-order moments of a passive scalar can grow. Comparison of the obtained results with those for dynamics of a passive scalar advected by a homogeneous isotropic and compressible turbulent flow with a given longitudinal two-point correlation function F=1-r(2) is performed (where r is the distance between two points measured in the units of the maximum scale of turbulent motions).


Comparison of eight and 12 hour shifts: impacts on health, wellbeing, and alertness during the shift.
The generally agreed view is that there is no ideal shift system, and that most systems will have both advantages and disadvantages. As such, attention has been placed on trying to identify good and bad features of shift systems, with a view to minimising the possible ill health as a consequence of shiftwork. The present study focuses on the duration of the shift and looks at the implications for individual health, wellbeing, and alertness during the shift of extending the shift from the traditional eight hours to 12. Two groups of chemical workers, one working 12 hour shifts and the other working eight hour shifts, took part. All completed a modified version of the standard shiftwork index (SSI), a set of self reported questionnaires related to health and wellbeing. The two groups did not differ on most outcome measures, although the differences that did exist suggested advantages for the 12 hour shift workers over the eight hour shift workers; with the notable exception of rated alertness at certain times of day. The results are explained in terms of the design of the 12 hour shift system and the specific sequencing of shifts that seem to minimise the potential for the build up of fatigue. Although the current data moderately favour 12 hour shifts, a cautionary note is sounded with regard to the implications of the alertness ratings for performance and safety.


Extremely premature (< or = 800 g) schoolchildren: multiple areas of hidden disability.
To examine the functional abilities of extremely low birthweight (ELBW, < or = 800 g) children at school age compared with full term children. ELBW children (n = 115) in a geographically defined regional cohort born between 1974 and mid-1985 (comprising 96% of 120 survivors of 400 ELBW infants admitted to the Provincial Tertiary neonatal intensive care unit), were compared with (n = 50) children of comparable age and sociodemographic status. Each child was categorised by the pattern and degree of disability, using a system derived from the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM IV). Psycho-educational, behavioural, and motor results for ELBW children free of severe/multiple neurosensory disabilities (n = 90; 91% return rate) were compared with the term children. Severe/multiple neurosensory disabilities were present in 16 ELBW children (14%), and 15 (13%) had borderline intelligence. ELBW children of global IQ > or = 85 scored significantly lower in standardised tests of fine and gross motor control, visuo-motor pencil output, visual memory, and academic achievement (reading, arithmetic, written language). ELBW survivors were three times more likely to have learning disorders (47% vs 18%) and 22 (41%) of the 54 ELBW children with learning disorders had multiple areas of learning difficulty. Of the ELBW group, 30 (26%) were not disabled compared with 41 (82%) of the term group. Only five (12%) of the ELBW boys were not disabled, compared with 25 (35%) of the ELBW girls. Finally, ELBW children had significantly worse scores on ratings of behaviour during testing by the psychologist and behaviour by parental report. The most likely outcome for ELBW survivors at school age is a learning disorder, often multiple, or borderline intellectual functioning, combined with behavioural and motor risk factors rather than severe/multiple disability. Mean scores on psycho-educational testing showed poorer performance of the ELBW children, but grossly understated the complex nature of the individual degree of educational difficulty faced by these children.


Sodium and Calcium Currents in Glial Cells of the Mouse Corpus Callosum Slice.
We studied Na+ and Ca2+ currents in glial cells during the development of the corpus callosum in situ. Glioblasts and oligodendrocytes from frontal brain slices of postnatal day (P) 3 to P18 mice were identified based on morphological and ultrastructural features after characterization of the currents with the patch-clamp technique. Slices from P3 - P8 mice contained predominantly glioblasts with immature morphological features. These cells showed Na+ and Ca2+ currents, but the population with these currents decreased between P3 and P8. Na+ currents were blocked in Na+-free bathing solution and in the presence of tetrodotoxin, Ca2+ currents were only observed when a high concentration of extracellular Ba2+ was present. The cells from the corpus callosum of P10 - P18 mice predominantly had morphological features of oligodendrocytes. In these cells, which in some cases were shown to form myelin, neither Na+ nor Ca2+ currents were detected. To compare these in situ results with those from the electrophysiologically and immunocytochemically well-characterized cultured glial cells, we determined the expression pattern of stage-specific antigens in the corpus callosum in situ. The first O4 antigen-positive glial precursors were observed at P1, the earliest stage examined. The oligodendrocytic antigens O7 and O10 appeared at P6 and P14, respectively, and prominent labelling with the corresponding markers was seen at P12 and P18, respectively. Despite the existence of numerous mature, O10-positive oligodendrocytes at P18, which expressed Ca2+ channels in vitro, we failed to detect Ca2+ currents in situ at this stage.


A role for the p53 tumour suppressor in regulating the balance between homologous recombination and non-homologous end joining.
Loss of p53, a transcription factor activated by cellular stress, is a frequent event in cancer. The role of p53 in tumour suppression is largely attributed to cell fate decisions. Here, we provide evidence supporting a novel role for p53 in the regulation of DNA double-strand break (DSB) repair pathway choice. 53BP1, another tumour suppressor, was initially identified as p53 Binding Protein 1, and has been shown to inhibit DNA end resection, thereby stimulating non-homologous end joining (NHEJ). Yet another tumour suppressor, BRCA1, reciprocally promotes end resection and homologous recombination (HR). Here, we show that in both human and mouse cells, the absence of p53 results in impaired 53BP1 focal recruitment to sites of DNA damage induced by ionizing radiation. This effect is largely independent of cell cycle phase and the extent of DNA damage. In p53-deficient cells, diminished localization of 53BP1 is accompanied by a reciprocal increase in BRCA1 recruitment to DSBs. Consistent with these findings, we demonstrate that DSB repair via NHEJ is abrogated, while repair via homology-directed repair (HDR) is stimulated. Overall, we propose that in addition to its role as an 'effector' protein in the DNA damage response, p53 plays a role in the regulation of DSB repair pathway choice.


Biosimilar infliximab for the management of rheumatoid arthritis in France: what are the expected savings?
Biosimilar infliximab, the first similar biological medicinal product containing monoclonal antibodies to be commercialised, is likely to contribute to a significant reduction in healthcare costs. We aimed to assess the cost savings potential over 1 year of the use of biosimilar infliximab for the treatment of rheumatoid arthritis (RA) patients in Alsace and in France, in a real-life setting. The analysis was based on a previously conducted observational study which evaluated the annual cost of the care of patients with RA treated with biological therapies in 2012 in Alsace. Average annual costs to manage RA patients were calculated, taking into account the decrease in the retail price between 2012 and 2015 (as given in the official national price list) and the local negotiated price for biosimilar infliximab. Annual cost savings for different biosimilar prescription scenarios were calculated using 2015 prices. Management of RA patients with biosimilar infliximab was significantly cheaper than with adalimumab or etanercept (€11 907 vs €12 981 and €13 551, respectively). The projected annual cost savings reached €13.6 million nationally, if all adult RA patients treated with the originator infliximab switched to the biosimilar drug. These savings, if fully reallocated for the treatment of RA, would enable the treatment of 1141 additional patients. The study showed a positive financial impact of introducing biosimilar infliximab for the treatment of RA patients in France. Such savings could contribute to improved patient care by allowing more patients to be treated without more money being spent.


Mass spectrometry-based proteomics: the road to lung cancer biomarker discovery.
Lung cancer is the leading cause of cancer death in men and women in Western nations, and is among the deadliest cancers with a 5-year survival rate of 15%. The high mortality caused by lung cancer is attributable to a late-stage diagnosis and the lack of effective treatments. So, it is crucial to identify new biomarkers that could function not only to detect lung cancer at an early stage but also to shed light on the molecular mechanisms that underlie cancer development and serve as the basis for the development of novel therapeutic strategies. Considering that DNA-based biomarkers for lung cancer showed inadequate sensitivity, specificity, and reproducibility, proteomics could represent a better tool for the identification of useful biomarkers and therapeutic targets for this cancer type. Among the proteomics technologies, the most powerful tool is mass spectrometry. In this review, we describe studies that use mass spectrometry-based proteomics technologies to analyze tumor proteins and peptides, which might represent new diagnostic, prognostic, and predictive markers for lung cancer. We focus in particular on those findings that hold promise to impact significantly on the clinical management of this disease.


Inflammatory activity following motor progression due to critical CNS demyelinating lesions.
New inflammatory activity is of unclear frequency and clinical significance in progressive multiple sclerosis (MS); it is uncertain in patient cohorts with motor progression due to critical demyelinating lesions. The aim of this study is to determine the likelihood of central nervous system (CNS) inflammatory activity, assessed by new clinical relapses or active magnetic resonance imaging (MRI) lesions, following onset of motor progression due to critical demyelinating lesions. Patients with progressive upper motor neuron impairment for ⩾1 year attributable to critical demyelinating lesions with single CNS lesion (progressive solitary sclerosis (PSS)), 2 to 5 total CNS demyelinating lesions (progressive "pauci-sclerosis" (PPS)), or >5 CNS demyelinating lesions and progressive exclusively unilateral monoparesis or hemiparesis (PUHMS) were identified. Clinical data were reviewed for acute MS relapses, and subsequent MRI was reviewed for active T1-gadolinium-enhancing or T2-demyelinating lesions. None of the 91 patients (22 PSS, 40 PPS, 29 PUHMS) identified experienced clinical relapses over a median clinical follow-up of 93 months (range: 12-518 months). Nine patients (10%) developed active lesions over median 84 months radiologic follow-up (range: 12-518 months). Active lesions occurred in 24% PUHMS, 5% PSS, and 3% PPS cohorts. New inflammatory activity, defined by active lesions and clinical relapses following motor progression in patients with critical demyelinating lesions, is low. Disease-modifying therapies that reduce demyelinating relapses and active MRI lesions are of uncertain benefit in these cohorts.


Single patient learning for adaptive radiotherapy dose prediction.
Throughout a patient's course of radiation therapy, maintaining accuracy of their initial treatment plan over time is challenging due to anatomical changes-for example, stemming from patient weight loss or tumor shrinkage. Online adaptation of their RT plan to these changes is crucial, but hindered by manual and time-consuming processes. While deep learning (DL) based solutions have shown promise in streamlining adaptive radiation therapy (ART) workflows, they often require large and extensive datasets to train population-based models. This study extends our prior research by introducing a minimalist approach to patient-specific adaptive dose prediction. In contrast to our prior method, which involved fine-tuning a pre-trained population model, this new method trains a model from scratch using only a patient's initial treatment data. This patient-specific dose predictor aims to enhance clinical accessibility, thereby empowering physicians and treatment planners to make more informed, quantitative decisions in ART. We hypothesize that patient-specific DL models will provide more accurate adaptive dose predictions for their respective patients compared to a population-based DL model. We selected 33 patients to train an adaptive population-based (AP) model. Ten additional patients were selected, and their respective initial RT data served as single samples for training patient-specific (PS) models. These 10 patients contained an additional 26 ART plans that were withheld as the test dataset to evaluate AP versus PS model dose prediction performance. We assessed model performance using Mean Absolute Percent Error (MAPE) by comparing predicted doses to the originally delivered ground truth doses. We used the Wilcoxon signed-rank test to determine statistically significant differences in terms of MAPE between the AP and PS model results across the test dataset. Furthermore, we calculated differences between predicted and ground truth mean doses for segmented structures and determined statistical significance in the differences for each of them. The average MAPE across AP and PS model dose predictions was 5.759% and 4.069%, respectively. The Wilcoxon signed-rank test yielded two-tailed p-value = 2.9802 × 10 - 8 $2.9802\ \times \ {10}^{ - 8}$ , indicating that the MAPE differences between the AP and PS model dose predictions are statistically significant, and 95% confidence interval = [-2.1610, -1.0130], indicating 95% confidence that the MAPE difference between the AP and PS models for a population lies in this range. Out of 24 total segmented structures, the comparison of mean dose differences for 12 structures indicated statistical significance with two-tailed p-values < 0.05. Our study demonstrates the potential of patient-specific deep learning models in application to ART. Notably, our method streamlines the training process by minimizing the size of the required training dataset, as only a single patient's initial treatment data is required. External institutions considering the implementation of such a technology could package such a model so that it only requires the upload of a reference treatment plan for model training and deployment. Our single patient learning strategy demonstrates promise in ART due to its minimal dataset requirement and its utility in personalization of cancer treatment.


Colocalization of connexin 43 and connexin 45 but absence of connexin 40 in granulosa cell gap junctions of rat ovary.
The expression and localization of gap junction family proteins (connexins) were examined in nonstimulated and gonadotrophin-stimulated ovarian follicles of immature rats. Immunoblot and RNA blot analysis showed the presence of connexin (Cx) 43, Cx40 and Cx45 in ovarian tissue. Of these connexin proteins, Cx43 and Cx45 were identified by immunofluorescent microscopy between granulosa cells in characteristic expression patterns related to follicular developmental stages, while Cx40 was not expressed in granulosa cells but was detected in blood vessels in ovarian stroma. In some plaques of gap junction between granulosa cells, Cx45 was found to be colocalized with Cx43. In immunofluorescent microscopy, the expression of Cx43 was increased with follicular growth, but decreased after induction of ovulation by injection of human chorionic gonadotrophin. In contrast, the Cx45 protein was constantly expressed through follicular development; however, after ovulation, no staining of Cx45 was detected in the corpus luteum. Dual expression and the functional role of Cx43 and Cx45 in cell-to-cell communication in ovarian granulosa cells at various developmental stages were discussed.


Identification and characterisation of midbrain nuclei using optimised functional magnetic resonance imaging.
Localising activity in the human midbrain with conventional functional MRI (fMRI) is challenging because the midbrain nuclei are small and located in an area that is prone to physiological artefacts. Here we present a replicable and automated method to improve the detection and localisation of midbrain fMRI signals. We designed a visual fMRI task that was predicted would activate the superior colliculi (SC) bilaterally. A limited number of coronal slices were scanned, orientated along the long axis of the brainstem, whilst simultaneously recording cardiac and respiratory traces. A novel anatomical registration pathway was used to optimise the localisation of the small midbrain nuclei in stereotactic space. Two additional structural scans were used to improve registration between functional and structural T1-weighted images: an echo-planar image (EPI) that matched the functional data but had whole-brain coverage, and a whole-brain T2-weighted image. This pathway was compared to conventional registration pathways, and was shown to significantly improve midbrain registration. To reduce the physiological artefacts in the functional data, we estimated and removed structured noise using a modified version of a previously described physiological noise model (PNM). Whereas a conventional analysis revealed only unilateral SC activity, the PNM analysis revealed the predicted bilateral activity. We demonstrate that these methods improve the measurement of a biologically plausible fMRI signal. Moreover they could be used to investigate the function of other midbrain nuclei.


Deciphering early events involved in hyperosmotic stress-induced programmed cell death in tobacco BY-2 cells.
Hyperosmotic stresses represent one of the major constraints that adversely affect plants growth, development, and productivity. In this study, the focus was on early responses to hyperosmotic stress- (NaCl and sorbitol) induced reactive oxygen species (ROS) generation, cytosolic Ca(2+) concentration ([Ca(2+)]cyt) increase, ion fluxes, and mitochondrial potential variations, and on their links in pathways leading to programmed cell death (PCD). By using BY-2 tobacco cells, it was shown that both NaCl- and sorbitol-induced PCD seemed to be dependent on superoxide anion (O2·(-)) generation by NADPH-oxidase. In the case of NaCl, an early influx of sodium through non-selective cation channels participates in the development of PCD through mitochondrial dysfunction and NADPH-oxidase-dependent O2·(-) generation. This supports the hypothesis of different pathways in NaCl- and sorbitol-induced cell death. Surprisingly, other shared early responses, such as [Ca(2+)]cyt increase and singlet oxygen production, do not seem to be involved in PCD.


[A new method for constructing linkage maps of molecular markers: three-point selfcross method].
The method for constructing linkage maps has almost been so far the three-point testcross in higher organisms. This method is, however, considerably limited to a requirement of a parent or line with three recessive genes that can be obtained by only cross breeding. In this paper, the three-point selfcross method for mapping was proposed. This method can also provide us with informations of mapping as the same as the three-point testcross method. However, the three-point selfcross method does not have any limitation of requiring a parent with three recessive genes. It was theoretically proved that this method could be used to map molecular marker loci in small sample of F2 population. Exactly to test both the methods for mapping, Fisher information content was applied to prove that the three-point selfcross method is powerful for mapping. Further to test this method, data of the first 6 loci were chosen from 12 RFLP loci detected in 333 F2 individuals in SAMPLE. RAW file in MAPMAKER/EXP version 3.0 that Lander et al. (1987) provided. The result showed that, like MAPMAKER program, the three-point selfcross method is powerful to detect linkage relationship among loci, to order them on linkage groups and to calculate distances between nearest neighbor loci. Besides, this method could provide us with the other information of map such as the positive or negative interference and couple or repulsion configuration.


Epirubicin chemotherapy in women with breast cancer: Alternating arms for intravenous administration to reduce chemical phlebitis.
To establish whether using alternating arms for peripheral intravenous epirubicin administration affects the severity or duration of epirubicin-induced phlebitis. An observational study of women with breast cancer (n = 237) in a UK Cancer Centre. Data were analysed after receiving three treatment cycles according to the arm used for epirubicin administration: same, alternating or mixed arm (two consecutive cycles in one arm and one in the alternate arm). Phlebitis severity was graded by clinical staff after each treatment; participants also self-reported symptoms during treatment and for up to 6 months after. The alternating arm group experienced significantly less severe symptoms than the other arm use groups, 6% (4 of 64) compared with 34% (p < 0.001, odds ratio: 0.13 (95% CI: 0.043-0.38) alternating arm compared with same arm group). The alternating arm group reported less pain (p = 0.013), lower overall impact (p = 0.009), lower effect on function (p = 0.032) and shorter duration of symptoms (p = 0.001) than the other arm use groups. Using alternating arms for peripheral administration of epirubicin significantly reduces the severity and duration of chemical phlebitis and is recommended to improve patient experience and reduce the need for central venous access devices.