Genome-wide analysis of iron-dependent growth reveals a novel yeast gene required for vacuolar acidification.
We conducted a genome-wide screen in the budding yeast Saccharomyces cerevisiae of 4,792 homozygous diploid deletions to identify genes that function in iron metabolism. Strains unable to grow on iron-restricted medium contained deletions of genes that encode the structural components of the high affinity iron transport system (FET3, FTR1), the iron-sensing transcription factor AFT1 or genes required for the assembly of the transport system. We also identified genes that were not previously known to play a role in iron metabolism. Deletion of the gene CWH36 resulted in a severe growth defect on iron-limited medium, as well as increased sensitivity to Congo red and calcofluor white. Iron transport studies demonstrated that Deltacwh36 cells have an inability to copper load apoFet3p. Furthermore, Deltacwh36 cells demonstrated additional phenotypes including distorted vacuole morphology and altered kinetics of FM4-64 trafficking. We show that Deltacwh36 cells have a defect in vacuolar acidification through the use of the pH-sensitive dye LysoSensor Green DND-189. In Deltacwh36 cells, the vacuolar H+-ATPase is not assembled and there are reduced levels of at least one subunit of the V0 complex. The open reading frame responsible for the Deltacwh36 phenotypes is YCL005W-A. This gene contains two introns, has homologues in other Saccharomyces strains, and shows weak homology to a component of the vacuolar H+-ATPase found in organisms as diverse as insect and cow.


Dysarthria in stroke: a narrative review of its description and the outcome of intervention.
Dysarthria is a frequent and persisting sequel to stroke and arises from varied lesion locations. Although the presence of dysarthria is well documented, for stroke there are scant data on presentation and intervention outcome. A literature search was undertaken to evaluate (a) the features of dysarthria in adult stroke populations relative to the conventional Mayo system for classification, which was developed from diverse pathological groups, and (b) the current status of evidence for the effectiveness of intervention in dysarthria caused by stroke. A narrative review of results is presented. The limited data available indicate that, regardless of stroke location, imprecise articulation and slow speaking rate are consistent features, and voice disturbances, especially harshness, and reduced prosodic variation are also common. Dysarthria is more prevalent in left than in right hemisphere lesions. There is a need for comprehensive, thorough analysis of dysarthria features, involving larger populations, with stroke and other variables controlled and with appropriate age-referenced control data. There is low level evidence for benefits arising from intervention in stroke-related dysarthria. Because studies involve few participants, without external control, and sometimes include stroke with other aetiologies, their results lack the required weight for confident evidence-based practice.


Associations of health status with subsequent blood donor behavior-An alternative perspective on the Healthy Donor Effect from Donor InSight.
In donor health research, the 'Healthy Donor Effect' (HDE) often biases study results and hampers their interpretation. This refers to the fact that donors are a selected 'healthier' subset of a population due to both donor selection procedures and self-selection. Donors with long versus short donor careers, or with high versus low donation intensities are often compared to avoid this HDE, but underlying health differences might also cause these differences in behaviour. Our aim was to estimate to what extent a donor´s perceived health status associates with donation cessation and intensity. All active whole blood donors participating in Donor InSight (2007-2009; 11,107 male; 12,616 female) were included in this prospective cohort study. We performed Cox survival and Poisson regression analyses to assess whether self-reported health status, medication use, disease diagnosed by a physician and recently having consulted a general practitioner (GP) or specialist were associated with (time to) donation cessation and donation intensity. At the end of 2013, 44% of the donors in this study had stopped donating. Donors in self-rated good health had a 15% lower risk to stop donating compared to donors in perceived poorer health. Medication use, disease diagnoses and consulting a GP were associated with a 20-40% increased risk to stop donating and a lower donation intensity, when adjusting for age, number of donations and new donor status. Both men and women reporting good health made on average 10% more donations. Donors with a "good" health status were less likely to stop donating blood and tended to donate blood more often than donors with perceived poorer health status. This implies that the HDE is an important source of selection bias in studies on donor health and this includes studies where comparisons within donors are made. This HDE should be adjusted for appropriately when assessing health effects of donation and donors' health status may provide estimates of future donation behavior.


Mathematical formulation and analysis of the nonlinear system reconstruction of the online image-guided adaptive control of hyperthermia.
A nonlinear system reconstruction can theoretically provide timely system reconstruction when designing a real-time image-guided adaptive control for multisource heating for hyperthermia. This clinical need motivates an analysis of the essential mathematical characteristics and constraints of such an approach. The implicit function theorem (IFT), the Karush-Kuhn-Tucker (KKT) necessary condition of optimality, and the Tikhonov-Phillips regularization (TPR) were used to analyze and determine the requirements of the optimal system reconstruction. Two mutually exclusive generic approaches were analyzed to reconstruct the physical system: The traditional full reconstruction and the recently suggested partial reconstruction. Rigorous mathematical analysis based on IFT, KKT, and TPR was provided for all four possible nonlinear reconstructions: (1) Nonlinear noiseless full reconstruction, (2) nonlinear noisy full reconstruction, (3) nonlinear noiseless partial reconstruction, and (4) nonlinear noisy partial reconstruction, when a class of nonlinear formulations of system reconstruction is employed. Effective numerical algorithms for solving each of the aforementioned four nonlinear reconstructions were introduced and formal derivations and analyses were provided. The analyses revealed the necessity of adding regularization when partial reconstruction is used. Regularization provides the theoretical support for one to uniquely reconstruct the optimal system. It also helps alleviate the negative influences of unavoidable measurement noise. Both theoretical analysis and numerical examples showed the importance of having a good initial guess for accomplishing nonlinear system reconstruction. Regularization is mandatory for partial reconstruction to make it well posed. The Tikhonov-Phillips regularized Gauss-Newton algorithm has nice theoretical performance for partial reconstruction of systems with and without noise. The Levenberg-Marquardt algorithm is a more robust algorithmic option compared to the Gauss-Newton algorithm for nonlinear full reconstruction. A severe limitation of nonlinear reconstruction is the time consuming calculations required for the derivatives of temperatures to unknowns. Developing a method of model reduction or implementing a parallel algorithm can resolve this. The results provided herein are applicable to hyperthermia with blood perfusion nonlinearly depending on temperature and in the presence of thermally significant blood vessels.


A New Score to Assess the Perioperative Period of the Cancer Patient Undergoing Non-Palliative Elective Surgery: A Retrospective Evaluation of a Case Report by PERIDIA Score.
The complexity of cancer patients and the use of advanced and demolitive surgical techniques frequently need post-operatory ICU hospitalization. To increase safety and to select the best medical strategies for the patient, a multidisciplinary team has performed a new peri-operatory assessment, arising from evidence-based literature data. Verifying that most of the cancer patients, admitted to the intensive care unit, undergo major surgery with localizations in the supramesocolic thoraco-abdominal area, the team focused the attention on supramesocolic peridiaphragmatic cancer surgery. Some scores already in use in clinical practice were selected for the peri-operatory evaluation process. None of them evaluate parameters relating to the entire peri-operative period. In detail, only a few study models were found that concern the assessment of the intra-operative period. Therefore, we wanted to see if using a mix of validated scores, it was possible to build a single evaluation score (named PERIDIAphragmatic surgery score or PERIDIA-score) for the entire peri-operative period that could be obtained at the end of the patient's hospitalization period in post-operative ICU. The main property sought with the creation of the PERIDIA-score is the proportionality between the score and the incidence of injuries, deaths, and the length of stay in the ward. This property could organize a tailor-made therapeutic path for the patient based on pre-rehabilitation, physiotherapy, activation of social assistance services, targeted counseling, collaborations with the continuity of care network. Furthermore, if the pre-operative score is particularly high, it could suggest different or less invasive therapeutic options, and if the intra-operative score is particularly high, it could suggest a prolongation of hospitalization in ICU. The retrospective prospective study conducted on 83 patients is still ongoing. The first data would seem to prove an increase of clinical complications in patients who were assigned a one-third score with respect to the maximum (16/48) of PERIDIA-score. Moreover, patients with a 10/16 score within each phase of the evaluation (pre, peri, and post) more frequently develop injuries. In the light of these evidence, the 29-point score assigned to our patient can be considered as predictive for the subsequent critical and fatal complications the patient faced up.


Review: Barrett's oesophagus in Taiwan.
Barrett's oesophagus is the eponym applied to the columnar epithelium-lined lower oesophagus which is acquired as a complication of chronic gastro-oesophageal reflux (GER). Various complications seen in the Barrett's oesophagus, such as peptic ulcer, stricture, adenocarcinoma are named as Barrett's ulcer, Barrett's stricture-and Barrett's carcinoma, respectively. It is now generally accepted that Barrett's oesophagus is an acquired condition resulting from chronic repetitive GER. The frequency of Barrett's oesophagus seems to be higher in Caucasian than in Oriental or Negro populations. There is a tendency towards increasing prevalence rates all over the world, including Taiwan, due to the Westernization of diet, rapid growth in the elderly population, obesity etc. Almost 6% of the patients who manifest heartburn in GI clinics in Taiwan now suffer from GER, which is almost similar to the 7% reported by Nabel, (USA) in 1976. During the last 30 years, the incidence of esophageal adenocarcinoma has increased rapidly. Patients with Barrett's oesophagus have an increased risk of developing oesophageal adenocarcinoma and should be kept under surveillance. Regular follow-up, at least twice a year or preferably, every 2-3 months, for those patients with SCE using endoscopic surveillance and biopsy for those with severe dysphasia (oesophageal columnar intraepithelial neoplasia) in the surrounding area to detect Barrett's oesophagus cancer, is very important.


A soft-polymer piezoelectric bimorph cantilever-actuated peristaltic micropump.
A peristaltic micropump was fabricated and characterized. The micropump was fabricated using soft lithography, and actuated using piezoelectric bimorph cantilevers. The micropump channel was formed by bonding two layers of PDMS, mixed at 5:1 and 30:1 ratios. The channel was fabricated in the 5:1 layer using replica molding (REM), where a very simple and inexpensive template was made by straddling a 75 microm wire over a glass substrate, followed by covering and smoothing over the wire with a piece of aluminium foil. Not only was this template inexpensive and extremely simple to fabricate, it also created a rounded cross-sectional geometry which is favorable for complete valve shutoff. The cantilevers were driven at Vp=+/-90 V with amplified square wave signals generated by a virtual function generator created in LabVIEW. Connections to the micropump were made by placing capillary tubes in the channel, and then sealed between the two layers of PDMS. Machined aluminium clamps were adhered to the tips of the cantilevers with general purpose adhesive. These clamps allowed for aluminium valves, with finely machined tips of dimensions 3 mm by 200 microm, to be held firmly in place. The variables characterized for this micropump were flow rate, maximum attainable backpressure, free cantilever deflection, valve shutoff, and valve leakage. Three actuation patterns with phase differences of 60, 90, and 120 degrees were compared for flow rate and maximum backpressure. It was determined that the 120 degrees signal outperformed the 60 degrees and 90 degrees signals for both maximum flowrate and maximum attainable backpressure. The maximum and minimum flowrates demonstrated by the micropump were 289 nL min(-1) and 53 nL min(-1), respectively. The maximum backpressure attained was 35 300 Pa. It was also demonstrated that the valves fully closed the channels upon actuation, with minimal observed leakage.


Maternal satisfaction with maternal-infant nursing care in Campeche, Mexico.
Evaluate and compare maternal-satisfaction (global and areas) with maternal-child nursing care (MSMINC) and to explore the relationship of MSMINC with wait time, length of visit, and maternal age and education. Cross-sectional descriptive study comprising 213 mothers. Group 1 (n = 84), mothers of children aged <1 year, and Group 2 (n = 129), mothers of children between 1 and 4 years of age. The patient satisfaction scale was applied. Global MSMINC was 76.26 and 79.21 for Groups 1 and 2, respectively. No associated factors were found in Group 1. In Group 2, wait time was associated with MSMINC in the technical-professional area (F = 3.13; df = 128; B = -0.21; p = 0.01). The fact that these study participants identified only MSMINC-associated factors in the technical-professional area may indicate that care is centered on technical procedures. Given that MSMINC-associated factors were not identified in Group 1, we recommend exploration of maternal expectations and perceptions of care.


A step towards understanding the mechanisms of running-related injuries.
To investigate the association between training-related characteristics and running-related injury using a new conceptual model for running-related injury generation, focusing on the synergy between training load and previous injuries, short-term running experience or body mass index (> or < 25 kg m(-2)). Prospective cohort study with a 9-month follow-up. The data of two previous studies using the same methodology were revisited. Recreational runners (n = 517) reported information about running training characteristics (weekly distance, frequency, speed), other sport participation and injuries on a dedicated internet platform. Weekly volume (dichotomized into < 2h and ≥ 2 h) and session frequency (dichotomized into < 2 and ≥ 2) were the main exposures because they were considered necessary causes for running-related injury. Non-training-related characteristics were included in Cox regression analyses as effect-measure modifiers. Hazard ratio was the measure of association. The size of effect-measure modification was calculated as the relative excess risk due to interaction. One hundred sixty-seven runners reported a running-related injury. Crude analyses revealed that weekly volume < 2h (hazard ratio = 3.29; 95% confidence intervals = 2.27; 4.79) and weekly session frequency < 2 (hazard ratio = 2.41; 95% confidence intervals = 1.71; 3.42) were associated with increased injury rate. Previous injury was identified as an effect-measure modifier on weekly volume (relative excess risk due to interaction = 4.69; 95% confidence intervals = 1.42; 7.95; p = 0.005) and session frequency (relative excess risk due to interaction = 2.44; 95% confidence intervals = 0.48; 4.39; p = 0.015). A negative synergy was found between body mass index and weekly volume (relative excess risk due to interaction = -2.88; 95% confidence intervals = -5.10; -0.66; p = 0.018). The effect of a runner's training load on running-related injury is influenced by body mass index and previous injury. These results show the importance to distinguish between confounding and effect-measure modification in running-related injury research.


Predicting the probability of meningioma recurrence in the preoperative and early postoperative period: a multivariate analysis in the midterm follow-up.
We reviewed the clinical, radiological, surgical, and histopathological features of patients with meningiomas to identify factors that can predict tumor recurrence after "microscopic total removal," to improve preoperative surgical planning, and to help determine the need for close radiological observation at shorter intervals or the need for radiotherapy as an adjuvant treatment in the early postoperative period. Clinical data, magnetic resonance imaging studies, angiographic data, operative reports, and histopathological findings were examined retrospectively in 137 patients with a meningioma treated microsurgically and with no evidence of residual tumor on postoperative MR images. Based on univariate analysis, tumor size, a mushroom shape, proximity to major sinuses, edema, osteolysis, cortical penetration, signal intensity on T2-weighted MRIs, pial-cortical arterial supply, presence of a brain-tumor interface in surgery, Simpson's criteria, and histopathological classification were significant predictors for recurrence. However, age, gender, location of tumor, dural tail, calcification, signal intensity on T1-weighted images, and histopathologic subtypes in the benign group were not significant predictors. By Cox regression analysis the most important variables related to the time to recurrence were mushroom shape, osteolysis, dural tail, and proximity to major sinuses. Aggressive surgical therapy with wider dural removal should be considered in the presence of the preoperative predictors of a recurrence. Close radiological observation at shorter intervals or radiotherapy should be considered as adjuvant therapy in high-risk patients based on surgical findings predicting recurrence related to the brain-tumor interface, Simpson's criteria, and histopathological findings in the early postoperative period.


[Reduced mortality after acute myocardial infarction].
The mortality of cardiovascular disease has decreased substantially in later years though it is uncertain whether this decrease is due to a better profile of risk factors in the population or to improvements in medical treatment. In 1982 to 1984 and 1997 to 1999 all patients admitted to Hedmark Central Hospital in Norway, with acute myocardial infarction were registered and followed for reinfarction and survival over up to three years. A total of 1,236 patients were included in the study, 641 in the first time period and 595 in the second. A significant decrease in case fatality was observed in the second population. The seven days fatality rate decreased from 17.9% to 11.4%, and the one month fatality rate from 22.9% to 16.1%. The median number of days in hospital decreased from ten to six. A Kaplan-Meier estimate for survival in the total follow-up period showed a 43% higher relative death risk in the 1982-1984 cohort compared to the 1997-1999 cohort. A Cox regression revealed that this difference could not be explained by demographic differences between the populations. By evaluating variables registered during the course of infarction in the multivariate Cox model, it is concluded that improved survival in the recent cohort is related to modern treatment of acute myocardial infarction.


Randomised comparison of needle aspiration and chest tube drainage in spontaneous pneumothorax.
Guidelines on spontaneous pneumothorax are contradictory as to intervention between needle aspiration (NA) and chest tube drainage (CTD). Studies show poor adherence to guidelines.Three Norwegian hospitals included patients with primary (PSP) and secondary (SSP) spontaneous pneumothorax. Patients underwent NA or CTD as the primary intervention. The main outcome was duration of hospital stay. Secondary outcomes were immediate- and 1-week success rates and complications.127 patients were included, including 48 patients with SSP. 65 patients underwent NA, 63 patients CTD. Median (interquartile range) hospital stay was significantly shorter for NA: 2.4 days (1.2-4.7 days), compared with CTD: 4.6 days (2.3-7.8 days) (p<0.001). The corresponding figures for the SSP subgroup were 2.54 days (1.17-7.79 days) compared with 5.53 days (3.65-9.21 days) (p=0.049) for NA and CTD, respectively. Immediate success rates were 69% for NA compared with 32% for CTD (p<0.001). The positive effect of NA remained significant in sub-analyses for SSP. There was no significant difference in 1-week success rates. Complications occurred only during the CTD-treatment.Our study shows shorter hospital stay and higher immediate success rates for NA compared with CTD. Subgroup analyses also show clear benefits for NA for both PSP and SSP.


A long-term evaluation of the treatment of osteoarthritis.
In a study of the long-term safety and efficacy of piroxicam (20 mg daily) in the treatment of osteoarthritis, 30 female patients with a mean duration of more than seven years of treatment were evaluated. Despite having had poor or no response with other drug therapies, in the majority of cases in which piroxicam was used half of the patients (15 of 30) reported feeling very good or good at their last visit, 13 said they felt fair, and only two reported feeling poor or very poor in terms of their sense of well-being. The incidence of adverse events was somewhat less than one event per patient year of exposure, and 94 percent of adverse events were mild or moderate. Laboratory measurements of drug safety did not reveal any evidence of renal, hepatic, or hematologic toxicity. It is significant that patients were willing to commit themselves to long-term piroxicam therapy for at least five years after an initial trial and that they preferred to continue taking the drug rather than switch to alternative forms of therapy.


Maturation of the limbic system revealed by MR FLAIR imaging.
Cortical signal intensity (SI) of the limbic system in adults is known to be higher than in neocortical structures, but time-related changes in SI during childhood have not been described. To detect maturation-related SI changes within the limbic system using a fluid-attenuated inversion recovery (FLAIR) MR sequence. Twenty children (10 boys, 10 girls; age 3.5-18 years, mean 11.2 years) with no neurological abnormality and normal MR imaging examination were retrospectively selected. On two coronal FLAIR slices, ten regions of interest (ROI) with a constant area of 10 mm2 were manually placed in the archeocortex (hippocampus), periarcheocortex (parahippocampal gyrus, subcallosal area, cingulate gyrus) and in the neocortex at the level of the superior frontal gyrus on both sides. Significant SI gradients were observed with a higher intensity in the archeocortex, intermediate intensity in the periarcheocortex and low intensity in the neocortex. Significant higher SI values in hippocampal and parahippocampal structures were detected in children up to 10 years of age. These differences mainly reflected differences in cortical structure and myelination state. Archeocortical structures especially showed significant age-related intensity progression suggesting ongoing organization and/or myelination until early adolescence.


The Relationship Between Symptoms of Depression and Anxiety and Disease Activity in IBD Over Time.
We aimed to examine associations between elevated symptoms of depression and anxiety and disease activity in inflammatory bowel disease (IBD). Previous findings have been inconsistent and have not accounted for variability in the courses of these conditions over time. We followed 247 participants with IBD (153 Crohn's disease [CD], 94 ulcerative colitis [UC]) for 3 years. Annually, participants underwent an abdominal examination, reported therapies used for IBD, and completed the Hospital Anxiety and Depression Scale (HADS) questionnaire. We evaluated associations of elevated symptoms (scores ≥11) of anxiety (HADS-A) and depression (HADS-D) with the presence of active IBD as measured using the Powell Tuck Index for UC and the Harvey-Bradshaw Disease Activity Index for CD. We employed logistic regression with generalized estimating equations, simultaneously estimating between-person and within-person effects. Of 247 participants, 15 (6.1%) had elevated symptoms of depression (HADS-D ≥11) at enrollment, 41 (16.6%) had elevated symptoms of anxiety (HADS-A ≥11), and 101 (40.9%) had active IBD. On average, individuals with elevated symptoms of depression (odds ratio [OR], 6.27; 95% CI, 1.39-28.2) and anxiety (OR, 2.17; 95% CI, 1.01-4.66) had increased odds of active IBD. Within individuals, elevations in symptoms of depression over time were associated with increased odds of active IBD (OR, 2.70; 95% CI, 1.15-6.34), but elevated symptoms of anxiety were not. After adjustment for covariates (including disease activity), elevated symptoms of depression were also associated with increased odds of biologic therapy use (OR, 2.02; 95% CI, 1.02-4.00). Symptoms of depression and anxiety are associated with disease activity in IBD over time. Reducing these symptoms should be incorporated into the management of IBD.


Nivaquine and urethral pain.
Two patients, one Jewish and the other Nigerian, were investigated for pain in the urethra. They were both fully treated along the usual lines without any change in the pain. The Jewish patient was later found to be sensitive to chloroquine. When ingestion of this drug was discontinued, his urethral pain disappeared after about four months. The Nigerian patient was advised along the same lines when it was found that he too took chloroquine for malarial attacks regularly. He had total symptomatic relief. The probable relationship between chloroquine and urethral pain is discussed.


From parallel to partnership.
In the USA, there has recently been an unprecedented convergence of complementary/alternative medicine (CAM) with mainstream biomedical care. This confluence may lead to a deeply rooted philosophical conflict. This qualitative study works to identify factors that health-care leaders can use, which will build a pathway to greater integrative practice between medical doctors and CAM practitioners - from parallel existence to partnership - by examining the tensions between biomedical medicine and naturopathic medicine. The purpose of this study is to offer short-term suggestions for partnership and long-term recommendations for better understanding. An original qualitative study using semi-structured with CAM practitioners and biomedical practitioners. Areas of conflict that are preventing synergy are identified and a pathway for health-care leaders to follow to create greater integration and partnerships is suggested. This is a qualitative and exploratory study that has significant limitations on generalizability. This study suggest steps that both types of health-care practitioners can take to increase their success at working together on an individual level, a group level, an organizational level and on an industry-wide basis, as well as provide a specific pathway to create greater integrative practice for health-care leaders. The results indicate that stronger partnerships between different types of medical practitioners increase patient choice, patient satisfaction and outcomes. Increasing interested in CAM modalities is driving more contact between CAM practitioners and biomedical practitioners. This contact is best established in partnership between practitioners rather than in parallel. This original research outlines the sources of conflict and provides recommendations for encouraging greater synergy.


Excitatory and inhibitory effects of second-generation cholinesterase inhibitors on rat gastrointestinal transit.
We investigated the influence of increasing oral doses of second generation acetylcholinesterase inhibitors (AChEI) such as tacrine (0.25, 0.5, 1, 2, 3, 4, 10, and 20 mg kg(-1)), eptastigmine (0.5, 4, 8, 12, 20 and 40 mg kg(-1)) and E2020 (0.18, 0.25, 0.5, 1, 2, 3, 4 and 10 mg kg(-1)) on the distance travelled by a charcoal meal administered 30 min after each compound, in comparison with physostigmine (0.5, 1, 2, 4, 8 and 12 mg kg(-1)). An inverted U regression was observed with a significant parabola between the centimetres travelled and the log of the doses for all AChEI. The maximal stimulating doses (mg kg(-1)) were 2 for physostigmine, 4 for eptastigmine, 3 for tacrine and E2020, while the inhibitory doses were 12 for physostigmine, 40 for eptastigmine, 20 for tacrine and 10 for E2020. The stimulating and inhibiting effects on gastrointestinal propulsion were significantly reversed by 0.25 mg kg(-1)of scopolamine hydrobromide. A dose of scopolamine hydrobromide (0.06 mg kg(-1)) or methylbromide (0.25 mg kg(-1)), pirenzepine dihydrochloride (0.25 mg kg(-1)) and mecamylamine hydrochloride (0.5 mg kg(-1)), which per se did not affect gastrointestinal propulsion, antagonized both the stimulating and inhibitory effect of eptastigmine. Thus, the biphasic effect is peripherally mediated through both muscarinic (at least M(1)) and nicotinic receptors.


Mammalian mitochondrial ribosomal proteins. N-terminal amino acid sequencing, characterization, and identification of corresponding gene sequences.
The integrity of healthy mitochondria is supposed to depend largely on proper mitochondrial protein biosynthesis. Mitochondrial ribosomal proteins (MRPs) are directly involved in this process. To identify mammalian mitochondrial ribosomal proteins and their corresponding genes, we purified mature rat MRPs and determined 12 different N-terminal amino acid sequences. Using this peptide information, data banks were screened for corresponding DNA sequences to identify the genes or to establish consensus cDNAs and to characterize the deduced MRP open reading frames. Eight different groups of corresponding mammalian MRPs constituted from human, mouse, and rat origin were identified. Five of them show significant sequence similarities to bacterial and/or yeast mitochondrial ribosomal proteins. However, MRPs are much less conserved in respect to the amino acid sequence among species than cytoplasmic ribosomal proteins of eukaryotes and bacteria.


Crystal structures of hydrophobin HFBII in the presence of detergent implicate the formation of fibrils and monolayer films.
Hydrophobins are small, amphiphilic proteins secreted by filamentous fungi. Their functionality arises from a patch of hydrophobic residues on the protein surface. Spontaneous self-assembly of hydrophobins leads to the formation of an amphiphilic layer that remarkably reduces the surface tension of water. We have determined by x-ray diffraction two new crystal structures of Trichoderma reesei hydrophobin HFBII in the presence of a detergent. The monoclinic crystal structure (2.2A resolution, R = 22, R(free) = 28) is composed of layers of hydrophobin molecules where the hydrophobic surface areas of the molecules are aligned within the layer. Viewed perpendicular to the aligned hydrophobic surface areas, the molecules in the layer pack together to form six-membered rings, thus leaving small pores in the layer. Similar packing has been observed in the atomic force microscopy images of the self-assembled layers of class II hydrophobin, indicating that the crystal structure resembles that of natural hydrophobin film. The orthorhombic crystal structure (1.0 A resolution, R = 13, R(free) = 15) is composed of fiber-like arrays of protein molecules. Rodlet structures have been observed on amphiphilic layers formed by class I hydrophobins; fibrils of class II hydrophobins appear by vigorous shaking. We propose that the structure of the fibrils and/or rodlets is similar to that observed in the crystal structure.


Porous bovine hydroxyapatite for drug delivery.
Biomaterials derived from natural sources have considerable interest in human health care. This study reports a simple method of designing a bone drug delivery system using porous bovine hydroxyapatite (BHA). The porous BHA blocks with different porosity were fabricated by a die-pressing method using polyvinylbutyral (PVB) as a porosifier. A model antibiotic drug, neomycin sulfate (NS) was loaded in the blocks and its in vitro release performance was studied. Fourier transform infrared (FTIR) analysis provided qualitative proof of drug molecule entrapment in the BHA blocks. The in vitro evaluation of the drug indicated that the rate of drug loading and release was directly proportional to the porosity of the blocks.


Multi-Institutional Analysis of Synchronous Prostate and Rectosigmoid Cancers.
Purpose: To perform a multi-institutional analysis of patients with synchronous prostate and rectosigmoid cancers. Materials and Methods: A retrospective review of Duke University and Durham Veterans Affairs Medical Center records was performed for men with both prostate and rectosigmoid adenocarcinomas from 1988 to 2017. Synchronous presentation was defined as symptoms, diagnosis, or treatment of both cancers within 12 months of each other. The primary study endpoint was overall survival. Univariate and multivariable Cox regression was performed. Results: Among 31,883 men with prostate cancer, 330 (1%) also had rectosigmoid cancer and 54 (16%) of these were synchronous. Prostate cancer was more commonly the initial diagnosis (59%). Fifteen (28%) underwent prostatectomy or radiotherapy before an established diagnosis of rectosigmoid cancer. Stage I, II-III, or IV rectosigmoid cancer was present in 26, 57, and 17% of men, respectively. At a median follow-up of 43 months, there were 18 deaths due rectosigmoid cancer and two deaths due to prostate cancer. Crude late grade ≥3 toxicities include nine (17%) gastrointestinal and six (11%) genitourinary. Two anastomotic leaks following low anterior resection occurred in men who received a neoadjuvant radiotherapy prostate dose of 70.6-76.4 Gy. Rectosigmoid cancer stages II-III (HR 4.3, p = 0.02) and IV (HR 16, p < 0.01) as well as stage IV prostate cancer (HR 31, p < 0.01) were associated with overall survival on multivariable analysis. Conclusions: Synchronous rectosigmoid cancer is a greater contributor to mortality than prostate cancer. Men aged ≥45 with localized prostate cancer should undergo colorectal cancer screening prior to treatment to evaluate for synchronous rectosigmoid cancer.


HER2/neu in systemic therapy for women with breast cancer: a systematic review.
Amplification and/or overexpression of the HER2/neu gene is associated with a poor prognosis in breast cancer. Many studies have suggested that this gene may be associated with the relative efficacy of chemotherapy and endocrine therapy options. A systematic review of the evidence was conducted. MEDLINE, EMBASE, the Cochrane Library, the American Society of Clinical Oncology annual meeting proceedings, and the San Antonio Breast Cancer Symposia proceedings were all searched to November 2006 for reports of analysis by HER2/neu status of the relative efficacy of the treatment arms in randomized controlled trials. Thirty-five trials were identified. A meta-analysis of trials of tamoxifen versus observation found no significant interaction between treatment and HER2/neu status, although one trial not included in the meta-analysis did find interaction. A meta-analysis of adjuvant anthracycline-based chemotherapy trials found a significant interaction (difference in disease-free survival log-hazard ratios -0.31, 95% confidence interval -0.50 to -0.13; difference in overall survival log-hazard ratios -0.34, 95% confidence interval -0.53 to -0.14). Significant interaction was also found in a meta-analysis of disease-free survival in trials of adjuvant taxane therapy versus non-taxane therapy (difference in disease-free survival log-hazard ratios -0.36, 95% confidence interval -0.68 to -0.04). HER2/neu overexpression and/or amplification was associated with greater efficacy of the anthracycline or taxane regimen. Current evidence supports the conclusion that the benefit of both anthracycline-based and taxane-based adjuvant chemotherapy is associated on HER2/neu status, with patients with HER2/neu-positive cancers benefiting more from these therapies than those with HER2/neu-negative cancers.


The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response.
Several lines of evidence suggest that the dopamine D3 receptor is involved in the pathophysiology of schizophrenia. The D3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser9 allele and the Ser9/Ser9 genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser9 and the Ser9/Ser9 genotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser9/Ser9 genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser9Gly in schizophrenia to date. We have therefore determined DRD3 Ser9Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser9 is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.


Formoterol 12 microg BID administered via single-dose dry powder inhaler in adults with asthma suboptimally controlled with salmeterol or on-demand salbutamol: a multicenter, randomized, open-label, parallel-group study.
Although salmeterol and formoterol are both long-acting beta(2) adrenergic receptor agonist bronchodilators, there are distinct differences between them that could translate into differences in clinical response in some patients. The goal of this study was to examine the efficacy of formoterol in patients with moderate to severe persistent asthma that was suboptimally controlled with an inhaled corticosteroid (ICS) combined with on-demand salbutamol (albuterol in the United States) with or without salmeterol. This multicenter, 4-week, randomized, open-label, parallel-group study included adult patients (age >/=18 years) with suboptimally controlled asthma (mean salbutamol use, >/=2 puffs/d via pressurized metered-dose inhaler [100 microg/puff]). Patients were randomized in a 2:1 ratio to receive formoterol 12 microg BID via single-dose dry powder inhaler plus on-demand salbutamol or to continue their existing treatment with either on-demand salbutamol alone or salmeterol 50 microg BID via multidose dry powder inhaler plus on-demand salbutamol. ICS regimens were unchanged during the trial. The primary efficacy variable was evening predose peak expiratory flow (PEF). Secondary variables included further measures of asthma symptom control. A total of 6239 adult patients entered the study; data from 6155 patients were available for analysis. Patients who were switched from salmeterol to formoterol reported a significant increase in mean (SD) evening predose PEF compared with patients who continued their existing treatment (402.9 [112.1] vs 385.5 [107.5] Umin, respectively; P < 0.001). Similarly, patients who were switched from on-demand salbutamol alone to formoterol plus on-demand salbutamol reported a significant increase in mean evening predose PEF compared with those who continued treatment with on-demand salbutamol alone (409.3 [105.6] vs 385.0 [105.3] L/min, respectively; P < 0.001). The results for the secondary efficacy measures mirrored the significant improvements seen in patients switched to formoterol compared with those who continued to receive on-demand salbutamol alone or salmeterol plus on-demand salbutamol. In this study, formoterol significantly improved lung function and control of asthma symptoms and decreased use of rescue medication in patients whose asthma had been suboptimally controlled with an ICS in combination with on-demand salbutamol with or without salmeterol.


Laser-Based Metastable Krypton Generation.
We demonstrate the generation of metastable krypton in the long-lived 1s^{5} state using laser excitation. The atoms are excited through a two-photon absorption process into the 2p^{6} state using a pulsed optical parametric oscillator laser operating near 215 nm, after which the atoms decay quickly into the metastable state with a branching ratio of 75%. The interaction dynamics are modeled using density matrix formalism and, by combining this with experimental observations, we are able to calculate photoionization and two-photon absorption cross sections. When compared to traditional approaches to metastable production, this approach shows great potential for high-density metastable krypton production with minimal heating of the sample. Here, we show metastable production efficiencies of up to 2% per pulse. The new experimental results gained here, when combined with the density matrix model we have developed, suggest that fractional efficiencies up to 30% are possible under optimal conditions.


[State-of-the-art cataract surgery and intraocular optical correction].
The paper provides current knowledge on cataract epidemiology worldwide and in the Russian Federation, including issues of cataractogenesis and prevention. An overview of medical equipment for preoperative and intraoperative diagnostics is provided. Key aspects of the conventional ultrasonic phacoemulsification method as well as the most marked trends in correction of aphakia with intraocular lenses and in design of the latter are presented. Major laser-assisted techniques, including those that imply the use of femtosecond laser systems, and results that they yielded to date are discussed in detail.


Role of acute diverticulitis in the development of complicated colonic diverticular disease and 1-year mortality after diagnosis in the UK: population-based cohort study.
To determine the risk of developing complicated colonic diverticular disease (CCDD) with prior episodes of acute diverticulitis and determine the mortality of the spectrum of CCDD. Population-based cohort study. Computerised records from the General Practice Research Database linked to Hospital Episode Statistics data from the UK. Patients and controls registered in the General Practice Research Database from 1990 to 2007. Mortality was calculated and Cox regression modelling used to provide adjusted HRs and 95% CI. Logistic regression was used to model the effect of prior acute diverticulitis on the development of complications. 2950 patients (1872 (63.5%) female) had a diagnosis of CCDD (8739 controls). A total of 1042 (35.3%) patients died compared with 2062 (23.6%) controls. Most excess deaths occurred in the first year after the complication. Patients with a perforation/abscess had a 4.5-fold increase in 1-year mortality (HR 4.55, 95% CI 3.74 to 5.52) compared with the general population, whereas those with a fistula or stricture had a 2.5-fold increase in mortality (fistula HR 2.60, 95% CI 1.47 to 4.62; stricture HR 2.41, 95% CI 1.86 to 3.11). Although most patients (2133 (72.3%)) had suffered no prior episodes of acute diverticulitis, increasing episodes of acute diverticulitis were associated with an increased risk of developing a fistula (two or more prior episodes, OR 1.54 95%, CI 1.08 to 2.19), but there was no clear relationship with stricture or perforation/abscess. Although most patients have experienced no prior episodes of acute diverticulitis, fistula formation is preceded by bouts of inflammation. Excess 1-year mortality across the spectrum of CCDD compared with the general population is substantial.


Small intestine follicular dendritic cell sarcoma with liver metastasis: A case report.
Follicular dendritic cell sarcoma (FDCS) is a rare neoplasia composed of spindle or oval cells with follicular dendritic cell differentiation, usually occurring in lymphoid tissue. In this report, we present a case of FDCS of the small intestine with liver metastasis. A 19-year-old female presented with recent onset of left upper abdominal pain. Abdominal computed tomography scan showed a large tumor mass in the liver lateral segment with compression to the pancreas upper part, and a smaller mass in the terminal ileum, respectively. High serum levels of amylase and lipase were noted. Resection of the tumors was performed. Microscopically, both tumors consisted of ovoid to spindle-shaped nuclei cells admixed with some lymphocytes arranged in fascicles, whorls, storiform arrays. Immunohistochemistry demonstrated that the tumor cells were positive for follicular dendritic cell markers, including CD21, CD23, and CD35. Epstein-Barr virus encoding small RNA (EBER; Inform EBER probe; Ventana Medical Systems, Tucson, AZ) in situ hybridization was negative. According to the clinicopathological features, diagnosis of FDCS of intestinal origin was made. Resection of tumors located in the liver and at the small intestine was performed. After the operation, patient received adjuvant vinblastin chemotherapy. There was no evidence of recurrence at 8-month follow-up. It was unusual for FDCS of intestinal origin with liver metastasis and expressing with high serum levels of pancreatic enzymes.


Plasma catecholamines with hemorrhage in the bullfrog, Rana catesbeiana.
The concentrations of plasma epinephrine (E) and norepinephrin (N) measured at rest in bullfrogs (Rana catesbeiana) were 12.0 and 8.2 nmol liter-1 respectively: the ratio of [E]/[N] was 1.33 (+/- SE 0.35). Adrenal glands contained high concentrations of epinephrine (2,923 nmole g wet weight-1) and norepinephrine (6,194), at a ratio of 0.46 (+/- SE 0.04) [E]/[N]. This differs from the measured plasma ratio and endogenous release ratios of about 2 for [E]/[N] reported for other Rana species, although the 95% confidence interval of our plasma ratio (0.97) spans the range of values from 0.36 to 2.3, including the observed plasma ratio of 0.46. Therefore, resting plasma catecholamine levels generally reflect the proportional adrenal content of catecholamines. Plasma epinephrine and norepinephrine concentrations significantly increased after activity to 50.4 and 18.1 nmol liter-1, respectively. The ratio of epinephrine to norepinephrine ([E]/[N]) also increased (but not significantly) to 8.53 (+/- SE 4.23), suggesting a shift away from some adrenal tone at rest to sympathetic nerve dominance with activity. Graded hemorrhage led to further increases in plasma epinephrine concentration and [E]/[N] but not norepinephrine, indicating sympathetic but not adrenal involvement. The in vitro epinephrine sensitivity of vascular beds indicates recruitment of the dorsal aorta vascular beds before the pulmocutaneous vascular bed. The minimum sensitivity of vascular beds to perfused epinephrine (10(4) nmol liter-1) was at higher concentrations than maximal plasma concentrations measured during hemorrhage. The bullfrog is less tolerant of hemorrhage than the cane toad Bufo marinus. The major difference in the catecholamine response of these two species was the massive contribution of adrenal catecholamines with severe hemorrhage in toads, which is absent in bullfrogs. This suggests that the enhanced hemorrhage and dehydration tolerance of toads may in part be the result of their greater adrenal gland development and activity.


Screening mammography use and chemotherapy among female stage II colon cancer patients: a retrospective cohort study.
Although chemotherapy is not a routine recommendation for stage II colon cancer by the U.S. national guidelines, 20-30% of patients have received chemotherapy. This study investigated whether screening mammography use before the cancer diagnosis was associated with chemotherapy use among female elderly patients with stage II colon cancer. Retrospective cohort study on 2910 female stage II colon cancer patients aged 67-79 using the Surveillance, Epidemiology and End Results (SEER)-Medicare data (1996-2002). Screening mammography use and chemotherapy use were identified using Medicare claims data. Multivariate logistic regression and Kaplan-Meier curves were used. About 25% of female elderly patients received chemotherapy. The chemotherapy rates increased from 22% in 1996-1998 to 26% in 2001-2002. After adjusting for socio-demographic variables, tumor characteristics and Charlson index for comorbidities, the odds of receiving chemotherapy were 28% higher among those who had a screening mammogram before the cancer diagnosis than those who did not (OR: 1.28, 95% CI: 1.07-1.54). Those with a prior mammogram also received chemotherapy earlier than those without. In addition, patients with unfavorable tumor characteristics were more likely to receive chemotherapy. Mammography use before the cancer diagnosis was associated with favorable tumor characteristics. Despite the controversy about the chemotherapy use among stage II colon cancer, female elderly patients still received chemotherapy at a high rate. Our findings suggest that patient's health beliefs and health care seeking behavior, together with physician's recommendation, play important roles in the cancer treatment decision.


Cervical ripening and labor induction with prostaglandin E2 gel: a placebo-controlled study.
A randomized double-blind, placebo-controlled study was undertaken to evaluate the effect of a single intracervical application of prostaglandin E2 gel on the ripening of the cervix and on the subsequent induction of labor with oxytocin in patients with low Bishop scores (less than or equal to 4). Compared to controls receiving gel only, the group receiving prostaglandin E2 gel had significant increases in their cervical Bishop scores, shorter induction-to-delivery intervals, shorter time requiring use of oxytocin, and more successful labor induction without oxytocin. Systemic side effects were minimal and fetal outcomes were comparable, as were the routes of delivery.


Potassium channels in human and avian fibroblasts.
The cell-attached and excised inside-out patch-clamp techniques were used to study single-channel characteristics of potassium channels in cultured human and avian fibroblasts. Six different potassium channels were distinguished with conductances of 235 +/- 25, 190 +/- 57, 114 +/- 27, 77 +/- 14, 40 +/- 6 and 21 +/- 4 pS in symmetric 140 mM potassium solutions. The channels were separable by their conductances, ion-selectivities, voltage-sensitivities and kinetic properties. All six channels were found in both fully differentiated human skin fibroblasts and primary cultures of 72 h chick sclerotome. The largest channel (235 pS) had a steep bimodal voltage dependence, being open only around the resting membrane potential. It was imperfectly selective for potassium, having a relative sodium:potassium permeability of 0.3. The 190 pS channel was very potassium-selective, had an S-shaped voltage sensitivity and was calcium-dependent. The two intermediate-size channels (114 and 77 pS) had open probabilities of less than 0.5 under all of the conditions we used. They were not completely selective for potassium and were not voltage-sensitive. The two smallest channels (40 and 21 pS) were not well characterized. They both had open probabilities of less than 0.2 and showed no evidence of voltage-sensitivity. The 40 pS channel seemed highly potassium-selective. A suction stimulus was used to test all observed channels for mechanosensitivity but none of the six potassium channels was mechanosensitive. Another small channel, with very clear mechanical sensitivity, was seen on a few occasions; this channel has not yet been characterized.


Sex-related differences and hormonal effects in the Dry Eye Assessment and Management (DREAM) study.
To compare dry eye disease (DED) signs and symptoms between men and women, as well as between premenopausal and postmenopausal women, in the Dry Eye Assessment and Management (DREAM) study. 434 women and 101 men self-reported prior medical history and underwent a standardised DED assessment using the Ocular Surface Disease Index, Brief Pain Inventory, Tear Break-Up Time (TBUT)(s), Schirmer's test 2 (mm/5 min), National Eye Institute-graded lissamine conjunctival staining, corneal staining, meibomian gland dysfunction evaluation and tear osmolarity (mOsms/L) at baseline, 6 months and 12 months. Multivariable linear regression models were used to compare these scores. Women experienced significantly worse DED signs than men with lower Schirmer's test scores (9.27 vs 12.16; p<0.001), higher corneal staining scores (3.59 vs 2.70; p=0.006) and worse composite DED sign scores (0.52 vs 0.40; p<0.001). Postmenopausal women experienced significantly worse DED signs than premenopausal women with higher corneal staining scores (3.74 vs 2.58, p<0.001), higher conjunctival staining scores (2.80 vs 2.22, p<0.001), higher tear osmolarity (304 vs 299, p=0.004), lower TBUT (3.37 vs 3.93, p=0.047), worse meibomian gland dysfunction (3.05 vs 2.62, p=0.04) and worse composite DED sign scores (0.54 vs 0.42, p<0.001). There were no significant differences in DED symptoms between sex and between premenopausal and postmenopausal women (all p≥0.08). In the DREAM study, women experienced more severe DED signs than men. Further, postmenopausal women presented with more severe DED signs than premenopausal women. Elucidating these differences may improve DED diagnosis and provide future direction in understanding sex-related differences in DED. NCT02128763.


Interference with the cytoplasmic tail of gp210 disrupts "close apposition" of nuclear membranes and blocks nuclear pore dilation.
We tested the hypothesis that gp210, an integral membrane protein of nuclear pore complexes (NPCs), mediates nuclear pore formation. Gp210 has a large lumenal domain and small COOH-terminal tail exposed to the cytoplasm. We studied the exposed tail. We added recombinant tail polypeptides to Xenopus nuclear assembly extracts, or inhibited endogenous gp210 tails using anti-tail antibodies. Both strategies had no effect on the formation of fused flattened nuclear membranes, but blocked NPC assembly and nuclear growth. Inhibited nuclei accumulated gp210 and some nucleoporin p62, but failed to incorporate nup214/CAN, nup153, or nup98 and were defective for nuclear import of lamin B3. Scanning and transmission EM revealed a lack of "closely apposed" inner and outer membranes, and the accumulation of novel arrested structures including "mini-pores." We conclude that gp210 has early roles in nuclear pore formation, and that pore dilation is mediated by gp210 and its tail-binding partner(s). We propose that membrane fusion and pore dilation are coupled, acting as a mechanism to control nuclear pore size.


Sports injury research. How to avoid bias.
A valid study is one that is accurate and without bias. Bias may occur in a study in four major ways. Susceptibility bias may arise if groups are not similar at the initial state. The potential for performance bias exists if procedures are not performed comparably. Detection bias may occur if outcomes are not measured comparably. Transfer bias occurs if there is differential loss at followup. The major advantage of a randomized clinical trial is in its attempt to prevent susceptibility bias. Despite the methodologically correct implementation of a study, however, results may not be generalizable due to the particular population, restrictive eligibility criteria, or poor participation. An investigator must balance dual goals: conducting a valid trial and providing generalizable results.


Protein arginine N-methyltransferase 2 plays a noncatalytic role in the histone methylation activity of PRMT1.
Protein arginine N-methyltransferases are a family of epigenetic enzymes responsible for monomethylation or dimethylation of arginine residues on histones. Dysregulation of protein arginine N-methyltransferase activity can lead to aberrant gene expression and cancer. Recent studies have shown that PRMT2 expression and histone H3 methylation at arginine 8 are correlated with disease severity in glioblastoma multiforme, hepatocellular carcinoma, and renal cell carcinoma. In this study, we explore a noncatalytic mechanistic role for PRMT2 in histone methylation by investigating interactions between PRMT2, histone peptides and proteins, and other PRMTs using analytical and enzymatic approaches. We quantify interactions between PRMT2, peptide ligands, and PRMT1 in a cofactor- and domain-dependent manner using differential scanning fluorimetry. We found that PRMT2 modulates the substrate specificity of PRMT1. Using calf thymus histones as substrates, we saw that a 10-fold excess of PRMT2 promotes PRMT1 methylation of both histone H4 and histone H2A. We found equimolar or a 10-fold excess of PRMT2 to PRMT1 can improve the catalytic efficiency of PRMT1 towards individual histone substrates H2A, H3, and H4. We further evaluated the effects of PRMT2 towards PRMT1 on unmodified histone octamers and mononucleosomes and found marginal PRMT1 activity improvements in histone octamers but significantly greater methylation of mononucleosomes in the presence of 10-fold excess of PRMT2. This work reveals the ability of PRMT2 to serve a noncatalytic role through its SH3 domain in driving site-specific histone methylation marks.


The spatial coexistence of TIGIT/CD155 defines poorer survival and resistance to adjuvant chemotherapy in pancreatic ductal adenocarcinoma.
Background: Targeting emerging T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT)/CD155 axis shows promise for restoring anti-tumor immunity, but its immune phenotypes and prognostic significance in a large cohort of pancreatic ductal adenocarcinoma (PDAC) are limited. Methods: Three seven-color multispectral panels were rationally designed to investigate the protein expression, immune-microenvironmental feature, prognostic value, and the response to adjuvant chemotherapy of TIGIT/CD155 in 272 PDAC specimens using multiplex immunohistochemistry. Results: We revealed low immunogenicity and high heterogeneity of the PDAC immune microenvironment featured by abundant CD3+ T cells and CD68+ macrophages and low infiltration of activated cytotoxic T lymphocytes. TIGIT and CD155 were highly expressed in PDAC tissues compared to paracancerous tissues. Tumor-infiltrating lymphocytes expressing TIGIT were correlated with high densities of CD45RO+ T cells; TIGTI+CD8+ T cells were associated with high infiltration of CD3+CD45RO+FOXP3+. CD155+CK+ were significantly related to high densities of CD3+ and CD3+CD8+CD45RO+ T cells. High positive rates for TIGIT in TCs, CD8+ T cells, and CD155 in macrophages were correlated with poor progression-free and disease-specific survival, respectively, and their clinical significance was correlated with PD-L1 status. Notably, spatial co-existence of TIGIT+CK+ or TIGIT+CD8+ and CD155+CD68+ indicated poor survival and resistance to adjuvant chemotherapy response in patients with PDAC. Conclusion: Our findings suggest that targeting TIGIT/CD155 immunosuppressive axis may guide patient stratification and improve the clinical outcome of PDAC.


Fluorous-phase soluble polymeric supports.
Fluorous phase soluble polymer supports derived from fluoroacrylate polymers are described. N-Acryloxysuccinimide-containing fluoroacrylate polymers were readily prepared from commercially available monomers. The activated acrylates so prepared were then converted into chelating and non-chelating ligands by amidation of the N-acryloxysuccinimide active ester residues. Phosphine ligands attached to these supports were used to prepare neutral and cationic rhodium(I) hydrogenation catalysts as well as palladium(0) catalysts. Similar substitution of pendant active ester groups to form hydroxamic acid ligands for metal sequestration is also feasible. Liquid/liquid extraction readily separated, recycled and reused these polymer-bound ligands and catalysts. While fluorous phase solubility could be attained with polymers containing only heptafluorobutyryl groups, selective solubility in a fluorous phase in contact with an organic phase was only seen with fluoroacrylates that contained larger fluorinated ester groups.


Tumor rejection requires a CTLA4 ligand provided by the host or expressed on the tumor: superiority of B7-1 over B7-2 for active tumor immunization.
Although transfection to express any of a multitude of immunomodulatory molecules can lead to the rejection of murine tumors in vivo, it is not clear which of these cofactors are truly important for the induction of tumor-specific CTL. Examination of the costimuli used by the host immune response during the normal rejection of immunogenic tumors should reveal critical cofactors for CTL differentiation in vivo. The involvement of a host B7 family costimulator molecule in the rejection of immunogenic tum- variants of the mastocytoma P815 was explored. Rejection of immunogenic P815 variants was prevented by mCTLA4 gamma 3, a fusion protein between the extracellular domain of murine CTLA4 and the Fc portion of a murine IgG3 Ab, indicating the importance of a CTLA4 ligand provided by the host in the rejection of B7- tumors. Tumor rejection also was prevented by mCTLA4 gamma 3 in the absence of CD4+ cells, suggesting that CD8+ lymphocytes may receive direct costimulation by B7 in vivo. Finally, although living transfectants of poorly immunogenic P1.HTR cells expressing B7-1 or B7-2 were equally rejected by syngeneic mice, if delivered as multiple injections of irradiated cells, only B7-1 transfectants successfully induced CTL activity and protected against living tumor challenge. Our results indicate that a CTLA4 ligand is normally involved in the generation of CD8+ CTL against tumor Ag and suggest that immunization with irradiated B7-1-transfected tumor cells may be superior to immunization with irradiated B7-2 transfectants as an approach to tumor Ag vaccination in patients.


Homicide-suicide in older persons.
The objective of this study was to determine the annual incidence of homicide-suicide and to compare patterns and antecedents in old and young spousal/consortial cases. Homicide-suicide cases were ascertained in four medical examiner districts covering seven entire Florida counties from 1988 to 1994. The districts were chosen to determine rates in two regions of Florida, comparable in size of the total population and proportion of older persons. Annual homicide-suicide incidence rates per 100,000 population and homicide-suicides as a percentage of total homicides and total suicides separately were calculated by age group and Florida region. Complete medical examiner files were obtained, and 160 variables were coded from medical examiner reports to compare features and clinical characteristics by age and region. Annual incidence rates ranged from 0.3 to 0.7 per 100,000 for persons under age 55 and from 0.4 to 0.9 per 100,000 for persons age 55 and older, with higher rates in the older group every year but two. Cases of spousal/consortial homicide-suicide were the most common in both age groups. The younger couples in both regions were comparable, except for racial composition, but the older couples differed. West central Florida couples were in their seventies, Caucasian, usually married, and both in poor health; and there were indications of depression or alcohol abuse in half the perpetrators. Two-thirds of the southeastern Florida couples were Hispanic; there was a mean age difference of 18 years between perpetrators and victims; and verbal discord, physical violence, and separation were prominent antecedents. The base rate for homicide-suicide in both age groups was higher than that reported in previous studies. Spousal/consortial homicide-suicides were the dominant form, and although psychopathology was strongly implicated, homicide-suicides are violent lethal acts resulting from additive or multiplicative effects of diathesis, including culture, and stressful experiences.


[Change in conflict strength measured by Color-Word Test in childhood, adulthood, and the aged].
A life span survey of conflict induced in color naming when words and colors appear in incongruent combination was carried out. Subjects' ages ranged from six years to 89 years, totaling 721. As the index of conflict, (C-B)/A was used. The result indicated that conflict scores were highest in six-year-old children and the next highest in the eldery of 70 to 89 years. The result of ANOVA indicated no sex difference on conflict scores, but showed a difference in faster performance by females on the color and color-word cards. The result suggested that six-year olds are immature in cognitive ability and that the 70-year olds and above declined in their cognitive ability. The elevation of conflict scores in 10 years may be due to the stage of puberty.


Glutathione-S-transferase of Trichinella spiralis regulates maturation and function of dendritic cells.
Immunomodulation by molecules from Trichinella spiralis (T. spiralis) has been widely reported. Glutathione-S-transferase (GST) is a major immune-modulator of the family of detoxification enzymes. Dendritic cells (DCs) are an important target for the regulation of the immune response by T. spiralis. In this study, the recombinant GST of T. spiralis (rTs-GST) was expressed and purified. rTs-GST induced low CD40 expression and moderate CD80, CD86 and MHC-II expressions and inhibited the increase of CD40, CD80 and CD86 on DCs induced by LPS. We showed that rTs-GST decreased the LPS-induced elevated level of pro-inflammatory cytokines of DCs and enhanced the level of regulatory cytokines IL-10 and TGF-β. Furthermore, co-culture of DCs and CD4+ T cells demonstrated that rTs-GST-treated DCs suppressed the proliferation of OVA-specific CD4+ T cells and increased the population of regulatory T cells (Tregs). rTs-GST-treated DCs induced a higher level of IL-4, IL-10 and TGF-β, but inhibited the level of IFN-γ. This indicates that rTs-GST-pulsed DCs induce both Th2-type responses and Tregs. These findings contribute to the current understanding of the immunomodulation of Ts-GST on cellular response and immunomodulation of T. spiralis.


[Chronic myasthenia gravis mimicking muscular dystrophy, in eastern Colombia].
INTRODUCTION. Myasthenia gravis is an apparently well-defined neuromuscular disease with some variants, including one recently described as chronic myasthenia gravis. CASE REPORT. We present a 22 year old Columbian woman who complained of progressive weakness for the previous four years, affecting her pelvic and shoulder girdles but with no clinical involvement of the extra-ocular muscles. Repetitive stimulation of the neuro-muscular junction of the abductor digiti quinti muscle was negative, but positive for myasthenia gravis in the trapezius muscle and the right orbital eye muscles. Her symptoms improved and the clinical neurophysiological studies were normal again after treatment with pyridostigimine, which confirmed the diagnosis.


Predictors of inpatient death and complications among postoperative elderly patients with metastatic brain tumors.
Risks of brain surgery in elderly patients with brain metastases are not well defined. This study was designed to quantify the postoperative risk for these patients after brain surgery for metastatic disease to the brain. We performed a retrospective analysis of the Nationwide Inpatient Sample (1998-2005). Patients aged 65 years or older who underwent tumor resection of brain metastases were identified by ICD-9 coding. Primary outcome was inpatient death. Other outcomes included systemic postoperative complications, length of stay (LOS), and total charges. A total of 4,907 patients (53.6% men) were identified. Mean age was 72.1 years. Mean Charlson comorbidity score was 7.8. Inpatient mortality was 4%. The most common adverse events were pulmonary complications (3.4%). Mean length of stay was 9.2 days. Mean total charges were $57,596.39. In multivariate analysis, patients up to age 80 years had no significantly greater odds of inpatient death, relative to their 65- to 69-year-old counterparts. Each 1-point increase in Charlson score was associated with 12% increased odds of death, 0.52 days increased LOS, and $1,710.61 higher hospital charges. Postoperative pulmonary complications, stroke, or thromboembolic events increased LOS and total charges by up to 9.6 days and $57,664.42, respectively. These associations were statistically significant (P < 0.05). Surgical resection of brain metastases among the elderly up to the ninth decade of life is feasible. Age older than 80 years and higher Charlson comorbidity scores were found to be important prognostic factors for inpatient outcome. Incorporating these factors into preoperative decision making may help to select appropriately those elderly candidates for neurosurgical intervention.


[Local cellular regulation in formation of postoperative commissures in peritonitis].
Influence of Perphtoran on cells of peritoneal fluid and intestinal serosa was studied experimentally in Wistar rats on the model of peritonitis and mechanic injury of the intestine. Stimulation of macrophage activity and proliferative activity of intestinal mesothelium was seen, number of adhesive surfaces was by half less than in the control group. Treatment of abdominal cavity with Perphtoran in patients led to fast recovery of intestinal peristalsis, more favorable course of postoperative period and better long-term results.


[Familial hypercholesterolemia: epidemiology, genetics, diagnosis, and screening].
Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder characterized by el- evated plasma levels of low-density lipoprotein-cholesterol (LDL-C) and increased risk of premature coronary heart disease. There are two types of FH, namely homozygous and heterozygous FH. FH is most commonly (85%) attributable to mutations in the LDL receptor (LDL-R) gene. Other rare causes are the mutations of genes encoding apolipoprotein B (Apo B), pro-protein convertase subtilisin/ kexin type 9 (PCSK9) and LDL adaptor protein 1 (LDLRAP 1). FH is both underdiagnosed and undertreated, particu- larly among children. Approximately 20% of patients are diagnosed and, of those, only a small minority receive ap- propriate treatment. The risk of premature coronary heart disease (CHD) is elevated about 20-fold in untreated FH patients. Early diagnosis of FH enables prompt treatment and prevention of consequent morbidity and mortality from premature CHD. There is no single internationally accepted set of criteria for the clinical diagnosis of FH. The most commonly used are the US (Make Early Diagnosis to Prevent Early Death) MEDPED, the UK (Simon Broome), and the Dutch Lipid Clinic sets of criteria that have been statistically and genetically validated. For early diagnosis and prevention of CVD, testing lipid levels in all first-degree relatives of diagnosed FH patients is necessary. Genetic screening for FH is generally not needed for diagnosis or clinical management, but may be useful when the diagnosis is uncertain.


On-treatment monitoring of chronic hepatitis B virus infection: an Asian-Pacific perspective.
Chronic infection with hepatitis B virus (HBV) is a major global health problem and an important cause of morbidity and mortality from sequelae of liver cirrhosis and hepatocellular carcinoma. In the past decades, better understanding of the natural history and immunopathogenesis of chronic HBV infection and of the development of many powerful antiviral agents has allowed us to improve therapeutic efficacy. Among these agents, nucleos(t)ide analogs are important and potent viral suppressors. However, when administered alone, they are not able to permanently eradicate HBV, and long-term maintenance therapy is required for therapeutic efficacy. Additionally, prolonged treatment is frequently associated with the emergence of drug-resistant HBV mutants. Before an 'ideal' drug(s), or drug combination, with optimal antiviral efficacy and negligible rates of drug resistance becomes available, the on-treatment monitoring approach using serum HBV DNA level as a predictor for therapeutic efficacy and drug resistance is useful. However, most countries in the Asia-Pacific region have low income economies, insufficient medical care systems, and low awareness of the disease among the general population and government officers. The easy approach of the road-map concept using an affordable drug to treat chronic HBV infection is more important in this region. There is already evidence that the long-term outcomes of chronic HBV infection can be improved under well-managed antiviral therapy. Profound and long-lasting suppression of HBV replication, either maintained on-therapy or sustained after stopping therapy, has been identified as the key determinant for achieving the goals of therapy, for reducing liver damage, and for preventing development of cirrhosis and/ or hepatocellular carcinoma.


Immunohistochemical localization of carbonic anhydrase in postnatal and adult rat kidney.
With use of specific antibodies against human and rat erythrocyte carbonic anhydrase C and human carbonic anhydrase B, only the isozyme C could be detected by immunofluorescence in rat kidney epithelial cells. In the postnatal kidney a few cells were positive after 2 days, but the number of fluorescent cells increased during the first few weeks of life to reach the final adult levels after 3 wk in the cortex and 5 wk in the medulla. In the postnatal and adult kidney a characteristic mosaic pattern of fluorescence was seen in the late distal tubule, the connecting segment, and the collecting tubule, where the mitochondria-rich dark cells were brightly fluorescent. In addition, in later postnatal stages and in the adult, the entire epithelium of the initial portion of descending thin limbs of Henle (long loops) was labeled. Some kidney regions that had previously been shown to contain carbonic anhydrase activity by biochemical and histochemical techniques stained only weakly with the immunocytochemical method. This suggests either that the enzyme in these regions does not cross-react strongly with our antibodies or that these regions contain only low amounts of carbonic anhydrase, at the limit of the detection threshold of our techniques.


[Reversible neurological deficit years after high grade glioma--the SMART syndrome].
Survival in patients with high grade glioma has been extended in recent years as a result of more intensive therapy. As a consequence, more late term complications of treatment may be observed. A 69-year-old woman presented at the outpatient department of Neurology with headache and loss of strength in the left arm. She had been treated 7 years previously for a high grade glioma with resection and radiotherapy. One year later she had received chemotherapy for a local recurrence. Since then she was free of complaints. At investigation a left sided hemiparesis was found. As recurrence of the tumour was suspected, MR imaging of the brain was performed, which showed abnormalities suggestive for the so called 'stroke-like migraine attacks after radiotherapy' (SMART) syndrome. The further clinical course, with spontaneous recovery of strength within a few weeks and the regression of the cortical hyperintensity on MRI, confirmed the probable diagnosis. The SMART syndrome is a relatively unknown condition and should be included in the differential diagnosis in patients who present with new complaints long after cerebral radiotherapy.


Surface dose and build-up region measurements with wedge filters for 6 and 18 MV photon beams.
High-energy photons are most commonly used in radiotherapy to treat cancer. Wedge filters are required to obtain homogeneous dose distribution in the patient. Different wedge filter types create different surface doses. In this study, the effect of the virtual and physical wedge filters on the surface and build-up region doses was examined for 6- and 18-MV high-energy photon beams. The measurements were made in a water equivalent phantom in the build-up region at a 100-cm source-to-surface distance for various field sizes using virtual and physical wedge filters having different angles. A parallel-plate ion chamber was used to measure the percent depth doses. The percentage dose at the surface increased as the field size increased for open, virtual, and physical wedged beams. For open, physical, and virtual wedged beams, the surface doses were found to be 15.4%, 9.9%, and 15.9% with 6-MV photons and 10.6%, 8.8%, 11.9% with 18-MV photons, respectively, at 10 x 10 cm(2) field size. Build-up doses of virtual wedged beams were similar to those of open beams. Surface and buildup doses of physical wedged beams were lower than those of open and virtual wedged beams.


Genetic Background and Antibiotic Resistance Profiles of K. pneumoniae NDM-1 Strains Isolated from UTI, ABU, and the GI Tract, from One Hospital in Poland, in Relation to Strains Nationally and Worldwide.
In recent years, there has been an observed increase in infections caused by carbapenem-resistant Klebsiella pneumonia (Kp) strains. The aim of this study was the phenotypic and genotypic analysis of eight K. pneumoniae NDM (Kp NDM) isolates, recovered in Poland during the years 2016 and 2018 from seven patients with urinary tract infections (UTIs), asymptomatic bacteriuria (ABU), or colonization of the gut. PCR melting profile genotyping indicated a close relationship between the strains derived from 2018, which were not related to the strain isolated in 2016. WGS results were analyzed in relation to international Kp isolates. Clonal and phylogenetic analyses were performed based on multilocus sequence typing (MLST) and single nucleotide polymorphisms (SNPs) of the core genome. The metallo-β-lactamase was assigned to the NDM-1 type and the sequence was identified as ST11. Eleven antimicrobial resistance genes were detected, mostly from plasmid contigs. Unprecedented profiles of plasmid replicons were described with the IncFII/pKPX-1 dominant replicon. In terms of the KL24 and O2v1 capsular antigen profiles, these isolates corresponded to Greek strains. Strains isolated from UTI, ABU, and colonization GI tract patients were not carrying environment-specific virulence genes. Based on the assessment of strain relationships at the genome level and their direction of evolution, the international character of the sublines was demonstrated, with a documented epidemic potential in Poland and Greece. In conclusion, some groups of patients, e.g., renal transplant recipients or those with complicated UTIs, who are frequently hospitalized and undergoing antibiotic therapy, should be monitored not only for the risk of UTI, but also for colonization by Kp NDM strains.


Clinicopathologic correlation of submacular membranectomy with retention of good vision in a patient with age-related macular degeneration.
We present the clinicopathologic features of the eye of a patient with age-related macular degeneration who underwent submacular membranectomy and had retention of good visual acuity for almost 4 years despite recurrent choroidal neovascularization treated with krypton laser photocoagulation and mild expansion of the laser lesion with time. Histopathologic study of the surgically removed membrane from the right eye disclosed a thin fibrovascular membrane lined by retinal pigment epithelium on one surface. Microscopic examination of the right eye obtained post mortem disclosed a 2.75-mm (horizontal) x 2.1-mm (vertical) retinal pigment epithelium defect with overlying photoreceptor cell atrophy centered on the temporal parafoveal area, and a 0.6 x 0.1-mm subretinal pigment epithelium fibrovascular membrane with an area of retinal pigment epithelial hyperplasia and vascularization from the retina 0.4 mm temporal to the fovea. Basal laminar deposit was present in the region of the fovea and nasal parafoveal area.


The impact of alcohol taxation changes on unrecorded alcohol consumption: A review and recommendations.
The diverse forms of unrecorded alcohol, defined as beverage alcohol not registered in official statistics in the country where it is consumed, comprise about one fourth of all alcohol consumed worldwide. Since unrecorded alcohol is usually cheaper than registered commercial alcohol, a standard argument against raising alcohol excise taxes has been that doing so could potentially result in an increase in unrecorded consumption. This contribution examines whether increases in taxation have in fact led to increases in consumption of unrecorded alcohol, and whether these increases in unrecorded alcohol should be considered to be a barrier to raising taxes. A second aim is to outline mitigation strategies to reduce unrecorded alcohol use. Narrative review of primary and secondary research, namely case studies and narrative and systematic reviews on unrecorded alcohol use worldwide. Unrecorded alcohol consumption did not automatically increase with increases in taxation and subsequent price increases of registered commercial alcohol. Instead, the level of unrecorded consumption depended on: a) the availability and type of unrecorded alcohol; b) whether such consumption was non-stigmatized; c) the primary population groups which consumed unrecorded alcohol before the policy change; and d) the policy measures taken. Mitigation strategies are outlined. Potential increases in the level of unrecorded alcohol consumption should be considered in the planning and implementation of substantial increases in alcohol taxation. However, unrecorded consumption should not be considered to be a principal barrier to implementing tax interventions, as evidence does not indicate an increase in consumption if mitigation measures are put in place by governments.


Molecular diagnosis of polycystic ovary syndrome in obese and non-obese women by targeted plasma miRNA profiling.
Polycystic ovary syndrome (PCOS) is diagnosed based on the clinical signs, but its presentation is heterogeneous and potentially confounded by concurrent conditions, such as obesity and insulin resistance. miRNA have recently emerged as putative pathophysiological and diagnostic factors in PCOS. However, no reliable miRNA-based method for molecular diagnosis of PCOS has been reported. The aim of this study was to develop a tool for accurate diagnosis of PCOS by targeted miRNA profiling of plasma samples, defined on the basis of unbiased biomarker-finding analyses and biostatistical tools. A case-control PCOS cohort was cross-sectionally studied, including 170 women classified into four groups: non-PCOS/lean, non-PCOS/obese, PCOS/lean, and PCOS/obese women. High-throughput miRNA analyses were performed in plasma, using NanoString technology and a 800 human miRNA panel, followed by targeted quantitative real-timePCR validation. Statistics were applied to define optimal normalization methods, identify deregulated biomarker miRNAs, and build classification algorithms, considering PCOS and obesity as major categories. The geometric mean of circulating hsa-miR-103a-3p, hsa-miR-125a-5p, and hsa-miR-1976, selected among 125 unchanged miRNAs, was defined as optimal reference for internal normalization (named mR3-method). Ten miRNAs were identified and validated after mR3-normalization as differentially expressed across the groups. Multinomial least absolute shrinkage and selection operator regression and decision-tree models were built to reliably discriminate PCOS vs non-PCOS, either in obese or non-obese women, using subsets of these miRNAs as performers. We define herein a robust method for molecular classification of PCOS based on unbiased identification of miRNA biomarkers and decision-tree protocols. This method allows not only reliable diagnosis of non-obese women with PCOS but also discrimination between PCOS and obesity. We define a novel protocol, based on plasma miRNA profiling, for molecular diagnosis of PCOS. This tool not only allows proper discrimination of the condition in non-obese women but also permits distinction between PCOS and obesity, which often display overlapping clinical presentations.


The association between compliance with antihypertensive drugs and modification of antihypertensive drug regimen.
Non-compliance is an important factor in lack of control of blood pressure. Uncontrolled blood pressure, as well as patients' complaints about the prescribed medication, may lead to modification of the initially prescribed antihypertensive drug regimen. The objective of this study was to assess the association between non-compliance and change in medication regimen. A nested case-control study within a cohort of new users of antihypertensive drugs between 1 January 1999 and 31 December 2002. We used data from the PHARMO database, a record linkage system containing drug-dispensing records from community pharmacies and linked hospital discharge records of approximately 950,000 subjects. Cases were subjects whose initial drug regimen was modified. Controls did not undergo such a modification. Conditional logistic regression was used to calculate odds ratios (OR) and their 95% confidence intervals (CI), and to adjust for confounders. In a cohort of 39,714 new users of antihypertensive drugs, we identified 11,937 cases and 11,937 matched controls. The percentage of non-compliant patients (compliance < 80%) among cases and controls was 5.1 and 3.6%, respectively [OR 1.39 (95% CI: 1.22-1.58)]. The association is stronger in females [OR 1.64 (95%CI: 1.37-1.94)] than in males [OR 1.14 (95% CI: 0.94-1.40)] and stronger if the duration of episode of use is longer than 6 months. Non-compliance is significantly associated with the occurrence of change in antihypertensive medication regimen. Pharmacists and physicians can use pharmacy data, although data tend to overestimate actual compliance, to assess and improve compliance with antihypertensive drugs, before modifying treatment regimens.


In vivo detection of clinically non-apparent ocular surface inflammation in patients with meibomian gland dysfunction-associated refractory dry eye symptoms: a pilot study.
The utility of in vivo confocal microscopy (IVCM) in the investigation of palpebral conjunctival and corneal inflammation in patients with meibomian gland dysfunction (MGD)-associated refractory dry eye symptoms following gland expression, despite objective clinical improvement. A retrospective, observational pilot study was conducted evaluating five patients with MGD-associated refractory dry eye symptoms and three control groups: symptomatic untreated MGD patients (n=3), treatment-responsive MGD patients with improved symptoms (n=3) and asymptomatic healthy normals (n=11). Ocular surface disease index (OSDI) scores, tear break-up time (TBUT), the number of meibomian glands yielding liquid secretion (MGYLS), palpebral conjunctival epithelial and substantia propria immune cell (EIC, SIC), and corneal dendritic cell (DC) densities were measured. Despite clinical improvement (TBUT: 6.4±1.2 s to 10.1±2.1 s, P=0.03; MGYLS: 3.5±0.8 glands to 7.0±1.1 glands, P=0.13) and a normal clinical examination post treatment, MGD patients remained symptomatic. IVCM revealed increased immune cells in the palpebral conjunctiva (refractory MGD EIC=592.6±110.1 cells/mm2 untreated MGD EIC=522.6±104.7 cells/mm2, P=0.69; responsive MGD EIC=194.9±119.4 cells/mm2, P<0.01; normals EIC=123.7±19.2 cells/mm2, P< 0.001), but not the cornea (refractory MGD DC=60.9±28.3 cells/mm2; normals DC=25.9±6.3 cells/mm2; P=0.43). EIC did not correlate with TBUT (Rs=-0.26, P=0.33). OSDI scores correlated with both EIC (Rs=0.76, P<0.001) and TBUT (Rs=-0.69, P<0.01) but not SIC. Intraglandular immune cells were also seen. MGD-associated refractory symptoms and the symptom-sign disparity may be explained by clinically non-apparent, active inflammation of the palpebral conjunctiva as detected by IVCM. These patients may benefit from anti-inflammatory therapy.


Rates and Methods of Contraception Among Korean Adolescents from 2007 to 2009.
This study was done to explore the rates and methods of contraception among Korean adolescents from 2007 to 2009. The study was a descriptive study. The data were taken from a web-based survey on risk behavior of Korean youth that was conducted between 2007 and 2009 by the Korea Centers for Disease Control and Prevention. Among adolescents, 4.7% in 2007, 4.6% in 2008, and 4.7% in 2009 reported having had sexual intercourse. In those who had sexual experiences, less than 30% reported consistent use of contraception, whereas more than 45% report no contraceptive use at all. A condom was the most frequently used contraceptive method and its use has increased continuously among contraceptive users. Some of the adolescents were, nevertheless, using unreliable methods such as withdrawal or the rhythm method. The results of this study indicate that most adolescents are not using contraception consistently and some were relying on unreliable contraceptive methods. Efforts to raise awareness about consistent and correct contraceptive use and the importance of dual protection are essential.


Methylation of trimethyltin compounds by estuarine sediments.
Both biologically active and autoclaved sediments convert trimethyltin hydroxide to the volatile tetramethyltin. Larger amounts of tetramethyltin were formed in the bioactive sediments than in the sterile sediments. No volatile tin compounds were detected in the absence of trimethyltin hydroxide or from trimethyltin hydroxide in seawater or in seawater containing bentonite. The formation of tetramethyltin is slow, taking over 80 days at 16 degrees C to reach a maximum. The extent of conversion, although significant, is not extensive. The formation of tetramethyltin occurs in estuarine sediments by both abiotic and biologically enhanced pathways. A redistribution mechanism accounts for at least the abiotic pathway and possibly both formation pathways.


[Determination of antibodies to the neuroleptic triftazin].
The reaction of the diazonium salt of an aminoderivative of phenothiazine with bovine serum albumin resulted in the conjugated antigen phenothiazine-BSA. Experiments of rabbits demonstrated that hyperimmunization with the conjugate obtained induces the synthesis of antibodies that specifically bind aminazin and triphtazine. A method has been devised for the detection of antibodies to triphtazine in rabbits and patients who received the drug for a long time. The method is based on passive hemagglutination with the use of sheep red blood cells covalently bound with phenothiazine derivatives. It was disclosed that the patients who received triphtazine for a long time show blood antibodies to the drug.


Genetic and environmental effects on complex traits in mice.
The interaction between genotype and environment is recognized as an important source of experimental variation when complex traits are measured in the mouse, but the magnitude of that interaction has not often been measured. From a study of 2448 genetically heterogeneous mice, we report the heritability of 88 complex traits that include models of human disease (asthma, type 2 diabetes mellitus, obesity, and anxiety) as well as immunological, biochemical, and hematological phenotypes. We show that environmental and physiological covariates are involved in an unexpectedly large number of significant interactions with genetic background. The 15 covariates we examined have a significant effect on behavioral and physiological tests, although they rarely explain >10% of the variation. We found that interaction effects are more frequent and larger than the main effects: half of the interactions explained >20% of the variance and in nine cases exceeded 50%. Our results indicate that assays of gene function using mouse models should take into account interactions between gene and environment.


The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers.
The phosphoinositide 3 kinase (PI3K)/Akt/mammalian (or mechanistic) target of rapamycin (mTOR) pathway is a complicated intracellular pathway, which leads to cell growth and tumor proliferation and plays a significant role in endocrine resistance in breast cancer. Multiple compounds targeting this pathway are being evaluated in clinical trials. These agents are generally well tolerated and can be used in combination with targeted therapies, endocrine therapy or cytotoxic agents. The identification of subtypes of tumors more likely to respond to these therapeutics cannot be overemphasized, since breast cancer is a very heterogeneous malignancy. Activation of pathways such as KRAS and MEK can act as escape mechanisms that lead to resistance, thus a combination of agents targeting multiple steps of the intracellular machinery is promising. There is evidence that tumors with PIK3CA mutations are more sensitive to inhibitors of the PI3K pathway but this has yet to be validated. Large clinical trials with correlative studies are necessary to identify reliable biomarkers of efficacy.


An efflux transporter of silicon in rice.
Silicon is an important nutrient for the optimal growth and sustainable production of rice. Rice accumulates up to 10% silicon in the shoot, and this high accumulation is required to protect the plant from multiple abiotic and biotic stresses. A gene, Lsi1, that encodes a silicon influx transporter has been identified in rice. Here we describe a previously uncharacterized gene, low silicon rice 2 (Lsi2), which has no similarity to Lsi1. This gene is constitutively expressed in the roots. The protein encoded by this gene is localized, like Lsi1, on the plasma membrane of cells in both the exodermis and the endodermis, but in contrast to Lsi1, which is localized on the distal side, Lsi2 is localized on the proximal side of the same cells. Expression of Lsi2 in Xenopus oocytes did not result in influx transport activity for silicon, but preloading of the oocytes with silicon resulted in a release of silicon, indicating that Lsi2 is a silicon efflux transporter. The identification of this silicon transporter revealed a unique mechanism of nutrient transport in plants: having an influx transporter on one side and an efflux transporter on the other side of the cell to permit the effective transcellular transport of the nutrients.


Carotid intima-media thickness in plaque-free area, carotid plaque and risk of ischemic stroke in high-risk population of North China.
Stroke is the leading cause of mortality and acquired disability in adults in China. In this study, we investigated the role of carotid artery intima-media thickness (IMT) and carotid plaques in new ischemic stroke of high-risk population in North China. The study was conducted in 4 towns in North China area. Subjects with three or more cardiovascular risk factors such as hypertension, dyslipidemia (or unknown), diabetes mellitus, currently smoking, over weight, family history of stroke, with a history of transient ischemic attack (TIA) and ischemic stroke were included in this study. The demographic data, carotid artery-IMT and number of segments with plaques (NSP) was recorded when they were recruited. The new ischemic stroke was recorded in 2129 subjects after 2.1 year's follow up. Risk analysis was performed between subject with or without new ischemic stroke. There were 69 new cases occurred ischemic stroke. The proportion of hypertension, ischemic stroke history and the plaque numbers were significantly higher in subjects with new ischemic strokes than those without new ischemic strokes. Cox regression showed remarkable positive correlation between the incidence of new ischemic stroke events with the presence of plaque as well as increased NSP. However, the increasing quartiles of common carotid artery intima-media thickness (CCA-IMT) has no difference in occurrence of new ischemic stroke events. Screening of carotid artery especially for carotid artery plaques should be taken into consideration among people with high risk of ischemic stroke.


Pustular eruption following administration of cephradine.
We report the case of an unusual generalized pustular drug eruption caused by the cephalosporin cephradine. Previously reported pustular drug reactions are briefly reviewed. We suggest that a reaction to an administered drug should be considered in the differential diagnosis when a patient presents with fever and a diffuse pustular eruption.