Net effect of an acute phase response--partial alleviation with probiotic supplementation.
The acute phase response (APR) is characterized by inflammation, fever, and altered organ metabolism resulting in muscle catabolism and anorexia. Lipopolysaccharide (LPS)-induced APR may reflect depressed growth and appetite loss. Therefore, a 1-wk growth experiment was conducted to examine whether dietary supplementation of a multispecies probiotic (PoultryStar) would alleviate growth suppression and anorexia caused by LPS-induced APR. The experiment was designed with 4 treatments (n = 8 cages/treatment; 6 birds/cage) starting at 14 d of age. Before (0 to 14 d of age) and for the experiment (14 to 21 d of age), male broiler chicks were fed diets devoid of probiotic or were supplemented with 1.7 x 10(8) cfu/kg of probiotic. At 14 d of age, birds fed the diet devoid of probiotic were further divided into 3 treatments: an unchallenged positive control, LPS-challenged negative control (LPS-NC), and a treatment that was pair-fed to LPS-NC. The probiotic-fed birds were also then challenged with LPS. The LPS (Escherichia coli 055:B5) was injected intraperitoneally 4 times at 48-h intervals at 1 mg/kg of BW. The LPS challenge dramatically depressed BW gain from 14 to 21 d of age by 22% (P < 0.001). However, 41% of growth depression was attributable to factors other than feed intake reduction when compared with the pair-fed treatment. Probiotic supplementation recovered 17% of depressed growth (vs. LPS-NC; P = 0.068), but this improved growth was not due to improvements in feed intake (P = 0.47). However, recovery of feed intake of the probiotic + LPS birds occurred 48-h earlier than the LPS-NC birds. Growth depression induced by LPS administration resulted in an overall relative feed intake (vs. positive control) of 0.83 and also decreased net energy and protein accretion. Probiotic supplementation did not alleviate the reduction in net energy or protein accretion induced by LPS. In conclusion, APR (induced by LPS administration) diverted a large portion of consumed nutrients from tissue accretion. Probiotic supplementation lessened the anorexic effects of LPS resulting in a trend toward BW gain improvement versus the LPS-NC.


Isoform-specific regulation of uridine diphosphate-glucuronosyltransferase 2B enzymes in the human prostate: differential consequences for androgen and bioactive lipid inactivation.
Androgens as well as monohydroxy-fatty acids are implicated in the pathogenesis of prostate cancer. Like a huge variety of endo- and xenobiotics, they are eliminated as glucuronide conjugates formed by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. In the present study, we observe that treatment of the prostate cancer cells LNCaP with natural and synthetic androgens, IL-1alpha, or epidermal growth factor (EGF) differently modulates the glucuronidation of androgen and bioactive lipid metabolites. Indeed, glucuronidation of 5alpha-androstane-3alpha,17beta-diol and 13-hydroxyoctadecadienoic acid was drastically reduced, whereas 12-hydroxyeicosatetraenoic acid conjugation by UGT was increased after androgen treatment. These effects reflected the reduction of UGT2B10, -B15, and -B17 enzyme expression, and the activation of the UGT2B11 gene. In human prostate epithelial cells, only UGT2B11 and -B15 mRNAs are detected and are regulated by androgens in a similar manner as in LNCaP cells. In LNCaP cells, IL-1alpha and EGF also regulate UGT2B expression in an isoform-specific manner; IL-1alpha induced UGT2B10 and reduced UGT2B17, while having no effects on UGT2B11 mRNA levels. EGF treatment resulted in a decreased UGT2B17 expression, whereas UGT2B10 and -B11 mRNA remained at their basal levels. Overall, these results demonstrate that in the human prostate, androgens do not only affect their own inactivation but also influence the levels of monohydroxy-fatty acids by regulating the expression of UGT2B enzymes in an isoform-specific manner. These differential effects of androgens, IL-1alpha, and EGF on lipid metabolism likely constitute an additional mechanism by which these endogenous factors promote prostate cancer development.


Quality of Care for Acute Kidney Disease: Current Knowledge Gaps and Future Directions.
Acute kidney injury (AKI) and acute kidney disease (AKD) are common complications in hospitalized patients and are associated with adverse outcomes. Although consensus guidelines have improved the care of patients with AKI and AKD, guidance regarding quality metrics in the care of patients after an episode of AKI or AKD is limited. For example, few patients receive follow-up laboratory testing of kidney function or post-AKI or AKD care through nephrology or other providers. Recently, the Acute Disease Quality Initiative developed a consensus statement regarding quality improvement goals for patients with AKI or AKD specifically highlighting efforts regarding quality and safety of care after hospital discharge after an episode of AKI or AKD. The goal is to use these measures to identify opportunities for improvement that will positively affect outcomes. We recommend that health care systems quantitate the proportion of patients who need and actually receive follow-up care after the index AKI or AKD hospitalization. The intensity and appropriateness of follow-up care should depend on patient characteristics, severity, duration, and course of AKI of AKD, and should evolve as evidence-based guidelines emerge. Quality indicators for discharged patients with dialysis requiring AKI or AKD should be distinct from end-stage renal disease measures. Besides, there should be specific quality indicators for those still requiring dialysis in the outpatient setting after AKI or AKD. Given the limited preexisting data guiding the care of patients after an episode of AKI or AKD, there is ample opportunity to establish quality measures and potentially improve patient care and outcomes. This review will provide specific evidence-based and expert opinion-based guidance for the care of patients with AKI or AKD after hospital discharge.


Starvation as cause of death in the Croatian Quarnero and hinterland between 1816 and 1825.
Our aim is to investigate starvation as cause of death and social and demographic consequences in the Croatian Quarnero and its hinterland between 1816 and 1825, paying particular attention to the infamous "year of famine" 1817. Our sources were: registers of births, marriages, and deaths from 21 parishes kept at the Croatian State Archives in Rijeka and Zagreb. We collected and processed data for statistical analysis according to the date of baptism (birth), marriage, and death, and according to sex and age. Our focus was on recorded causes of death. Between 1816 and 1825, 15,701 children were baptised (born), and 11,021 people died. Starvation was recorded as cause of death in 255 cases, of which 198 were recorded in the infamous 1817. It was the only year with negative growth in virtually all parishes, with the birth-to-death ratio of 1147:1545. In 1817, the proportion of death by starvation to the total death rate was 12.8% for the entire area, with the highest share recorded in Veprinac (33.3%), Crikvenica (23.3%), and Kastav (15.8%). Death by starvation was more common in men than in women (56.7% vs. 43.3%, respectively). Age distribution was as follows; in the population below 20 years of age the death rate was 42 (16.5% of total deaths), but the most affected age group were infants and children aged 1-4 years (69.0%) whereas in adult population the death rate was 213 (83.5% of total deaths) and the most affected group were the elderly between 60 and 69 years (26.3%). Analysis shows lower birth and marriage rates between 1816 and 1818, followed by a steep rise and a plateau with minimal variation. This study shows that the Croatian Quarnero and its hinterland suffered a great famine in the early 19th century and 1817 in particular, which had left a deep mark on local demography, just like in the neighbouring parts of Croatia and Europe.


Increased sensitivity in objective monitoring of tissue expansion.
The end point for incremental filling of any tissue expander normally may reliably be assessed using subjective parameters, especially pain, as a guideline. However, in unusual circumstances, such as within denervated areas, the presence of marginal skin circulation, or if rapid expansion is required, an objective monitor may be beneficial to ensure safer expansion. We have previously examined the role of serial measurement of transcutaneous oxygen in this regard. In an effort to refine this sometimes cumbersome approach, a comparison using laser Doppler flowmetry as well has been undertaken in 13 consecutive patients. Both monitoring devices demonstrated a progressive impediment to blood flow with increased expansion. At the pain threshold, both techniques recorded values consistent with adequate skin circulation, thereby proving in general the relative safety of subjective evaluation during the usual course of tissue expansion. Greater sensitivity was noted for the laser Doppler as a monitor, though, via the recording of earlier changes in flow characteristics and more rapid identification of critical thresholds for nonviability. From a more practical standpoint, immediate application without a period for equilibration is another major asset of laser Doppler flowmetry as a system for objective monitoring.


Novel imaging in prostate cancer.
Imaging of prostate cancer (Pca) presents many challenges as imaging tools aim to improve cancer detection, assessment in biochemical relapse, and disease progression in advanced metastatic stages. Current imaging modalities have strengths but also weaknesses, such as the lack of ability to diagnose micrometastases, to differentiate significant from nonsignificant cancer, and to diagnose advanced disease at low prostate-specific antigen values. Some of the modalities appear promising in increasing the sensitivity and specificity rate, particularly in recurrent and advanced disease (e.g., prostate-specific membrane antigen-positron emission tomography). Others can prove valuable in delivering focal therapy for Pca. Finally, the combination of two modalities could provide improved results in the diagnosis of Pca. Despite promising results, most guidelines still recommend traditional imaging modalities, such as 99mTc bone scintigraphy and computed tomography, for the estimation of metastatic spread in bones and lymph nodes, and the routine use of the novel techniques is not considered. Prospective studies clarify the value of the modalities and determine their role in clinical practice.


[Study of urinary outflow in pregnancy].
Anatomical and physiological changes in the urinary tract develop during pregnancy. These changes may affect the urinary outflow. Urinary symptoms may develop during pregnancy in previously asymptomatic patients. Most of these symptoms will vanish after delivery. Some of them remain and others will become worse in consecutive pregnancies. A study was designed to compare if there was any difference in the urinary outflow between pregnant and non-pregnant women. Changes in the urinary outflow at different gestacional ages were studies too. In general, the urinary volume is higher in pregnant than in non-pregnant patients. Having said this, during the pregnancy this volume decrease in the third trimester. Peak urinary outflow is higher in pregnancy, being statically significant during the second and third trimester. Opposite to the non-pregnant patient, peak urinary outflow does not decrease with urinary volumes over 500 ml in pregnant patients. Significant differences were not found in the mean urinary outflow in both groups.


Spin-filter device based on the Rashba effect using a nonmagnetic resonant tunneling diode.
We propose an electronic spin-filter device that uses a nonmagnetic triple barrier resonant tunneling diode (TB-RTD). This device combines the spin-split resonant tunneling levels induced by the Rashba spin-orbit interaction and the spin blockade phenomena between two regions separated by the middle barrier in the TB-RTD. Detailed calculations using the InAlAs/InGaAs material system reveal that a splitting of a peak should be observed in the I-V curve of this device as a result of the spin-filtering effect. The filtering efficiency exceeds 99.9% at the peak positions in the I-V curve.


Candidate's thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss.
Oxidative stress plays a substantial role in the genesis of noise-induced cochlear injury that causes permanent hearing loss. We present the results of three different approaches to enhance intrinsic cochlear defense mechanisms against oxidative stress. This article explores, through the following set of hypotheses, some of the postulated causes of noise-induced cochlear oxidative stress (NICOS) and how noise-induced cochlear damage may be reduced pharmacologically. 1) NICOS is in part related to defects in mitochondrial bioenergetics and biogenesis. Therefore, NICOS can be reduced by acetyl-L carnitine (ALCAR), an endogenous mitochondrial membrane compound that helps maintain mitochondrial bioenergetics and biogenesis in the face of oxidative stress. 2) A contributing factor in NICOS injury is glutamate excitotoxicity, which can be reduced by antagonizing the action of cochlear -methyl-D-aspartate (NMDA) receptors using carbamathione, which acts as a glutamate antagonist. 3) Noise-induced hearing loss (NIHL) may be characterized as a cochlear-reduced glutathione (GSH) deficiency state; therefore, strategies to enhance cochlear GSH levels may reduce noise-induced cochlear injury. The objective of this study was to document the reduction in noise-induced hearing and hair cell loss, following application of ALCAR, carbamathione, and a GSH repletion drug D-methionine (MET), to a model of noise-induced hearing loss. This was a prospective, blinded observer study using the above-listed agents as modulators of the noise-induced cochlear injury response in the species chinchilla langier. Adult chinchilla langier had baseline-hearing thresholds determined by auditory brainstem response (ABR) recording. The animals then received injections of saline or saline plus active experimental compound starting before and continuing after a 6-hour 105 dB SPL continuous 4-kHz octave band noise exposure. ABRs were obtained immediately after noise exposure and weekly for 3 weeks. After euthanization, cochlear hair cell counts were obtained and analyzed. RESULTS ALCAR administration reduced noise-induced threshold shifts. Three weeks after noise exposure, no threshold shift at 2 to 4 kHz and <10 dB threshold shifts were seen at 6 to 8 kHz in ALCAR-treated animals compared with 30 to 35 dB in control animals. ALCAR treatment reduced both inner and outer hair cell loss. OHC loss averaged <10% for the 4- to 10-kHz region in ALCAR-treated animals and 60% in saline-injected-noise-exposed control animals. Noise-induced threshold shifts were also reduced in carbamathione-treated animals. At 3 weeks, threshold shifts averaged 15 dB or less at all frequencies in treated animals and 30 to 35 dB in control animals. Averaged OHC losses were 30% to 40% in carbamathione-treated animals and 60% in control animals. IHC losses were 5% in the 4- to 10-kHz region in treated animals and 10% to 20% in control animals. MET administration reduced noise-induced threshold shifts. ANOVA revealed a significant difference (P <.001). Mean OHC and IHC losses were also significantly reduced (P <.001). These data lend further support to the growing body of evidence that oxidative stress, generated in part by glutamate excitotoxicity, impaired mitochondrial function and GSH depletion causes cochlear injury induced by noise. Enhancing the cellular oxidative stress defense pathways in the cochlea eliminates noise-induced cochlear injury. The data also suggest strategies for therapeutic intervention to reduce NIHL clinically.


[Influence of mucinous and signet-ring cell differentiation on epidemiological, histological, molecular biological features, and outcome in patients with colorectal carcinoma].
Colorectal cancer (CRC) is one of the most common malignancies in the Western world. Histopathologically, adenocarcinomas are mostly diagnosed. Mucinous and signet-ring cell subtypes occur with a very low incidence. However, these subtypes differ remarkably in terms of clinical, histological and molecular biological characteristics. The aim of this review is to present a detailed analysis of current knowledge regarding differences between classical adenocarcinoma and mucinous, and signet-ring cell CRC along with potential consequences for daily practice. For this report all articles with relevant information on differences between classical adenocarcinoma and mucinous, and signet-ring cell CRC found via Pubmed searches were analysed. Furthermore, findings of our previous study were included. Mucinous CRC occur with a reported incidence of 10 - 20 % in Western countries and are predominantly found in younger patients and females. They are more often diagnosed in the proximal colon and present with a higher stage at diagnosis. Furthermore, there is a higher rate of lymph node-positive tumours and peritoneal carcinomatosis. Results of molecular biological studies confirm that they may represent a different tumour entity. The response to well established chemotherapy regimens is poorer which may be attributed to the higher rate of microsatellite-instable tumours and an increased mucin secretion. The poorer outcome is likely related to the higher stage at the time of diagnosis. Signet-ring cell type CRC are rare with an incidence ranging between 0,9 % to 4 %. They are also more common in the right colon and are associated with a poorer outcome compared to adenocarcinoma and mucinous CRC. However, it should be noted that most of the results come from studies with a very low number of patients which can be attributed to the low incidence of mucinous and signet-ring cell CRC. Based on the findings of the present analysis, a more radical surgical approach should be considered providing that the exact preoperative histology is available. Furthermore, the histological subtype should be taken into account in future chemotherapy trials to avoid unnecessary therapy. A closer follow-up, especially for patients with signet-ring cell CRC should be discussed. In the near future, a more tailored therapy in patients with colorectal cancer would be highly desirable.


Total arthroplasty of the hip after childhood sepsis.
Total hip arthroplasty was performed in 45 hips of 44 patients who had pyogenic arthritis of the hip during childhood. The average age of the patients was 36.4 years (range 19 to 50). The interval between active infection and arthroplasty ranged from 11 to 40 years, and average follow-up was 65.4 months (range 58 to 80). Specimens of tissue taken before and during operation gave negative cultures in all hips, and no patient had reactivation of infection. The mean functional rating of the hips was 58 points before operation and 90 at the final review. Complications were seen in 11 cases (24%), loosening of components occurred in six (13%) and one hip had to be revised for acetabular component migration. Acetabular allografts were required in 27 hips (60%). All allografts united but there was partial resorption of the graft in the non-weight-bearing area in all.


Current status of immunotherapy for the treatment of lung cancer.
Immunotherapy is a novel approach for the treatment of systemic malignancies. Passive and adaptive immunotherapy have been applied to the treatment of a wide variety of solid tumors such as malignant melanoma (1), renal cell carcinoma (2) and ovarian cancer (3). Several early clinical trials of immune based therapy for both non-small (NSCLC) and small cell lung cancer (SCLC) have demonstrated limited or no success (3),(4) but recent trials of antigen-specific cancer immunotherapy have shown early therapeutic potential and are now being rigorously evaluated on a larger scale (5). In this communication we briefly review the historic aspects of immune based therapy for solid cancer, describe therapeutic strategies aimed at targeting lung cancer, and discuss limitations of current therapy and future directions of this field.


Exercise-induced asthma in figure skaters.
Many highly trained athletes experience exercise-induced bronchospasm (EIB): studies describing EIB in figure skaters, who may be at increased risk of EIB due to rink temperatures (7 to 10 degrees C), have not been published. We studied professionally coached figure skaters (n = 124) for EIB by spirometry at rinkside immediately before a simulated long program and at 0 to 1, 5, 10, and 15 min postexercise. Postexercise spirometry revealed the presence of EIB (a decrease from baseline in FEV1 of at least 10%) in 43 skaters, while the remainder (n = 81, control group) remained relatively stable. Pre-exercise FEV1, FVC, and FEV1/FVC ratio were not different between groups. The EIB group had significantly lower FEV1 vs baseline at each measurement following exercise: baseline, 3.08 +/- 0.13; 0 to 1 min postexercise, 2.81 +/- 0.13 (p < 0.05); 5 min postexercise, 2.77 +/- 0.14 (p < 0.05); 10 min postexercise, 2.78 +/- 0.13 (p < 0.05); 15 min postexercise, 2.78 +/- 0.13 (p < 0.05). The EIB group also had lower FVC: baseline, 3.48 +/- 0.16; 0 to 1 min postexercise, 3.16 +/- 0.15 (p < 0.05); 5 min postexercise, 3.19 +/- 0.15 (p < 0.05); 10 min postexercise, 3.27 +/- 0.16 (p < 0.05); 15 min postexercise, 3.26 +/- 0.16 (p < 0.05). Control subjects, however, experienced no decline in these variables. In conclusion, the incidence of EIB in the figure skaters measured during this investigation (43 of 124 = 35%) is greater than that of the population at large and other highly trained athletes, signifying that screening for EIB and therapeutic follow-up are reasonable considerations for participants in this sport.


Intestinal Permeability of Drugs in Caco-2 Cells Cultured in Microfluidic Devices.
Microfluidic devices are attracting attention for their ability to provide a biomimetic microenvironment wherein cells are arranged in a particular pattern and provided fluidic and mechanical forces. In this study, we evaluated drug transport across Caco-2 cell layers in microfluidic devices and investigated the effects of fluid flow on drug transport and metabolism. We designed a microfluidic device that comprises two blocks of polydimethylsiloxane and a sandwiched polyethylene terephthalate membrane with pores 3.0 µm in diameter. When cultured in a dynamic fluid environment, Caco-2 cells were multilayered and developed microvilli on the surface as compared with a static environment. Drugs with higher lipophilicity exhibited higher permeability across the Caco-2 layers, as well as in the conventional method using Transwells, and the fluidic conditions had little effect on permeability. In the Caco-2 cell layers cultured in Transwells and microfluidic devices, the basal-to-apical transport of rhodamine 123, a substrate of P-glycoprotein, was greater than the apical-to-basal transport, and the presence of tariquidar, an inhibitor of P-glycoprotein, completely diminished asymmetric transport. Furthermore, fluidic conditions promoted the metabolism of temocapril by carboxylesterases. On the other hand, we showed that fluidic conditions have little effect on gene expression of several transporters and metabolic enzymes. These results provide useful information regarding the application of microfluidic devices in drug transport and metabolism studies.


"Brother's Keeper: A Story From the Edge of Medicine".
Jamie Heywood's younger brother Stephen was diagnosed with Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig's disease). Trying to save his brother, Jamie ventured on a roller-coaster ride right on the edge of medicine.


R124C and R555W TGFBI mutations in Spanish families with autosomal-dominant corneal dystrophies.
Mutations in the transforming growth factor beta I (TGFBI) gene cause several types of autosomal-dominant corneal dystrophies. We investigated the role of this gene in two Spanish families affected by lattice type I or granular type I corneal dystrophies. We recruited 13 subjects from two unrelated families diagnosed with autosomal dominant lattice type I or granular type I corneal dystrophies. Corneal phenotypes were assessed by slit lamp examination. Genomic DNA was obtained from blood samples, and exons 4, 11, 12, and 14, which contained mutation hot spots of the TGFBI gene, were screened for mutations by PCR DNA sequencing. We identified two TGFBI mutations: R124C (exon 4), which segregated with lattice type I corneal dystrophy, and R555W (exon 12), which segregated granular type I corneal dystrophy. Two single-nucleotide polymorphisms were also found, of which H428H was novel and F540F was previously reported. This is the first report of mutations in the TGFBI gene in Spanish families affected by corneal dystrophy. R124C and R555W TGFBI mutations cause lattice and granular type I corneal dystrophies in the studied families. Our results indicate that the genetic defects underlying corneal dystrophies in Spanish patients are similar to those found in other populations.


Health at Every Size®-Based Interventions May Improve Cardiometabolic Risk and Quality of Life Even in the Absence of Weight Loss: An Ancillary, Exploratory Analysis of the Health and Wellness in Obesity Study.
We examined whether weight loss following HAES®-based interventions associates with changes in cardiometabolic risk factors and quality of life of women with obesity. This was an exploratory, ancillary analysis of a 7-month, mixed-method, randomized controlled trial. Fifty-five women (age: 33.0 ± 7.2; BMI: 30-39.9 kg/m2) were included in this study. Body weight, cardiovascular risk factors, clustered cardiometabolic risk, and quality of life were assessed before (Pre) and after HAES®-based interventions (Post). Delta scores (Post-Pre) were calculated for each outcome and used in linear regression models. After adjusting by potential confounders, weight loss was associated with improvements in waist circumference (β = 0.83, p <0.001), fasting glycemia (β = 0.45, p = 0.036), total cholesterol (β = 1.48, p = 0.024), LDL (β = 1.33, p = 0.012), clustered cardiometabolic risk (β = 0.18, p = 0.006), and quality of life (β = -1.05, p = 0.007). All participants but one who reduced body weight (n = 11) improved clustered cardiometabolic risk and quality of life. Of relevance, 34% and 73% of the participants who maintained or gained weight improved clustered cardiometabolic risk and quality of life, respectively, although the magnitude of improvements was lower than that among those who lose weight. Improvements in cardiovascular risk factors and quality of life following HAES®-based interventions associated with weight loss as expected. However, most of the participants who maintained or even gained weight experienced benefits to some extent. This suggests that weight-neutral, lifestyle-modification interventions may improve wellness and health-related outcomes, even in the absence of weight loss.


[Diagnostic workup of chronic inflammatory bowel disease in the horse].
The present retrospective study describes the diagnostic workup and collected findings in 7 horses with chronic inflammatory bowel disease over the years 2000-2006. The diagnosis could be confirmed histologically with biopsies taken during laparoscopy or laparotomy or during post mortem examination. Weight loss and chronic diarrhoea were the most commonly reported clinical findings. Among ancillary examinations (fecal analysis, gastroscopy, abdominal ultrasonography, rectal mucosal biopsy) the D-xylose absorption test provided the most useful information. Although clinical signs and laboratory findings are helpful diagnostic tools, a definitive diagnosis is only possible by histological analysis of the intestinal segment.


Chronic kidney disease and mortality in implantable cardioverter-defibrillator recipients.
Incidence of sudden cardiac death (SCD) in end-stage renal disease (ESRD) remains high. Limited data is available about whether implantable cardioverter-defibrillators (ICDs) can prevent arrhythmic death in patients with chronic kidney disease (CKD). The purpose of this retrospective study was to determine the impact of CKD on all-cause and sudden cardiac death in ICD recipients. We evaluated 441 consecutive patients who underwent ICD implantation at our center between 1994 and 2002. We found that mortality rate was higher in patients with eGFR <60 mL/min and those with ESRD on hemodialysis (43%, n = 69/162 and 54%, n = 12/22, resp.) than in patients with eGFR >/=60 mL/min (23%, n = 58/257; P < .0005). The SCD rate was also higher in the patients with ESRD (50%) than in CKD patients not on dialysis (10.2%; P < .0005). Mortality rate for single-chamber ICDs was 56.8% in comparison with dual-chamber ICDs (38.1%) and for biventricular ICDs (5.0%) (P < .0005).


Early repolarization: a rare primary arrhythmic syndrome and common modifier of arrhythmic risk.
Despite longstanding beliefs, early repolarization is not always a benign electrocardiographic observation. Its association with increased arrhythmic events has been observed in 2 strikingly different groups of individuals, retrospectively in young subjects with idiopathic ventricular fibrillation and in long-term cohort studies from the general population. This form of primary electrical disease is now referred to as the early repolarization syndrome and has mechanistically been demonstrated to occur secondary to a transmural gradient of early cellular repolarization, resulting in the presence of an ST-elevation pattern and J-waves merged within or offset from the terminal QRS complex. In addition to creating a milieu of increased arrhythmic risk in isolation, an increasing number of studies have highlighted that the presence of early repolarization and J-waves may provide a baseline electrical substrate that modifies the risk of malignant arrhythmias in other clinical settings, such as acute myocardial ischemia. The challenge ahead lies in discerning when early repolarization may represent an ominous ECG marker, as opposed to a benign entity.


Projected Impact of HPV and LBC Primary Testing on Rates of Referral for Colposcopy in a Canadian Cervical Cancer Screening Program.
To estimate the impact of implementing primary human papilloma virus liquid-based cytology (LBC) screening on four-year rates of referral for colposcopy in the British Columbia screening program. We used data on referral for colposcopy from an RCT (HPV FOCAL) comparing HPV testing every four years with LBC testing every two years. We also used data from population screening with conventional cytology among women aged 25 to 69. The predicted effect of adoption of either trial protocol on rates of referral for colposcopy was estimated using trial age-specific result and screening result-specific rates weighted by their screening program distribution. The cumulative age-specific rates of referral for colposcopy over four years were calculated. Use of HPV testing initially increased rates of referral for colposcopy in the trial, but over four years the cumulative rates of referral were similar to those for LBC except in women aged 25 to 29, in whom a substantial excess persisted. Four-year rates of referral for colposcopy declined with age in women screened with HPV testing, LBC, and conventional cytology. Extrapolating the trial results to the distribution in the provincial screening program, implementation of either HPV or LBC throughout the provincial population would approximately double the current rates of referral for colposcopy. Compared with LBC screening, primary screening for HPV increased rates of referral for colposcopy only among women aged 25 to 29. In contrast to current practice, referral for colposcopy was largely driven by the trial protocol recommendations for the management of abnormal results and not by which screening test was used.


Genetic profile of acute myeloid leukemia.
Understanding genomic events and the cascade of their effects in cell function is crucial for identifying distinct subsets of acute myeloid leukemia and developing new therapeutic strategies. Conventional cytogenetics, fluorescence in situ hybridization investigations and molecular studies have provided much information over the past few years. This review will focus on major genomic mechanisms in acute myeloid luekemia and on the genes implicated in the pathogenesis of specific subtypes.


Prolonged effect of stress (water and food deprivation) at weaning or in adult age on the triiodothyronine and histamine content of immune cells.
We used two days of total water and food deprivation as stress for female rats at weaning (three weeks old) and at adult age (two and a half months old). Triiodothyronine (T3) and histamine content of immune cells (lymphocytes, mast cells and monocyte-macrophage-granulocyte group in peritoneal fluid; lymphocytes, granulocytes and monocytes in blood; and lymphocytes in thymus) were studied three weeks after stress application using specific antibodies for flow cytometry and confocal microscopy. The stress at weaning increased T3 content of thymus lymphocytes. In case of adult T3, there was a cell type independent significant effect of stress, decreasing values in peritoneal fluid and slightly increasing effect in the blood. Histamine content of granulocytes was also significantly elevated. The experiments demonstrate that not only fetal or neonatal stress has long-lasting consequences, but also stress events in later periods of life in cells (organs) that are continuously differentiating. We will go on to discuss the importance of T3 and histamine in connection with stress and immunity.


Direct Synthesis of Photosensitizable Bacterial Cellulose as Engineered Living Material for Skin Wound Repair.
Living materials based on bacterial cellulose (BC) represent a natural and promising candidate for wound dressing. Both physical adsorption and chemical methods have been applied to BC for realizing antibacterial function. However, effective and long-lasting incorporation of bactericidal moieties to BC remains challenging. Herein, a Komagataeibacter sucrofermentans-based direct synthetic method to fabricate photosensitizer-grafted BC through in situ bacterial metabolism in the presence of TPEPy-modified glucose is explored. The results verify that the direct biosynthesis method is efficient and convenient to endow BC with outstanding fluorescence and light-triggered photodynamic bactericidal activity for skin wound repair. This work presents a new approach to fabricate eco-friendly and active wound dressing with light-controlled bactericidal activity by microbial metabolism. The successful modification of the glucose carbon source of microorganisms also offers insights for biosyntheses of other living materials through microbial metabolism.


Update on micronutrients in bariatric surgery.
Obesity is a growing worldwide epidemic. Obese patients are often deficient in micronutrients despite macronutrient excess. Bariatric surgery is an increasingly utilized modality in the treatment of obesity and obesity-related conditions. Bariatric surgery itself may cause or exacerbate micronutrient deficiencies with serious sequelae. This review will focus on perioperative strategies to detect, prevent and treat micronutrient deficiencies in patients undergoing bariatric surgery, and will highlight practical and clinical aspects of these nutritional problems. Micronutrient deficiency is common in obese patients undergoing bariatric surgery both preoperatively and postoperatively. Bariatric procedures with a malabsorptive component are more likely to result in postoperative micronutrient deficiency. A system-based approach will facilitate clinical suspicion of specific or combined micronutrient deficiencies, leading to appropriate laboratory tests for confirmation. Supplementation by the oral route is always tried first, reserving parenteral administration for specific situations. Clinicians should be aware that micronutrient deficiencies are common in obese patients who may have macronutrient excess. Micronutrient deficiency may exist preoperatively or be caused by bariatric procedures themselves. A systematic and team-based approach will decrease morbidity associated with delays in diagnosis and treatment.


Crocin alleviates cognitive impairment associated with atherosclerosis via improving neuroinflammation in LDLR-/- mice fed a high-fat/cholesterol diet.
Crocin has been extensively investigated in treating neurodegenerative diseases. However, its effect on cognitive impairment associated with atherosclerosis remains unknown. The present study aimed to explore the potential mechanism of crocin on cognitive impairment in a mouse model of atherosclerosis. LDLR-/- mice fed a high-fat/cholesterol diet were administered variable-dose crocin for 56 days through gavage. Biochemical tests showed that serum triglycerides and circulating lipopolysaccharide decreased in mice treated with crocin. Behavioral tests indicated that crocin alleviated cognitive impairment by reducing latency to the platform and increasing the swimming distance in the target quadrant. This mechanism might be associated with crocin inhibiting Aβ deposition by decreasing Aβ1-42 and tau phosphorylation. Crocin improved neuroinflammation by inhibiting the increase in reactive microglia and astrocytes, weakening NLRP3 inflammasome activation accompanied by a reduction in Caspase-1 and IL-1β, and blocking TLR4 signaling accompanied by a decrease in NF-kB p65 and MyD88. In addition, crocin raised the protein expression of ZO-1 and occludin. These findings provide experimental support that crocin attenuates cognitive impairment associated with atherosclerosis by repressing neuroinflammation, which is attributed to its suppression on the activation of microglia and astrocytes, and the production of inflammatory cytokines via targeting the NLRP3 inflammasome and TLR4 signaling.


Active Extensile Stress Promotes 3D Director Orientations and Flows.
We use numerical simulations and linear stability analysis to study an active nematic layer where the director is allowed to point out of the plane. Our results highlight the difference between extensile and contractile systems. Contractile stress suppresses the flows perpendicular to the layer and favors in-plane orientations of the director. By contrast extensile stress promotes instabilities that can turn the director out of the plane, leaving behind a population of distinct, in-plane regions that continually elongate and divide. This supports extensile forces as a mechanism for the initial stages of layer formation in living systems, and we show that a planar drop with extensile (contractile) activity grows into three dimensions (remains in two dimensions). The results also explain the propensity of disclination lines in three dimensional active nematics to be of twist type in extensile or wedge type in contractile materials.


Anti-idiotypic response to antigrowth factor receptor monoclonal antibodies.
The immunogenicity of the idiotypic portions of two antigrowth factor receptor monoclonal antibodies (MAbs) was studied. Immunisation of allogeneic but not syngeneic mice with antihuman epidermal growth factor receptor (EGF-R) MAb MINT5 or anti-HER-2/neu MGR6 MAb elicited a detectable titre of circulating antibodies, particularly when the MAb was coupled with the keyhole limpet haemocyanin and administered together with Freund's adjuvant. The anti-Ab1 response to MAb MINT5 was slightly delayed as compared with the response obtained with MAb MGR6 and was mainly directed to the variable regions. In both cases, all anti-Ab1-positive sera specifically competed with the binding of homologous radiolabelled Ab1 to the relevant EGF-R+ or HER-2/neu+ target cells. Fusion of splenocytes from MINT5-immunised animals failed to produce MAb, whereas cell fusion was successful in generating a paratope-related MAb in the case of MGR6. The anti-MGR6 MAb-produced IdM6.4 inhibited the binding of MAb MGR6 on breast carcinoma cells, suggesting that it recognises an idiotope in or near the antigen combining site, and can be considered useful in the identification and purification of the Ab1 or its derivatives. We analysed whether a possible recognition of murine EGF-R by MAb MINT5 or a mimicry of EGF by the MAb idiotype prevented or delayed the development of an idiotypic cascade in mice. MINT5 inhibited human and murine EGF binding to the human EGF-R, whereas the anti-Ab1 response competed with MINT5 but not with murine EGF binding to A431 human epidermoid carcinoma cells. Moreover, MINT5 did not recognise the murine EGF-R. In a phase I clinical study, no detectable levels of human antimouse antibody response were observed in 5 of the 6 treated cancer patients. The ability of MAb MINT5 to block human EGF-R function, together with its low immunogenicity in patients, raise the possibility of its application in carcinoma immunotherapy.


Surgery option in the management of delayed diplopia after radiation therapy for nasopharyngeal carcinoma.
Radiation therapy is a standard treatment for nasopharyngeal carcinoma. Diplopia due to radiation damage to the sixth nerve significantly erodes the patient's quality of life. This study investigated the effectiveness of extraocular surgery in the treatment of delayed diplopia caused by radiation therapy. A retrospective case series of 16 patients (7 men and 9 women) with delayed diplopia after radiation therapy for nasopharyngeal carcinoma was enrolled in the study. Unilateral lateral rectus resection was performed under topical anesthesia. Follow-up time was more than 12 months. Outcome measures were prism diopter and self-reported symptoms. All patients diagnosed with sixth nerve palsy reported elimination of symptoms on postoperative day 1 without complications. One patient required a second procedure due to recurrence of symptoms. At 12-month follow-up, no patient reported recurrence of symptoms. The absolute horizontal deviation significantly decreased from a preoperative value of 16 prism diopter to a value of 1.5 prism diopter postoperatively (p < 0.001). These results suggest that unilateral lateral rectus resection under topical anesthesia is an effective treatment for delayed diplopia after radiation therapy for nasopharyngeal carcinoma. A large randomized prospective study to confirm these findings is warranted.


Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report.
Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.


Decreased susceptibility to salt-induced hypertension in subtotally nephrectomized mice lacking the vasopressin V1a receptor.
By examining vasopressin V1a receptor (V1aR) knockout (KO) mice, we previously found that the V1aR is critically involved in the regulation of normal blood pressure. The present study was undertaken to elucidate the role of the V1aR in salt-induced hypertension. We compared haemodynamic responses induced by subtotal nephrectomy + salt loading in V1aR KO mice with those of wild-type (WT) controls. The time course of changes in the systolic blood pressure and heart rate during the salt loading was attenuated in the KO mice compared with that for the WT mice. The elevation of the plasma norepinephrine level caused by the subtotal nephrectomy + salt loading was also reduced in the V1aR KO mice. A V1aR antagonist markedly lowered the arterial blood pressure in the salt-loaded WT mice but not in the normotensive WT mice or in the salt-loaded or normotensive V1aR KO mice. Whereas arginine vasopressin (AVP) administered to the lateral ventricle of the brain induced pressor and tachycardiac responses accompanied by sympathetic activation in the WT mice, these events were completely abolished in the V1aR KO mice. Also, pressor and tachycardiac responses induced by intraventricularly administered hypertonic saline in the WT mice were diminished in the V1aR KO mice. Moreover, the pressor response induced by intraventricularly administered AVP was reduced in alpha(1d) adrenoceptor KO mice, whereas the tachycardiac response did not differ from that of the WT mice. These results suggest that the V1aR is involved in the elevation of arterial blood pressure caused by dietary salt and that a V1aR antagonist, in particular regarding its effect in the brain, could have significant therapeutic potential in the treatment of hypertension.


Establishment of a pregnancy following intravaginal insemination with epididymal semen from a dog castrated due to benign prostatic hyperplasia.
Benign prostatic hyperplasia was diagnosed in an American Staffordshire Terrier of high breeding value presenting concurrent haematuria. Castration as a treatment was synchronized with the oestrus cycle of a bitch selected for insemination. After castration the cauda epididymis was flushed with Gent semen extender and collected spermatozoa were filtered and analysed by Hamilton Thorn computer assisted sperm analysis. A total of 7 ml semen containing 742 x 10(6) spermatozoa with 76.5% mean motility was used for insemination. Intravaginal insemination of the bitch was performed with an insemination catheter for dogs (Kruuse, Marslev, Denmark) on the day when plasma progesterone levels reached 9.9 ng/ml. Normal pregnancy without complications resulted in eight live-born puppies 63 days after insemination. This is the first report of a normal pregnancy and birth of puppies from a bitch inseminated with epididymal semen obtained from a dog affected by benign prostate hyperplasia.


[Conchal cartilaginous delta graft in secondary or post-traumatic rhinoplasties].
The authors study several cases of surgical revision in post-traumatic or secondary rhinoplasty. Cartilaginous grafts with temporal fascia are recommended. The removal of ear cartilage is performed via a posterior approach for the concha cartilage associated with a septum or an alar cartilage removal. They describe the delta graft associating a concha cartilage supported by a prop (auricular or septal) to repair a defect of the middle or lower third of the pyramid.


Effect of L-364,718 on pancreatic endocrine function following partial pancreatectomy.
This study was designed to determine the effect of a potent cholecystokinin antagonist, L-364,718, on canine pancreatic endocrine function following partial pancreatectomy. Plasma glucose, insulin, and glucagon were determined over a 2-hr interval following an intravenous bolus of 0.5 g/kg glucose in a 50% solution. The following groups were established: normal animals (group A, n = 5), normal animals pretreated with 20 nmole/kg L-364,178 (group B, n = 5), partially pancreatectomized animals (group C, n = 5), and partially pancreatectomized animals pretreated with 20 nmole/kg L-364,178 (group D, n = 5). In contrast to animals with an intact pancreas, pretreatment with L-364,718 following partial pancreatectomy resulted in a significant decrease in peak insulin (group C = 132.8 +/- 13.0 microU/ml vs Group D = 90.4 +/- 16.1 microU/ml, P < 0.05) and the basal-to-peak insulin difference (group C = 111.9 +/- 11.5 microU/ml vs group D = 77.5 +/- 16.6 microU/ml, P < 0.05). Despite this, the rate of glucose utilization (K value) was significantly increased in the partially pancreatectomized animals given the antagonist (group C = -1.22 +/- 0.22%/min vs group D = -2.79 +/- 0.427%/min) and there were no significant differences in basal or peak glucose when comparing the groups given L-364,718 with the groups given placebo (group A vs B and group C vs D). Thus, the CCK antagonist L-364,718 significantly decreases peak insulin in partially pancreatectomized animals but not in nonoperative control animals. There is a paradoxical increase in the rate of glucose utilization but no effect on glucose homeostasis. The effect of this antagonist in other models of reduced islet cell reserve (i.e., pancreas transplantation) remains to be determined.


Role of anaerobic bacteria in liver abscesses in children.
Aspirates from pyogenic liver abscesses obtained from 14 children were cultured for aerobic and anaerobic bacteria. Of 29 organisms that were recovered, 17 were anaerobic and 12 were aerobic or facultative. The predominant organisms were Peptostreptococcus spp. (5 isolates). Bacteroides fragilis group (4), Fusobacterium spp. (3) and Staphylococcus aureus (4). Aerobic or facultative bacteria only were recovered in five cases, anaerobic bacteria only in four and mixed aerobic and anaerobic bacteria in five. Anaerobic bacteria were recovered in liver abscesses that were associated with other infection in which these organisms were predominant (i.e. abdominal infection, abscesses). This study highlights the potential importance of anaerobic bacteria in pyogenic liver abscess.


Real time monitoring of membrane GPCR reconstitution by plasmon waveguide resonance: on the role of lipids.
G-protein coupled receptors (GPCRs) are important therapeutic targets since more than 40% of the drugs on the market exert their action through these proteins. To decipher the molecular mechanisms of activation and signaling, GPCRs often need to be isolated and reconstituted from a detergent-solubilized state into a well-defined and controllable lipid model system. Several methods exist to reconstitute membrane proteins in lipid systems but usually the reconstitution success is tested at the end of the experiment and often by an additional and indirect method. Irrespective of the method used, the reconstitution process is often an intractable and time-consuming trial-and-error procedure. Herein, we present a method that allows directly monitoring the reconstitution of GPCRs in model planar lipid membranes. Plasmon waveguide resonance (PWR) allows following GPCR lipid reconstitution process without any labeling and with high sensitivity. Additionally, the method is ideal to probe the lipid effect on receptor ligand binding as demonstrated by antagonist binding to the chemokine CCR5 receptor.


Purification and characterization of nitrous oxide reductase from Pseudomonas aeruginosa strain P2.
Nitrous oxide reductase, which catalyzes the reduction of N2O to N2, was purified in a largely oxidized form from Pseudomonas aeruginosa strain P2 by a simple anaerobic procedure to yield an enzyme with a peptide purity of 95-98%. For the native (dimeric) enzyme, Mr = 120,000 and for the denatured subunit, Mr = 73,000. The enzyme contained four Cu atoms/subunit, was purple in color, and exhibited a broad absorption band at 550 nm with an extinction coefficient of about 11,000 M-1 x cm-1 referenced to the dimer. It was nearly inactive as prepared but could be activated by incubation with 2-(N-cyclohexylamino)ethane sulfonate buffer, pH 10, to specific activities as high as 27 mumol of N2O x min-1 x mg-1.Km for N2O and benzyl viologen radical cation was about 2 and 4 microM, respectively, both before and after enzyme activation. Activation increased the t1/2 for turnover-dependent inactivation from about 30 s to 5-10 min. Reduction of the enzyme by dithionite was kinetically biphasic and resulted in the loss of the 550-nm band and ultimate appearance of a 670-nm band. Isoelectric focusing revealed five components with pI values from 5.2 to 5.7. The pI values did not change following activation. The copper CD spectrum of the enzyme as prepared was different from that for the activated enzyme, whereas those for the enzyme after exposure to air and the activated enzyme were similar. Because the activated enzyme is a mixture of activated and inactive species, the specific activity of the activated species must be substantially greater than the observed value. Molecular heterogeneity may also explain the decreased optical absorbance and CD amplitude that resulted from the activation process. The data overall reinforce the view that the absorption spectrum of nitrous oxide reductase is not a good predictor of absolute activity.


Mineralocorticoid receptor antagonists in elderly patients with heart failure: a systematic review and meta-analysis.
Mineralocorticoid receptor antagonists (MRAs) improve outcomes in several populations of patients with heart failure (HF), but there has been no systematic review of MRAs in older patients. Systematic review and meta-analysis of the efficacy and safety of MRA treatment in elderly HF patients. Trials were identified through a literature search until 24 January 2015. Randomised controlled trials (RCTs) of MRAs in patients with HF and/or left ventricular systolic dysfunction aged ≥65 years, with subgroup analysis of patients ≥65 years or with mean participant age ≥70 years. Efficacy outcomes were mortality, hospitalisation for cardiovascular causes, symptom status or functional capacity. Safety outcomes were hyperkalaemia and renal dysfunction. Data were analysed using relative risk ratios with 95% confidence intervals. Relative risk ratios were pooled where more than three estimates were available. Seven RCTs were included (total n = 8,638). Three RCTs in HF with reduced ejection fraction (HEFREF) reported overall benefit from MRA therapy with no significant treatment interaction for age; the effects of MRAs on mortality in patients ≥75 years displayed marked inter-study heterogeneity. In four RCTs of HF with preserved ejection fraction (HEFPEF), MRA treatment had no significant effect on any efficacy outcome. MRAs improve clinical outcomes in selected cohorts of older patients with HEFREF but not HEFPEF. In patients ≥75 years with HEFREF, the effect of MRA treatment on overall mortality is uncertain. Further study is required in subgroups of elderly patients with both HEFREF and HEFPEF.


Acetaldehyde stimulates collagen and noncollagen protein production by human fibroblasts.
The mechanisms responsible for the increased hepatic collagen deposition in alcoholic cirrhosis remain unknown. The question of whether ethanol or acetaldehyde has a direct effect on collagen and noncollagen protein production was investigated in human fibroblasts with no detectable activity of alcohol dehydrogenase to distinguish the effects of these metabolites. To eliminate environmental factors, protein production by confluent human skin, fetal and hepatic fibroblasts was studied after three passages. Cells were labeled with [5-3H]proline for 4 hr in the presence of 0.2 mM ascorbate alone or with addition of either ethanol (50 mM) or acetaldehyde (0 to 300 microM). Rates of protein production were calculated from the radioactivities of collagenase-sensitive and collagenase-resistant proteins. Skin fibroblasts from alcoholic individual either with cirrhosis or without liver disease have comparable rates of collagen and noncollagen protein production. Acetaldehyde, in a concentration found in the liver during ethanol abuse, significantly increased collagen production by human skin fibroblasts (up to 140%), fetal fibroblasts (up to 240%) and hepatic fibroblasts (up to 70%) but the addition of ethanol had no significant effect on basal collagen production. The effect of acetaldehyde was dose-related and affected noncollagen protein production in a similar manner. Acetaldehyde did not cause changes in either proline transport or the specific activity of the proline precursor pool. This newly recognized stimulation of collagen production by acetaldehyde may be a possible mechanism of fibrogenesis in alcoholic individuals.


Trends in Second-Hand Tobacco Smoke Exposure Levels at Home among Viet Nam School Children Aged 13-15 and Associated Factors.
Second-hand tobacco smoke (SHS) exposure at home, especially among children, is a serious issue in Viet Nam. During the past decade, much effort has been taken for tobacco control in the country, including various prgorammes aiming to reduce SHS exposure among adults and children. This article analysed trends and factors associated with SHS exposure at home among school children aged 13-15 in Viet Nam, using the Global Youth Tobacco Surveys conducted in 2007 and 2014. Descriptive and inferential statistical methods with logistic regression were applied. Overall, there was a significant reduction in the level of exposure, from 58.5% (95%CI: 57.6-59.3) in 2007 to 47.1% (95%CI: 45.4-48.8) in 2014. Of the associated factors, having one or both parents smoking was significantly associated with the highest odds of SHS exposure at home (OR=5.0; 95%CI: 4.2-6.1). Conversely, having a mother with a college or higher education level was found to be a protective factor (OR=0.5; 95%CI: 0.3-0.8).


Modeling Parkinson's disease in midbrain-like organoids.
Modeling Parkinson's disease (PD) using advanced experimental in vitro models is a powerful tool to study disease mechanisms and to elucidate unexplored aspects of this neurodegenerative disorder. Here, we demonstrate that three-dimensional (3D) differentiation of expandable midbrain floor plate neural progenitor cells (mfNPCs) leads to organoids that resemble key features of the human midbrain. These organoids are composed of midbrain dopaminergic neurons (mDANs), which produce and secrete dopamine. Midbrain-specific organoids derived from PD patients carrying the LRRK2-G2019S mutation recapitulate disease-relevant phenotypes. Automated high-content image analysis shows a decrease in the number and complexity of mDANs in LRRK2-G2019S compared to control organoids. The floor plate marker FOXA2, required for mDAN generation, increases in PD patient-derived midbrain organoids, suggesting a neurodevelopmental defect in mDANs expressing LRRK2-G2019S. Thus, we provide a robust method to reproducibly generate 3D human midbrain organoids containing mDANs to investigate PD-relevant patho-mechanisms.


Refractory asthma in the UK: cross-sectional findings from a UK multicentre registry.
Refractory asthma represents a significant unmet clinical need where the evidence base for the assessment and therapeutic management is limited. The British Thoracic Society (BTS) Difficult Asthma Network has established an online National Registry to standardise specialist UK difficult asthma services and to facilitate research into the assessment and clinical management of difficult asthma. Data from 382 well characterised patients, who fulfilled the American Thoracic Society definition for refractory asthma attending four specialist UK centres--Royal Brompton Hospital, London, Glenfield Hospital, Leicester, University Hospital of South Manchester and Belfast City Hospital--were used to compare patient demographics, disease characteristics and healthcare utilisation. Many demographic variables including gender, ethnicity and smoking prevalence were similar in UK centres and consistent with other published cohorts of refractory asthma. However, multiple demographic factors such as employment, family history, atopy prevalence, lung function, rates of hospital admission/unscheduled healthcare visits and medication usage were different from published data and significantly different between UK centres. General linear modelling with unscheduled healthcare visits, rescue oral steroids and hospital admissions as dependent variables all identified a significant association with clinical centre; different associations were identified when centre was not included as a factor. Whilst there are similarities in UK patients with refractory asthma consistent with other comparable published cohorts, there are also differences, which may reflect different patient populations. These differences in important population characteristics were also identified within different UK specialist centres. Pooling multicentre data on subjects with refractory asthma may miss important differences and potentially confound attempts to phenotype this population.


Low peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is associated with increased tumor T-cell infiltration and favorable outcomes to first-line pembrolizumab in non-small cell lung cancer.
An elevated peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is a negative prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy and immune checkpoint inhibitors. Whether dNLR is also associated with clinical outcomes to first-line pembrolizumab among patients with NSCLC and a programmed cell death ligand 1 (PD-L1) Tumor Proportion Score (TPS) of ≥50% is uncertain. How dNLR relates to the tumor immune microenvironment is also unclear. In two participating academic centers, we retrospectively analyzed the dNLR (defined as the absolute neutrophil count/white cell count - absolute neutrophil count) prior to initiation of first-line pembrolizumab in patients with metastatic NSCLC and a PD-L1 TPS ≥50% and lacking genomic alterations in EGFR and ALK. An unbiased recursive partitioning algorithm was used to investigate an optimal dNLR cut-off with respect to objective response rate (ORR). Multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 was performed on a separate cohort of NSCLCs to determine the immunophenotype associated with dNLR. A total of 221 patients treated with first-line pembrolizumab were included in this study. The optimal dNLR cut-off to differentiate treatment responders from non-responders was 2.6. Compared with patients with a dNLR ≥2.6 (n=97), patients with dNLR <2.6 (n=124) had a significantly higher ORR (52.4% vs 24.7%, p<0.001), a significantly longer median progression-free survival (mPFS 10.4 vs 3.4 months, HR 0.48, 95% CI 0.35 to 0.66, p<0.001), and a significantly longer median overall survival (mOS 36.6 vs 9.8 months, HR 0.34, 95% CI 0.23 to 0.49, p<0.001). After adjusting for age, sex, tobacco use, performance status, histology, serum albumin level, oncogenic driver status, and PD-L1 distribution (50%-89% vs ≥90%), a dNLR <2.6 was confirmed to be an independent predictor of longer mPFS (HR 0.47, 95% CI 0.33 to 0.67, p<0.001) and mOS (HR 0.32, 95% CI 0.21 to 0.49, p<0.001). Among advanced NSCLC samples with a PD-L1 TPS of ≥50%, those with a dNLR <2.6 had significantly higher numbers of tumor-associated CD8+, FOXP3+, PD-1 +immune cells, and PD-1 +CD8+T cells than those with a dNLR ≥2.6. Among patients with NSCLC and a PD-L1 TPS ≥50%, a low dNLR has a distinct immune tumor microenvironment and more favorable outcomes to first-line pembrolizumab.


[Diagnosis of neurocysticercosis: a case report].
Neurocysticercosis is the most frequent parasitosis of central nervous system in the world. Neurological manifestations are in relation with locations number and topography, inflammatory reactions level and state of development of the parasite. Epilepsy is the main revealing symptom. Among other neurological manifestations, chronic headache, focal neurological signs, ataxia, language and behaviour disorder are the most anecdotal. The authors report a case of neurocysticercosis in a 71-year-old man with dysarthria and memory problems. Suspected by computed tomography, diagnosis was confirmed by immunoserologic assays such as enzyme-linked immunosorbent assay (ELISA) or enzyme-linked immunoelectrotransfer blot assay (EITB). This later emphasized on active form of the cyst. Specific treatment used albendazole as antihelminthic drug. Clinical evolution was good: neuroimaging and immunoserology results were normal respectively 2 and 6 months after the drug therapy.


[Treatment of gastric cancer].
From a global perspective, gastric cancer including adenocarcinoma of the esophagogastric junction is the fourth most common malignant tumor and the second most common cause of cancer-related death. Due to the lack of specific symptoms of early cancer, most gastric cancers are diagnosed in advanced stages. Staging should include high-resolution computed tomography of the thorax, abdomen, and pelvis and documented video-endoscopy and endoscopic ultrasound. In mucosal gastric cancer, endoscopic resection can replace surgical resection. In more advanced stages, perioperative chemotherapy has been established as a standard of care. In the metastatic setting, treatment goals are palliative. Chemotherapy can prolong survival, improve symptoms, and enhance the quality of life. Combination chemotherapy including a platinum salt plus fluoropyrimidine is the standard of care. About 16 % of gastric cancers exhibit overexpression of the growth factor receptor HER2. Trastuzumab has shown to prolong survival when combined with chemotherapy in HER2-positive gastric cancer.


Enzymological analysis of the tumor suppressor A-C1 reveals a novel group of phospholipid-metabolizing enzymes.
A-C1 protein is the product of a tumor suppressor gene negatively regulating the oncogene Ras and belongs to the HRASLS (HRAS-like suppressor) subfamily. We recently found that four members of this subfamily expressed in human tissues function as phospholipid-metabolizing enzymes. Here we examined a possible enzyme activity of A-C1. The homogenates of COS-7 cells overexpressing recombinant A-C1s from human, mouse, and rat showed a phospholipase A½ (PLA½) activity toward phosphatidylcholine (PC). This finding was confirmed with the purified A-C1. The activity was Ca²⁺ independent, and dithiothreitol and Nonidet P-40 were indispensable for full activity. Phosphatidylethanolamine (PE) was also a substrate and the phospholipase A₁ (PLA₁) activity was dominant over the PLA₂ activity. Furthermore, the protein exhibited acyltransferase activities transferring an acyl group of PCs to the amino group of PEs and the hydroxyl group of lyso PCs. As for tissue distribution in human, mouse, and rat, A-C1 mRNA was abundantly expressed in testis, skeletal muscle, brain, and heart. These results demonstrate that A-C1 is a novel phospholipid-metabolizing enzyme. Moreover, the fact that all five members of the HRASLS subfamily, including A-C1, show similar catalytic properties strongly suggests that these proteins constitute a new class of enzymes showing PLA½ and acyltransferase activities.


Chiral Brønsted Acid-Catalyzed Metal-Free Asymmetric Direct Reductive Amination Using 1-Hydrosilatrane.
The asymmetric direct reductive amination of prochiral ketones with aryl amines using 1-hydrosilatrane with a chiral Brønsted acid catalyst is reported. This is the first known example of chiral Brønsted acid-catalyzed asymmetric reductive amination using a silane as the hydride source. The reaction features a highly practical reducing reagent and proceeds efficiently at room temperature without a specialized reaction setup or equipment to exclude air or moisture. This method provides high conversion and enantiomeric excess up to 84% of the desired chiral secondary amines with minimal side products.


The miR-10 microRNA precursor family.
The miR-10 microRNA precursor family encodes a group of short non-coding RNAs involved in gene regulation. The miR-10 family is highly conserved and has sparked the interest of many research groups because of the genomic localization in the vicinity of, coexpression with and regulation of the Hox gene developmental regulators. Here, we review the current knowledge of the evolution, physiological function and involvement in cancer of this family of microRNAs.


Spiritual Health and Stress in Pregnant Women During the Covid-19 Pandemic.
Stress is one of the effective factors in the occurrence of negative effects during pregnancy that can cause adverse outcomes such as preterm delivery and reduced intrauterine growth of the fetus in pregnant women. Therefore, one of the serious concerns during the COVID-19 pandemic is the physical health and mental health of pregnant women. This study aimed to evaluate the physical health status with the spiritual and mental health of pregnant women during the COVID-19 pandemic. The study is a descriptive study in 2019-2020 and the samples were randomly selected from all pregnant women who referred to hospitals and private maternity centers before and during the COVID-19 pandemic and performed all pregnancy and fetal health tests. It was performed on 560 pregnant female samples. The mental status of pregnant women was assessed using the DASS Spiritual Health and Stress Questionnaire. Data analysis was performed using SPSS statistical software (version 24). The results of this study showed that preterm birth, height, weight, and head circumference of babies and lungs and respiratory status of children with mental health and stress levels of pregnant women during the corona are significant compared with the previous of corona (p < 0.05). Increasing stress and decreasing the mental health of pregnant women during COVID-19 pandemic can increase the influencing factors in preterm delivery and unhealthy birth.


Role of metapneumovirus in viral respiratory infections in young children.
The contribution of human metapneumovirus (hMPV) relative to that of other respiratory viruses as a cause of respiratory infections in children less than 1 year old has been evaluated. From October 2003 to April 2004, nasopharyngeal samples from 211 children less than 1 year old were analyzed to detect respiratory viruses. Respiratory syncytial virus (RSV) was the predominant virus isolated (96 children [45.5%]), followed by influenza A virus, parainfluenza virus, adenovirus, cytomegalovirus, and herpes simplex virus type 1, which were only occasionally detected. From January 2004 to April 2004, a nested retrotranscription-PCR, using in-house primers directed to the matrix protein gene of hMPV, was carried out on samples in which no other viruses were detected. hMPV was detected in 18 (16.2%) children, indicating that this virus was the second-most-frequent cause of viral respiratory infections in children less than 1 year old. The rate of hospitalization for RSV- and hMPV-infected children was higher than 75%. While RSV had a peak from December to February, hMPV was increasingly detected from January to April. The mean age of hMPV-infected children (6.44 +/- 3.64 [mean +/- standard deviation] months) was significantly higher than that of RSV-infected children (3.99 +/- 2.96 [mean +/- standard deviation] months). On the other hand, 64.3% of the RSV-infected children and 12.5% of the hMPV-infected children showed high levels of C-reactive protein. Although several authors have reported that clinical symptoms of hMPV-positive patients mirrored those of RSV-positive patients, differences between the two viruses can be found.


Significance of platelet and AFP levels and liver function parameters for HCC size and survival.
Hepatocellular carcinoma (HCC) is a heterogeneous disease with both tumor and liver factors being involved. To investigate HCC clinical phenotypes and factors related to HCC size. Prospectively-collected HCC patients' data from a large Italian database were arranged according to the maximum tumor diameter (MTD) and divided into tumor size terciles, which were then compared in terms of several common clinical parameters and patients' survival. An higer MTD tercile was significantly associated with increased blood alpha-fetoprotein (AFP), gamma-glutamyl transpeptidase (GGTP), and platelet levels. Patients with higher platelet levels had larger tumors and higher GGTP levels, with lower bilirubin levels. However, patients with the highest AFP levels had larger tumors and higher bilirubin levels, reflecting an aggressive biology. AFP correlation analysis revealed the existence of 2 different groups of patients: those with higher and with lower AFP levels, each with different patient and tumor characteristics. The Cox proportional-hazard model showed that a higher risk of death was correlated with GGTP and bilirubin levels, tumor size and number, and portal vein thrombosis (PVT), but not with AFP or platelet levels. An increased tumor size was associated with increased blood platelet counts, AFP and GGTP levels. Platelet and AFP levels were important indicators of tumor size, but not of survival.


A Qualitative Transcriptional Signature for the Risk Assessment of Precancerous Colorectal Lesions.
It is meaningful to assess the risk of cancer incidence among patients with precancerous colorectal lesions. Comparing the within-sample relative expression orderings (REOs) of colorectal cancer patients measured by multiple platforms with that of normal colorectal tissues, a qualitative transcriptional signature consisting of 1,840 gene pairs was identified in the training data. Within an evaluation dataset of 16 active and 18 inactive (remissive) ulcerative colitis subjects, the median incidence risk score of colorectal carcinoma was 0.6402 in active ulcerative colitis subjects, significantly higher than that in remissive subjects (0.3114). Evaluation of two other independent datasets yielded similar results. Moreover, we found that the score significantly positively correlated with the degree of dysplasia in the case of colorectal adenomas. In the merged dataset, the median incidence risk score was 0.9027 among high-grade adenoma samples, significantly higher than that among low-grade adenomas (0.8565). In summary, the developed incidence risk score could well predict the incidence risk of precancerous colorectal lesions and has value in clinical application.


A Comparative Analysis of the Place of Death of Older Adults in Hawai'i, 2003-2018.
Studies from around the world have found that the preferred place of death is at home. Although desired, the ability to die at home requires personal, social, and structural factors to be in place. In the United States, between 2003 and 2017, there were decreased hospital and nursing facility deaths and increased home and hospice facility deaths. This study aims to determine whether a change in the place of death in those greater than 65 years of age in Hawai'i is similar to the overall United States data and if these changes in place of death are similar across islands/counties in the state of Hawai'i. Data from the Centers for Disease Control and Prevention database were analyzed for natural deaths between 2003 and 2018 in Hawai'i. Between 2003 and 2018, there were 120 115 natural deaths in Hawai'i, with a decrease in the overall percentage of deaths in hospitals from 53% in 2003 to 33% in 2018. During the same period, home deaths increased from 23% to 33%, and nursing facility deaths increased from 14% to 16%. This study found that the change in the place of death in those greater than 65 years in Hawai'i is similar to the overall United States data as a whole, but not within individual Hawai'i counties.


[Effect of NAD+ against radiation injury and its dose-effect relationship].
To explore the effect of NAD+ against radiation injury and its dose-effect relationship. L02 liver cells cultured in RPMI 1640 medium containing 10% fetal calf serum were exposed to X-ray irradiation followed by immediate application of NAD+. The cellular viability was analyzed by MTT assay and the apoptotic cells were detected by TUNEL methods to observe the damages of L02 liver cells induced by X-ray exposure and analyze the dose-effect relationship of NAD+. The viability of L02 liver cells was decreased with increasing dose of X-ray irradiation. The most obvious growth inhibition of L02 cells occurred 24 h after the irradiation. NAD+ significantly increased the cell survival rate after irradiation, and this effect was gradually increased within the concentration range of 100-1000 microg/ml; at higher concentrations, the survival rate of the irradiated L02 cells showed no significant increase. NAD+ provides partial protection of the liver cells against radiation injury, and the effect is positively correlated to NAD+ concentration within a certain range.


Corneal collagen cross-linking (CXL) combined with refractive procedures for the treatment of corneal ectatic disorders: CXL plus.
To discuss current combined corneal collagen cross-linking (CXL) and refractive surgical techniques (herein termed "CXL plus") for the treatment of corneal ectatic disorders to improve functional visual acuity in addition to corneal stability from CXL alone. Literature review. Efficacious combined treatments with CXL include: photorefractive keratectomy, transepithelial phototherapeutic keratectomy, intrastromal corneal ring segments implantation, phakic intraocular lens implantation, and multiple combined procedures. Some uncertainty remains as to the optimal strategies for each patient. A decision tree is proposed to facilitate optimal patient management. With multiple adjuvant techniques, CXL plus is likely to benefit many patients with corneal ectatic disorders. The appropriate combined procedure will depend on multiple factors, such as refraction, corneal thickness, and degree of irregular astigmatism.


Effects of cisapride on gastroparesis in patients with insulin-dependent diabetes mellitus. A double-blind controlled trial.
Fourteen insulin-dependent diabetics with symptoms and signs of delayed gastric emptying were treated with a new prokinetic agent, cisapride. In a placebo-controlled cross-over trial no significant differences from placebo was found regarding overall symptomatic effects and effects on gastric emptying of a mixed solid/liquid isotope marked test meal. Solid emptying was most markedly delayed in diabetics compared with healthy controls, but the emptying rate was not correlated to the severity of symptoms as observed for liquid emptying. During active treatment with cisapride the amelioration of symptoms was correlated to increased emptying rates assessed by combined measure of liquid/solid gastric emptying.


Light-Responsive Polymer Micro- and Nano-Capsules.
A significant amount of academic and industrial research efforts are devoted to the encapsulation of active substances within micro- or nanocarriers. The ultimate goal of core⁻shell systems is the protection of the encapsulated substance from the environment, and its controlled and targeted release. This can be accomplished by employing "stimuli-responsive" materials as constituents of the capsule shell. Among a wide range of factors that induce the release of the core material, we focus herein on the light stimulus. In polymers, this feature can be achieved introducing a photo-sensitive segment, whose activation leads to either rupture or modification of the diffusive properties of the capsule shell, allowing the delivery of the encapsulated material. Micro- and nano-encapsulation techniques are constantly spreading towards wider application fields, and many different active molecules have been encapsulated, such as additives for food-packaging, pesticides, dyes, pharmaceutics, fragrances and flavors or cosmetics. Herein, a review on the latest and most challenging polymer-based micro- and nano-sized hollow carriers exhibiting a light-responsive release behavior is presented. A special focus is put on systems activated by wavelengths less harmful for living organisms (mainly in the ultraviolet, visible and infrared range), as well as on different preparation techniques, namely liposomes, self-assembly, layer-by-layer, and interfacial polymerization.


Assembly, Thermodynamics, and Structure of a Two-Wheeled Composite of a Dumbbell-Shaped Molecule and Cylindrical Molecules with Different Edges.
A carbonaceous dumbbell was able to spontaneously glue two tubular receptors to form a unique two-wheeled composite through van der Waals interactions, thus forcing the wheel components into contact with each other at the edges. In the present study, two tubular receptors with enantiomeric carbon networks were assembled on the dumbbell joint, and the handedness of the receptors was discriminated, thus leading to the self-sorting of homomeric receptors from a mixture of enantiomeric tubes. The crystal structures of the composites revealed the structural origins of the molecular recognition driven by van der Waals forces as well as the presence of a columnar array of C120 molecules in a 1:1 composite.


[Empirical psychotherapy research].
Current bibliography on epistemological status of psychoanalysis is reviewed. In particular, claims from several fields of knowledge, including those from "hard" sciences as physics, mathematics or philosophy of sciencies about empirical demonstration of efficacy and theoretical basis of the discipline are discussed.


Chimeras of alpha1-adrenergic receptor subtypes identify critical residues that modulate active state isomerization.
We have identified previously two amino acids, one in each of the fifth and sixth transmembrane segments of both the alpha1a-adrenergic receptor and the alpha1b-adrenergic receptor (AR), that account almost entirely for the selectivity of agonist binding by these receptor subtypes (Hwa, J., Graham, R. M., and Perez, D. M. (1995) J. Biol. Chem. 270, 23189-23195). Thus reversal of these two residues, from those found in the native receptor of one subtype to those in the other subtype, produces complementary changes in subtype selectivity of agonist binding. Here we show that mutating only one of these residues in either the alpha1b-AR or the alpha1a-AR to the corresponding residue in the other subtype (Ala204 --> Val for the alpha1b; Met292 --> Leu for the alpha1a-AR) results in chimeras that are constitutively active for signaling by both the phospholipase C and phospholipase A2 pathways. This is evident by an increased affinity for agonists, increased basal phospholipase C and phospholipase A2 activation, and increased agonist potency. Although mutation of the other residue involved in agonist binding selectivity, to the corresponding residue in the other subtype (Leu314 --> Met for the alpha1b-AR; Val185 --> Ala for the alpha1a-AR) does not alter receptor binding or signaling, per se, when combined with the corresponding constitutively activating mutations, the resulting chimeras, Ala204 --> Val/Leu314 --> Met ( alpha1b-AR) and Val185 --> Ala/Met292 --> Leu ( alpha1a-AR), display wild type ligand binding and signaling. A simple interpretation of these results is that the alpha1a- and alpha1b-ARs possess residues that critically modulate isomerization from the basal state, R, to the active state R*, and that the native receptor structures have evolved to select residues that repress active state isomerization. It is likely that the residues identified here modulate important interhelical interactions between the fifth and sixth transmembrane segments that inhibit or promote receptor signaling.


[Effect of PbO on emission properties of YAG:Ce3+ phosphor].
Doubly doped YAG:Ce3+, Pb2+ phosphor was obtained by doping YAG:Ce3+ phosphor with PbO. Compared with the emission spectra of YAG:Ce3+ phosphor without PbO, the Ce3+ emission band of YAG:Ce3+, Pb2+ shifts to longet wave, which can enhance the red component of spectrum. Meanwhile, the intensity of Ce3+ emission is increased by 10% when the concentration of PbO is 5%, SEM image indicates that PbO may act as a flux. Temperature-dependent emission spectra of YAG: Ce3+, Pb2+ phosphor show a better thermal quenching characteristics than YAG:Ce3+ phosphor.


Important role for NKp30 in synapse formation and activation of NK cells.
Natural killer (NK) cells play an important role in host defense against viral infections and tumor cells. NK cells require contact with target cells and must subsequently form an NK cell immunological synapse (NKIS). The NKIS represents the interface formed between NK cells and their target cells via receptor recognition and adhesion molecule binding, and it is essential for NK cell cytotoxicity, which is mediated through degranulation and release of cytolytic enzymes. In this study, NKp30-mediated signaling and the role of NKp30 in the formation of the NKIS were investigated. The results from confocal microscopy studies showed that the activating receptor, NKp30, and the adhesion molecule, LFA-1 (CD11a), accumulated at the interface between NK92 cells, which are a human NK cell line, and HeLa cells, which are a human tumor cell line (NK92-HeLa). Blockade of NKp30 inhibited NK cell degranulation, cytotoxicity and cytokine secretion but did not affect the conjugation between NK and target cells. Additionally, ligation with HeLa cells activated the Erk1/2 signaling pathway in NK92 cells, and blockade of NKp30 decreased the phosphorylation of Erk1/2. Therefore, NKp30 is a triggering receptor downstream of adhesion and plays an important role in NK cell activation, degranulation and cytotoxicity.


Specific somatostatin receptors on human pituitary adenoma cell membranes.
Specific somatostatin (SRIH) receptors on human pituitary adenoma cell membranes were characterized using [125I]Tyr11-SRIH as the radioligand. Specific binding of [125I] Tyr11-SRIH to adenoma cell membranes reached a steady state within 30 min at 25 C, and semilogarithmic analysis of the data revealed that the rate of the binding was linear at 25 C with a t1/2 of 13.2 min. Specific binding increased linearly with 5-160 micrograms plasma membrane protein. SRIH-14 and SRIH-28 inhibited [125I]Tyr11-SRIH binding to adenoma cell membranes with ID50S of 0.32 and 0.50 nM, respectively, while secretin, glucagon, gastrin, cholecystokinin-8, bombesin, TRH, LHRH, human GH-releasing factor-(1-44)-NH2, D-Ala2-met-enkephalin, gamma-aminobutyric acid and taurine did not significantly inhibit binding. All of 13 GH-secreting adenomas investigated had specific and high affinity SRIH receptors, with a dissociation constant (Kd) of 0.80 +/- 0.15 nM (mean +/- SEM) and a maximal binding capacity (Bmax) of 234.2 +/- 86.9 fmol/mg protein (mean +/- SEM). Among five of the nonsecreting pituitary adenomas examined, two had SRIH receptors with Kd values of 0.18 and 0.32 nM and Bmax values of 17.2 and 48.0 fmol/mg protein, respectively. In the remaining three, SRIH receptors were not detected. These results indicate that GH-secreting adenomas as well as some nonfunctioning adenomas have specific SRIH receptors, and hence, the function of the adenomas could be altered by SRIH.


[Static Retinal Vessel Analysis in Population-based Study SHIP-Trend].
Interdisciplinary investigations of possible connections between general diseases and ophthalmological changes are difficult to perform in the clinical environment. But they are gaining in importance as a result of the age-related increase in chronic diseases. The collection of health-related parameters in the Study of Health in Pomerania (SHIP) project allows to derive conclusions for the general population. The population-based SHIP trend study was conducted between 2008 and 2012 in Greifswald. The baseline cohort included 4420 subjects (response 50.1%) at the age of 20 to 84 years. The pre-existence of arterial hypertension, diabetes mellitus and smoking status were questioned in a standardized questionnaire, the blood pressure and the HbA1c were determined by the laboratory. The vascular diameter of retinal arterioles and venules were determined by means of non-mydriatic fundus images and the retinal arterial (CRAE) and venous equivalent (CRVE) were calculated therefrom. The association of diabetes mellitus, HbA1c, smoking status and blood pressure with the retinal vascular parameters was tested for age and sex with linear regression models. In 3218 subjects with evaluable standardized fundus photographs, significant associations of elevated HbA1c (> 6.5%), smoking status and systolic and diastolic blood pressure were found with the retinal vessel widths CRAE and CRVE. Anamnestic diabetes mellitus, on the other hand, was not associated with any of the vascular parameters. This research study reveals a relevant correlation between general diseases and the retinal blood flow in the eye. Therefore, general diseases can induce ophthalmological changes and eye examination can provide information for the assessment of general diseases.


Relationship between brain structure on magnetic resonance imaging and motor outcomes in children with cerebral palsy: a systematic review.
Magnetic resonance imaging (MRI) is recommended in all children with cerebral palsy (CP) where the aetiology has not been established, and the major presenting problem in CP is reduced motor capacity. A systematic review of the literature was performed to investigate the relationship between brain structure on MRI and motor outcomes in children with CP. A total of 37 studies met inclusion criteria, and were analysed in terms of (a) population characteristics, (b) MRI data, (c) motor outcome data, and (d) the relationship between MRI data and motor outcomes. All studies used a qualitative system to classify brain lesions; however, few reported information about the location and extent of lesions. Valid and reliable classifications of motor abilities were not always used, and three studies did not link motor findings to MRI features. There was, however, a relationship between the type of brain lesion on MRI and two specific motor outcomes, namely gross motor functional classification (using GMFCS) and motor type. This relationship could aid in the prediction and optimisation of early interventions for children with CP. There is also need for a quantitative MRI classification measure which includes detailed information about the location and severity of lesions.


Protection of T cells against infectivity and cytopathic effect of HTLV-III in vitro.
A recently discovered member of the human T-cell leukemia virus (HTLV) family of retroviruses has been etiologically linked to the acquired immunodeficiency syndrome (AIDS). This virus, which has been designated HTLV-III, is tropic for OKT4+ (helper/inducer) T-cells. Moreover, the virus is cytopathic for these cells. Suramin is a drug used in the therapy of Rhodesian trypanosomiasis and onchocerciasis, and it inhibits the reverse transcriptase of a number of retroviruses including HTLV-III. In the present work, we report our findings that suramin can block the in vitro infectivity and cytopathic effect of HTLV-III at doses that are clinically attainable in human beings. We believe these results may have relevance in planning experimental therapeutic strategies for various diseases associated with members of the HTLV-family of pathogenic human retroviruses.


New structural information on a humic acid from two-dimensional 1H-13C correlation solid-state nuclear magnetic resonance.
New information on the chemical structure of a peat humic acid has been obtained using a series of two-dimensional 1H-13C heteronuclear correlation solid-state NMR (HETCOR) experiments with different contact times and with spectral editing by dipolar dephasing and 13C transverse relaxation filtering. Carbon-bonded methyl groups (C-CH3) are found to be near both aliphatic and O-alkyl but not aromatic groups. The spectra prove that most OCH3 groups are connected directly with the aromatic rings, as is typical in lignin. As a result, about one-third of the aromatic C-O groups is not phenolic C-OH but C-OCH3. Both protonated and unprotonated anomeric O-C-O carbons are identified in the one- and two-dimensional spectra. COO groups are found predominantly in OCHn-COO environments, but some are also bonded to aromatic rings and aliphatic groups. All models of humic acids in the literature lack at least some of the features observed here. Compositional heterogeneity was studied by introducing 1H spin diffusion into the HETCOR experiment. Comparison with data for a synthetic polymer, polycarbonate, indicates that the separation between O-alkyl and aromatic groups in the humic acid is less than 1.5 nm. However, transverse 13C relaxation filtering under 1H decoupling reveals heterogeneity on a nanometer scale, with the slow-relaxing component being rich in lignin-like aromatic-C-O-CH3 moieties and poor in COO groups.


Sequence of a 10.5 kbp fragment of Clostridium pasteurianum genomic DNA encompassing the hydrogenase I gene and two spore germination genes.
The gene encoding hydrogenase I from Clostridium pasteurianum had previously been cloned and sequenced as part of a 2.3 kbp Sau3A genomic DNA fragment. The analysis of the regions surrounding the hydrogenase gene has been extended by cloning and sequencing two EcoRI fragments, both partially overlapping the 2.3 kbp Sau3A fragment. An uninterrupted genomic sequence of 10.5 kbp has thus been obtained, including 6.7 kbp upstream of the hydrogenase gene, and 2 kbp downstream. The hydrogenase gene is separated by 473 bp from the next open reading frame on its 5' side and by 366 bp from the next open reading frame on its 3' side. It is preceded by putative promoter regions, and followed by a strong transcription termination signal. Therefore the hydrogenase I gene from C. pasteurianum probably belongs to a monocistronic operon. This is consistent with previous biochemical evidence showing that the enzyme is monomeric. The sequence data also show that in the case of this Fe-hydrogenase, in contrast to the NiFe-hydrogenases, there are no accessory genes cotranscribed with, or located near, the structural genes. The sequenced region contains six open reading frames in addition to the hydrogenase gene. One of these probably encodes phosphatidylserine decarboxylase, and two others are homologous to two of the three genes of the gerA and gerB loci (spore germination) from Bacillus subtilis. These are the first spore germination gene sequences obtained from a bacterium of the genus Clostridium.


CD200R signaling inhibits pro-angiogenic gene expression by macrophages and suppresses choroidal neovascularization.
Macrophages are rapidly conditioned by cognate and soluble signals to acquire phenotypes that deliver specific functions during inflammation, wound healing and angiogenesis. Whether inhibitory CD200R signaling regulates pro-angiogenic macrophage phenotypes with the potential to suppress ocular neovascularization is unknown. CD200R-deficient bone marrow derived macrophages (BMMΦ) were used to demonstrate that macrophages lacking this inhibitory receptor exhibit enhanced levels of Vegfa, Arg-1 and Il-1β when stimulated with PGE2 or RPE-conditioned (PGE2-enriched) media. Endothelial tube formation in HUVECs was increased when co-cultured with PGE2-conditioned CD200R(-/-) BMMΦ, and laser-induced choroidal neovascularization was enhanced in CD200R-deficient mice. In corroboration, signaling through CD200R results in the down-regulation of BMMΦ angiogenic and pro-inflammatory phenotypes. Translational potential of this pathway was investigated in the laser-induced model of choroidal neovascularization. Local delivery of a CD200R agonist mAb to target myeloid infiltrate alters macrophage phenotype and inhibits pro-angiogenic gene expression, which suppresses pathological angiogenesis and CNV development.


Trauma-Informed Personalized Scripts to Address Partner Violence and Reproductive Coercion: Preliminary Findings from an Implementation Randomized Controlled Trial.
Background: Family planning (FP) providers are in an optimal position to address harmful partner behaviors, yet face several barriers. We assessed the effectiveness of an interactive app to facilitate implementation of patient-provider discussions about intimate partner violence (IPV), reproductive coercion (RC), a wallet-sized educational card, and sexually transmitted infections (STIs). Materials and Methods: We randomized participants (English-speaking females, ages 16-29 years) from four FP clinics to two arms: Trauma-Informed Personalized Scripts (TIPS)-Plus and TIPS-Basic. We developed an app that prompted (1) tailored provider scripts (TIPS-Plus and TIPS-Basic) and (2) psychoeducational messages for patients (TIPS-Plus only). Patients completed pre- and postvisit surveys. We compared mean summary scores of IPV, RC, card, and STI discussions between TIPS-Plus and TIPS-Basic using Wilcoxon rank-sum tests, explored predictors with ordinal regression, and compared implementation with historical data using chi-square. Results: Of the 240 participants, 47.5% reported lifetime IPV, 12.5% recent IPV, and 7.1% recent RC. No statistically significant differences emerged from summary scores between arms for any outcomes. Several significant predictors were associated with higher scores for patient-provider discussions, including race, reason for visit, contraceptive method, and condom nonuse. Implementation of IPV, RC, and STI discussions increased significantly (p < 0.0001) when compared with historical clinical data for both TIPS-Basic and TIPS-Plus. Conclusions: We did not find an added benefit of patient activation messages in increasing frequency of sensitive discussions. Several patient characteristics appear to influence providers' likelihood of conversations about harmful partner behaviors. Compared with prior data, this pilot study suggests potential benefits of using provider scripts to guide discussions.