Iron deficiency markers in patients undergoing iron replacement therapy: a 9-year retrospective real-world evidence study using healthcare databases.
The diagnosis and treatment of iron deficiency is a primary public health goal. This study aimed to make an inventory of the use of biomarkers to assess the iron supply in patients given iron replacement therapy. A retrospective longitudinal real-world study of a cohort of patients receiving iron replacement therapy was conducted using data from healthcare coverage databases between January 2006 and December 2015 in France. The frequency of oral or intravenous iron treatment episodes preceded and/or followed by a biological assessment of iron deficiency was described. We then differentiate patients with or without chronic inflammatory diseases, which could impact the prescription. The evolution between 2006 and 2015 was also studied. The 96,724 patients received an average of 4.9 administrations of iron per patient, corresponding to 1.7 treatment episodes. In one-third of treatment episodes (34.6%), patients had a pre-treatment biological assessment, 15.5% a post-treatment assessment, and 7.3% both. The post-treatment measure of iron supply markers (i.e., Ferritin and transferrin saturation) was more frequent in patients suffering from chronic inflammatory diseases than in those without underlying chronic condition (22.6% to 41.0% vs. 3.1%; p < 0.0001). Serum ferritin was measured 30 times more than transferrin saturation measurements. The use of both tests increased steadily during the study period, although remaining low. Despite the recommendations, biological assessments of iron status are seldom prescribed and/or performed in the context of a pre- or post-treatment assessment, although more frequently realized in patients with chronic inflammatory diseases.


Effects of fructans and probiotics on the inhibition of Klebsiella oxytoca and the production of short-chain fatty acids assessed by NMR spectroscopy.
Generally, the selection of fructans prebiotics and probiotics for the formulation of a symbiotic has been based on arbitrary considerations and in vitro tests that fail to take into account competitiveness and other interactions with autochthonous members of the intestinal microbiota. However, such analyzes may be a valuable step in the development of the symbiotic. The present study, therefore, aims to investigate the effect of lactobacilli strains and fructans (prebiotic compounds) on the growth of the intestinal competitor Klebsiella oxytoca, and to assess the correlation with short-chain fatty acids production. The short-chain fatty acids formed in the fermentation of the probiotic/prebiotic combination were investigated using NMR spectroscopy, and the inhibitory activities were assessed by agar diffusion and co-culture methods. The results showed that Lactobacillus strains can inhibit K. oxytoca, and that this antagonism is influenced by the fructans source and probably associated with organic acid production.


Regulation of insulin signaling and glucose transporter 4 (GLUT4) exocytosis by phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase, skeletal muscle, and kidney enriched inositol polyphosphate phosphatase (SKIP).
The glucose transporter 4 (GLUT4) is responsible for glucose uptake in the skeletal muscle. Insulin-induced translocation of GLUT4 to the plasma membrane requires phosphatidylinositol 3-kinase activation-mediated generation of phosphatidylinositol 3,4,5-trisphosphate PIP(3) and subsequent activation of Akt. Previous studies suggested that skeletal muscle and kidney enriched inositol polyphosphate phosphatase (SKIP) has negative effects on the regulation of insulin signaling in the skeletal muscle cells. Here, we compared its effects on insulin signaling by selective inhibition of SKIP, SHIP2, and phosphatase and tensin homologue on chromosome 10 (PTEN) by short interfering RNA in the C2C12 myoblast cells. Suppression of SKIP significantly increased the insulin-stimulated phosphatidylinositol 3,4,5-trisphosphate levels and Akt phosphorylation. Furthermore, silencing of SKIP, but not of PTEN, increased the insulin-dependent recruitment of GLUT4 vesicles to the plasma membrane. Taken together, these results imply that SKIP negatively regulates insulin signaling and glucose uptake by inhibiting GLUT4 docking and/or fusion to the plasma membrane.


Population-based analysis of 10,766 hospitalizations for mandibular fractures in California, 1991 to 1993.
This study describes mandibular fracture incidence, causes, and consequences in a large population. California hospital discharge data from 1991 to 1993 were examined to describe causes, lengths of stay, and hospital charges for patients hospitalized for mandibular fractures. Rates were calculated per 100,000 population. There were 10,766 discharges with mandibular fracture as principal diagnosis or as diagnoses two through five on the discharge record (rate=11.5). Of these, 2,694 had mandibular fracture as the only diagnosis (principal diagnosis). For all 10,766 cases, assaults were responsible for more than half (54.0%) of all admissions for mandibular fracture. The highest rates were found among males (18.7), blacks (43.0), and adults aged 16 to 20 (26.5). Charges for the initial hospitalization (excluding physician's fees) for the 2,694 cases with only a diagnosis of mandibular fracture were used to estimate mean charges ($8,740). The total extrapolated 1993 inflation-adjusted hospital charges for mandibular fractures were $34 million per year. Most patients' bills were submitted to government payers, such as Medicaid. Treatment of mandibular fractures represents a considerable cost to public-supported programs as well as to patients.


Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options.
Necrobiosis lipoidica (NL) is a rare chronic granulomatous disease that has historically been associated with diabetes mellitus. Debate exists regarding the etiology and pathogenesis of NL with a widely accepted theory that microangiopathy plays a significant role. NL typically presents clinically as erythematous papules on the front of the lower extremities that can coalesce to form atrophic telangiectatic plaques. NL is usually a clinical diagnosis, but if the clinical suspicion is uncertain, skin biopsy specimen can help differentiate it from sarcoidosis, necrobiotic xanthogranuloma, and granuloma annulare. NL is a difficult disease to manage despite a large armamentarium of treatment options that include topical and intralesional corticosteroids, immunomodulators, biologics, platelet inhibitors, phototherapy, and surgery. Randomized control trials are lacking to evaluate the many treatment methods and establish a standard regimen of care. Disease complications such as ulceration are common, and lesions should also be monitored for transition to squamous cell carcinoma, a less common sequelae.


Is Ocular Toxicity Expected in Chloroquine/Hydroxychloroquine Prescription as a Therapeutic or Prophylactic Option in COVID-19?
On 11th March 2020, WHO announced novel coronavirus infectious (COVID-19) as a pandemic. New Coronavirus Pneumonia (NCP) that emerge on 31st December 2019 from China and quickly became a Public Health Emergency of International Concern (PHEIC). In the absence of evidence-based proven prophylactic or therapeutic options, chloroquine/hydroxychloroquine (CQ/HCQ) patented as first line choice in COVID- 19 treatment, which raised concerns about drug poisoning, especially ocular toxicity. This study aims to investigate the possibility of ocular toxicity and the need for ophthalmic counseling to prescribing this therapeutic protocol. All the articles that were most relevant to the COVID-19 therapeutic or prophylactic options and CQ derivative ocular toxicity, were founded by a literature search and were thoroughly reviewed. Anecdotal recent reports introduce CQ/HCQ as an effective therapeutic or prophylactic choice for COVID-19. Because of the short time prescribe and the insignificant cumulative dose of the drug on the one hand and a higher risk of cross-infection during an ophthalmic examination, on the other hand, an ophthalmologic consult is not recommended except in highrisk patients for retinal toxicity. This study recommended ophthalmic evaluation before CQ/HCQ prescription for treatment or prophylaxis of COVID-19 only in preexisting maculopathy.


Do we need more generalists?
The author identifies the confluent forces that have structured U.S. medicine in favor of specialism since World War II. He concludes that any effort to increase the number and proportion of generalists in medicine is problematic in the absence of antecedent and concurrent transformations in the structure and functioning of academic health centers and in the financing of medical care, and of major, long-lasting changes in the delivery of health care. Only after these larger considerations have been addressed can the benefits of a generalist-oriented system be anticipated. Even then, the gains expected to accrue from a greater number of generalists might prove illusory.


IGF binding proteins in cancer: mechanistic and clinical insights.
The six members of the family of insulin-like growth factor (IGF) binding proteins (IGFBPs) were originally characterized as passive reservoirs of circulating IGFs, but they are now understood to have many actions beyond their endocrine role in IGF transport. IGFBPs also function in the pericellular and intracellular compartments to regulate cell growth and survival - they interact with many proteins, in addition to their canonical ligands IGF-I and IGF-II. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment. Tissue or circulating IGFBPs might also be useful as prognostic biomarkers.


Thermal inactivation kinetics of proteases and polyphenoloxidase in brown shrimp (Crangon crangon).
To optimize product quality of the cooked brown shrimp (Crangon crangon), quantitative data on the influence of all relevant process parameters (treatment time and temperature) on several quality attributes is required. Surprisingly, kinetic data and models on heat induced inactivation of important endogenous spoilage enzymes of the brown shrimp are not available today. In this study the thermal inactivation kinetics of the most important spoilage enzymes, proteases and polyphenoloxidase (PPO), were determined from isothermal heat treatments of enzyme extracts of the cephalothorax. For both enzymes, inactivation kinetics showed first order decay(s). Proteases showed two distinct stability fractions. A labile fraction, representing 42±2% of the total activity with kl,60°C=0.94±0.14 min(-1) and Ea,l=178±8.5 kJ/mol, and a stable fraction, representing 58±2%, with ks,60°C=0.020±0.002 min(-1) and Ea,s=155±7.0 kJ/mol. PPO showed a single fraction with k60°C=1.58±0.02 min(-1) and Ea=161±2.2 kJ/mol. Based on these results, the proteolytic activity, in particular the thermostable fraction, should be considered as a target in thermal processing of brown shrimp in relation to enzyme induced product quality changes during storage.


Immobilization and transformation of co-existing arsenic and antimony in highly contaminated sediment by nano zero-valent iron.
Arsenic (As) and antimony (Sb) are usually coexistent in mine wastes and pose a great threat to human health. The As immobilization by nano zero-valent iron (nZVI) is promising, however, the stabilization for co-occurring As and Sb is not known. Herein, the immobilization and transformation of As and Sb in nZVI-treated sediments were evaluated using complementary leaching experiments and characterization techniques. Raw sediment samples from a gold-antimony deposit revealed the co-existence of ultrahigh As and Sb at 50.3 and 14.9 g/kg, respectively. Leaching results show that As was more efficiently stabilized by nZVI than Sb, which was primarily due to the soluble fraction that was readily absorbed by nZVI of As was higher. As the nZVI treatment proceeds, the oxidation and reduction of As and Sb occur simultaneously as evidenced by XPS analysis. The primary oxidant, hydroxyl radicals, was detected by EPR studies, proving the occurrence of nZVI induced Fenton reaction. This study sheds light on differences in the interaction and immobilization of nZVI with Sb and As in co-contaminated sediments.


Deriving cell survival curves from the overall responses of irradiated tumours: analysis of published data for tumour spheroids.
Curves of growth delay (GD) or 'cure' after graded doses of radiation have been analysed for 16 lines of human and animal tumours grown as multicellular spheroids in vitro. Dose-survival curves were derived for those cellular units from which spheroids regrow after unsuccessful irradiation (spheroid-regenerating cellular units, SRU). For 10 sets of data from 6 spheroid lines, the Do's and extrapolation numbers of the SRU derived by GD could be compared with the response of the clonogenic cells of the spheroids. For Do, a good correlation (r = 0.910) was found between the two; this was true also for Do derived from curves of spheroid 'cure' (7 sets of data from 6 spheroid lines) and clonogenic cells (r = 0.986). Using GD, the correlation of extrapolation numbers was less good (r = 0.682), the values for SRU commonly being higher than those for clonogenic cells. This may reflect features of the growth curves of spheroids after the lower range of doses of radiation. For human and animal tumour spheroids of 250 microns or less, derived Do ranged from 0.5 to 2.5 Gy. For spheroids of 350 microns or more, derived Do for animal tumour lines ranged from 3.4 to 4.2 Gy, for human lines from 1.5 to 2.1 Gy.


Sialic-Acid-Related Enzymes of B Cells and Monocytes as Novel Markers to Discriminate Improvement Categories and to Fulfill Two Remission Definitions in Rheumatoid Arthritis.
The enzymes α-2,6-sialyltransferase 1 (ST6Gal1), neuraminidase 1 (Neu1), α-2,3-sialyltransferase 1 (ST3Gal1), and neuraminidase 3 (Neu3) are known to affect immune cell function. However, it is not known whether the levels of these enzymes relate to remission definitions or differentiate American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) responses in patients with rheumatoid arthritis (RA). We measured the ST6Gal1, Neu1, ST3Gal1, and Neu3 levels of B cells and monocytes in RA patients and correlated the cells' enzyme levels/ratios with the improvement in the ACR, EULAR and SDAI responses and with the two remission definitions. The difference in the B-cell Neu1 levels differed between the ACR 70% improvement and non-improvement groups (p = 0.043), between the EULAR good major response (improvement) and non-good response groups (p = 0.014), and also between the SDAI 50% or 70% improvement and non-improvement groups (p = 0.001 and 0.018, respectively). The same held true when the RA patients were classified by positive rheumatoid factor or the use of biologics. The B-cell Neu1 levels significantly indicated 2005 modified American Rheumatism Association and 2011 ACR/EULAR remission definitions (area under the curve (AUC) = 0.674 with p = 0.001, and AUC = 0.682 with p < 0.001, respectively) in contrast to the CRP and ESR (all AUCs < 0.420). We suggest that B-cell Neu1 is superior for discriminating ACR, EULAR, and SDAI improvement and is good for predicting two kinds of remission definitions.


Anxiety and public responses to covid-19: Early data from Thailand.
Any new pandemic has the potential to arouse considerable anxiety, with this anxiety associated in previous work with economic disruption and societal disruption. We examined anxiety, symptom awareness, trust and associated behavioural responses in the first three weeks of the SARS-CoV-2 (covid-19) outbreak in Thailand. We collected data on-street at randomly selected locations in Bangkok. Of 274 potential respondents, 203 (74.7%) responded. A four-item measure assessed anxiety, with open-ended questions assessing knowledge of symptoms, trusted information sources and measures taken to avoid infection. Respondents reported good awareness of the prime symptoms of the Coronovirus. Binary logistic regressions controlling for sex and age found the more anxious avoided the Chinese, people who were coughing, crowded places and public transport or flying. Younger respondents reported greater trust in foreign media and older populations information from national government. Trust in doctors online was positively associated with avoidance of coughing people and keeping fit; trust in national government with avoiding coughing people, keeping fit, and avoiding public transport . We conclude that anxiety can motivate both desirable and undesirable behaviours during pandemic outbreaks. Effective and targeted communication by trusted sources is needed to motivate preventive actions but also to limit unnecessary or disruptive behaviours.


Measurement of the evoked cardiac response: the problem of prestimulus variability.
This paper discusses the problem of prestimulus variability in cardiac activity and its implications for the measurement of evoked cardiac responses (ECRs). Two methods which have been proposed to reduce error arising from respiratory sinus arrhythmis (SA) were reviewed critically. The first approach attempts to control only for the error associated with the sampling of the prestimulus level. This is considered inappropriate since it does not take into account the continuation of SA into the poststimulus period. The second approach reviewed was time series analysis which provides an elegant statistical solution of the problem. Unfortunately, the application of time series analysis has not yet been evaluated for adult cardiac data. A third approach which utilizes an adjustment for SA by employing the actual prestimulus values of an SA cycle was proposed. The application of this technique in the case of a pseudostimulus demonstrated that correction for SA results in significantly smaller 'responses' with less variance than does a conventional procedure which does not take prestimulus variability into account.


Bidirectional modifications of visual acuity induced by monocular deprivation in juvenile and adult rats.
Recent electrophysiological studies of rodent visual cortex suggest that, in addition to deprived-eye depression, monocular deprivation (MD) also shifts ocular dominance by potentiation of open-eye responses. We used computer-based, two-choice discrimination tasks to assess the behavioral significance of these findings in rats. As expected, prolonged MD, from postnatal day 21 until adulthood (>150 d) markedly decreased visual acuity through the deprived eye. However, we also found that the acuity through the nondeprived eye was significantly enhanced compared with normally reared controls. Interestingly, when the deprived eye was opened in adults, there was a gradual but incomplete recovery of acuity in the deprived eye preceded by a loss of the enhanced acuity in the nondeprived eye. These changes were reversed by again reclosing the eye. These findings suggest that the bidirectional changes in visually evoked responses after MD are behaviorally meaningful and that significant plasticity is exhibited well into adulthood.


A new facile trinitrophenylated substrate for peptide alpha-amidation and its use to characterize PAM activity in chromaffin granules.
Carboxyl terminal alpha-amidation is a prevalent post translational modification in neuropeptide hormones, with amidation being essential for biological activity. We report a direct demonstration and characterization of peptidyl alpha-amidating monooxygenase (PAM) activity in chromaffin granules, secretory vesicles long known as loci for synthesis and storage of catecholamines but only recently recognized as processing and storage sites for neuropeptides. This finding, together with the recently recognized competence of dopamine-b-monooxygenase to carry out N-dealkylation, provides important information regarding the co-localization and co-secretion of multiple neuromodulators. In addition, we introduce a new substrate for both pituitary and chromaffin granule PAM--TNP-D-Tyr-Val-Gly. This substrate exhibits high turnover, and has the important advantage of allowing quantitative activity determinations using standard spectrophotometric techniques, thus facilitating mechanistic studies and inhibitor development.


Lactation-induced WAP-SV40 Tag transgene expression in C57BL/6J mice leads to mammary carcinoma.
Two transgenic lineages were generated by directing the expression of SV40 T antigen to the mammary gland of inbred C57BL/6J mice using the whey acidic protein (WAP) promoter. In one lineage, WAPTag 1, multiparous female mice developed mammary adenocarcinoma with an average latency period of 13 months. The histopathological phenotype was heterogeneous, tumours occurred in a stochastic fashion, normal tissue was located next to neoplastic tissue, the mammary tumours usually developed and were remarkably similar to that observed in human cases. In addition, male and virgin females developed a poorly differentiated SV40 T antigen-positive soft tissue sarcoma, also at 13 months of age. In the other lineage, WAPTag 3, some parous females developed mammary tumours, but most mice succumbed to osteosarcomas arising from the os petrosum at 5.5 to 6 months of age and on necropsy, renal adenocarcinomas were also found. Appearance of these unexpected tumour types demonstrates the non-specific expression of SV40 Tag under the control of the WAP promoter. The expression of SV40 Tag in mammary glands at different stages of development was also examined, and only actively lactating glands were positive. This suggests that the abundant cyclic synthesis of SV40 Tag associated with pregnancy is required for mammary tumorigenesis in these lineages.


[Anesthetic problems and complications in the thermocoagulation of Gasser's ganglion].
We report about hypertensive crises, cardial arrhythmia and respiratory complications in 47 patients undergoing thermocoagulation of the gasserian ganglion. Therapeutic proposals are discussed.


CT angiography predicts use of tertiary interventional services in acute ischemic stroke patients.
Patients with acute stroke are often transferred to tertiary care centers for advanced interventional services. We hypothesized that the presence of a proximal cerebral artery occlusion on CT angiography (CTA) is an independent predictor of the use of these services. We performed a historical cohort study of consecutive ischemic stroke patients presenting within 24 h of symptom onset to an academic emergency department who underwent emergent CTA. Use of tertiary care interventions including intra-arterial (IA) thrombolysis, mechanical clot retrieval, and neurosurgery were captured. During the study period, 207/290 (71%) of patients with acute ischemic stroke underwent emergent CTA. Of the patients, 74/207 (36%) showed evidence of a proximal cerebral artery occlusion, and 22/207 (11%) underwent an interventional procedure. Those with proximal occlusions were more likely to receive a neurointervention (26% vs. 2%, p < 0.001). They were more likely to undergo IA thrombolysis (9% vs. 0%, p = 0.001) or a mechanical intervention (19% vs. 0%, p < 0.0001), but not more likely to undergo neurosurgery (5% vs. 2%, p = 0.2). After controlling for the initial NIH stroke scale (NIHSS) score, proximal occlusion remained an independent predictor of the use of neurointerventional services (OR 8.5, 95% CI 2.2-33). Evidence of proximal occlusion on CTA predicted use of neurointervention with sensitivity of 82% (95% CI 59-94%), specificity of 71% (95% CI 64%-77%), positive predictive value (PPV) of 25% (95% CI 16%-37%), and negative predictive value (NPV) of 97% (95% CI 92%-99%). Proximal cerebral artery occlusion on CTA predicts the need for advanced neurointerventional services.


Food Allergies Caused by Allergenic Lipid Transfer Proteins: What Is behind the Geographic Restriction?
To critically examine evidence suggesting that food allergy induced by lipid transfer proteins (LTPs) follows a geographic pattern. LTP syndrome remains most common in the Mediterranean basin, with a clear gradient seen in prevalence of LTP sensitization between northern and southern Europe. We hypothesize that high levels of birch pollen seem to protect against LTP allergy, as these higher levels correlate with a lower prevalence of LTP hypersensitivity. Nevertheless, LTP food allergy cases still appear in areas having a high environmental level of birch pollen. Food allergy caused by LTP may be related to (1) primary sensitization to a food LTP allergen in the absence of pollinosis, (2) primary sensitization to LTP from a pollen source, and (3) co-sensitization to LTP from pollen and food.


Metabolic pathway of magnetized fluid-induced relaxation effects on heart muscle.
The effect of magnetized physiological solution (MPS) on isolated, perfused snail heart muscle contractility, (45)Ca uptake and intracellular level of cAMP, and cGMP was studied. The existence of the relaxing effect of MPS on heart muscle at room temperature (22 degrees C) and its absence in cold medium (4 degrees C) was shown. The MPS had a depressing effect on (45)Ca uptake by muscles and intracellular cAMP content and an elevating effect on intracellular cGMP level. It is suggested that the relaxing effect of MPS on heart muscle is due to the decrease of intracellular Ca ions as the result of activation of cGMP-dependent Ca efflux. The MPS induced decrease of intracellular cAMP content can be considered as a consequence of intracellular Ca loss, leading to the Na + K-ATPase reactivation, and causing the decrease of the intracellular level of ATP, serving as a substrate and positive modulator of cyclase activity.


Exchangeable sodium measured serially in DOC-salt, post-DOC-salt, and Goldblatt hypertension in the rat.
A method for serial estimation of exchangeable sodium (NaE) levels in rats was developed and validated. The method can detect differences of 0.5 mmol per rat. The NaE level was found to have a constant relationship to the total body sodium content. Changes in the NaE level were found not to be a necessary accompaniment of two-kidney, one-clip hypertension. The NaE level was increased throughout 6 weeks of one-kidney, one-clip hypertension and reverted to control values with relief of hypertension after unclipping. The NaE level increased during the development of deoxycorticosterone (DOC)-salt hypertension but subsequently decreased during post-DOC-salt hypertension, although blood pressure remained elevated. Thus an increased NaE level was not necessary for the persistence of post-DOC hypertension.


Efficacy and safety of different regimens in the treatment of patients with latent tuberculosis infection: a systematic review and network meta-analysis of randomized controlled trials.
Treatment of latent tuberculosis infection (LTBI) is effective in preventing progression to TB disease. This study aimed to synthesize available evidence on the efficacy, adherence, and safety of LTBI treatment in order to assist policymakers to design appropriate national treatment policies and treatment protocols. The PRISMA-NMA was used to review and report this research. Randomized controlled trials which compared the efficacy and safety of LTBI treatments were included. A systematic literature search was done to identify relevant articles from online databases PubMed/ MEDLINE, Embase, and Cochrane Center for Clinical Trial database (CENTRAL). The network meta-analysis was done using R- studio Version 1.4.1103. In this review, 42 studies were included, which enrolled 46,022 people who had recent contact with patients with active tuberculosis, evidence radiological of previous tuberculosis, tuberculin test equal or greater than 5 mm, radiographs that indicated inactive fibrotic or calcified parenchymal and/or lymph node lesions, had conversion to positive results on a tuberculin skin test, participants living with HIV, chronic Silicosis, immigrants, prisoners, old people, and pregnant women who were at risk for latent TB were included. The incidence of TB among people living with HIV who have taken 3RH as TPT was lower, followed by 48%,followed by 6H (41%). However, 3HP has also the potential to reduce the incidence of TB by 36% among HIV negative patients who had TB contact history. Patients' adherence to TPT was higher among patients who have taken 4R (RR 1.38 95% CI 1.0,1.89) followed by 3RH (34%). The proportion of subjects who permanently discontinued a study drug because of an adverse event were three times higher in the 3RH treatment group. Furthermore, the risk of grade 3 and 4 liver toxicity was significantly higher in 9H followed by 1HP, and 6H. From this review, it can be concluded 3RH and 6H has a significant impact on the reduction of TB incidence among PLWH and 3HP among HIV negative people who had TB contact history. However, combinations of rifampicin either with isoniazid were significantly associated with adverse events which resulted in permanent discontinuation among adult patients. Furthermore, grade 3 and 4 liver toxicity was more common in patents who have taken 9H, 1HP, and 6H. This may support the current recommended TPT regimen of 3HP, 3RH, and 6H.


Hepatoid carcinoma of the stomach.
A patient with primary gastric carcinoma exhibiting hepatoid differentiation is described. The tumor itself was not associated with a high serum alpha-fetoprotein, but the cells stained positive for alpha-fetoprotein and alpha-1 antitrypsin. The patient underwent a total gastrectomy and wedge excision of the liver metastasis. The presence of metastatic hepatoid adenocarcinoma of the stomach should be considered in a patient who, during surgery for a primary gastric carcinoma, is found to have a liver metastasis that is diagnosed by frozen-section biopsy as a hepatoma. Because of lymph node and liver metastasis, prognosis appears to be poor for such patients.


Teaching alcohol and smoking counselling in times of COVID-19 to 6th-semester medical students: experiences with a digital-only and a blended learning teaching approach using role-play and feedback.
Objectives: Digital teaching formats have seen increased use, and not just since the beginning of the pandemic. They can also be used to teach cognitive, practical and communicative learning objectives effectively. We describe the implementation of an online-only course on alcohol/smoking counselling in the COVID-19 summer semester (SS) 2020 and an inverted classroom (IC) concept in the winter semester (WS) 2020/21 at the University Hospital of Würzburg. Methodology: The interdisciplinary subject of "prevention" teaches students about high-risk alcohol consumption/smoking and how to conduct a brief verbal intervention. All 143 (SS) and 131 (WS) 6th-semester medical students completed a 90-minute course: module 1 included a Prezi® presentation on alcohol/smoking basics. Module 2 introduced a counselling concept (alcohol or smoking) online or classroom-based (WS only), depending on the participants' choice. In the online practical component, each student created a counselling video and reflections at home, and later received written feedback from lecturers/tutors. Supervised role-playing was used in the classroom-based format in the WS. There were 2 exam questions on module 1 at the end of each semester. Results: The students surveyed (11%) were satisfied with module 1. Practical exercises and feedback received praise in the evaluation of the classroom-based format (response: 97%). It was not possible for all students to perform counselling due to time constraints. A majority of participants filmed live role-playing in the online practical component. The exam questions were answered correctly by 31% (SS) and 36% (WS) respectively. Conclusions: Counselling can also be taught digitally: creating one's own videos with delayed written feedback is an innovative form of teaching. We are now aiming for a mix of both aspects as an IC with 90 minutes of classroom-based practical exercises.


Neurotensin stimulates the sperm acrosome reaction and reduces percentages of fertilization in vitro.
To determine the impact of neurotensin (NTS), a naturally occurring peptide, on the function of human and nonhuman primate sperm. Experimental study. University-based research laboratory. Consenting normozoospermic human donors and cynomolgus macaques. None. Sperm acrosome status was assessed. Computer-assisted semen analysis assessed sperm motility, progression, and velocity. Immunocytochemistry and receptor selective agonists were used to identify specific NTS receptors on sperm. Monkey oocytes were obtained after ovarian stimulation, and NTS-treated monkey sperm were used for in vitro fertilization. Neurotensin treatment of human sperm stimulated the acrosome reaction in both a dose-dependent (0.1-10 μmol/L) and time-dependent (5-30 minutes) manner. Neurotensin treatment did not alter sperm motility or progression. Both a general NTS receptor antagonist (SR142948) and a NTSR1 selective antagonist (SR48692) reduced the ability of NTS to stimulate the acrosome reaction. The neurotensin receptor NTSR1, but not NTSR2 or SORT1, was detected in monkey sperm using immunostaining. Neurotensin treatment also compromised the ability of sperm to fertilize an oocyte. Percentage of fertilization with untreated monkey sperm and monkey oocytes was 72%. Sperm pre-treated with NTS yielded a significantly lower fertilization rate of 18%. Neurotensin effectively stimulates the acrosome reaction in human and monkey sperm. Neurotensin produced by the oviduct or cumulus cells may promote natural fertilization. Pretreatment of sperm with NTS significantly reduces fertilization. Exposure of sperm to NTS prior to reaching the oviduct has the potential for contraceptive development. Identification of NTSR1 as the mediator of NTS action provides a specific target for future studies.


Guidelines for conducting bulletproof workplace investigations: part I--preparation and interviewing issues.
Conducting proper and thorough investigations is one of the most important and most difficult responsibilities for today's health care manager in terms of avoiding or successfully defending lawsuits. This article provides guidance for managers on how to use proper interview and investigative techniques while avoiding a violation of employees' rights to privacy. Suggestions are provided on how to protect confidential information obtained by the investigation. Interview questions that may be asked during the investigation are provided. By asking appropriate questions and documenting all aspects of the investigative process, employers can provide useful information to their legal counsel and be on the winning side if the situation results in litigation.


[Modified technique in transsphenoidal operations of pituitary adenomas. Technical note (author's transl)].
High pressure lumbar air insufflation and endoscopical surgical technique and control improve surgical results and widen indications for the transsphenoidal approach to pituitary adenomas. These complementary methods require a sitting position for the patient and an axial approach to the sella turcica. By lumbar high pressure insufflation even very big pituitary adenomas may often be brought into the operation field and make possible a complete extirpation by a transsphenoidal approach. This possibility is increased by an operative technique under endoscopic control, the latter contributing considerably to complete tumour extirpation, especially with endocrine-active tumours.


Impact of climate change on foodborne infections and intoxications.
Temperature, precipitation, and humidity are important factors that can influence the spread, reproduction, and survival of pathogens. Climate change affects these factors, resulting in higher air and water temperatures, increased precipitation, or water scarcity. Climate change may thus have an increasing impact on many infectious diseases. The present review considers those foodborne pathogens and toxins in animal and plant foods that are most relevant in Germany, on the basis of a selective literature review: the bacterial pathogens of the genera Salmonella, Campylobacter and Vibrio, parasites of the genera Cryptosporidium and Giardia, and marine biotoxins. As climate change continues to progress, all infections and intoxications discussed here can be expected to increase in Germany. The expected increase in foodborne infections and intoxications presents a growing public health risk in Germany.


A variant in sperm-specific glycolytic enzyme enolase 4 (ENO4) causes human male infertility.
Although defects in sperm morphology and physiology lead to male infertility, in many instances, the exact disruption of molecular pathways in a given patient is often unknown. The glycolytic pathway is an essential process to supply energy in sperm cell motility. Enolase 4 (ENO4) is crucial for the glycolytic process, which provides the energy for sperm cells in motility. ENO4 is located in the sperm principal piece and is essential for the motility and organization of the sperm flagellum. In the present study, we characterized a family with asthenozoospermia and abnormal sperm morphology as a result of a variant in the enolase 4 (ENO4) gene. Computer-assisted semen analysis, papanicolaou smear staining and scanning electron microscopy were used to examine sperm motility and morphology for semen analysis in patients. For genetic analysis, whole-exome sequencing followed by Sanger sequencing was performed. Two brothers in a consanguineous family were being clinically investigated for sperm motility and morphology issues. Genetic analysis by whole-exome sequencing revealed a homozygous variant [c.293A>G, p.(Lys98Arg)] in the ENO4 gene that segregated with infertility in the family, shared by affected but not controls. In view of the association of asthenozoospermia and abnormal sperm morphology in Eno4 knockout mice, we consider this to be the first report describing the involvement of ENO4 gene in human male infertility. We also explore the possible involvement of another variant in explaining other phenotypic features in this family.


Silicon carbide coating of nitinol stents to increase antithrombogenic properties and reduce nickel release.
The use of stents in the superficial femoral artery is still limited by the number of restenoses. Influencing factors include thrombus formation and smooth muscle cell proliferation as well as motion stress. A reduction of thrombogenicity can be achieved by passive coating with silicon carbide, which induces less thrombus formation due to its semiconducting properties. Self-expanding peripheral stents with and without silicon carbide coating were examined in a chandler loop model. Assessed parameters included thrombocyte count, beta-thromboglobulin (TG), thrombin-antithrombin (TAT) III complex, and polymorphonuclear elastase. Nickel release was quantified at Days 1, 3, and 223 using graphite furnace atomic absorption spectrometry. To visualize thrombus formation on the surface, scanning electron microscopy was conducted. The tests showed a superiority of the coated stents regarding beta-TG (484.0+/-180.2 IU/l vs 2189.1+/-898.9 IU/l) as well as formation of TAT III complex (16.0+/-19.1 microg/l vs 458.3+/-761.0 microg/l). Scanning electron microscopy revealed a nearly absent thrombus formation on the coating. Nickel release was reduced by more than 90% at all time points. In the provided in vitro setting, silicon carbide coating applied to self-expanding peripheral stents showed an advantage regarding thrombogenicity. The passive barrier resulted in a limited release of nickel from the alloy itself. These features seem promising for the use in the peripheral vasculature.


A comparison study of the utilization of National Cholesterol Education Program guidelines by cardiology and internal medicine practices: implications for the advanced practice nurse.
To determine whether patients with hypercholesterolemia were being treated according to the updated 2001 National Cholesterol Education Program (NCEP) clinical guidelines and whether a difference existed between internists and cardiologists in the implementation of these guidelines. This retrospective study used data obtained from a review of 200 patient charts that were compared with the NCEP guidelines. Results indicated that 67% of internal medicine patients and 71% of cardiology patients who qualified for pharmaceutical treatment received prescriptions for cholesterol-lowering medications. The difference between internal medicine and cardiology physicians was not statistically significant. Like physicians, nurse practitioners should become familiar with and utilize the updated guidelines as standards of practice to promote and improve patient outcomes over the life span.


Functional polymorphisms among HLA-DR4+ DR beta chains associated with limited peptide diversity.
Tryptic peptide map analysis by high-pressure liquid chromatography of DR4- associated DR beta chains revealed limited structural variation within DR beta polypeptides. Comparison of 3H-leucine-labelled tryptic peptide maps of Dw4 and Dw14 homozygous cells identified distinct peaks corresponding to Dw4 and Dw14-associated DR beta polypeptides. HPLC analysis of cell line 256, heterozygous for two DR4-related specificities, Dw4 and Dw14, displayed both peptides, corresponding to the variable Dw4 and Dw14 chromatograms. This observation was confirmed using a deletion mutant cell line derived from 256 lacking Dw4-associated class II genes. The observed peptide variation correlated precisely with predicted nucleotide-derived amino acid sequences implicating amino acids 66-71 of the DR beta chain as contributing to HLA-D structural and functional polymorphisms.


A new HLA-DRB1*11 allele, DRB1*1144, identified by cloning and sequencing.
We report here the identification of a novel DRB1*11 allele, DRB1*1144, identified during sequence-based HLA-DRB1 typing. Molecular cloning and direct sequencing confirmed that the new allele is identical to DRB1*110401 at exon 2, except for a single nucleotide substitution (GTG-->GCG) changing codon 38 from Valine to Alanine.


Behavioural interventions could reduce dental anxiety and improve dental attendance in adults.
PubMed and Psychlit were searched from 1966 to 2001. Reference lists from retrieved articles were also examined for more studies. Study authors were contacted for additional information where necessary. For inclusion, an article had to satisfy the following criteria: the study sample should be adult subjects with documented high dental fear or avoidance; outcome measures should include at least self-reported changes in dental fear; outcomes should preferably include changes in dental behaviour or attendance post-treatment. Studies were categorised into 3 behavioural interventions: behaviourally oriented approaches, cognitively oriented approaches and educational interventions. Attendance measures were grouped into <6 months, 6 months to 4 years after the intervention and longer term. The effect size (ES) for self-reported dental anxiety and for dental attendance post-treatment was calculated. Homogeneity tests were conducted. The search identified 80 articles, of which 38 met the inclusion criteria. The calculated ES for self-reported anxiety after intervention indicated positive changes in 36 out of the 38 studies and no change in two. The overall ES was 1.78 [95% confidence interval (CI), 1.67-1.89]. The proportion of subjects with post-treatment dental visits in the first 6 months varied between 50 and 100%. The overall ES for attendance at dental visits, weighted by sample size, was 1.4 (95% CI, 1.27-1.58). The homogeneity analysis indicated that the studies could not be adequately described in one ES. The reported proportion of subjects with a dental visit between 6 months and 4 years post-treatment varied from 48 to 100%. The overall weighted ES for visiting the dentist, adjusted for drop-outs in the studies, was 1.17 (95% CI, 0.99-1.35). Despite extensive heterogeneity, changes in self-reported anxiety represented a medium to large ES. Patients signing up for a behavioural intervention for dental fear can be expected to report a significant reduction in their fear, and this effect generally seems to be lasting. Mean long-term attendance (>4 years after treatment) was 77%.


Age and donor safety in living-donor liver transplant in 110 consecutive cases at 1 institute.
Since Japan began doing living-donor liver transplants, the demographics of living donors, including their age, have changed. We sought to assess the impact of aging on the feasibility and safety of doing a hepatectomy in living donors. We analyzed data from 110 consecutive liver donors who had undergone a hepatectomy at our institution. To extract the graft, 34 patients had a lateral segmentectomy, 38 had a left lobectomy, and 38 had a right lobectomy. Mean intraoperative blood loss was significantly greater in older donors (age > 40 years) than it was in younger donors (age = 40 years). In addition, the mean number of days required for the serum albumin level to return to normal after surgery was significantly longer in older donors (34.3 -/+ 11.9 days vs 17.1 -/+ 9.7 days). A multivariate analysis showed donor age to be a significant risk factor for prolonged serum albumin recovery. Donor age is a significant factor affecting postoperative liver functioning in the donor.


Dynamic pH junction technique for on-line preconcentration of peptides in capillary electrophoresis.
A method based on the presence of a dynamic pH junction within the capillary to induce band narrowing for enhanced detection sensitivity for some peptides is presented. This technique is predicated on a sharp reduction in an analyte's migration velocity following a reversal of its electrophoretic direction from the acidic sample zone to the basic BGS zone. Larger-than-usual injection volumes of samples in relatively high-conductivity matrices were enabled, without degrading peak shape, resolution and efficiency. The size of the original sample plug was reduced by as much as 38-fold, and improvement in detector response in terms of peak height by as much as 124-fold was obtained. The effects of pH and concentration of the sample matrix, and the length of sample injection on the efficiency of the technique are discussed.


Structural investigation of the interactions of biotinylruthenocene with avidin.
The crystal structure of avidin, a protein from hen egg white, was determined in the form of a complex with biotinylruthenocene. This biotin-derived organometallic ligand is a potential anticancer agent for targeted therapy based upon avidin-biotin technology. Isothermal titration calorimetry experiments, involving avidin complexes with biotin (vitamin H or B7) derivatives, show differences in their affinity to the protein in comparison to its avidin-biotin complex, the strongest known biochemical interaction in Nature. The crystal structure of the first complex of avidin with biotinylruthenocene, determined at 2.5Å resolution (PDB: 4I60), shows unique interactions of the ruthenocene moiety with avidin. Biotin derivatives exhibit weaker affinity to avidin then biotin, which allows their wider use in biotechnology. The specific properties of biotinylruthenocene and the knowledge of its interactions with avidin may be useful in biochemical, medical, and nanotechnological applications.


Distribution of calretinin during development of the olfactory system in the brown trout, Salmo trutta fario: Comparison with other immunohistochemical markers.
Immunocytochemical techniques were used to investigate the appearance and distribution of calretinin in the olfactory system of developing and adult brown trout (Salmo trutta fario L.). The earliest calretinin-immunoreactive (CR-ir) cells were detected in the olfactory placode of 5-mm embryos. In 8-mm embryos, a CR-ir olfactory nerve was observed. The number of CR-ir olfactory receptor cells increased rapidly, and in fry and adults they were characterized by light and electron microscopy as pertaining to three morphological types of receptor cell, called microvillous, ciliated and rod-like cells or crypt cells. Comparisons of the cells labeled with CR and with more general olfactory markers (acetylated tubulin and keyhole limpet haemocyanin) in alevins and fry revealed that CR-ir cells represent only a subpopulation of olfactory receptor cells. Large cells located in the primordial mitral cell layer were the first CR-ir neuronal population of the olfactory bulbs and were observed in 7-mm embryos. These cells express high HuC/D immunoreactivity and were negative for glutamic acid decarboxylase and tyrosine hydroxylase. CR immunoreactivity diminished with development and most large cells of the mitral cell layer were CR-negative in fry. In later embryos and in alevins, CR-ir granule-like cells were observed in the olfactory bulbs. Comparisons of the terminal fields of primary olfactory fibers labeled with CR and with a more general olfactory marker in the olfactory bulbs of fry and adults revealed significant differences, with most glomeruli of the dorsomedial field receiving CR-negative olfactory fibers. These results suggest new criteria for understanding the organization of the olfactory system of the trout, and hence of teleosts. Our results also suggest that CR is involved in specific functions in the olfactory system during development.


Association between adherence to a home exercise program and central sensitization, pain intensity, and functionality in individuals with knee osteoarthritis.
To analyze the association between adherence to a home exercise program and central sensitization, pain intensity, and functionality in individuals with knee osteoarthritis (KOA). A cross-sectional study was conducted involving 57 individuals with KOA. Evaluations were performed using the Exercise Adherence Rating Scale (EARS), the numerical rating scale (NRPS), the International Knee Documentation Committee (IKDC), The Central Sensitization Inventory (CSI), and the 30 sec sit and stand test (30SSST). Histograms were created to determine the normality of the data. The Kolmogorov-Smirnov test was used to determine the normality of the data. Thus, Pearson's (r) and determination (R2) correlation coefficients were calculated to determine the strength of associations between variables. No significant association was found between adherence behavior or reasons for adherence and central sensitization symptoms, the intensity of pain on rest and movement, knee disability symptoms, and functionality. No significant association was identified between adherence to a home exercise program and central sensitization, pain intensity, and functionality in individuals with KOA.


Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy.
Immune checkpoint inhibitors are being prescribed increasingly widely for a range of malignancies. They are effective at treating certain cancers, but also have significant side effects. Evidence suggests that efficacy is greatest in patients who experience one or more immune-related adverse events (irAEs). Common irAEs include skin and hepatic reactions, and a range of immune-related endocrinopathies. These include hypophysitis, thyroid disease, and autoimmune diabetes mellitus, and rarer endocrinopathies such as primary adrenal insufficiency, diabetes insipidus, parathyroid disease, autoimmune polyglandular syndrome, lipodystrophy, and ACTH-dependent Cushing's syndrome. Herein, we review the current literature related to these rarer immunotherapy-induced endocrinopathies.


4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes.
1. We recently described that several 2-(2,5-dimethoxy-4-substituted phenyl)ethylamines (PEAs), including 4-I=2C-I, 4-Br=2C-B, and 4-CH(3)=2C-D analogs, are partial agonists at 5-HT(2C) receptors, and show low or even negligible intrinsic efficacy at 5-HT(2A) receptors. These results raised the proposal that these drugs may act as 5-HT(2) antagonists. 2. To test this hypothesis, Xenopus laevis oocytes were microinjected with the rat clones for 5-HT(2A) or 5-HT(2C) receptors. The above-mentioned PEAs and its 4-H analog (2C-H) blocked the 5-HT-induced currents at 5-HT(2A), but not at the 5-HT(2C) receptor, revealing 5-HT(2) receptor subtype selectivity. The 5-HT(2A) receptor antagonism required a 2-min preincubation to attain maximum inhibition. 3. All PEAs tested shifted the 5-HT concentration-response curves to the right and downward. Their potencies varied with the nature of the C(4) substituent; the relative rank order of their 5-HT(2A) receptor antagonist potency was 2C-I>2C-B>2C-D>2C-H. 4. The present results demonstrate that in X. laevis oocytes, a series of 2,5-dimethoxy-4-substituted PEAs blocked the 5-HT(2A) but not the 5-HT(2C) receptor-mediated responses. As an alternative hypothesis, we suggest that the psychostimulant activity of the PEAs may not be exclusively associated with partial or full 5-HT(2A) receptor agonism.


Sulfonylurea binding sites associated with ATP-regulated K+ channels in the central nervous system: autoradiographic analysis of their distribution and ontogenesis, and of their localization in mutant mice cerebellum.
The localization of a putative ATP-regulated K+ channel in normal rat and neurological mutant mice was studied by light microscopic quantitative autoradiography using a tritiated glibenclamide, an antidiabetic sulfonylurea. Glibenclamide binding sites presented a heterogeneous distribution in the rat central nervous system. Their density was particularly important in substantia nigra reticulata, septohippocampal nucleus, globus pallidus, neocortex, molecular layer of cerebellum, CA3 field and dentate gyrus of hippocampus. Conversely hypothalamic areas, medulla oblongata and spinal cord contained only low amounts of glibenclamide receptors. The ontogenesis of sulfonylurea binding sites was a postnatal phenomenon and seemed to correlate with the maturation of neuronal connectivity. In the cerebellum of neurological mutant mice, the autoradiographic patterns were different to that of wild-type cerebellum. In particular, in the molecular layer of weaver cerebellum, a decrease of 82% of binding site density suggested a presynaptic position of glibenclamide receptors in parallel fibers.


Fractionation and analysis of veterinary antibiotics and their related degradation products in agricultural soils and drainage waters following swine manure amendment.
The fate of antimicrobial active compound residues in the environment, and especially antibiotics used in swine husbandry are of particular interest for their potential toxicity and contribution to antibiotic resistance. The presence of relatively high concentrations of bioactive compounds has been reported in agricultural areas but few information is available on their degradation products. Veterinary antibiotics reach terrestrial environments through many routes, including application of swine manure to soils. The objectives of this project were first, to develop an analytical method able to quantify and identify veterinary antibiotics and their degradation products in manure, soil and water samples; and second, to study the distribution of these target compounds in soils and drainage waters. A brief evaluation of their potential toxicity in the environment was also made. In order to achieve these objectives, liquid chromatography coupled to high-resolution mass spectrometry was used for its ability to quantify contaminants with sensitivity and selectivity, and its capacity to identify degradation products. Samples of manure, soil and water came from a long-term experimental site where swine manure containing veterinary antibiotics has been applied for many years. In this study, tetracycline antibiotics were found at several hundred μg L(-1) in the swine manure slurry used for fertilization, several hundred of ng L(-1) in drainage waters and several ng g(-1) in soils, while degradation products were sometimes found at concentrations higher than the parent compounds.


Nurse uniform wearing practices and associated factors among nurses working in Northwest Ethiopia: a cross-sectional institution based study.
Wearing uniforms help in the formation of professional identity in healthcare. It fosters a strong self image and professional identity which can lead to good confidence and better performance in nursing practice. However, most nurses in Ethiopia are not wearing nursing uniforms and the reasons remain unclear. Therefore, the aim of this research is to assess nurse uniform wearing practices among nurses and factors associated with such practice in hospitals in Northwest Ethiopia. A hospital based cross-sectional study was conducted from March to April, 2014 in five hospitals located in Northwest Ethiopia. A total 459 nurses participated in the study. Data was collected using a pre-tested self-administered questionnaire. Descriptive statistics were analyzed in order to characterize the study population. Bivariate and multiple logistic regression models were fitted. Odds ratios with 95 % confidence intervals were computed to identify factors associated with nursing uniform practice. Nurse uniform wearing practice was found to be 49.2 % of the total sample size. Around 35 % of the respondents that did not implement nurse uniform wearing practices stated that there was no specific uniform for nurses recommended by hospital management. In addition to this, nurse uniform wearing practices were positively associated with being female [AOR = 1.58, 95 % CI (1.02, 2.44)], studying nursing by choice [AOR =3.16, 95 % CI (2.03, 4.92)], and the appeal of nursing uniforms to nurses [AOR = 3.43 95 % CI (1.96, 5.98)]. Nurse uniform wearing practices were not exceptionally prevalent in Northwest Ethiopian hospitals. However, encouraging students to pursue interest-based careers and implementing a nurse uniform wearing policy may have the potential to improve such practices.


High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology.
KCNE1 encodes a 129-residue cardiac potassium channel (IKs) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility. Here, we demonstrate the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein coding KCNE1 variants. We comprehensively assayed KCNE1 variant cell surface expression (2,554/2,709 possible single amino acid variants) and function (2,539 variants). We identified 470 loss-of-surface expression and 588 loss-of-function variants. Out of the 588 loss-of-function variants, only 155 had low cell surface expression. The latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation were in predicted close contact with binding partners KCNQ1 or calmodulin. Our data were highly concordant with gold standard electrophysiological data (ρ = -0.65), population and patient cohorts (32/38 concordant variants), and computational metrics (ρ = -0.55). Our data provide moderate-strength evidence for the ACMG/AMP functional criteria for benign and pathogenic variants. Comprehensive variant effect maps of KCNE1 can both provide insight into IKs channel biology and help reclassify variants of uncertain significance.


Assessment of synaptic loss in mouse models of β-amyloid and tau pathology using [18F]UCB-H PET imaging.
In preclinical research, the use of [18F]Fluorodesoxyglucose (FDG) as a biomarker for neurodegeneration may induce bias due to enhanced glucose uptake by immune cells. In this study, we sought to investigate synaptic vesicle glycoprotein 2A (SV2A) PET with [18F]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer's disease (AD). A total of 29 PS2APP, 20 P301S and 12 wild-type mice aged 4.4 to 19.8 months received a dynamic [18F]UCB-H SV2A-PET scan (14.7 ± 1.5 MBq) 0-60 min post injection. Quantification of tracer uptake in cortical, cerebellar and brainstem target regions was implemented by calculating relative volumes of distribution (VT) from an image-derived-input-function (IDIF). [18F]UCB-H binding was compared across all target regions between transgenic and wild-type mice. Additional static scans were performed in a subset of mice to compare [18F]FDG and [18F]GE180 (18 kDa translocator protein tracer as a surrogate for microglial activation) standardized uptake values (SUV) with [18F]UCB-H binding at different ages. Following the final scan, a subset of mouse brains was immunohistochemically stained with synaptic markers for gold standard validation of the PET results. [18F]UCB-H binding in all target regions was significantly reduced in 8-months old P301S transgenic mice when compared to wild-type controls (temporal lobe: p = 0.014; cerebellum: p = 0.0018; brainstem: p = 0.0014). Significantly lower SV2A tracer uptake was also observed in 13-months (temporal lobe: p = 0.0080; cerebellum: p = 0.006) and 19-months old (temporal lobe: p = 0.0042; cerebellum: p = 0.011) PS2APP transgenic versus wild-type mice, whereas the brainstem revealed no significantly altered [18F]UCB-H binding. Immunohistochemical analyses of post-mortem mouse brain tissue confirmed the SV2A PET findings. Correlational analyses of [18F]UCB-H and [18F]FDG using Pearson's correlation coefficient revealed a significant negative association in the PS2APP mouse model (R = -0.26, p = 0.018). Exploratory analyses further stressed microglial activation as a potential reason for this inverse relationship, since [18F]FDG and [18F]GE180 quantification were positively correlated in this cohort (R = 0.36, p = 0.0076). [18F]UCB-H reliably depicts progressive synaptic loss in PS2APP and P301S transgenic mice, potentially qualifying as a more reliable alternative to [18F]FDG as a biomarker for assessment of neurodegeneration in preclinical research.


Mononuclear cell factors that inhibit fibroblast collagen synthesis. I. In vitro conditions determining their production and expression.
Peripheral blood mononuclear cells (PBMC) incubated either with phytohaemagglutinin-P (PHA) under serum-free conditions or with tuberculin purified protein derivative in the presence of 5% human blood group AB serum released into the culture medium factors that decreased collagen synthesis by dermal fibroblasts. These factors were first detected after incubation of PBMC with PHA for 24 h and were produced by non-adherent cells. The decrease in collagen synthesis was observed despite changes in conditions of fibroblast culture, the addition of a cross-linking inhibitor, and the use of different fibroblast cell lines.


The effect of observed biological and non biological movements on action imitation: an fMRI study.
Past research has indicated that when individuals observe biological movements many areas in the observer's motor system become active. Nonetheless, recent behavioral evidence showed that observed movements can interfere with execution of incompatible movements, especially the biological ones. However, the hypothesis that the interference originates within a common neural network, encoding both movement observation and execution, and responding preferentially to biological movements, still awaits confirmation. To test this hypothesis, in the present fMRI study we compared patterns of activation obtained when participants executed finger-movements after having observed either a biological or a non biological model performing compatible (imitative) or incompatible (non imitative) movements. Moreover, we tested the possibility that imitative responses are influenced by the emotional facial expression (sad, neutral, angry) presented before the observed movement. Behaviorally, participants showed a marginally larger compatibility effect (compatible movements faster than incompatible movements) in the biological condition than in the non biological condition. In the imaging data, the interaction testing for areas more active when the observed model was biological (compared with non biological) and performed compatible movements (compared with incompatible movements), activated a network including the motor, premotor and parietal cortices. Notably, the interaction was significant for the neutral and sad facial expressions only. We showed that observing biological movements modulates the activation of motor-related regions, by facilitating the execution of compatible movements and/or interfering with the execution of incompatible movements.


Consent for rapid genomic sequencing for critically ill children: legal and ethical issues.
Although rapid genomic sequencing (RGS) is improving care for critically ill children with rare disease, it also raises important ethical questions that need to be explored as its use becomes more widespread. Two such questions relate to the degree of consent that should be required for RGS to proceed and whether it might ever be appropriate to override parents' decisions not to allow RGS to be performed in their critically ill child. To explore these questions, we first examine the legal frameworks on securing consent for genomic sequencing and how they apply to the specific context of RGS for critically ill children. We then use a tool from clinical ethics, the Zone of Parental Discretion, to explore two case studies and identify under which circumstances it might be appropriate for parental refusal of RGS to be overridden. We argue that RGS may be a context where, in addition to assessing the complexity of the test offered, it is ethically appropriate to consider an effect on patient outcomes when deciding the degree of consent required. We also suggest that there are some contexts where it may be ethically justified to perform RGS, even when it is actively against the wishes of the parents. More work is needed to examine exactly how 'time-sensitive' exceptions to current guidance on consent for genomic sequencing could be formulated and operationalised for RGS for critically ill-children.


Influence of electrically and aconitine induced arrhythmias on the prostaglandin efflux in coronary sinus blood in dogs.
Tachyarrhythmias and extrasystoles produced an increase of PGE and PGF2alpha in canine coronary sinus blood (CSB). After application of aconitine the PG efflux was nearly unchanged before arrhythmia occurred. However, the PG efflux increased after arrhythmia had occurred.


Acute myocardial infarction in pregnancy following unlicensed use of methylenedioxymethamphetamine ('Ecstasy').
Acute myocardial infarction is rare in pregnancy; however, the emerging trend towards advanced maternal age and the rising prevalence of obesity and diabetes suggest that more cases of myocardial infarction are likely to be encountered in pregnancy. However, there is scanty evidence on the risk of myocardial infarction with regard to socially misused substances in pregnancy. We describe the management of a case of acute myocardial infarction following unlicensed use of 3,4-methylenedioxymethamphetamine ('Ecstasy') in pregnancy. The case highlights a rare but serious risk associated with substance misuse in pregnancy.


Metabolomics analysis of oral mucosa reveals profile perturbation in reticular oral lichen planus.
Oral lichen planus (OLP) is a chronic inflammatory mucosal disorder and potentially oral premalignant lesion affecting the stratified squamous epithelia. In OLP, reticular type is the most common clinical form of the disease. However, little is known about it. Metabolomics analysis may help to investigate the disease pathogenesis and to improve clinical treatment. Liquid chromatography (LC)-mass spectrometry (MS) system, XCMS software, SIMCA software, and OSI / SMMS software were integrated to identify differentially expressed metabolites for the pathways and pathology analysis. Totally, 21 modulated metabolites were identified, whose dysregulations affected 30 metabolic pathways. Through an impact-value screen (impact-value>0.1), 8 pathways were selected as the significantly dysregulated pathways. Pathological network showed that these metabolites participated in 5 pathological processes, that is, inflammatory lesion, DNA damage and repair disorder, apoptosis process, oxidative stress injury, and abnormal energy expenditure. The study revealed the metabolic perturbation of oral mucosa in reticular OLP, which may provide an important reference for the understanding of the pathogenesis of the disease and the discovery of therapeutic targets.


Kupffer cells and liver metastasis. Optimization and limitation of activation of tumoricidal activity.
Kupffer cells, tissue-fixed macrophages located in the sinusoids of the liver, represent the highest concentration of mononuclear phagocytes in the body. Their ability to act as scavengers of particulate material in the blood has given rise to speculation that they play a role in controlling hepatic metastases derived from blood-borne tumor cells. Circumstantial evidence for such a role has been obtained from animal studies where Kupffer cell function has been compromised or inhibited, and from anecdotal clinical observations. Current evidence suggests that Kupffer cells are capable of nonspecifically eliminating some circulating tumor cells from the circulation via phagocytosis. This surveillance mechanism would appear to be limited in capacity, and subject to a number of external factors. Recent studies have demonstrated that Kupffer cells can be activated to a tumoricidal state via the administration of biological response modifiers such as gamma interferon or muramyl peptides. The localization of liposomes within Kupffer cells after systemic administration has provided a considerable stimulus for the efficient targeting of macrophage-activating compounds to these cells. Such therapeutic intervention, while capable of inducing Kupffer cell tumoricidal activity in situ and inhibiting tumor growth, is limited with respect to the location of the tumor cells (sinusoidal versus parenchymal) and to the size of the metastatic nodule. Therapeutic intervention using liposomes containing macrophage-activating agents may only be of benefit in patients with minimal tumor load who are at risk for hepatic metastases, rather than those patients who already have clinically detectable liver tumors.


Unique enzymes of purified microsomes from pig fundic mucosa. K+-stimulated adenosine triphosphatase and K+-stimulated pNPPase.
Microsomal fractions from homogenates of pig gastric fundic mucosa showed high levels of K+-stimulated adenosine triphosphatase (ATPase) and K+-stimulated phosphatase. Similar preparations from antral mucosa showed virtually no such activity. Because of mitochondrial contamination the fundic microsomes were further separated by sucrose density gradient centrifugation. A low density band of membranes (peak 1.12 to 1.13 g per ml) possessed all of the K+-stimulated enzyme activities. Morphological features and the abundant glycoproteins of the low density microsomes suggested they might be derived from the tubulovesicles of oxyntic cells. Mitochondrial and ribosomal markers were associated with membranes with much higher densities (greater than 1.22). The K+-stimulated ATPase has a pH optimum of 7.5 and required Mg++, but neither Na+ nor ouabain had any appreciable effect on the activity. Stimulation of basal ATPase by K+ ranged from 1.5 to 3.0-fold with an apparent Ka for activation between 0.2 to 0.4 mM K+. Addition of various K+ ionophoretic substances (e.g., gramicidin) produced further stimulation of K+-ATPase up to 6 times the basal rate. The mean activities for seven separate preparations of purified low density pig fundic microsomes were as follows (micromoles of ATP hydrolyzed per mg protein per hr +/- SEM); basal ATPase, 15.8 +/- 2.8; plus 10 mM K+, 29.3 +/- 4.5; plus 10 mM K+ and 10(-5) M gramicidin, 45.2 +/- 5.2. Neither the basal ATPase nor the K+-stimulated rates were altered by HCO3- or Cl-. The occurrence of these active and unique enzyme activities in the oxyntic region of gastric mucosa suggest some relation with secretory activity. Possible functional roles are discussed.


Neural Dysfunction in Cognitive Control Circuits in Persons at Clinical High-Risk for Psychosis.
Cognitive control, a set of functions that develop throughout adolescence, is important in the pathogenesis of psychotic disorders. Whether cognitive control has a role in conferring vulnerability for the development of psychotic illness is still unknown. The aim of this study was to investigate the neural systems supporting cognitive control in individuals deemed to be potentially prodromal for psychotic illness. We recruited 56 participants at clinical high-risk (CHR) for psychosis based on the Structured Interview for Psychosis-Risk Syndromes (SIPS) and 49 healthy controls. Twelve of the CHR participants eventually developed psychosis. We compared functional magnetic resonance imaging (fMRI) BOLD signal during the performance of the Simon task. We tested for differences between CHR individuals and controls in conflict-related functional activity. In the CHR group when compared with controls, we detected smaller conflict-related activations in several cortical areas, including the Dorsolateral Prefrontal Cortex (DLPFC). Furthermore, conflict-related activations in the DLPFC of those CHR individuals who ultimately developed psychosis (CHR converters) were smaller than in non-converters (CHR non-converters). Higher levels of conflict-related activation were associated with better social and role outcome. Risk for psychosis was associated at the neural level with reduced conflict-related brain activity. This neural phenotype appears correlated within the DLPFC with the development of psychosis and with functional outcome.


Cancer cell-secreted proteomes as a basis for searching potential tumor markers: nasopharyngeal carcinoma as a model.
Nasopharyngeal carcinoma (NPC) is commonly diagnosed late due to its deep location and vague symptoms. To identify biomarkers for early NPC diagnosis, secreted proteomes of two NPC cell lines were analyzed. Proteins in the NPC cell-line cultured media were systematically identified by SDS-PAGE combined with MALDI-TOF MS. Twenty-three proteins were found in cultured media from both NPC cell lines. Among them, fibronectin, Mac-2 binding protein (Mac-2 BP), and plasminogen activator inhibitor 1 (PAI-1) were further confirmed by Western blot analysis. These three proteins were highly expressed in NPC biopsies, but weakly or not expressed in normal nasopharyngeal tissues. The serum levels of the three proteins were significantly higher in NPC patients (n = 46) than in normal controls (n = 47) (p < 0.01). NPC nude mice model (n = 9) also showed elevated levels of serum Mac-2 BP and PAI-1 compared with tumor-free mice (n = 9) (p < 0.01). Systematic analysis of cancer cell-secreted proteomes combined with animal tumor models can be a feasible, convenient strategy for searching multiple potential tumor markers. Furthermore, our work shows that fibronectin, Mac-2 BP, and PAI-1 may be potential markers for diagnosis of NPC.


Cognitive, creative, functional, and clinical symptom improvements in schizophrenia after an integrative cognitive remediation program: a randomized controlled trial.
This study analyzed the effectiveness of an integrative cognitive remediation program (REHACOP) in improving neurocognition, social cognition, creativity, functional outcome, and clinical symptoms in patients with schizophrenia. In addition, possible mediators predicting improvement in functional outcomes were explored. The program combined cognitive remediation with social cognitive training and social and functional skill training over 20 weeks. The sample included 94 patients, 47 in the REHACOP group and 47 in the active control group (occupational activities). Significant differences were found between the two groups in change scores of processing speed, working memory, verbal memory (VM), inhibition, theory of mind, emotion processing (EP), figural creative strengths, functional competence, disorganization, excitement, and primary negative symptoms. A mediational analysis revealed that changes in VM, inhibition, and EP partially explained the effect of cognitive remediation on functional competence improvement. This study provides initial evidence of the effect of integrative cognitive remediation on primary negative symptoms and creativity.


Influence of disclusion time reduction on changes in posterior implant prosthesis occlusion and its association with crestal bone loss: A clinical study.
A prolonged period of high magnitude occlusal contact can be associated with rapid changes of the occlusal surfaces and, in turn, may lead to overloading of an implant-supported prosthesis. Crestal bone loss may be one of the repercussions of overloading, but the influence of disclusion time (DT) reduction (DTR) is unclear. The purpose of this clinical study was to evaluate the role of DTR in preventing the occlusal changes and crestal bone loss at progressive time intervals of 1 week, 3 months, and 6 months in posterior implant-supported prostheses. Twelve participants with posterior implant-supported prostheses and opposing natural teeth were enrolled in the study. Occlusion time (OT) and DT were evaluated with the T-scan Novus (version 9.1). By performing immediate complete anterior guidance development (ICAGD) coronoplasty, prolonged contacts were selectively ground to achieve OT ≤0.2 seconds and DT ≤0.4 seconds in maximum intercuspal position and laterotrusion after cementation and during follow-up visits after 1 week, 3 months, and 6 months. Crestal bone levels were evaluated after cementation and at the 6-month follow-up. Repeated measures ANOVA and Bonferroni post hoc analysis were done for OT and DT. Student paired t test was done for crestal bone level evaluation (α=.05 for all tests). A significant decrease in OT from 0.59 ±0.24 seconds to 0.21 ±0.06 seconds (P<.001) and in DT from 1.51 ±0.6 seconds to 0.37 ±0.06 seconds (P<.001) were detected in posterior implant-supported occlusion immediately after attaining ICAGD and at the 6-month follow-up period. The mean crestal bone levels at the mesial and distal sides of the implant from day 1 (0.4 ±0.13 mm, 0.36 ±0.20 mm) to 6 months (0.40 ±0.13 mm, 0.37 ±0.19 mm) showed no significant changes (P>.05). Minimal occlusal changes in implant prosthesis and negligible crestal bone loss were observed up to 6 months by achieving DTR according to the ICAGD protocol.


Intestinal adenomagenesis involves core molecular signatures of the epithelial-mesenchymal transition.
The epithelial-mesenchymal transition (EMT) occurs commonly during carcinoma invasion and metastasis, but not during early tumorigenesis. Microarray data demonstrated elevation of vimentin, a mesenchymal marker, in intestinal adenomas from Apc Min/+ (Min) mice. We have tested the involvement of EMT in early tumorigenesis in mammalian intestines by following EMT-associated markers. Elevated vimentin RNA expression and protein production were detected within neoplastic cells in murine intestinal adenomas. Similarly, vimentin protein was detected in both adenomas and invasive adenocarcinomas of the human colon, but not in the normal colonic epithelium or in hyperplastic polyps. Expression of E-cadherin varied inversely with vimentin. In addition, the expression of fibronectin was elevated while that of E-cadherin decreased. Canonical E-cadherin suppressors, such as Snail, were not elevated in the same tumor. Elevated vimentin expression in the adenoma was not correlated with persistent Ras signaling, but was strongly correlated with reduced proliferation indices, active Wnt signaling, and TGF-beta signaling, as demonstrated by its dependence on Smad3. We designate our observations of expression of only some of the canonical features of EMT as "truncated EMT". These unexpected observations are interpreted as reflecting the involvement of a core of the EMT system during the tissue remodeling of early tumorigenesis.


Single-cell RNA-seq analysis to identify potential biomarkers for diagnosis, and prognosis of non-small cell lung cancer by using comprehensive bioinformatics approaches.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths worldwide. Identification of gene biomarkers and their regulatory factors and signaling pathways is very essential to reveal the molecular mechanisms of NSCLC initiation and progression. Thus, the goal of this study is to identify gene biomarkers for NSCLC diagnosis and prognosis by using scRNA-seq data through bioinformatics techniques. scRNA-seq data were obtained from the GEO database to identify DEGs. A total of 158 DEGs (including 48 upregulated and 110 downregulated) were detected after gene integration. Gene Ontology enrichment and KEGG pathway analysis of DEGs were performed by FunRich software. A PPI network of DEGs was then constructed using the STRING database and visualized by Cytoscape software. We identified 12 key genes (KGs) including MS4A1, CCL5, and GZMB, by using two topological methods based on the PPI networking results. The diagnostic, expression, and prognostic potentials of the identified 12 key genes were assessed using the receiver operating characteristics (ROC) curve and a web-based tool, SurvExpress. From the regulatory network analysis, we extracted the 7 key transcription factors (TFs) (FOXC1, YY1, CEBPB, TFAP2A, SREBF2, RELA, and GATA2), and 8 key miRNAs (hsa-miR-124-3p, hsa-miR-34a-5p, hsa-miR-21-5p, hsa-miR-155-5p, hsa-miR-449a, hsa-miR-24-3p, hsa-let-7b-5p, and hsa-miR-7-5p) associated with the KGs were evaluated. Functional enrichment and pathway analysis, survival analysis, ROC analysis, and regulatory network analysis highlighted crucial roles of the key genes. Our findings might play a significant role as candidate biomarkers in NSCLC diagnosis and prognosis.


Histochemistry of proteases in ependyma, choroid plexus and leptomeninges.
Aminopeptidase M (APM), aminopeptidase A (APA), dipeptidyl peptidase IV (DPP IV) and gamma-glutamyl transferase (GGT) were demonstrated histochemically in cryostat sections of the rat brain to show the reaction pattern of ependyma, choroid plexus and leptomeninges. GGT was only demonstrable in the cell membranes of ependymal cells and in the leptomeninges; however, APA, APM and DAP IV showed a variable degree of activity in the capillary endothelium of the choroid plexus as well as in the leptomeninges. On the basis of these results, it is postulated that peptides in the cerebrospinal fluid can be cleaved extraventricularly by the enzymes demonstrated in the leptomeninges.


Combined effects of salinity and polystyrene microplastics exposure on the Pacific oysters Crassostrea gigas: Oxidative stress and energy metabolism.
Microplastics (MPs) pollution and salinity variation are two environmental stressors, but their combined effects on marine mollusks are rarely known. Oysters (Crassostrea gigas) were exposed to 1 × 104 particles L-1 spherical polystyrene MPs (PS-MPs) of different sizes (small polystyrene MPs (SPS-MPs): 6 μm, large polystyrene MPs (LPS-MPs): 50-60 μm) under three salinity levels (21, 26, and 31 psu) for 14 days. Results demonstrated that low salinity reduced PS-MPs uptake in oysters. Antagonistic interactions between PS-MPs and low salinity mainly occurred, and partial synergistic effects were mainly induced by SPS-MPs. SPS-MPs induced higher lipid peroxidation (LPO) levels than LPS-MPs. In digestive glands, low salinity decreased LPO levels and glycometabolism-related gene expression, which was related to salinity levels. Low salinity instead of MPs mainly affected metabolomics profiles of gills through energy metabolism and osmotic adjustment pathway. In conclusion, oysters can adapt to combined stressors through energy and antioxidative regulation.


Concurrent Improvement Observed in Patient-Reported Burden and Sensor-Collected Medication Use Among Patients Enrolled in a COPD Digital Health Program.
Background: The COPD assessment test (CAT) is an 8-item questionnaire widely used in clinical practice to assess patient burden of disease. Digital health platforms that leverage electronic medication monitors (EMMs) are used to track the time and date of maintenance and short-acting beta-agonist (SABA) inhaler medication use and record patient-reported outcomes. The study examined changes in CAT and SABA inhaler use in COPD to determine whether passively collected SABA and CAT scores changed in a parallel manner. Methods: Patients with self-reported COPD enrolled in a digital health program, which provided EMMs to track SABA and maintenance inhaler use, and a companion smartphone application ("app") to provide medication feedback and reminders. Patients completing the CAT questionnaire in the app at enrollment and at 6 months were included in the analysis. Changes in CAT burden category [by the minimally important difference (MID)] and changes in EMM-recorded mean SABA inhaler use per day were quantified at baseline and 6 months. Results: The analysis included 611 patients. At 6 months, mean CAT improved by -0.9 (95% CI: -1.4, -0.4; p < 0.001) points, and mean SABA use decreased by -0.6 (-0.8, -0.4; p < 0.001) puffs/day. Among patients with higher burden (CAT ≥ 21) at enrollment, CAT improved by -2.0 (-2.6, -1.4; p < 0.001) points, and SABA use decreased by -0.8 (-1.1, -0.6; p < 0.001) puffs/day. Conclusion: Significant and parallel improvement in CAT scores and SABA use at 6 months were noted among patients enrolled in a digital health program, with greater improvement for patients with higher disease burden.


Lack of impact of salt restriction advice on hypertensive patients.
The response of known hypertensives to advice on sodium restriction was examined as part of a 5-year study on hypertension screening in family practice. The study comprised 34 family practices, pair-matched for location, activity level, and length of time in present practice. One practice in each matched pair was randomly allocated to an experimental or a control group. All hypertensive patients in each experimental practice were exposed to a management program which included dietary counseling to restrict sodium intake. A sample of hypertensive patients (N = 1,001) in both control and experimental groups was interviewed 3.5 years into the study. Although more subjects in experimental practices reported not adding salt (22.9%) compared with those in control practices (17.3%), the results of multivariate analysis showed that type of practice (experimental or control) was not significantly associated with salt use. Salt avoidance was strongly related to lower levels of education and to sex (men were less likely to use salt). Subjects who did not use salt also tended to avoid high-sodium foods. The response to nutritional advice was less favorable than expected. Difficulties in compliance with dietary recommendations are discussed.


Can noncontact mapping distinguish between endo- and epicardial foci?
Noncontact mapping has been demonstrated to facilitate RF ablation of ventricular arrhythmias, but the reproducibility in the localization of endocardial exit sites during focal ventricular tachycardia ("VT") originating from defined myocardial layers has not been systematically studied. Furthermore, it remains unclear whether noncontact mapping can distinguish between endo- and epicardial foci. In six dogs, constant pacing was applied through octopolar needle electrodes in the left ventricle to mimic VT of subendocardial, midmyocardial (mid1; mid2) or subepicardial origin. Using noncontact mapping, the site of origin was determined for each of 50 consecutive beats of all "VTs" and the variation between respective exit sites was measured. Exit sites were reconstructed for 50 consecutive beats of each "VT" and the time span between site of origin and exit site was measured as a parameter of intramural conduction. While subendocardial and midmyocardial (mid1, mid2) foci were pinpointed with a variation of <or=2 mm, a variation of 4 mm was encountered for subepicardial foci. A gradual increase in intramural conduction was evident from endocardial towards epicardial foci, with significant differences between subendocardial (4.8 +/- 0.9 ms), midmyocardial (mid1 = 11.1 +/- 4.6 ms; mid2 = 11.8 +/- 3.5 ms) and subepicardial (16.8 +/- 3.6 ms) foci (P < 0.005). Systematic differences in the morphology of virtual waveforms depending on the site of origin could not be detected. Except for subepicardial foci, noncontact mapping localized focal activity in the LV with high reproducibility. In contrast to morphological parameters, the determination of intramural conduction provides a fair estimate of the depth of foci and is proposed as a novel parameter to identify a subepicardial origin.


The Geriatric Depression Scale should be shortened: results of Rasch analysis.
The purpose of this study was to examine the unidimensionality, item fit, redundancy and differential item functioning (DIF) of the 15-item version of the Geriatric Depression Scale (GDS) in a community sample of 300 Hong Kong Chinese patients with pneumoconiosis. Participants were randomly selected from the case register of the Pneumoconiosis Compensation Fund Board of Hong Kong. A trained research assistant administered the GDS to all participants. A psychiatrist, who was blind to the GDS scores, conducted a structured clinical interview to diagnose depressive disorders according to the Diagnostic and Statistical Manual for Mental Disorders, Version IV (DSM-IV) criteria. Of the 300 participants, 37 (12.3%) had a DSM-IV diagnosis of depressive disorders. Eleven out of 15 items (73.3%) had INFIT/OUTFIT statistics between 0.7-1.3. Abbreviated versions were created by removal of misfit and redundant items resulting in similar overall performance as the original 15-item GDS. None of the items had significant DIF for age, level of education and cognitive impairment. Although the GDS was overall unidimensional, there was evidence of item redundancy indicating that a shortened version would be as adequate as the original version.


Influence of exogenous selenomethionine and selenocystine on uptake and accumulation of Se in winter wheat (Triticum aestivum L. cv. Xinong 979).
Soil selenium (Se) is mainly inorganic including selenate and selenite but organic forms such as selenomethionine (SeMet) and selenocystine (SeCys2) are commonly present. Although organic Se is bioavailable or potentially bioavailable to plants, whether the effects of the organic Se on uptake and accumulation of Se in winter wheat differ in forms is still not clear. Both hydroponic experiments and a pot trial of whole plant growth stage were conducted to investigate the effects of SeMet and L-selenocystine (SeCys2) on uptake and accumulation of Se in winter wheat (Triticum aestivum L. cv. Xinong 979). Not only metabolic inhibitor (carbonyl cyanide m-chlorophenylhydrazone (CCCP)) inhibited SeMet (44%) influx into wheat roots but also aquaporin inhibitor (AgNO3) or putative inhibitor (H2SiO4 and H3BO3) suppressed 83%, 62%, or 64% SeMet influx into the roots. However, these inhibitors had insignificant effects on SeCys2 influx into the roots. Wheat grain possessed more effective Se accumulation under SeCys2 treatments than under SeMet treatments, which was contributed to more efficiently translocation of Se from husk to grain, more remobilization of tissue Se to grain, and significantly higher concentration of soluble Se (SOL-Se) and exchangeable and carbonate-bound Se (EXC-Se) in the rhizosphere of winter wheat. The present study indicated that the effects of organic Se on uptake and accumulation of Se in winter wheat differed in forms and that SeCys2 exhibited the potential to increase grain Se concentration in winter wheat. The results from the present study will replenish information about the effects and related mechanisms of SeMet or SeCys2 on uptake and accumulation of Se in winter wheat and provide insights of effects of organic Se on wheat grain Se accumulation.


Attenuated strains of tobacco mosaic virus. Reduced synthesis of a viral protein with a cell-to-cell movement function.
Attenuated strains of tobacco mosaic virus (TMV) have been used to protect crops against virulent strains. The synthesis of viral proteins and RNAs was investigated in protoplasts that had been infected separately with three tomato strains of TMV, virulent type L, and attenuated strains L11 and L11A. It was revealed that the mutations, which are responsible for the viral attenuation and have been mapped in the p126 (p184) gene, caused a reduction of the synthesis of the viral-coded p30 protein with a cell-to-cell movement function and its mRNA, but it had no significant effect on the synthesis of other viral proteins and RNAs in virus-infected protoplasts. Thus, it was shown that the attenuated strains can multiply as efficiently as the virulent strain in initially inoculated cells, but they can not spread efficiently outside the infected cells. In addition, it is suggested that a non-structural protein, p126 or p184, of TMV is involved in the synthesis of viral subgenomic p30 mRNA.


Secondary intraocular lens implantation.
The visual, refractive, and surgical results with 190 consecutive secondary implantations of an anterior chamber intraocular lens were studied. Best-corrected postoperative visual acuity was either better than or within 1 Snellen line of best-corrected preoperative vision in 87% of the cases. Vision worsened by more than two Snellen lines in ten cases (5%), which included three cases of retinal detachment and one case of ischemic optic neuropathy; however, in only one case (0.5%) did we feel that the visual decrease was directly attributable to the secondary implantation procedure. We believe that secondary intraocular lens implantation can improve functional visual acuity in aphakic patients, especially those unable to tolerate aphakic correction with contact lenses or spectacles.


Insomnia and depressive behavior of MyD88-deficient mice: Relationships with altered microglial functions.
Myeloid differentiation primary response gene 88 (MyD88) is essential for microglial activation. Despite the significant role of microglia in regulating sleep homeostasis, the contribution of MyD88 to sleep is yet to be determined. To address this, we performed electroencephalographic and electromyographic recordings on MyD88-KO mice and wild-type mice to investigate their sleep/wake cycles. In the daytime, MyD88-KO mice exhibited prolonged wakefulness and shorter non-rapid eye movement sleep duration. Tail suspension and sucrose preference tests revealed that MyD88-KO mice displayed a depressive-like phenotype. We determined monoamines in the prefrontal cortex (PFC) using high-performance liquid chromatography and observed a decreased content of serotonin in the PFC of MyD88-KO mice. Flow cytometry revealed that CD11b, CD45, and F4/80 expressions were elevated at Zeitgeber time (ZT) 1 compared to at ZT13 only in wild-type mice. Furthermore, MFG-E8 and C1qB-tagged synapses were enhanced at ZT1 in the PFC of wild-type mice but not in MyD88-KO mice. Primary cultured microglia from MyD88-KO mice revealed decreased phagocytic ability. These findings indicate that genetic deletion of MyD88 induces insomnia and depressive behavior, at least in part, by affecting microglial homeostasis functions and lowering the serotonergic neuronal output.


Biochemical modulation therapy for pancreatic cancer.
It is well known that the clinical course in most patients with advanced pancreatic cancer is not influenced substantially by chemotherapy and/or radiotherapy. However, new chemotherapy, based on the synergistic antitumor activities of 5-fluorouracil (5-FU) and cisplatin (CDDP) producing biochemical modulation in solid cancers diagnosed as adenocarcinoma, has recently been reported to be effective. In gastrointestinal cancers, the optimal concentrations of each drug and the duration of the anticancer effects, as well as adverse effects have been confirmed in pharmacodynamic studies. Our experience of this treatment for advanced pancreatic cancer (stage IV) indicates the usefulness of the antitumor effect in terms of both effect on the tumor size in unresectable patients and prognosis in resectable patients. These results were remarkable in patients diagnosed as stage IV b and/or curability C. Although there were adverse effects, none were severe. However, anything compromising the patient's quality of life must be prevented. Randomized prospective studies of the combination of 5-FU and CDDP are expected in the near future.


Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe.
The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4-12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.