Effects of time-of-day on oxidative stress, cardiovascular parameters, biochemical markers, and hormonal response following level-1 Yo-Yo intermittent recovery test.
The aim of this study was to investigate the effect of time-of-day on oxidative stress, cardiovascular parameters, muscle damage parameters, and hormonal responses following the level-1 Yo-Yo intermittent recovery test (YYIRT). A total of 11 healthy subjects performed an intermittent test (YYIRT) at two times-of-day (i.e., 07:00 h and 17:00 h), with a recovery period of ≥36 h in-between, in a randomized order. Blood samples were taken at the rest (baseline) and immediately (post-YYIRT) after the YYIRT for measuring oxidative stress, biochemical markers, and hormonal response. Data were statistically analyzed using one-way and two-way repeated measures ANOVA and Bonferroni test at p < 0.05. Observed power (α = 0.05) and partial eta-squared were used. Our results showed that oxygen uptake (VO2max), maximal aerobic speed, and the total distance covered tended to be higher in the evening (17:00 h). There was also a main effect of time-of-day for cortisol and testosterone concentration, which were higher after the YYIRT in the morning (p < 0.05). The heart rate peak and the rating of perceived exertion scales were lower in the morning (p < 0.05). However, the plasma glucose (p < 0.01), malondialdehyde, creatine kinase (p < 0.01), lactate dehydrogenase (p < 0.05), high-density lipoprotein (p < 0.01), total cholesterol (p < 0.01), and triglycerides (p < 0.05) were higher after the YYIRT in the evening. Low-density lipoprotein, systolic blood pressure, diastolic blood pressure, and lactate levels (p > 0.05) were similar for the morning and evening test. In conclusion, our findings suggest that aerobic performance presents diurnal variation with great result observed in the evening accompanied by an improvement of hormonal, metabolic, and oxidative responses. These data may help to guide athletes and coaches and contribute to public health recommendations on exercise and muscle damage particularly in the competitive periods.


Effect of pertussis toxin and neomycin on G-protein-regulated polyphosphoinositide phosphodiesterase. A comparison between HL60 membranes and permeabilized HL60 cells.
The promyelocytic HL60 cell can be differentiated with dimethyl sulphoxide or dibutyryl cyclic AMP leading to the appearance of fMetLeuPhe receptors on the cell surface. G-protein-stimulated polyphosphoinositide phosphodiesterase (PPI-pde) activity was assessed in membranes prepared from both differentiated and non-differentiated HL60 cells. Both the extent of the response and the rank order of potency of the GTP analogues to stimulate PPI-pde activation (guanosine 5'-[gamma-thio]triphosphate (GTP[S]) greater than guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) greater than guanosine 5'-[beta gamma-methylene]triphosphate (p[CH2]ppG) remains unchanged after differentiation with dimethyl sulphoxide. In comparison, differentiation by dibutyryl cyclic AMP leads to diminution of PPI-pde activity when stimulated by GTP[S] or fluoride, but not by millimolar concentrations of Ca2+. GTP[S]-stimulated PPI-pde in membranes is sensitive to the presence of Ca2+ (pCa 8-5). Pertussis-toxin pretreatment of intact HL60 cells leads to inhibition of both the secretory response and the formation of inositol phosphates when stimulated by fMetLeuPhe. In contrast, pertussis-toxin pretreatment has no effect on either GTP[S]- or fluoride-stimulated PPI-pde. Neomycin in a concentration-dependent manner inhibits both GTP[S] plus Ca2+ (pCa 5)-stimulated secretion and PPI-pde activation in streptolysin-O-permeabilized cells. The extent of PPI-pde activation in membranes compared with streptolysin-O-permeabilized cells reveals that the membrane preparation does not possess all the components that make up the inositide signalling system.


Hemolysis as a rare but potentially life-threatening complication of hemodialysis: a case report.
The burden of end-stage renal disease (ESRD) in the United States has increased dramatically over the past 30 years with almost 613,000 patients receiving renal replacement therapy in 2011. That same year, more than 112,000 new patients initiated dialysis with 92% of them receiving hemodialysis (HD). These patients experience significant morbidity and mortality with very frequent emergency room visits. Acute hemolysis associated with HD is a rare complication; however, if it's not recognized early and managed adequately, it can be associated with life-threatening complications such as hyperkalemia and even myocardial infarction. 66-year-old African-American female with a history of ESRD secondary to hypertension developed a blood infiltration on the arterial side of her arteriovenous fistula followed by sudden onset of diffuse abdominal pain with nausea and vomiting during her regular HD treatment. She was referred to the emergency department where she was found to have shortness of breath with improved gastrointestinal symptoms. Her initial work-up revealed a severe anemia with a hematocrit of 10%. Further work-up revealed massive hemolysis, likely mechanical in nature and believed to be induced by malpositioning of her HD needle in the fistula. Her hospital course was complicated by rhabdomyolysis and acute myocardial infarction thought to be secondary to supply-demand ischemia in the setting of her profound anemia. Within a week, she eventually had a full recovery. It is extremely important for physicians and particularly emergency department physicians to be aware of this potentially life-threatening complication of HD and have a high index of suspicion in the setting of acute anemia with hemolysis in this population.


Phenotypic plasticity, the Baldwin effect, and the speeding up of evolution: the computational roots of an illusion.
An increasing number of dissident voices claim that the standard neo-Darwinian view of genes as 'leaders' and phenotypes as 'followers' during the process of adaptive evolution should be turned on its head. This idea is older than the rediscovery of Mendel's laws of inheritance, with the turn-of-the-twentieth-century notion eventually labeled as the 'Baldwin effect' as one of the many ways in which the standard neo-Darwinian view can be turned around. A condition for this effect is that environmentally induced variation such as phenotypic plasticity or learning is crucial for the initial establishment of a trait. This gives the additional time for natural selection to act on genetic variation and the adaptive trait can be eventually encoded in the genotype. An influential paper published in the late 1980s claimed the Baldwin effect to happen in computer simulations, and avowed that it was crucial to solve a difficult adaptive task. This generated much excitement among scholars in various disciplines that regard neo-Darwinian accounts to explain the evolutionary emergence of high-order phenotypic traits such as consciousness or language almost hopeless. Here, we use analytical and computational approaches to show that a standard population genetics treatment can easily crack what the scientific community has granted as an unsolvable adaptive problem without learning. Evolutionary psychologists and linguists have invoked the (claimed) Baldwin effect to make wild assertions that should not be taken seriously. What the Baldwin effect needs are plausible case-histories.


[Comorbidity of substance use and other psychiatric disorders--theoretical foundation and evidence based therapy].
The coincidence of two or more psychiatric disorders in the same person (comorbidity or dual diagnosis) is no rare exception. It is rather common and therapeutically highly relevant. Comorbid patients exhibit frequently severe manifestations of the disorder(s) and they require intensive treatment to meet their special needs and the interdependencies of their disorders. The present overview deals with the theoretical foundations of comorbidity of substance use and other psychiatric disorders. We present data on the prevalence of different comorbidities and discuss the models, which have been proposed to explain how substance use and other disorders relate with each other. Furthermore, we describe the clinical characteristics and long-term course of comorbid patients, as well as some general therapeutic principles including the advantages of integrated therapeutic programmes. In addition, we carried out a systematic literature search on specific pharmaco- and psychotherapies for common comorbidities using the databases MEDLINE, EMBASE and PsycInfo (up to December 2007), and assessed the methodological quality of the identified trials. Based on this search we present the empirical evidence for the effectiveness of specific treatments and make therapeutic recommendations which are graded according to the strength of existing evidence. In conclusion, integrated treatment programs are more effective, provided they take into account the multiple deficits of comorbid patients, adjust and adapt the different therapeutic components to each other, and set realistic goals. The next step should be a broader application of integrated treatment programs and their adoption as standard treatment within the national health systems.


Maintaining quality of litchi fruit with acidified calcium sulfate.
The effect of acidified calcium sulfate (ACS) on the quality of litchi ( Litchi chinensis Sonn. cv. 'Brewster') fruit after harvest was evaluated. ACS at 1.25% or higher concentrations significantly inhibited the activities of polyphenol oxidase and peroxidase in the pericarp during storage at both 5 and 10 degrees C. These treatments also effectively prevented browning and retained the red color of the outer shell of the fruit. Total phenolic and total anthocyanin contents in pericarp were increased by ACS treatments in a dose-dependent manner. The radical scavenging activities for ROO(*), DPPH(*), (*)OH and O(2)(*-) were also enhanced by ACS, particularly by 2.5 and 5% concentrations. The activities of several antioxidant enzymes and enzymes of ascorbate-glutathione cycle including catalase, ascorbate peroxidase, glutathione peroxidase, glutathione reductase, dehydroascorbate reductase, and monodehydroascorbate reductase gradually declined during storage. However, ACS enhanced the activities of these enzymes, especially at the beginning of the storage. Samples treated with ACS generally had higher flavonoid levels than the control. The three major flavonoids, cyanidin-3-rutinoside, cyanidin-3-glucoside and quercetin-3-rutinoside, were found to be significantly increased by 2.5 and 5.0% ACS at both 5 and 10 degrees C. No differences were detected among various treatments in soluble solids content or sugar and organic acid levels in the pulp of litchi fruit, indicating that the internal quality of the fruit was not adversely affected by ACS treatment.


Fatal heat stroke based on foudroyant irreversible multiple organ dysfunction in German summer.
Heat stroke is a serious condition that might lead from moderate organ impairment to multiple organ dysfunction syndrome. Appropriate diagnosis-finding, fast initiation of cooling and intensive care are key measures of the initial treatment. Scientific case report based on i) clinical experiences obtained in the clinical management of a particularly rare case and ii) selected references from the medical scientific literature. We present a case of a young and healthy construction worker who suffered from an exertional heat stroke with a body core temperature exceeding 42 °C by previous several hour work at 35 °C ambient temperature. Heat stroke was associated with foudroyant, not reversible multiple organ dysfunction syndrome, in particular, early disturbed coagulation, microcirculatory, liver and respiratory failure, and subsequent fatal outcome despite immediate diagnosis-finding, rapid external cooling and expanded intensive care management. Basic knowledge on an adequate diagnosis(-finding in time) and treatment of heat stroke is important for (almost each) physician in the summertime as well as is essential for the initiation of an appropriate management. Associated high morbidity and mortality rates indicate the need for implementation of standard operation protocols.


Cytologic aspects of T-cell acute lymphoblastic leukemia presenting as a massive pericardial effusion: a case report.
Acute lymphoblastic leukemia (ALL) with a clinical presentation of cardiac tamponade and the presence of blasts in the pericardial fluid is an uncommon event. A cytopathologist needs to adopt a cautious interpretive approach while dealing with a lymphoid-rich pericardial effusion in order to prevent a false negative diagnosis. A 27-year-old male presented with breathlessness, ascites, bilateral pedal edema and fever. He had mild hepatomegaly. On detailed clinical examination, a diagnosis of anemia with cardiac tamponade was made. Cytology of pericardial fluid revealed a large number of lymphoid cells in a hemorrhagic background that, under low magnification, closely resembled mature lymphocytes. However, a careful examination of May-Grünwald-Giemsa-stained cytologic smears, under an oil immersion objective (x 1,000), showed atypical lymphoid cells having blastoid morphology. Rare lymphoid cells displayed a "hand mirror" appearance. A hematologic workup was carried out to exclude leukemia/lymphoma. Complete blood count revealed pancytopenia with abnormal lymphoid cells. Bone marrow showed replacement by 90% lymphoblasts exhibiting periodic acid-Schiff stain, CD3 and terminal deoxynucleotidyl transferase positivity. A diagnosis of T-cell acute lymphoblastic leukemia (FAB L1) was offered, and the patient was started on a remission and induction regimen. However, he had a rapid downhill course and died of cardiorespiratory arrest. Both clinicians and cytopathologists need to be aware of rare instances in which ALL may present with a pericardial effusion as an initial manifestation. The abnormal lymphoid cells found in the pericardial fluid in such situations need to be interpreted cautiously, as their presence is of clinical significance.


Is Three a Crowd? The Influence of Companions on a Patient's Decision to Transition to a Biosimilar.
Involving patients in treatment decisions is commonplace in healthcare, and patients are frequently accompanied by a companion (support person). Companions are often actively involved in medical consultations, yet their impact on decisions to change medications is unknown. This study examines the influence of companions on a patient's decision to transition from their bio-originator therapy to a biosimilar. A parallel, two-arm randomized controlled trial was conducted with 79 patients taking a bio-originator for rheumatic diseases who regularly attend clinic with a companion. Patients were randomized to receive an explanation about a hypothetical transition to a biosimilar alone or with their companion. Patients reported willingness to transition, risk perceptions, difficulty understanding, social support, and completed the Decisional Conflict Scale and Satisfaction with Decision Scale. Companions did not influence decisions to transition to biosimilars or cognitive and affective risk perceptions. Accompanied patients reported more difficulty understanding the explanation (p = .006, Cohen's d = .64) but thought it was more important to receive information with companions (p = .023, Cohen's d = -.52). Companions did not impact decision satisfaction or decisional conflict. Receiving emotional, but not practical support, was associated with less decisional conflict in accompanied patients (p = .038, r2 = 0.20). The presence of companions does not seem to influence risk perceptions or decisions about transitioning to biosimilars. Companions, however, impact the patient's reporting of their ability to understand treatment explanations. Providers should check understanding in all patients but may need to provide additional time or educational resources to accompanied patients and companions. Australian New Zealand Clinical Trial Registry: ACTRN12619001435178.


Ageing patients in forensic psychiatric settings: A review of the literature.
The prevalence of ageing patients in forensic psychiatric settings is increasing. However, limited research has reported around this population. The aim of this scoping review is to synthesise the current evidence around ageing forensic psychiatric patients. The literature was searched through four databases and Google searches. The identified outputs were screened for suitability and assessed for quality. Quantitative data were extracted and analysed on SPSS; qualitative data were extracted and analysed onto NVivo. Seven studies were included in the review. Quantitative results reported around demographics, service contact, offending patterns, mental, and physical health of ageing patients. Qualitative findings focused on age-friendliness of services, staff-patient rapport, activities, security issues, and discharge planning. Ageing forensic psychiatric patients present with complex and unique needs in relation to treatment, activities, mental, physical, and support. Further research looking at individual patients' needs is paramount to inform policy development and good practice in this area.


CD2 Regulates Pathogenesis of Asthma Induced by House Dust Mice Extract.
Characteristic of allergic asthma, CD4+Th2 lymphocytes secrete Th2 cytokines, interleukin (IL)-4, IL-13, and IL-5 that mediate the inflammatory immune response. Surface expression of CD2 and its ligand, CD58, is increased on the monocytes and eosinophils of asthma patients, which correlate with elevated serum IgE levels, suggesting that CD2 may contribute to allergic airway inflammation. Using a murine model of asthma, we observed that house dust mice extract (HDME)-exposed Balb/c mice have increased airway hyperresponsiveness (AHR), lung inflammation, goblet cell hyperplasia, and elevated levels of Th2 cytokines in the lungs, as well as increased serum IgE levels as compared to the control mice. In contrast, with the exception of serum IgE levels, all the other parameters were significantly reduced in HDME-treated Cd2-/- mice. Interestingly, Il13 but not Il4 or Il5 gene expression in the lungs was dramatically decreased in HDME-exposed Cd2-/- mice. Of note, the gene expression of IL-13 downstream targets (Muc5b and Muc5ac) and high affinity IL-13Rα2 were upregulated in the lungs of HDME-exposed Balb/c mice but were significantly reduced in HDME-exposed Cd2-/- mice. Consistently, gene expression of microRNAs regulating mucin production, inflammation, airway smooth muscle cell proliferation and IL-13 transcripts were increased in the lungs of HDME-exposed Cd2-/- mice. Given the established role of IL-13 in promoting goblet cell hyperplasia, lung inflammation and AHR in allergic asthma, our studies reveal a unique role for CD2 in the regulation of Th2-associated allergic asthma.


Combined cerebrospinal fluid metabolomic and cytokine profiling in tuberculosis meningitis reveals robust and prolonged changes in immunometabolic networks.
Much of the high mortality in tuberculosis meningitis (TBM) is attributable to excessive inflammation, making it imperative to identify targets for host-directed therapies that reduce pathologic inflammation and mortality. In this study, we investigate how cytokines and metabolites in the cerebral spinal fluid (CSF) associate with TBM at diagnosis and during TBM treatment. At diagnosis, TBM patients (n = 17) demonstrate significant increases of cytokines and chemokines that promote inflammation and cell migration including IL-17A, IL-2, TNFα, IFNγ, and IL-1β versus asymptomatic controls without known central nervous system pathology (n = 20). Inflammatory immune signaling had a strong positive correlation with immunomodulatory metabolites including kynurenine, lactic acid, and carnitine and strong negative correlations with tryptophan and itaconate. Inflammatory immunometabolic networks were only partially reversed with two months of effective TBM treatment and remained significantly different compared to CSF from controls. Together, these data highlight a critical role for host metabolism in regulating the inflammatory response to TBM and indicate the timeline for restoration of immune homeostasis in the CSF is prolonged.


Analysis of alternative splicing associated with aging and neurodegeneration in the human brain.
Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)-dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)-dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration.


The Benefits of Using a Small Caliber Ureteroscope in Evaluation and Management of Urethral Stricture.
The proper evaluation of urethral strictures is an essential part of the surgical planning in urethral reconstruction. The proper evaluation of the stricture can be challenging in certain situations, especially when the meatus is involved. We propose that the use of a small caliber ureteroscope (4.5 Fr and 6.5 Fr) can offer additional help and use for the surgical planning in urethroplasty. We prospectively collected data on 76 patients who underwent urethroplasties in Kulkarni Reconstructive Urology Center, Pune, India and Thunder Bay Regional Health Sciences Center, Thunder Bay, Canada. Patients had retrograde and micturition urethrograms performed preoperatively. The stricture was assessed visually using a 6.5 Fr ureteroscope. If the stricture was smaller than 6.5 Fr, we attempted using the 4.5 Fr ureteroscope. In nonobliterated strictures, we attempted bypassing the stricture making sure not to dilate the stricture. A glide wire would be passed to the bladder under vision. Stricture length, tissue quality, presence of other proximal strictures, false passages, and bladder tumors or stones would be assessed visually. If the penile stricture was near obliterative (smaller than 4.5 Fr caliber), a two-staged procedure is elected to be performed. For proximal bulbar strictures, if the urethral caliber is less than 4.5 Fr and the stricture length is less than 1 cm, we perform a nontransecting anastomotic urethroplasty (NTAU). If the stricture length is >1 cm, we perform a double-face augmented urethroplasty (DFAU). If the urethral caliber is >4.5 Fr and particularly those who are sexually active, ventral inlay with buccal mucosal grafts (BMGs) is performed. In mid to distal bulbar strictures, if the urethral caliber is >4.5 Fr, our procedure of choice is dorsal onlay with BMG. For those with urethral caliber <4.5 Fr and a stricture less than 1 cm, we perform a NTAU. For strictures longer than 1 cm, we perform a DFAU. With the exception of trauma, we very rarely transect the urethra. For panurethral strictures, we almost exclusively perform Kulkarni one-sided dissection. Urethroscopy was performed in 76 patients who presented for urethroplasty from July 2014 to September 2014 (in Pune) and between April 2016 and September 2017 (in Thunder Bay). Bypassing the stricture was achieved in 68 patients (89%) while it was unsuccessful in 8 patients (11%). In all unsuccessful urethroscopies, the stricture was near obliterative <4.5 Fr. Our surgical planning changed in (13) 17% of the cases. Out of 43 bulbar strictures, the decision was changed in (9) 21% where we performed 4 DFAU, 3 AAU (augmented anastomotic urethroplasty), and 2 EAU (end anastomotic urethroplasty). In 13 penile strictures, we opted for staged urethroplasty including 3 Johansons and 1 first-stage Asopa in 30.7%. In 20 panurethral urethroplasties, 1 patient (5%) had a urethral stone found in a proximal portion of the bulbar urethra distal to a stricture ring that was removed using an endoscopic grasper. The use of the small caliber ureteroscope can help in evaluation of the stricture caliber, length, and tissue quality. The scope can also aid in placing a guide wire, evaluating the posterior urethra, and screening for urethral or bladder stones. It can also improve the preoperative patient counselling and avoid unwanted surprises.


MiR-181b-5p downregulates NOVA1 to suppress proliferation, migration and invasion and promote apoptosis in astrocytoma.
MicroRNAs (miRNAs) are small, short noncoding RNAs that modulate the expression of numerous genes by targeting their mRNA. Numerous abnormal miRNA expression patterns are observed in various human malignancies, and certain miRNAs can act as oncogenes or tumor suppressors. Astrocytoma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans. In our previous studies, we found that the downregulation of miR-181b-5p in astrocytomas is associated with a poor prognosis. The aim of the present study was to investigate the functional role of miR-181b-5p and its possible target genes. miR-181b-5p was significantly downregulated in astrocytoma specimens, and the reduced expression of miR-181b-5p was inversely correlated with the clinical stage. The ectopic expression of miR-181b-5p inhibited proliferation, migration and invasion and induced apoptosis in astrocytoma cancer cells in vitro. The NOVA1 (neuro-oncological ventral antigen 1) gene was further identified as a novel direct target of miR-181b-5p. Specifically, miR-181b-5p bound directly to the 3'-untranslated region (UTR) of NOVA1 and suppressed its expression. In clinical specimens, NOVA1 was overexpressed, and its protein levels were inversely correlated with miR-181b-5p expression. Furthermore, the changing level of NOVA1 was significantly associated with a poor survival outcome. Similar to restoring miR-181b-5p expression, downregulating NOVA1 inhibited cell growth, migration and invasion. Overexpression of NOVA1 reversed the inhibitory effects of miR-181b-5p. Our results indicate that miR-181b-5p is a tumor suppressor in astrocytoma that inhibits tumor progression by targeting NOVA1. These findings suggest that miR-181b-5p may serve as a novel therapeutic target for astrocytoma.


A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip.
Drug discovery is often impeded by the poor predictability of in vitro assays for drug toxicity. One primary reason for this observation is the inability to reproduce the pharmacokinetics (PK) of drugs in vitro. Mathematical models to predict the pharmacokinetics-pharmacodynamics (PK-PD) of drugs are available, but have several limitations, preventing broader application. A microscale cell culture analog (microCCA) is a microfluidic device based on a PK-PD model, where multiple cell culture chambers are connected with fluidic channels to mimic multi-organ interactions and test drug toxicity in a pharmacokinetic-based manner. One critical issue with microfluidics, including the microCCA, is that specialized techniques are required for assembly and operation, limiting its usability to non-experts. Here, we describe a novel design, with enhanced usability while allowing hydrogel-cell cultures of multiple types. Gravity-induced flow enables pumpless operation and prevents bubble formation. Three cell lines representing the liver, tumor and marrow were cultured in the three-chamber microCCA to test the toxicity of an anticancer drug, 5-fluorouracil. The result was analyzed with a PK-PD model of the device, and compared with the result in static conditions. Each cell type exhibited differential responses to 5-FU, and the responses in the microfluidic environment were different from those in static environment. Combination of a mathematical modeling approach (PK-PD modeling) and an in vitro experimental approach (microCCA) provides a novel platform with improved predictability for testing drug toxicity and can help researchers gain a better insight into the drug's mechanism of action.


Transcriptional control of terminal nephron differentiation.
Terminal differentiation of epithelial cells into more specialized cell types is a critical step in organogenesis. Throughout the process of terminal differentiation, epithelial progenitors acquire or upregulate expression of renal function genes and cease to proliferate, while expression of embryonic genes is repressed. This exquisite coordination of gene expression is accomplished by signaling networks and transcription factors which couple the external environment with the new functional demands of the cell. While there has been much progress in understanding the early steps involved in renal epithelial cell differentiation, a major gap remains in our knowledge of the factors that control the steps of terminal differentiation. A number of signaling molecules and transcription factors have been recently implicated in determining segmental nephron identity and functional differentiation. While some of these factors (the p53 gene family, hepatocyte nuclear factor-1beta) promote the terminal epithelial differentiation fate, others (Notch, Brn-1, IRX, KLF4, and Foxi1) tend to regulate differentiation of specific nephron segments and individual cell types. This review summarizes current knowledge related to these transcription factors and discusses how diverse cellular signals are integrated to generate a transcriptional output during the process of terminal differentiation. Since these transcriptional processes are accompanied by profound changes in nuclear chromatin structure involving the genes responsible for creating and maintaining the differentiated cell phenotype, future studies should focus on identifying the nature of these epigenetic events and factors, how they are regulated temporally and spatially, and the chromatin environment they eventually reside in.


Profile of urinary arsenic metabolites during pregnancy.
Chronic exposure to inorganic arsenic (In-As) from drinking water is associated with different health effects, including skin, lung, bladder, and kidney cancer as well as vascular and possibly reproductive effects. In-As is metabolized through the process of methylation, resulting in the production and excretion of methylated species, mainly monomethylarsenate (MMA) and dimethylarsenate (DMA). Because a large percentage of the dose is excreted in urine, the distribution of urinary In-As, MMA, and DMA is considered a useful indicator of methylation patterns in human populations. Several factors affect these patterns, including sex and exposure level. In this study, we investigated the profile of urinary In-As, MMA, and DMA of pregnant women. Periodic urine samples were collected from early to late pregnancy among 29 pregnant women living in Antofagasta, Chile, who drank tap water containing 40 micro g/L In-As. The total urinary arsenic across four sampling periods increased with increasing weeks of gestation, from an initial mean value of 36.1 to a final value of 54.3 micro g/L. This increase was mainly due to an increase in DMA, resulting in lower percentages of In-As and MMA and a higher percentage of DMA. Our findings indicate that among women exposed to moderate arsenic from drinking water during pregnancy, changes occur in the pattern of urinary arsenic excretion and metabolite distribution. The toxicologic significance of this is not clear, given recent evidence suggesting that intermediate methylated species may be highly toxic. Nevertheless, this study suggests that arsenic metabolism changes throughout the course of pregnancy, which in turn may have toxicologic effects on the developing fetus. Key words: arsenic, arsenic metabolism, arsenic methylation, Chile, pregnancy, urinary arsenic.


Was phenserine a failure or were investigators mislead by methods?
Over 200 Alzheimer's disease (AD) drug candidates have failed in development, and other neuropsychiatric trials have had their validity compromised. Studies suggest that methodological errors can be a source for these compromises and failures. We gained access to documentation for phenserine, an experimental AD drug that reached phase III clinical trials. The 06 Phase III trial was cited by the developers as grounds for their abandonment of the development. We compared evidence for interventions to control methodological errors and grounds for moving through phases of drug development to 40 other randomly selected AD developments we had studied. We analyzed methods and conditions of the 06 phenserine clinical trial, for biases able to account for its abandonment during development. The phenserine development failed to control error sources able to affect the outcomes. There are statistically significant relationships in the 06 clinical trial between outcomes at research sites and levels of variance, placebo group improvements and other factors. We conclude that phenserine was abandoned, at least in part, due to a clinical trial invalidated by relationships among its methods and outcomes.


[Assessment of Long COVID in Medical Rehabilitation].
The aim of the study was to provide an insight into the care situation of long COVID patients in inpatient medical rehabilitation facilities in Germany. For this purpose, a standardized online survey was conducted among 1,080 inpatient medical rehabilitation facilities in Germany. A total of 338 cases were available for the analysis. Of these, 173 (51%) reported treating long COVID. The cumulative total number of rehabilitants with long COVID treated in the facilities up to the time of the survey was 11,948. The results showed that rehabilitation facilities were mostly prepared for the care of patients with Long COVID. Lack of capacity was reported especially by those rehabilitation facilities that treated rehabilitants with long COVID in pneumology departments. Furthermore, capacity bottlenecks were related to the total number of patients with long COVID in the rehabilitation facility ("proportion of rehabilitants with long COVID to all rehabilitants in the department"). Heterogeneity was found in the treatment concept for long COVID and the allocation of patients to a specific department. The results of the long COVID inventory underline the importance of medical rehabilitation in the treatment of the long-term health and participation-related consequences of COVID-19.


Elastometry of Complex Fluid Pendant Capsules.
Oil/water interfaces are ubiquitous in nature. Opposing polarities at these interfaces attract surface-active molecules, which can seed complex viscoelastic or even solid interfacial structure. Biorelevant proteins such as hydrophobin, polymers such as PNIPAM, and the asphaltenes in crude oil (CRO) are examples of some systems where such layers can occur. When a pendant drop of CRO is aged in brine, it can form an interfacial elastic membrane of asphaltenes so stiff that it wrinkles and crumples upon retraction. Most of the work studying CRO/brine interfaces focuses on the viscoelastic liquid regime, leaving a wide range of fully solidified, elastic interfaces largely unexplored. In this work, we quantitatively measure elasticity in all phases of drop retraction. In early retraction, the interface shows a fluid viscoelasticity measurable using a Gibbs isotherm or dilatational rheology. Further retraction causes a phase transition to a 2D elastic solid with nonisotropic, nonhomogeneous surface stresses. In this regime, we use new techniques in the elastic membrane theory to fit for the elasticities of these solid capsules. These elastic measurements can help us develop a deeper understanding not only of CRO interfaces but also of the myriad fluid systems with solid interfacial layers.


Estimation of intrasynaptic norepinephrine concentrations in humans.
Levels of synaptic cleft norepinephrine associated with pressor responses were estimated in humans by measuring blood pressure and arterial plasma norepinephrine during norepinephrine infusion and during yohimbine-induced release of endogenous norepinephrine. Linear pressor response-log norepinephrine concentration relationships were observed during the infusions. At a pressor response of 20 mm Hg, arterial norepinephrine averaged 3647 pg/ml. The pressor-log norepinephrine relationship was shifted more than fivefold to the left during combined ganglionic, alpha 2-adrenergic receptor, and Uptake1 (neuronal norepinephrine uptake) blockade: arterial norepinephrine averaged 684 pg/ml at a 20 mm Hg pressor response. During yohimbine-induced release of endogenous norepinephrine in desipramine-pretreated subjects, arterial norepinephrine averaged 467 pg/ml at a 20 mm Hg pressor response. Since the norepinephrine concentration in the synaptic clefts must have been between the values for plasma norepinephrine during its infusion and during its endogenous release, we estimated that in healthy people, a 20 mm Hg sympathetically mediated pressor response is associated with about a 560 pg/ml (3.3 nM) concentration of norepinephrine in the average neuroeffector junction.


Faculty appointment and tenure policies in medical schools: a 1997 status report.
The authors present recent data on changes under way in and the current status of faculty appointment and tenure policies in U.S. medical schools. The data are drawn from a survey conducted by the Association of American Medical Colleges in 1997, to which deans at all 125 U.S. allopathic medical schools responded, supplemented by follow-up telephone and electronic mail inquiries. Faculty evaluation systems and faculty compensation systems top the list of areas in which medical schools are most frequently making policy changes, with approximately half of the schools involved in each area. Changes in evaluation systems reflect an increasing emphasis on post-tenure review. Changes in compensation systems are characterized by the division of pay into separate components, each with its own financial guarantees and with the level of compensation tied specifically to measures of individual and group productivity. Other policy changes include introducing new faculty tracks and career pathways, redefining or clarifying the portion of salary or compensation that is defined by tenure, lengthening the pre-tenure probationary period, and modifying the link between promotion and tenure. Of the 125 medical schools in the United States, only five do not award tenure, while another six effectively limit eligibility for tenure to basic science faculty. These numbers are unchanged from those reported in 1994. Only two schools indicated that eliminating tenure or ceasing to make tenure-eligible appointments was being considered, and neither reported that a policy change was imminent. Current data on the status of tenure guarantees, tenure probationary periods, other tenure eligibility criteria, and special clinical tracks are provided. Nearly three fourths of the medical schools in the United States now have a separate and distinct faculty track for full-time clinical faculty whose primary responsibilities are in patient care and teaching. The vast majority of these tracks do not permit faculty to be tenured, but 71% require evidence of scholarship for promotion. The authors conclude that faculty personnel policies in medical schools are likely to continue to evolve, consistent with a growing insinuation of the corporate culture into academia.


A review of vision physiology.
As one of the most important aspects of aviation physiology, vision is a virtual sine qua non of the aviation field. A basic understanding of vision is vitally important in the field of aviation medicine. Following is a summary of some aspects of visual physiology, including visual acuity, night vision, dark adaptation, and acceleration effects on vision.


Chemically modified nylons as supports for enzyme immobilization. Polyisonitrile-nylon.
Four-component condensations between amine, carboxyl, isocyanide and aldehyde lead to the formation of N-substituted amides (Ugi, 1962). The present paper describes the use of such condensations for the introduction of chemically reactive groups on to the polyamide backbone of nylon. Polyisonitrile-nylon was synthesized by partial hydrolysis of nylon-6 powder, followed by resealing of the newly formed -CO(2)... NH(2) (-) pairs via a four-component condensation, by using acetaldehyde and 1,6-di-isocyanohexane. Polyisonitrile-nylon could also be converted into a diazotizable arylamino derivative, polyaminoaryl-nylon, by a four-component condensation by using a bifunctional amine, pp'-diaminodiphenylmethane, in the presence of an aldehyde and a carboxylate compound. The versatility of four-component condensations involving the isocyanide functional group of polyisonitrile-nylon allowed coupling of proteins, in an aqueous medium at neutral pH, through either their amino or carboxyl groups. Trypsin and papain were bound to polyisonitrile-nylon through their amino groups by a four-component condensation by using acetaldehyde and acetate; conversely, succinyl-(3-carboxypropionyl-)trypsin, pepsin and papain were coupled through their carboxyl groups in the presence of acetaldehyde and an amine (Tris). Diazotized polyaminoaryl-nylon could be utilized for the immobilization of papain, via the tyrosine residues of the enzyme.


Serum levels of thrombomodulin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in the acute phase of Plasmodium vivax malaria.
Elevated plasma or serum levels of thrombomodulin (TM), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin have been reported in several diseases. However, plasma or serum levels of TM, ICAM-1, VCAM-1, and E-selectin have not been investigated in the acute phase of Plasmodium vivax malaria. Serum TM, ICAM-1, VCAM-1, E-selectin, and creatinine levels were determined in six Japanese patients in the acute phase of vivax malaria and in seven healthy Japanese controls. Parasitemias of the peripheral blood were < 0.1% in five patients and 0.8% in one patient. The patients' mean +/- SD serum levels of TM, ICAM-1, VCAM-1, and E-selectin were 5.7 +/- 1.3 Fujirebio units/ml, 709 +/- 397 ng/ml, 2,112 +/- 782 ng/ml, and 99 +/- 28 ng/ml, respectively, and all were significantly greater than those in the controls (TM; P < 0.005, ICAM-1; P < 0.025, VCAM-1; P < 0.005, E-selectin; P < 0.025). However, no significant difference was identified between patients and controls for serum creatinine values. The serum levels of TM and VCAM-1 were not related to parasitemia. The elevation of serum TM levels suggests that endothelial cell damage occurs in the acute phase of vivax malaria.


Proptosis--Correlation and Agreement between Hertel Exophthalmometry and Computed Tomography.
To determine the correlation and agreement between Hertel exophthalmometry and computed tomography (CT) of the orbits in measuring proptosis. 80 patients (40 normal and 40 with proptosis) were recruited for this study. Exophthalmometry were performed on all of them using the Hertel exophthalmometer and CT. Values and correlations between the modalities were analysed with unpaired t-tests, intraclass correlation coefficients (ICC), and Pearson correlation coefficients (PCC). The Bland-Altman method was used to analyse the agreement between the two modalities. Hertel exophthalmometer and CT measurements did not differ significantly (p > 0.05), although exophthalmometry measurements of the normal (14.5 ± 2.2 mm) and proptosis groups (20.5 ± 3.9 mm) were higher than those obtained from CT (13.9 ± 2.4 mm and 20.0 ± 3.7 mm, respectively). ICC for both the Hertel exophthalmometer and CT measurements were both 0.99, indicating high intra-observer reliability and reproducibility. PCC between Hertel exophthalmometer and CT measurements in both normal and proptosis groups were strongly correlated (r = 0.96 and 0.93, respectively, p = 0.01). The 95% limits of agreement (LOA) between Hertel exophthalmometer and CT measurements for the normal and proptosis groups were -0.70 to 1.78 mm and -2.36 to 3.33 mm, respectively. Although Hertel exophthalmometer and CT measurements are similar and strongly correlated, they do not agree well with each other in the presence of proptosis. The measurements should not be used interchangeably as the differences between them may lead to errors in clinical interpretation.


Cervical cancer screening improvements with self-sampling during the COVID-19 pandemic.
At the onset of the COVID-19 pandemic cervical screening in the capital region of Sweden was canceled for several months. A series of measures to preserve and improve the cervical screening under the circumstances were instituted, including a switch to screening with HPV self-sampling to enable screening in compliance with social distancing recommendations. We describe the major changes implemented, which were (1) nationwide implementation of HPV screening, (2) switch to primary self-sampling instead of clinician sampling, (3) implementation of HPV screening in all screening ages, and (4) combined HPV vaccination and HPV screening in the cervical screening program. A temporary government regulation allowed primary self-sampling with HPV screening in all ages. In the Stockholm region, 330,000 self-sampling kits were sent to the home address of screening-eligible women, instead of an invitation to clinician sampling. An increase in organized population test coverage was seen (from 54% to 60% in just 1 year). In addition, a national campaign for faster elimination of cervical cancer with concomitant screening and vaccination for women in ages 23-28 was launched. The COVID-19 pandemic necessitated major changes in the cervical cancer preventive strategies, where it can already be concluded that the strategy with organized primary self-sampling for HPV has resulted in a major improvement of population test coverage. Funded by the Swedish Association of Local Authorities and Regions, the Swedish Cancer Society, the European Union's Horizon 2020 Research and Innovation Program, the Swedish government, and the Stockholm county.


Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma.
Currently, there is no effective treatment for Burkitt's lymphoma in patients aged above 60 years, and thus research on effective treatment options for Burkitt's lymphoma has been gaining increasing attention. Artesunate has been identified as a novel effective growth suppressor in Burkitt's lymphoma. Here, we utilized molecular biology, transcriptome analysis, and other techniques to study artesunate-induced death of the Burkitt's lymphoma cells DAUDI and CA-46, the effect of artesunate on gene expression in DAUDI and CA-46 cells, and the effect of artesunate-induced ATF4-CHOP-CHAC1 pathway on ferroptosis. We also studied the inhibitory effects and ferroptosis induction of artesunate on CA-46 cells in mouse xenografts. Results showed that artesunate induced ferroptosis in DAUDI and CA-46 cells, as evidenced by the protective effect of liproxstatin-1, ferrostatin-1, and desferoxamine, resulting in an endoplasmic reticulum stress response, activation of the ATF4-CHOP-CHAC1 pathway enhanced ferroptosis in DAUDI and CA-46 cells. A mouse-transplanted tumor model showed that artesunate can inhibit the proliferation and induce ferroptosis of CA-46 cells in vivo. This study provides a novel perspective for the development of drugs against different types of Burkitt's lymphomas.


Prescribing Posttraumatic Growth.
This article introduces questions in psychiatric ethics regarding the substantial field of qualitative and quantitative research into 'posttraumatic growth', which investigates how, after devastating experiences, individuals can come to feel that they have developed warmer relationships, increased spirituality, or a clearer vision of their priorities. In one area of this research, researchers of posttraumatic growth outline strategies for clinicians interested in assisting their patients in achieving such growth. In this article, I articulate two ethical concerns about this account of posttraumatic growth and the practice of growth-oriented therapy. The first is a concern about the status and effects of the ideal of posttraumatic health implicit in their account, and the second a concern about the ethical implications of the clinical recommendations for the post-trauma patient. I argue for the need for more attention to the hazardous implications of relating to patients as though they are on their way to, and themselves largely in control of, their own posttraumatic growth.


Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency.
Premature adrenarche and functional adolescent androgen excess are common disorders which may evolve into polycystic ovary syndrome (PCOS). In all three disorders, ACTH-stimulated 17-hydroxyprogesterone concentrations are often somewhat elevated. To determine the role of 21-hydroxylase (CYP21) gene mutations in these disorders, we performed molecular genotype analysis on 48 children and adolescents referred for evaluation of hyperandrogenic findings and diagnosed as having premature adrenarche or functional androgen excess. For comparison, DNA samples from 80 healthy adults were genotyped. Seventeen of the 48 hyperandrogenic patients were found to be heterozygotic carriers of CYP21 mutations. The frequency of heterozygosity was significantly greater among symptomatic patients (35%) than among the healthy controls (6%), P < 0.001. Seven mutation-positive patients (50%) and only one mutation-negative patient had ACTH-stimulated 17-hydroxyprogesterone concentrations typical for heterozygotic carriers of 21-hydroxylase deficiency, 400-1000 ng/dl. The significant difference in heterozygote frequency between symptomatic patients and healthy controls suggests that heterozygosity for 21-hydroxylase deficiency may be associated with premature adrenarche and functional adolescent hyperandrogenism. Longitudinal studies are necessary to determine if heterozygosity for 21-hydroxylase deficiency predicts risk for PCOS.


Therapeutic Effects of Wenxin Keli in Cardiovascular Diseases: An Experimental and Mechanism Overview.
Cardiovascular diseases (CVDs) are the major public health problem and a leading cause of morbidity and mortality on a global basis. Wenxin Keli (WXKL), a formally classical Chinese patent medicine with obvious efficacy and favorable safety, plays a great role in the management of patients with CVDs. Accumulating evidence from various animal and cell studies has showed that WXKL could protect myocardium and anti-arrhythmia against CVDs. WXKL exhibited its cardioprotective roles by inhibiting inflammatory reaction, decreasing oxidative stress, regulating vasomotor disorders, lowering cell apoptosis, and protection against endothelial injure, myocardial ischemia, cardiac fibrosis, and cardiac hypertrophy. Besides, WXKL could effectively shorten the QRS and Q-T intervals, decrease the incidence of atrial/ventricular fibrillation and the number of ventricular tachycardia episodes, improve the severity of arrhythmias by regulating various ion channels with different potencies, mainly comprising peak sodium current (INa), late sodium current (INaL), transient outward potassium current (Ito), L-type calcium current (ICaL), and pacemaker current (If).


[Gender differences in the perception of professional achievement in family medicine, Spain].
The concept of achievement is important to study the professional development. In medicine there are gender inequalities in career. The purpose was to know and compare the professional achievement's perceptions and attributions of female and male primary care physicians in Andalusia. Qualitative study with 12 focus groups (October 2009 to November 2010). primary care physicians. intentionally segmented by age, sex and health care management. Were conducted by sex: two groups with young physicians, two groups with middle aged and two with health care management. TOTAL: 32 female physician and 33 male physicians. Qualitative content analysis with Nuddist Vivo. Female and male physicians agree to perceive internal achievements and to consider aspects inherent to the profession as external achievements. The most important difference is that female physician related professional achievement with affective bond and male physician with institutional merit. Internal attributions are more important for female physician who also highlight the importance of family, the organization of working time and work-family balance. Patients, continuing education, institutional resources and computer system are the most important attributions for male physician. There are similarities and differences between female and male physicians both in the understanding and the attributions of achievement. The differences are explained by the gender system. The perception of achievement of the female physicians questions the dominant professional culture and incorporates new values in defining achievement. The attributions reflect the unequal impact of family and organizational variables and suggest that the female physicians would be changing gender socialization.


[A course for continuing medical education].
To promote continuing medical education, the Central Military Hospital of Mexico offers a course in which the student may develop his skills for finding and using sources of information, applying the scientific method to biomedical research, and communicating the results thereof in writing. The methodology is more self-instructional than expository. The course program is divided into three modules geared to the general objectives, and the duration varies between 10 and 14 weeks. The course is attended in the final stage of the professional training, when the student has just completed his specialization, or when he is beginning it, on the premise that this is the best time to make clear to the physician the need to continue studying and learning throughout life. The author of this article explains why the course is important, states its specific objectives and, in an annex, presents the content of the program.


Fatal Rhinofacial Mycosis Due to Aspergillus nomiae: Case Report and Review of Published Literature.
A 73-year-old female suffering from acute myeloid leukemia presented with progressive rhinofacial mycosis. Suspecting it to be mucormycosis, the antifungal amphotericin B (AMB) was administered empirically, but the patient did not respond as planned. The fungus was then isolated from the biopsied tissue and morphologically identified as a species of Aspergillus. Necrosis progressed and she died of cerebral hemorrhage. Since Aspergillus flavus is susceptible to AMB, and several other Aspergillus species can be misidentified as A. flavus, the observed resistance necessitated a re-examination of the fungal isolate. The fungal strain was re-isolated and re-examined morphologically. Additionally, genomic DNA was extracted from the fungus and sequences were obtained from three genomic regions [the rDNA internal transcribed spacer (ITS) region, and portions of the β-tubulin and calmodulin genes] to more accurately identify this Aspergillus strain. Its antifungal susceptibility was assessed using multiple compounds and our findings were compared with literature data. The fungal culture again yielded an Aspergillus isolate morphologically identical to A. flavus. Molecular analyses, however, revealed the strain to be A. nomiae, a close relative of A. flavus in section Flavi, and it exhibited resistance to AMB. Reviewing the literature, only five other cases of A. nomiae infection in humans have been reported worldwide. The rhinofacial mycosis of the patient was actually due to A. nomiae. The initial misidentification of the fungus, coupled with its resistance to AMB, could be the reason treatment did not help the patient. We postulate that clinical A. nomiae infections may be underreported and that accurate and speedy pathogen identification is important so that an effective antifungal regimen can be administered.


[Immunological and clinical evaluation about mixed sistemic allogenic chimerism by transplantation].
A critical revision of the data in the literature regarding mixed allogeneic systemic chimerism by transplantation permits to perceive the aspects of undoubted interest in the immunological and clinical field. The usefulness of the cellular exchange, with the aim of the acceptance of the transplantation, that is carried out between recipient and the transplanted organ and which constitutes a completely peculiar immunological situation, comparable to the immunotolerance of the fetal period even though with same not totally identificable is pointed out.


First report of two complete Clostridium chauvoei genome sequences and detailed in silico genome analysis.
Clostridium (C.) chauvoei is a Gram-positive, spore forming, anaerobic bacterium. It causes black leg in ruminants, a typically fatal histotoxic myonecrosis. High quality circular genome sequences were generated for the C. chauvoei type strain DSM 7528T (ATCC 10092T) and a field strain 12S0467 isolated in Germany. The origin of replication (oriC) was comparable to that of Bacillus subtilis in structure with two regions containing DnaA boxes. Similar prophages were identified in the genomes of both C. chauvoei strains which also harbored hemolysin and bacterial spore formation genes. A CRISPR type I-B system with limited variations in the repeat number was identified. Sporulation and germination process related genes were homologous to that of the Clostridia cluster I group but novel variations for regulatory genes were identified indicative for strain specific control of regulatory events. Phylogenomics showed a higher relatedness to C. septicum than to other so far sequenced genomes of species belonging to the genus Clostridium. Comparative genome analysis of three C. chauvoei circular genome sequences revealed the presence of few inversions and translocations in locally collinear blocks (LCBs). The species genome also shows a large number of genes involved in proteolysis, genes for glycosyl hydrolases and metal iron transportation genes which are presumably involved in virulence and survival in the host. Three conserved flagellar genes (fliC) were identified in each of the circular genomes. In conclusion this is the first comparative analysis of circular genomes for the species C. chauvoei, enabling insights into genome composition and virulence factor variation.


Oxygen and lack of oxygen in fetal and placental development, feto-placental coupling, and congenital heart defects.
Low oxygen concentration (hypoxia) is part of normal embryonic development, yet the situation is complex. Oxygen (O2 ) is a janus gas with low levels signaling through hypoxia-inducible transcription factor (HIF) that are required for development of fetal and placental vasculature and fetal red blood cells. This results in coupling of fetus and mother around midgestation as a functional feto-placental unit (FPU) for O2 transport, which is required for continued growth and development of the fetus. Defects in these processes may leave the developing fetus vulnerable to O2 deprivation or other stressors during this critical midgestational transition when common septal and conotruncal heart defects (CHDs) are likely to arise. Recent human epidemiological and case-control studies support an association between placental dysfunction, manifest as early onset pre-eclampsia (PE) and increased serum bio-markers, and CHD. Animal studies support this association, in particular those using gene inactivation in the mouse. Sophisticated methods for gene inactivation, cell fate mapping, and a quantitative bio-reporter of O2 concentration support the premise that hypoxic stress at critical stages of development leads to CHD. The secondary heart field contributing to the cardiac outlet is a key target, with activation of the un-folded protein response and abrogation of FGF signaling or precocious activation of a cardiomyocyte transcriptional program for differentiation, suggested as mechanisms. These studies provide a strong foundation for further study of feto-placental coupling and hypoxic stress in the genesis of human CHD.


Thermostable refractive index sensors based on whispering gallery modes in a microsphere coated with poly(methyl methacrylate).
This study proposes a thermostable refractive index (RI) sensor consisting of a silica microsphere coated with a poly(methyl methacrylate) (PMMA) layer. The first-order and second-order whispering gallery modes (WGMs) of both TE and TM polarizations are considered theoretically. The layer thickness is carefully optimized to eliminate the thermal drift and enhance the RI sensitivity and detection limit. In various WGMs, at the thermostable thickness of the PMMA layer, the first-order TM mode corresponds to the highest sensitivity and the smallest detection limit. The theoretical predictions provide guidelines for the design and fabrication of thermostable RI sensors.


Carcinoembryonic antigen in experimental rat gastrointestinal carcinoma.
Detection of gastric carcinoma in the experimental rat can be difficult. We investigated whether or not serological testing for carcinoembryonic antigen might aid in the diagnostic process. Twenty-five young adult male Wistar rats were studied; 15 were treated with the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and 10 received no treatment. A complete autopsy was done on the 22 animals (12 in MNNG group, 10 in control group) that completed the 37-week study. Serum obtained at autopsy was evaluated by radioimmunoassay for the presence of CEA-like immunoreactivity. Grossly normal stomach, as well as gastric and small bowel cancers, were also stained for CEA. Of the 12 autopsied animals in the MNNG group, eight had a total of 12 cancers (seven gastric and five proximal small bowel); in no animal was an elevated serum CEA level detected. Immunoreactive tissue CEA was demonstrable in normal stomach and in gastrointestinal cancers; the tumors usually stained less intensely than adjacent normal stomach and did not exhibit normal intracellular CEA distribution.


The other side of the coin in primary tricuspid valve disease: The incremental value of 3D echocardiography.
Primary tricuspid valve regurgitation may be encountered in daily practice as a result of multiple etiologies. Described herein are the cases of 2 patients with severe primary tricuspid regurgitation. The underlying mechanism was posterior leaflet prolapse due to spontaneous chordae rupture in 1 case, and iatrogenic posterior leaflet tissue loss during removal of a permanent pacemaker in the other. Transthoracic and transesophageal echocardiography, which permit assessment of the tricuspid valve with multilevel imaging, are the techniques of choice for accurate detection and understanding of the etiology, the severity of valve regurgitation, and the determination of treatment options, in addition to providing assistance with timing and guidance during intervention. Three-dimensional echocardiography offers the ability to visualize the entire tricuspid valve and to identify which leaflets are affected by the pathology.


Calculation of diffraction effects on the average phase of an optical field.
We report on algorithms for the computation of the average phase of a beam over a detector in the near field. The basic idea is to reconstruct the optical field numerically and then use a quadrature algorithm to evaluate the quantity of interest. The various algorithms that employ discrete Fourier transform techniques for the computation of the field are described, and numerical tests that assess the accuracy of these algorithms are presented. No particular algorithm delivers the desired accuracy over the entire range of Fresnel numbers of interest, but each can produce satisfactory results within a particular range. Finally, new methods to evaluate the average phase are introduced, and their efficiency is assessed.


A DSL-Based Approach for Detecting Activities of Daily Living by Means of the AGGIR Variables.
In this paper, we propose a framework for studying the AGGIR (Autonomie Gérontologique et Groupe Iso Ressources-Autonomy Gerontology Iso-Resources Groups) grid model, with the aim of assessing the level of independence of elderly people in accordance with their capabilities of performing daily activities as well as interacting with their environments. In order to model the Activities of Daily Living (ADL), we extend a previously proposed Domain Specific Language (DSL), by defining new operators to deal with constraints related to time and location of activities and event recognition. The proposed framework aims at providing an analysis tool regarding the performance of elderly/disabled people within a home environment by means of data recovered from sensors using a smart-home simulator environment. We perform an evaluation of our framework in several scenarios, considering five of the AGGIR variables (i.e., feeding, dressing, toileting, elimination, and transfers) as well as health-care devices for tracking the occurrence of elderly activities. The results demonstrate the accuracy of the proposed framework for managing the tracked records correctly and, thus, generate the appropriate event information related to the ADL.


X-linked myopathy with excessive autophagy: a failure of self-eating.
Autophagic vacuolar myopathies (AVMs) are a group of disorders united by shared histopathological features on muscle biopsy that include the aberrant accumulation of autophagic vacuoles. The classic conditions that compose the AVMs include Pompe Disease, Danon Disease and X-linked myopathy with excessive autophagy (XMEA). Other disorders, including acquired myopathies like chloroquine toxicity, also have features of an autophagic myopathy. This review is focused on XMEA, a myopathy with onset of slowly progressive proximal weakness and elevated serum creatine kinase (2× to 20× normal) typically in the first decade of life. However, both late-adult onset and severe, sometimes lethal, neonatal cases also occur. Skeletal muscle pathology is characterized by numerous cytoplasmic autophagic vacuoles, complex muscle fiber splitting with internalization of capillaries, and complement C5b-9 deposition within vacuoles and along the sarcolemma. The autophagic vacuoles have sarcolemmal features. Mutations in the VMA21 gene at Xq28 cause XMEA by reducing the activity of lysosomal hydrolases. The VMA21 protein regulates the assembly of the V-ATPase required to acidify the lysosome. Increased lysosomal pH and poor degradation of cellular debris may secondarily induce autophagy, the net effect being accumulation of autophagolysosomes. The relationship of XMEA to other lysosomal disorders of muscle and potential therapeutic interventions for XMEA are discussed.


Widespread angiokeratomas and tuberous sclerosis.
We report a 29-year-old woman who had prominent cutaneous markers of tuberous sclerosis, with subependymal nodules and renal cysts on computerized tomographic scan, who also showed multiple angiokeratomas widely distributed on the buttocks and posterior thighs. Enzymatic studies ruled out Fabry's disease and other lysosomal storage disorders. This is the first reported association of widespread angiokeratomas and tuberous sclerosis.


Long-term survival in small cell carcinoma of the lung.
From June 1973 to August 1977, three hundred thirty-seven patients with small cell carcinoma of the lung were included in randomized therapeutic trials. By February 1979, fifty-one patients (15%) had survived for 18 months, including 29 (9%) in clinical complete remission. Of the latter patients, readmitted for restaging, including bone marrow examination, peritoneoscopy, and bronchomediastinoscopy, residual tumor was found in four. Treatment was discontinued in the remaining patients; six subsequently had relapses, while three patients died, free of disease, of other causes. Sixteen patients are still alive and free of disease more than 19 to 50 months after the primary diagnosis; seven were treated with combination chemotherapy alone, including four who initially had distant metastatic disease. The remaining nine patients had regional disease and were treated with both chemotherapy and radiotherapy, including prophylactic brain irradiation in four patients. Long-term survival can be achieved in a small number of patients in all stages of small cell carcinoma with intensive combination chemotherapy.


Brain mechanisms underlying the placebo effect in neurological disorders.
The potential of placebo treatments to alleviate a variety of medical conditions has long been recognised. Although the placebo effect is widely known, the physiological mechanisms underlying this phenomenon are not well understood. This review focuses on the existing evidence for placebo responses in different neurological conditions, including pain, Parkinson's disease, depression, sleep and immune-mediated disorders. Special attention is paid to the neural changes associated with placebo treatments, as revealed by in vivo neurophysiological and functional neuroimaging studies. Converging evidence suggests that placebo analgesia is linked to the activation of the endogenous opioid analgesia network, whilst dopaminergic pathways seem to play a central role in the placebo effect in movement disorders and neuroimmunomodulation. Further research on the placebo response is needed, both to improve the efficacy of its application in clinical practice and to shed more light on the complexity of mind-body interactions.


Transcriptomes of Frankia sp. strain CcI3 in growth transitions.
Frankia sp. strains are actinobacteria that form N2-fixing root nodules on angiosperms. Several reference genome sequences are available enabling transcriptome studies in Frankia sp. Genomes from Frankia sp. strains differ markedly in size, a consequence proposed to be associated with a high number of indigenous transposases, more than 200 of which are found in Frankia sp. strain CcI3 used in this study. Because Frankia exhibits a high degree of cell heterogeneity as a consequence of its mycelial growth pattern, its transcriptome is likely to be quite sensitive to culture age. This study focuses on the behavior of the Frankia sp. strain CcI3 transcriptome as a function of nitrogen source and culture age. To study global transcription in Frankia sp. CcI3 grown under different conditions, complete transcriptomes were determined using high throughput RNA deep sequencing. Samples varied by time (five days vs. three days) and by culture conditions (NH4+ added vs. N2 fixing). Assembly of millions of reads revealed more diversity of gene expression between five-day and three-day old cultures than between three day old cultures differing in nitrogen sources. Heat map analysis organized genes into groups that were expressed or repressed under the various conditions compared to median expression values. Twenty-one SNPs common to all three transcriptome samples were detected indicating culture heterogeneity in this slow-growing organism. Significantly higher expression of transposase ORFs was found in the five-day and N2-fixing cultures, suggesting that N starvation and culture aging provide conditions for on-going genome modification. Transposases have previously been proposed to participate in the creating the large number of gene duplication or deletion in host strains. Subsequent RT-qPCR experiments confirmed predicted elevated transposase expression levels indicated by the mRNA-seq data. The overall pattern of gene expression in aging cultures of CcI3 suggests significant cell heterogeneity even during normal growth on ammonia. The detection of abundant transcription of nif (nitrogen fixation) genes likely reflects the presence of anaerobic, N-depleted microsites in the growing mycelium of the culture, and the presence of significantly elevated transposase transcription during starvation indicates the continuing evolution of the Frankia sp. strain CcI3 genome, even in culture, especially under stressed conditions. These studies also sound a cautionary note when comparing the transcriptomes of Frankia grown in root nodules, where cell heterogeneity would be expected to be quite high.


Sex differences in functional activation patterns revealed by increased emotion processing demands.
Two [O(15)] PET studies assessed sex differences regional brain activation in the recognition of emotional stimuli. Study I revealed that the recognition of emotion in visual faces resulted in bilateral frontal activation in women, and unilateral right-sided activation in men. In study II, the complexity of the emotional face task was increased through tje addition of associated auditory emotional stimuli. Men again showed unilateral frontal activation, in this case to the left; whereas women did not show bilateral frontal activation, but showed greater limbic activity. These results suggest that when processing broader cross-modal emotional stimuli, men engage more in associative cognitive strategies while women draw more on primary emotional references.


Geometric hysteresis of alveolated ductal architecture.
Low Reynolds number airflow in the pulmonary acinus and aerosol particle kinetics therein are significantly conditioned by the nature of the tidal motion of alveolar duct geometry. At least two components of the ductal structure are known to exhibit stress-strain hysteresis: smooth muscle within the alveolar entrance rings, and surfactant at the air-tissue interface. We hypothesize that the geometric hysteresis of the alveolar duct is largely determined by the interaction of the amount of smooth muscle and connective tissue in ductal rings, septal tissue properties, and surface tension-surface area characteristics of surfactant. To test this hypothesis, we have extended the well-known structural model of the alveolar duct by Wilson and Bachofen (1982, "A Model for Mechanical Structure of the Alveolar Duct," J. Appl. Physiol. 52(4), pp. 1064-1070) by adding realistic elastic and hysteretic properties of (1) the alveolar entrance ring, (2) septal tissue, and (3) surfactant. With realistic values for tissue and surface properties, we conclude that: (1) there is a significant, and underappreciated, amount of geometric hysteresis in alveolar ductal architecture; and (2) the contribution of smooth muscle and surfactant to geometric hysteresis are of opposite senses, tending toward cancellation. Quantitatively, the geometric hysteresis found experimentally by Miki et al. (1993, "Geometric Hysteresis in Pulmonary Surface-to-Volume Ratio during Tidal Breathing," J. Appl. Physiol. 75(4), pp. 1630-1636) is consistent with little or no smooth muscle tone in anesthetized rabbits in control conditions, and with substantial smooth muscle activation following methacholine challenge. The observed local hysteretic boundary motion of the acinar duct would result in irreversible acinar flow fields, which might be important mechanistic contributors to aerosol mixing and deposition deep in the lung.


Determinants of quality of life in epilepsy.
Although depression is associated with diminished quality of life (QOL) in epilepsy patients, the relative contributions of epilepsy-specific concerns, as well as clinical and cognitive variables of QOL, have not been simultaneously investigated. A comprehensive neuropsychological test battery including the Beck Depression Inventory (BDI), Epilepsy Foundation of America's (EFA) Concerns Index, MMPI-2, QOLIE-89, WAIS-III, and Selective Reminding was administered to 115 epilepsy surgery candidates with normal Full Scale IQs. Linear regression analyses were performed to identify significant predictor combinations of QOLIE-89 total score. Regression analysis demonstrated that depressive symptomatology, whether reflected by the BDI (R2=0.45) or Depression scale of the MMPI-2 (R2=0.36), was a robust individual QOL predictor. Seizure Worry from the EFA Concerns Index was nearly as effective as the BDI in predicting QOLIE-89 (R2=0.42). When the BDI and EFA Concerns Index were combined into the same regression, both factors continued to contribute significantly to the QOLIE-89 total score, with both variables accounting for 61% of the variance. Although patients who developed their seizures at an older age had poorer QOL and patients with higher educational levels reported higher QOL, neither factor was related to QOL after accounting for the effects of psychological variables and epilepsy-related concerns. Although quality of life has multiple determinants, symptoms of depression and seizure worry are the most important factors affecting QOL in patients with intractable epilepsy.


Transgenic Expression of a Viral Cystatin Gene CpBV-CST1 in Tobacco Confers Insect Resistance.
A viral gene, CpBV-CST1, was identified from a polydnavirus Cotesia plutellae bracovirus (CpBV). Its protein product was significantly toxic to lepidopteran insects. This study generated a transgenic tobacco plant expressing CpBV-CST1 Expression of transgene CpBV-CST1 was confirmed in T1 generation (second generation after transgenesis) in both mRNA and protein levels. Young larvae of Spodoptera exigua (Hübner) suffered high mortalities after feeding on transgenic tobacco. All 10 T1 transgenic tobacco plants had no significant variation in speed-to-kill. In order to further explore insect resistance of these transgenic tobaccos, bioassays were performed by assessing antixenosis and antibiosis. S. exigua larvae significantly avoided T1 plants in a choice test. Larvae fed with T1 plant exhibited significant decrease in protease activity in the midgut due to consuming CpBV-CST1 protein produced by the transgenic plant. Furthermore, the transgenic tobacco exhibited similar insect resistance to other tobacco-infesting insects, including a leaf-feeding insect, Helicoverpa assulta, and a sap-feeding insect, Myzus persicae These results demonstrate that a viral cystatin gene can be used to develop insect-resistant transgenic plant, suggesting a prospective possibility of expanding the current transgenic approach to high-valued crops.


Comparative analysis of macrophage migration inhibitory factors (MIFs) from the parasitic nematode Onchocerca volvulus and the free-living nematode Caenorhabditis elegans.
The macrophage migration inhibitory factors (MIFs) from the filarial parasite Onchocerca volvulus (OvMIF) were compared to the MIFs from the free-living nematode Caenorhabditis elegans (CeMIF) with respect to molecular, biochemical and immunological properties. Except for CeMIF-4, all other MIFs demonstrated tautomerase activity. Surprisingly, OvMIF-1 displayed oxidoreductase activity. The strongest immunostaining for OvMIF-1 was observed in the outer cellular covering of the adult worm body, the syncytial hypodermis; moderate immunostaining was observed in the uterine wall. The generation of a strong humoral immune response towards OvMIF-1 and reduced reactivity to OvMIF-2 was indicated by high IgG levels in patients infected with O. volvulus and cows infected with the closely related Onchocerca ochengi, both MIFs revealing identical amino acid sequences. Using Litomosoides sigmodontis-infected mice, a laboratory model for filarial infection, MIFs derived from the tissue-dwelling O. volvulus, the rodent gut-dwelling Strongyloides ratti and from free-living C. elegans were recognized, suggesting that L. sigmodontis MIF-specific IgM and IgG1 were produced during L. sigmodontis infection of mice and cross-reacted with all MIF proteins tested. Thus, MIF apparently functions as a target of B cell response during nematode infection, but in the natural Onchocerca-specific human and bovine infection, the induced antibodies can discriminate between MIFs derived from parasitic or free-living nematodes.


Determination of short-chain fatty acids in equine caecal liquor by ion exchange high performance liquid chromatography after solid phase extraction.
A high performance liquid chromatography (HPLC) method was developed for the determination of seven short-chain fatty acids in equine caecal liquor. Samples were cleaned up on a Sep-pak (C18) cartridge, and the analyte was eluted from the extraction cartridge and filtered through a 0.45 micron cellulose nitrate filter. The analyte was chromatographed by ion exchange HPLC. Detection was by UV at 210 nm. Recovery from phosphate buffer (0.05 M, pH 7.0) and equine caecal liquor was 76.95% (lactic), 76.76% (valeric). The limit of (propionic), 89.35% (isobutyric), 88.73% (butyric), 80.33% (isovaleric) and 72.61% (valeric). The limit of detection of the short-chain fatty acids in phosphate buffer was 0.00006 M (lactic), 0.0001 M (acetic), 0.0002 M (propionic), 0.0001 M (isobutyric), 0.0002 M (butyric), 0.0002 M (isovaleric) and 0.0003 M (valeric). The specificity and sensitivity of this method was sufficiently high to allow the characterization of the pattern of these short-chain fatty acids in equine caecal liquor following intravenous administration of oxytetracycline at the recommended dose rate in a pony.


Contagious bovine pleuropneumonia-protection following natural infection and vaccination.
Cattle that recover from contagious bovine pleuropneumonia, the disease caused by Mycoplasma mycoides var. mycoides, are usually immune to reinfection. Prohylactic inoculation against the disease has been practiced for over a century and utilizes the fact that even virulent strains of M. mycoides inoculated subcutaneously into fully susceptible cattle only very rarely produce pneumonia, but instead produce subcutaneous lesions which may or may not kill the animals depending on various factors including the site of the inoculation and virulence of the strains. Animals that survive are immune to further local infections or to the natural disease. The most successful vaccines at present consist of live attenuated strains of M. mycoides which produce a slight local reaction at the site of inoculation. It appears that vaccines made from inactivated organisms are poorly immunogenic and may even sensitize the animals thereby causing them to react more severely to subsequent challenge.


Associations between apolipoprotein E genotype and circulating F2-isoprostane levels in humans.
Apolipoprotein E (apoE), an important determinant of plasma lipoprotein metabolism, has three common alleles (epsilon2, epsilon3, and epsilon4). Population studies have shown that the risk of diseases characterized by oxidative damage, such as coronary heart disease and Alzheimer's disease, is significantly higher in epsilon4 carriers. We evaluated the association between apoE genotypes and plasma F2-isoprostane levels, an index of lipid peroxidation, in humans. Two hundred seventy-four healthy subjects (104 males, 170 females; 46.9 +/- 13.0 yr; 200 whites, 74 blacks; 81 nonsmokers, 64 passive smokers, and 129 active smokers) recruited for a randomized clinical antioxidant intervention trial were included in this analysis. ApoE genotype was determined by PCR and restriction enzyme digestion. Free plasma F2-isoprostane was measured by GC-MS. Genotype groups were compared using multiple regression analysis with adjustment for sex, age, race, smoking status, body mass index, plasma ascorbic acid, and beta-carotene. Subjects with epsilon3/epsilon4 and epsilon4/epsilon4 genotype (epsilon4-carriers) and with epsilon2/epsilon3 and epsilon3/epsilon3 (non-epsilon4-carriers) were pooled for analysis. In subjects with high cholesterol levels (total cholesterol above 200 mg/dl), plasma F2-isoprostane levels were 29% higher in epsilon4 carriers than in non-epsilon4-carriers (P= 0.0056). High-cholesterol subjects that are epsilon4 carriers have significantly higher levels of lipid peroxidation as assessed by circulating F2-isoprostane levels.


The evaluation of eye-catching effect in freeway tunnel entrance zone based on fixation behavior characteristics.
The visual attraction of the freeway tunnel entrance zone will affect the driver's visual performance and visual workload, and then affect the driving safety. The purpose of this study is to explore the influence of different visual attraction conditions in the entrance zone of the freeway tunnel on driver's fixation behavior, and then evaluate the impact of eye-catching effect on driving safety. Thirty-five participants were recruited for the naturalistic driving experiment. Four different visually attractive driving scenarios (baseline, landscape-style architecture, tip slogan, and billboard) were selected. Participants' fixation behavior data were collected using an eye-tracking device. The effects of the visual attraction conditions in the freeway tunnel entrance zones were analyzed on driver fixation duration, number of fixations, fixation deviation, and pupil diameter. The results demonstrated significant effects of different visual attractions in the entrance zone of the freeway tunnel on drivers' fixation behavior. Under the visual attraction of the billboard, drivers exhibited the most number of fixations. And under the visual attraction of tip slogan, drivers had the longest average fixation duration, the smallest horizontal fixation deviation, the largest vertical fixation deviation, and the highest pupil diameter and its coefficient of variation. It can be concluded that different visual attractions in the freeway tunnel entrance zone have different effects on the eye-catching effect of drivers, by influencing the fixation behavior characteristics of drivers. Billboard is most effective in capturing drivers' visual attention, and tip slogan requires greater attention allocation and visual cognitive effort from drivers, resulting in the highest visual cognitive workload. This study highlights the complex relationship between visual attraction and its performance on driver fixation behavior. The insights from this study can provide valuable references for the design and optimization of the visual environment in the entrance zone of freeway tunnels.


Biomedical engineering in heart-brain medicine: a review.
New reports have emerged exploring the use of electrical stimulation of peripheral nerves in patients for the treatment of depression, heart failure, and hypertension. Abolishing renal sympathetic nerve activity in resistant hypertension has also been described. Since nerve bundles carry a variety of signals to multiple organs, it is necessary to develop technologies to stimulate or block targeted nerve fibers selectively. Mathematical modeling is a major tool for such development. Purposeful modeling is also needed to quantitatively characterize complex heart-brain interactions, allowing an improved understanding of physiological and clinical measurements. Automated control of therapeutic devices is a possible eventual outcome.


Purinergic signalling - a possible mechanism for KCNQ1 channel response to cell volume challenges.
A number of K(+) channels are regulated by small, fast changes in cell volume. The mechanisms underlying cell volume sensitivity are not known, but one possible mechanism could be purinergic signalling. Volume activated ATP release could trigger signalling pathways that subsequently lead to ion channel stimulation and cell volume back-regulation. Our aim was to investigate whether volume sensitivity of the voltage-gated K(+) channel, KCNQ1, is dependent on ATP release and regulation by purinergic signalling. We used Xenopus oocytes heterologously expressing human KCNQ1, KCNE1, water channels (AQP1) and P2Y2 receptors. ATP release was monitored by a luciferin-luciferase assay and ion channel conductance was recorded by two-electrode voltage clamp. The luminescence assay showed that oocytes released ATP in response to mechanical, hypoosmotic stimuli and hyperosmotic stimuli. Basal ATP release was approx. three times higher in the KCNQ1 + AQP1 and KCNQ1 injected oocytes compared to the non-injected ones. Exogenously added ATP (0.1 mm) did not have any substantial effect on volume-induced KCNQ1 currents. Nevertheless, apyrase decreased all currents by about 50%. Suramin inhibited about 23% of the KCNQ1 volume sensitivity. Expression of P2Y2 receptors stimulated endogenous Cl(-) channels, but it also led to 68% inhibition of the KCNQ1 currents. Adenosine (0.1 mm) also inhibited the KCNQ1 currents by about 56%. Xenopus oocytes release ATP in response to mechanical stimuli and cell volume changes. Purinergic P2 and P1 receptors confer some of the KCNQ1 channel volume sensitivity, although endogenous adenosine receptors and expressed P2Y2 receptors do so in the negative direction.


Carboxyl-Functionalized, Europium Nanoparticle-Based Fluorescent Immunochromatographic Assay for Sensitive Detection of Citrinin in Monascus Fermented Food.
A fluorescent immunochromatographic test strip (FICTS) based on the use of europium nanoparticles (EuNPs) was developed and applied to detect citrinin (CIT) in Monascus fermented food. The sensitivity of the immunoassay to detect CIT was greatly improved by the use of a specific monoclonal antibody to attach EuNPs to form a probe. Under optimum conditions, the visual detection limit was 2.5 ng/mL, and the detection limit of the instrument was 0.05 ng/mL. According to the results, the IC50 was 0.4 ng/mL. Matrix interference from various Monascus fermented foods was investigated in food sample detection. The immunosensor also demonstrated high recoveries (86.8-113.0%) and low relative standard deviations (RSDs) (1.8-15.3%) when testing spiked Monascus fermented food. The detection results of this method showed a good correlation (R2 > 0.98) with high-performance liquid chromatography (HPLC). The results showed that the FICTS method could be used as a rapid, sensitive method to detect CIT in Monascus fermented food.


Knowledge about influenza and adherence to the recommendations for influenza vaccination of pregnant women after an educational intervention in Greece.
Pregnant women and young infants are at increased risk for influenza-associated severe disease, complications and hospitalizations. In Greece influenza vaccination during pregnancy remains extremely low. We studied the knowledge about influenza and the adherence to the recommendations for influenza vaccination of pregnant women following an educational intervention in a large maternity hospital. A standardized questionnaire was used. A knowledge score was calculated for each woman. A total of 304 pregnant women were studied [mean age: 31.5 years (standard deviation (SD): 5.4 years), mean gestational age: 27.8 weeks (SD: 9.6 weeks)]. Their mean knowledge score was 87%. Sixty pregnant women (19.5%) were vaccinated against influenza at a mean gestational age of 24.6 weeks (SD: 7.5 weeks). Multiple regression analysis revealed that previous influenza vaccination and information about the need to get vaccinated were the only significant factors associated with an increased probability for influenza vaccination during pregnancy (47% versus 17% in women with and without a history of influenza vaccination in the past, respectively; odds ratio = 3.6; p-value = 0.016, and 32% versus 4% in women informed compared to those uninformed about the need for vaccination during pregnancy, respectively; odds ratio = 17.8; p-value<0.001). Seventy women provided a reason for refusing influenza vaccination. "Fear of adverse events" (for them or the fetus) was the prevalent reason for refusing influenza vaccination (19 women; 27%), followed by the statements "influenza vaccination is not necessary" (13; 18.5%) and "not at risk to get influenza" (9; 13%). In conclusion, an educational intervention was associated with an influenza vaccination rate of 19.5% among pregnant women compared to <2% the past years. In order to improve vaccine uptake by pregnant women and protect them and their babies, more intensified interventions should be explored.


VvBBX44 and VvMYBA1 form a regulatory feedback loop to balance anthocyanin biosynthesis in grape.
Anthocyanins are essential for the quality of perennial horticultural crops, such as grapes. In grapes, ELONGATED HYPOCOTYL 5 (HY5) and MYBA1 are two critical transcription factors that regulate anthocyanin biosynthesis. Our previous work has shown that Vitis vinifera B-box protein 44 (VvBBX44) inhibits anthocyanin synthesis and represses VvHY5 expression in grape calli. However, the regulatory mechanism underlying this regulation was unclear. In this study, we found that loss of VvBBX44 function resulted in increased anthocyanin accumulation in grapevine callus. VvBBX44 directly represses VvMYBA1, which activates VvBBX44. VvMYBA1, but not VvBBX44, directly modulates the expression of grape UDP flavonoid 3-O-glucosyltransferase (VvUFGT). We demonstrated that VvBBX44 represses the transcriptional activation of VvUFGT and VvBBX44 induced by VvMYBA1. However, VvBBX44 and VvMYBA1 did not physically interact in yeast. The application of exogenous anthocyanin stimulated VvBBX44 expression in grapevine suspension cells and tobacco leaves. These findings suggest that VvBBX44 and VvMYBA1 form a transcriptional feedback loop to prevent overaccumulation of anthocyanin and reduce metabolic costs. Our work sheds light on the complex regulatory network that controls anthocyanin biosynthesis in grapevine.


Automatic Design of High-Sensitivity Color Filter Arrays with Panchromatic Pixels.
In most of existing digital cameras, color images have to be reconstructed from raw images which only have one color sensed at each pixel, as their imaging sensors are covered by color filter arrays (CFAs). At each pixel a CFA usually allows only a portion of the light spectrum to pass through and thereby reduces the light sensitivity of pixels. To address this issue, previous works have explored adding panchromatic pixels into CFAs. However, almost all existing methods assign panchromatic pixels empirically, making the designed CFAs prone to aliasing artifacts. In this paper, based on a mathematical model we propose a fully automatic approach to designing high-sensitivity CFAs using panchromatic pixels. By the frequency structure representation of CFAs, we formulate high-sensitivity CFA design as a continuous multi-objective optimization problem, where robustness to aliasing artifacts and percentage of panchromatic pixels are simultaneously maximized. We analyze the characteristics of our new formulation. According to the analysis, we develop a new method to propose frequency structure candidates, which can produce CFAs that reach a desired percentage of panchromatic pixels. Then for each candidate, we optimize parameters to obtain the final CFA, which is an appropriately balanced solution to the multi-objective optimization problem. We formulate the two design procedures as constrained optimization problems and solve them using the alternating direction method (ADM). Extensive experiments confirm the advantage of the proposed method in both low-light and normal-light conditions.


Localization of immunoreactivity for calcitonin gene-related peptide in the rat anterior pituitary during ontogeny and gonadal steroid manipulations and detection of its messenger ribonucleic acid.
Localization of calcitonin gene-related peptide (CGRP) expression in the rat anterior pituitary and its changes during ontogeny and after gonadal steroid manipulations were studied by immunocytochemistry, RIA, and in situ hybridization. Colocalization studies and the combined use of immunocytochemistry and in situ hybridization revealed that CGRP immunoreactivity is localized mainly in gonadotropes and alpha- and beta-CGRP messenger RNAs were detected in CGRP-immunoreactive cells. Immunoreactivity for CGRP also was detected in nerve fibers and colocalized with substance P immunoreactivity. Cells immunoreactive to CGRP antiserum were first detected in fetal rats at gestational day 18, and the incidence considerably increased between postnatal days 5 and 14. CGRP immunoreactivity was low in control adults of both sexes and in pregnant and ovariectomized females but increased in lactating, estrogen-supplemented ovariectomized and high-dose estrogen-treated females, and in high-dose estrogen-treated and castrated males. Testosterone supplement suppressed the effect of castration on CGRP immunoreactivity in males. Quantities of extractable immunoreactive CGRP under conditions of estrogen manipulation corresponded well to the immunocytochemical findings (females: controls, 96.4 +/- 13.1 fmol/gland; ovariectomized, 107.6 +/- 19.2; high-dose estrogen-treated, 212 +/- 23.0; estrogen-supplemented ovariectomized, 680 +/- 42.1). The present study suggests that pituitary CGRP is synthesized and stored in gonadotropes, is modulated by gonadal steroids, and may have a functional link with gonadotropins.