Temporal relationship between single unit activity in superior olivary complex and scalp-derived auditory brainstem response in guinea pig.
Single unit activities in the region of the superior olivary complex were recorded from 8 guinea pigs concurrently with the recording of auditory brainstem potentials from the scalp. At any one anatomical site, be it a fiber tract (e.g. trapezoid body) or a nucleus (e.g. medial nucleus of the trapezoid body), the modal latency of the onset discharge of the units encountered corresponded in time with the latencies of several different waves (waves P2-P5) of the auditory brainstem response (ABR). Moreover, at the time of occurrence of just one of the ABR waves, single units in several diverse anatomical sites in and around the superior olive were found with modal latencies of onset discharge at that same time period. The slopes of the latency/intensity functions for both the peaks of the ABR and the modal latency of the onset discharge for most of the single units studied in the superior olive and its adjacent fiber tracts were remarkably similar. These data support the hypothesis of multiple rather than single generator site(s) for components of the ABR, at least, for waves P2-P5 in the guinea pig. These data do not distinguish whether the ABR are generated in part by travelling nerve action potentials or graded synaptic events.


Successful surgical cricothyroidotomy following an obstetric "can't oxygenate" scenario: a narrative of enabling factors.
The airway management of a patient requiring emergency caesarean delivery for fetal distress and pre-eclampsia with severe features is described. A difficult obstetric airway was anticipated prior to induction and managed with the use of decision-support guidelines and cognitive aids. Failed tracheal intubation later progressed to a "can't oxygenate" scenario necessitating front-of-neck-access via surgical cricothyroidotomy. We discuss the factors which facilitated the preparation and implementation of interventions required to successfully execute this high-acuity task.


Immobilizing photogenerated electrons from graphitic carbon nitride for an improved visible-light photocatalytic activity.
Reducing the recombination probability of photogenerated electrons and holes is pivotal in enhancing the photocatalytic ability of graphitic carbon nitride (g-C3N4). Speeding the departure of photogenerated electrons is the most commonly used method of achieving this. To the best of our knowledge, there is no report on suppressing the recombination of photogenerated electron-hole pairs by immobilizing the electrons with ester functional groups. Here, for the first time the mesoporous g-C3N4 (mpg-C3N4) was integrated with polymethyl methacrylate, a polymer abundant in ester groups, which showed a photocatalytic activity unexpectedly higher than that of the original mpg-C3N4 under visible-light irradiation. Experimental observations, along with theoretical calculations, clarified that the impressive photocatalytic ability of the as-modified mpg-C3N4 was mainly derived from the immobilization of photogenerated electrons via an electron-gripping effect imposed by the ester groups in the polymethyl methacrylate. This novel strategy might also be applied in improving the photocatalytic performance of other semiconductors.


Evidence of a neurotransmitter role for aspartate and gamma-aminobutyric acid in the rat olfactory cortex.
1. Using a cortical cup technique, the release of seven endogenous amino acids from the isolated rat olfactory cortex slice has been monitored.2. Electrical stimulation of the lateral olfactory tract at a frequency of 4 min(-1) was accompanied by a significant increase in the release of aspartate, GABA and taurine; the release of GABA and aspartate but not that of taurine was Ca(2+)-dependent.3. Chronic unilateral bulbectomy was accompanied by a specific, significant fall in the aspartate content of the olfactory cortex which reached a maximum 5 days after surgery and persisted for at least a further 5 days. Electrical stimulation of the lateral olfactory tract of such preparations did not release any of the amino acids under investigation.4. When slices from the unoperated side were exposed to solutions containing 25 mM-K+ or stimulated with electrodes placed directly on the cortex enclosed by the cup there was a Ca(2+)-dependent release of aspartate and GABA accompanied by a Ca(2+)-independent release of taurine. Following chronic bulbectomy, these procedures failed to evoke significant release of aspartate whereas the characteristics of GABA and taurine release were unaltered.5. It is concluded that aspartate may be the excitatory transmitter of some of the terminals of the lateral olfactory tract fibres and that GABA may be a transmitter at some inhibitory synapses of the rat olfactory cortex.


Differential effects of nongenotoxic and genotoxic carcinogens on the preneoplastic lesions in the rat liver.
Glutathione S-transferase placental form (GST-P) positive foci development and its expression in liver exposed by nongenotoxic carcinogens phenobarbital (PB) and clofibrate (CF), and genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) were investigated as a measure of carcinogenic potential of these chemicals. Male F344 rats were initially given a single intraperitioneal injection of diethylnitrosamine (200 mg/kg), and 2 weeks later, animals were fed diets containing 0.03% IQ or 0.5% CF or 0.05% PB or basal diet as a control for 6 weeks. All rats were subjected to two-thirds partial hepatectomy (PH) at week 3. Sequential sacrifice of rats was performed at 8 weeks or 52 weeks, and liver tissues were examined for immunohistochemical staining of GST-P positive foci. The numbers (No./cm2) and areas (mm2/cm2) of GST-P positive foci were increased by IQ or PB, but were decreased by CF compare to the control. Consistent with the development of GST-P positive foci, a time-related increase in the expression of GST-P mRNA was found in the rats treated with IQ, whereas CF decreased it. The incidence of hepatocellular carcinoma at 52 weeks was increased by all three chemicals. These results show that PB and IQ induced GST-P positive foci, but the peroxisome proliferator CF did not, which suggest that the prediction of carcinogenic potency based on the development of prenoplastic foci may cause false negative in a particular category compounds like peroxisome proliferators.


Descriptive Epidemiology of Injuries Sustained in National Collegiate Athletic Association Men's and Women's Volleyball, 2013-2014 to 2014-2015.
There were 18,844 volleyball players in the National Collegiate Athletic Association (NCAA) in the 2014-2015 academic year. Little research has examined sex-based differences among these athletes. To examine injury epidemiology in NCAA men's and women's volleyball athletes. Descriptive epidemiology study. Level 3. Injury surveillance data from the 2013-2014 through 2014-2015 academic years were obtained from the NCAA Injury Surveillance Program for 6 men's and 33 women's collegiate volleyball teams. Injury rates per 1000 athlete-exposures (AEs) and injury rate ratios (IRRs) with 95% CIs were calculated. Time-loss (TL) injuries resulted in participation restriction for at least 24 hours, and non-time-loss (NTL) injuries resulted in participation restriction of less than 24 hours. Overall, 83 and 510 injuries were reported in men and women, respectively, leading to injury rates of 4.69 and 7.07 per 1000 AEs. The injury rate was greater in women than men (IRR, 1.51; 95% CI, 1.19-1.90). TL injury rates were 1.75 and 2.62 per 1000 AEs for men and women, respectively. The ankle was the most commonly injured body part among TL injuries (men, 25.8%; women, 24.3%); the knee was the most commonly injured body part among NTL injuries (men, 25.5%; women, 16.3%). Among TL injuries, common diagnoses included sprains (men, 25.8%; women, 31.2%) and concussions (men, 19.4%; women, 14.8%). Most TL concussions were due to ball contact (men, 83.3%; women, 53.6%). Compared with men, women had a greater NTL overuse injury rate (IRR, 3.47; 95% CI, 1.61-7.46). Compared with women, men had a greater TL injury rate associated with ball contact (IRR, 2.24; 95% CI, 1.07-4.68). There are differences in injury patterns and rates between male and female intercollegiate volleyball players. Although a limited-contact sport, a notable number of concussions were sustained, mostly from ball contact. Understanding injury patterns may aid clinicians in injury diagnosis, management, and prevention.


A new Papulaspora species from the infected eye of a horse: Papulaspora equi sp. nov.
An unusual fungus, probably traumatically introduced into the eye of a horse while grazing, was studied on various mycological media. Upon examination of colonies the organism produced bulbils and clearly exhibited the characteristics of a new species of Papulaspora, P. equi Shadomy & Dixon.


Reduced Attention in Former Smokers with and without COPD.
Attention difficulties are often reported by patients with chronic obstructive pulmonary disease (COPD); however, limited research exists using objective tests designed specifically to measure attention in this population. This study aimed to (1) identify specific attention deficits in COPD and (2) determine which demographic/clinical characteristics are associated with reduced attention. Eighty-four former smokers (53 COPD, 31 no COPD) completed questionnaires, pulmonary function testing, and the Conner's Continuous Performance Test II (CPT-II). Participants with and without COPD were compared on CPT-II measures of inattention, impulsivity, and vigilance. CPT-II measures that differed significantly between the two groups were further examined using hierarchical regression modeling. Demographic/clinical characteristics were entered into models with attention as the dependent variable. Participants with COPD performed worse than those without COPD on CPT measures of inattention and impulsivity (i.e., detectability [discrimination of target from non-target stimuli], perseverations [reaction time under 100 ms], omissions [target stimuli response failures], and commissions [responses to non-target stimuli]). More severe COPD (measured by greater airflow limitation) was associated with poorer ability to detect targets vs. foils and perseverative responding after adjusting for age and other covariates in the model. Former smokers with COPD experience problems with attention that go beyond slowed processing speed, including aspects of inattention and impulsivity. Clinicians should be aware that greater airflow limitation and older age are associated with attention difficulties, as this may impact functioning.


Alpha-bungarotoxin binding sites on sensory neurones and their axonal transport in sensory afferents.
The autoradiographic localization of [125I]alpha-bungarotoxin binding sites on primary sensory fibres was investigated. Nicotinic alpha-bungarotoxin binding sites were localized to a small sub-population of large dorsal root ganglion cells in the rat, monkey, cat and human dorsal root ganglia. Ligation of the sciatic nerve or dorsal root in the rat resulted in an anterograde accumulation of binding sites proximal to the dorsal root ganglion, and a small retrograde accumulation. Unilateral dorsal root section in the rat produced a loss of toxin binding sites mainly within lamina III of the dorsal horn. These results suggest that nicotinic alpha-bungarotoxin binding sites manufactured in large dorsal root ganglion cell bodies are transported both centrally to the spinal cord and also peripherally.


Life-history patterns of populations of the limpet Patella granularis: the dominant roles of food supply and mortality rate.
Rates of algal production were measured at 6 rocky intertidal sites on the southwestern Cape coast, South Africa, where populations of the limpet Patella granularis occur. Rates of algal production and limpet mortality were recorded at each site and both factors affected limpet reproductive fitness. Limpet growth rates and biomass at different sites were significantly correlated with rates of algal production, and limpet mortality was related to the density of African Black Oystercatchers, important predators of P. granularis. Life-time gametic output of a hypothetical cohort of limpets at each site was modelled using the measurements of growth, reproduction and mortality made at each site. Limpet cohorts at sites with rapid rates of algal production were predicted to have a larger life-time production of gametic material than cohorts at sites with slow algal production rates, except in instances of acute predatory pressure. In the light of the overriding influence of food supply on the expression of limpet life-history parameters, it is imperative that researchers consider food availability before assuming that local, population-specific differences in life-history patterns are due to genetic differences.


Value of the bronchodilator response in assessing controller naïve asthmatic children.
To define the bronchodilator response (BDR) cutoff point that best identified asthma to determine the frequency of abnormal spirometry results across severity. Controller naïve children were evaluated with clinical criteria alone to establish a diagnosis of asthma and severity classification, then compared with the BDR, which was calculated as the percent change from the initial forced expiratory volume in 1 second. Receiver operator characteristic analysis determined the cutoff point for asthma diagnosis that gave the best combination of sensitivity and specificity. Children with asthma (n = 346) and 51 children without asthma, aged 4 to 17 years, who met entry criteria for spirometry were identified. The mean BDR in asthmatics was 8.6% (95% CI, 7.5-9.8), compared with 2.2% (95% CI, 0.2-4.3) for non-asthmatics (P < .001). A BDR > or = 9% best differentiated these populations with a sensitivity rate of 42.5% and a specificity rate of 86.3%. Abnormal spirometry results, defined as a BDR > or = 9%, a forced expiratory volume in 1 second < 80% predicted, or both, ranged from 44.4% for mild intermittent bronchial asthma to 57.0% for severe persistent bronchial asthma. Spirometric criteria that include BDR can potentially identify children who have clinically mild asthma and might benefit from controller therapy.


Predictive factors of biliary complications after bariatric surgery.
Obesity and rapid weight loss are risk factors for gallstone development. Bariatric surgery and significant postoperative weight loss are associated with postoperative biliary complications. We aim to identify predictive factors of biliary complications after bariatric surgery. University hospital. After Institutional Review Board approval, charts at a single institution were reviewed to identify patients with biliary complications after bariatric surgery from 2005 to 2012. Data collected included baseline patients demographic characteristics, perioperative parameters, and postoperative biliary complications. Parameters were analyzed using paired and unpaired Student t test for continuous variables and χ2 test for categorical variables. Univariate and multivariate analyses were used to assess risk factors for complications after bariatric surgery. All tests were 2 tailed; results with P<.05 were considered statistically significant. One hundred thirty-eight (3.6%) of 3765 patients who underwent bariatric surgery developed postoperative biliary complications. Mean time from surgery to biliary complication was 1.8±1.4 years. Complications included acute cholecystitis (18.1%), chronic cholecystitis (70.2%), acute pancreatitis (9.4%), choledocholithiasis (5.7%), and jaundice (2.8%). Interventions were laparoscopic (n = 134, 97.0%) and open (n = 1, .7%) cholecystectomy. Forty patients (28.9%) had known cholelithiasis before surgery. There were no mortalities. Univariate analysis identified female gender, age>50, cholelithiasis at time of bariatric procedure, and Roux-en-Y gastric bypass independent of excess weight loss as predictive factors of biliary complications. Multivariate analysis confirmed advanced age as an independent predictive factor. The results of our study suggest that patients of advanced age are at higher risk of biliary complications. However, the indications for prophylactic cholecystectomy at time of bariatric surgery remain unclear.


Structure-dependent genotoxic potencies of selected pyrrolizidine alkaloids in metabolically competent HepG2 cells.
1,2-unsaturated pyrrolizidine alkaloids (PAs) are natural plant constituents comprising more than 600 different structures. A major source of human exposure is thought to be cross-contamination of food, feed and phytomedicines with PA plants. In humans, laboratory and farm animals, certain PAs exert pronounced liver toxicity and can induce malignant liver tumors in rodents. Here, we investigated the cytotoxicity and genotoxicity of eleven PAs belonging to different structural classes. Although all PAs were negative in the fluctuation Ames test in Salmonella, they were cytotoxic and induced micronuclei in human HepG2 hepatoblastoma cells over-expressing human cytochrome P450 3A4. Lasiocarpine and cyclic diesters except monocrotaline were the most potent congeners both in cytotoxicity and micronucleus assays with concentrations below 3 μM inducing a doubling in micronuclei counts. Other open di-esters and all monoesters exhibited weaker or much weaker geno- and cytotoxicity. The findings were in agreement with recently suggested interim Relative Potency (iREP) factors with the exceptions of europine and monocrotaline. A more detailed micronuclei analysis at low concentrations of lasiocarpine, retrorsine or senecionine indicated that pronounced hypolinearity of the concentration-response curves was evident for retrorsine and senecionine but not for lasiocarpine. Our findings show that the genotoxic and cytotoxic potencies of PAs in a human hepatic cell line vary in a structure-dependent manner. Both the low potency of monoesters and the shape of prototype concentration-response relationships warrant a substance- and structure-specific approach in the risk assessment of PAs.


Fast-Scan Cyclic Voltammetry (FSCV) Reveals Behaviorally Evoked Dopamine Release by Sugar Feeding in the Adult Drosophila Mushroom Body.
Drosophila melanogaster, the fruit fly, is an excellent model organism for studying dopaminergic mechanisms and simple behaviors, but methods to measure dopamine during behavior are needed. Here, we developed fast-scan cyclic voltammetry (FSCV) to track in vivo dopamine during sugar feeding. First, we employed acetylcholine stimulation to evaluate the feasibility of in vivo measurements in an awake fly. Next, we tested sugar feeding by placing sucrose solution near the fly proboscis. In the mushroom body medial tip, 1 pmol acetylcholine and sugar feeding released 0.49±0.04 μM and 0.31±0.06 μM dopamine, respectively but sugar-evoked release lasted longer than with acetylcholine. Administering the dopamine transporter inhibitor nisoxetine or D2 receptor antagonist flupentixol significantly increased sugar-evoked dopamine. This study develops FSCV to measure behaviorally evoked release in fly, enabling Drosophila studies of neurochemical control of reward, learning, and memory behaviors.


Current and Developing Liquid Biopsy Techniques for Breast Cancer.
Breast cancer is the most commonly diagnosed cancer and leading cause of cancer mortality among woman worldwide. The techniques of diagnosis, prognosis, and therapy monitoring of breast cancer are critical. Current diagnostic techniques are mammography and tissue biopsy; however, they have limitations. With the development of novel techniques, such as personalized medicine and genetic profiling, liquid biopsy is emerging as the less invasive tool for diagnosing and monitoring breast cancer. Liquid biopsy is performed by sampling biofluids and extracting tumor components, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free mRNA (cfRNA) and microRNA (miRNA), proteins, and extracellular vehicles (EVs). In this review, we summarize and focus on the recent discoveries of tumor components and biomarkers applied in liquid biopsy and novel development of detection techniques, such as surface-enhanced Raman spectroscopy (SERS) and microfluidic devices.


A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients.
p53 accumulation and TP53 mutations are known prognostic markers for breast cancer. To clarify their interrelationship and the importance of different TP53 mutation types, these markers were investigated in tumours from 630 patients with breast cancer. Tumour sections were stained for p53 and scored based on staining intensity and percentages of invasive tumour cells with nuclear staining. TP53 mutations were identified by sequencing. Patient cohorts were from the DBCG (Danish Breast Cancer Cooperative Group) protocols DBCG82 and DBCG89. TP53 was mutated in 29% of the patients. The disease-specific survival (DSS) at 15 years of follow-up for patients with missense mutations directly involved in DNA or zinc binding was 21+/-8%. Patients with the remaining missense mutations within the structural/conserved domains and patients with null mutations had a DSS of 36+/-6% and 31+/-17%, respectively. For patients without TP53 mutations and patients with mutations affecting amino acids outside these domains, the 15 year DSS was 51+/-3% and 71+/-10%, respectively. p53 accumulation was successfully scored in 567 patients and categorized into three groups. Tumours with no p53 expression had a high frequency of null mutations (37% compared to 10% in the whole cohort), and tumours with high p53 expression contained 82% of the missense mutations inside structural/conserved domains including those directly involved in DNA or zinc binding. The clinical outcome for breast cancer patients is significantly different for different TP53 mutation types, but further functional studies are required to clarify the exact role of these mutation types. Most of the mutations that lead to mutant p53 protein accumulation can be detected by immunohistochemistry but the specificity is low. Samples showing lack of detectable p53 protein should be considered as an indication of a possible null mutation.


High transferability of bread wheat EST-derived SSRs to other cereals.
The increasing availability of expressed sequence tags (ESTs) in wheat (Triticum aestivum) and related cereals provides a valuable resource of non-anonymous DNA molecular markers. In this study, 300 primer pairs were designed from 265 wheat ESTs that contain microsatellites in order to develop new markers for wheat. Their level of transferability in eight related species [Triticum durum, T. monococcum, Aegilops speltoides, Ae. tauschii, rye (Secale cereale), barley (Hordeum vulgare), Agropyron elongatum and rice (Oryza sativa)] was assessed. In total, 240 primer pairs (80%) gave an amplification product on wheat, and 177 were assigned to wheat chromosomes using aneuploid lines. Transferability to closely related Triticeae species ranged from 76.7% for Ae. tauschii to 90.4% for T. durum and was lower for more distant relatives such as barley (50.4%) or rice (28.3%). No clear putative function could be assigned to the genes from which the simple sequence repeats (SSRs) were developed, even though most of them were located inside ORFs. BLAST: analysis of the EST sequences against the 12 rice pseudo-molecules showed that the EST-SSRs are mainly located in the telomeric regions and that the wheat ESTs have the highest similarity to genes on rice chromosomes 2, 3 and 5. Interestingly, most of the SSRs giving an amplification product on barley or rice had a repeated motif similar to the one found in wheat, suggesting a common ancestral origin. Our results indicate that wheat EST-SSRs show a high level of transferability across distantly related species, thereby providing additional markers for comparative mapping and for following gene introgressions from wild species and carrying out evolutionary studies.


MARCKS regulates tonic and chronic active B cell receptor signaling.
Tonic or chronic active B-cell receptor (BCR) signaling is essential for the survival of normal or some malignant B cells, respectively. However, the molecular mechanism regulating the strength of these two types of BCR signaling remains unknown. Here, using high-speed high-resolution single-molecule tracking in live cells, we identified that PKCβ, STIM1, and IP3R1/2/3 molecules affected the lateral Brownian mobile behavior of BCRs on the plasma membrane of quiescent B cells, which was correlated to the strength of BCR signaling. Further mechanistic studies revealed that these three molecules influenced BCR mobility by regulating the membrane tethering of MARCKS to the inner leaflet of the plasma membrane. Indeed, membrane-untethered or deficiency of MARCKS significantly decreased, while membrane-tethered or overexpression of MARCKS drastically increased the lateral mobility of BCRs. Functional experiments indicated that the membrane-tethered MARCKS suppressed the survival and/or proliferation in both B-cell tumor cells and mouse primary splenic B cells in vitro and in vivo. Mechanistically, we found that membrane-tethered MARCKS increased BCR lateral mobility, and thus decreased BCR nanoclustering by disturbing the interaction between cortical F-actin and the inner leaflet of the plasma membrane, resulting in the suppression of the strength of both tonic and chronic active BCR signaling. Conclusively, MARCKS is a newly identified molecule regulating the strength of BCR signaling by modulating cytoskeleton and plasma membrane interactions, both in the physiological and pathological conditions, suggesting that MARCKS is a putative target for drug design.


Selective activation of TRPA1 ion channels by nitrobenzene skin sensitizers DNFB and DNCB.
2, 4-dinitrofluorobenzene (DNFB) and 2, 4-dinitrochlorobenzene (DNCB) are well known as skin sensitizers that can cause dermatitis. DNFB has shown to more potently sensitize skin; however, how DNFB and DNCB cause skin inflammation at a molecular level and why this difference in their sensitization ability is observed remain unknown. In this study, we aimed to identify the molecular targets and mechanisms on which DNFB and DNCB act. We used a fluorescent calcium imaging plate reader in an initial screening assay before patch-clamp recordings for validation. Molecular docking in combination with site-directed mutagenesis was then carried out to investigate DNFB and DNCB binding sites in the TRPA1 ion channel that may be selectively activated by these tow sensitizers. We found that DNFB and DNCB selectively activated TRPA1 channel with EC50 values of 2.3 ± 0.7 μM and 42.4 ± 20.9 μM, respectively. Single-channel recordings revealed that DNFB and DNCB increase the probability of channel opening and act on three residues (C621, E625, and Y658) critical for TRPA1 activation. Our findings may not only help explain the molecular mechanism underlying the dermatitis and pruritus caused by chemicals such as DNFB and DNCB, but also provide a molecular tool 7.5-fold more potent than the current TRPA1 activator allyl isothiocyanate (AITC) used for investigating TRPA1 channel pharmacology and pathology.


Activated platelets interact with lung cancer cells through P-selectin glycoprotein ligand-1.
Hematogenous metastasis always leads to the poor prognosis of non-small cell lung cancers (NSCLC). Activated platelets are involved in hematogenous metastasis and may be a potential therapeutic target. P-selectin is an important adhesion molecule and expressed on the surface of activated platelets. P-selectin glycoprotein ligand-1 (PSGL-1) as a transmembrane protein is expressed on the surface of various cell types. P-selectin can bind to PSGL-1, and thereby initiate the platelet-mediated cell adhesion. The aim of the study was to investigate the degree of platelet activation in NSCLC and the roles of PSGL-1 in the activation of platelets. Purified platelets were obtained from NSCLC patients (40 lung adenocarcinomas and 26 lung squamous cell carcinomas), and P-selectin expression was detected by fluorescence-activated cell sorter. The population of peripheral blood platelets with P-selectin expression in lung adenocarcinoma was 63.16 ± 25.44 %, and significantly higher than that in lung squamous cell carcinoma (35.97 ± 17.19 %) and the healthy population (9.12 ± 7.66 %, n = 30). A specific small hairpin RNA (shRNA) for PSGL-1 was transfected into A549 human alveolar cell carcinoma cells. The expressions of PSGL-1 mRNA and protein were significantly reduced with the PSGL-1 shRNA (p < 0.01). Furthermore, the knockdown of PSGL-1 also resulted in the significantly reduced aggregate formation of activated platelets and A549 cells. Thus, activated platelets may interact with lung cancer cells through PSGL-1. Inhibiting platelet activation and/or down-regulating PSGL-1 expression may be useful for suppression of tumor metastasis.


The multidisciplinary management of a mechanical mitral valve thrombosis in pregnancy: a case report and review of the literature.
The management of anticoagulation for mechanical heart valves during pregnancy poses a unique challenge. Mechanical valve thrombosis is a devastating complication for which surgery is often the treatment of choice. However, cardiac surgery for prosthetic valve dysfunction in pregnant patients confers a high risk of maternofetal morbidity and mortality. A 39-year-old woman in her first pregnancy at 30 weeks gestation presented to hospital with a mechanical mitral valve thrombosis despite therapeutic anticoagulation with low-molecular-weight heparin. She underwent an emergent caesarean section followed immediately by a bioprosthetic mitral valve replacement. This occurred after careful planning and organization on the part of a large multidisciplinary team. A proactive, rather than reactive, approach to the surgical management of a mechanical valve thrombosis in pregnancy will maximize the chances of successful maternal and fetal outcomes.


Optimizing nutrient channel spacing and revisiting TGF-beta in large engineered cartilage constructs.
Cartilage tissue engineering is a promising approach to treat osteoarthritis. However, current techniques produce tissues too small for clinical relevance. Increasingly close-packed channels have helped overcome nutrient transport limitations in centimeter-sized chondrocyte-agarose constructs, yet optimal channel spacings to recapitulate native cartilage compositional and mechanical properties in constructs this large have not been identified. Transient active TGF-β treatment consistently reproduces native compressive Young׳s modulus (EY) and glycosaminoglycan (GAG) content in constructs, but standard dosages of 10ng/mL exacerbate matrix heterogeneity. To ultimately produce articular layer-sized constructs, we must first optimize channel spacing and investigate the role of TGF-β in the utility of channels. We cultured ∅10mm constructs with 0, 12, 19, or 27 nutrient channels (∅1mm) for 6-8 weeks with 0, 1, or 10ng/mL TGF-β; subsequently we analyzed them mechanically, biochemically, and histologically. Constructs with 12 or 19 channels grew the most favorably, reaching EY=344±113kPa and GAG and collagen contents of 10.8±1.2% and 2.2±0.2% of construct wet weight, respectively. Constructs with 27 channels had significantly less deposited GAG than other groups. Channeled constructs given 1 or 10ng/mL TGF-β developed similar properties. Without TGF-β, constructs with 0 or 12 channels exhibited properties that were indistinguishable, and lower than TGF-β-supplemented constructs. Taken together, these results emphasize that nutrient channels are effective only in the presence of TGF-β, and indicate that spacings equivalent to 12 channels in ∅10mm constructs can be employed in articular-layer-sized constructs with reduced dosages of TGF-β.


Analysis of interaction in binary odorant mixtures.
An understanding of the olfactory system of any animal must account for how odor mixtures are perceived and processed. The present experiments apply associationist models to the study of how elements are processed in binary odorant mixtures. Using experimental designs for Proboscis Extension Conditioning of honey bees, I show that learning about a pure odorant element is frequently affected by its occurrence in a mixture with a second odorant. Presence of a background odor when an odorant is associated with sucrose reinforcement decreases the rate and/or asymptotic level of associative strength that accumulates to that odorant. This interaction is in part due to synthetic qualities that arise in sensory transduction and initial processing. In addition, it involves an attention-like processing system like that involved in overshadowing. Therefore, a model that includes representations of the component and configural qualities of odorants in mixtures is needed to provide a more complete account of learning about odor mixtures.


Isolated mammillary body involvement on MRI in Wernicke's encephalopathy.
A 48-year-old woman, with a remote history of gastric-banding as well as recent-onset post-prandial vomiting and excessive wine-drinking, was admitted with progressively-worsening gait incoordination. She showed gaze-evoked nystagmus and gait ataxia. Brain MRI revealed conspicuous, isolated, symmetrical T2/FLAIR-hyperintensities and gadolinium-enhancement of the mammillary bodies. Serum thiamine and folate were low. Following thiamine and folate replacement therapy, her ataxia resolved. Given the rising number of bariatric procedures, we discuss the importance of recognizing thiamine-deficiency in these patients. Additionally, while isolated involvement of the mammillary bodies is a rare finding in this disorder, we highlight radiologic changes that neurologists should recognize.


Effect of dexamethasone on various stages of experimental brain abscess.
Rats were inoculated with staphylococcus aureus to produce cerebral abscesses and treated with either antibiotic or dexamethasone and with antibiotic plus dexamethasone at sequential stages of abscess formation. Antibiotic alone shortened the cerebritis stage, accelerated the encapsulation and affected the bacterial clearance in the abscess centre when it was started early in the course of cerebritis. Dexamethasone impaired the lymphocytic and fibroblastic responses and delayed the collagen deposition as well as suppressed the efficacy of antibiotic. However, it did not halt entirely the encapsulation and did reduce the associated cerebral oedema.


Transfusion therapy in critically ill children.
Critically ill children in pediatric intensive care units are commonly indicated for blood transfusion due to many reasons. Children are quite different from adults during growth and development, and that should be taken into consideration. It is very difficult to establish a universal transfusion guideline for critically ill children, especially preterm neonates. Treating underlying disease and targeted replacement therapy are the most effective approaches. Red blood cells are the first choice for replacement therapy in decompensated anemic patients. The critical hemoglobin concentration may be higher in critically ill children for many reasons. Whole blood is used only in the following conditions or diseases: (1) exchange transfusion; (2) after cardiopulmonary bypass; (3) extracorporeal membrane oxygenation; (4) massive transfusion, especially in multiple component deficiency. The characteristics of hemorrhagic diseases are so varied that their therapy should depend on the specific needs associated with the underlying disease. In general, platelet transfusion is not needed when a patient has platelet count greater than 10,000/mm3 and is without active bleeding, platelet functional deficiency or other risk factors such as sepsis. Patients with risk factors or age less than 4 months should be taken into special consideration, and the critical thrombocyte level will be raised. Platelet transfusion is not recommended in patients with immune-mediated thrombocytopenia or thrombocytopenia due to acceleration of platelet destruction without active bleeding or life-threatening hemorrhage. There are many kinds of plasma-derived products, and recombinant factors are commonly used for hemorrhagic patients due to coagulation factor deficiency depending on the characteristics of the diseases. The most effective way to correct disseminated intravascular coagulation (DIC) is to treat the underlying disease. Anticoagulant therapy is very important; heparin is the most common agent used for DIC but the results are usually not satisfactory. Antithrombin III, protein C, or recombinant thrombomodulin has been used successfully to treat this condition. For reducing the risk of organism transmission and adverse reactions resulting from blood transfusion, the following measures have been suggested: (1) replacement therapy using products other than blood (e.g., erythropoietin, iron preparation, granulocyte colony-stimulating factor); (2) special component replacement therapy for specific diseases; (3) autotransfusion; (4) subdividing whole packed blood products into smaller volumes to reduce donor exposure; (5) advances in virus-inactivating procedures. To avoid viral transmission, vapor-heated or pasteurized products and genetic recombinant products are recommended. Cytomegalovirus (CMV)-seronegative blood, leukoreduced and/or irradiated blood are recommended for prevention of CMV infection, graft-versus-host-disease and alloimmunization in neonate and immunocompromised patient transfusion. There is no reason to prescribe a plasma product for nutritional supplementation because of the risk of complications. The principle: complications of transfusion must be avoided, the rate of blood exposure should be reduced and the safety of the transfused agents or components should be maintained must always be kept in mind.


Identification and characterization of a serine protease inhibitor (PtSerpin) in the swimming crab Portunus trituberculatus.
Serine protease inhibitors (Serpins) play a key role in diverse immune biological processes. A serine protease inhibitor (Serpin), namely PtSerpin, was identified from the haemocyte cDNA library of swimming crab Portunus trituberculatus. The full-length PtSerpin cDNA was 1593 bp, including an open reading frame (ORF) of 1227 bp encoding a polypeptide of 408 amino acids with estimated molecular mass of 45.048 kDa and theoretical isoelectric point of 7.23. Predicted tertiary structure of PtSerpin contained three β-sheets and nine α-helices. Multiple sequence alignment revealed that deduced amino acid sequence of PtSerpin shared the highest similarity with serpin SPI from green mud crab Scylla paramamosain (SpSerpin). Phylogenetic analysis supported PtSerpin and SpSerpin were closely related to serpins from Penaeus monodon and Daphnia pulex while other decapods formed a separate group. Although the mRNA transcripts of PtSerpin could be detected in all the examined tissues, the higher levels were present in haemocytes and gills which are the major organs respond to pathogenic microorganism. After challenged by Vibrio alginolyticus, Micrococcus luteus and Pichia pastoris, the temporal expression of PtSerpin gene in haemocytes showed different activation times against bacteria and fungi within the experimental period of 72 h. These findings suggest that PtSerpin is involved in the antibacterial defense mechanism of P. trituberculatus crab.


Prolactin response to dexamethasone: a study on normal controls and depressed patients.
Pre- and post-dexamethasone prolactin and cortisol levels of 40 endogenous and non-endogenous depressive patients and of 20 controls were studied. Dexamethasone had a suppressive effect on prolactin levels, which was expressed more in normal controls and in non-endogenous depressive patients than in endogenous depression. A "prolactin suppression test" by dexamethasone was constructed and provided comparable results to the usual DST. However, it failed to be a specific marker for endogenous depression. There are close relationships between various endocrine axes, which might be altered in depression.


Etiology of Crohn's disease: Do certain food additives cause intestinal inflammation by molecular mimicry of mycobacterial lipids?
Crohn's disease is a chronic granulomatous inflammation of the gastrointestinal tract which was first described in the beginning of the 20th century. The histological similarity with intestinal tuberculosis has led to the assumption of an involvement of mycobacteria and mycobacterial antigens, respectively, in the etiology. A major defense mechanism against mycobacterial lipid antigens is the CD1 system which includes CD1 molecules for antigen presentation and natural killer T cells for recognition and subsequent production of cytokines like interferon-gamma and tumour necrosis factor-alpha. These cytokines promote granulomatous transformation. Various food additives, especially emulsifiants, thickeners, surface-finishing agents and contaminants like plasticizers share structural domains with mycobacterial lipids. It is therefore hypothesized, that these compounds are able to stimulate by molecular mimicry the CD1 system in the gastrointestinal mucosa and to trigger the pro-inflammatory cytokine cascade. The understanding of Crohn's disease as a CD1-mediated delayed-type hypersensitivity to certain food additives would lead to strong emphasis on a dietary treatment. Related aspects of pathology, physiology and epidemiology of Crohn's disease are presented.


High Dose Thoracic Re-Irradiation and Chemo-Immunotherapy for Centrally Recurrent NSCLC.
Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation. A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients. Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3-25.1), median progression free survival (PFS) was nine months (range 4.5-16), and median loco-regional control (LRC) was 12.1 months (range 6.5-20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033). The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.


Multiple myeloma.
Multiple myeloma is a clonal plasma cell malignancy that accounts for slightly more than 10% of all hematologic cancers. In this paper, we present a historically focused review of the disease, from the description of the first case in 1844 to the present. The evolution of drug therapy and stem-cell transplantation for the treatment of myeloma, as well as the development of new agents, is discussed. We also provide an update on current concepts of diagnosis and therapy, with an emphasis on how treatments have emerged from a historical perspective after certain important discoveries and the results of experimental studies.


Oxygen extraction ratio: a valid indicator of myocardial metabolism in anemia.
We have shown that primates adequately compensate for acute normovolemic anemia to hematocrits (HCT) of 10%. We have described a whole-body extraction ratio (O2 consumption/O2 delivery; ER) of 50% as a reliable physiologic indicator of transfusion need. There is concern that whole-body ER may not accurately reflect impaired myocardial metabolism. The onset of significant lactate production by the left ventricle is an indicator of anaerobic metabolism. Our purpose is to compare left ventricular lactate metabolism (arterial-coronary sinus lactate; delta [L]) to ER in acute normovolemic anemia. Fourteen adult baboons were anesthetized, paralyzed, and ventilated on room air. Left atrial, coronary sinus, aortic, and Swan-Ganz catheters were inserted. Experimental animals (N = 7) were hemodiluted, at constant left atrial pressure (LAP), with 5% human serum albumin (HSA) to a HCT below 4%. Control animals (N = 7) underwent similar volume exchanges, also at constant LAP, with homologous RBCs resuspended in HSA. Whole-body extraction ratio and left ventricular lactate production were measured at baseline and at hematocrits of 20, 10, 6, and 4% in the experimental group. Data were obtained at similar volume exchange points in the control group. Significant lactate production occurred only in the experimental animals (P less than 0.05) when extraction ratio exceeded 50%. Significant lactate production does not occur before the whole-body ER exceeds 50%. ER appears to be a valid indicator of myocardial metabolism in anemia, in this setting.


A strategy to identify protein-N-myristoylation-dependent phosphorylation reactions of cellular proteins by using Phos-tag SDS-PAGE.
To establish a strategy for identifying protein-N-myristoylation-dependent phosphorylation of cellular proteins, Phos-tag SDS-PAGE was performed on wild-type (WT) and nonmyristoylated mutant (G2A-mutant) FMNL2 and FMNL3, phosphorylated N-myristoylated model proteins expressed in HEK293 cells. The difference in the banding pattern in Phos-tag SDS-PAGE between the WT and G2A-mutant FMNL2 indicated the presence of N-myristoylation-dependent phosphorylation sites in FMNL2. Phos-tag SDS-PAGE of FMNL2 mutants in which the putative phosphorylation sites listed in PhosphoSitePlus (an online database of phosphorylation sites) were changed to Ala revealed that Ser-171 and Ser-1072 are N-myristoylation-dependent phosphorylation sites in FMNL2. Similar experiments with FMNL3 demonstrated that N-myristoylation-dependent phosphorylation occurs at a single Ser residue at position 174, which is a Ser residue conserved between FMNL2 and FMNL3, corresponding to Ser-171 in FMNL2. The facts that phosphorylation of Ser-1072 in FMNL2 has been shown to play a critical role in integrin β1 internalization mediated by FMNL2 and that Ser-171 in FMNL2 and Ser-174 in FMNL3 are novel putative phosphorylation sites conserved between FMNL2 and FMNL3 indicate that the strategy used in this study is a useful tool for identifying and characterizing physiologically important phosphorylation reactions occurring on N-myristoylated proteins.


Solid-phase synthesis of an arylsulfone hydroxamate library.
Synthesis of an arylsulfone hydroxamate lead optimization library is presented. Biological activity of representative examples is given to demonstrate the value of this approach for lead optimization.


Do deletions of Mos1-like elements occur randomly in the Drosophilidae family?
We compared deleted copies of the seven mauritiana subfamilies of mariner transposable elements in species of the Drosophilidae. All elements were detected by PCR using the inverted terminal repeats of the Mos1 element of Drosophila mauritiana as primers. A higher frequency of breakpoints in the 5prime prime or minute part of the element compared to the 3prime prime or minute part was observed. Of the 27 deletions, 9 (33%) occurred between short direct repeats (SDR) of 5 to 8 bp. The SDRs can be at or close to the breakpoints of the deletion. A deleted copy of D. simulans (St. Martin population) had three repeats of a motif present only once in the complete consensus sequence. The high frequency of SDRs at or near the breakpoints of the deletions strongly suggests that some of them do not occur at random. Mechanisms that might explain these deletions, such as unequal crossing-over, ectopic recombination, and abortive gap repair, are discussed.


Statistical Challenges of Big Brain Network Data.
We explore the main characteristics of big brain network data that offer unique statistical challenges. The brain networks are biologically expected to be both sparse and hierarchical. Such unique characterizations put specific topological constraints onto statistical approaches and models we can use effectively. We explore the limitations of the current models used in the field and offer alternative approaches and explain new challenges.


Androgen receptor splice variant 7 in castration-resistant prostate cancer: Clinical considerations.
Constitutively-active ligand-independent splice variants of the androgen receptor are an adaptive response by prostate cancer cells to escape androgen deprivation therapy and novel androgen receptor-directed treatments. Androgen receptor splice variant 7 is the most common splice variant detected in clinical biospecimens, and emerging data now suggest that the presence of tumoral androgen receptor splice variant 7 might be indicative of primary and acquired resistance to next-generation androgen pathway inhibitors, such as abiraterone and enzalutamide. At the same time, taxane chemotherapy might retain its efficacy regardless of androgen receptor splice variant 7 status, thus suggesting the potential for a predictive biomarker guiding treatment selection in men with metastatic castration-resistant prostate cancer. Herein, we review the preclinical data elucidating the structure and function of androgen receptor splice variant 7, we describe the existing clinical data using this biomarker in metastatic castration-resistant prostate cancer, and we highlight potential therapeutic strategies to target androgen receptor splice variant 7-expressing prostate cancer.


Colonic complications of renal transplantation.
Colonic complications of renal transplantation occur in 1.9 per cent of the cases. In our series of 587 consecutive renal transplants recipients 3 (0.51 per cent) had colonic complications, including 2 with ischemic colitis and 1 with pseudomembranous colitis. A review of 8 large series describing 2,539 additional renal transplant patients revealed 55 with significant colonic complications. The most common complication was ischemic colitis, which occurred in 29 patients, followed by diverticulitis in 17, pseudomembranous colitis in 5, appendicitis in 3, hemorrhagic proctitis in 1, a disrupted appendiceal stump in 1 and fecal impaction in 1. Etiological factors that may be important in the development of these colonic complications are uremia, blood volume redistribution, immunosuppressive therapy, antibiotic therapy, irradiation and previous retroperitoneal surgery.


Antimicrobial efficacy of biocides tested on skin using an ex-vivo test.
An ex-vivo test was used to evaluate the activity of antimicrobials against three microorganisms, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The ex-vivo test is a carrier test using freshly excised animal skin samples maintained in viable conditions for a short period of time. Skin samples came from a veterinary practice and were excised from either dogs or cats. The antimicrobial activity of povidone iodine, chlorhexidine diacetate, cetrimide and benzalkonium chloride was also evaluated with suspension and glass-carrier tests. Generally, the activity of the antimicrobials tested was reduced when applied to the skin surface. Apart from povidone iodine (2%) against S. aureus, the biocides investigated failed to achieve a 5 log10 reduction in bacterial titre when tested with the ex-vivo method. There was no significant difference in reduction of bacterial titres after treatment with antimicrobials between the glass-carrier and the suspension tests. Furthermore, the drying process of bacterial inoculum was less detrimental on skin than on glass surfaces. This study confirmed that the activity of a biocide tested in suspension or on an inanimate surface did not reflect its activity when tested on skin. Further development of the ex-vivo test may be useful, especially for testing the antimicrobial activity of formulations with antiseptic properties.


Dynamic analysis of metabolic effects of chloroacetaldehyde and cytochalasin B on tumor cells using bioelectronic sensor chips.
To study the interplay of drugs and energy metabolism of tumor cells, metabolic changes induced by chloroacetaldehyde and cytochalasin B were analyzed in colon carcinoma cells LS174T. O(2)-consumption and extracellular acidification were recorded using a bioelectronic sensor-chip system, which monitors these parameters in a culture continuously for at least 24 h. In parallel cultures cell number, cellular ATP-content, mitochondrial transmembrane potential, and the content of reactive oxygen species (ROS) were determined. When cell death was induced by chloroacetaldehyde (50 muM), the rate of acidification declined gradually for the next 15 h, while O(2)-consumption decreased rapidly within 30 min. This correlated with a loss in mitochondrial potential. However, cellular ATP-level showed a transient increase at 2 h; also ROS levels increased up to 6 h. In cells treated with cytochalasin B (2 muM), which inhibits glucose uptake, the rate of O(2)-consumption increased and the acidification activity dropped, even upon glutamine depletion. Mitochondrial membrane potential transiently increased after 1 h, while ATP-content decreased; there was no change in the level of ROS. The pattern of changes in basic energy metabolism differs with the type of cell death and growth inhibition involved in the cytotoxic action of two different drugs.


Effect of Helicobacter pylori eradication on the incidence of gastric cancer: a systematic review and meta-analysis.
Helicobacter pylori (H. pylori) is considered to be the most important risk factor for gastric cancer (GC). The International Agency for Research on Cancer reported that H. pylori eradication could reduce the risk of developing GC. Several clinical studies have investigated this relationship as well; however, their results are inconsistent owing to the varied inclusion criteria. To address the effect of H. pylori eradication on GC incidence, we conducted a comprehensive meta-analysis with several subgroup analyses to resolve these inconsistencies. We searched MEDLINE and Ichushi-Web to identify randomized control trial and cohort study articles (English or Japanese) through December 2016. Manual searches were also conducted to identify unlisted references in these databases. Eligible studies reported GC incidence as an outcome, with comparisons between H. pylori eradication and control groups. Subgroup analyses were conducted by country, conditions at baseline, and follow-up periods. We selected 28 studies among 1583 references in the databases and 4 studies by manual searches. The H. pylori eradication group showed significantly lower risk of GC [odds ratio (OR) 0.46; 95% confidence interval 0.39-0.55]. The subgroup analyses indicated that the beneficial effect of eradication was greater in Japan (OR 0.39; 95% CI 0.31-0.49), particularly among those with benign conditions (OR 0.32; 95% CI 0.19-0.54), although none of them was statistically significant. However, reduction of gastric cancer after eradication was significantly greater (p = 0.01) in the groups with long-term (5 years or longer) follow-up (OR 0.32; 95% CI 0.24-0.43) as compared to those with shorter follow-up (less than 5 years) (OR 0.55; 95% CI 0.41-0.72). Real world data showed that large-scale eradication therapy has been performed mostly for benign conditions in Japan. Since eradication effects in preventing gastric cancer are conceivably greater there, GC incidence may decline faster in Japan than expected from the previous meta-analyses data which were based on multi-national, mixed populations with differing screening quality and disease progression.


Interposition grafting of collagen-gelatin sponge impregnated with basic fibroblast growth factor in primary palatoplasty.
An oronasal fistula is a challenging post-operative complication of palatoplasty due to impaired velopharyngeal function or its high recurrence rate. Muscle repositioning, a key procedure in palatoplasty, causes dead space at the junction between the hard and soft palates. Consequently, thin oral and nasal mucosae are prone to break down and form fistulas. In this study, we used basic fibroblast growth factor-impregnated collagen gelatin sponge (bFGF-CGS) in primary palatoplasty to reduce fistula formation. This retrospective study assessed the complications and efficacy of bFGF-CGS to reduce fistula formation. Patients who underwent primary palatoplasty with bFGF-CGS were included. The same number of patients who underwent primary palatoplasty without bFGF-CGS was included as a control group. The outcomes included post-operative oronasal fistula formation, delayed healing, bleeding, and infection. Both groups included 44 patients. Except for age at palatoplasty, there were no statistically significant demographic differences between the two groups; however, the rates of fistula formation in the study and control group were 2.3% and 13.6%, respectively. There were no infections among the patients. The grafting of bFGF-CGS in primary palatoplasty was safe and probably effective in reducing post-operative oronasal fistula formation.


Alterations of membrane phosphorylation in erythrocyte membranes from patients with Duchenne muscular dystrophy.
The phosphorylation of spectrin, band 3 protein, and the phospholipids of erythrocyte membranes (ghosts) was examined in 10 patients with Duchenne muscular dystrophy (DMD) and in healthy age- and sex-matched controls. The rates of phosphorylation of spectrin and band 3 protein were significantly higher in ghosts prepared from patient blood than from control blood at both 30 degrees C and 37 degrees C. However, the mean increases in the rate of phosphorylation of both spectrin and band 3 protein in response to a temperature change from 30 degrees C to 37 degrees C were identical in ghosts from patient and controls. Phosphorylation of phospholipid and its temperature response did not differ between patients and controls. These results complement previous observations of differences in erythrocytes from patients with DMD. The similarity of the changes in phosphorylation of both spectrin and band 3 protein indicates a common cause, possibly their lipid environment.


Morphogenetic fields in embryogenesis, regeneration, and cancer: non-local control of complex patterning.
Establishment of shape during embryonic development, and the maintenance of shape against injury or tumorigenesis, requires constant coordination of cell behaviors toward the patterning needs of the host organism. Molecular cell biology and genetics have made great strides in understanding the mechanisms that regulate cell function. However, generalized rational control of shape is still largely beyond our current capabilities. Significant instructive signals function at long range to provide positional information and other cues to regulate organism-wide systems properties like anatomical polarity and size control. Is complex morphogenesis best understood as the emergent property of local cell interactions, or as the outcome of a computational process that is guided by a physically encoded map or template of the final goal state? Here I review recent data and molecular mechanisms relevant to morphogenetic fields: large-scale systems of physical properties that have been proposed to store patterning information during embryogenesis, regenerative repair, and cancer suppression that ultimately controls anatomy. Placing special emphasis on the role of endogenous bioelectric signals as an important component of the morphogenetic field, I speculate on novel approaches for the computational modeling and control of these fields with applications to synthetic biology, regenerative medicine, and evolutionary developmental biology.


Cost effectiveness analysis of using multiple neuromodalities in treating severe traumatic brain injury in a developing country like Malaysia.
The aim of this study was to determine the cost-effectiveness of using baseline neuromonitoring (BNM) compared with multimodality monitoring (M3) for severe traumatic brain injury (TBI). Sixty-two patients with severe TBI underwent a prospective observational study where they were divided into two groups of patients receiving treatment with M3 (32 patients) and BNM (30 patients). The macro and micro costings were performed on each patient. The Barthel Index score after 1 year was used as an outcome measurement tool for both groups. The cost-effectiveness (CE) ratio was calculated using the Poisson regression model. The costs of equipment and consumables between the groups was statistically significant (p < 0.001) after correcting for age and severity of injury. Other cost categories were not significantly different. The crude CE ratios were 168.66 (95% CI: 168.32, 169.03) and 144.16 (95% CI: 143.87, 144.45) for BNM and M3 respectively. The two crude CE ratios were significantly different (p < 0.001). It was calculated by controlling or adjusting age, gender, Glasgow Coma Score, Marshalls classification at admission and type of injury. The adjusted CE ratios were 171.32 (95% CI: 170.97, 171.68) and 141.50 (95% CI: 141.26, 141.79) for BNM and M3, respectively. The two adjusted CE ratios were significantly different ( p< 0.001). The application of M3 for severe TBI was more cost-effective than BNM. All calculations were made at 3.8 Malaysian Ringgit (MYR) to the United States dollar (USD).


Cytological diagnosis of genital ureaplasma urealyticum and its importance in cervical inflammation.
Cervical smear cytology, which is a gynecological cervical cancer screening test, can provide information about the presence of pathogenic microorganisms or the inflammation they cause. Among them, Ureaplasma urealyticum (Uu), which is a subspecies of Mycoplasma was held responsible for high-grade cervical intraepithelial lesions and malignancy due to long-lasting complicated vulvovaginitis clinic. We aimed at investigating the role of Uu in the inflammatory process of the cervix and to describe the cytological features that enable it to be recognized microscopically in cervical smear test. Cervical smear and mycoplasma culture data of 123 women with complicated vulvovaginitis findings were evaluated. According to the Uu culture results, women were divided into two groups: the Uu-positive (n=59) and the Uu-negative group (n=64). The groups were compared in terms of cervical smear results, macroscopic view of the cervix, and secondary cytological evaluation results. The presence of inflammatory signs (83.1%) in the Uu-positive group was observed to be 83.1%, whereas 67.2% in the Uu-negative group, and the difference between the two groups was found to be significant (p=0.04). Besides, the difference in aggregated polymorphonuclear leukocytes (PMNL) between Uu-positive group (59.3%) and Uu-negative group (40.6%) was statistically significant (p=0.04). Similarly, nuclear atypia of epithelial cells in the Uu-positive group (33.9%) was observed to be higher than in the Uu-negative group (17.2%) (p=0.03). Uu causes inflammation of the cervix and cervical intraepithelial lesions. Aggregated PMNL observed in cervical smear cytology may be one of the findings that will give clues for Uu.


Identification of a novel stress-inducible glycoprotein in Saccharomyces cerevisiae. I. Preliminary characterization.
We have identified a novel stress-inducible protein in Saccharomyces cerevisiae by pulse-labeling with [35S]methionine and two-dimensional gel analysis. The protein was characterized biochemically to gain further insight into mechanisms regulating the stress response. It has a Mr = 118,000 and exists in two forms of pI = 4.2 (p118A) and pI = 4.3 (p118B). p118A and p118B are modified by N-glycosylation. Tunicamycin treatment revealed the presence of precursor proteins of Mr = 105,000, pI = 4.1 (p105A) and pI = 4.25 (p105B). The synthesis of p118A and p118B was almost completely shut off in cycling cells and was increased 11-fold following a mild heat shock. Both forms of p118 decayed in a biphasic manner under induced conditions. A tight correlation was observed in the kinetics of thermotolerance induction and p118A synthesis. Other forms of stress such as sulfur starvation which lead to arrest in the unbudded phase also resulted in enhanced synthesis of both p118A and p118B. However, in cell division cycle mutants blocked at various stages at the restrictive temperature, p118A and p118B had different synthetic patterns. Taken together, these data imply a role for induced p118 in proliferation arrest in the unbudded state.


Faecal consistency and risk factors for diarrhoea and constipation in cats in UK rehoming shelters.
Objectives The aim of the study was to describe faecal consistency, prevalence and risk factors for diarrhoea and constipation in a rescue cat population. Methods Faecal samples in litter trays from a stratified random sample of cats in pens at 25 UK rehoming centres were scored for consistency in two discrete time periods, summer and winter. A six-point scale was used, with diarrhoea ⩽3, severe diarrhoea ⩽2 and constipation as 6. The effect on faecal consistency of age, number of cats per pen and season was investigated using multivariable hierarchical logistic regression with centre and pen as random effects. Intraclass correlation coefficients were used to estimate the effect of pen and centre. Results Overall, 11.9% (95% confidence interval [CI]:10.4-13.7) of cats had diarrhoea, 2.4% (95% CI 1.6-3.7) had severe diarrhoea and 5.6% (95% CI 4.2-7.5) were constipated. The prevalence of diarrhoea (median 11.0%, interquartile range [IQR] 5.0-14.5%) and constipation (median 4.2%, IQR 1.8-5.9) varied at the centre level. Diarrhoea was associated with being a kitten (odds ratio [OR] 2.54, 95% CI 1.45-4.46; P = 0.001) and being in a multi-cat pen (OR 1.24, 95% CI 1.04-1.48; P = 0.02) but not with season (OR 0.99, 95% CI 0.55-1.77; P = 0.96). Severe diarrhoea was associated with senior cats (OR 4.66, 95% CI 1.25-17.44; P = 0.02). Constipation was associated with increasing age (OR 1.01; 95% CI 1.00-1.01; P = 0.02) and winter (OR 0.43, 95% CI 0.21-0.89; P = 0.02). Both diarrhoea and constipation showed moderate correlation with pens within a centre. Conclusions and relevance From IQRs, we suggest acceptable levels for diarrhoea and constipation of 11% and 4%, respectively, targets of 5% and 2%, and intervention at 15% and 6%. Increasing age was associated with decreased risk of diarrhoea and increased risk of constipation. However, severe diarrhoea was associated with being a senior cat. Season (winter) was a risk factor for constipation; multi-cat pens were a risk factor for diarrhoea. Describing the prevalence and risk factors for diarrhoea and constipation in cats will assist their management in this population. Understanding and managing constipation may be more important than interventions to reduce severe diarrhoea.


Validation of the Jefferson Scale of Physician Empathy in Spanish medical students who participated in an Early Clerkship Immersion programme.
The Jefferson Scale of Physician Empathy is the most widely used instrument to measure empathy in the doctor-patient relationship. This work pursued cultural adaptation and validation of the original scale, in its health professions version (JSE-HP), for medical students who participate in an Early Clerkship Immersion Programme of a Spanish university. The questionnaire was replied by 506 1st, 2nd, 3rd and 5th year medical students from Universidad Francisco de Vitoria, Madrid, in 2014 and 2016. Internal consistency was analysed by means of Cronbach's alpha, and reliability by means of test-retest using the intraclass correlation coefficient and the Bland-Altman method. The construct validity was checked by means of confirmatory factor analysis and association with other empathy-related variables. Criterion validity was compared using Davis' Interpersonal Reactivity Index. Cronbach's alpha was 0.82 (range 0.80-0.85). Item-total score correlations were positive and significant (median 0.45, p < 0.01). The test-retest intraclass correlation coefficient was 0.68 (0.42-0.82). The factor analysis confirmed the three original factors: "perspective taking", "compassionate care" and "standing in the patient's shoes". Women and students who preferred specialities focused on persons obtained the best scores. The JSE-HP scores were positively correlated with Interpersonal Reactivity Index, personality traits were associated with empathy, clinical interview skills and Objective Structured Clinical Examinations. The results support the validity and reliability of JSE-HP applied to Spanish medical students.


Congenital adrenal hyperplasia presenting as hematuria and acute renal faliure.
We present a neonate who presented with hematuria and acute renal failure. Classical 21 hydroxylase deficiency was diagnosed on the basis of features of salt wasting, response to treatment with corticosteroids and mineralocorticoids and a positive ACTH stimulation test. Renal vein thrombosis secondary to hemoconcentration due to salt wasting was attributed as the cause of hematuria. Follow-up revealed clinical improvement and normalization of renal parameters. This is the first report of congenital adrenal hyperplasia presenting as hematuria and renal failure to the best of our knowledge.


[A preparative method for isolating the synaptonemal complexes from mammalian spermatocytes].
A method of isolation of synaptonemal complexes (SC) from mouse, rat and Syrian hamster spermatocytes is described. A fraction of pachytene spermatocyte nuclei was obtained by centrifugation of the testis homogenate in stepwise sucrose gradient and then lysed. The resulting chromatine was hydrolysed with DNAse II, and a fraction of isolated SCs was obtained by ultracentrifugation of the hydrolysate. The method can be applied for obtaining the SC fraction from spermatocytes sufficient for cytological, biochemical and molecular biology studies.


Unreported location and presentation for a parasitic ovarian dermoid cyst in an indirect inguinal hernia.
Extragonadal mature cystic teratomas (dermoid cysts) have been reported occasionally, with the most common site being the omentum. We report a rare case of a parasitic dermoid cyst that was incidentally found in an indirect inguinal hernia sac in a 66-year-old woman. The right ovary was absent from its proper anatomical location. Histopathologic study revealed a mature cystic teratoma with viable ovarian tissue. These findings suggested auto-amputation of the ovary either by inflammation or torsion.


Targeted Sequencing of Circulating Cell Free DNA Can Be Used to Monitor Therapeutic Efficacy of Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients.
Circulating tumor DNA (ctDNA) bears specific mutations derived from tumor cells. The amount of mutant ctDNA may reflect tumor burden. In this study, we detected epidermal growth factor receptor (EGFR) mutations in ctDNA as a monitoring marker for the response of non-small cell lung cancer (NSCLC) patients to tyrosine kinase inhibitors (TKIs). Serial plasma samples from eight NSCLC patients during TKI treatment were collected. Libraries with barcoded adapters were constructed from ctDNA of these plasma samples using a PCR-based targeted DNA panel. The libraries were then sequenced for measuring EGFR mutations. In addition, carcinoembryonic antigen (CEA) was also measured in these patients. In six patients who suffered disease progression (PD), five had elevated EGFR mutation reads before PD. In the two patients who did not develop PD, EGFR mutations remained undetectable in their plasma. The CEA levels were higher than the cutoff value in most samples and had a poor correlation with disease status. The mutation count of tumor-specific mutations can be a monitoring marker of TKI treatment in NSCLC patients.


The role of computed tomography in the evaluation of pneumatosis intestinalis.
Computed tomography (CT) is useful in evaluating patients with pneumatosis intestinalis while excluding other causes of abdominal pain and sepsis. We present a case along with additional illustrative CT sections to show its usefulness in such cases.


Successful implementation of a nurse-navigator-run program using natural language processing identifying patients with an abdominal aortic aneurysm.
Abdominal aortic aneurysms (AAA) are often identified incidentally on imaging studies. Patients and/or providers are frequently unaware of these AAA and the need for long-term follow-up. We sought to evaluate the outcome of a nurse-navigator-run AAA program that uses a natural language processing (NLP) algorithm applied to the electronic medical record (EMR) to identify patients with imaging report-identified AAA not being followed actively. A commercially available AAA-specific NLP system was run on EMR data at a large, academic, tertiary hospital with an 11-year historical look back (January 1, 2010, to June 2, 2021), to identify and characterize AAA. Beginning June 3, 2021, a direct link between the NLP system and the EMR enabled for real-time review of imaging reports for new AAA cases. A nurse-navigator (1.0 full-time equivalent) used software filters to categorize AAA according to predefined metrics, including repair status and adherence to Society for Vascular Surgery imaging surveillance protocol. The nurse-navigator then interfaced with patients and providers to reestablish care for patients not being followed actively. The nurse-navigator characterized patients as case closed (eg, deceased, appropriate follow-up elsewhere, refuses follow-up), cases awaiting review, and cases reviewed and placed in ongoing surveillance using AAA-specific software. The primary outcome measures were yield of surveillance imaging performed or scheduled, new clinic visits, and AAA operations for patients not being followed actively. During the prospective study period (January 1, 2021, to December 30, 2021), 6,340,505 imaging reports were processed by the NLP. After filtering for studies likely to include abdominal aorta, 243,889 imaging reports were evaluated, resulting in the identification of 6495 patients with AAA. Of these, 2937 cases were reviewed and closed, 1183 were reviewed and placed in ongoing surveillance, and 2375 are awaiting review. When stratifying those reviewed and placed in ongoing surveillance by maximum aortic diameter, 258 were 2.5 to 3.4 cm, 163 were 3.5 to 3.9 cm, 213 were 4 to 5 cm, and 49 were larger than 5 cm; 36 were saccular, 86 previously underwent open repair, 274 previously underwent endovascular repair, and 104 were other. This process yielded 29 new patient clinic visits, 40 finalized imaging studies, 29 scheduled imaging studies, and 4 AAA operations in 3 patients among patients not being followed actively. The application of an AAA program leveraging NLP successfully identifies patients with AAA not receiving appropriate surveillance or counseling and repair. This program offers an opportunity to improve best practice-based care across a large health system.


Effects of resveratrol on alterations in cerebrum energy metabolism caused by metabolites accumulated in type I citrullinemia in rats.
We investigated the in vitro effects of citrulline (0.1, 2.5 and 5.0 mM) and ammonia (0.01, 0.1 and 1.0 mM), and the influence of resveratrol (0.01 mM, 0.1 mM and 0.5 mM) on pyruvate kinase, citrate synthase, succinate dehydrogenase (SDH), complex II, and cytochrome c oxidase activities in cerebral cortex, cerebellum and hippocampus homogenates of 60-day-old male Wistar rats. Results showed that 2.5 and 5.0 mM citrulline decreased pyruvate kinase activity in cerebral cortex and, at a concentration of 5.0 mM, increased its activity in hippocampus. Additionally, 5.0 mM citrulline increased citrate synthase activity in the cerebellum of rats. Citrulline (5.0 mM) reduced complex II and cytochrome c oxidase activities in cerebral cortex and hippocampus. With regard to ammonia, at 0.1 and 1.0 mM, decreased complex II activity in cerebral cortex and at 1.0 mM decreased its activity in cerebellum and hippocampus. Ammonia (1.0 mM) also decreased cytochrome c oxidase activity in cerebral cortex and cerebellum of rats. Resveratrol was able to prevent most of the alterations caused by these metabolites in the biomarkers of energy metabolism measured in the cerebrum of rats. Data suggest that these alterations in energy metabolism, caused by citrulline and ammonia, are probably mediated by the generation of free radicals, which can in turn be scavenged by resveratrol.


Myotonometry demonstrates changes of lingual musculature in obstructive sleep apnoea.
Upper airway dilator muscles are important in the pathogenesis of obstructive sleep apnoea (OSA). Previously, soft palate and tongue muscles of patients with OSA have been studied from a histological point of view. Electromyographic studies revealed increased activity of upper airway dilator muscles. We used computerized endopharyngeal myotonometry (CEM) to measure the biomechanical properties of lingual musculature, mainly the genioglossal muscle, to characterize changes of tongue muscles in patients with OSAS. The method records and analyzes the response of the tongue sublingually after a brief mechanical impact. It enabled us to evaluate the most important parameters of tissue tone--stiffness, which is expressed as a frequency, and elasticity, as a logarithmic decrement of the damped oscillation. The results of CEM indicated that patients with OSAS show an increased stiffness (14.1 +/- 0.7 Hz) of the tongue in comparison with non-snoring subjects (11.5 +/- 0.2 Hz). The elasticity of the tongue is decreased, which is numerically expressed as an increased decrement (4.0 +/- 0.2) in patients with OSA in comparison with non-snorers (2.2 +/- 0.2). Changes in the biomechanical characteristics of lingual musculature during wakefulness could result from pathophysiological processes caused by obstructive sleep apnoea.


A mixed-methods investigation of health professionals' perceptions of a physiological track and trigger system.
Physiological track and trigger systems (PTTSs) regulate the monitoring of patients' vital signs and facilitate the detection and treatment of deteriorating patients. These systems are widely used, although compliance with protocol is often poor. This study aimed to examine the perceptions of a national PTTS among nurses and doctors and to identify the variables that impact on intention to comply with protocol. A mixed-methods research design was employed. During the initial qualitative phase, 30 hospital-based nurses and doctors participated in a series of semistructured interviews. During the subsequent quantitative phase, 215 nurses and doctors (24.1% response rate) responded to a questionnaire designed to assess attitudes towards the PTTS and factors that influence adherence to protocol. Interview data revealed largely positive attitudes towards the PTTS but highlighted a number of barriers to its implementation and indicated that it is sometimes a source of tension between doctors and nurses. Quantitative data confirmed the validity of these findings, although nurses appeared to have more positive attitudes towards, and to perceive fewer barriers to, the usage of PTTS than were reported by the participating doctors. These findings reveal that non-compliance with PTTS protocol is unlikely to be attributable to negative perceptions of PTTSs. Instead, there are a number of barriers to the implementation of the system. These findings suggest that interprofessional training in PTTSs is essential while increased support for PTTS implementation among senior doctors would also yield improved adherence to protocol.


[Evaluation by case managers dementia : An explorative practice based study on types and content].
This practice based explorative study aims to provide insight into the ways in which case managers shape and fill up the evaluation phase of their support of the informal care network of persons with dementia. A combination of quantitative and qualitative research methods were used. A group of 57 case managers of persons with dementia in three different organisational networks took part in this study. Results from the quantitative and qualitative data are organized into four themes: (1) attitude towards evaluation, (2) forms of evaluation, (3) implementation of evaluation and (4) content of evaluation. There are different ways in shaping evaluation and the content of it. The importance of interim and final evaluation is recognized, but is difficult to realize in a methodical way. Barriers experienced by the case managers include various factors associated both with clients as professionals. Case managers evaluate continuously and in an informal way to assess whether the extent of their assistance is meeting the needs of the client and informal network. Case managers do not use systematic evaluation to measure the quality of care they offer to persons with dementia and their caregivers. The findings demand a discussion on the level of clients, as well as on the professional and societal level about the way case managers should evaluate their support.


Low-contrast detectability and potential for radiation dose reduction using deep learning image reconstruction-A 20-reader study on a semi-anthropomorphic liver phantom.
A novel deep learning image reconstruction (DLIR) algorithm for CT has recently been clinically approved. To assess low-contrast detectability and dose reduction potential for CT images reconstructed with the DLIR algorithm and compare with filtered back projection (FBP) and hybrid iterative reconstruction (IR). A customized upper-abdomen phantom containing four cylindrical liver inserts with low-contrast lesions was scanned at CT dose indexes of 5, 10, 15, 20 and 25 mGy. Images were reconstructed with FBP, 50% hybrid IR (IR50), and DLIR of low strength (DLL), medium strength (DLM) and high strength (DLH). Detectability was assessed by 20 independent readers using a two-alternative forced choice approach. Dose reduction potential was estimated separately for each strength of DLIR using a fitted model, with the detectability performance of FBP and IR50 as reference. For the investigated dose levels of 5 and 10 mGy, DLM improved detectability compared to FBP by 5.8 and 6.9 percentage points (p.p.), and DLH improved detectability by 9.6 and 12.3 p.p., respectively (all p < .007). With IR50 as reference, DLH improved detectability by 5.2 and 9.8 p.p. for the 5 and 10 mGy dose level, respectively (p < .03). With respect to this low-contrast detectability task, average dose reduction potential relative to FBP was estimated to 39% for DLM and 55% for DLH. Relative to IR50, average dose reduction potential was estimated to 21% for DLM and 42% for DLH. Low-contrast detectability performance is improved when applying a DLIR algorithm, with potential for radiation dose reduction.


Vitamin D and COVID-19: How Much Vitamin D Does a Man Need?
A number of observational studies and reviews on the potential role of vitamin D in COVID-19 have been published since the beginning of this ongoing global pandemic [...].


Endobronchial ultrasound-guided transbronchial needle aspiration in peripheral pulmonary lesions: a systematic review and meta-analysis.
The diagnosis of peripheral pulmonary lesions (PPLs) remains a challenge for physicians. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been applied in the diagnosis of PPLs, but its diagnostic rate varies widely. The systematic review and meta-analysis was conducted to figure out the accuracy and safety of EBUS-TBNA in the diagnosis of PPLs. We searched the PubMed and Embase databases for relevant studies published from January 1, 2000 to December 30, 2021 and used PICO (Participants, Intervention, Comparison, and Outcome) to worked out the diagnostic rate of EBUS-TBNA in PPLs. Two reviewers independently performed the data extraction and assessed study quality. Statistical analysis was carried out via R software. In 7 studies of totally 510 patients of PPLs, the overall EBUS-TBNA diagnosis yield is 0.75 (95% CI 0.67-0.84) by the random effect model. EBUS-TBNA showed a higher accuracy of 0.64 (95% CI 0.53-0.74) compared to 0.46 (95% CI 0.19-0.72) of endobronchial ultrasound-guided transbronchial biopsy (EBUS-TBB) when EBUS probe is adjacent to lesions. In the case of malignant lesions, the diagnostic rate of EBUS-TBNA is 0.79 (95% CI 0.72-0.88). Combined EBUS-TBNA with conventional bronchoscopy procedures showed the highest diagnostic yield (0.83 (95% CI 0.79-0.87)). Collectively, EBUS-TBNA should be performed firstly in patients with PPLs suspected to lung cancer especially when the EBUS probe was adjacent to the lesions. No serious procedure-related complications were observed.


Chromosome 6p amplification detected in blood cell-free DNA in advanced intraocular retinoblastoma.
In patients with retinoblastoma, gains of chromosome 6p have been associated with less differentiated tumors. In cell-free DNA from the aqueous humor (AH), 6p gain has been associated with an increased risk of enucleation. While the identification of somatic copy number alterations (SCNAs) via the AH has been well established, these alterations are not routinely identified in the blood due to low tumor fraction. SCNAs were considered positive at 20% deflection from the baseline. Somatic RB1 pathogenic variants were identified with targeted sequencing using a panel including all RB1 exons. A 24-month-old patient presented with unilateral retinoblastoma (Group D/AJCC Stage cT2B) and was treated with primary enucleation. In the peripheral blood, a heterozygous mutation (c.3920T>A) in the APC gene was reported. Genomic analysis of the tumor and AH revealed two novel somatic RB1 mutations (c.1589_1590del and c.2330dupC). Both also demonstrated highly recurrent RB-related SCNAs. Chromosome 6p gain was detected in the blood with an amplitude suggesting approximately 12% tumor fraction. At a follow-up of 24 months, there has been no evidence of metastatic disease. To our knowledge, this is the first time an SCNA has been detected in the blood of an RB patient, suggesting in some advanced eyes there may be a high enough tumor fraction to detect these alterations (>5% needed). It remains unclear whether 6p gain or increased tumor fraction in the blood is indicative of increased risk of metastatic disease or new primary cancer; studies to address this are ongoing.


Primary sclerosing cholangitis associated with CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly and telangiectasia) in an elderly woman: a case report.
CREST (calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia) syndrome comprising calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia and primary sclerosing cholangitis are both chronic fibrotic diseases but the association between them is extremely rare. While primary sclerosing cholangitis has been associated with diffuse cutaneous scleroderma, the association with limited cutaneous scleroderma or CREST has not been previously reported in the literature. This case report illustrates the association between CREST and primary sclerosing cholangitis. We report the case of an 84-year-old Asian woman with a long history of CREST who was admitted with abdominal pain, fatigue and progressive derangement of her liver enzymes. This was initially thought to be secondary to her bosentan therapy for pulmonary hypertension but it persisted despite bosentan being ceased. Primary sclerosing cholangitis was subsequently diagnosed on magnetic resonance cholangiopancreatography and she was referred to a hepatologist for treatment. This case highlights the need to consider primary sclerosing cholangitis in patients with CREST who present with abdominal symptoms and deranged liver enzymes when other causes have been excluded. Relevant differential diagnoses for this presentation, which can be difficult to exclude, include immunoglobulin G4-associated cholangitis and antimitochondrial antibody negative primary biliary cirrhosis. It is of particular significance to rheumatologists and gastroenterologists but has broader relevance to all medical specialists involved in the care of patients with CREST.


Postnatal vascular growth in the neocortex of normal and protein-deprived rats. Morphometric studies.
The postnatal vascular growth in the neocortical area 18 of normal and pre- and postnatally protein-deprived rats was examined. For control rats the specific length, the specific surface and the volume fraction of vessels increased rapidly between 7 and 20 days of age. Thereafter, only a minor increase was seen. In protein-deprived rats there was no increase in the specific length of vessels between 7 and 10 days of age and this variable was still reduced at 30 days of age compared to controls. This reduction was due to a decrease in the specific length of thin vessels (luminal diameter less than 8.25 mu) whereas the specific length of wider vessels was not affected by the protein deprivation. There were no significant differences in the specific surface or volume fraction of vessels between control and protein-deprived rats. These findings indicate an adaptive increase in luminal diameter of vessels in the protein deprived rats during postnatal development. At 90 days of age no significant differences between vascular variables of control and protein-deprived rats were seen.


Effects of vanadate on the molybdoproteins xanthine oxidase and nitrate reductase: kinetic evidence for multiple site interaction.
The inhibition of the activity of xanthine oxidase by vanadate was strikingly similar to vanadate inhibition of another molybdoprotein nitrate reductase. Although the main catalytic activity of both enzymes was inhibited, the partial NADH oxidase activity associated with these enzymes was stimulated several fold. It appears that the metal ion binds at multiple site in both enzymes. In the absence of any enzymes a combination of vanadium (V) and molybdenum (V) in air was found to oxide NADH rapidly.


Association of a history of varicella virus infection with multiple sclerosis.
To analyze the association of a previous history of varicella virus infection with multiple sclerosis (MS) and its subtypes. We performed a case-control study including 126 cases and 157 controls. Subjects were divided into subgroups according to MS subtype and the history of varicella virus infection along with other variables was assessed. History of varicella zoster virus (VZV) infection was positive in 42% of controls and 66% of MS cases (p<or=0.001). Patients with a history of VZV infection had a threefold risk increase of having MS. Regarding MS subtypes, relapsing-remitting (RR) MS had four times the risk and secondary progressive had a threefold increase in risk when compared with control patients. An association between varicella infection history and MS was found, particularly in the RR subtype.


Post-stimulatory activity in primate auditory cortex evoked by sensory stimulation during passive listening.
Under certain circumstances, cortical neurons are capable of elevating their firing for long durations in the absence of a stimulus. Such activity has typically been observed and interpreted in the context of performance of a behavioural task. Here we investigated whether post-stimulatory activity is observed in auditory cortex and the medial geniculate body of the thalamus in the absence of any explicit behavioural task. We recorded spiking activity from single units in the auditory cortex (fields A1, R and RT) and auditory thalamus of awake, passively-listening marmosets. We observed post-stimulatory activity that lasted for hundreds of milliseconds following the termination of the acoustic stimulus. Post-stimulatory activity was observed following both adapting, sustained and suppressed response profiles during the stimulus. These response types were observed across all cortical fields tested, but were largely absent from the auditory thalamus. As well as being of shorter duration, thalamic post-stimulatory activity emerged following a longer latency than in cortex, indicating that post-stimulatory activity may be generated within auditory cortex during passive listening. Given that these responses were observed in the absence of an explicit behavioural task, post-stimulatory activity in sensory cortex may play a functional role in processes such as echoic memory and temporal integration that occur during passive listening.


The microsurgical treatment of cranio-orbital tumors assisted by intraoperative electrophysiologic monitoring and neuronavigation.
Total resection of cranio-orbital tumors without any major complications is still a challenge for neurosurgeons. Intraoperative electrophysiologic monitoring and neuronavigational system have been widely used in microneurosurgery, but their effects during microsurgical treatment of cranio-orbital tumors warrant further investigation. Thirty-eight patients with cranio-orbital tumors admitted to our hospital underwent microsurgery assisted by intraoperative electrophysiologic monitoring. We also simultaneously performed intraoperative neuronavigation in 20 patients. A retrospective review of clinical notes, operation records and prognoses of all patients was performed. Gross total resection was achieved in 29 patients (76%), near total resection in 5 (13%), subtotal resection in 3 (8%) and partial resection in 1 (3%). With the helps of electromyogram (EMG) monitoring of levator palpebrae superioris (LPS) muscle and navigation system, no surgical damages to the oculomotor nerve and other important structures occurred. A follow-up study showed that 31 patients (82%) resumed normal lives (Glasgow Outcome Scale (GOS) score 5), 5 patients (13%) had independent lives (GOS score 4), and 2 patients (5%) were unable to live independently (GOS score 3). Microsurgical treatment assisted by intraoperative electrophysiologic monitoring and neuronavigation might be a useful method for resection of cranio-orbital tumors, especially better for protection of the important cranial nerve and structure in the kull base.


[Cardiological aspects of pregnancy in women with tetralogy of Fallot. Description of a case of multiple pregnancies and review of the literature].
A case report concerning a patient who received a late surgical correction of a tetralogy of Fallot, at the age of 26, and then had the chance of two pregnancies with no or little risk. The patient was severely cyanotic (erythrocytes 6,440,000/ml-Ht 58.3%-Hb 19.5 g/100 ml) with balanced pressures between the two ventricular cavities and 72 mmHg gradient between right ventricle and pulmonary artery. Before the operation two pregnancies resulted in abortions: the former was before the correction of the cardiac malformation and the latter just after. Then two pregnancies were successful and both the newborn males were healthy and completely free from congenital diseases, and in particular cardiac. Brief examination of literature.


Ultrastructural changes in the heart of rats treated with chloroquine.
Effects of prolonged chloroquine administration on ultrastructure of the heart was studied in albino rats. Chloroquine when administered orally (30-40 mg/kg/day) or subcutaneously (20 mg/kg/day) for two to four weeks, produced marked degenerative changes in the mitochondria and myofibrils of the myocardium. The mitochondria were more susceptible to the toxic effect of chloroquine than were other cell organelles. Moreover, the cytotoxic effect of the drug appeared to be related to total dose. Chloroquine-induced abnormalities were reversible on terminating medication. These results indicate that prolonged chloroquine administration impairs ultrastructure of the myocardium.


Functional correlation between kallikrein and factor XII activated in human plasma.
Plasma kallikrein and FXIIa were assayed in acetone-treated human citrated plasma (CPLa) with the chromogenic peptide Bz-Ile-Glu-Gly-Arg-pNA (S-2222) as substrate. In end point assays with short incubation periods (1-10 min.) nearly all kallikrein present could be blocked by a low concentration of soybean trypsin inhibitor (STI). In 30 min. assays the main part of the kallikrein was recovered in a functional state not inhibited by STI, and at the same time the level of FXIIa (as amidase activity blocked by corn inhibitor, C.I.) was reduced to about 2/3 of the initial value. The formation of an association between FXIIa and kallikrein is suggested. In fractions from gel filtration of CPLa kallikrein was assayed as S-2302 amidase, high molecular weight kininogen (HK) was measured in rocket immunoassays, and HK and FXII were studied in PAGE immunoblot experiments. Kallikrein appeared as one peak together with HK (gel mol. wt. 300 KD), about 40% of HK was free (220 KD), and no FXII was observed in the kallikrein or HK peaks, but in two areas corresponding to 78-79 KD and 39-42 KD. When experiments, however, were carried out with plasma acetone-activated and gel filtered in the presence of benzamidine (5 mM), part of the amidase activity present in kallikrein peak fractions was blocked by C.I. This observation supports the above suggestion of an association between FXIIa and kallikrein.