Malignant small-bowel neoplasms: spectrum of disease on MR imaging.
Malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for only 2% of all gastrointestinal neoplasms. Owing both to the intrinsic difficulty of common radiographic and endoscopic methods in visualising the entire small bowel and the lack of typical physical findings, a delay in diagnosis is common. Recently, magnetic resonance (MR) imaging has become a widely accepted imaging modality in the study of suspected small-bowel neoplasms due to its ability to depict, without exposure to ionising radiation and with excellent soft-tissue contrast, intraluminal disorders in conjunction with mural, extraparietal and regional abnormalities. The aim of this pictorial review is to illustrate the MR appearance of malignant small-bowel neoplasms.


Validation of the Computerized Suicide Risk Scale--a backpropagation neural network instrument (CSRS-BP).
Medically serious suicide attempts have been recognized as the most important predictor of suicide. The Computerized Suicide Risk Scale based on backpropagation neural networks (CSRS-BP) has been recently found efficient in the detection of records of patients who performed medically serious suicide attempts (MSSA). OBJECTIVES. To validate the CSRS-BP by: 1) using the CSRS-BP with patients instead of records; 2) comparing the ability of expert psychiatrists to detect MSSA, using the CSRS checklist; and 3) comparing the results of the Risk Estimator for Suicide (RES) and the self-rating Suicide Risk Scale (SRS) with the CSRS-BP. Two hundred fifty psychiatric inpatients (35 MSSA and 215 non-MSSA) were diagnosed by clinicians using the SCID DSM-IV. Three expert psychiatrists completed the CSRS checklist, and the RES for each patient, and the patients completed the self-report SRS assessment scale. The CSRS-BP was run for each patient. Five other expert psychiatrists assessed the CSRS checklists and estimated the probability of MSSA for each patient. Comparisons of sensitivity and specificity rates between CSRS-BP, assessment scales and experts were done. Initially, the CSRS-BP, RES, SRS, and experts performed poorly. Although sensitivity and specificity rates significantly improved (two to four times) after the inclusion of information regarding the number of previous suicide attempts in the input data set, results still remained insignificant. The CSRS-BP, which was very successful in the detection of MSSA patient records, failed to detect MSSA patients in face-to-face interviews. Information regarding previous suicide attempts is an important MSSA predictor, but remains insufficient for the detection of MSSA in individual patients. The detection rate of the SRS and RES scales was also poor and could therefore not identify MSSA patients or be used to validate the CSRS-BP.


Proficiency in interscalene anesthesia-how many blocks are necessary?
To determine the number of interscalene blocks that are necessary for a resident in anesthesiology to complete so as to achieve autonomous success with that specific block. Survey questionnaire of all CA1 and CA2 residents in the Department of Anesthesiology, Mount Sinai School of Medicine. University hospital. Seventeen CA-1 and CA-2 residents reported their experiences in performing interscalene blocks over an 8-month period. Data were collected regarding the number of previous attempts, technique, attending supervisor, patient weight, level of autonomy in the performance of the current block, and adequacy of the block for surgery. Eighty-two blocks were performed (1 to >15 per resident), supervised by 7 attending physicians, and 96.3% of blocks were reported as adequate for surgery. With an experience of seven to nine previous blocks, only 50% of residents were able to perform an interscalene block autonomously, whereas with >15 blocks, 87.5% reported autonomous success. Experience with only 40 unspecified peripheral nerve blocks, as currently required by the Residency Review Committee as of January 2001, may not provide adequate opportunity for an individual to develop expertise in regional anesthesia.


Preclinical Evidence for the Pharmacological Actions of Glycyrrhizic Acid: A Comprehensive Review.
Glycyrrhiza glabra L. (Family: Fabaceae) is one of the important traditional medicinal plant used extensively in folk medicine. It is known for its ethnopharmacological value in curing a wide variety of ailments. Glycyrrhizin, an active compound of G. glabra, possesses anti-inflammatory activity due to which it is mostly used in traditional herbal medicine for the treatment and management of chronic diseases. The present review is focused extensively on the pharmacology, pharmacokinetics, toxicology, and potential effects of Glycyrrhizic Acid (GA). A thorough literature survey was conducted to identify various studies that reported on the GA on PubMed, Science Direct and Google Scholar.


Association of Food Parenting Practices on Child BMI z Score and Waist Circumference in Mexican Preschool Children After 1 Year of Follow-Up.
To evaluate the association between food parenting practices (FPPs) and weight status among preschoolers and the directionality of this association at 1-year follow-up. A longitudinal exploratory study was conducted using linear regression and structural equation modeling to determine directional associations between FPPs and children's body mass index z score and waist circumference. The FPPs were estimated using Child Feeding Questionnaire subscales. A total of 91 parent-child dyads completed the study. In structural equation modeling analysis, when identifying the FPPs in a latent variable with its indicators of indulgent feeding, food as a reward and restriction predicted higher body mass index z score at follow-up. Higher baseline waist circumference was also negatively associated with the use of food as a reward. Feeding-weight associations are likely bidirectional. Understanding them, as well as the pathways between them, is critical to developing effective prevention and treatment strategies.


Isolated intraspinal germinoma in a child with congenital adrenal hyperplasia.
Case report. To report an intramedullary germinoma associated with congenital adrenal hyperplasia (CAH). We report a 14-year-old white male with CAH who was found to have an intramedullary germinoma of the conus medullaris. Presentation and evaluation were for progressive urinary incontinence. A brief review of relevant literature was presented. Cases where germinomas have occurred simultaneously with CAH have been identified intracranially, but to our knowledge, this is the first case of CAH and intramedullary spinal cord germinoma occurring simultaneously. Although rare, primary intramedullary germinomas do occur. The association between CAH and spinal cord germinoma should be considered by clinicians.


Simulated global warming affects endophytic bacterial and fungal communities of Antarctic pearlwort leaves and some bacterial isolates support plant growth at low temperatures.
Antarctica is one of the most stressful environments for plant life and the Antarctic pearlwort (Colobanthus quitensis) is adapted to the hostile conditions. Plant-associated microorganisms can contribute to plant survival in cold environments, but scarce information is available on the taxonomic structure and functional roles of C. quitensis-associated microbial communities. This study aimed at evaluating the possible impacts of climate warming on the taxonomic structure of C. quitensis endophytes and at investigating the contribution of culturable bacterial endophytes to plant growth at low temperatures. The culture-independent analysis revealed changes in the taxonomic structure of bacterial and fungal communities according to plant growth conditions, such as the collection site and the presence of open-top chambers (OTCs), which can simulate global warming. Plants grown inside OTCs showed lower microbial richness and higher relative abundances of biomarker bacterial genera (Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Aeromicrobium, Aureimonas, Hymenobacter, Novosphingobium, Pedobacter, Pseudomonas and Sphingomonas) and fungal genera (Alternaria, Cistella, and Vishniacozyma) compared to plants collected from open areas (OA), as a possible response to global warming simulated by OTCs. Culturable psychrotolerant bacteria of C. quitensis were able to endophytically colonize tomato seedlings and promote shoot growth at low temperatures, suggesting their potential contribution to plant tolerance to cold conditions.


Carbonic anhydrase activators. VII. Isozyme II activation by bisazolyl-methanes, -ethanes and related azoles.
A correlation was found between the carbonic anhydrase II activating power and the pKa values for a series of azoles, bisazolylmethanes and bisazolylethanes. Strong activations were found for compounds with pKa's in the interval 6.5-8.0. The mechanism of action for such activators is discussed.


Sequencing, de novo assembly, annotation and SSR and SNP detection of sabaigrass (Eulaliopsis binata) transcriptome.
Eulaliopsis binata is one of the best fiber grass plants for its high fiber quality and production. Large scale trancriptome sequencing of E. binata was first performed using mixed leaf samples of 20 wild clusters. A total of 26,438,832 clean reads were generated and were assembled into 59,134 isogenes with an average length of 845bp. BLAST against the NCBI non-redundant protein, KEGG and GO databases has classified these isogenes into functional categories for understanding gene functions and regulation pathways. Only 15.0% of the assembled isogenes were similar to known proteins and 24.4% has no hits in the nr protein database. The total isogenes and 5306 highly expressed isogenes were performed by BLASTx with the MAIZEWALL, the cell wall navigator and the PlantTFDB databases. A total of 6681 simple sequence repeats (SSRs) and 147,177 single nucleotide polymorphisms (SNPs) were detected in the isogenes and 5723 pairs of SSR primers were designed.


Platelet aggregability in patients with a VVI pacemaker.
Several studies have suggested an increased incidence of thromboembolic events in patients with VVI pacemaker (VVI patients); furthermore, other authors have demonstrated that a treatment with anticoagulants or antiplatelet drugs may be effective in reducing thromboembolic events, thus suggesting an increased formation of platelet thrombi in these patients. In this respect, platelet aggregability was investigated in ten VVI patients and ten age- and sex-matched subjects. beta-thromboglobulin (beta-Tg) and platelet factor 4 (PF4) plasma levels were determined as well as platelet aggregation induced by ADP, collagen, epinephrine, and arachidonic acid. Plasma beta-Tg levels were increased in the patient group (86 +/- 24 vs 24 +/- 13 ng/mL; P < 0.001) in presence of normal PF4 values (14 +/- 11 vs 13 +/- 6 ng/mL; NS). Aggregation curves showed abnormal values of maximal amplitude, slope, and lag time. In particular, maximal amplitude was significantly higher in VVI patients as compared with controls (ADP P < 0.01, collagen P < 0.001, adrenaline P < 0.01, arachidonic acid P < 0.05). These findings strongly suggest an increase of platelet activity in VVI patients.


Differential involvement of N-type calcium channels in transmitter release from vasoconstrictor and vasodilator neurons.
1. The effects of calcium channel blockers on co-transmission from different populations of autonomic vasomotor neurons were studied on isolated segments of uterine artery and vena cava from guinea-pigs. 2. Sympathetic, noradrenergic contractions of the uterine artery (produced by 200 pulses at 1 or 10 Hz; 600 pulses at 20 Hz) were abolished by the N-type calcium channel blocker omega-conotoxin (CTX) GVIA at 1-10 nm. 3. Biphasic sympathetic contractions of the vena cava (600 pulses at 20 Hz) mediated by noradrenaline and neuropeptide Y were abolished by 10 nm CTX GVIA. 4. Neurogenic relaxations of the uterine artery (200 pulses at 10 Hz) mediated by neuronal nitric oxide and neuropeptides were reduced <50% by CTX GVIA 10-100 nm. 5. Capsaicin (3 microm) did not affect the CTX GVIA-sensitive or CTX GVIA-resistant neurogenic relaxations of the uterine artery. 6. The novel N-type blocker CTX CVID (100-300 nm), P/Q-type blockers agatoxin IVA (10-100 nm) or CTX CVIB (100 nm), the L-type blocker nifedipine (10 microm) or the 'R-type' blocker SNX-482 (100 nm), all failed to reduce CTX GVIA-resistant relaxations. The T-type channel blocker NiCl(2) (100-300 microm) reduced but did not abolish the remaining neurogenic dilations. 7. Release of different neurotransmitters from the same autonomic vasomotor axon depends on similar subtypes of calcium channels. N-type channels are responsible for transmitter release from vasoconstrictor neurons innervating a muscular artery and capacitance vein, but only partly mediate release of nitric oxide and neuropeptides from pelvic vasodilator neurons.


Retinyl palmitate reduces hepatic fibrosis in rats induced by dimethylnitrosamine or pig serum.
Lipid peroxidation has been found to be associated with Ito cell activation. Ito cells are the principal collagen-producing cells and the main storage sites of retinoids. However, the relationship between retinoids and hepatic fibrosis is complex. The aim of this study was to elucidate the role of retinoids as a fibrosuppressant: the effects of retinoids on hepatic fibrosis induced in rats by dimethylnitrosamine or pig serum, as well as on rat Ito cells in primary culture, were examined in order to assess the antioxidant activity of retinoids. Male Wistar rats were given a single injection of 40 mg/kg dimethylnitrosamine or 0.5 ml PS twice weekly for 10 weeks. In each model, rats were treated with retinyl palmitate for 2 weeks before hepatotoxin treatments or for the last 2 weeks of the treatments. The cumulative amount of retinyl palmitate administered in each experiment was 2, 10, or 20x10(4) IU/rat. Retinyl palmitate treatment before or after administration of dimethylnitrosamine or pig serum suppressed the induction of hepatic fibrosis, restored hepatic retinyl palmitate levels, prevented increases in hepatic levels of collagen and malondialdehyde, a product of lipid peroxidation, and prevented increases in deposition of type III collagen and the number of alpha-smooth muscle actin (alpha-SMA) positive-Ito cells in the liver. Retinyl palmitate supplementation resulted in a dose-dependent reduction of alpha-SMA expression and an oxidative burst in cultured Ito cells. In addition, retinyl palmitate inhibited Fe2+/adenosine 5'-diphosphate-induced lipid peroxidation in rat liver mitochondria and showed radical scavenging activity. These findings suggest that retinyl palmitate may suppress the induction of hepatic fibrosis, at least in part, by the inhibition of Ito cell activation through its antioxidant activity.


The invasion speed of cell migration models with realistic cell cycle time distributions.
Cell proliferation is typically incorporated into stochastic mathematical models of cell migration by assuming that cell divisions occur after an exponentially distributed waiting time. Experimental observations, however, show that this assumption is often far from the real cell cycle time distribution (CCTD). Recent studies have suggested an alternative approach to modelling cell proliferation based on a multi-stage representation of the CCTD. In this paper we investigate the connection between the CCTD and the speed of the collective invasion. We first state a result for a general CCTD, which allows the computation of the invasion speed using the Laplace transform of the CCTD. We use this to deduce the range of speeds for the general case. We then focus on the more realistic case of multi-stage models, using both a stochastic agent-based model and a set of reaction-diffusion equations for the cells' average density. By studying the corresponding travelling wave solutions, we obtain an analytical expression for the speed of invasion for a general N-stage model with identical transition rates, in which case the resulting cell cycle times are Erlang distributed. We show that, for a general N-stage model, the Erlang distribution and the exponential distribution lead to the minimum and maximum invasion speed, respectively. This result allows us to determine the range of possible invasion speeds in terms of the average proliferation time for any multi-stage model.


Case Report: The success of face analysis technology in extremely rare genetic diseases in Korea: Tatton-Brown-Rahman syndrome and Say-Barber -Biesecker-Young-Simpson variant of ohdo syndrome.
Tatton-Brown-Rahman syndrome (TBRS) and Say-Barber-Biesecker- Young-Simpson variant of Ohdo syndrome (SBBYSS) are extremely rare genetic disorders with less than 100 reported cases. Patients with these disorders exhibit a characteristic facial dysmorphism: TBRS is characterized by a round face, a straight and thick eyebrow, and prominent maxillary incisors, whereas SBBYSS is characterized by mask-like facies, blepharophimosis, and ptosis. The usefulness of Face2Gene as a tool for the identification of dysmorphology syndromes is discussed, because, in these patients, it suggested TBRS and SBBYSS within the top five candidate disorders. Face2Gene is useful for the diagnosis of extremely rare diseases in Korean patients, suggesting the possibility of expanding its clinical applications.


Flexor digitorum longus transfer and medial displacement calcaneal osteotomy for the treatment of stage II posterior tibial tendon dysfunction: kinematic and functional results of fifty one feet.
Stage II posterior tibial tendon dysfunction (PTTD) can be treated by flexor digitorum longus (FDL) tendon transfer and medial displacement calcaneal osteotomy (MDCO). Numerous authors have studied the clinical and radiographic results of this procedure. However, little is known about the kinematic changes. Therefore, the purpose of this study was to assess plantar-pressure distribution in these patients. Seventy-three patients with PTTD stage II underwent FDL tendon transfer and MDCO. Plantar pressure distribution and American Orthopaedic Foot and Ankle Society (AOFAS) score were assessed 48 months after surgery. Pedobarographic parameters included lateral and medial force index of the gait line, peak pressure (PP), maximum force (MF), contact area (CA), contact time (CT) and force-time integral (FTI). In the lesser-toe region, PP, MF, CT, FTI and CA were reduced and MF in the forefoot region was increased. These changes were statistically significant. We found statistically significant correlations between AOFAS score and loading parameters of the medial midfoot. Study results reveal that FDL tendon transfer and MDCO leads to impaired function of the lesser toes during the stance phase. However, there seems to be a compensating increased load in the forefoot region.


Fall events among people with stroke living in the community: circumstances of falls and characteristics of fallers.
To describe the frequency and circumstances of falls among a community sample of people with stroke and to compare characteristics of fallers and nonfallers. Cross-sectional, observational study. Community. Forty-one community-dwelling people with stroke (26 men, 15 women; mean age, 69.7 +/- 11.6y), of which 23 had right-hemisphere infarction, 16 left-hemisphere infarction, and 2 had a brainstem lesion. Time since onset of stroke ranged from 3 to 288 months (mean, 50mo). Not applicable. Standardized tests were used to measure mobility, upper limb function, activities of daily living (ADL ability), and mood. Information about fall events was collected by using a questionnaire. Twenty-one participants (50%) were classed as fallers, of whom 10 had fallen repeatedly. No significant differences were found between fallers and nonfallers on any of the measures used. However, those who had 2 or more falls (n = 10) had significantly reduced arm function (P = .018) and ADL ability (P = .010), compared with those who had not fallen or experienced near falls (n = 5). Loss of balance, misjudgment, and foot dragging during walking, turning, and sit to stand were reported by fallers as the suspected causes and activities leading to falls. The high risk of falling among people with stroke was evident in this community-based sample. Repeat fallers had greater mobility deficits and significantly reduced arm function and ADL ability than those who did not report any instability.


Influence of CCR7 ligand DNA preexposure on the magnitude and duration of immunity.
The CC chemokine receptor (CCR) 7 ligands CCL21 and CCL19 were recently described as essential elements for establishing the microenvironment needed to initiate optimal immune responses in secondary lymphoid tissues. In the present study we have kinetically investigated the primary responses of naive DO11.10 TCR-transgenic CD4+ T cells (OVA323-339 peptide specific) adoptively transferred into normal BALB/c mice given plasmid DNA encoding CCR7 ligands. The primary responses of CD4+ Tg-T cells in CCR7 ligand DNA recipients occurred more promptly, reaching levels higher than those observed in vector controls. In line with enhanced specific immunity, the T-cell population in CCR7 ligand recipients underwent more in vivo cell division following Ag stimulation, and a higher percentage of Ag-specific T cells expressed an activation phenotype. Moreover, the enhanced primary responses of naive CD4+ T cells appeared to act via affects on migration and maturation of CD11c+ dendritic cells in the draining lymph nodes. In addition following mucosal challenge of herpes simplex virus-immune mice with virus, those that had received CCL21 or CCL19 during priming contained a higher frequency of responding CD4 T cells in lymph nodes and the site of infection. Moreover, CCL21- and CCL19-treated mice showed less severe disease and better survival following challenge. Our results are discussed in terms of the relevance of CCR7 ligand preimmunization to improve vaccine.


The focal adhesion scaffolding protein HEF1 regulates activation of the Aurora-A and Nek2 kinases at the centrosome.
Although HEF1 has a well-defined role in integrin-dependent attachment signalling at focal adhesions, it relocalizes to the spindle asters at mitosis. We report here that overexpression of HEF1 causes an increase in centrosome numbers and multipolar spindles, resembling defects induced by manipulation of the mitotic regulatory kinase Aurora-A (AurA). We show that HEF1 associates with and controls activation of AurA. We also show that HEF1 depletion causes centrosomal splitting, mono-astral spindles and hyperactivation of Nek2, implying additional action earlier in the cell cycle. These results provide new insight into the role of an adhesion protein in coordination of cell attachment and division.


Large cell neuroendocrine - Adenocarcinona mixed tumour of colon: Collision tumour with peculiar behaviour. What do we know about these tumours?
Mixed glandular-endocrine carcinomas are rare tumours of gastrointestinal tract (MANEC). They are more frequent in stomach and hardly one hundred cases have been described in colon. According to Lewis, they are classified into collision (side by side pattern), composite (intermingled) or amphicrine (neuroendocrine and glandular features inside a same cell). Collision tumours are related to biclonal theory: two simultaneous cancerogenic events. Conversely, multidirectional differentiation from a stem cell is accepted as origin of composite tumours. The aim of this paper is to analyse the behaviour of these tumours, with an especial concern about how these tumours metastasise, and the different theories about carcinogenesis. We report a rare case of collision adenocarcinoma-large cell neuroendocrine tumour of colon that after a three-year period of follow-up has presented a retroperitoneal recurrence that features adenocarcinoma and large cell neuroendocrine components. After an exhaustive review of the English literature, we found that only two cases of collision tumour of colon with metastases showing glandular and endocrine components have been described up to date, so we report the third case, and the first happening in transverse colon. We conclude that not all collision tumours follow the biclonal theory and more studies are needed to clarify the origin of these neoplasms, and consequently, to reach an adequate treatment.


[Notes on the indication of corrective osteotomy in Perthes' disease (author's transl)].
The results of surgical (corrective osteotomy) and conservative therapy (Thomas splint treatment) are compared in 88 patients suffering from Perthes' disease. It is attempted to show whether the age of the patients, the stage of disease, centric or excentric head of femur, Cattherall's stage or any risk factors influence the results. Statistics show that only young children profit from surgical treatment whereas it offers no advantage to children over six years of age. Among the young children only those with excentric head of femur, show significantly better results as opposed to conservative splint treatment. Surgery is otherwise only indicated when it is seen as an alternative to prolonged splint treatment.


Eusociality is linked to caste-specific differences in metabolism, immune system, and somatic maintenance-related processes in an ant species.
The social organization of many primate, bird and rodent species and the role of individuals within that organization are associated with specific individual physiological traits. However, this association is perhaps most pronounced in eusocial insects (e.g., termites, ants). In such species, genetically close individuals show significant differences in behavior, physiology, and life expectancy. Studies addressing the metabolic changes according to the social role are still lacking. We aimed at understanding how sociality could influence essential molecular processes in a eusocial insect, the black garden ant (Lasius niger) where queens can live up to ten times longer than workers. Using mass spectrometry-based analysis, we explored the whole metabolome of queens, nest-workers and foraging workers. A former proteomics study done in the same species allowed us to compare the findings of both approaches. Confirming the former results at the proteome level, we showed that queens had fewer metabolites related to immunity. Contrary to our predictions, we did not find any metabolite linked to reproduction in queens. Among the workers, foragers had a metabolic signature reflecting a more stressful environment and a more highly stimulated immune system. We also found that nest-workers had more digestion-related metabolites. Hence, we showed that specific metabolic signatures match specific social roles. Besides, we identified metabolites differently expressed among behavioral castes and involved in nutrient sensing and longevity pathways (e.g., sirtuins, FOXO). The links between such molecular pathways and aging being found in an increasing number of taxa, our results confirm and strengthen their potential universality.


Restorative proctocolectomy without diverting ileostomy in children with ulcerative colitis.
The safety of performing a restorative proctocolectomy (RP) and J-pouch ileoanal anastomosis (IPAA) without diverting ileostomy for children with ulcerative colitis (UC) is a subject of extensive debate. Our goal was to examine pediatric outcomes of RP and IPAA without ileostomy. We performed a single-institution review of UC patients who had RP and IPAA with (+Ostomy) or without (-Ostomy) diverting ileostomy from 2002 to 2010. Surgeon and patient preference determined ileostomy decision. The study included 50 patients (28 +Ostomy, 22 -Ostomy). Preoperative demographics were similar between 2 groups in age (13.5 ± 3.5 years -Ostomy, 14.3 ± 3 years +Ostomy), serum albumin (3.6 ± 0.7 -Ostomy, 3.6 ± 0.7 +Ostomy), body mass index (20.8 ± 6.9 -Ostomy, 21.3 ± 8.6 +Ostomy), and daily corticosteroid dose (22.4 ± 17.7 mg -Ostomy, 23.5 ± 13.7 mg +Ostomy). Operating time was less in -Ostomy with mean times of 6:22 ± 2:04 vs 9:07 ± 2:57. The -Ostomy group required fewer ileoanal anastomotic dilations per patient (0.4 ± 0.8 vs 1.4 ± 1.9). Functional outcomes were not significantly different regarding pouchitis episodes per patient (0.6 ± 1.1 -Ostomy, 0.6 ± 1.1 +Ostomy), daily bowel movements (5.5 ± 1.9 -Ostomy, 6.7 ± 4.0 +Ostomy), and daily postoperative loperamide dose (8.4 ± 4.3 mg -Ostomy, 6.8 ± 4.0 mg +Ostomy). Short- and long-term outcomes can be equivalent in patients with and without diverting ileostomy, but questions remain regarding patient selection and quality of life impact.


Case Report: Cutaneous chilblains-like lesions (CCLL) versus COVID-19 toes during the pandemic. Confocal findings and proposal for new acronym, CCLL - is there a diagnostic window?
The COVID-19 outbreak caused by the novel coronavirus, SARS-CoV-2, typically presents with symptoms including fever, cough, headache, myalgia, asthenia, anosmia, diarrhea, and sometimes pneumonia, which can be fatal. Recently, new dermatologic findings have been described in association with the disease that can potentially be a distinguishing feature of infection. One such feature resembles chilblains and this case report represents a unique presentation of this feature.


Patterns of mandibular invasion by gingival squamous cell carcinoma.
This study examined patterns of invasion of lower gingiva cancer into the mandible. Our goal was to clarify the most common routes for gingival squamous cell carcinoma to enter and spread within the mandible. The subjects were 176 patients with lower gingival squamous cell carcinoma who underwent mandibulectomy; all tumors were examined histopathologically. The method of mandibulectomy was decided on the basis of conventional plain radiographic and computed tomographic findings. The tumor extended to the periosteum in 33%, to the cortical bone in 23%, and to the bone marrow in 9% of the patients who underwent mandibular resection. The remaining 35% of our patients had no evidence of mandibular invasion. The area of bone resorption on preoperative clinical and radiographic examinations often disagreed with the extent of mandibular invasion on histopathologic examination.


Arginase activity in prostatic tissue of patients with benign prostatic hyperplasia and prostatic carcinoma.
We studied arginase activity in human prostatic tissue in 15 patients with benign hyperplasia and 27 patients with prostatic carcinoma. Arginase specific activity is greater (p less than 0.0001) in prostatic carcinomas than in hyperplastic prostates. Arginase specific activity is correlated inversely (p less than 0.0001) with the histological grade of the tumor.


Two-to-one A-V block with four-to-three A-V nodal wenckebach, a form of spontaneous multilevel block.
Electrophysiologic studies in one patient with spontaneous 2:1 atrioventricular block and variable PR intervals revealed two sites of conduction block. Typical 4:3 A-V nodal Wenckebach was present in addition to Mobitz type II infra-His block. The HV of conducted complexes was 120 msec and the shortest recorded AH interval was 250 msec. When 2:1 A-V block with fixed PR interval was present, only 2:1 Mobitz type II infra His-block was present. The mechanism of this example of spontaneous multilevel A-V block is discussed and compared to other previously reported cases.


Children diagnosed with presymptomatic type 1 diabetes through public health screening have milder diabetes at clinical manifestation.
We aimed to determine whether disease severity was reduced at onset of clinical (stage 3) type 1 diabetes in children previously diagnosed with presymptomatic type 1 diabetes in a population-based screening programme for islet autoantibodies. Clinical data obtained at diagnosis of stage 3 type 1 diabetes were evaluated in 128 children previously diagnosed with presymptomatic early-stage type 1 diabetes between 2015 and 2022 in the Fr1da study and compared with data from 736 children diagnosed with incident type 1 diabetes between 2009 and 2018 at a similar age in the DiMelli study without prior screening. At the diagnosis of stage 3 type 1 diabetes, children with a prior early-stage diagnosis had lower median HbA1c (51 mmol/mol vs 91 mmol/mol [6.8% vs 10.5%], p<0.001), lower median fasting glucose (5.3 mmol/l vs 7.2 mmol/l, p<0.05) and higher median fasting C-peptide (0.21 nmol/l vs 0.10 nmol/l, p<0.001) compared with children without previous early-stage diagnosis. Fewer participants with prior early-stage diagnosis had ketonuria (22.2% vs 78.4%, p<0.001) or required insulin treatment (72.3% vs 98.1%, p<0.05) and only 2.5% presented with diabetic ketoacidosis at diagnosis of stage 3 type 1 diabetes. Outcomes in children with a prior early-stage diagnosis were not associated with a family history of type 1 diabetes or diagnosis during the COVID-19 pandemic. A milder clinical presentation was observed in children who participated in education and monitoring after early-stage diagnosis. Diagnosis of presymptomatic type 1 diabetes in children followed by education and monitoring improved clinical presentation at the onset of stage 3 type 1 diabetes.


Expenditures of medicine use in hypertensive/diabetic elderly and physical activity and engagement in walking: cross secctional analysis of SABE Survey.
The literature shows the inverse association between physical activity level (PAL) and chronic diseases that have a significant burden over health care costs. However, in upper-middle income countries and in elderly population this information are scarce. To describe the annual drug expenditures for the hypertensive and diabetic elderly population in Brazil and to analyze the association with PAL and engagement in walking. This cross sectional study is part of SABE Survey and comprised 806 hypertensive and/or diabetic elderly (≥60 years old). The annual expenditures of medicine use was estimated for all medications for hypertension and/or diabetes they were taking. The PAL was considered insufficient when moderate physical activity was <150 min/week or vigorous physical activity was < 75 min/week. Engagement in walking was considered by at least 1 day a week. All expenditures were presented through the descriptive values (in American Dollars US$) according PAL and engagement in walking. The association analysis between annual expenditures, PAL and engagement in walking were performed by multiple logistic regression models adjusted for gender, age and body mass index. The average annual cost was higher in diabetic and insufficient physically activity elderly. The 1-year estimated.cost was US$ 73386,09 and 295% higher in insufficiently physically active. Older people who reported not walking had a higher risk to higher annual expenditures of medicine use (OR = 1.57, 95% CI 1.03-2.40). The annual expenditures of medicine use for controlling hypertension and diabetes of Brazilian elderly were higher and inversely associated with physical activity level and engagement in walking.


Thyroid-stimulating hormone-thyroid hormone signaling contributes to circadian regulation through repressing clock2/npas2 in zebrafish.
Thyroid-stimulating hormone (TSH) is important for the thyroid gland, development, growth, and metabolism. Defects in TSH production or the thyrotrope cells within the pituitary gland cause congenital hypothyroidism (CH), resulting in growth retardation and neurocognitive impairment. While human TSH is known to display rhythmicity, the molecular mechanisms underlying the circadian regulation of TSH and the effects of TSH-thyroid hormone (TH) signaling on the circadian clock remain elusive. Here we show that TSH, thyroxine (T4), triiodothyronine (T3), and tshba display rhythmicity in both larval and adult zebrafish and tshba is regulated directly by the circadian clock via both E'-box and D-box. Zebrafish tshba-/- mutants manifest congenital hypothyroidism, with the characteristics of low levels of T4 and T3 and growth retardation. Loss of tshba or overexpression of tshba alters the rhythmicity of locomotor activities and expression of core circadian clock genes and hypothalamic-pituitary-thyroid (HPT) axis-related genes. Furthermore, TSH-TH signaling regulates clock2/npas2 via the thyroid response element (TRE) in its promoter, and transcriptome analysis reveals extensive functions of Tshba in zebrafish. Together, our results demonstrate that zebrafish tshba is a direct target of the circadian clock and in turn plays critical roles in circadian regulation along with other functions.


Expression, purification and preliminary structural analysis of the head domain of Deinococcus radiodurans RecN.
Deinococcus radiodurans is well known for its extreme tolerance to harsh conditions and for its extraordinary ability to repair DNA. Double-strand breaks (DSBs) are the most hazardous lesions that can be induced by ionizing radiation, and homologous recombination (HR) is the principal mechanism by which the integrity of the DNA is restored. In D. radiodurans the RecFOR complex is the main actor in HR and the RecN protein is believed to play an important role in DSB recognition. Here, SAXS and preliminary X-ray diffraction studies are presented of the head domain, which is the globular region formed upon interaction of the N- and C-terminal domains of RecN. The crystal structure of this domain was solved using the single-wavelength anomalous dispersion method. Model building and refinement are in progress.


Diversity of bacterial endophytes in Panax ginseng and their protective effects against pathogens.
Although endophytic bacteria are known to colonize Panax ginseng, little is known about their diversity and roles. We addressed in the present study by comparing endophytic bacterial populations in P. ginseng plants of different ages (2-6 years) and in various tissue types (root, stem, leaf, and flower stalk). A total of 116 strains assigned to 42 species were identified by 16S rDNA sequencing. The predominant phylum was Firmicutes. Two-year-old ginseng plants and root tissues showed the greatest diversity of endophytic bacteria, with Bacillales being the predominant order. The antifungal activity of isolates against two pathogens, Cylindrocarpon destructans and/or Botrytis cinerea, was evaluated in dual-culture assays. In total, 28 strains showed antifungal activity with PgBE14 (Bacillus amyloliquefaciens), PgBE40 (B. megaterium), PgBE39, PgBE45 (Pseudomonas frederiksbergensis), and PgBE42 (Staphylococcus saprophyticus) inhibiting both pathogens. These results improve our understanding of the structure and diversity of endophytic bacterial communities of P. ginseng and identify strains with antifungal activity that have potential applications as biocontrol agents.


Body composition and osteoporotic fracture using anthropometric prediction equations to assess muscle and fat masses.
Obesity is protective of bone health; however, abdominal obesity is associated with a higher fracture risk. Little is known about whether body composition protects or adversely affects osteoporotic fractures because of practical issues regarding assessment tools. This study aimed to evaluate the association of predicted body composition with fracture risk to determine the distinctive and differing effects of muscle or fat mass on bone health outcomes in the general population. This population-based, longitudinal cohort study used 2009-2010 Korean National Health Insurance Service data and follow-up data from 1 January 2011 to 31 December 2013, to determine the incidence of osteoporotic fracture (total, spine, and non-spine) defined using the International Classification of Diseases, Tenth Revision codes. The study participants were aged ≥50 years (men, 158 426; women, 131 587). The predicted lean body mass index (pLBMI), appendicular skeletal muscle index (pASMI), and body fat mass index (pBFMI) were used to assess body composition, using anthropometric prediction equations. Over a 3 year follow-up, we identified 2350 and 6175 fractures in men and women, respectively. The mean age of the participants was 60.2 ± 8.3 and 60.7 ± 8.4 years in men and women, respectively. In a multivariable-adjusted Cox proportional hazards regression model, increasing pLBMI or pASMI was significantly associated with a decreased risk of total fractures in men and women. When comparing individuals in the lowest pLBMI and pASMI (reference groups), men with the highest pLBMI and pASMI had adjusted hazard ratios of 0.63 [95% confidence interval (CI) 0.47-0.83] and 0.62 (95% CI 0.47-0.82), and women with the highest pLBMI and pASMI had adjusted hazard ratios of 0.72 (95% CI 0.60-0.85) and 0.71 (95% CI 0.60-0.85), respectively, for total fractures. The pBFMI had no significant association with total fractures in men or women. Regarding sex-specific or site-specific differences, the protective effects of the pLBMI and pASMI on fractures were greater in men and reduced the risk of spinal fractures. An increased pBFMI was associated with an increased risk of spinal fractures in women. An increased pLBMI or pASMI was significantly associated with decreased total osteoporotic fracture risk; however, the pBFMI showed no statistically significant association. Muscle mass was more important than fat mass in preventing future osteoporotic fractures based on anthropometric prediction equations.


Vitamin E levels in premenstrual syndrome.
To determine whether changes in peripheral vitamin E levels are associated with symptoms of premenstrual syndrome, 10 patients with premenstrual syndrome and 10 control subjects were studied. They gave blood at 2- or 3-day intervals throughout three menstrual cycles. The vitamin E was measured by fluorometry after hexane extraction and luteinizing hormone was measured by radioimmunoassay. In the control group, vitamin E values were 854 +/- 45 micrograms/dl (mean +/- SE) during the luteal phase and 925 +/- 55 micrograms/dl during the follicular phase. No significant changes were noted between the two values. In the patients with premenstrual syndrome, the values were 849 +/- 53 micrograms/dl during the luteal phase, which was not significantly different from 858 +/- 48 micrograms/dl during the follicular phase. No significant changes were noted between the control group and the patients with premenstrual syndrome in either the luteal or the follicular phase. Vitamin E deficiency in patients with premenstrual syndrome was not shown by peripheral vitamin E levels in our study.


The maintenance of shore-level size gradients in an intertidal snail (Littorina sitkana).
The size of many intertidal animals varies with tidal height. These size gradients could be produced by growth or survival varying with tidal height, or by animals moving to a preferred tidal level. The body size of the snail, Littorina sitkana, increases steadily with tidal height in rocky high intertidal habitats of British Columbia. To determine how size gradients were maintained in L. sitkana, I quantified how growth, survival, and snail movement varied with tidal height. I studied populations of L. sitkana found on sheltered pebble beach and exposed basaltic shelf habitats. Mark-recapture studies and experimental transplants showed that growth could not have produced the size gradients because snail growth rates in both habitats were as fast or faster at low tidal levels (where the snails were the smallest) than at high tidal levels. However, survival rates were lowest at low tidal levels. On pebble beaches, this was due to size selective predation on large snails by the pile perch, Rhacochilus vacca. On basaltic shelves, heavy wave action at low tidal levels may have caused the poor survival rates. Transplanted snails moved homeward on pebble beaches, but not on basaltic shelves. Reduced survival rates at low tidal levels cause size gradients in both habitats, and snail movement helps to maintain size gradients on pebble beaches.


Differential systemic decellularization in vivo to study molecular changes in each vasculature layer in murine models of disease.
Vascular dysfunction underlies the onset and progression of many life-threatening diseases, highlighting the need for improved understanding of its molecular basis. Here, we present differential systemic decellularization in vivo (DISDIVO), a protocol that enables systemic and independent study of the molecular changes in each vasculature layer in murine models of disease. We describe steps for anesthesia, perfusion surgery, and exsanguination. We then detail detachment and collection of glycocalyx and decellularization and collection of both endothelial and smooth muscle cells. For complete details on the use and execution of this protocol, please refer to Serra et al., Gallart-Palau et al., and Vinaiphat et al.1,2,3.


Increased Brainstem Serotonergic Transporter Availability in Adult Migraineurs: an [(18)F]FP-CIT PET Imaging Pilot Study.
Recent studies have proposed central serotonergic dysfunction as a major pathophysiology of migraine. We investigated serotonin transporter (SERT) availability in migraineurs using F-18-N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([(18)F]FP-CIT) positron emission tomography (PET). Brain [(18)F]FP-CIT PET images were obtained in eight women with migraine during headache free phase and 12 healthy adult women, 120 min after injection of 185 MBq. Non-displaceable binding potential (BP ND) of [(18)F]FP-CIT, which is an estimate of SERT availability, was calculated at the brainstem and compared with clinical parameters. BP ND at the brainstem was significantly higher in adult migraineurs (n = 6, 1.15 ± 0.17) than healthy subjects (0.95 ± 0.14) (p = 0.04). Healthy subjects demonstrated negative correlation between brainstem BP ND and age (r = -0.64, p = 0.02), whereas this age-related decline pattern was not found in the migraineurs. Severity of migraine attack was significantly correlated with brainstem BP ND (r = 0.66, p = 0.02), when age and duration of illness were corrected. Increased SERT availability in the brainstem of adult migraineurs indicates low serotonin neurotransmission during headache-free phase. Patients who experience more painful headaches have lower serotonin neurotransmission. [(18)F]FP-CIT PET is a useful in vivo imaging technique for evaluating brainstem SERT availability in migraineurs.


Frequency of recurrence of atrial fibrillation within 48 hours after ablation and its impact on long-term outcome.
Because of delayed structural and electrophysiologic effects of radiofrequency ablation of atrial fibrillation (AF), early recurrence of AF after ablation does not necessarily indicate long-term ablation failure. This study was intended to assess the prognostic value of early recurrence of AF within 48 hours after ablation. The study included 234 patients (aged 23 to 80 years; 72% men) with symptomatic drug-resistant paroxysmal (n = 165) or persistent AF (n = 69) who underwent either Lasso-guided segmental pulmonary vein isolation (n = 83) or CARTO-guided left atrial circumferential ablation (n = 151). After a median follow-up of 12.7 months, 64% of patients with paroxysmal and 45% of patients with persistent AF were AF free. Early recurrence of AF occurred in 43% of patients and was more frequently observed in the persistent-AF group (paroxysmal vs persistent 39% vs 54%; p = 0.037). Early recurrence of AF was a significant predictor of long-term ablation failure in univariate (hazard ratio [HR] 2.29, p <0.001) and multivariate (HR 2.17. p <0.001) Cox regression analysis. Nevertheless, 46% of patients with early recurrence of AF were AF free during long-term follow-up compared with 68% of patients without early recurrence of AF. The prognostic value of early recurrence of AF was found in patients with paroxysmal (HR 2.05, p = 0.005) and persistent AF (HR 2.35, p = 0.013). In conclusion, early recurrence of AF within 48 hours after ablation was a significant predictor of a poor long-term ablation outcome. However, because nearly half the patients with early recurrence of AF remained AF free during long-term follow-up, early recurrence of AF should not automatically result in an early repeated procedure.


Using failure mode and effects analysis to improve patient safety.
Failure mode and effects analysis (FMEA) (ie, prospective risk analysis) involves close examination of high-risk processes to identify needed improvements that will reduce the chance of unintended adverse events. This risk assessment process is used in other industries (ie, manufacturing, aviation) to evaluate system safety. Health care organizations now are using it to evaluate and improve the safety of patient care activities. The FMEA process promotes systematic thinking about the safety of patient care processes (ie, what could go wrong, what needs to be done to prevent failures.) The steps of the FMEA process are described and applied to a high-risk perioperative process.


Impact of warm saline irrigation, hyperthermic intraperitoneal chemotherapy on postoperative pain in primary ovarian cancer from the KOV-HIPEC-01 randomized trial.
Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a treatment option at the time of cytoreductive surgery after neoadjuvant chemotherapy. The effect of active warming of HIPEC on postoperative pain needs to be investigated. This study aimed to investigate whether HIPEC reduces postoperative pain. From the KOV-HIPEC-01 trial, a randomized controlled trial of HIPEC for advanced primary ovarian cancer, 184 patients with a residual tumor size <1 cm were randomly assigned to the HIPEC and control groups at a 1:1 ratio. The consumption of analgesics and pain scales were analyzed. Hyperthermic intraperitoneal chemotherapy was administered after cytoreductive surgery. The primary objective was to compare the consumption of opioids measured in morphine milligram equivalents and non-opioids measured as the maximum daily dose between the HIPEC and control groups. The secondary objective was to compare the minimum and maximum pain intensities on numeric rating scales between the two groups using a linear mixed model. Lesser consumption of non-opioids, with a lower mean maximum daily dose on postoperative days 1 and 2, was observed. The HIPEC group also experienced lower maximum pain intensities on postoperative day 1. No overall differences in the minimum or maximum pain intensities were observed on postoperative day 7. The addition of HIPEC to cytoreductive surgery did not lead to increased postoperative pain, as demonstrated by a reduction in the use of analgesics and lower scores on postoperative pain scales during the early postoperative period.


Differentiating solitary brain metastases from glioblastoma by radiomics features derived from MRI and 18F-FDG-PET and the combined application of multiple models.
This study aimed to explore the ability of radiomics derived from both MRI and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) images to differentiate glioblastoma (GBM) from solitary brain metastases (SBM) and to investigate the combined application of multiple models. The imaging data of 100 patients with brain tumours (50 GBMs and 50 SBMs) were retrospectively analysed. Three model sets were built on MRI, 18F-FDG-PET, and MRI combined with 18F-FDG-PET using five feature selection methods and five classification algorithms. The model set with the highest average AUC value was selected, in which some models were selected and divided into Groups A, B, and C. Individual and joint voting predictions were performed in each group for the entire data. The model set based on MRI combined with 18F-FDG-PET had the highest average AUC compared with isolated MRI or 18F-FDG-PET. Joint voting prediction showed better performance than the individual prediction when all models reached an agreement. In conclusion, radiomics derived from MRI and 18F-FDG-PET could help differentiate GBM from SBM preoperatively. The combined application of multiple models can provide greater benefits.


Lymphocyte clones from old subjects: growing rate and functional activity.
Old subjects exhibit a decline in circulating T cells and an impaired proliferative response to mitogens, plus a relative increase in cells with NK phenotype not associated with a concomitant increase in their cytolitic activity.In the present study a limiting dilution assay was used to evaluate the phenotype, the functional activity and the proliferative capacity of clones obtained from peripheral blood lymphocytes of old and young subjects. CD5+ CD8+ clones from old people showed a significant impairment in their proliferative capacity and a decreased lytic activity against K562 and P815-IgG cell lines.


A new perspective to environmental degradation: the linkages between higher education and CO2 emissions.
Although there have been many studies, focusing on basic determinants of carbon dioxide emissions (CO2), the effect of higher education, which has the potential to be an important determinant of CO2, has been neglected. The paper aims to display the potential mechanisms between higher education and CO2 and expand the environmental economics literature. In the paper, the trade-off between higher education and CO2 is tested by autoregressive distributed lag (ARDL) during the period 1983-2017 in Turkey. Results denote that cointegration exists and an increase in higher education negatively affects CO2. We also find that economic growth and energy consumption positively affect CO2 both in the long run and short run. Vector error correction model (VECM) reveals that higher education, economic growth, energy consumption, trade openness, and exchange rates are the causes of CO2 in the long run. Also, energy consumption and economic growth are the causes of CO2 in the short run. Therefore, higher education can be used to overcome environmental problems.


Therapeutic hypothermia for cardiac arrest: a practical approach.
Therapeutic hypothermia (TH), which prevents and ameliorates the cascade of secondary neurologic injury after the return of spontaneous circulation, is the most effective neuroprotective therapy for encephalopathic survivors of cardiac arrest. Acute management of patients with severe hypoxic-ischemic encephalopathy requires rapid and well-coordinated efforts involving emergency medicine, neurology, cardiology, critical care medicine, and palliative care. This effort is complex, and broad implementation of TH has been slow in the United States and Europe. This review summarizes recent developments in the practical application of TH, reviews the role of the neurologist, and suggests an algorithm for coordination of care of cardiac arrest survivors by physicians of divergent subspecialties, with the goals of maximizing neurologic and cardiac recovery.


Comparative proteomic study of the response to hypoxia in the muscle of oriental river prawn (Macrobrachium nipponense).
Adaptation to hypoxia is a complex process involving up- or down-regulation of numerous different proteins. In order to understand the molecular responses to hypoxia in crustacean muscle tissue, flow cytometry and oxidative stress analysis were used to explore the (hypoxia) physiological response on Macrobrachium nipponense. A 2D-gel-based proteomic approach was performed to compare the muscle proteome of hypoxic and normoxic M. nipponense. MALDI-TOF/TOF identified 15 and five proteins were significantly up- and down-regulated, respectively, in M. nipponense muscle under hypoxic conditions for 24h. Five spots were confirmed as hemocyanin, indicating an important role in environmental regulation. Real-time quantitative PCR confirmed that hemocyanin, heat shock protein 70, glutathione S-transferases, metallothionein, phosphofructokinase, and pyruvate kinase 2 were all up-regulated by hypoxia stress. These results suggest that the cellular response to hypoxia involves regulating proteins that function in maintaining antioxidative capacity, energy levels and muscle structure. Western blotting confirmed that the well-known hypoxic stress markers hemocyanin and heat shock protein 70 were up-regulated. These results increase our understanding of hypoxia-induced proteomic and transcriptional changes in M. nipponense muscle tissue. This 2-DE proteomic study investigated differentially expressed proteins in the muscle of prawns following hypoxia. Identified proteins may have roles in the response to hypoxia. These results improve our understanding of hypoxic stress in crustaceans and aquatic ecosystems.


Normal mitral and aortic valve areas assessed by three- and two-dimensional echocardiography in 168 children and young adults.
Our purpose was to investigate the effects of body size on the sizes of mitral (MV) and aortic valve (AV) areas by three-dimensional (3-D) and two-dimensional (2-D) echocardiography and to create the normal values for 3-D echocardiography. A total of 168 healthy subjects aged 2-27 years were studied by digitized 3-DE, 2-DE, and Doppler echocardiography.3-D echocardiography was performed by using rotational acquisition of planes at 18 degrees intervals from a parasternal view with electrocardiogram gating and without respiratory gating. The annular levels of MV and AV were identified from short-axis cut planes and their areas were measured by planimetry. The diameters of mitral annulus, left ventricular outflow tract (LVOT), and aortic annulus were measured by 2-DE from the apical and parasternal long-axis views. Flow indices were measured by Doppler from MV inflow and the flow in LVOT and in the ascending aorta. Both MV and AV annular areas increased linearly in relation to body size. In the total study group the estimated areas for MV were 5.2 +/- 0.9 cm2/m2 by 3-DE, 3.7 +/- 0.5 cm2/m2 by 2-DE, and 2.0 +/- 0.4 cm2/m2 by continuity equation. The respective values for AV were 2.7 +/- 0.5, 2.1 +/- 0.3, and 1.8 +/- 0.4 cm2/m2. MV velocity time integral (VTI)/ascending aorta VTI increased from 0.80 (0.26) to 0.95 (0.23) with increased body surface area (BSA), whereas MV VTI/LVOT VTI was 1.2 (0.2) in all BSA groups. MV and AV annulus areas increase linearly in relation to body size. 3-DE gives greater estimates for the areas than 2-DE and Doppler equation methods. The data obtained from 168 healthy subjects may serve as a reference for clinical use in patients with various cardiac abnormalities.


Update on extracorporeal membrane oxygenation.
Extracorporeal membrane oxygenation (ECMO) consists of the application of intermediate-term cardiopulmonary bypass for the treatment of potentially reversible heart and/or lung failure in the neonate, child, and adult. Applications in the neonate include congenital diaphragmatic hernia, pulmonary hypertension, meconium aspiration syndrome, and pre- and post-operative congenital heart surgery support. In the older child, myocarditis, infections, and respiratory failure (RSV and ARDS) are the most frequent indications, in addition to peri-operative cardiac surgical support. A review of the institutional experiences at the University of Louisville spanning a 15-year period and comparison international data will be presented, along with a pertinent review of the literature. Technical considerations, complications, and long-term outcomes will be reviewed, and the potential interface between ECMO and other, less invasive technologies, i.e., high-frequency ventilation, replacement surfactant, and nitric oxide, will be discussed.


Effect of adalimumab on the expression of genes encoding TNF-α signal paths in skin fibroblasts in vitro.
Tumour necrosis factor (TNF-α) is one of the main cytokines participating in inflammation and immune response. Biological effects of the cytokine action, mediated by two receptors: TNFRSF1A and TNFRSF1B involve activation of many signal paths, thus change the transcription activity of many genes. The mechanism of action of an anti-TNF medicine consists in blocking TNF-α though preventing activation of signal paths. To single out mRNA and microRNA genes relating to TNF-α signal paths, the expression of which could indicate sensitivity of cells to the medicine in question. The material used in the research consisted in the cell line of regular human skin fibroblasts NHDF (CC-2511 Lonza, Basel, Switzerland) exposed to adalimumab with a concentration of 8.00 μg/ml of the medium for 2, 8 and 24 h, compared with the control material, i.e. non-stimulated cells. Molecular analysis was performed using the oligonucleotide expressive micro-matrices technology HG-U133A, miRNA 2.0 Array micro-matrices and RTqPCR. mRNA: BIRC5, MAP3K4, ZFAND5, JUN differentiate cells exposed to the anti-TNF medicine, regardless of the time of cell/medicine incubation. TNF-α transcription activity is reduced during exposure of NHDF cells to adalimumab. miRNA regulating transcription activity of the said 4 mRNA and miRNA related to TNF-α and its receptors was also singled out. It was ascertained that adalimumab has therapeutic potential and affects genes engaged in signal paths activated by TNF-α. The results indicate the TNF-α usefulness as the molecular, supplementary marker in diagnostics and control of treatment effects.


[Primary pigmented breast adenocarcinoma in a male patient].
Pigmented mammary tumours are rare. Herein, we report the third case of primary pigmented breast adenocarcinoma in a male patient with clinical mimicking of nodular melanoma of the nipple. A male patient presented with a pigmented nodule of the right nipple. Histological examination of the lesion showed dermal and subcutaneous adenocarcinomatous proliferation. The perilesional stroma contained melanin both inside and outside macrophages, leading us to conclude on primary pigmented breast adenocarcinoma clinically mimicking nodular melanoma of the nipple. Local production of melanin by neoplastic cells in the mammary carcinoma was postulated as the cause of hyperpigmentation of the tumour. Other possible causes are transfer of melanin from overlying melanocytes of the pigmented areolar epidermis to the underlying neoplastic cells, or melanin synthesis by intratumoral melanocytes migrating from the epidermis (which strikes us as the most convincing interpretation for the reported case). Breast adenocarcinoma is a rare tumour in men and may present clinically as a pigmented lesion of the nipple, resulting in the problem of differential diagnosis with primary or metastasised nodular melanoma.


Comparative evaluation of the reinforcing effect of different post systems in the restoration of endodontically treated human anterior teeth at two different lengths of post space preparation- an in vitro study.
Comparative evaluation of the reinforcing effect of different post systems in the restoration of endodontically treated human anterior teeth at two different lengths of post space preparation- an in vitro study. 135 extracted human incisors were endodontically treated, out of which 120 teeth were decoronated 2mm above the cementoenamel junction and divided into four experimental groups based on the post system to be used: Glass fiber post (GFP) and stainless steel post (SSP), titanium post (TTP), cast metal post (CMP). Each group was divided into two sub-groups according to the length of post space preparation: 5mm and 10mm. All the samples were restored with metal crowns. The fracture resistance was measured by applying loads at an angle of 135º to the long axis of teeth in an instron universal testing machine. Fracture mode was analyzed for all the samples. Results from the four test groups were compared and analysed using one-way ANOVA test and the Post-hoc Bonferroni test to demonstrate differences between pairs of groups. The results revealed that SSP group at 10mm post space length showed the significantly ("P-value< 0.05") highest fracture resistance (793.7787 N). Decrease in post length resulted in the decrease in fracture resistance in all the groups reduced to values even lesser than the control (437.8733N). The different post systems used in the study were able to reinforce endodontically treated teeth only at 10mm post space length.


Expression of the Escherichia coli trpE gene in E. coli K12 bacteria: maximum level, rate and time of initiation of anthranilate synthetase production.
We have investigated the effect of alterations in the structure of the plasmid-borne Escherichia coli tryptophan (trp) coding region and other regions of the same replicon on the level, rate and time of initiation of anthranilate synthetase component I (ASase) synthesis in E. coli K12. The maximum level of ASase produced corresponds to 60%-65% of the total cellular proteins. Adding sequences downstream of the trpE coding region decreases the level but does not affect the time of initiation and rate of trpE expression (ASase synthesis). The presence of additional protein coding sequences on the plasmid outside the trpE-A region causes ASase production to start earlier and decreases the rate of ASase synthesis. A second copy of the trpE coding sequences, if present within or outside the trpE-A coding region on the same replicon, doubles the rate of synthesis of ASase and slightly increases its final level of production. The initiation of ASase production occurs earlier when the two trpE copies are located within two distinct transcription units.


Influenza outbreak management on a locked behavioral health unit.
In January 2006, 8 patients on a locked behavioral health (BH) ward were identified with influenza-like illness (ILI) based on syndrome of fever, malaise, myalgia, cough, and rhinitis. Two patients initially had rapid antigen testing positive for influenza and confirmed by polymerase chain reaction. All patients present on the ward (N=26) had been ordered influenza immunizations 6 weeks earlier: 46% (12/26) were immunized, 42% (11/26) refused, 12% (3/26) had no record of immunization. All direct care staff who worked on the unit during the outbreak had been offered immunizations in the fall: 55% (22/40) were immunized. When first symptoms were identified, provider notified infection control nurse and hospital epidemiologist, who instituted control measures: patients were confined to unit, unit was closed to admissions, nonimmunized asymptomatic patients were offered immunization, temperatures were recorded every 4hours, and nonimmunized providers were offered immunizations and prophylaxis. Patients with ILI were either admitted to acute care and placed in Droplet/Contact Precautions until afebrile for 48hours or managed on the unit with modified isolation. All patients remaining on the unit were instructed in hand hygiene and respiratory etiquette; asymptomatic patients were offered oseltamivir phosphate prophylaxis; and previously nonimmunized patients and staff were again offered the vaccine. Twenty-six patients and 28 staff were on the unit during the outbreak. Eight patients and 8 staff members reported ILI within 5 days. Of the ill patients, 3 had been immunized, 5 had not (2 refused, 3 reason unclear presumed to have refused), and 4 were admitted to acute care and placed in Droplet/Contact Precautions until asymptomatic for 48hours. Of 22 patients who remained on the unit, 4 were symptomatic; 18 asymptomatic patients took prophylaxis, and 1 refused; 8 (89%) patients who had earlier refused vaccine were immunized. Of the 40 staff members, 55% (22/40) were immunized, and 20% (8/40) were symptomatic (all presumptive, encouraged to remain off duty). Fifty percent (4/8) of symptomatic staff had been immunized. After 7 days, no new cases had been identified, and the unit was reopened to admissions. No ill effects resulted from the prophylaxis. Prompt detection of ILI and institution of control measures effectively contained the outbreak; the relatively high immunization rates among both patients and staff helped curtail spread. Refusal of immunization is a long-standing problem among BH patients and staff. Our study shows importance of immunization in preventing outbreaks in inpatient BH settings. Recommendations included development of more aggressive immunization campaign for patients and staff who historically refuse and continued high priority for provider vigilance in immunization campaign and surveillance for symptoms.


Synthesis and cytotoxicity of novel sansalvamide A derivatives.
Described are the syntheses of 14 derivatives of the natural product Sansalvamide A, where two are more active against HCT 116 colon cancer cell lines than the natural product. These derivatives were synthesized using a combinatorial-type strategy that permits elucidation of the amino acid role in the cytotoxicity, and they lay the groundwork for development of new anticancer agents. [structure: see text]


CT before transcatheter aortic valve replacement: Value of venous phase imaging for detection and interpretation of findings with impact on the TAVR procedure.
Multidetector CT (MDCT) is performed to evaluate patients before transcatheter aortic valve replacement (TAVR). MDCT can uncover relevant nonvascular incidental findings. The use of venous phase imaging (VPI) in MDCT before TAVR has not been evaluated. To evaluate the incidence of nonvascular findings in MDCT before TAVR with effect on the TAVR procedure and the value of VPI in this setting. Sixty-four-slice MDCT angiography with VPI (100 mL contrast agent with 370-mg iopromide per mL) in 76 patients was retrospectively evaluated by 2 readers. Nonvascular findings were separately assessed on arterial and venous phase images and categorized in consensus as nonsignificant (no effect on TAVR), intermediate (further workup or surveillance necessary, no effect on TAVR), or significant (effect on TAVR). Radiation dose was recorded as dose-length product (DLP) and effective dose was calculated. A total of 169 findings were detected, of which 155 (91.7%) were nonsignificant, 13 (7.7%) were intermediate, and 1 (0.6%) was significant. TAVR was canceled in 1 patient (1.3%) because of suspected pancreatic cancer. No significant finding was seen on VPI only. Mean total DLP was 1137.9 mGy·cm (16.07 mSv) and the proportional mean DLP of VPI was 403 mGy·cm (6.85 mSv). The incidence of nonvascular significant findings in MDCT before TAVR is low and VPI in our series did not add value. However, it may be considered in selected patients.


Theory of mind and its relevance in schizophrenia.
Social cognitive impairments are considered to be core features of schizophrenia and have been hypothesized to play a mediator role between basic neurocognition and patients' outcomes. In this context, theory of mind (ToM) abilities are of special relevance, and deficits in this area may represent trait markers of schizophrenia. In this review, studies published since September 2010 have been summarized with a particular focus on the relationships between ToM and psychopathology, neurocognition, and psychosocial outcomes in patients with schizophrenia, as well as on ToM abilities in high-risk individuals. In addition, recent neuroimaging data as well as treatment interventions have been described. The reviewed literature strengthens the hypothesis that ToM deficits have the potential to be valid markers for schizophrenia.


Chudley McCullough syndrome.
Chudley McCullough syndrome is characterized by partial agenesis of the corpus callosum, interhemispheric cyst, cerebral and cerebellar cortical dysplasias, and hydrocephalus. This syndromic form of sensorineural hearing loss is rare. Our literature search has located 13 siblings in 6 families with this syndrome. We report a case of Chudley McCullough syndrome and discuss the relevant literature. It is amply clear from the review of literature that treatment of ventricular dilatation or drainage of arachnoid cysts in these cases will not improve the sensorineural hearing loss. A 14-month-old female child presented with bilateral profound sensorineural hearing loss. Neuroimaging revealed partial agenesis of the corpus callosum, colpocephaly, and an interhemispheric arachnoid cyst. These associations suggested a diagnosis of Chudley McCullough syndrome.


Magnetism in Ln molecular systems with 4f/valence-shell interplay (FV-magnetism).
The hunt for high-performance single-molecule magnets (SMM) revealed that atomic and molecular lanthanide systems combining 4f-shell and valence magnetism (FV-magnetism) may show magnetic bistability up to unexpectedly high temperatures. Here we rationalize the stability of the magnetism in the FV-systems from first principles on the example of LnII(CpiPr5)2 molecules.


AS1411 aptamer modified carbon dots via polyethylenimine-assisted strategy for efficient targeted cancer cell imaging.
Carbon dots (CDs), as a fascinating class of fluorescent carbon nanomaterials, have been proven to be powerful tools in the field of bioimaging and biosensing due to their small size, suitable photostability and favourable biocompatibility. However, the cellular uptake of free CDs lacks selectivity and the same negative charges as cell membranes may cause inefficient cell internalization. In this study, an efficient detecting and targeting nanosystem was developed based on the DNA aptamer AS1411 modified CDs with polyethyleneimine (PEI) as connecting bridge. Hydrothermally prepared CDs were assembled with positive-charged PEI, followed by conjugation with AS1411 through electrostatic interaction to form CDs-PEI-AS1411 nanocomplexes. The CDs, CDs-PEI and CDs-PEI-AS1411 were characterized by transmission electron microscopy (TEM), fourier transform infrared (FTIR) spectra, UV-vis spectra, zeta potential measurements and capillary electrophoresis characterizations. The cytotoxicity investigation of the CDs-PEI-AS1411 and CDs-PEI in both MCF-7 and L929 cells was carried out by the CCK-8 assay. The cellular uptake of the CDs-PEI-AS1411 was studied with confocal microscopy and flow cytometry. The as-prepared nanosystem possessed good photostability and no obvious cytotoxicity. On the basis of the confocal laser scanning microscope observation and the flow cytometry studies, the cellular uptake of CDs-PEI-AS1411 nanosystem in MCF-7 cells was significantly higher than that of L929 cells, which revealed the highly selective detection ability of nucleolin-positive cells. The results of this study indicated that the CDs-PEI-AS1411 nanosystem had a potential value in cancer cell targeted imaging.


Trace determination of perfluorooctane sulfonate and perfluorooctanoic acid in environmental samples (surface water, wastewater, biota, sediments, and sewage sludge) using liquid chromatography - Orbitrap mass spectrometry.
An analytical method was established and validated for the analysis of the most frequently monitored representatives among the group of perfluorinated compounds (PFAS), namely, perfluorooctanoic acid (PFOA) and prefluorooctane sulfonate (PFOS) in environmental samples (surface water, wastewater, sediments, sewage sludge, and biota). High performance liquid chromatography (HPLC) coupled to Orbitrap mass spectrometry (Orbitrap-MS) employing a heated electrospray ionization (HESI) interface operated in negative mode was used for the quantitative determination of these contaminants. HPLC separation of analytes was achieved using a reversed phase C18 (RP-C18) analytical column. The efficiency of various solid phase extraction (SPE) columns for the pre-concentration and clean-up as well as the performance of different ionization sources and detection modes for the instrumental determination were evaluated. The validation results indicate recoveries of analytes between 88 and 116%, while the intra-day and inter-day precision parameters in terms of relative standard deviations (RSDs) were in the range of 1.0-5.9% and 1.5-7.3%, respectively. The measured values for certified reference material (CRM) agreed with the provided reference values, revealing the accuracy of obtained concentrations in the range of 107-108%. The trueness of the method was verified by a successful participation in a proficiency testing (PT) program. These performance characteristics of the method permit reliable monitoring of PFOS and its derivatives in environmental samples according to the environmental quality standard (EQS) criteria regarding the maximum allowable concentrations and taking into account the annual average concentrations stated in Directive 2013/39/EU. The elaborated method was applied for the routine analysis of selected PFAS in environmental samples from the Baltic region.


Fluorescent chemodosimeters using "mild" chemical events for the detection of small anions and cations in biological and environmental media.
Mild chemical processes of various analytes and detection methods involving revolutionary strategies in the fields of analytical chemistry, biology and environmental sciences have been extensively developed. This critical review focuses on representative examples of mild chemical processes that can be used in fluorescent chemodosimeters for ion sensing (anions and cations). A systematisation according to the type of reaction mechanism is established. Numerous examples including extensions combined with catalytic and material sciences applicable in fluorescence imaging and water treatment are also discussed (151 references).


TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons.
TRPV1 receptors have classically been defined as heat-sensitive, ligand-gated, nonselective cation channels that integrate nociceptive stimuli in sensory neurons. TRPV1 receptors have also been identified in the brain, but their physiological role is poorly understood. Here we report that TRPV1 channel activation is necessary and sufficient to trigger long-term synaptic depression (LTD). Excitatory synapses onto hippocampal interneurons were depressed by either capsaicin, a potent TRPV1 channel activator, or the endogenously released eicosanoid, 12-(S)-HPETE, whereas neighboring excitatory synapses onto CA1 pyramidal cells were unaffected. TRPV1 receptor antagonists also prevented interneuron LTD. In brain slices from TRPV1-/- mice, LTD was absent, and neither capsaicin nor 12-(S)-HPETE elicited synaptic depression. Our results suggest that, in the hippocampus, TRPV1 receptor activation selectively modifies synapses onto interneurons. Like other forms of hippocampal synaptic plasticity, TRPV1-mediated LTD may have a role in long-term changes in physiological and pathological circuit behavior during learning and epileptic activity.


Skin Pretreatment With Conventional Non-Fractional Ablative Lasers Promote the Transdermal Delivery of Tranexamic Acid.
Laser pretreatment of skin can be used to enable drugs used in dermatology to penetrate the skin to the depth necessary for their effect to take place. To compare the permeation of tranexamic acid after conventional non-fractionated ablative Er:YAG and CO2 laser pretreatment in a laser-aided transdermal delivery system. An erbium-doped yttrium aluminium garnet (Er:YAG) and a CO2 laser were used to pretreat dorsal porcine skin. Scanning electron microscopy was used to examine disruption of the skin surface. Confocal laser scanning microscopy was used to determine the depth of penetration of a reporter molecule (fluorescein isothiocyanate) into the skin. A Franz diffusion assembly was used to examine fluency-related increases in transdermal delivery of transexamic acid. Transdermal delivery of tranexamic acid increased as Er:YAG laser fluency increased. Transdermal delivery was higher when CO2 laser pretreatment was used than when Er:YAG laser pretreatment was used, but a "ceiling effect" was present and increasing the wattage did not cause a further increase in delivery. CO2 laser pretreatment also caused more extensive and deeper skin disruption than Er:YAG laser pretreatment. For conventional, non-fractionated ablative laser pretreatment, the Er:YAG laser would be an optimal choice to enhance transdermal penetration of transexamic acid.


Developing a taste for sweets.
Lymphocytes are covered with sugars. Some of the oligosaccharides on lymphocytes may be recognized by specific lectins such as the selectins, but what other functions do all of these oligosaccharides serve? Two recent papers in Cell (Moody et al., 2001) and Immunity (Daniels et al., 2001) describe a novel role for glycosylation in the thymus--regulating the interaction of MHC class I molecules with CD8 during thymocyte maturation.


Identification of risk factors for postpartum urinary retention following vaginal deliveries: A retrospective case-control study.
Postpartum urinary retention (PUR) is an uncommon complication of vaginal delivery, defined as a failure to void spontaneously in the six hours following vaginal birth. The objective of this study was to identify risk factors for PUR in order to provide prompt management. A retrospective, comparative, case-control study, including two groups of 96 patients who delivered vaginally, was conducted at the Women and Children's University Hospital in Lyon, France. Patients were selected based on data extraction from the medical records of the obstetrics and gynecology department. The first group included patients with postpartum urinary retention and the second group, without PUR, was selected randomly, respecting 1:1 matching criteria, paired according to the year of delivery and patient's age at delivery. Logistic regression analysis found that instrumental delivery (OR 13.42, 95%CI [3.34;53.86], p = 0.0002), absence of spontaneous voiding before leaving the delivery room (OR 6.14, 95%CI [2.56;14.73], p < 0.0001), no intact perineum (OR 3.29, 95%CI [1.10;9.90], p = 0.03) and vulvar edema or perineal hematoma (OR 8.05, 95%CI [1.59;40.67], p = 0.01) were independent risk factors associated with PUR. The present study identified risk factors for PUR that should be taken into consideration as soon as delivery is over in order to implement appropriate management. Future studies are needed to assess the contribution of early systematic bladder scanning in patients with risk factors for early diagnosis of PUR.


Complex alternative RNA splicing of epsilon-immunoglobulin transcripts produces mRNAs encoding four potential secreted protein isoforms.
In RNA from human IgE-producing lymphocytes, we previously discovered two alternatively spliced epsilon-immunoglobulin mRNA isoforms that encode a novel secreted form of IgE and a membrane-bound species. Further analysis using epsilon-specific reverse transcriptase polymerase chain reactions has elucidated several additional alternatively spliced species of epsilon mRNA. One RNA isoform is generated by splicing the CH4 exon to a novel distal splice acceptor site, forming an epsilon RNA species (designated CH4-M2") that encodes a secreted epsilon protein 6 amino acids larger than the classic secreted epsilon protein. The other three novel epsilon RNAs are generated by splicing from within CH4 to a new exon structure (designated CH5) that is located between CH4 and the membrane exons. Since the three new mRNAs using CH5 share the same stop codon in CH5, they all encode the same novel protein, which is 10 amino acids shorter than the classic secreted epsilon heavy chain. The new alternatively spliced epsilon mRNAs reported here, in addition to the previously reported forms encoding membrane and larger secreted IgE, appear to reflect the normal splicing pattern in humans, as we have detected all these epsilon RNAs in all the human IgE-secreting cells and cell lines tested.


Genetic transformation and mutagenesis via single-stranded DNA in the unicellular, diazotrophic cyanobacteria of the genus Cyanothece.
We describe a genetic system for producing specific gene knockouts in Cyanothece sp. strain PCC 7822 using a single-stranded DNA technique (B. Zorin, P. Hegemann, and I. Sizova, Eukaryot. Cell 4:1264-1272, 2005). The first fully segregated mutant was a ΔnifK mutant, and it was unable to grow on medium lacking combined nitrogen and produced virtually no hydrogen.


Microdialysis combined with liquid chromatography-tandem mass spectrometry for the determination of levo-tetrahydropalmatine in the rat striatum.
Levo-tetrahydropalmatine (l-THP), one of the main active alkaloids isolated from Rhizoma corydalis, was recently found to elicit profound effects on the dopaminergic system in the striatum, which plays an important role in regulating nociception. A rapid and sensitive method based on microdialysis combined with liquid chromatography-tandem mass spectrometry was developed for the determination of l-THP in the rat striatum. Microdialysis probes were stereotactically placed in the striatal hemisphere, and l-THP was measured from the microdialysates collected using LC-MS/MS. Reverse-phase LC separation was accomplished on a Diamonsil™ C18 column (50 mm × 2.1 mm ID, 5μm) with the mobile phase composed of methanol-water (50:50, v/v) at a flow rate of 0.2 ml/min. The method had a chromatographic total run time of 5 min. Detection was performed in electrospray positive mode and quantification was executed in selected reaction monitoring mode. The following transitions were monitored: m/z 356.0→191.9 for l-THP and 256.0→167.1 for the internal standard diphenhydramine. The method was sensitive with a lower limit of quantitation (LLOQ) of 0.1 ng/ml for l-THP, with good linearity in the range of 0.1-1000 ng/ml (r(2)≥0.999). All the validation data, such as accuracy, precision, and inter-day repeatability were within the required limits. The method was successfully applied to pharmacokinetic study of the l-THP in the rat striatum.


Recombinant human prothrombin (MEDI8111) prevents bleeding in haemophilia A and B mice.
Haemophilia A and B are treated with FVIII and FIX replacement therapy. Treatment may be complicated by inhibitory antibodies that require bypass therapy such as FEIBA(®) in which prothrombin (FII) is suggested to be the main active component. To evaluate the effect of FII on haemophilia recombinant human (rh) FII (MEDI8111) or plasma-derived human FII (pdhFII) was given as single doses to anaesthetized haemophilia A and B mice 3 min before tail transection and rhFVIII or rhFIX was used for comparison. After tail transection, automatic bleeding registration was used to continuously measure blood loss (BL) and bleeding time (BT). Thrombin generation and plasma concentrations of human FVIII, FIX, FII and thrombin-antithrombin complex (TAT) were measured. Blood loss and BT were dose-dependently decreased by rhFVIII or rhFIX. The concentrations that decreased BL and BT for rhFVIII by 50% (EC50) were 0.06 and 0.01 IU mL(-1) and for rhFIX 0.07 and 0.07 IU mL(-1) , respectively. Administration of rhFVIII and rhFIX dose-dependently increased thrombin generation potential but did not affect TAT. MEDI8111 and pdhFII dose-dependently decreased BL and BT in haemophilia A mice, EC50 37 and 87 and 100 and 155 mg L(-1) respectively. In haemophilia B mice given MEDI8111 EC50 was for BL 56 mg L(-1) and for BT 67 mg L(-1) . TAT and thrombin generation increased dose-dependently for MEDI8111 and pdhFII. MEDI8111 dose-dependently decreased bleeding and increased procoagulant activity in haemophilia A and B mice and suggest that MEDI8111 may be useful for preventing bleeding in patients with haemophilia A and B.


Novel subunit structure observed for noncooperative hemoglobin from Urechis caupo.
Tetrameric hemoglobin from the "fat innkeeper" worm Urechis caupo possesses a novel subunit arrangement having an "inside out" quaternary structure in that the G/H helices are located on the outer surface of the tetramer. A 5-A resolution crystal structure reveals that although the individual subunits are beta-like, having a distinct D helix and the general myoglobin fold, the subunit contacts are very different from those previously observed for hemoglobins. Furthermore, the hemoglobin from U. caupo is also quite different from the unusual hemoglobin tetramer from clam which also has its G/H helices on the outer surface but with the hemes in close proximity through E-F helical contacts (Royer, W. E., Jr., Love, W. E., and Fenderson, F. F. (1985) Nature 316, 277-280).


Heart Failure Clinical Trials in East and Southeast Asia: Understanding the Importance and Defining the Next Steps.
Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.


Analysis and multiple index evaluation of SPO distribution of bone traction needles for pelvic fracture reduction.
For robot-assisted pelvic fracture reduction, at least two bone needles need to be inserted into the ilium of the affected pelvis, and the robot clamping device is connected with the bone needles. The biomechanical properties of the pelvic musculoskeletal tissues are different with the different Spatial Position and Orientation (SPO) of the bone needles. In order to determine the optimal SPO of bone needle pairs, the constraints between the bone needles and the pelvis are analyzed, and the SPO vectors of 150 groups bone needles are obtained by the KNN-hierarchical clustering method; a batch modeling method of bone needles with different SPO is proposed. 150 finite element models of damaged pelvic musculoskeletal tissue with different SPO of bone needles are established and simulated. The stress and strain distribution homogenization of musculoskeletal tissue with bone needles as evaluation index, the simulation results of 150 models are evaluated. Results show that, the anterior superior iliac spine and the anterior inferior iliac spine are suitable regions to place bone needles in the pelvis, and the optimal distribution of the needle combination is found in this region. The overall stress and strain distribution of the damaged pelvic musculoskeletal tissue under the large reduction force is the best.


Treatment outcomes of immature permanent necrotic evaginated teeth: A retrospective study comparing regenerative endodontic procedures with apexification.
Few studies have compared the outcomes of regenerative endodontic procedures (REPs) and calcium hydroxide apexification focusing on necrotic teeth with dens evaginatus. To qualitatively and quantitatively compare the treatment outcomes of REPs and calcium hydroxide apexification in teeth with dens evaginatus. Immature permanent necrotic evaginated teeth treated with REPs or calcium hydroxide apexification for a follow-up period of at least 12 months were included. Tooth success and survival rates were analyzed. Changes in radiographic root length, apical diameter, and radiographic root area (RRA) were quantified. Prognostic factors that might influence RRA were identified via multivariate linear regression analysis. A total of 112 teeth (50 REP cases and 62 apexification cases) with a median follow-up period of 26.5 months were included. Regenerative endodontic procedures and calcium hydroxide apexification exhibited similar satisfactory success and survival rates (p > .05). Additionally, 88 teeth were quantitatively analyzed. The REP group presented a significantly greater percentage increase in RRA and less decrease in apical diameter than the calcium hydroxide apexification group (p < .05). Teeth treated with REPs and with Stages 7 and 8 of root development showed a better gain in RRA (p < .05). While REP and calcium hydroxide apexification had similar success and survival rates, teeth with REPs showed an increase in RRA, indicating that REP is the preferred choice.


Limb-Leaf designs for adaptive exploration of the dose-response curve.
We propose a two-stage strategy, called the Limb-Leaf method, to explore the dose-response curve using dose promotion and addition in the context of adaptive seamless Phase II/III trials. Strong control of the overall type 1 familywise error rate of the proposed method is enforced by the closed testing principle. The design constants are determined to minimize the risk-adjusted expected total sample size while maintaining a target power. In the case of a nonmonotonic dose response curve where more doses are required to adequately explore the curve, substantial savings in sample size are achieved compared with a traditional strategy which offers only selection and promotion from among initial first stage doses.


Concise classification of the genomic porcine endogenous retroviral gamma1 load to defined lineages.
We investigated the infection history of porcine endogenous retroviruses (PERV) gamma1 by analyzing published env and LTR sequences. PERV sequences from various breeds, porcine cell lines and infected human primary cells were included in the study. We identified a considerable number of retroviral lineages indicating multiple independent colonization events of the porcine genome. A recent boost of the proviral load in an isolated pig herd and exclusive occurrence of distinct lineages in single studies indicated the ongoing colonization of the porcine genome with endogenous retroviruses. Retroviral recombination between co-packaged genomes was a general factor for PERV gamma1 diversity which indicated the simultaneous expression of different proviral loci over a period of time. In total, our detailed description of endogenous retroviral lineages is the prerequisite for breeding approaches to minimize the infectious potential of porcine tissues for the subsequent use in xenotransplantation.


Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: the BioCycle Study.
Conflicting findings have been reported regarding the effect of menstrual cycle phase and sex hormones on insulin sensitivity. The aim was to determine the pattern of insulin resistance over the menstrual cycle and whether variations in sex hormones explain these patterns. The BioCycle study is a longitudinal study that measured hormones at different phases of the menstrual cycle. Participants had up to eight visits per cycle; each visit was timed using fertility monitors to capture sensitive windows of hormonal changes. The study was conducted in the general community of the University at Buffalo (Buffalo, NY). A total of 257 healthy, premenopausal women (age, 27±8 yr; body mass index, 24±4 kg/m2) participated in the study. We measured fasting insulin, glucose, and insulin resistance by the homeostasis model of insulin resistance (HOMA-IR). Significant changes in HOMA-IR were observed over the menstrual cycle; from a midfollicular phase level of 1.35, levels rose to 1.59 during the early luteal phase and decreased to 1.55 in the late-luteal phase. HOMA-IR levels primarily reflected changes in insulin and not glucose. After adjustment for age, race, cycle, and other sex hormones, HOMA-IR was positively associated with estradiol (β=0.082; P<0.001) and progesterone (β=0.025; P<0.001), and inversely associated with FSH (adjusted β=-0.040; P<0.001) and SHBG (β=-0.085; P<0.001). LH was not associated with HOMA-IR. Further adjustment for BMI weakened the association with SHBG (β=-0.057; P=0.06) but did not affect other associations. Insulin exhibited minor menstrual cycle variability. Estradiol and progesterone were positively associated with insulin resistance and should be considered in studies of insulin resistance among premenopausal women.


Simultaneous analysis of verapamil and norverapamil enantiomers in human plasma by high-performance liquid chromatography.
An improved HPLC method for the simultaneous determination of the enantiomers of verapamil (V) and its major metabolite norverapamil (NV) in human plasma samples is presented. NV is acetylated immediately to N-acetylnorverapamil (ANV) in the extraction solvent (2% butanol in hexane). Acetylation is so rapid that it does not delay sample processing. ANV and V enantiomers are then separated on an alpha 1-acid glycoprotein chiral column with a mobile phase of phosphate buffer (0.01 M, pH 6.65) and acetonitrile. The fluorescence detector wavelengths are set at 227 nm for excitation and 308 nm for emission. Introduction of the internal standard (I.S.) (+)-glaucine improves accuracy, precision and robustness of the method. The assay is sensitive and specific. Baseline separation is achieved for both V and ANV. Limits of quantitation are 3 ng/ml for V and 2 ng/ml for NV (single enantiomer) with precision and accuracy better than 15% at those levels. Detector response is linear in the range tested (3-200 ng/ml for V and 2-100 ng/ml for NV, single enantiomer). This assay has been applied to a clinical study of the pharmacodynamics of V involving six healthy volunteers.


Spoilage of hydrogel contact lenses by lipid deposits. Tear-film potassium depression, fat, protein, and alcohol consumption.
"Jelly-bump" deposits, which are composed mainly of lipids, on high water content, extended-wear hydrogel lenses, are a clinically significant problem of unknown etiology. The authors explored the effect of nutrition on the frequency of deposition of these jelly bumps. Forty-three patients were included in this masked case-control study from five contact lens practices in North America. Thirty patients were lipid-depositor cases and 13 were controls. Tear specimens were drawn and analyzed for potassium by atomic-absorption spectrophotometry. Detailed dietary histories were conducted and diet nutrient composition was computed. Patients with diminished tear-potassium concentrations have an increased risk of jelly-bump deposition. Elevated intake of protein, alcohol, and cholesterol also appeared to be correlated significantly with increased jelly-bump deposition. The authors found that diabetics and the use of diuretics, anticholinergics, sympathomimetics, were associated with tear-film potassium depletion and lipid deposit formation.