Biochemical and biological differences between E7 oncoproteins of the high- and low-risk human papillomavirus types are determined by amino-terminal sequences.
Differences in the biological characteristics of the high-risk human papillomavirus type 16 (HPV-16) and the low-risk HPV-6 E7 proteins were analyzed and shown to correlate with certain biochemical properties. To ascertain which region of E7 conferred these properties, chimeric E7 genes were constructed by the exchange of the amino and carboxyl coding halves of the HPV-6 and HPV-16 E7 genes. The amino-terminal half of E7 determined the affinity for binding to the retinoblastoma protein pRB, the transformation properties, and the ability to abrogate transforming growth factor beta-mediated repression of the c-myc promoter. This region of E7 is therefore responsible for the biological and biochemical differences between the E7 proteins of the low-risk and the high-risk HPVs and consequently is one of the critical determinants distinguishing these two groups of viruses. Transcriptional transactivation of the adenovirus E2 promoter, in contrast, was a property shared by E7 proteins of both low-risk and high-risk HPVs.


Isolated rat hepatocytes differentially bind and internalize bovine lactoferrin N- and C-lobes.
Isolated rat hepatocytes bind and internalize bovine lactoferrin (Lf) and its bound iron in a Ca2+-dependent manner. In this study, we determined if one or both halves of Lf (N- and C-lobes) were responsible for the interaction of Lf with hepatocytes. We isolated three tryptic fragments of bovine Lf. Cleavage at Arg284-Ser285 generated two fragments: N-terminal pp36 that contained 80% of Lf N-lobe and C-terminal pp51. A second cleavage at Arg338-Ala339 generated a smaller fragment (pp44) that contained all of the C-lobe with no N-lobe elements. Hepatocytes bound Lf and pp51 in a Ca2+-dependent manner with the same affinity (Kd approx. 75 nM) and to nearly identical extents (approx. 10(6) sites per cell). Lf and pp51 competed with each other for binding to cells over a similar titration range. Hepatocytes internalized Lf at a faster rate than pp51 (kin=0.28 and 0.19 min-1 respectively), but cells degraded pp51 at approx. twice the rate of native Lf. pp44 competed with 125I-labelled Lf for binding to Ca2+-dependent binding sites on hepatocytes as well as native Lf or pp51. In contrast, hepatocytes bound pp36 (Kd=90 nM, <=5x10(6) sites per cell) but did not internalize or degrade it appreciably. Moreover, pp36 binding to cells was not Ca2+-dependent, and pp36 competed poorly with native Lf and pp51 for binding to cells. We conclude from these findings that the Lf determinants responsible for binding to the Ca2+-dependent receptor on hepatocytes is present within the C-lobe of Lf.


Clinical Approach to Neuroendocrine Neoplasm Associated With Ovarian Teratoma.
Neuroendocrine neoplasms are a heterogeneous group of cancers that develop from enterochromaffin cells of the diffuse endocrine system, with an increase in incidents over the last years. Ovarian neuroendocrine tumors (NET) are rare neoplasms, comprising 0.1% of all ovarian neoplasms and less than 5% of all neuroendocrine tumors. They may arise alone (as monodermal, specialized teratoma - ovarian carcinoid) or as a part of other ovarian lesion: cystic mature or immature teratomas. Due to the rarity and limited amount of such cases reported in the literature, there is no consensus on diagnostic and therapeutic procedures in this group of patients. The group of 10 patients at the age of 19 to 77 years (mean 42.8 ± 17.9), diagnosed with unilateral NET within ovarian teratoma were analyzed. The histopathological type of tumor, progression free survival after surgical treatment and presence of hormonally active syndrome were assessed. 70% (n=7) of patients was diagnosed with mature cystic teratomas containing NET component and 30% (n=3) with monodermal teratoma (strumal carcinoid). All cases of monodermal teratomas were found in women at premenopausal age. Determined Ki67 ranged from 2% to 9%. Ninety percent of lesions (n=9) stained positive for synaptophysin and chromogranin, while markers: CK20, CK7, TTF-1 and CDX2 were negative in all cases, which ruled out their metastatic nature. None of the patients presented with carcinoid syndrome. All followed-up patients remain progression-free, which confirms surgical intervention being a crucial and sufficient method of treatment. The prognosis and clinical behavior of NETs associated with ovarian teratomas are good with long progression-free survival.


The perioperative management of patients with left ventricular assist devices undergoing noncardiac surgery.
To describe the perioperative management of patients with left ventricular assist devices (LVADs) who require general anesthesia while undergoing noncardiac surgery (NCS) at a single, large tertiary referral center. Electronic medical records from September 2, 2005, through May 31, 2012, were retrospectively reviewed to evaluate the perioperative management and outcomes in LVAD patients undergoing NCS. Patients were included only if they required a general anesthetic and had previously been discharged from the hospital after initial LVAD implantation. Thirty-three patients with LVADs underwent general anesthesia for 67 noncardiac operations. The mean ± SD time from LVAD implantation to NCS was 317 ± 349 days. All but 1 patient had axial flow LVADs. Anticoagulation or antiplatelet agents were present within 7 days before NCS in 49 procedures (73%) and reversed in 32 of 49 (65%). No perioperative thrombotic complications related to anticoagulation or antiplatelet reversal were noted. Red blood cell, fresh frozen plasma, and platelet transfusions were administered during 10, 6, and 4 operations, respectively. The only intraoperative complication was surgical bleeding. Postoperative complications were present in 12 patients after NCS and were mainly composed of bleeding. Three patients died within 30 days of NCS, with the causes of death not attributed to NCS. Patients with LVAD safely underwent NCS in a multidisciplinary setting that included preoperative optimization by cardiologists familiar with LVADs when feasible. Anticoagulation or antiplatelet agents were present preoperatively in most patients with LVADs and were safely reversed when necessary for NCS. The relatively high occurrence of postoperative bleeding is consistent with previous series.


Initial clinical impressions of the U.C. Davis large animal lift and its use in recumbent equine patients.
The U.C. Davis Large Animal Lift (LAL) is a lightweight sling developed to help lift horses in clinical and rescue situations. Here we report on its first use in 16 recumbent horses with neurologic, muscular and musculoskeletal disorders. For each horse, history, sedation, ease and time of LAL application and hoisting, standing ability, LAL tolerance and outcome were recorded. The LAL was easily and safely applied in all horses in less than five minutes and the procedure was well tolerated with minimal to no sedation. While 10 horses were able to stand in the LAL after being hoisted, 6 horses were unable to stand and were eventually euthanized due to the inability to regain weight bearing function. The LAL has shown to be a useful devise to evaluate the standing ability of recumbent horses and can be used alone or in combination with the Anderson Sling Support Devise to allow standing support of horses with a variety of debilitating problems.


Occupational Exposures Among Hair and Nail Salon Workers: a Scoping Review.
To review the literature published from 2014 to 2019 on hair and nail salon workers concerning exposure assessment, reproductive and respiratory endpoints, and endocrine disruption, in relation to workplace exposures. We identified 29 relevant peer-reviewed publications. Overall, there were insufficient studies to determine whether working in these settings is associated with reproductive health endpoints, although prior studies suggest that reproductive effects are of concern. There is consistent evidence that working in hair and nail salons may increase the risk of respiratory effects. Also, despite the fact that many hair and nail care products contain endocrine disrupting compounds, no recent studies have evaluated endocrine-related endpoints. Moreover, few studies have evaluated chemical exposures in these settings and biomonitoring studies are sparse. Improved exposure assessment of chemical hazards in hair and nail salons is necessary to properly characterize occupational exposures and assess their potential health risks. Further studies on endpoints related to endocrine disruption and reproductive health outcomes among hair and nail salon workers are needed. Improved exposure and epidemiologic studies will help inform chemical exposure mitigation efforts in a vulnerable occupational population, as well as policies related to workplace and consumer product safety.


IGH translocations in chronic lymphocytic leukemia: Clinicopathologic features and clinical outcomes.
The prevalence, clinicopathologic correlates, and outcomes of previously untreated chronic lymphocytic leukemia (CLL) patients with IGH-BCL2 and IGH-BCL3 translocations are not well known. Using the Mayo Clinic CLL database, we identified patients seen between March 1, 2002 and September 30, 2016 who had FISH testing performed within 3 years of CLL diagnosis. The prognostic profile, time to first therapy (TTT), and overall survival (OS) of patients with IGH-BCL2 and IGH-BCL3 translocation were compared to patients without these abnormalities (non-IGH group). Of 1684 patients who met the inclusion criteria, 38 (2.2%) had IGH-BCL2, and 16 (0.9%) had IGH-BCL3 translocation at diagnosis. Patients with IGH-BCL3 translocation were more likely to have high and very-high CLL-International Prognostic Index, compared to patients with IGH-BCL2 translocation and the non-IGH group. The 5-year probability of requiring therapy was significantly higher for IGH-BCL3 compared to IGH-BCL2 and non-IGH groups (84% vs 33% vs 29%, respectively, P < 0.0001). The 5-year OS was significantly shorter for IGH-BCL3 compared to IGH-BCL2 and non-IGH groups (45% vs 89% vs 86%, respectively, P < 0.0001). On multivariable analyses, IGH-BCL3 translocation was associated with a shorter TTT (hazard ratio [HR] = 2.7; P = 0.005) and shorter OS (HR = 5.5; P < 0.0001); IGH-BCL2 translocation did not impact TTT and OS. In conclusion, approximately 3% of all newly diagnosed CLL patients have either an IGH-BCL2 or IGH-BCL3 translocation. Patients with IGH-BCL3 translocations have a distinct prognostic profile and outcome. These results support the inclusion of an IGH probe during the routine evaluation of FISH abnormalities in newly diagnosed CLL.


Jacquet erosive diaper dermatitis: a complication of adult urinary incontinence.
Jacquet erosive diaper dermatitis is typically described as a severe irritant dermatitis of the perianal region. However, Jacquet erosive diaper dermatitis, perianal pseudoverrucous papules and nodules, and granuloma gluteale infantum/ adultorum have been regarded as discrete entities or all part of the same clinical spectrum, representing the result of chronic, severe, irritant contact dermatitis. We present a case of Jacquet erosive diaper dermatitis and a discussion of the clinical spectrum of diseases to which it belongs.


The impacts of observing flawed and flawless demonstrations on clinical skill learning.
Clinical skills expertise can be advanced through accessible and cost-effective video-based observational practice activities. Previous findings suggest that the observation of performances of skills that include flaws can be beneficial to trainees. Observing the scope of variability within a skilled movement allows learners to develop strategies to manage the potential for and consequences associated with errors. This study tests this observational learning approach on the development of the skills of central line insertion (CLI). Medical trainees with no CLI experience (n = 39) were randomised to three observational practice groups: a group which viewed and assessed videos of an expert performing a CLI without any errors (F); a group which viewed and assessed videos that contained a mix of flawless and errorful performances (E), and a group which viewed the same videos as the E group but were also given information concerning the correctness of their assessments (FA). All participants interacted with their observational videos each day for 4 days. Following this period, participants returned to the laboratory and performed a simulation-based insertion, which was assessed using a standard checklist and a global rating scale for the skill. These ratings served as the dependent measures for analysis. The checklist analysis revealed no differences between observational learning groups (grand mean ± standard error: [20.3 ± 0.7]/25). However, the global rating analysis revealed a main effect of group (d.f.2,36 = 4.51, p = 0.018), which describes better CLI performance in the FA group, compared with the F and E groups. Observational practice that includes errors improves the global performance aspects of clinical skill learning as long as learners are given confirmation that what they are observing is errorful. These findings provide a refined perspective on the optimal organisation of skill education programmes that combine physical and observational practice activities.


Efficient photon management with nanostructures for photovoltaics.
Efficient photon management schemes are crucial for improving the energy conversion efficiency of photovoltaic devices; they can lead potentially to reduced material usage and cost for these devices. In this review, photon trapping mechanisms are discussed briefly in the beginning, followed by a summary of recent progress on a number of major categories of nanostructures with intriguing photon management properties. Specifically, nanostructures including nanowires, nanopillars, nanopyramids, nanocones, nanospikes, and so forth, have been reviewed comprehensively with materials including Si, Ge, CdS, CIGS, ZnO, etc. It is found that these materials with diverse configurations have tunable photon management properties, namely, optical reflectance, transmittance and absorption. Investigations on these nanostructures have not only shed light on the fundamental interplay between photons and materials at the nanometer scale, but also suggested a potential pathway for a new generation of photovoltaic devices.


Studies on the lysozyme independence of immune immobilisation of Treponema pallidum and the frequency of lysozyme autoantibodies in syphilitic sera.
The role of lysozyme in the immune immobilisation of Treponema pallidum is not yet fully understood. The T. pallidum immobilisation assay was used to demonstrate that the immobilisation and lysis of T. pallidum in vitro by antibodies (serum, IgG fraction or IgM fraction) and complement proceed in a lysozyme-independent mode. In the presence of lysozyme the rate of immobilisation increased. In contrast with its effect on Escherichia coli, the effect of lysozyme on T. pallidum was governed exclusively by its enzymic activity rather than by the cationic protein nature of the molecule. Lysozyme, released from stimulated phagocytes, induced formation of lysozyme antibodies in 59.6% of syphilis patients as determined by lysozyme antibody ELISA. The highest frequency was found in patients with untreated secondary syphilis, whereas untreated primary syphilis was only rarely accompanied by the presence of lysozyme antibodies. Cross-reactivities between lysozyme and treponemal antigens were excluded by immunoblotting. The autoantibodies did not influence the lysozyme activity. It was concluded that the formation of lysozyme antibodies is only an epiphenomenon in the host defence against treponemal infection.


Maternal fibrinogen/fibrin degradation products to high density lipoprotein cholesterol ratio for predicting delivery of small and large for gestational age infants: a pilot study.
The purpose of this pilot study was to investigate associations between fibrinogen/fibrin degradation products (FDP) to high density lipoprotein-cholesterol (HDL-C) ratio (FHR) of mothers and the risk of delivering large/small for gestational age (LGA/SGA) infants and to evaluate the predictive power of FHR on LGA/SGA. This study retrospectively reviewed 11,657 consecutive women whose lipid profiles and FDP levels were investigated at the time of admission for delivery at a specialized hospital. The FHR was calculated, and perinatal outcomes, including clinical parameters, were analyzed. The prevalence of SGA was 9% (n = 1034), and that of LGA was 15% (n = 1806) in this cohort study. FHR was significantly lower in women who delivered SGA infants (4.0 ± 3.2 vs. 4.7 ± 3.3 mg/mmol, P < 0.01) and higher in women who delivered LGA infants (5.7 ± 3.8 vs. 4.7 ± 3.3 mg/mmol, P < 0.01) compared with those who delivered infants of normal size for their gestational age. Women in the top quartile for FHR (> 5.9 mg/mmol) had a 2.9-fold higher risk of delivering LGA infants [adjusted odds ratio (OR) = 2.9, P < 0.01] and a 47% lower risk of delivering SGA infants (adjusted OR = 0.47, P < 0.01) than those in the bottom quartile (< 2.7 mg/mmol). In addition, adding FHR to the conventional models significantly improved the area under the curve for the prediction of delivering LGA (0.725 vs. 0.739, P < 0.01) and SGA (0.717 vs. 0.727, P < 0.01) infants. These findings suggest that the FHR calculated in late pregnancy is an innovative predictor of delivering LGA and SGA infants. Combining FHR with perinatal parameters could thus enhance the predictive ability for predicting the delivery of LGA/SGA infants.


Granulomas in bone marrow biopsies: clinicopathological significance and new perspectives.
Bone marrow granulomas in trephine biopsies are a rare and usually incidental finding. Possible causes include infectious (especially tuberculous and rarer non-tuberculous mycobacteria, but also many other bacterial, viral, fungal and parasitic agents) and non-infectious causes (especially medications, autoimmune disease, sarcoidosis, haematological and non-haematological malignancy). Necrotising granulomas are generally suggestive of an infectious aetiology (tuberculosis being the most common), whereas fibrin ring granulomas are associated with Q-fever and Epstein Barr Virus, although exceptions are possible. Every case suspicious for infectious aetiology should undergo further analysis like special staining (Ziehl-Neelsen for acid-fast rods) or molecular studies. The histomorphology should always be clinically correlated. In cases in which no infectious cause can be identified, untargeted metagenomics may represent a valid diagnostic tool that may become standard in the near future for bone marrow diagnostics. In this review, we have analysed the published data from 1956 up to today, and we report aspects of epidemiology, aetiology, diagnostic algorithms, differential diagnosis and the role of metagenomics in bone marrow biopsies with granulomas.


Formation of tethers linking the epiphysis and metaphysis is regulated by vitamin d receptor-mediated signaling.
Rat tibial growth plates have X-ray opaque tethers that link the epiphysis and metaphysis and increase with age as the growth plate (GP) becomes thinner. To determine if tether formation is a regulated process of GP maturation, we tested the hypotheses that tether properties and distribution can be quantified by micro-computed tomography (microCT), that rachitic GPs typical of vitamin D receptor knockout (VDR(-/-)) mice have fewer tethers and altered tether distribution, and that tether formation is regulated by signaling via the VDR. Distal femoral GPs from VDR(+/+) and VDR(-/-) 8-week-old mice were analyzed with microCT and then processed for decalcified and undecalcified histomorphometry. A wide range of parameters that assessed GP and tether geometry and morphology, along with tether distribution, were measured using both microCT and histology. Growth plates of 10-week-old VDR(+/+) and VDR(-/-) mice on a high-calcium, phosphorus, lactose, and vitamin D(3) rescue diet were also analyzed. Both microCT and histology showed tethers present throughout normal mice GPs, while reduction in tether number and volume percentage occurred in VDR(-/-) GPs with localization to the central region. Decreased shrinkage in the axial direction during decalcified histological processing correlated with tether formation, suggesting mechanical stability due to tethers. Tether formation increased greatly between 8 and 10 weeks. Rescue diets restored VDR(-/-) GP size but not tether volume percentage. Overall, these results demonstrate microCT imaging's utility for analyzing tether formation and suggest that signaling via the VDR plays a pivotal role in tether formation.


Urgent need for individual mobile phone and institutional reporting of at home, hospitalized, and intensive care unit cases of SARS-CoV-2 (COVID-19) infection.
Approximately 90 days of the SARS-CoV-2 (COVID-19) spreading originally from Wuhan, China, and across the globe has led to a widespread chain of events with imminent threats to the fragile relationship between community health and economic health. Despite near hourly reporting on this crisis, there has been no regular, updated, or accurate reporting of hospitalizations for COVID-19. It is known that many test-positive individuals may not develop symptoms or have a mild self-limited viral syndrome consisting of fever, malaise, dry cough, and constitutional symptoms. However some individuals develop a more fulminant syndrome including viral pneumonia, respiratory failure requiring oxygen, acute respiratory distress syndrome requiring mechanical ventilation, and in substantial fractions leading to death attributable to COVID-19. The pandemic is evolving in a clustered, non-inform fashion resulting in many hospitals with preparedness but few or no cases, and others that are completely overwhelmed. Thus, a considerable risk of spread when personal protection equipment becomes exhausted and a large fraction of mortality in those not offered mechanical ventilation are both attributable to a crisis due to maldistribution of resources. The pandemic is amenable to self-reporting through a mobile phone application that could obtain critical information on suspected cases and report on the results of self testing and actions taken. The only method to understand the clustering and the immediate hospital resource needs is mandatory, uniform, daily reporting of hospital censuses of COVID-19 cases admitted to hospital wards and intensive care units. Current reports of hospitalizations are delayed, uncertain, and wholly inadequate. This paper urges all the relevant stakeholders to take up self-reporting and reporting of hospitalizations of COVID-19 as an urgent task in combating this devastating pandemic.


Genomic architecture of habitat-related divergence and signature of directional selection in the body shapes of Gnathopogon fishes.
Evolution of ecomorphologically relevant traits such as body shapes is important to colonize and persist in a novel environment. Habitat-related adaptive divergence of these traits is therefore common among animals. We studied the genomic architecture of habitat-related divergence in the body shape of Gnathopogon fishes, a novel example of lake-stream ecomorphological divergence, and tested for the action of directional selection on body shape differentiation. Compared to stream-dwelling Gnathopogon elongatus, the sister species Gnathopogon caerulescens, exclusively inhabiting a large ancient lake, had an elongated body, increased proportion of the caudal region and small head, which would be advantageous in the limnetic environment. Using an F2 interspecific cross between the two Gnathopogon species (195 individuals), quantitative trait locus (QTL) analysis with geometric morphometric quantification of body shape and restriction-site associated DNA sequencing-derived markers (1622 loci) identified 26 significant QTLs associated with the interspecific differences of body shape-related traits. These QTLs had small to moderate effects, supporting polygenic inheritance of the body shape-related traits. Each QTL was mostly located on different genomic regions, while colocalized QTLs were detected for some ecomorphologically relevant traits that are proxy of body and caudal peduncle depths, suggesting different degree of modularity among traits. The directions of the body shape QTLs were mostly consistent with the interspecific difference, and QTL sign test suggested a genetic signature of directional selection in the body shape divergence. Thus, we successfully elucidated the genomic architecture underlying the adaptive changes of the quantitative and complex morphological trait in a novel system.


California community residential facilities for individuals with intellectual and developmental disabilities.
Evolving residential requirements for individuals with mild and moderate intellectual disabilities and related developmental disabilities increasingly place these people in community settings. The increasing numbers of these individuals are dependent upon local practitioners for needed health services. National and California data are reviewed in an effort to provide a general awareness of these community living arrangements, which in turn may assist in the delivery and the follow-up of oral health services.


A Review on Automatic Mammographic Density and Parenchymal Segmentation.
Breast cancer is the most frequently diagnosed cancer in women. However, the exact cause(s) of breast cancer still remains unknown. Early detection, precise identification of women at risk, and application of appropriate disease prevention measures are by far the most effective way to tackle breast cancer. There are more than 70 common genetic susceptibility factors included in the current non-image-based risk prediction models (e.g., the Gail and the Tyrer-Cuzick models). Image-based risk factors, such as mammographic densities and parenchymal patterns, have been established as biomarkers but have not been fully incorporated in the risk prediction models used for risk stratification in screening and/or measuring responsiveness to preventive approaches. Within computer aided mammography, automatic mammographic tissue segmentation methods have been developed for estimation of breast tissue composition to facilitate mammographic risk assessment. This paper presents a comprehensive review of automatic mammographic tissue segmentation methodologies developed over the past two decades and the evidence for risk assessment/density classification using segmentation. The aim of this review is to analyse how engineering advances have progressed and the impact automatic mammographic tissue segmentation has in a clinical environment, as well as to understand the current research gaps with respect to the incorporation of image-based risk factors in non-image-based risk prediction models.


Comparison of two diets of varying glycemic index on carotid subclinical atherosclerosis in obese children.
Childhood obesity is associated with an increased carotid intima-media thickness (IMT) and stiffness. Increased carotid wall thickening and rigidity are considered markers of subclinical atherosclerosis. The aim of the present study was to test the effect of two hypocaloric diets of varying glycemic index on weight loss and markers of subclinical atherosclerosis in obese children. Seventy consecutive obese children attending the Outpatient Weight Clinic of the Department of Pediatrics were invited to participate in an intensive dietary protocol. Twenty-six accepted and were randomly assigned to two different groups: the first group followed a hypocaloric low-glycemic index diet and the second a hypocaloric high-glycemic index diet. Anthropometric measures and biochemical tests were performed in all children. Quantitative B-mode ultrasound scans were used to measure intima-media thickness (IMT) and diameters of the common carotid artery. Considering both groups together, at 6 months, body mass index decreased from 28.3 +/- 3.1 to 25.8 +/- 3.3 kg/m(2), systolic blood pressure from 119 +/- 12 to 110 +/- 11 mmHg (P< 0.001), diastolic blood pressure from 78 +/- 8 to 74 +/- 7 mmHg (P< 0.001), IMT from 0.48 +/- 0.05 to 0.43 +/- 0.07 mm (P< 0.001), stiffness from 3.57 +/- 1.04 to 2.98 +/- 0.94 mm (P = 0.002), and high-sensitivity C-reactive protein from 1.5 +/- 0.9 (values log transformed) to 0.4 +/- 1.1 (P < 0.001). No differences were detectable in fasting serum triglycerides, total cholesterol, and high-density lipoprotein cholesterol. Insulin resistance (calculated by the HOmeostatic Model Assessment index [HOMA] score) significantly reduced only in the low-glycemic-index diet group (P < 0.04). In conclusion, this study confirms a benefit of hypocaloric diets on carotid IMT and stiffness in obese children and demonstrates, for the first time, an amelioration of insulin sensitivity in obese children after a low-glycemic index diet. These results justify the advice to obese children to follow a low-glycemic index diet in order to improve their cardiometabolic profile.


[Clinico-psychopathological aspects of borderline mental disorders in infancy].
The authors summarize the data obtained during a comprehensive examination of 200 children of the first year of life with borderline mental disorders. Abnormalities of vegetative and instinctive regulation, psychomotor and affective disorders which are, as a rule, of the borderline nature, occupy the leading position in the structure of the above-indicated disorders. The latter ones are associated frequently enough with different types of development retardation and neurological deviations from normal. The signs of differentiating between these disorders and analogous ones within the framework of endogenous mental pathology are depicted. The role is demonstrated of etiological factors (perinatal encephalopathy, constitutional, psychosocial, disturbances of the mother-child system). The studies attest to the basic demonstrability of psychopathological abnormalities and to their great diversity in infants.


Gintonin, a ginseng-derived exogenous lysophosphatidic acid receptor ligand, enhances blood-brain barrier permeability and brain delivery.
Gintonin is a ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin induces [Ca2+]i transient and biological effects through LPA receptor and increases the permeability of the blood-brain barrier (BBB). However, little is known about its mechanisms on the BBB. We examined the in vitro effects of gintonin using primary human brain microvascular endothelial cells (HBMECs) and the in vivo effects of gintonin on brain delivery. Fluorescent-labeled gintonin bound to HBMECs and co-localized with the LPA1 receptor. Gintonin caused morphological changes, increased junctional spaces, and induced differential effects on junctional protein levels such as vascular endothelial-cadherin, occludin, zonula occludens 1, and claudin-5, in HBMECs. Gintonin led to the opening of gap junctions between HBMECs, and allowed Texas red-dextran to enter the cells, which was blocked by Ki16425, an LPA1/3 receptor antagonist, and Y27632, a Rho-associated kinase inhibitor. Intravenous administration of gintonin in rodents also increased the delivery of fluorescein isothiocyanate-dextran or erythropoietin to the brain. Furthermore, fluorescent-labeled gintonin bound to endothelial cells, neurons, and glia in the brain following its entry. Our findings show that gintonin facilitates entry to the brain through the paracellular pathway. Thus, gintonin may be an herbal medicine-derived candidate to overcome the BBB in drug delivery.


Oral challenges are needed in the diagnosis of beta-lactam hypersensitivity.
beta-lactams continue to remain the most commonly involved drug family in allergic drug reactions. They are often essential and there is a cost-effective and favourable risk-benefit ratio for the exploration of all suspicions of beta-lactam allergy. A firm diagnosis is always based on skin tests and sometimes on provocation tests. Recommendations have been published by allergy societies and distinguished scientists but they are not always concordant and can lead to some confusion for the practicing allergologist. The situation has even worsened since the world wide withdrawal of these penicillin determinants and since the predominance of amoxicillin and cephalosporin prescriptions in most countries. OBJECTIVE - METHOD: In a recent article, it was stated that patients with a penicillin allergy history and negative skin tests to major and minor penicillin determinants are at a low risk of relapse (0-5%) when receiving a beta-lactam. In this paper, our Drug Allergy and Hypersensitivity Database, a cohort database, was used to demonstrate that this statement is false. Standardized European Network for Drug Allergy questionnaires, skin test and challenge procedures were followed. One-thousand two-hundred and eighteen subjects, 69.8% of female, 51.7% of atopics, were included. 21.1% had a true beta-lactam allergy confirmed by skin tests (178, 69.3%) or by drug provocation (79, 30.7%). 17.4% of the patients with negative skin tests to major and minor penicillin determinants were positive for a beta-lactam. In the diagnosis of beta-lactams allergy, if all skin tests are negative, skin tests with other determinants and provocation tests under strict surveillance are mandatory.


Anorexia nervosa: the patient, her family and key family therapy interventions.
In a nation in which jogging, diets, and weight consciousness are so prevalent, it is easy to understand why middle class teenage girls want to become or stay thin. It is harder for us all to understand why some of these young women become so emaciated that they may die. We have tried to present information that will enable health care professionals to achieve a broader understanding of the clinical syndrome of anorexia nervosa and the family of the anorexic. Some key family therapy interventions that will enable the family system to become more adaptive to change have been highlighted and explained through the use of actual case material.


A randomized comparative study of levofloxacin versus amoxicillin/clavulanate for treatment of infants and young children with recurrent or persistent acute otitis media.
The need for alternative antimicrobial therapy for recurrent and persistent acute otitis media (AOM) in children has raised interest in assessing the efficacy and safety of fluoroquinolones for treatment of these infections. In an evaluator-blinded, active-comparator, noninferiority, multicenter study, children (6 months to <5 years) were randomized 1:1 to receive levofloxacin (10 mg/kg twice daily) or amoxicillin/clavulanate (14:1; amoxicillin 45 mg/kg twice daily) for 10 days, with evaluations 4-6 days of therapy (visit 2), 2-5 days after completing therapy (visit 3), and 10-17 days after last dose (visit 4). Primary outcome was clinical cure at visit 3 based on resolution of clinical signs and symptoms of AOM. A total of 1650 children were randomized and 1305 were clinically evaluable at visit 3 (630 levofloxacin, 675 comparator). Clinical cure rates were 72.4% (456 of 630) in levofloxacin-treated and 69.9% (472 of 675) in amoxicillin/clavulanate-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (< or =24 months: 68.9% versus 66.2%; >24 months: 76.9% versus 75.1%; respectively). Cure rates at visit 4 were 74.9% and 73.8% in levofloxacin and amoxicillin/clavulanate groups, respectively. The upper limits of the confidence intervals were less than the noninferiority margin of 10% indicating that levofloxacin treatment is noninferior to comparator treatment overall and in both infants (6 months to 2 years) and children 2-5 years. No differences between treatment groups regarding the frequency or type of adverse events were apparent. Levofloxacin was not inferior to amoxicillin/clavulanate for the treatment of recurrent and/or persistent AOM in infants and children.


[Karyotype study of 5 species of Costa Rican snakes of the colubrid family].
The karyotypes of five species of colubrid snakes from Costa Rica are as follows: Imantodes cenchoa and Drymobius margaritiferus have a diploid number of 36, with 16 macro- and 20 microchromosomes. The fourth pair is heteromorphic in females of I. cenchoa, with a metacentric Z and a submetacentric W chromosomes. Karyotypes of Erythrolampius bizonus and Leimadophis epinephalus have 28 chromosomes, without a clearcut separation between macro- and microchromosomes. In the case of E. bizomus, the fourth pair contains the sex chromosomes Z and W, both are submetacentric, but the W is smaller. Xenedon rabdocephalus has a diploid number of 34 chromosomes (22 macro- and 12 microchromosomes); pair 3 is heteromorphic in females, with a submetacentric Z and a smaller metacentric W. The karyotype of X. rabdocephalus may be derived from a primitive karyotype by means of reduction in the number of microchromosomes and centric fissions of two pairs of metacentric autosomes.


Comparison of hemiarthroplasty and reverse shoulder arthroplasty for the treatment of proximal humeral fractures in elderly patients.
Treatment of complex three and four-part proximal humeral fractures with hemiarthroplasty in elderly patients has yielded mixed clinical results. Reverse shoulder arthroplasty has emerged as a treatment option for comminuted proximal humeral fractures for these patients. The purpose of the study was to perform a prospective evaluation of patient outcomes comparing hemiarthroplasty and reverse shoulder arthroplasty for the treatment of comminuted proximal humeral fractures in elderly patients. Fifty-three consecutive elderly patients (average age, 74.4 years) underwent an arthroplasty for a complex proximal humeral fracture. Indications for arthroplasty were four-part fractures, three-part fractures with severe comminution of the greater tuberosity, and fractures that involved an articular split of the humeral head. Twenty-six patients underwent hemiarthroplasty (the HA group), followed by twenty-seven patients who underwent reverse shoulder arthroplasty (the RSA group). A total of forty-seven patients (twenty-three in the HA group and twenty-four in the RSA group) were available for follow-up at a minimum of two years. Final average outcome scores were lower in the HA group than in the RSA group (American Shoulder and Elbow Surgeons [ASES] score of 62 versus 77 [p = 0.0001] and Simple Shoulder Test [SST] of 5.8 versus 7.4 [p = 0.0062]), and patient-reported satisfaction was lower in the HA group than in the RSA group (61% versus 91%; p = 0.038). Radiographic healing of the tuberosities occurred in 61% of the patients in the HA group compared with 83% of the patients in the RSA group (p = 0.17). Forward elevation of the arm was higher in the RSA group (139°) than in the HA group (100°) (p = 0.0002), but no significant differences were observed for shoulder external rotation or internal rotation. Complication rates in both groups were similar. Three patients (13%) in the HA group elected revision to reverse shoulder arthroplasty because of failed tuberosity healing and resultant shoulder pseudoparesis. In this series, reverse shoulder arthroplasty resulted in better clinical outcomes and a similar complication rate compared with hemiarthroplasty for the treatment of comminuted proximal humeral fractures in the elderly.


Evaluation of modified alginate-chitosan-polyethylene glycol microcapsules for cell encapsulation.
A bioartificial pancreas, a medical device entrapping islets of Langerhans (islets) in an immunoisolative membrane, has been regarded as one of the most promising approaches to treat insulin-dependent diabetic patients. In this study, various modifications of alginate-chitosan microcapsules were made such as the inclusion of polyethylene glycol (PEG) and the use of crosslinkers such as carbodiimide (EDC) and glutaraldehyde (GA) in the core and onto the microcapsule membrane surface. A characterization of the modified microcapsules in terms of mechanical stability and albumin diffusion as well as their surface properties using SEM was performed. A mild GA treatment greatly enhanced the mechanical stability of the microcapsules, and this treatment did not affect the coating process of chitosan or PEG. The biological response to such microcapsules was evaluated by microencapsulation of red blood cells (RBC) and subsequent observation of their hemoglobin release. The encapsulated RBC in the PEG-GA coated microcapsules were found to be less hemolytic and had improved stability and biocompatibility. The results suggest the possibility of developing biological assist organs by microencapsulation of mammalian cells such as islets or liver cells in immunoisolative microcapsules in the near future.


Mechanisms of GnRH-induced extracellular signal-regulated kinase nuclear localization.
Gonadotropin-releasing hormone receptors (GnRHR) mediate activation and nuclear translocation of the extracellular signal regulated kinases 1 and 2 (ERK) by phosphorylation on the TEY motif. This is necessary for GnRH to initiate transcriptional programmes controlling fertility, but mechanisms that govern ERK targeting are unclear. Using automated microscopy to explore ERK regulation in single cells, we find that GnRHR activation induces marked redistribution of ERK to the nucleus and that this effect can be uncoupled from the level of TEY phosphorylation of ERK. Thus, 5 min stimulation with 100 nM GnRH increased phospho-ERK levels (from 89 ± 34 to 555 ± 45 arbitrary fluorescence units) and increased the nuclear:cytoplasmic (N:C) ERK ratio (from 1.36 ± 0.06 to 2.16 ± 0.05) in the whole cell population, but it also significantly increased N:C ERK in cells binned according to phospho-ERK levels. This phosphorylation unattributable component of the ERK translocation response occurs at a broad range of GnRHR expression levels, in the presence of tyrosine phosphatase and protein synthesis inhibitors, and in ERK mutants unable to undergo catalytic activation. It also occurred in mutants incapable of binding the DEF (docking site for ERK, F/Y-X-F/Y-P) domains found in many ERK binding partners. It was however, reduced by MEK or PKC inhibition and by mutations preventing TEY phosphorylation or that abrogate ERK binding to D (docking) domain partners. We therefore show that TEY phosphorylation of ERK is necessary, but not sufficient for the full nuclear localization response. We further show that this "phosphorylation unattributable" component of GnRH-mediated ERK nuclear translocation requires both PKC activity and association with partner proteins via the D-domain.


Vasopressin and insulin-like growth factors synergistically induce myogenesis in serum-free medium.
Terminal differentiation of myogenic cells has long been known to be positively regulated by insulin-like growth factors (IGFs). Arg8-vasopressin (AVP) has been recently reported to potently induce myogenic differentiation. In the present study, the effects and the mechanisms of action of AVP and IGFs on myogenic cells have been investigated under conditions allowing growth and differentiation of myogenic cells in a simple serum-free medium. Under these conditions, L6 and L5 myogenic cells slowly proliferate and do not undergo differentiation (less than 1% fusion up to 7 days). AVP rapidly (2-3 days) and dose-dependently induces the formation of multinucleated myotubes. Creatine kinase activity and myosin accumulation are strongly up-regulated by AVP. Insulin or IGF-I or IGF-II, at concentrations that cause extensive differentiation in serum-containing medium, induces a modest degree of differentiation in serum-free medium. The simultaneous presence of AVP and of one of the IGFs in the synthetic medium induces maximal differentiation of L6, L5, and satellite cells. The expression of both myogenin and Myf-5 is dramatically stimulated by AVP. Our results indicate that AVP induces a significant level of myogenic differentiation in the absence of other factors. Furthermore, they suggest that to express their full myogenic potential, IGFs require the presence of other factors normally present in serum and fully mimicked by AVP. These studies support the conclusion that terminal myogenic differentiation may depend on the presence of differentiation factors rather than the absence of growth factors.


Cytokine profiles contribute to understanding the pathogenic difference between Good syndrome and oral lichen planus: two case reports and literature review.
We described and analyzed the pathogenic difference between Good syndrome (GS) and oral lichen planus (OLP) in oral mucosa. Good syndrome (GS) is a rare disease characterized by B and T cell immunodeficiency associated with hypogammaglobulinemia and thymoma. GS patients frequently develop oral lichenoid lesions with lymphocytic infiltration beneath the basal layer. Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa characterized by destruction of basal cells by Langerhans cells, macrophages, and T lymphocytes. Although the histological features of the lesions of both diseases are very similar, the pathogenesis of GS in the oral mucosa remains unknown. In this study, we thus investigated the expression of infiltrating lymphocyte subsets (CD3, CD20, CD4, and CD8) and T helper (Th) cytokines including interferon (IFN)-γ (Th1 type), interleukin (IL)-4 (Th2 type), IL-17 (Th17 type), and IL-10 (regulatory T cell type) by immunohistochemistry in buccal mucosa specimens from 2 GS patients compared with 15 OLP patients. All patients showed a predominance of CD3 T cells over CD20 B cells, and CD4 Th cells over CD8 cytotoxic T cells. This polarization was especially prominent in GS. IFN-γ and IL-10 were strongly detected in the infiltrating lymphocytes of all patients. However, IL-4 and IL-17 were detected in OLP patients only. These results suggest that the pathogenesis of GS is different from that of OLP. GS is a unique inflammatory disorder characterized by dysfunction of Th2 and Th17 immune reactions via abnormal T-B cell interaction.


PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway.
Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hematopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.


Buckling Behavior of Sandwich Cylindrical Shells Covered by Functionally Graded Coatings with Clamped Boundary Conditions under Hydrostatic Pressure.
The buckling behavior of sandwich shells with functionally graded (FG) coatings operating under different external pressures was generally investigated under simply supported boundary conditions. Since it is very difficult to determine the approximation functions satisfying clamped boundary conditions and to solve the basic equations analytically within the framework of first order shear deformation theory (FOST), the number of publications on this subject is very limited. An analytical solution to the buckling problem of FG-coated cylindrical shells under clamped boundary conditions subjected to uniform hydrostatic pressure within the FOST framework is presented for the first time. By mathematical modeling of the FG coatings, the constitutive relations and basic equations of sandwich cylindrical shells within the FOST framework are obtained. Analytical solutions of the basic equations in the framework of the Donnell shell theory, obtained using the Galerkin method, is carried out using new approximation functions that satisfy clamped boundary conditions. Finally, the influences of FG models and volume fractions on the hydrostatic buckling pressure within the FOST and classical shell theory (CT) frameworks are investigated in detail.


PZT thin film actuated elastic fin micromotor.
A piezoelectric elastic fin micromotor based on a PbZr(0.53 )Ti(0.47)O(3) thin film driving a micromachined silicon membrane was fabricated and studied. The stator was characterized by interferometry, and a laser set-up was used to measure the angular velocity and acceleration of the motor. The torque, the output power, and the efficiency of the device were extracted from these measurements. Values up to 1020 rpm and 0.94 microNm were observed for the velocity and the torque, respectively, which would be sufficient for a wristwatch application. The present version exhibited an efficiency of 0.17%, which could theoretically be increased to 4.8%


Cardiovascular control after spinal cord injury.
Spinal cord injury (SCI) leads to profound haemodynamic changes. Constant outflows from the central autonomic pattern generators modulate the activity of the spinal sympathetic neurons. Sudden loss of communication between these centers and the sympathetic neurons in the intermediolateral thoracic and lumbar spinal cord leads to spinal shock. After high SCI, experimental data demonstrated a brief hypertensive peak followed by bradycardia with escape arrhythmias and marked hypotension. Total peripheral resistance and cardiac output decrease, while central venous pressure remains unchanged. The initial hypertensive peak is thought to result from direct sympathetic stimulation during SCI and its presence is anaesthetic agent dependent. Hypotension improves within days in most animal species because of reasons not totally understood, which may include synaptic reorganization or hyper responsiveness of alpha receptors. No convincing data has demonstrated that the deafferented spinal cord can generate significant basal sympathetic activity. However, with the spinal shock resolution, the deafferented spinal cord (in lesions above T6) will generate life-threatening hypertensive bouts with compensatory bradycardia, known as autonomic hyperreflexia (AH) after stimuli such as pain or bladder/colonic distension. AH results from the lack of supraspinal control of the sympathetic neurons and altered neurotransmission (e.g. glutamatergic) within the spinal cord. Despite significant progress in recent years, further research is necessary to fully understand the spectrum of haemodynamic changes after SCI.


Extended-spectrum beta-lactamase-producing Escherichia coli in patients with travellers' diarrhoea.
The identification of patients carrying extended-spectrum beta-lactamase (ESBL)-producing bacteria is important, since these patients are at risk of receiving inappropriate empirical therapy if they become infected. The purpose of this study was to investigate the occurrence of ESBL-producing bacteria in patients with travellers' diarrhoea. Patients with travellers' diarrhoea (N = 242) having delivered stool samples for the diagnosis of Salmonella, Shigella, Yersinia or Campylobacter, were also examined for ESBL-producing Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. The overall prevalence of faecal carriage of ESBL-producing bacteria was 24% (58/242). Of the patients who had travelled in Europe, 3% (2/63) were found to be ESBL carriers in comparison to 36% (50/138) of those who had travelled outside Europe. ESBL-producing E. coli was especially common among patients returning from India (11/14), Egypt (19/38; 50%) and Thailand (8/38; 22%). In total, 90% of the genes of the ESBL-positive samples were of CTX-M type. The CTX-M-1 group dominated, followed by the CTX-M-9 group. The repetitive sequence-based PCR fingerprint pattern showed that there was no similarity between the ESBL strains found. Patients who have travelled outside Europe are at high risk of being colonized with ESBL-producing Enterobacteriaceae, and, if infected, are also at risk of receiving inappropriate empirical antibiotic therapy.


Varying Definitions of Carotid Intima-Media Thickness and Future Cardiovascular Disease: A Systematic Review and Meta-Analysis.
Carotid intima-media thickness (cIMT) has been widely used as a predictor of future cardiovascular disease (CVD); however, various definitions of cIMT exist. This study provides a systematic review and meta-analysis of the associations between different cIMT definitions and CVD. A systematic review of the different cIMT definitions used in prospective cohort studies was performed. The relationships between cIMT of different definitions (common carotid artery IMT [CCA-IMT], internal carotid artery IMT [ICA-IMT], combined segments [combined-IMT], mean CCA-IMT, and maximum CCA-IMT) with future stroke, myocardial infarction (MI), and CVD events were analyzed using random effects models. Among 2287 articles, 18 articles (14 studies) with >10 different cIMT definitions were identified and included in our meta-analysis. After adjusting for age and sex, a 1-SD increase in CCA-IMT was associated with future stroke (hazard ratio [HR], 1.32 [95% CI, 1.27-1.38]), MI (HR, 1.27 [95% CI, 1.22-1.33]), and CVD events (HR, 1.28 [95% CI, 1.19-1.37]). A 1-SD increase in ICA-IMT was related to future stroke (HR, 1.25 [95% CI, 1.11-1.42]) and CVD events (HR, 1.25 [95% CI, 1.04-1.50]) but not MI (HR, 1.26 [95% CI, 0.98-1.61]). A 1-SD increase in combined-IMT was associated with future stroke (HR, 1.30 [95% CI, 1.08-1.57]) and CVD events (HR, 1.36 [95% CI, 1.23-1.49]). Maximum CCA-IMT was more strongly related than mean CCA-IMT with risk of MI, and both measures were similarly associated with stroke and CVD events. Combined-IMT is more strongly associated with CVD events compared with single-segment cIMT definitions. Maximum CCA-IMT shows a stronger association with MI than mean CCA-IMT. Further research is warranted to validate our findings and to standardize the cIMT measurement protocol, as well as to explore underlying mechanisms.


Prophylactic intravenous calcium therapy for exchange blood transfusion in the newborn.
Exchange blood transfusion (EBT) is a form of whole blood transfusion in which the total blood volume is replaced within a few hours. In perinatal and neonatal medicine, EBT is most often used in the management of severe anaemia or severe hyperbilirubinaemia in the first week of life. Hypocalcaemia, one of the common morbidities associated with EBT, is thought to arise from the chelating effects of the citrate commonly used as an anticoagulant in the donor's blood. This disorder manifests with muscular and nervous irritability and cardiac arrhythmias. To determine whether the use of prophylactic calcium reduces the risk of hypocalcaemia-related morbidities and death among newborn infants receiving EBT. We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 5), MEDLINE via PubMed (1966 to 29 June 2016), Embase (1980 to 29 June 2016), and CINAHL (1982 to 29 June 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. All randomised and quasi-randomised trials of prophylactic intravenous calcium in EBT for newborns. Two review authors independently assessed and extracted data on methods, participants, interventions, and outcomes (mean total and ionised serum calcium before and after EBT and the presence of adverse events such as hypoglycaemia, apnoea, cardiac arrest, and death immediately after EBT). We reported results as means difference (MD) with 95% confidence intervals (CI) for continuous outcomes and risk ratio (RR) and risk differences (RD) and 95% CIs for dichotomous outcomes. We assessed quality using the Cochrane 'Risk of bias' assessment tool and the GRADE system. We found only one quasi-randomised trial with 30 participants that met our inclusion criteria. In the small trial, total and ionised serum calcium levels were measured immediately before and immediately after EBT. All the participants were included in the final analysis and all the important outcomes were reported. Primary outcomesThere was one death in each group (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1). The study did not report the presence of cardiac arrhythmias within one week of EBT and the number of infants with serum calcium levels (total less than 8 mg/dL (2 mmol/L) or ionised less than 4.4 mg/dL (1.1 mmol/L)).Pair-wise comparison of EBT with intravenous 10% calcium gluconate versus EBT without intravenous calcium (change from baseline) showed mean total serum calcium was raised in the intervention group compared to the control group (MD -0.46, 95% CI -0.81 to -0.11; participants = 30; studies = 1). Very low-quality evidence also indicated an increase in the levels of mean ionised serum calcium in the intervention group compared to the control group (MD -0.22, 95% CI -0.33 to -0.11; participants = 30; studies = 1). Secondary outcomesAdverse reactions to intravenous calcium therapy included cardiac arrest in one neonate in the intervention arm (RR 3.00, 95% CI 0.13 to 68.26; RD 0.07, 95% CI -0.10 to 0.23; participants = 30; studies = 1). There was apnoea and hypoglycaemia (RR 1.00, 95% CI 0.07 to 14.55; RD 0.00, 95% CI -0.18 to 0.18; participants = 30; studies = 1) in the two neonates who died. Data were not available for other major secondary outcomes such as the number of infants with reduced serum magnesium, reduced parathormone, increased calcitonin, presence of seizures, carpopedal spasm, jitteriness and prolonged QTc interval on electrocardiography within one week of EBT. Very low-quality data from one quasi-randomised controlled trial suggested that the mean serum total and ionised calcium increased in the study group but decreased in the control group immediately after EBT. However, the mean values of total and ionised calcium in both arms of studies remained within international reference ranges. Unfortunately, data were not available to assess the trend of total and ionised serum calcium to the end of the first week after EBT. Therefore, due to the very low quality of evidence available, it is difficult to support or reject the continual use of prophylactic intravenous calcium in newborn infants receiving EBT. Researchers are encouraged to conduct more robustly designed trials with larger numbers of participants, and particularly, addressing the pattern of differences based on gestational age of participants, type of anticoagulant used, and the volume of blood used.


Epidemiology of burn injuries in the East Mediterranean Region: a systematic review.
Burn injuries remain one of the leading causes of injury morbidity and mortality in the World Health Organization's East Mediterranean Region. To provide an overview on the epidemiology of burn injuries in this region, a systematic review was undertaken. Medline, Embase and CINAHL were searched for publications on burns in this region published between 01/01/1997 and 16/4/2007. Data were extracted to a standard spreadsheet and synthesised using a narrative synthesis. No attempt has been made to quantitatively synthesise the data due to the large degree of clinical heterogeneity between study populations. Seventy one studies were included in the review, from 12 countries. Burn injuries were found to be one of the leading causes of injury morbidity and mortality. The reported incidence of burns ranged from 112 to 518 per 100,000 per year. Burn victims were more frequently young and approximately one third of the victims were children aged 0-5 years. Hospital mortality ranged from 5 to 37%, but was commonly above 20%. Intentional self-harm burns particularly involving women were common in some countries of the region and were associated with a very high mortality of up to 79%. Burn injuries remain an important public health issue in the East Mediterranean Region therefore further research is required to investigate the problem and assess the effectiveness of intervention programmes.


Porous Carbon Nanofibers Encapsulated with Peapod-Like Hematite Nanoparticles for High-Rate and Long-Life Battery Anodes.
Fe2 O3 is regarded as a promising anode material for lithium-ion batteries (LIBs) and sodium-ion batteries (SIBs) due to its high specific capacity. The large volume change during discharge and charge processes, however, induces significant cracking of the Fe2 O3 anodes, leading to rapid fading of the capacity. Herein, a novel peapod-like nanostructured material, consisting of Fe2 O3 nanoparticles homogeneously encapsulated in the hollow interior of N-doped porous carbon nanofibers, as a high-performance anode material is reported. The distinctive structure not only provides enough voids to accommodate the volume expansion of the pea-like Fe2 O3 nanoparticles but also offers a continuous conducting framework for electron transport and accessible nanoporous channels for fast diffusion and transport of Li/Na-ions. As a consequence, this peapod-like structure exhibits a stable discharge capacity of 1434 mAh g-1 (at 100 mA g-1 ) and 806 mAh g-1 (at 200 mA g-1 ) over 100 cycles as anode materials for LIBs and SIBs, respectively. More importantly, a stable capacity of 958 mAh g-1 after 1000 cycles and 396 mAh g-1 after 1500 cycles can be achieved for LIBs and SIBs, respectively, at a large current density of 2000 mA g-1 . This study provides a promising strategy for developing long-cycle-life LIBs and SIBs.


Predicting the multi-domain progression of Parkinson's disease: a Bayesian multivariate generalized linear mixed-effect model.
It is challenging for current statistical models to predict clinical progression of Parkinson's disease (PD) because of the involvement of multi-domains and longitudinal data. Past univariate longitudinal or multivariate analyses from cross-sectional trials have limited power to predict individual outcomes or a single moment. The multivariate generalized linear mixed-effect model (GLMM) under the Bayesian framework was proposed to study multi-domain longitudinal outcomes obtained at baseline, 18-, and 36-month. The outcomes included motor, non-motor, and postural instability scores from the MDS-UPDRS, and demographic and standardized clinical data were utilized as covariates. The dynamic prediction was performed for both internal and external subjects using the samples from the posterior distributions of the parameter estimates and random effects, and also the predictive accuracy was evaluated based on the root of mean square error (RMSE), absolute bias (AB) and the area under the receiver operating characteristic (ROC) curve. First, our prediction model identified clinical data that were differentially associated with motor, non-motor, and postural stability scores. Second, the predictive accuracy of our model for the training data was assessed, and improved prediction was gained in particularly for non-motor (RMSE and AB: 2.89 and 2.20) compared to univariate analysis (RMSE and AB: 3.04 and 2.35). Third, the individual-level predictions of longitudinal trajectories for the testing data were performed, with ~80% observed values falling within the 95% credible intervals. Multivariate general mixed models hold promise to predict clinical progression of individual outcomes in PD. The data was obtained from Dr. Xuemei Huang's NIH grant R01 NS060722 , part of NINDS PD Biomarker Program (PDBP). All data was entered within 24 h of collection to the Data Management Repository (DMR), which is publically available ( https://pdbp.ninds.nih.gov/data-management ).


Office-based management of diarrhea.
Diarrhea of unknown cause is a particularly challenging diagnostic problem as it may be trivial and self-limiting or the presenting symptom of a life-threatening disorder. Antibiotic-associated diarrhea is a frequent complication of antimicrobial therapy, especially in the elderly. The more severe form, pseudomembranous colitis, is now known to be caused by a toxin produced in the colon by Clostridium difficile.


Sex difference in brain nerve conduction velocity in normal humans.
Nerve conduction velocity (NCV), the speed at which impulses travel along nerves, has been extensively determined in human peripheral nerves because of its clinical utility. In contrast, almost no studies have been made of human brain NCV. We determined brain NCVs in the visual nerve pathway for 185 male and 200 female university students ages 18-25 years. In each of three independent test conditions, we found that the mean NCV of male students is about 4% faster than in females (P < or = 0.0001 for each condition). These male students also have a shorter reaction time in each of seven different RT tests than do females, even though, on the null hypothesis of equal NCVs, we would expect males to have longer RT times because of their greater physical size. Four of these comparisons are significant at or below the 0.001 level. These males also increase their NCVs with increasing age, in contrast to females. These sex differences in NCV parallel reported sex differences in age changes in white matter in the brain. These age changes may largely explain these NCV differences.


Olfactory discrimination: when vision matters?
Many previous studies have attempted to investigate the effect of visual cues on olfactory perception in humans. The majority of this research has only looked at the modulatory effect of color, which has typically been explained in terms of multisensory perceptual interactions. However, such crossmodal effects may equally well relate to interactions taking place at a higher level of information processing as well. In fact, it is well-known that semantic knowledge can have a substantial effect on people's olfactory perception. In the present study, we therefore investigated the influence of visual cues, consisting of color patches and/or shapes, on people's olfactory discrimination performance. Participants had to make speeded odor discrimination responses (lemon vs. strawberry) while viewing a red or yellow color patch, an outline drawing of a strawberry or lemon, or a combination of these color and shape cues. Even though participants were instructed to ignore the visual stimuli, our results demonstrate that the accuracy of their odor discrimination responses was influenced by visual distractors. This result shows that both color and shape information are taken into account during speeded olfactory discrimination, even when such information is completely task irrelevant, hinting at the automaticity of such higher level visual-olfactory crossmodal interactions.


Generalised lymphangiomatosis in an 8-year-old girl who presented with cardiomegaly.
Generalised lymphangiomatosis is a rare disease that is characterized by widespread bony and soft tissue involvement of lymphangioma. Radiological evaluation is crucial because the site and extent of the lymphangioma are important prognostic factors. The computed tomography, ultrasonography and magnetic resonance images showed sharply defined, non-enhanced cystic lesions involving the mediastinum, bones, spleen, lung, and lower neck. We report here a case that was referred to us for investigation of marked cardiomegaly.


A shortened beta-hexosaminidase alpha-chain in an Italian patient with infantile Tay-Sachs disease.
Fibroblasts derived from a beta-hexosaminidase A (HexA)-deficient infant with clinically classic Tay-Sachs disease synthesized a precursor alpha-chain that was smaller than its normal counterpart. Fibroblasts from the infant's parents, who were consanguinous, produced both normal and mutant alpha-chains. The size difference, estimated to be 2-3 kilodaltons on the basis of sodium dodecyl sulfate-polyacrylamide-gel electrophoresis, persisted after removal of oligosaccharides with endo-H and is therefore attributable to a shortened polypeptide. The mutant alpha-chain did not undergo the further posttranslational modifications characteristic of its normal counterpart--i.e., synthesis of the mannose phosphate recognition marker, association with the beta-chain to give HexA, and proteolytic conversion to the mature form. Nor was it secreted, even in the presence of NH4Cl. Instead, it disappeared in the course of a 20-h chase. These results suggest that the mutant alpha-chain was trapped in an early biosynthetic compartment, either the endoplasmic reticulum or the cis-Golgi. The mutation appears to be different from all those previously described in patients with clinically classic Tay-Sachs disease.


Atlantoaxial instability in individuals with Down syndrome: epidemiologic, radiographic, and clinical studies.
Atlantoaxial instability is a relatively frequent finding in individuals with Down syndrome. We examined 404 patients with this chromosome disorder and observed their atlanto-dens intervals and spinal canal widths to be significantly different from children without Down syndrome. Significant differences were also noted between boys and girls with Down syndrome in spinal canal widths but not in atlanto-dens interval measurements. When different neck positions were compared, measurements obtained in flexion were significantly greater than in extension or in neutral position. In addition, more patients had greater than or equal to 5 mm atlanto-dens interval measurements in flexion than in extension or neutral. A total of 59 (14.6%) of 404 patients displayed atlantoaxial instability. Fifty-three (13.1%) patients had asymptomatic atlantoaxial instability, and special precautions will have to be taken with this group of children. Six (1.5%) patients had symptomatic atlantoaxial instability who underwent surgery to prevent further injury to the spinal cord. In our follow-up studies of 95 patients with Down syndrome, we did not find any significant changes during either clinical or radiographic reexaminations.


[The effect of alpha adrenergic agents on lipolysis in rat adipose tissue; the effect of nonselective alpha adrenomimetics and alpha adrenolytics in an experiment in vitro].
It is now generally accepted, that in most of the animal species the adrenergic control of lipolysis from adipose tissue is mediated by adrenergic beta 1 and alpha 2 receptors. Therefore, the problem we deal with in this article is concerned with the role of alpha adrenergic receptors in lipolysis in the rat adipose tissue because only in this species the function of alpha adrenergic receptors in lipolysis is still not clear. In in vitro experiments with epididymal adipose tissue of adult rats (where we followed up the release of free fatty acids into the albumin medium) we found: 1) Alpha adrenergic blocking agents phentolamine and phenoxybenzamine had no influence on the lipid mobilizing effect of adrenergic agonists. This effect was absent also when drugs with the strong alpha sympathomimetic effects, e.g. norepinephrine and noroxedrine, were used. 2) On the other hand, alpha adrenergic agonist phenylephrine was able to antagonize in rat adipose tissue the lipid mobilizing effect of beta adrenergic agonist isoproterenol. 3) From our experiments it can be concluded, that phenylephrine acts as a competitive dualist on beta adrenergic receptors, it reduces the effect of full agonist (e.g. isoproterenol) to the level of its own maximum lipolytic effect. No participation of alpha adrenergic receptors in described effects of phenylephrine were detected, because neither the lipolytic, nor the lipolysis blocking effects of phenylephrine were influenced by alpha adrenergic blocking agents. Our studies using alpha adrenergic agonist phenylephrine or nonselective alpha adrenergic blocking agents did not indicate the presence of any alpha adrenergically controlled lipolysis in the rat adipose tissue. However, the role of antilipolytic alpha 2 adrenoceptors in rat adipose tissue cannot be completely excluded, some of these receptors were found on the membranes of rat adipocytes. Our future study deals with this problem.


Prevalence of substance use disorders among African Americans and Caribbean Blacks in the National Survey of American Life.
We sought to estimate the prevalence of substance disorders for African Americans and Caribbean Blacks in the United States using data from the National Survey of American Life. A national household probability sample of noninstitutionalized African Americans (n=3570) and Caribbean Blacks (n=1621) was obtained between February 2001 and June 2003 using a slightly modified version of the Composite International Diagnostic Interview. Overall differences in prevalence of substance disorders between the ethnic groups were not significant. Prevalence rates of substance disorders among African Americans exceeded that of Caribbean Blacks among women, those aged 45 to 59 years, and those who were divorced. African Americans in major metropolitan areas had higher prevalence rates, and those in the South had lower ones, compared with those living in other areas. Overall, first-generation Caribbean Blacks were significantly less likely, but second-generation more likely, than were African Americans to meet criteria for overall substance disorders. Failure to distinguish between African Americans and Caribbean Blacks masks important differences in substance use patterns among the Black population in the United States.


Simultaneous sparsity model for histopathological image representation and classification.
The multi-channel nature of digital histopathological images presents an opportunity to exploit the correlated color channel information for better image modeling. Inspired by recent work in sparsity for single channel image classification, we propose a new simultaneous sparsity model for multi-channel histopathological image representation and classification (SHIRC). Essentially, we represent a histopathological image as a sparse linear combination of training examples under suitable channel-wise constraints. Classification is performed by solving a newly formulated simultaneous sparsity-based optimization problem. A practical challenge is the correspondence of image objects (cellular and nuclear structures) at different spatial locations in the image. We propose a robust locally adaptive variant of SHIRC (LA-SHIRC) to tackle this issue. Experiments on two challenging real-world image data sets: 1) mammalian tissue images acquired by pathologists of the animal diagnostics lab (ADL) at Pennsylvania State University, and 2) human intraductal breast lesions, reveal the merits of our proposal over state-of-the-art alternatives. Further, we demonstrate that LA-SHIRC exhibits a more graceful decay in classification accuracy against the number of training images which is highly desirable in practice where generous training per class is often not available.


Incidence and outcomes of contrast-induced AKI following computed tomography.
Most studies of contrast-induced acute kidney injury (CIAKI) have focused on patients undergoing angiographic procedures. The incidence and outcomes of CIAKI in patients undergoing nonemergent, contrast-enhanced computed tomography in the inpatient and outpatient setting were assessed. Patients with estimated glomerular filtration rates (GFRs) <60 ml/min per 1.73 m(2) undergoing nonemergent computed tomography with intravenous iodinated radiocontrast at an academic VA Medical Center were prospectively identified. Serum creatinine was assessed 48 to 96 h postprocedure to quantify the incidence of CIAKI, and the need for postprocedure dialysis, hospital admission, and 30-d mortality was tracked to examine the associations of CIAKI with these medical outcomes. A total of 421 patients with a median estimated GFR of 53 ml/min per 1.73 m(2) were enrolled. Overall, 6.5% of patients developed an increase in serum creatinine >or=25%, and 3.5% demonstrated a rise in serum creatinine >or=0.5 mg/dl. Although only 6% of outpatients received preprocedure and postprocedure intravenous fluid, <1% of outpatients with estimated GFRs >45 ml/min per 1.73 m(2) manifested an increase in serum creatinine >or=0.5 mg/dl. None of the study participants required postprocedure dialysis. Forty-six patients (10.9%) were hospitalized and 10 (2.4%) died by 30-d follow-up; however, CIAKI was not associated with these outcomes. Clinically significant CIAKI following nonemergent computed tomography is uncommon among outpatients with mild baseline kidney disease. These findings have important implications for providers ordering and performing computed tomography and for future clinical trials of CIAKI.


Self-organization of gold nanoparticles on silanated surfaces.
The self-organization of monolayer gold nanoparticles (AuNPs) on 3-aminopropyltriethoxysilane (APTES)-functionalized glass substrate is reported. The orientation of APTES molecules on glass substrates plays an important role in the interaction between AuNPs and APTES molecules on the glass substrates. Different orientations of APTES affect the self-organization of AuNps on APTES-functionalized glass substrates. The as grown monolayers and films annealed in ultrahigh vacuum and air (600 °C) were studied by water contact angle measurements, atomic force microscopy, X-ray photoelectron spectroscopy, UV-visible spectroscopy and ultraviolet photoelectron spectroscopy. Results of this study are fundamentally important and also can be applied for designing and modelling of surface plasmon resonance based sensor applications.


[Libernan-Cole-Golts syndrome. Focal dermic hypoplasia. Report of a case].
A case is reported corresponding to the so-called focal dermic hypoplasia and that we have named Liberman-Cole-Goltz syndrome. This is possibly the fourth case published in Mexican literature and is an additional report to those described in the international literature. This syndrome is characterized by variable ectodermal and mesodermal defects with congenital lesions most frequently found in skin and in the skeleton. The clinical, radiological and histopathological finds in the case studied are pointed out.


The accumulated evidence on lung cancer and environmental tobacco smoke.
To estimate the risk of lung cancer in lifelong non-smokers exposed to environmental tobacco smoke. Analysis of 37 published epidemiological studies of the risk of lung cancer (4626 cases) in non-smokers who did and did not live with a smoker. The risk estimate was compared with that from linear extrapolation of the risk in smokers using seven studies of biochemical markers of tobacco smoke intake. Relative risk of lung cancer in lifelong non-smokers according to whether the spouse currently smoked or had never smoked. The excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker (P < 0.001). Adjustment for the effects of bias (positive and negative) and dietary confounding had little overall effect; the adjusted excess risk was 26% (7% to 47%). The dose-response relation of the risk of lung cancer with both the number of cigarettes smoked by the spouse and the duration of exposure was significant. The excess risk derived by linear extrapolation from that in smokers was 19%, similar to the direct estimate of 26%. The epidemiological and biochemical evidence on exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke, provides compelling confirmation that breathing other people's tobacco smoke is a cause of lung cancer.


No Association Between T-peak to T-end Interval on the Resting ECG and Long-Term Incidence of Ventricular Arrhythmias Triggering ICD Interventions.
Potential of using the T-peak to T-end (TpTe) interval as an electrocardiographic parameter reflecting the transmural dispersion of ventricular repolarization (TDR) to identify patients (pts.) with higher risk of malignant ventricular arrhythmias (MVA) for better selection of candidates for implantable cardioverter-defibrillator (ICD) in primary prevention (PP) of sudden cardiac death (SCD) remains controversial. The primary objective of this study was to investigate the relationship between the TpTe interval in patient's preimplantation resting 12-lead electrocardiogram (ECG) and the incidence of MVA resulting in appropriate ICD intervention (AI). The secondary objective was to assess its relationship to overall mortality. A total of 243 consecutive pts. with severe left ventricular (LV) systolic dysfunction after myocardial infarction (MI) with a single-chamber ICD for PP of SCD from one implantation center were included. Excluded were all pts. with any other disease that could interfere with the indication of ICD implantation. Primarily investigated intervals were measured manually in accordance with accepted methodology. Data on ICD interventions were acquired from device interrogation during regular outpatient visits. Survival data were collected from the databases of health insurance and regulatory authorities. We did not find a significant relationship between the duration of the TpTe interval and the incidence of MVA (71.5 ms in pts. with MVA vs. 70 ms in pts. without MVA; p = 0.408). Similar results were obtained for the corrected TpTe interval (TpTec) and the ratio of TpTe to QT interval (76.3 ms vs. 76.5 ms; p = 0.539 and 0.178 vs. 0.181; p = 0.547, respectively). There was also no significant difference between the duration of TpTe, TpTec and TpTe/QT ratio in pts. groups by overall mortality (71.5 ms in the deceased group vs. 70 ms in the survivors group; HR 1.01; 95% CI, 0.99-1.02; p = 0.715, 76.3 ms vs. 76.5 ms; HR 1.01; 95% CI, 0.99-1.02; p = 0.208 and 0.178 vs. 0.186; p = 0.116, respectively). This study suggests no significant association of overall or MVA-free survival with ECG parameters reflecting TDR (TpTe, TpTec) in patients with systolic dysfunction after MI and ICD implanted for primary prevention.


Glutathione S-aralkyltransferase.
1. The name ;glutathione S-aralkyltransferase' is proposed for the enzyme catalysing the reaction of benzyl chloride with GSH. 2. Results from heat-inactivation studies, ammonium sulphate-fractionation and acid-precipitation experiments, and studies of the distribution of activities in rat liver, in rat kidney and in the livers of other animals indicate that glutathione S-aralkyltransferase differs from glutathione S-alkyltransferase, S-aryltransferase, S-epoxidetransferase and an S-alkenetransferase. 3. The distribution of these enzymes in the livers of the animal species examined was different. 4. Glutathione S-alkyltransferase, S-aralkyltransferase and the S-alkenetransferase that are present in rat liver supernatant were inhibited by GSSG, and the nature of the inhibition varied in each case. 5. 3,5-Di-tert.-butyl-4-hydroxybenzyl acetate reacts spontaneously with GSH, but the rat liver-supernatant-catalysed reaction of GSH with this and other aralkyl esters was weak. 6. A probable function of the glutathione S-transferases is the protection of cellular constituents from strong electrophilic agents.


Characterization of the FtsZ C-Terminal Variable (CTV) Region in Z-Ring Assembly and Interaction with the Z-Ring Stabilizer ZapD in E. coli Cytokinesis.
Polymerization of a ring-like cytoskeletal structure, the Z-ring, at midcell is a highly conserved feature in virtually all bacteria. The Z-ring is composed of short protofilaments of the tubulin homolog FtsZ, randomly arranged and held together through lateral interactions. In vitro, lateral associations between FtsZ protofilaments are stabilized by crowding agents, high concentrations of divalent cations, or in some cases, low pH. In vivo, the last 4-10 amino acid residues at the C-terminus of FtsZ (the C-terminal variable region, CTV) have been implicated in mediating lateral associations between FtsZ protofilaments through charge shielding. Multiple Z-ring associated proteins (Zaps), also promote lateral interactions between FtsZ protofilaments to stabilize the FtsZ ring in vivo. Here we characterize the complementary role/s of the CTV of E. coli FtsZ and the FtsZ-ring stabilizing protein ZapD, in FtsZ assembly. We show that the net charge of the FtsZ CTV not only affects FtsZ protofilament bundling, confirming earlier observations, but likely also the length of the FtsZ protofilaments in vitro. The CTV residues also have important consequences for Z-ring assembly and interaction with ZapD in the cell. ZapD requires the FtsZ CTV region for interaction with FtsZ in vitro and for localization to midcell in vivo. Our data suggest a mechanism in which the CTV residues, particularly K380, facilitate a conformation for the conserved carboxy-terminal residues in FtsZ, that lie immediately N-terminal to the CTV, to enable optimal contact with ZapD. Further, phylogenetic analyses suggest a correlation between the nature of FtsZ CTV residues and the presence of ZapD in the β- γ-proteobacterial species.


The physical state dependence of carboxypeptidase Aalpha and Agamma kinetics.
Spectrochemical probes have demonstrated that the conformations of carboxypeptidase A (EC 126.96.36.199) differ in solution and in the crystalline state. Detailed kinetic studies of carboxypeptidase A(alpha) and A(gamma) crystals and solutions now show that the physical state of the enzyme is also a critical parameter that affects the function of the A(alpha) and A(gamma) enzymes in the same manner. The kinetic profiles and the corresponding kinetic constants of substrate hydrolysis are, therefore, important functional indices of the known conformational differences of the enzyme in these two physical states. The complex kinetic behavior of this enzyme, however, precludes meaningful comparisons of activity measurements for crystals and solutions obtained at only one substrate concentration. Underlying differences in varying substrate-inhibiting or -activating binding modes can result in either high or low activity ratios, concealing the true, functional consequences of the change in physical state. Thus, for all substrates examined, crystallization of the enzyme markedly reduces catalytic efficiency, k(cat), from 20- to 1000-fold. Equally as important, the substrate inhibition, apparent in solution for some di- and depsipeptides, is abolished with crystals, while for longer substrates the normal solution kinetics may acquire activation with the crystals. Hypothetical modes of substrate-enzyme interaction, generated by superimposing substrate models on the crystal structure of carboxypeptidase to simulate kinetics in solution, have failed to detect both of these changes, which affect inhibitory or activating binding modes. The only structure of carboxypeptidase yet published and that of its functionally inert complex with the pseudosubstrate, glycyl-L-tyrosine, derive from a unique form of carboxypeptidase A(alpha) crystals. These crystals differ from all others with regard both to their spectral properties and activity toward carbobenzoxy-glycyl-L-phenylalanine, which is 30% of that in solution, though the significance of this value cannot be gauged without knowledge of the relevant kinetic constants. The rapidly accumulating evidence for functional and conformational differences between crystals and solutions and the recent stress on the nonproductive aspects of the carboxypeptidase A(alpha)-glycyl-L-tyrosine complex, based on 30% site occupancy, suggest that the functional implications of its structural features require reevaluation.


Modified selective and differential isolation medium for Vibrio parahaemolyticus.
The semiselective salt-starch-agar formulation of Baross and Liston was modified as the result of a systematic study of the effect of each constituent on the growth of Vibrio parahaemolyticus and competitive species characteristic of the marine environment. The selection of nutrient constituents depended on an analysis of their effect on generation time. The addition of inhibitors depended on an analysis of minimal inhibitory concentrations. The modified formulation included: peptone, 2.0%; yeast extract, 0.2%; corn starch, 0.5%; NaCl, 3.0%; agar, 1.5% (pH 8.0). Penicillin at 2 to 5 units/ml increased selectivity without significantly inhibiting Vibrio in pure suspensions. Over 62% of the most sensitive strain (YM-K33) was recovered at a concentration of 5 units of penicillin per ml. The per cent recovery of V. parahaemolyticus from fish homogenate compared favorably with other selective formulations. At an initial concentration of 10(5) cells/ml, recovery varied with the strain used from 60 to 119%, whereas at 10(2) cells/ml the range was 36 to 94%. Applications of the medium for Vibrio quantification are discussed.


Growth hormone and prolactin in the fetus.
Growth hormone is released from pituitary glands maintained in tissue culture as early as 5 weeks after conception. It has been identified in the fetal anterior pituitary gland by immunologic and biologic techniques between 7 and 15 weeks of gestation. Immunoreactive pituitary GH levels increase rapidly between 10 and 14 weeks of gestation to maximal levels at 30-34 weeks. Serum GH levels are detectable by 10-weeks postconception and reach maximal values at 20-24 weeks declining thereafter until term. Pospartum GH concentrations decline over several weeks to lower values, GH levels remaining higher in preterm than in term infants. The biologic role of pituitary GH in the fetus is unknown. Although birth-weights and lengths are reported to be normal in infants with anencephaly, aplasia, or hypoplasia of the pituitary gland and in isolated deficiency of growth hormone, in whom pituitary and serum GH levels are low, careful inspection of large series of such infants reveals that their birthweights may indeed be low and that cell numbers in many organs may be subnormal. In experimental animals prenatal administration of GH increases maternal weight and gestational length. Reported effects on neuronal growth and adult intelligence of animals treated prenatally may reflect these phenomena rather than a direct transplacental effect of GH. Prolactin is also elaborated by the pituitary gland of very young human fetuses. It has been identified immunologically by 10-weeks gestation and biologically at 18 weeks. Pituitary content of immunoreactive prolactin remains low until 16.5-weeks gestation and then increases steadily until term. The plasma concentration of prolactin is low until 30-weeks gestation and increases thereafter until term. In anencephalic fetuses prolactin levels are normal and respond to appropriate stimuli. Very high concentrations of (possibly fetal) prolactin are found in the amniotic fluid. The role of prolactin in the fetus is also unknown. It has been suggested that prolactin may be important for growth of the fetal adrenal cortex and/or for suppression of the immune response during pregnancy. It is apparent that a great deal of additional work is necessary before the importance of either growth hormone of prolactin for normal fetal growth and development will be known.


Interaction of systolic blood pressure and resting heart rate with clinical outcomes in takotsubo syndrome: insights from the International Takotsubo Registry.
The present study aimed to determine the prognostic impact of resting heart rate (HR) and systolic blood pressure (SBP) in takotsubo syndrome (TTS). Patients from the International Takotsubo Registry with complete data on HR and SBP were enrolled. We analysed all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE) in tertiles of HR (<77 b.p.m., 77-94 b.p.m., >94 b.p.m.) and SBP (<119 mmHg, 119-140 mmHg, >140 mmHg). In addition, linear splines with interactions between HR and SBP were analysed. The risk of all-cause mortality was higher in the second HR tertile (1.89, 1.15-3.10; P = 0.012) and the third HR tertile (3.01, 1.90-4.79; P < 0.001) than in the first tertile. Similar effects were observed for MACCE. Low SBP was related to an increased risk of all-cause mortality (P < 0.001) and MACCE (P = 0.002). In a multivariable analysis of all-cause mortality, at HR >70 b.p.m., every 1 b.p.m. increase in HR was associated with a 1.7% increase (P < 0.001), and every 1 mmHg increase in SBP up to 130 mmHg was associated with a 2% risk reduction (P < 0.001). The risk of all-cause mortality thus was particularly elevated when low SBP occurred together with high HR. High HR and low SBP are associated with an increased risk of all-cause mortality in TTS. HR reduction might be worthy of being investigated as a therapeutic strategy for this condition and high HR and low SBP can be used to evaluate risk in this acute presentation of TTS. ClinicalTrials.gov NCT01947621.


Enzymatic deglycation--a new paradigm or an epiphenomenon?
Following the discovery of FN3K (fructosamine 3-kinase), and more recently of FN3KRP (FN3K-related protein), research in our laboratory has been focused on testing the enzymatic deglycation hypothesis and investigating the roles of FN3K and FN3KRP. Thus far, using human erythrocytes as a model system, we have obtained the following evidence of enzymatic deglycation: (a) production of GHb (glycated haemoglobin) by D-glucose in intact erythrocytes is 5-fold lower than in haemolysates; (b) glycation of GHb by D-glucose in intact erythrocytes is 5-fold lower than that by L-glucose; (c) inhibition of ATP production in erythrocytes leads to an acceleration in the rate of GHb production by D-glucose; and (d) inhibition of FN3K in erythrocytes by a competitive inhibitor increases the accumulation of GHb. In spite of these data supporting the enzymatic deglycation hypothesis, some outstanding issues remain. These include, among others, the fact that while the apparent deglycation mechanism does not operate on L-glucose, semi-purified FN3K appears to be able to use both D- and L-fructosamines as substrates. Moreover, analysis of the fructoselysine 3-phosphate content of haemoglobin from diabetic subjects suggests that, in addition to FN3K, another deglycating mechanism may be operative in human erythrocytes. Elucidation of these issues is a challenge in the evolving field of deglycation research. Most important, however, is the question of whether enzymatic deglycation is truly an important defence mechanism or merely an epiphenomenon.


Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis.
Multiple genetic factors contribute to the clinical variability of spontaneous systemic lupus erythematosus (SLE) but their role in drug-induced SLE remain largely unknown. Hydrocarbon oil-induced SLE depends on mesothelial cell apoptosis and Toll-like receptor (TLR)-7-mediated induction of type I interferons. Hence, we hypothesized that TIR8/SIGIRR, an endogenous TLR inhibitor, prevents oil-induced SLE. Sigirr-deficient dendritic cells expressed higher TLR7 mRNA levels and TLR7 activation resulted in increased IL-12 production in vitro. In vivo, lack of SIGIRR increased surface CD40 expression on spleen CD11c(+) dendritic cells and MX-1, TNF, IL-12, BAFF and BCL-2 mRNA expression 6 months after pristane injection. Spleen cell counts of CD4(-)/CD8(-) 'autoreactive' T cells and B220(+) B cells were also increased in Sigirr(-/-) mice. Serum autoantibody analysis revealed that Sigirr deficiency specifically enhanced the production of rheumatoid factor (from 4 months of age) and anti-snRNP IgG (from 5 months of age), while anti-Smith IgG or anti-dsDNA IgG were independent of the Sigirr genotype. This effect was sufficient to significantly aggravate lupus nephritis in Sigirr-deficient mice. Structure model prediction identified the BB loop of SIGIRR's intracellular TIR domain to interact with TLR7 and MyD88. BB loop deletion was sufficient to completely abrogate SIGIRR's inhibitory effect on TLR7 signalling. Thus, TIR8/SIGIRR protects from hydrocarbon oil-induced lupus by suppressing the TLR7-mediated activation of dendritic cells, via its intracellular BB loop.


High yield synthesis of pure alkanethiolate-capped silver nanoparticles.
One-phase, one-pot synthesis of Ag(0) nanoparticles capped with alkanethiolate molecules has been optimized to easily achieve a pure product in quantitative yield. We report the synthesis of dodecanethiolate-capped silver particles and the chemophysical, structural, and morphologic characterization performed by way of UV-vis, (1)H NMR, and X-ray photoelectron (XPS) spectroscopies, X-ray powder diffraction (XRD) and X-ray absorption fine structure analysis (XFAS), electron diffraction and high-resolution transmission electron microscopy (HR-TEM), and scanning and transmission electron microscopy (SEM and TEM). Depending on the molar ratio of the reagents (dodecylthiosulphate/Ag(+)), the mean Ag(0) particle size D(XRD) is tuned from 4 to 3 nm with a narrow size distribution. The particles are highly soluble, very stable in organic solvents (hexane, toluene, dichloromethane, etc.), and resistant to oxidation; the hexane solution after one year at room temperature does not show any precipitation or formation of oxidation byproducts.