Targeted delivery of small interfering RNA to human dendritic cells to suppress dengue virus infection and associated proinflammatory cytokine production.
Dengue is a common arthropod-borne flaviviral infection in the tropics, for which there is no vaccine or specific antiviral drug. The infection is often associated with serious complications such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), in which both viral and host factors have been implicated. RNA interference (RNAi) is a potent antiviral strategy and a potential therapeutic option for dengue if a feasible strategy can be developed for delivery of small interfering RNA (siRNA) to dendritic cells (DCs) and macrophages, the major in vivo targets of the virus and also the source of proinflammatory cytokines. Here we show that a dendritic cell-targeting 12-mer peptide (DC3) fused to nona-D-arginine (9dR) residues (DC3-9dR) delivers siRNA and knocks down endogenous gene expression in heterogenous DC subsets, (monocyte-derived DCs [MDDCs], CD34(+) hematopoietic stem cell [HSC])-derived Langerhans DCs, and peripheral blood DCs). Moreover, DC3-9dR-mediated delivery of siRNA targeting a highly conserved sequence in the dengue virus envelope gene (siFvE(D)) effectively suppressed dengue virus replication in MDDCs and macrophages. In addition, DC-specific delivery of siRNA targeting the acute-phase cytokine tumor necrosis factor alpha (TNF-alpha), which plays a major role in dengue pathogenesis, either alone or in combination with an antiviral siRNA, significantly reduced virus-induced production of the cytokine in MDDCs. Finally to validate the strategy in vivo, we tested the ability of the peptide to target human DCs in the NOD/SCID/IL-2Rgamma(-/-) mouse model engrafted with human CD34(+) hematopoietic stem cells (HuHSC mice). Treatment of mice by intravenous (i.v.) injection of DC3-9dR-complexed siRNA targeting TNF-alpha effectively suppressed poly(I:C)-induced TNF-alpha production by DCs. Thus, DC3-9dR can deliver siRNA to DCs both in vitro and in vivo, and this delivery approach holds promise as a therapeutic strategy to simultaneously suppress virus replication and curb virus-induced detrimental host immune responses in dengue infection.


Medicolegal response to violence against women in India.
This article examines women's experiences in India with health and legal interventions that address domestic violence, dowry-related violence, and rape. By examining the experiences of survivors of abuse with the medicolegal system in New Delhi, it considers the extent to which women are able to access their legal rights within the special protection system constructed specifically for them. The use of primary data highlights the impact of state procedures on women, and it demonstrates how procedures designed to enhance women's access to the law actually inhibit it. Using semistructured interviews with female survivors of abuse, police officers, case workers, nongovernmental organization leaders, lawyers, physicians, and government officials in a 4-year period, this article examines women's access to state services designed to address violence against women, and raises questions about state tolerance of domestic and sexual violence.


Intramolecular activation mechanism of the Dictyostelium LRRK2 homolog Roco protein GbpC.
GbpC is a large multidomain protein involved in cGMP-mediated chemotaxis in the cellular slime mold Dictyostelium discoideum. GbpC belongs to the Roco family of proteins that often share a central core region, consisting of leucine-rich repeats, a Ras domain (Roc), a Cor domain, and a MAPKKKinase domain. In addition to this core, GbpC contains a RasGEF domain and two cGMP-binding domains. Here, we report on an intramolecular signaling cascade of GbpC. In vitro, the RasGEF domain of GbpC specifically accelerates the GDP/GTP exchange of the Roc domain. Moreover, cGMP binding to GbpC strongly stimulates the binding of GbpC to GTP-agarose, suggesting cGMP-stimulated GDP/GTP exchange at the Roc domain. The function of the protein in vivo was investigated by rescue analysis of the chemotactic defect of gbpC null cells. Mutants that lack a functional guanine exchange factor (GEF), Roc, or kinase domain are inactive in vivo. Together, the results suggest a four-step intramolecular activation mechanism of the Roco protein GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation of the GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain.


Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation.
Bispecific antibodies targeting GPRC5D demonstrated promising efficacy in multiple myeloma, but acquired resistance usually occurs within a few months. Using a single-nucleus multi-omic strategy in three patients from the MYRACLE cohort (ClinicalTrials.gov registration: NCT03807128 ), we identified two resistance mechanisms, by bi-allelic genetic inactivation of GPRC5D or by long-range epigenetic silencing of its promoter and enhancer regions. Molecular profiling of target genes may help to guide the choice of immunotherapy and early detection of resistance in multiple myeloma.


Risk of childhood cancer and adult lung cancer after childhood exposure to passive smoke: A meta-analysis.
We identified more than 30 studies on the association between exposure to maternal tobacco smoke during pregnancy and cancer in childhood. We combined their results in meta-analyses based on a random effects model. The results of the meta-analyses suggest a small increase in risk of all neoplasms [relative risk (RR) 1.10; 95% confidence interval (CI), 1.03-1.19; based on 12 studies], but not of specific neoplasms such as leukemia (RR 1.05; CI, 0.82-1.34; 8 studies) and central nervous system tumors (RR 1.04; CI, 0.92-1. 18; 12 studies). Results for other specific neoplasms were sparse, but the available data did not suggest a strong association for any type of tumor. No clear evidence of dose response was present in the studies that addressed this issue. The results on exposure to maternal tobacco smoke before or after pregnancy are too sparse to allow a conclusion. The results on exposure to paternal tobacco smoke suggest an association with brain tumors (RR 1.22; CI, 1.05-1. 40; based on 10 studies) and lymphomas (RR 2.08; CI, 1.08-3.98; 4 studies). The data are too sparse for the other neoplasms, although the results of a few recent large studies are compatible with a weak carcinogenic effect of paternal smoke. For exposure from either maternal or paternal smoke, bias and confounding cannot yet be ruled out. Further studies are needed to confirm the hypothesis that parental tobacco smoke, from the father in particular, is a risk factor of childhood cancer. Results on the risk of lung cancer in adulthood and childhood passive smoking exposure are available from 11 studies: they do not provide evidence of an increased risk (summary RR 0.91; CI, 0.80-1.05).


Action Spectrum for the Light-Dependent Step in Gametic Differentiation of Chlamydomonas reinhardtii.
Differentiation of Chlamydomonas reinhardtii vegetative cells to gametes requires two environmental signals: nitrogen starvation and light. Vegetative cells incubated without nitrogen differentiate into pregametes. Pregametes can be converted into sexually mature gametes by irradiation with light. The action spectrum for the light-dependent step in gamete formation showed two maxima at 370 and 450 nanometers. This is similar to the spectrum of other blue light/ultraviolet light-A-absorbing photoreceptors.


Intergenerational Transmission of Resilience? Sense of Coherence Is Associated between Lithuanian Survivors of Political Violence and Their Adult Offspring.
Little is known about intergeneration effects on mental health in the families of survivors of political oppression of communist regime in Central and Eastern Europe. We aimed to explore post-traumatic stress in the second generation of the Lithuanian survivors of political violence, and analyze links between parental and adult offsprings' sense of coherence in the families exposed to political violence during the oppressive communist regime in Lithuania. A total of 110 matched pairs of communist regime political violence survivors (mean age = 73.22 years) and their adult offspring (mean age = 44.65 years) participated in this study. Life-time traumatic experiences and sense of coherence were measured in both parents and their offspring. Post-traumatic stress symptoms were assessed in the second generation of survivors. We found a high vulnerability in the second generation of the Lithuanian families of political violence survivors, with a 29% of probable PTSD in the second generation based on self-report measures. A significant positive correlation between parental and adult offsprings' sense of coherence was found. Post-traumatic stress symptoms were associated negatively with a sense of coherence in the second generation. Our study indicates the links between parental and the second generation's sense of coherence in the families of survivors of political violence. The study raises broader questions about the intergenerational aspects of resilience. Further studies are needed to explore the links between parental and child sense of coherence in other samples.


A comparison of open and closed catheterization techniques in rehabilitation patients.
An effective method was sought to decrease the incidence of urinary tract infections acquired by hospitalized rehabilitation patients requiring catheterization. The purpose of this study was to determine whether there was a difference in the incidence of urinary tract infections that occurred following use of two types of intermittent catheterization techniques: open catheterization and closed catheterization. The incidence of infection in both the control (open catheterization) and experimental (closed catheterization) groups was analyzed. In the control group, 9 of 14 patients (5 stroke, 4 spinal cord injured [SCI]) completed all four urine tests. Two patients developed a 20,000 colony count of enterococcus on the fourth urine sample using open catheterization. In the experimental group, 11 (4 stroke, 7 SCI) out of 16 patients maintained colony counts below 100,000 organisms per ml; one patient had a 16,000 colony count using closed catheterization. Qualitative data revealed that patients had a positive response to the closed system.


Power of two: combination of therapeutic approaches involving glucose transporter (GLUT) inhibitors to combat cancer.
Cancer research of the Warburg effect, a hallmark metabolic alteration in tumors, focused attention on glucose metabolism whose targeting uncovered several agents with promising anticancer effects at the preclinical level. These agents' monotherapy points to their potential as adjuvant combination therapy to existing standard chemotherapy in human trials. Accordingly, several studies on combining glucose transporter (GLUT) inhibitors with chemotherapeutic agents, such as doxorubicin, paclitaxel, and cytarabine, showed synergistic or additive anticancer effects, reduced chemo-, radio-, and immuno-resistance, and reduced toxicity due to lowering the therapeutic doses required for desired chemotherapeutic effects, as compared with monotherapy. The combinations have been specifically effective in treating cancer glycolytic phenotypes, such as pancreatic and breast cancers. Even combining GLUT inhibitors with other glycolytic inhibitors and energy restriction mimetics seems worthwhile. Though combination clinical trials are in the early phase, initial results are intriguing. The various types of GLUTs, their role in cancer progression, GLUT inhibitors, and their anticancer mechanism of action have been reviewed several times. However, utilizing GLUT inhibitors as combination therapeutics has received little attention. We consider GLUT inhibitors agents that directly affect glucose transporters by binding to them or indirectly alter glucose transport by changing the transporters' expression level. This review mainly focuses on summarizing the effects of various combinations of GLUT inhibitors with other anticancer agents and providing a perspective on the current status.


Dual specificity of the interleukin 1- and tumor necrosis factor-activated beta casein kinase.
Tumor necrosis factor (TNF) and interleukin 1 (IL1) activate a protein kinase, TIP kinase, which phosphorylates beta casein in vitro. We have now identified its main phosphorylation site on beta casein, Ser124 (Km approximately 28 mu M), and a minor phosphorylation site, Ser142 (Km approximately 0.7 mM). The sequence motif that determined the phosphorylation of Ser124 by the kinase was studied with synthetic peptides bearing deletions or substitutions of the neighboring residues. This allowed synthesis of improved substrates (Km approximately 6 mu M) and showed that efficient phosphorylation of Ser124 was favored by the presence of large hydrophobic residues at positions +1, +9, +11, and +13 (counted relative to the position of the phosphoacceptor amino acid) and of a cysteine at position -2. Peptides in which Ser124 was replaced by tyrosine were also phosphorylated by TIP kinase, showing it to have dual specificity. It is unable to phosphorylate the MAP kinases in vitro and is therefore not directly involved in their activation. Its biochemical characteristics indicate that TIP kinase is a novel dual specificity kinase, perhaps related to the mixed lineage kinases. It copurified with a phosphoprotein of about 95 kDa, which could correspond either to the autophosphorylated kinase or to an associated substrate.


Use of toxicokinetics to support chemical evaluation: Informing high dose selection and study interpretation.
Toxicokinetic (TK) information can substantially enhance the value of the data generated from toxicity testing, and is an integral part of pharmaceutical safety assessment. It is less widely used in the chemical, agrochemical and consumer products industries, but recognition of its value is growing, as reflected by increased reference to the use of TK information in new and draft OECD test guidelines. To help promote increased consideration of the important role TK can play in chemical risk assessment, we have gathered practical examples from the peer-reviewed literature, as well as in-house industry data, that highlight opportunities for the use of TK in the selection of dose levels. Use of TK can help to ensure studies are designed to be of most relevance to assessing potential risk in humans, and avoid the use of excessively high doses that could result in unnecessary suffering in experimental animals. Greater emphasis on the potential contribution of TK in guiding study design and interpretation should be incorporated in regulatory data requirements and associated guidance.


Characterization of Chromatin Accessibility and Gene Expression upon Cold Stress Reveals that the RAV1 Transcription Factor Functions in Cold Response in Vitis Amurensis.
Cold tolerance is regulated by a variety of transcription factors (TFs) and their target genes. Except for the well-characterized C-repeat binding factors (CBFs)-dependent transcriptional cascade, the mechanisms of cold tolerance mediated by other transcriptional regulatory networks are still largely unknown. Here, we used the assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq to identify cold responsive TFs in Vitis amurensis, a grape species with high cold hardiness. Nine TFs, including CBF4, RAV1 and ERF104, were identified after cold treatment. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) analysis revealed that these TFs may regulate cold response through different pathways. As a prime candidate TF, overexpression of VaRAV1 in grape cells improved its cold tolerance. The transgenic cells exhibited low electrolyte leakage and malondialdehyde content and high peroxidase activity. Moreover, the TF gene TCP8 and a gene involving in homogalacturonan biosynthesis were found to be regulated by VaRAV1, suggesting that the contribution of VaRAV1 to cold tolerance may be achieved by enhancing the stability of cell membrane and regulating the expression of target genes involved in plant cell wall composition. Our work provides novel insights into plant response to cold stress and demonstrates the utility of ATAC-seq and RNA-seq for the rapid identification of TFs in response to cold stress in grapevine. VaRAV1 may play an important role in adaption to cold stress.


[Research advances in contact lens-associated dry eye].
Dry eye is the most common disease in ophthalmic clinics besides refractive error, which seriously affects the life quality of patients and has become an important public health problem in China. Dry eye as a kind of multifactorial disease can be induced or accelerated by contact lens wear, which is considered as one of the risk factors of dry eye. Studies have shown that the incidence of dry eye is higher in contact lens wearers than in normal people. In 2017, the Tear Film and Ocular Surface Society included contact lens-associated dry eye (CLADE) in the iatrogenic dry eye for the first time, and its importance is evident. However, ophthalmologists mostly used to focus on serious complications such as keratitis caused by contact lens wear, and CLADE has not been well valued and understood. This article reviews the latest studies on the epidemiology, pathogenesis, diagnosis, prevention, and treatment of CLADE.


Current use of combined hormonal contraception is associated with glucose metabolism disorders in perimenopausal women.
The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. The study is a prospective longitudinal population-based cohort study. The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3-3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1-9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3-3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5-13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2-3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.


Pancreatic cystadenoma. Angiographic and histologic findings illustrated by two cases.
Two cases of pancreatic cystadenoma are presented, demonstrating the typical angiographic and histologic pattern as given in previous literature. Although computed tomography and ultrasound examinations may be useful [11], angiography seems to play a decisive role in establishing the diagnosis, demonstrating the localization and extent of the tumor, and permitting the possible differentiation of benign and malignant lesions.


Negative-lens field expander for patients with concentric field constriction.
An oversized, negative-power spectacle lens may be used as a field expander to improve mobility and general orientation ability of patients with peripheral field loss but intact central vision. The device is inexpensive and simple to use for brief spotting periods.


Bile duct emptying in response to fat: a validation study.
Fatty meal sonography has been suggested to assess patients with biliary pain after cholecystectomy, but the effects of gallbladder removal on biliary dynamics has not been studied prospectively. Before elective cholecystectomy, 25 patients had their common hepatic ducts' diameter measured by ultrasonography before and after a fat stimulus. In 23, tests were repeated 1 month, 1 year, and 5 years after surgery. In preoperative studies, 5 patients showed dilatation after fat and 2 of these had stones in the common bile duct. However, another 4 patients with stones or sludge in the duct did not show dilatation, so that the response to fat was a poor indicator of patients requiring common bile duct exploration. No patient had major symptoms after surgery. At 1 month and 12 months, the response to fat was variable with more than half of those tested showing no decrease in duct size. A more consistent pattern emerged at 5 years, when 14 of 18 patients tested showed a decrease in common hepatic duct after fat; 3 were unchanged and 1 increased by 1 mm. The response to fat was less consistent and more difficult to measure in the common bile duct, even 5 years after operation. It was concluded that not all patients with indications for exploration of the common bile duct on operative cholangiography show a dilatation response to fat on preoperative testing. Also, fatty meal sonography should be used with caution because the response to fat in asymptomatic patients soon after operation is unpredictable, with occasional patients showing dilation without apparent obstruction. Measurement of common hepatic duct is preferred to common bile duct and increases in diameter of 1 mm are probably not significant.


[Geriatric aspects of modern plastic surgery.]
Aging of the human body is a natural physiological process. In the last century, the main reasons for people turning to plastic surgeons were congenital and acquired deformities, as well as age-related changes in the skin of the face. Nowadays, a person's appearance has become the main factor in his success in society. The work determines the motivation of elderly and senile people to perform plastic surgeries, and also analyzes the work of clinics in performing plastic surgeries for people of older age groups. It was found that 96,4% of men and 86,9% of women in older age groups have a fairly complete understanding of plastic surgery. Among the elderly and old people, 27,7% of men and 17,2% of women have a desire to perform plastic surgery for themselves, however, women are 10,9 times more likely to go to plastic surgeons. Analysis of the plastic surgery clinics showed a steady trend of increasing the number of elderly and senile people, regardless of gender, to plastic surgeons to perform operations aimed mainly at improving the aesthetics of the face, neck and body shaping by eliminating gravitational ptosis and removing excess subcutaneous fat. deposits on the trunk. The main reason for refusal to perform the operation desired by the patient and recommended by the plastic surgeon is the lack of funds.


Stereoselective synthesis of (Z)-alpha-haloacrylic acid derivatives, and (Z)-haloallylic alcohols from aldehydes and trihaloesters or amides promoted by Rieke manganese.
A Mn*-promoted sequential process directed toward the synthesis of (Z)-alpha-halo-alpha,beta-unsaturated esters or amides is described. In both cases, the process takes place with complete Z-stereoselectivity. In addition, (Z)-alpha-chloro-alpha,beta-unsaturated ketones and carboxylic acids, and (Z)-haloallylic alcohols were readily prepared from (Z)-alpha-halo-alpha,beta-unsaturated amides derived from morpholine, or esters. A mechanism has been proposed to explain the sequential process and the stereoselectivity observed.


Origin of the complex main and satellite features in Fe 2p XPS of Fe2O3.
Although the origin and assignment of the complex XPS features of the cations in ionic compounds has been the subject of extensive theoretical work, agreement with experimental observations remains insufficient for unambiguous interpretation. This paper presents a rigorous ab initio treatment of the main and satellite features in the Fe 2p XPS of Fe2O3. This has been possible using a unique methodology for the selection of orbitals that are used to form the ionic wavefunctions. This orbital selection makes it possible to treat both the angular momentum coupling of the open shell core and valence electrons as well the shake excitations from the closed shell orbitals associated with the O ligands into the valence open shell orbitals associated with the Fe 3d shell. This allows the character of the ionic states in terms of the occupations of the open shell core and valence orbitals and of the contributions of 2p1/2 and 2p3/2 ionization to the XPS intensities to be determined. Our analysis gives strong evidence that many body effects are essential for a correct description of the ionic states and, in general the states cannot be described by a single configuration over the open shell orbitals. An important consequence is that the Fe 2p XPS intensity in most of the features arises from small contributions from the ionization to many, tens to hundreds, of often unresolved ionic states. While the usual understanding of the lower binding energy main and satellite features as being dominantly from 2p3/2 ionization is confirmed, this is not the case for the higher binding energy features where 2p1/2 and 2p3/2 ionization and shake excitations in the valence space mix strongly. Furthermore, we have been able to show that a very large fraction, 88%, of the total Fe 2p XPS intensity is contained in a relatively small binding energy range of ∼35 eV. This is relevant if one wants to extract the stoichiometry of Fe2O3 from Fe 2p/O 1s intensity ratios. Similar considerations about the importance of many-body effects are likely to be relevant for other ionic compounds as well.


Isolation, structure, and antibacterial activity of philipimycin, a thiazolyl peptide discovered from Actinoplanes philippinensis MA7347.
Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. Thiazolyl peptides are a class of natural products that are architecturally complex potent antibiotics but generally suffer from poor solubility and pharmaceutical properties. To discover new thiazolyl peptides potentially with better desired properties, we designed a highly specific assay with a pair of thiazomycin sensitive and resistant strains of Staphylococcus aureus, which led to the discovery of philipimycin, a new thiazolyl peptide glycoside. It was isolated along with an acid-catalyzed degradation product by bioassay-guided fractionation. Structure of both compounds was elucidated by extensive application of 2D NMR, 1D TOCSY, and HRESIFT-MS/MS. Both compounds showed strong antibacterial activities against gram-positive bacteria including MRSA and exhibited MIC values ranging from 0.015 to 1 microg/mL. Philipimycin was significantly more potent than the degradation product. Both compounds showed selective inhibition of protein synthesis, indicating that they targeted the ribosome. Philipimycin was effective in vivo in a mouse model of S. aureus infection exhibiting an ED50 value of 8.4 mg/kg. The docking studies of philipimycin suggested that a part of the molecule interacts with the ribosome and another part with Pro23, Pro22, and Pro26 of L11 protein, which helped in explaining the differential of activities between the sensitive and resistant strains. The design and execution of the bioassay, the isolation, structure, in vitro and in vivo antibacterial activity, and docking studies of philipimycin and its degradation product are described.


LONGITUDINAL CHANGES IN QUANTITATIVE AUTOFLUORESCENCE DURING PROGRESSION FROM INTERMEDIATE TO LATE AGE-RELATED MACULAR DEGENERATION.
To prospectively investigate the development of quantitative autofluorescence (qAF) during progression from intermediate to late age-related macular degeneration (AMD). Quantitative autofluorescence images from patients with intermediate AMD were acquired every three months with a Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) using a built-in autofluorescence reference. The association between changes in longitudinal qAF and progression toward late AMD was assessed using Cox regression models with time-dependent covariates. One hundred and twenty-one eyes of 71 patients were included, and 653 qAF images were acquired. Twenty-one eyes of 17 patients converted to late AMD (median follow-up: 21 months; 12 eyes: atrophic AMD; nine eyes: neovascular AMD). The converting patients' mean age was 74.6 ± 4.4 years. Eleven eyes in the converting group (52.4%) were pseudophakic. The presence of an intraocular lens did not affect the qAF regression slopes (P > 0.05). The median change for atrophic AMD was -2.34 qAF units/3 months and 0.78 qAF units/3 months for neovascular AMD. A stronger decline in qAF was significantly associated with an increased risk of developing atrophic AMD (hazard ratio = 1.022, P < 0.001). This association, however, was not present in the group progressing toward neovascular AMD (hazard ratio = 1.001, P = 0.875). The qAF signal declines with progression to atrophy, contrary to developing neovascularization. Quantitative autofluorescence may allow identification of patients at risk of progressing to late AMD and benefits individualized patient care in intermediate AMD.


The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells.
Systemic gamma-aminobutyric acid (GABA) therapy prevents or ameliorates type 1 diabetes (T1D), by suppressing autoimmune responses and stimulating pancreatic beta cells. In beta cells, it increases insulin secretion, prevents apoptosis, and induces regeneration. It is unclear how GABA mediates these effects. We hypothesized that Klotho is involved. It is a multi-functional protein expressed in the kidneys, brain, pancreatic beta cells, other tissues, and is cell-bound or soluble. Klotho knockout mice display accelerated aging, and in humans Klotho circulating levels decline with age, renal disease and diabetes. Here, we report that GABA markedly increased circulating levels of Klotho in streptozotocin (STZ)-induced diabetes. GABA also increased Klotho in the islet of Langerhans of normal mice, as well as the islets and kidneys of STZ-treated mice. In vitro, GABA stimulated production and secretion of Klotho by human islet cells. Knockdown (KD) of Klotho with siRNA in INS-1E insulinoma cells abrogated the protective effects of GABA against STZ toxicity. Following KD, soluble Klotho reversed the effects of Klotho deficiency. In human islet cells soluble Klotho protected against cell death, and stimulated proliferation and insulin secretion. NF-κB activation triggers beta-cell apoptosis, and both GABA and Klotho suppress this pathway. We found Klotho KD augmented NF-κB p65 expression, and abrogated the ability of GABA to block NF-κB activation. This is the first report that GABAergic stimulation increases Klotho expression. Klotho protected and stimulated beta cells and lack of Klotho (KD) was reversed by soluble Klotho. These findings have important implications for the treatment of T1D.


Inflammatory linear verrucous epidermal naevus (ILVEN) versus linear psoriasis. A clinical, histological and immunohistochemical study.
Inflammatory Linear Verrucous Epidermal Nevus (ILVEN) has been suggested to be a separate disease entity. However, the distinction from linear psoriasis has been discussed in the literature over recent decades. The aim of the present study was to investigate, in addition to the clinical and histological criteria, the immunohistochemical aspects of inflammation, epidermal proliferation and keratinization. From a clinical and histological point of view, ILVEN and psoriasis, according to the established criteria, have been proved to overlap. The immunohistochemical study suggests that the following procedures have an additional diagnostic impact: assessment of elastase-positive cells, assessment of keratin 16 and of keratin 10.


A Direct Method for Mapping the Center of Pressure Measured by an Insole Pressure Sensor System to the Shoe's Local Coordinate System.
A direct method to express the center of pressure (CoP) measured by an insole pressure sensor system (IPSS) into a known coordinate system measured by motion tracking equipment is presented. A custom probe was constructed with reflective markers to allow its tip to be precisely tracked with motion tracking equipment. This probe was utilized to activate individual sensors on an IPSS that was placed in a shoe fitted with reflective markers used to establish a local shoe coordinate system. When pressed onto the IPSS the location of the probe's tip was coincident with the CoP measured by the IPSS (IPSS-CoP). Two separate pushes (i.e., data points) were used to develop vectors in each respective coordinate system. Simple vector mathematics determined the rotational and translational components of the transformation matrix needed to express the IPSS-CoP into the local shoe coordinate system. Validation was performed by comparing IPSS-CoP with an embedded force plate measured CoP (FP-CoP) from data gathered during kinematic trials. Six male subjects stood on an embedded FP and performed anterior/posterior (AP) sway, internal rotation, and external rotation of the body relative to a firmly planted foot. The IPSS-CoP was highly correlated with the FP-CoP for all motions, root mean square errors (RMSRRs) were comparable to other research, and there were no statistical differences between the displacement of the IPSS-CoP and FP-CoP for both the AP and medial/lateral (ML) axes, respectively. The results demonstrated that this methodology could be utilized to determine the transformation variables need to express IPSS-CoP into a known coordinate system measured by motion tracking equipment and that these variables can be determined outside the laboratory anywhere motion tracking equipment is available.


Structure of winter groundfish feeding guilds in Pacific herring Clupea pallasii and walleye pollock Gadus chalcogrammus nursery fjords.
The contents of 1056 stomachs were included in a trophic-guild analysis to document separation amongst 16 groundfish species inhabiting Pacific herring Clupea pallasii and walleye pollock Gadus chalcogrammus nursery fjords in Prince William Sound, Alaska and to determine the relative contribution of C. pallasii and G. chalcogrammus to that separation. A total of five multi-species feeding guilds and one outlier species were determined through multivariate analyses. Major gradients of trophic separation spanned from invertebrates (mostly shrimps, crabs and unidentified decapods) to fishes (mostly unidentified fishes, C. pallasii and G. chalcogrammus) a pattern that was influenced by intra and interspecific differences in predator lengths. While C. pallasii and G. chalcogrammus were important to the overall guild structure, within-guild similarities were consistently highest due to unidentified fishes. In general, larger predators consumed the largest C. pallasii and G. chalcogrammus, with the smaller-on-average predators consuming smaller C. pallasii and fewer or smaller G. chalcogrammus. Regardless of guild inclusion, groundfishes primarily consumed pre-recruit C. pallasii and G. chalcogrammus (i.e., younger than age 3 years fishes), which has the potential to negatively influence recruitment of these forage fishes to the adult, spawning population.


Reversible acute anuric kidney injury after surgical evacuation of perinephric hematomas as a complication of renal transplant biopsies.
Percutaneous renal transplant biopsy is the gold standard investigation to diagnose the cause of renal allograft dysfunction. There are inherent risks to this investigation, despite the procedure becoming safer due to the increased utilization of ultrasound-guided techniques. These biopsy risks can be increased when there is acute rejection present with a swollen transplanted kidney. Subcapsular hematomas are not uncommon after percutaneous renal transplant biopsies, but we describe two cases of post-biopsy subcapsular hematoma which were associated with acute renal allograft dysfunction in pediatric renal transplant recipients who did not have acute rejection.


Noninvasive respiratory support following extubation in critically ill adults: a systematic review and network meta-analysis.
Systematic review and network meta-analysis to investigate the efficacy of noninvasive respiratory strategies, including noninvasive positive pressure ventilation (NIPPV) and high-flow nasal cannula (HFNC), in reducing extubation failure among critically ill adults. We searched databases from inception through October 2021 for randomized controlled trials (RCTs) evaluating noninvasive respiratory support therapies (NIPPV, HFNC, conventional oxygen therapy, or a combination of these) following extubation in critically ill adults. Two reviewers performed screening, full text review, and extraction independently. The primary outcome of interest was reintubation. We used GRADE to rate the certainty of our findings. We included 36 RCTs (6806 patients). Compared to conventional oxygen therapy, NIPPV (OR 0.65 [95% CI 0.52-0.82]) and HFNC (OR 0.63 [95% CI 0.45-0.87]) reduced reintubation (both moderate certainty). Sensitivity analyses showed that the magnitude of the effect was highest in patients with increased baseline risk of reintubation. As compared to HFNC, no difference in incidence of reintubation was seen with NIPPV (OR 1.04 [95% CI 0.78-1.38], low certainty). Compared to conventional oxygen therapy, neither NIPPV (OR 0.8 [95% CI 0.61-1.04], moderate certainty) or HFNC (OR 0.9 [95% CI 0.66-1.24], low certainty) reduced short-term mortality. Consistent findings were demonstrated across multiple subgroups, including high- and low-risk patients. These results were replicated when evaluating noninvasive strategies for prevention (prophylaxis), but not in rescue (application only after evidence of deterioration) situations. Our findings suggest that both NIPPV and HFNC reduced reintubation in critically ill adults, compared to conventional oxygen therapy. NIPPV did not reduce incidence of reintubation when compared to HFNC. These findings support the preventative application of noninvasive respiratory support strategies to mitigate extubation failure in critically ill adults, but not in rescue conditions.


The Impact of Tocilizumab on Radiological Changes Assessed by Quantitative Chest CT in Severe COVID-19 Patients.
(1) Background: We aimed to analyze the characteristics associated with the in-hospital mortality, describe the early CT changes expressed quantitatively after tocilizumab (TOC), and assess TOC timing according to the oxygen demands. (2) Methods: We retrospectively studied 101 adult patients with severe COVID-19, who received TOC and dexamethasone. The lung involvement was assessed quantitatively using native CT examination before and 7−10 days after TOC administration. (3) Results: The in-hospital mortality was 17.8%. Logistic regression analysis found that interstitial lesions above 50% were associated with death (p = 0.01). The other variables assessed were age (p = 0.1), the presence of comorbidities (p = 0.9), the oxygen flow rate at TOC administration (p = 0.2), FiO2 (p = 0.4), lymphocyte count (p = 0.3), and D-dimers level (p = 0.2). Survivors had a statistically significant improvement at 7−10 days after TOC of interstitial (39.5 vs. 31.6%, p < 0.001), mixt (4.3 vs. 2.3%, p = 0.001) and consolidating (1.7 vs. 1.1%, p = 0.001) lesions. When TOC was administered at a FiO2 ≤ 57.5% (oxygen flow rate ≤ 13 L/min), the associated mortality was significantly lower (4.3% vs. 29.1%, p < 0.05). (4) Conclusions: Quantitative imaging provides valuable information regarding the extent of lung damage which can be used to anticipate the in-hospital mortality. The timing of TOC administration is important and FiO2 could be used as a clinical predictor.


[Histological differential diagnosis of hydatidiform moles and hydropic abortions].
To describe the diagnostic methods enabling histological differential diagnosis of complete hydatidiform mole, immature complete hydatidiform mole, partial hydatidiform mole, proliferative mole and hydropic abortion. Our study consists of 1321 partial hydatidiform moles, 805 complete hydatidiform moles, 524 proliferative moles, and over 2500 hydropic abortuses diagnosed and treated at the Trophoblastic Disease Center in the Czech Republic (TDC-CZ), Institute for the Care of Mother and Child, plus 2896 of these lesions examined at the TDC-CZ by referral. The material was examined by routine histopathological methods, which in selected cases were supplemented by immunohistological examination and correlated with cytogenetic and molecular genetic results and clinical features. The study describes the diagnostic procedures enabling differential diagnosis between mature complete hydatidiform mole, immature complete hydatidiform mole, partial hydatidiform mole, proliferative mole and hydropic abortion. Fourteen histological parameters have been defined which are most common, individually or in combination, in various types of hydatidiform moles and hydropic abortions. Warning is given to errors in histological diagnosis, correlated with cytogenetic and molecular genetic results. We propose a reliable method of eliminating the influence of these errors on the possible development of trophoblastic disease. The study describes a histological differential diagnosis of complete hydatidiform mole, immature complete hydatidiform mole, partial hydatidiform mole, proliferative mole and hydropic abortion.


Bipyridine-based iridium(iii) triplet emitters for organic light-emitting diodes (OLEDs): application and impact of phenyl substitution at the 5'-position of the N-coordinating pyridine ring.
Three blue phosphorescent homoleptic iridium(iii) complexes based on a bipyridine ligand were synthesized. The structures of these Ir(C^N)3 analogues were determined by single-crystal X-ray diffraction analysis. Two geometrical isomers, facial and meridional, formed as the major products, and the ratio of the products depended on the substituents. The photophysical and electrochemical properties of the complexes were analyzed, and they were used as dopants for the fabrication of phosphorescent organic light-emitting diodes (PHOLEDs). The dependence of current density on dopant concentration in the devices, as well as their external quantum efficiencies and current efficiencies, were evaluated. All complexes exhibited intense, sky-blue phosphorescent emission at λmax = 479, 484 and 488 nm, and the absolute quantum efficiencies in the thin films were high at 0.72, 0.75 and 0.81. A maximum current efficiency of 39.8 cd A-1 and an external quantum efficiency (EQE) of 14.9% were obtained, which signified superior performance among blue phosphorescent organic light-emitting diodes. High efficiencies of 39.2 cd A-1 and 14.0% EQE were still achieved at a luminance of 1000 cd m-2.


Effect of Low-Dose Persistent Organic Pollutants on Mitochondrial Function: Human and in Vitro Evidence.
Chronic exposure to low-dose persistent organic pollutants (POPs) can induce mitochondrial dysfunction. This study evaluated the association between serum POP concentrations and oxygen consumption rate (OCR) as a marker of mitochondrial function in humans and in vitro cells. Serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in 323 adults. The OCRs of platelets and peripheral blood mononuclear cells (PBMCs) were assessed in 20 mL of fresh blood using a Seahorse XF analyzer. Additionally, the in vitro effects of Arochlor-1254, β-hexachlorocyclohexane, and p,p´-dichlorodiphenyltrichloroethane at concentrations of 0.1 pM to 100 nM were evaluated in human platelets, human PBMCs, and Jurkat T-cells. The association between serum POP concentrations and OCR differed depending on the cell type. As serum OCP concentrations increased, basal platelet OCR levels decreased significantly; according to the OCP quintiles of summary measure, they were 8.6, 9.6, 8.2, 8.0, and 7.1 pmol/min/μg (P trend=0.005). Notably, the basal PBMC OCR levels decreased remarkably as the serum PCB concentration increased. PBMC OCR levels were 46.5, 34.3, 29.1, 16.5, and 13.1 pmol/min/μg according to the PCB quintiles of summary measure (P trend <0.001), and this inverse association was consistently observed in all subgroups stratified by age, sex, obesity, type 2 diabetes mellitus, and hypertension, respectively. In vitro experimental studies have also demonstrated that chronic exposure to low-dose POPs could decrease OCR levels. The findings from human and in vitro studies suggest that chronic exposure to low-dose POPs can induce mitochondrial dysfunction by impairing oxidative phosphorylation.


Corticosteroid therapy in critically ill pediatric asthmatic patients.
IV corticosteroids are routinely prescribed to treat critically ill children with asthma. However, no specific dosing recommendations have been made for children admitted to the PICU. We aim to determine current asthma corticosteroid dosing preferences in PICUs within North America. Cross-sectional, self-administered survey. North American PICUs. Pediatric intensivists working in the United States and Canada. None. A total of 104 intensivists completed the survey. Of these, 70% worked in the United States, 67% attended in PICUs with at most 20 beds, and 79% had more than 10 years of PICU experience. The majority of asthmatics were admitted to PICUs based on clinical asthma examination/score or because the patient was receiving continuous albuterol. IV methylprednisolone is prescribed by a large majority of intensivists (96%). Of those who prescribe methylprednisolone, 66% use a starting dose of 4 mg/kg/d, whereas 31% use a starting dose of 2 mg/kg/d, and only 3% use 1 mg/kg/d. The large majority of respondents (85%) use "clinical experience" as their rationale for their preferred dosage. In multivariate logistic regression analysis, only knowledge of the National Heart, Lung, and Blood Institute guidelines was an independent predictor of prescribing an initial corticosteroid dose of 4 mg/kg/d (odds ratio, 3.69 [95% CI, 1.26-10.80]; p = 0.017). Country of practice, years of experience, and PICU size were not associated with corticosteroid dosing preference. Most intensivists administer methylprednisolone to critically ill asthmatics at doses 2 to 4 times higher than recommended by the National Heart, Lung, and Blood Institute guidelines for hospitalized asthmatic children. The rationale for these decisions is likely multifactorial, but in the absence of evidence-based data, most of them cite clinical experience as their deciding factor. Future research is needed to determine the most appropriate corticosteroid dosage in this critically ill patient population.


[Neurological symptoms as the first sign of prostate carcinoma].
Three male patients aged 82, 56 and 60 years presented with cognitive impairment and hemiparesis, weakness of the tongue and facial muscles, and pain and weakness of the left arm, respectively. They were found to have carcinoma of the prostate with cerebral, skull and cervical spine metastases. They were treated with hormonal therapy and local radiotherapy for bone metastases. The first patient died within 2 weeks, the second after 1.5 year, and the third was still alive after 6 years. The diagnostic work-up in men with unexplained neurological symptoms should probably include a rectal exam and assessment of prostate-specific antigen.


[Expression of growth-factor independence 1 in patients with leukemia and its significance].
This study was purposed to investigate the expression of the growth-factor independence 1 (GFI1) in patients with leukemia and its clinical significance. Bone marrow mononuclear cells were obtained from 65 newly diagnosed leukemia patients including 24 acute myeloid leukemia (AML), 18 chronic myelogenous leukemia (CML), 6 acute lymphoblastic leukemia (ALL), 17 blast crisis of chronic myelogenous leukemia and 13 patients with iron deficiency anemia (IDA) were used as controls. The relative expression of gene gfi1 was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and taqman quantitative real-time reverse transcription polymerase chain reaction (QRT-PCR). The results showed that gene expression of gene gfi1 in leukemia patients was obviously higher than that in controls and the difference was statistically significant (p < 0.01), in which the expression of gene gfi1 in newly diagnosed CML patients was higher than that in newly diagnosed AML, newly diagnosed ALL, CML-BCP patients and the difference was significant (p < 0.01). Expression of gene gfi1 in lymphocytic blast crisis of CML was higher than that in nonlymphocytic blast crisis of CML, and the difference was significant. It is concluded that gene gfi1 may play an important role in leukemia, especially in CML incidence and progression. The high level expression of gene gfi1 may be participate in the development of lymphoma.


Quality of life of older adults in nursing homes in Vietnam.
This study evaluated the quality of life of older adults in Vietnam. A survey was conducted on 291 old people at eight public and private nursing homes using cluster sampling. Quality of life was predicted by gender, duration of stay, center activities and community tangible support, and connection with family. Results were consistent across the four subscales of the Quality of Life Index. Quality of life of Vietnamese older adults depends not only on the quality of services provided by the nursing homes but also on family and community connections.


Features of pedestrian behavior in car-to-pedestrian contact situations in near-miss incidents in Japan.
The objective of this study is to evaluate the severe conditions between car-to-pedestrian near-miss situations using pedestrian time-to-vehicle (pedestrian TTV) which is the time when the pedestrian would reach the forward moving car line. Since the information available from the real-world accidents was limited, the authors focused on the near-miss situations captured by driving recorders installed in passenger cars. In their previous study, the authors found there were some similarities between accidents and near-miss incidents. It was made clear that the situations in pedestrians' accidents could be estimated from the near-miss incident data which included motion pictures capturing pedestrian behaviors. In their previous study, the vehicle time-to-collision (vehicle TTC) was investigated from the near-miss incident data. The authors analyzed data for 101 near-miss car-to-pedestrian incident events in which pedestrians were crossing the roads in front of a forward-moving car at an intersection or on a straight road. Using a video of near-miss car-to-pedestrian incidents captured by drive recorders and collected by the Society of Automotive Engineers of Japan (J-SAE) from 2005 to 2009, the pedestrian TTV was calculated. Based on the calculated pedestrian TTV, one of the severe conditions between car-to-pedestrian near-miss situations was evaluated for pedestrians who emerged from behind an obstruction such as a building, a parked vehicle and a moving vehicle. Focusing on the cases of the pedestrians who emerged from behind an obstruction, the averages of the vehicle TTC and pedestrian TTV were 1.31 and 1.05 seconds, respectively, and did not demonstrate a significant difference. Since the averages of the vehicle TTC and pedestrian TTV were similar, there would be a higher possibility of the contact between a car and pedestrian if the driver and pedestrian were not paying any attention. The authors propose that a moving speed of a pedestrian surrogate "dummy" should be determined considering the near-miss incident situations for the evaluation of a CDMBS for pedestrian detection. The authors also propose that the time-to-collision of the dummy to the tested car during the evaluation of the performance of the CDMBS for pedestrian detection should be determined considering the time such as the vehicle TTC in this study. Additionally or alternatively, the pedestrian TTV should be considered, in which the worst situation was assumed for a car that was moving toward a pedestrian without braking due to the car driver's inattentiveness and the pedestrian not slowing down their walking speed or stopping.


Abnormalities of esophageal and gastric emptying in progressive systemic sclerosis.
Gastric and esophageal emptying were assessed using scintigraphic techniques in 12 patients with progressive systemic sclerosis and 22 normal volunteers. Esophageal emptying was significantly delayed in the patient group, with 7 of the 12 patients beyond the normal range. Gastric emptying was slower in patients than in controls, with 9 patients being outside the normal range for solid emptying and 7 patients outside the normal range for liquid emptying. Findings from gastric and esophageal emptying tests generally correlated well with symptoms of dysphagia and gastroesophageal reflux. However, 2 patients with normal emptying studies had symptomatic heartburn, and 2 patients with delay of both solid and liquid gastric emptying gave no history of gastroesophageal reflux. Delayed gastric emptying may be an important factor in the development of upper gastrointestinal symptoms in patients with progressive systemic sclerosis.


Leprosy and the peripheral nervous system: basic and clinical aspects.
Leprosy is one of the most common causes of nontraumatic peripheral neuropathy in the developing world. The causative agent, Mycobacterium leprae, has a predilection for Schwann cells, where the organism multiplies unimpeded by organism-specific host immunity, resulting in destruction of myelin, secondary inflammatory changes, and destruction of the nerve architecture. The cardinal diagnostic features of leprosy are anesthetic skin lesions, neuropathy, and positive skin smears for the bacilli. However, patients may rarely present without skin lesions in pure neuritic leprosy. Electrodiagnostic findings early in the disease reveal demyelinating features, such as slowing of conduction velocity and prolongation of latencies, but as the disease progresses secondary axonal damage commonly ensues. Electrodiagnostic studies are also useful to monitor for toxicity secondary to therapy, particularly thalidomide-associated neuropathy. Nerve biopsy of a sensory cutaneous nerve is sometimes essential to confirm a diagnosis of leprosy. Significant advances in understanding of the pathogenesis, mapping of the genome, and other advances in molecular biology may result in better preventive and therapeutic modalities, and the goal of eradicating leprosy as a global problem may yet be realized.


[Inconsistency in quantitation of estrogen receptor and progesterone receptor with dextran charcoal method and enzyme immunoassay].
Six hundred and eighty-eight breast specimens including 442 breast cancers were studied to investigate the consistency and correlations between dextran charcoal assay (DCC) and enzyme immunoassay (EIA) for estrogen receptor (ER) and progesterone receptor (PgR). In DCC, ER was quantitated with competition of 16 alpha-125I-estradiol and diethyl stilbesterol, and PgR with 3H-R5020 and R5020. In EIA, kit from Abbott was used in ER and PgR quantitation. The mean age of the patients was 52 years and the mean age of patients with benign lesions was 39 years. The consistency rate was 95% for ER, and 83% for PgR, while the consistency coefficient kappa was 0.90 and 0.66, respectively. For the specimens in which the number of binding sites was calculated in both DCC (x) and EIA (y), the correlation coefficient was 0.787 and the linear regression formula was y = 0.5x + 58. For PgR, the correlation coefficient kappa was 0.612 and the regression formula was y = 2.6x + 91. In multiple regression analysis for consistency of DCC and EIA, for ER, there was an inconsistent trend for positive PgR and a consistent trend for patients in their fifties. For PgR, the trend was inconsistent for benign lesions and positive ER. In comparison with the efficacy of endocrine treatment, no responder was found in ER negative patients for both DCC and EIA. In PgR-negative patients a responder was found for both DCC and EIA. By Western blot analysis, anti-ER antibody provided in the ER.EIA kit showed affinity only for ER alpha and not for beta. In conclusion, in terms of the treatment efficacy for both ER and PgR, the current use of ER with EIA instead of DCC seems to give equivalent result, and old DCC data can be converted into the regression formula. However, PgR calculated by EIA was not equivalent with that of DCC.


Prospects for a schistosome vaccine.
After some 20 years experience it is generally agreed that chemotherapy against schistosomiasis, a parasitic disease which should be considered a consequence of a chronic infection, does have significant limitations. In particular, chemotherapy does not affect transmission of the infection or the high re-infection rates and so limits the success by demanding frequently re-scheduled mass treatments. For this reason, a complementary approach that can be integrated and could sustain chemotherapy-based control programs, i.e. vaccination, is very much needed. The rationale is that drug treatment would provide short-term reduction of worm burdens and vaccination, long-term protective immune response. Vaccination can either be targeted towards the prevention of infection or to the reduction of parasite fecundity. A reduction in worm numbers is the "gold standard" for anti-schistosome vaccine development but, as schistosome eggs are responsible for both pathology and transmission, a vaccine targeted on parasite fecundity and egg viability also appears to be entirely relevant. This review considers various aspects of anti-schistosome protective immunity that are important in the context of vaccine development. The current status in the development of vaccines against the African (Schistosoma mansoni and S. haematobium) and Asian (S. japonicum) schistosomes is then discussed as the new approaches that may improve on the efficacy of the available vaccines and aid in the identification of new targets for immune attack.


[Mechanism of intracellular calcium homeostasis in heat-exposed cardiomyocytes of rats].
The activity of Ca(2+)-ATPase and calcium content were measured in sarcoplasmic reticulum (SR) and mitochrondria of myocardium from 40 adult female Wistar rats after exposure to 37 degrees C, 39 degrees C, 41 degrees C and 43 degrees C for 40 min respectively in vitro. The 45Ca uptake, intracellular free Ca2+ concentration ([Ca2+]i) and the relatively active calmodulin content were also observed in cultured cardiomyocytes from 120 neonatal Wistar rats under the same condition of heat exposure. The results showed that (1) the activity of Ca(2+)-ATPase of SR and mitochrondria of myocardium decreased after heat exposure, (2) the calcium content of SR and mitochrondria also showed a tendency of decrease with increase of exposure temperature, (3) the 45Ca uptake and mean [Ca2+]i increased, whereas the calmodulin content decreased. It is suggested that disturbances of intracellular calcium homeostasis may be responsible for cardiac functional disorder after heat exposure.


Orthopaedic Surgeons' View on Strategies for Improving Patient Safety.
Many strategies have been introduced to improve safety in health care, but it is not clear that these efforts have reduced errors. This study assessed the experienced safety culture and preferred means of improving safety among orthopaedists. Members of the Science of Variation Group and Ankle Platform were invited to complete an eighty-nine-question survey. Outcomes measured were the modified Patient Safety Climate in Healthcare Organizations (PSCHO) questionnaire, which measures safety as perceived by hospital personnel, and the degree of enthusiasm expressed for seventeen means of improving safety. The questionnaire was completed by 387 (92%) of the 422 participants. The rate of problematic responses, those implying a lack of safety climate, in the modified PSCHO questionnaire was 18%. In multivariable linear regression analysis, working in a non-teaching hospital (β, 3.7; 95% confidence interval [95% CI], 1.3 to 6.2; p = 0.003), having a safety program (β, 4.8; 95% CI, 0.74 to 8.8; p = 0.020), and male sex (β, 3.7; 95% CI, 0.079 to 7.3; p = 0.045) were associated with higher perceived safety as measured by the PSCHO questionnaire. The majority of participants were very enthusiastic about making safety everyone's responsibility (75%), promoting better communication (80%), standardizing procedures (58%), and standardizing equipment and supplies (63%) to improve safety. We found a high problematic response rate concerning the perceived safety climate among surgeons, but there was a high rate of enthusiasm for means of improving safety. Knowledge of the variation in perceived safety and the enthusiasm for strategies to improve safety among surgeons can serve as a starting point for cultural change.


Characterization of central axon terminals of putative stretch receptors in leeches.
Sensory feedback from stretch receptors, neurons that detect position or tension, is crucial for generating normal, robust locomotion. Among the eight pairs of putative stretch receptors associated with longitudinal muscles in midbody segments of medicinal leeches, only the ventral stretch receptor has been characterized in detail. To achieve the identification of all such receptors, we penetrated large axons in the nerve roots of nerve cords from adult leeches with dye-filled (Alexa Fluor hydrazide) electrodes. We identified the terminal arborizations of two additional putative stretch receptors with axons in anterior nerve roots and four more such receptors with axons in posterior roots of midbody ganglia. The axons are nonspiking and are individually identifiable by their entry point into the CNS; their projections within the neuropile; the pattern, extent, and orientation of their terminal branches; and the characteristics of small "spike-like" events. At least two of these axons undergo membrane potential oscillations that are phase locked to the swimming rhythm expressed in nerve cord-body wall preparations and, at a different phase angle, also in isolated nerve cords. Thus the membrane potentials of at least two axons are phasically modulated by the periphery and hence could provide cycle-by-cycle sensory input to coordinate swimming activity. One of these neurons has a soma associated with the dorsal body wall and hence is a putative stretch receptor in dorsal longitudinal muscle. Thus the traveling body wave expressed by swimming leeches may be regulated by sensory feedback from both ventral and dorsal longitudinal muscles.


Multimodal therapy for painful bladder syndrome/interstitial cystitis.
Most patients who suffer from PBS/IC can now be simply and effectively treated. The first step to successful management is accurate and timely diagnosis, which has become easier with available and validated screening and diagnostic tools such as PUF and PST. Once PBS/IC is correctly diagnosed, prompt treatment should address the main components of the disease, a dysfunctional urothelium, mast cell activation and neural upregulation. Multimodal treatment that has shown benefit includes oral PPS plus an antihistamine, such as hydroxyzine, and a TCA, such as amitriptyline. Behavioral interventions and intravesical instillation therapy are adjunctive measures that will promote symptom relief. Intravesical "rescue" solutions using lidocaine and heparin or PPS (dissolved in water or in the instillation solution [off-label use of PPS]) can provide immediate relief while patients develop a response to oral PPS. Patient education and support are critical in managing this complex but treatable disorder.


High performance photovoltaic applications using solution-processed small molecules.
Energy remains a critical issue for the survival and prosperity of humancivilization. Many experts believe that the eventual solution for sustainable energy is the use of direct solar energy as the main energy source. Among the options for renewable energy, photovoltaic technologies that harness solar energy offer a way to harness an unlimited resource and minimum environment impact in contrast with other alternatives such as water, nuclear, and wind energy. Currently, almost all commercial photovoltaic technologies use Si-based technology, which has a number of disadvantages including high cost, lack of flexibility, and the serious environmental impact of the Si industry. Other technologies, such as organic photovoltaic (OPV) cells, can overcome some of these issues. Today, polymer-based OPV (P-OPV) devices have achieved power conversion efficiencies (PCEs) that exceed 9%. Compared with P-OPV, small molecules based OPV (SM-OPV) offers further advantages, including a defined structure for more reproducible performance, higher mobility and open circuit voltage, and easier synthetic control that leads to more diversified structures. Therefore, while largely undeveloped, SM-OPV is an important emerging technology with performance comparable to P-OPV. In this Account, we summarize our recent results on solution-processed SM-OPV. We believe that solution processing is essential for taking full advantage of OPV technologies. Our work started with the synthesis of oligothiophene derivatives with an acceptor-donor-acceptor (A-D-A) structure. Both the backbone conjugation length and electron withdrawing terminal groups play an important role in the light absorption, energy levels and performance of the devices. Among those molecules, devices using a 7-thiophene-unit backbone and a 3-ethylrhodanine (RD) terminal unit produced a 6.1% PCE. With the optimized conjugation length and terminal unit, we borrowed from the results with P-OPV devices to optimize the backbone. Thus we selected BDT (benzo[1,2-b:4,5-b']dithiophene) and DTS (dithienosilole) to replace the central thiophene unit, leading to a PCE of 8.12%. In addition to our molecules, Bazan and co-workers have developed another excellent system using DTS as the core unit that has also achieved a PCE greater than 8%.


[Agrin acts at the nerve-muscle synapse in the glomerular basal membrane and on T-lymphocytes].
The role of agrin, a large proteoglycan containing heparan-sulfate in the synaptic cleft, has been elucidated in recent years. The molecule released from the motor-neuron endplate, binds to a complex of 2 adjacent receptors at the post-synaptic myotube surface. It binds first to MASC (myotube associated specific component) and thus triggers a signal at the MuSK (muscle-specific kinase) receptor that generates tyrosine phosphorylation. A cascade of further responses of RATL and rapsyn leads to the aggregation of acetylcholine receptors. Lately, agrin is also implicated as a sulfated proteoglycan in the glomerular basement membrane as a barrier preventing albuminuria. It is also hypothesized that agrin functions at the surface of activated T-lymphocytes as a part of the recognition process between antigen-presenting-lymphocytes and responding T cells.


Interaction of ionizing radiation with topotecan in two human tumor cell lines.
The effect of topotecan, a topoisomerase I inhibitor, on ionizing radiation-induced cytotoxicity was studied in 2 human tumor cell lines characterized by a different expression of the target enzyme. The cytotoxicity of topotecan alone or in combination with radiation was assessed in exponentially growing non-small-cell lung cancer (H460) and glioblastoma (GBM) cells using the colony-forming assay. An isobologram method was used to evaluate the treatment interaction. An apparent supra-additive effect in cell killing following drug-radiation-combined treatment was observed only in GBM cells exposed to topotecan for 24 hr. In the case of H460 cells, interaction varied from a strong infra-additive effect at low radiation doses to a slight supra-additive effect when cells were exposed to radiation doses greater than 3 Gy. Northern blot analysis indicated that topoisomerase I expression in H460 cells was 8-fold higher than that of GBM cells. Although the H460 cell line exhibited an increased sensitivity to topotecan, only in the GBM cell line (which expressed a lower level of topoisomerase I) did the drug potentiate the radiation cytotoxicity. The observation that the radiosensitization by topotecan was related to topoisomerase I level is consistent with a putative role of the enzyme in processes involved in the repair of radiation damage. It is conceivable that the modulation of enzyme function results in an effective reduction of cellular capability for repair of radiation damage only if the enzyme is not over-expressed. Although a precise role of topoisomerase I in the cellular response to ionizing radiations (in particular, in DNA repair) remains to be documented, such results suggest the potential interest of topoisomerase I inhibitors in combination with radiation therapy for tumors expressing low topoisomerase I levels.


Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ.
Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.


Parallel G-quadruplex-specific fluorescent probe for monitoring DNA structural changes and label-free detection of potassium ion.
Here we demonstrate an anionic porphyrin, protoporphyrin IX (PPIX), as a parallel G-quadruplex-specific fluorescent probe for monitoring DNA structural changes and utilize it to develop a DNA-based K(+) sensor. The interactions of PPIX with different DNA structures in K(+) or Na(+) solution are investigated by using circular dichroism, fluorescence, and UV-vis spectroscopy. The observations reveal that PPIX has an ∼100-fold selectivity for parallel G-quadruplexes against duplexes and antiparallel G-quadruplexes. Meanwhile, the fluorescence intensity of PPIX increases by over 10-fold upon binding to parallel G-quadruplexes. On the basis of the selectivity and fluorescence property of PPIX, we introduce a facile, label-free approach to monitoring DNA structural changes via fluorescence signal readout that is tuned by PPIX binding and release. To illustrate it, we utilize PPIX and a G-rich DNA PS2.M to construct a fluorescent K(+) sensor based on an antiparallel-to-parallel conformation transition of the G-quadruplex. PS2.M adopts an antiparallel quadruplex structure in Na(+) solution, whereas it gradually converts into a parallel G-quadruplex upon addition of increasing K(+). This conformational change is indicated by a sharp increase in the fluorescence intensity of PPIX, owing to the good ability of PPIX to discriminate parallel G-quadruplexes from antiparallel ones. Even in the presence of 100 mM Na(+), such a "turn-on" fluorescent sensor can respond to low concentrations of K(+), with a limit of detection (0.5 mM) for K(+) analysis. In addition, this sensor exhibits a high selectivity for K(+) over other common metal ions, which ensures its practical applications to real samples. These results reveal that PPIX is promising for use as a specific DNA structural probe in sensing applications.


Vitrifying immature equine oocytes impairs their ability to correctly align the chromosomes on the MII spindle.
Vitrified-warmed immature equine oocytes are able to complete the first meiotic division, but their subsequent developmental competence is compromised. Therefore, the present study investigated the effects of vitrifying immature horse oocytes on the chromosome and spindle configuration after IVM. Cumulus-oocytes complexes (COCs) were collected and divided into two groups based on mare age (young ≤14 years; old ≥16 years). COCs were then either directly matured invitro or vitrified and warmed before IVM. Spindle morphology and chromosome alignment within MII stage oocytes were assessed using immunofluorescent staining, confocal microscopy and three-dimensional image analysis. Vitrification reduced the ability of oocytes to reach MII and resulted in ultrastructural changes to the meiotic spindle, including shortening of its long axis, and an increased incidence of chromosomes failing to align properly at the metaphase plate. We hypothesise that aberrant chromosome alignment is an important contributor to the reduced developmental competence of vitrified equine oocytes. Contrary to expectation, oocytes from young mares were more severely affected than oocytes from older mares; we propose that the reduced effect of vitrification on oocytes from older mares is related to pre-existing compromise of spindle assembly checkpoint control mechanisms in these mares.


Lactate consumption mediates repeated high-intensity interval exercise-enhanced executive function in adult males.
Lactate is a principal energy substrate for the brain during exercise. A single bout of high-intensity interval exercise (HIIE) can increase the blood lactate level, brain lactate uptake, and executive function (EF). However, repeated HIIE can attenuate exercise-induced increases in lactate level and EF. The lactate levels in the brain and blood are reported to be correlated with exercise-enhanced EF. However, research is yet to explain the cause-and-effect relationship between lactate and EF. This study examined whether lactate consumption improves the attenuated exerciseenhanced EF caused by repeated HIIE. Eleven healthy men performed two sets of HIIE, and after each set, 30 min were given for rest and examination. In the 2nd set, the subjects consumed experimental beverages containing (n = 6) and not containing (n = 5) lactate. Blood, cardiovascular, and psychological variables were measured, and EF was evaluated by the computerized color-word Stroop test. The lactate group had a higher EF (P < 0.05) and tended to have a higher blood lactate level (P = 0.082) than the control group in the 2nd set of HIIE. Moreover, blood lactate concentration was correlated with the interference score (i.e., reverse score of EF) (r = -0.394; P < 0.05). Our results suggest that the attenuated exercise-enhanced EF after repeated HIIE can be improved through lactate consumption. However, the role of lactate needs to be elucidated in future studies, as it can be used for improving athletes' performance and also in cognitive decline-related clinical studies.


Allogeneic SCT for relapsed composite and transformed lymphoma using related and unrelated donors: long-term results.
Outcome is poor with conventional therapy for relapsed transformed non-Hodgkin's lymphoma (NHL). Autologous SCT has been successfully employed; however the impact of allogeneic SCT has not been well defined. We therefore studied 40 consecutive patients who received allogeneic SCT for relapsed composite and transformed NHL (25 transformed, 8 composite (same site) and 7 discordant (different sites)) with related (n=25) and unrelated donors (n=15) to evaluate long-term outcome. Conditioning was myeloablative in the majority (39 of 40). Of 40 patients, 11 survive with median follow-up of 25 months. Death occurred in similar proportions due to relapsed NHL (n=14) or treatment-related complications (transplant-related mortality, TRM; n=15). The cumulative incidence of TRM was 36% at 3 years and disease relapse was 42% at 5 years. Probability of 2- and 5-year event-free survival is 36 and 23% with overall survival 39 and 23%. Performance of SCT within 1 year of NHL diagnosis predicted improved outcome. Relapse and TRM remain significant problems in this setting, indicating the need for strategies whereby patients at high risk of transformation should be selected for early SCT, ideally before their actual transformation.


Capitation pricing: adjusting for prior utilization and physician discretion.
As the number of Medicare beneficiaries receiving care under at-risk capitation arrangements increases, the method for setting payment rates will come under increasing scrutiny. A number of modifications to the current adjusted average per capita cost (AAPCC) methodology have been proposed, including an adjustment for prior utilization. In this article, we propose use of a utilization adjustment that includes only hospitalizations involving low or moderate physician discretion in the decision to hospitalize. This modification avoids discrimination against capitated systems that prevent certain discretionary admissions. The model also explains more of the variance in per capita expenditures than does the current AAPCC.


Styrene-Based Elastomer Composites with Functionalized Graphene Oxide and Silica Nanofiber Fillers: Mechanical and Thermal Conductivity Properties.
The mechanical and thermal conductivity properties of two composite elastomers were studied. Styrene-butadiene rubber (SBR) filled with functionalized graphene oxide (GO) and silica nanofibers, and styrene-butadiene-styrene (SBS) block copolymers filled with graphene oxide. For the SBR composites, GO fillers with two different surface functionalities were synthesized (cysteamine and dodecylamine) and dispersed in the SBR using mechanical and liquid mixing techniques. The hydrophilic cysteamine-based GO fillers were dispersed in the SBR by mechanical mixing, whereas the hydrophobic dodecylamine-based GO fillers were dispersed in the SBR by liquid mixing. Silica nanofibers (SnFs) were fabricated by electrospinning a sol-gel precursor solution. The surface chemistry of the functionalized fillers was studied in detail. The properties of the composites and the synergistic improvements between the GO and SnFs are presented. For the SBS composites, GO fillers were dispersed in the SBS elastomer at several weight percent loadings using liquid mixing. Characterization of the filler material and the composite elastomers was performed using x-ray photoelectron spectroscopy, x-ray diffraction, transmission electron microscopy, scanning electron microscopy, thermogravimetric analysis, dynamic mechanical analysis, tensile testing, nanoindentation, thermal conductivity and abrasion testing.


Comparative neurotransmitter reuptake and anticholinergic potencies of the 8-hydroxy metabolites of clomipramine.
We hypothesize that 8-hydroxy-clomipramine (8-OH-CMI), the major hydroxy metabolite of clomipramine (CMI), may have antidepressant properties with less anticholinergic potency than CMI. We compared the potencies of 8-OH-CMI and CMI for inhibition of serotonin and norepinephrine reuptake and the potencies of these compounds for blockade of muscarinic receptors. We also compared the antimuscarinic potencies of desmethylclomipramine (DCMI) and 8-hydroxy-desmethylclomipramine (8-OH-DCMI). We found that 8-OH-CMI inhibits the uptake of serotonin and norepinephrine to the same extent as CMI and that 8-OH-CMI has far less antimuscarinic potency than CMI. We also found that 8-OH-DCMI has about one-tenth the antimuscarinic potency of DCMI. Since the therapeutic efficacy of CMI may be related to its effect on the reuptake of neurotransmitters, and since the extent of clinical anticholinergic effects of tricyclic antidepressants has been shown to be related to their in vitro antimuscarinic potencies, these results raise the possibility that 8-OH-CMI may be an analogue of CMI with fewer anticholinergic side effects than the parent compound.


In vitro assembly of a functional nucleocapsid from the negative-stranded genome RNA of a defective interfering particle of vesicular stomatitis virus.
The template for transcription and replication of negative-stranded RNA viruses is a ribonucleoprotein structure, the nucleocapsid. We have developed a system that supports assembly of the negative-stranded RNA genome of a defective interfering (DI) particle of vesicular stomatitis virus (VSV) into a nucleocapsid in vitro. This system uses extracts from wild-type VSV-infected cells as a source of proteins to encapsidate the RNA. In vitro assembled nucleocapsids were compared to in vivo-derived nucleocapsids by the following characteristics: nuclease resistance of the encapsidated RNA, CsCl density banding of labeled RNA in a position coincident with nucleocapsids, correct sedimentation rate in sucrose gradients, the presence of the nucleocapsid protein on the nucleocapsids, and the infectivity of the in vitro assembled nucleocapsids. We conclude that the system we present is capable of assembling the isolated genome of a rhabdovirus DI particle into nucleocapsids indistinguishable from those produced during the course of intracellular DI replication.


Influence of propylthiouracil and methimazole pre-treatment on the outcome of iodine-131 therapy in hyperthyroid patients with Graves' disease.
There is ongoing controversy about potential differences in the influence of the anti-thyroid drugs propylthiouracil (PTU) and methimazole (MMI) on radioiodine treatment of Graves' hyperthyroidism. This retrospective study investigated the influence of PTU and MMI pre-treatment, individually or sequentially, on the outcome of iodine-131 ((131)I) therapy in 199 patients with Graves' disease who had been treated with (131)I for the first time and followed up at 3 and 6 months after treatment. Pre-treatment with PTU, or sequential PTU and MMI pre-treatment, increased the failure rate of (131)I therapy and reduced the rate of hypothyroidism. MMI pre-treatment alone had no significant influence on the results of (131)I therapy. Logistic regression analyses indicated that PTU pre-treatment and having a thyroid gland of > 60 g were both significantly related to (131)I therapy failure.


Chromosomal DNA from both flagellate and non-flagellate Bordetella species contains sequences homologous to the Salmonella H1 flagellin gene.
The genus Bordetella contains four species: two are non-motile, the human pathogens B. pertussis and B. parapertussis; and two are motile, the broad host-range mammalian pathogen B. bronchiseptica, and the avian pathogen B. avium. The motility of the latter two species is due to peritrichous flagella. Here we show that strains of all four species contain DNA sequences homologous to flagellin genes. Two types of gene probe were hybridised to Bordetella chromosomal DNa in Southern blots: the structural gene for H1 flagellin of Salmonella typhimurium and an oligonucleotide derived from the conserved N-terminal amino acid sequences of various flagellin proteins. ClaI-digested DNa from all four Bordetella species hybridised with both probes in Southern blots, although each species gave a characteristic pattern of hybridisation. This indicates that the non-motile B. pertussis and B. parapertussis species contain non-expressed flagellin genes.


Respiratory effects of clonidine alone and combined with morphine, in humans.
Because only limited and controversial data exist concerning the respiratory effects of clonidine in humans, the authors evaluated the respiratory effects of clonidine alone and in combination with morphine, in 12 healthy adult males. Subjects received clonidine (0.3-0.4 mg orally), morphine (0.21 mg/kg intramuscularly), or the same doses of the two drugs combined, at three separate sessions in a randomized fashion. The study was balanced for all possible sequences of drug administration. Blood pressure, heart rate, hemoglobin oxygen saturation via finger pulse oximetry, and ventilatory and occlusion pressure responses to CO2 were obtained before and 20, 40, 60, 90, 120, 180, 240, 300, and 360 min after administration of drug or drug combination. Systolic blood pressure decreased significantly only in the clonidine and clonidine plus morphine groups (P less than 0.05). Hemoglobin oxygen saturation decreased by a statistically significant (P less than 0.05), though clinically minor, degree only in the morphine or morphine plus clonidine groups. Clonidine alone did not depress the slope of either the ventilatory or the occlusion pressure response to CO2. In addition, clonidine did not significantly worsen morphine-induced depression of the slope of the ventilatory and occlusion pressure responses in the drug combination group. Both the ventilatory and occlusion pressure responses to CO2 were shifted to the right in all three drug groups (P less than 0.05) but were shifted to a significantly lesser degree by clonidine alone than by morphine and morphine plus clonidine. In healthy young adult males, clonidine alone produces little respiratory depression and does not significantly potentiate morphine-induced respiratory depression.


Evaluation of Human Corneal Lenticule Quality After SMILE With Different Cap Thicknesses Using Scanning Electron Microscopy.
To evaluate the surface characteristics of lenticules created by small-incision lenticule extraction (SMILE) with different cap thicknesses. This prospective study included 20 consecutive patients who underwent bilateral SMILE. Surface regularity of the extracted corneal lenticule was analyzed using scanning electron microscopy (SEM) combined with 2 methods: qualitative and quantitative regularity. Qualitative regularity of SEM images was graded by masked observers using an established scoring system. Quantitative regularity of SEM images was assessed by counting the total number and areas of tissue bridges using Image-Pro Plus software. Four different cap thickness of 120, 130, 140, and 150 μm were compared. Refractive outcomes of patients were measured at baseline and 1 month after surgery. As 10 specimens were not analyzable, only 30 eyes were included. Postoperatively, all eyes had postoperative uncorrected distance visual acuity of 20/20 or better; 43% had an unchanged corrected distance visual acuity; 43% gained 1 line; 10% lost 1 line. Ultrastructurally, surface irregularity was primarily caused by tissue bridges. The average surface regularity score obtained was 10.87 ± 2.40 for 120 μm, 10.78 ± 2.60 for 130 μm, 8.76 ± 2.16 for 140 μm, and 8.70 ± 2.66 for 150 μm (P < 0.001). The total number and areas of tissue bridges of 120 to 130 μm were significantly less than 140 to 150 μm (P < 0.05). Surface regularity decreased as cap thickness increased (P < 0.05). There is smoother appearance of the lenticular surface as seen through SEM when a thin cap is created compared with a thick cap qualitatively and quantitatively.


A Strange Twist.
A 16-year-old female presented to the emergency department with acute onset of right lower quadrant abdominal pain for several hours. The patient was afebrile and physical examination was notable for isolated tenderness in the right lower quadrant. Ultrasound and computed tomography demonstrated an adnexal cystic structure. Pelvic magnetic resonance imaging was ordered to better characterize the pathology. Isolated fallopian tube torsion is an uncommon entity requiring prompt surgical intervention. Recognition and appropriate management are essential.


[The history of the Confederation of historians of medicine].
The article deals with a brief essay of history and actual state of activities of the Confederation of historians of medicine which before Perestroika was named the All-Union history medical society.


Volume threshold for micturition. Influence of filling rate on sensory and motor bladder function.
Filling at physiological rates (natural filling) is the specific stimulus for activation of the micturition reflex. In urodynamic studies this has rarely been taken into consideration. In the vast majority of clinical urodynamic studies 50 ml/min has been the preferred filling rate. A comparative study in 17 healthy volunteers of cystometry at 50 and 100 ml/min (CMG) and ambulatory monitoring (AM) during natural filling has been performed by other authors (3). It was found that CMG increases volume threshold for micturition, impairs detrusor contractility and has lower sensitivity for detecting spontaneous phasic detrusor activity. These results are discussed in the present article. The nearest explanation is at the cellular level. Filling rates above physiological range (> 15 HD (Hour-Diuresis units)) are a mechanical trauma to receptors, nerve endings, cells and cell junctions, which are temporarily functionally disturbed.


Plasma Levels of Macrophage Migration Inhibitory Factor and d-Dopachrome Tautomerase Show a Highly Specific Profile in Early Life.
Macrophage migration inhibitory factor (MIF) is a pleiotropic, constitutively expressed, pro-inflammatory cytokine and an important regulator of immune responses. d-dopachrome tautomerase (DDT), a newly described member of the MIF protein superfamily, shares sequence homology and biological activities with MIF. We recently reported that high expression levels of MIF sustain innate immune responses in newborns. Here, we elected to further characterize age-dependent MIF expression and to define whether DDT shares a similar expression profile with MIF. Therefore, we delineated the circulating concentrations of MIF and DDT throughout life using a large cohort of 307 subjects including fetuses, newborns, infants, children, and adults. Compared to levels measured in healthy adults (median: 5.7 ng/ml for MIF and 16.8 ng/ml for DDT), MIF and DDT plasma concentrations were higher in fetuses (median: 48.9 and 29.6 ng/ml), increased further at birth (median: 82.6 and 52.0 ng/ml), reached strikingly elevated levels on postnatal day 4 (median: 109.5 and 121.6 ng/ml), and decreased to adult levels during the first months of life. A strong correlation was observed between MIF and DDT concentrations in all age groups (R = 0.91, P < 0.0001). MIF and DDT levels correlated with concentrations of vascular endothelial growth factor, a protein upregulated under low oxygen tension and implicated in vascular and lung development (R = 0.70, P < 0.0001 for MIF and R = 0.65, P < 0.0001 for DDT). In very preterm infants, lower levels of MIF and DDT on postnatal day 6 were associated with an increased risk of developing bronchopulmonary dysplasia and late-onset neonatal sepsis. Thus, MIF and DDT plasma levels show a highly specific developmental profile in early life, supporting an important role for these cytokines during the neonatal period.


[Surgical treatment of instable per- and subtrochanteric femure fractures with the 130 degrees double-T-plate. Clinico-experimental report].
1. Operative treatment of instable inter- and subtrochanteric fractures with a new 130 degrees double-T plate allowed, in spite of high-risk patients (age mean = 85 years, multimorbidity approximately 92%), full maximum stress by the third day after the operation and a shorter time of hospitalisation of 22.5 days. Lethality was 12.2%. - 2. Load experiments showed that the double-T-profiled 130 degrees plate with increased lateral moment of resistance could support a weight five times greater than that supported by 130 degrees implants with transversal blades, and had a resistance to bending two-and-a-half times greater than hip compression screws. In an 'intertrochanteric' position the plate could carry 3000 N and in a 'subtrochanteric' position 1000 N without permanent deformity. - 3. A review was carried out in 62.6% of the patients 6-32 months after double-T-plate osteosynthesis. Acceptable results were revealed in 80.7%. Of the 98 patients reviewed 44% had complete freedom of movement, 34.6% walked with a stick, 15.4% required crutches and 6% were unable to walk.


Effects of monoclonal antibody against CD45RB on peripheral blood mononuclear cell proliferation and on HLA-DR and adhesion molecule expression on thyrocytes of patients with autoimmune thyroid disease.
To evaluate the role of CD45 (especially that of the ectodomain region B) on immunocyte-thyrocyte signaling in patients with autoimmune thyroid disease (AITD), we have examined the in vitro and in vivo effects of a monoclonal antibody (mAb) against with CD45RB, termed MT3. MT3 was added to cultured peripheral blood mononuclear cells (PBMC) from patients with AITD and was additionally injected into severe combined immunodeficient (SCID) mice to which Graves' thyroid cells and intrathyroidal lymphocytes were engrafted. MT3 stimulated proliferation of PBMC when cultured for 2 to 3 days in patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD) and in normal controls (NC). However, when cultured for 7 days, the stimulation index [SI: counts per minute (cpm) with mAb/cpm without mAb] was lowered by MT3 in NC and GD patients. However, the mean SI was not lowered in patients with HT. In SCID mice, the concentrations of human immunoglobulin G, antithyroglobulin and antithyroperoxidase antibodies in sera were not significantly changed by injecting MT3. The expression of human leukocyte antigen (HLA)-DR and intercellular adhesion molecule (ICAM)-1 on engrafted human thyrocytes decreased after the tissues were engrafted into the control mice to which vehicle alone was injected. However, in the mice injected with MT3, HLA-DR and ICAM-1 expression remained high or up-regulated by the injection.(ABSTRACT TRUNCATED AT 250 WORDS)


Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic intermittent hypoxia in mice.
Chronic intermittent hypoxia (CIH) increases sympathetic tone and respiratory instability. Our previous work showed that chronic hypoxia induces the oxygen-sensing enzyme heme oxygenase-1 (HO-1) within the C1 sympathoexcitatory region and the pre-Bötzinger complex (pre-BötC). We therefore examined the effect of CIH on time course of induced expression of HO-1 within these regions and determined whether the induction of HO-1 correlated with changes in respiratory, sigh frequency, and sympathetic responses (spectral analysis of heart rate) to acute hypoxia (10% O2) during 10 days of exposure to CIH in chronically instrumented awake wild-type (WT) and HO-1 null mice (HO-1-/-). HO-1 was induced within the C1 and pre-BötC regions after 1 day of CIH. There were no significant differences in the baseline respiratory parameters between WT and HO-1-/- Prior to CIH, acute hypoxia increased respiratory frequency in both WT and HO-1-/-; however, minute diaphragm electromyogram activity increased in WT but not HO-1-/- The hypoxic respiratory response after 1 and 10 days of CIH was restored in HO-1-/- CIH resulted in an initial significant decline in 1) the hypoxic sigh frequency response, which was restored in WT but not HO-1-/-, and 2) the baseline sympathetic activity in WT and HO-1-/-, which remained stable subsequently in WT but not in HO-1-/- We conclude that 1) CIH induces expression of HO-1 in the C1 and pre-BötC regions within 1 day and 2) HO-1 is necessary for hypoxia respiratory response and contributes to the maintenance of the hypoxic sigh responses and baseline sympathetic activity during CIH.


Sleep Disturbances in Newborns.
The purpose of this review is to serve as an introduction to understanding sleep in the fetus, the preterm neonate and the term neonate. Sleep appears to have numerous important roles, particularly in the consolidation of new information. The sleep cycle changes over time, neonates spend the most time in active sleep and have a progressive shortening of active sleep and lengthening of quiet sleep. Additionally, the sleep cycle is disrupted by many things including disease state and environment, and the amplitude integrated EEG can be a useful tool in evaluating sleep, and sleep disturbances, in neonates. Finally, there are protective factors for infant sleep that are still being studied.


[Studies on the pathogenesis of congenital hypoplastic anemia (Diamond-Blackfan syndrome)].
CFU-E growth from fractionated bone marrow cells of five patients with Diamond Blackfan syndrome was studied. In all patients, CFU-E growth was reduced in mononuclear cell rich fraction. In two patients out of five, CFU-E growth was returned to normal by the depletion of E-rosette forming cells of monocytes from mononuclear cell rich fraction. In the patient whose CFU-E growth returned to normal by the depletion of E-rosette forming cells, cocultivation between bone marrow buffy coat cells and autologous bone marrow E-rosette forming cells resulted in a significant decrease of CFU-E growth, and there was a significant increase in CFU-E growth by the treatment of OKT 4. In other three patients out of five, there was no significant increase in CFU-E growth by the depletion of monocytes and/or E-rosette forming cells. It is concluded that immunologic causes such as cellular factors may play a role, at least in part, on the pathogenesis of Diamond-Blackfan syndrome.