Laminins Regulate Placentation and Pre-eclampsia: Focus on Trophoblasts and Endothelial Cells.
Pre-eclampsia is a systemic vascular disease characterized by new-onset hypertension and/or proteinuria at ≥20 weeks of gestation and leads to high rates of maternal and perinatal morbidity and mortality. Despite the incomplete understanding of pre-eclampsia pathophysiology, it is accepted that insufficient spiral artery remodeling and endothelial dysfunction are major contributors. Laminins (LNs) are a vital family of extracellular matrix (ECM) molecules present in basement membranes that provide unique spatial and molecular information to regulate implantation and placentation. LNs interact with cell surface receptors to trigger intracellular signals that affect cellular behavior. This mini-review summarizes the role of LNs in placental development during normal pregnancy. Moreover, it describes how LN deficiency can lead to the pre-eclampsia, which is associated with trophoblast and vascular endothelial dysfunction. New research directions and the prospect of clinical diagnosis of LN deficiency are discussed, and the gaps in basic and clinical research in this field are highlighted.


Cancer and normal adipose-derived mesenchymal stem cells (ASCs): Do they have differential effects on tumor and immune cells?
Adipose-derived mesenchymal stem cells (ASCs) are known to have immunomodulatory properties through soluble factors or by direct cell-to-cell contact. This study aimed to assess the expression of HLA-G and IDO activity in breast cancer and normal ASCs and to see whether ASC is capable of modulating both tumor cells and immune system cells in vitro. ASCs were enzymatically isolated from 15 breast cancer patients and 10 normal individuals. Then they were cultured, and the impact of their conditioned media on the movement of the MDA-MB-231 breast cancer cell line was studied in wound healing scratch assay. Next, PBLs from the peripheral blood of normal individuals were separated and co-cultured with breast cancer and normal ASCs. PBLs proliferation and apoptosis were assessed using CFSE labeling dye and annexin V/7AAD staining, respectively. IDO activity and HLA-G protein expression in ASCs were examined using kynurenine assay and Western blotting, respectively. Tumor-derived ASCs, especially those from higher stages of breast cancer, have stronger effects on the proliferation and movement of MDA-MB-231 cells than normal ASCs (P-value < 0.05). Apoptosis in PBLs increased in the presence of ASCs compared to PBLs cultured alone (P-value < 0.05). In contrast, necrosis of PBLs decreased in the presence of ASCs compared to apoptosis in these cells (P-value < 0.001). Collectively, ASCs may have strategic effects on both tumor cells and cells of the immune system in the tumor microenvironment, resulting in tumor development, growth, and metastasis.


Assessment of Antimicrobial Properties of Phenolic Acid Extracts from Grain Infected with Fungi from the Genus Fusarium.
Problems related with biological contamination of plant origin raw materials have a considerable effect on prevention systems at each stage of food production. Concerning the antimicrobial action of phenolic acids, studies were undertaken to investigate antibacterial properties against bacterial strains of Escherichia coli (EC), Pseudomonas fluorescence (PF), Micrococcus luteus (ML) and Proteus mirabilis (PM), as well as antifungal properties targeting microscopic fungi Fusarium spp., extracts of phenolic compounds coming from inoculated grain from various genotypes of cereals. This study evaluated the antimicrobial action of phenolic acids extracts obtained from both naturally infested and inoculated with microorganisms. For this purpose a total of 24 cereal cultivars were selected, including 9 winter and 15 spring cultivars. The analyses showed a bactericidal effect in the case of 4 extracts against Micrococcus luteus (ML), 14 extracts against Pseudomonas fluorescence (PF), 17 extracts against Escherichia coli (EC) as well as 16 extracts against Proteus mirabilis (PM). It was found that 3 out of the 24 extracts showed no antibacterial activity. In turn, fungicidal action was observed in the case of 17 extracts against Fusarium culmorum (FC) (NIV), 16 extracts against FC (3AcDON), 12 extracts against Fusarium graminearum (FG) (3AcDON), while 12 other extracts showed antifungal action against FG (NIV) and 19 extracts against Fusarium langsethiae (FL). Based on the conducted analyses it was found that grain of small-grained cereals exposed to fungal infection is a source of bioactive compounds exhibiting antimicrobial properties. It was observed that the qualitative and quantitative profiles of polyphenols vary depending on the cereal cultivar. This extracts may be used to develop an antimicrobial preparation applicable in organic farming.


Bioactivation of aflatoxin B1 in the nasal and tracheal mucosa in swine.
Whole-body autoradiography of 3H-labeled aflatoxin B1 in young pigs showed a localization of bound label in the nasal olfactory and respiratory mucosa, in the tracheo-laryngeal mucosa, and in the conjunctiva, in addition to the liver. Whole-body and microautoradiography also showed a labeling of pigmented tissues, which can be ascribed to a melanin binding of AFB1. In vitro experiments with microsomal preparations of various tissues from sows revealed that the nasal respiratory and olfactory mucosa had the highest capacity to form DNA-bound aflatoxin B1-metabolites. The tracheal mucosa and the liver, in order, had lesser binding capacity. The lung was found to be devoid of aflatoxin B1-bioactivating capacity. In vitro microautoradiography revealed bound label in specific cell types in the nose and trachea and in some cells of the conjunctiva. A drastic decrease in the aflatoxin B1-DNA binding was observed when microsomal preparations of the nasal respiratory and olfactory mucosa were incubated in the presence of reduced glutathione, but without any addition of cytosolic glutathione-S-transferases. In incubations of liver microsomes under these conditions a somewhat lower inhibition of the aflatoxin B1-DNA binding was seen. Our results demonstrate that the nasal olfactory and respiratory mucosa and the tracheal mucosa have a higher capacity than the liver to bioactivate aflatoxin B1 in swine. Our data further show that microsomal-associated glutathione-S-transferases with a high capacity to catalyze the conjugation of the reactive aflatoxin B1-epoxide to reduced glutathione are present in the nasal olfactory and respiratory mucosa of swine.


Glial and neuronal glutamate transport following glutamine synthetase inhibition.
Glutamate transport into striatal tissue preparations was studied following inhibition of glutamine synthetase with methionine sulfoximine (MSO). Glutamate uptake in striatal tissue prisms was elevated for up to 7 days following an intraventricular (i.c.v.) injection of MSO. Kinetic analysis of glutamate uptake revealed that a high- and a low-affinity carrier system mediated the transport of glutamate into tissue slices. MSO altered the transport of glutamate via the high-affinity carrier without changing the characteristics of low-affinity glutamate transport. MSO increased the Km for glutamate and the Vmax at the high-affinity uptake site. The changes in the Km and the Vmax for glutamate uptake were maximal 24 hr after administration of MSO, but the transport system returned to normal by 14 days after injection. In addition, MSO increased high-affinity aspartate uptake into tissue slices, but it was without effect on leucine uptake. Glutamate uptake into striatal synaptosomes and bulk-isolated glial cells or neurons was, in all cases, mediated by a low- and high-affinity carrier. The Km and Vmax values for high-affinity glial-glutamate uptake were increased 24 hr after i.c.v. injection of MSO, while the low-affinity kinetic parameters for glial glutamate uptake were not altered by MSO. Neither high-affinity nor low-affinity glutamate uptake into bulk-isolated neurons or synaptosomes was altered by MSO 24 hr after injection. These results suggest that MSO induced alterations in glutamate transport within striatal slices may be due to changes in glial glutamate transport arising from the disruption of glutamate metabolism.


Lymphotropic HCV strain can infect human primary naïve CD4+ cells and affect their proliferation and IFN-γ secretion activity.
Lymphotropic hepatitis C virus (HCV) infection of B and T cells might play an important role in the pathogenesis of hepatitis C. Recently, we showed that a lymphotropic HCV (SB strain) could infect established T-cell lines and B-cell lines. However, whether HCV replication interferes with cell proliferation and function in primary T lymphocytes is still unclear. The aim of this study was to analyze whether HCV replication in primary T lymphocytes affected their development, proliferation, and Th1 commitment. SB strain cell culture supernatant (2 × 10(4) copies/ml HCV) was used to infect several kinds of primary lymphocyte subsets. Mock, UV-irradiated SB-HCV, JFH-1 strain, and JFH-1 NS5B mutant, which could not replicate in T cells, were included as negative controls. Carboxyfluorescein succinimidyl ester (CFSE) and CD45RA double staining was used to evaluate the proliferative activity of CD4(+)CD45RA(+)CD45RO(-) naïve CD4(+) cells. Interferon (IFN)-γ and interleukin (IL)-10 secretion assays magnetic cell sorting (MACS) were carried out. Negative strand HCV RNA was detected in CD4(+), CD14(+), and CD19(+) cells. Among CD4(+) cells, CD4(+)CD45RA(+)RO(-) cells (naïve CD4(+) cells) were most susceptible to replication of the SB strain. The levels of CFSE and CD45RA expression gradually declined during cell division in uninfected cells, while HCV-infected naïve CD4(+) cells expressed higher levels of CFSE and CD45RA than Mock or UV-SB infected naïve CD4(+) cells. Moreover, the production of IFN-γ was significantly suppressed in SB-infected naïve CD4(+) cells. Lymphotropic HCV replication suppressed proliferation and development, including that towards Th1 commitment, in human primary naïve CD4(+) cells.


Visual event-related potentials to biological motion stimuli in autism spectrum disorders.
Atypical visual processing of biological motion contributes to social impairments in autism spectrum disorders (ASD). However, the exact temporal sequence of deficits of cortical biological motion processing in ASD has not been studied to date. We used 64-channel electroencephalography to study event-related potentials associated with human motion perception in 17 children and adolescents with ASD and 21 typical controls. A spatio-temporal source analysis was performed to assess the brain structures involved in these processes. We expected altered activity already during early stimulus processing and reduced activity during subsequent biological motion specific processes in ASD. In response to both, random and biological motion, the P100 amplitude was decreased suggesting unspecific deficits in visual processing, and the occipito-temporal N200 showed atypical lateralization in ASD suggesting altered hemispheric specialization. A slow positive deflection after 400 ms, reflecting top-down processes, and human motion-specific dipole activation differed slightly between groups, with reduced and more diffuse activation in the ASD-group. The latter could be an indicator of a disrupted neuronal network for biological motion processing in ADS. Furthermore, early visual processing (P100) seems to be correlated to biological motion-specific activation. This emphasizes the relevance of early sensory processing for higher order processing deficits in ASD.


Nasal cavity reirradiation: a challenging case for comparison between proton therapy and volumetric modulated arc therapy.
The aim of this case report is to report on a dosimetric comparison between volumetric modulated arc therapy (RapidArc technique and active scanning proton therapy (single-field (SFO) and multifield (MFO) techniques) in a case of nasal cavity cancer recurrence. A 72-year-old man, who received adjuvant radiotherapy for a carcinoma of the nasal cavity, experienced an unresectable local recurrence in the previous surgical bed. Hence, the patient was evaluated for reirradiation by comparing different modalities, with a total prescribed dose of 50 Gy in standard fractionation. RA plan was revealed to be equivalent to the MFO plan in terms of target dose coverage and conformity index. SFO plan was not able to respect a maximum dose of 9 Gy to nervous structures, in contrast to RA and MFO plans. In this challenging scenario, although a clear preference would be given to the MFO proton plan, the RA plan was revealed to be adequate for the clinical goal of target coverage and sparing of organs at risk.


Soluble CD23 and other receptors (CD4, CD8, CD25, CD71) in serum of patients with chronic lymphocytic leukemia.
We measured the soluble (s) receptors CD23, CD8, CD4, interleukin-2 receptor (IL-2R, CD25), and transferrin receptor (TfR, CD71), in normal serum and in patients with chronic lymphocytic leukemia (CLL) and evaluated them in relation to clinical and biological parameters of the disease, as well as serum immunoglobulin E (IgE). Compared to 31 normal individuals, 42 CLL patients had increased levels of sCD23 (98.4 +/- 127.7 versus 0.9 +/- 0.3 U/ml, p < 0.001), sIL-2R (6080 +/- 7030 versus 1420 +/- 640 pg/ml, p < 0.001), sTfR (12,100 +/- 11,250 versus 5000 +/- 1050 ng/ml, p < 0.001), and sCD8 (510 +/- 191 versus 234 +/- 89 U/ml, p < 0.001), but normal sCD4 levels. Mean sCD23 levels remained normal in patients with non-Hodgkin's lymphoma (other than small lymphocytic), Hodgkin's disease, hairy cell leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), multiple myeloma, or solid tumors. Advancing Rai clinical stage was associated with a progressive elevation of sCD23 (p < 0.001), while sCD8 (p < 0.05), sIL-2R (p < 0.001), and sTfR (p < 0.005) were highest in stage 2 patients. Discriminant analysis confirmed the value of soluble receptor determinations in the clinical evaluation of CLL patients. sCD23 correlated with sIL-2R (p < 0.001) and sTfR (p < 0.05) but not with sCD4 or sCD8, and displayed an inverse relationship with serum IgE (NS) and total gamma-globulin (p < 0.05). sIL-2R correlated with sCD23 (p < 0.001), sTfR (p < 0.001), sCD4 (p < 0.01), and sCD8 (p < 0.01). The lymphocyte count correlated with serum lactate dehydrogenase (LDH) (p < 0.05), sCD23 (p < 0.001) and sIL-2R (p < 0.01) but not sTfR, sCD8, or sCD4. Chemotherapy produced consistent reductions of sCD23 levels in two responding patients. We conclude that: (i) sCD23 is considerably elevated in CLL, correlates with the tumor mass and clinical stage, and could be helpful in monitoring these patients; and (ii) sIL-2R, sCD8, and sTfR levels are less specifically increased and could be influenced by other factors such as immune activation and erythropoiesis.


GAP-43 Immunoreactivity in the brain of the developing and adult wallaby ( Macropus eugenii).
We have examined the distribution of immunoreactivity for GAP-43 in the developing and adult brain of a diprotodontid metatherian, the tammar wallaby ( Macropus eugenii). The distribution of GAP-43 immunoreactivity in the neonatal wallaby brain was strikingly heterogeneous, in contrast to that reported for the newborn polyprotodontid opossum. Immunoreactivity for GAP-43 in the developing wallaby brain showed a caudal-to-rostral spatiotemporal gradient, with the brainstem well in advance of the telencephalon throughout the first 100 days of postnatal life. In many regions examined, GAP-43 immunoreactivity passed through the following phases: 1. intense immunoreactivity in developing fiber tracts and occasional somata; 2. diffuse homogeneous immunoreactivity; 3. selective loss of immunoreactivity in particular nuclei or cortical regions. In the isocortex, selective loss of GAP-43 immunoreactivity in the somatosensory and visual cortex (at postnatal day 115) coincided with the maturation of the laminar distribution of terminal thalamocortical axonal fields. Within adult cortical regions, GAP-43 immunoreactivity was highest in layer I of all regions, lower layers (V and VI) of primary somatosensory and visual cortices, layers II/III of motor and cingulate cortex, and layer IV of entorhinal cortex. Our findings suggest that, while patterning of GAP-43 immunoreactivity in the mature brain is similar across meta- and eutheria, there may be early developmental differences in the distribution of GAP-43 immunoreactivity between poly- and diprotodontid metatheria.


In vivo gene therapy of ovarian cancer by adenovirus-mediated thymidine kinase gene transduction and ganciclovir administration.
Efficacy and toxicity of adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene followed by administration of ganciclovir were studied in vivo. A human epithelial ovarian cancer animal model was established in nude mice using the serous ovarian adenocarcinoma cell line Ov-ca-2774. Intraperitoneal (ip) injection of 1 x 10(8) Ov-ca-2774 cells resulted in tumor growth and formation of malignant ascites in all 15 animals. In a prospective randomized experimental design mice were treated 1, 3, or 7 days after ip injection of 1 x 10(8) cells with ip injection of 2 x 10(8), 6.7 x 10(8), or 2 x 10(9) pfu ADV.RSV-TK followed by administration of ganciclovir (10 microgram /ml, ip, bid) for 6 consecutive days. End points were survival and toxicity. Mice treated with GCV or HSV-TK alone died from 14.4 +/- 1.7 to 19.5 +/- 3.5 days after treatment as did untreated controls. No toxicity of ADV.RSV-TK was found up to 2 x 10(9) pfu (2 x 10(11) particles). The mice with the highest tumor burden treated with the lowest viral dose lived significantly longer than controls (P < 0.05). Median survival in all other groups of mice treated with ADV.RSV-TK plus GCV was even longer (P < 0.01). Treatment benefit was dependent on ADV/RSV-TK dose and tumor burden. Adenovirus-mediated thymidine kinase gene therapy is a realistic approach to ovarian cancer treatment that warrants investigation in the clinical setting.


Restriction landmark cDNA scanning (RLCS): a novel cDNA display system using two-dimensional gel electrophoresis.
We have developed a new method, designated restriction landmark cDNA scanning (RLCS), which displays many cDNA species quantitatively and simultaneously as two-dimensional gel spots. In this method cDNA species of uniform length were prepared for each mRNA species using restriction enzymes. After the restriction enzyme sites were radiolabeled as landmarks, the labeled fragments were subjected to high resolution two-dimensional gel electrophoresis. In analyses of cDNA samples from adult mouse liver and brain (cerebral cortex, cerebellum and brain stem) we detected approximately 500 and >1000 discrete gel spots respectively of various intensities at a time. The spot patterns of the three brain regions were very similar, although not identical, but were quite different from the pattern for the liver. RNA blot hybridization analysis using several cloned spot DNAs as probes showed that differences in intensity of the spots among RLCS profiles correlated well with expression levels of the corresponding mRNA species in the brain regions. Because the spots and their intensities reflect distinct mRNA species and their expression level respectively, the RLCS is a novel cDNA display system which provides a great deal of information and should be useful for systematic documentation of differentially expressed genes.


How to choose the best control strategy? Mathematical models as a tool for pre-intervention evaluation on a macroparasitic disease.
During the last century, emerging diseases have increased in number, posing a severe threat for human health. Zoonoses, in particular, represent the 60% of emerging diseases, and are a big challenge for public health due to the complexity of their dynamics. Mathematical models, by allowing an a priori analysis of dynamic systems and the simulation of different scenarios at once, may represent an efficient tool for the determination of factors and phenomena involved in zoonotic infection cycles, but are often underexploited in public health. In this context, we developed a deterministic mathematical model to compare the efficacy of different intervention strategies aimed at reducing environmental contamination by macroparasites, using raccoons (Procyon lotor) and their zoonotic parasite Bayilsascaris procyonis as a model system. The three intervention strategies simulated are raccoon depopulation, anthelmintic treatment of raccoons and faeces removal. Our results show that all these strategies are able to eliminate the parasite egg population from the environment, but they are effective only above specific threshold coverages. Host removal and anthelmintic treatment showed the fastest results in eliminating the egg population, but anthelmintic treatment requires a higher effort to reach an effective result compared to host removal. Our simulations show that mathematical models can help to shed light on the dynamics of communicable infectious diseases, and give specific guidelines to contain B. procyonis environmental contamination in native, as well as in new, areas of parasite emergence. In particular, the present study highlights that identifying in advance the appropriate treatment coverage is fundamental to achieve the desired results, allowing for the implementation of cost- and time-effective intervention strategies.


Helminths: an unrecognised disease burden prevalent among migrants in the gastroenterology clinic.
To estimate the prevalence of, and implement a diagnostic strategy for, imported helminth infection in the gastroenterology clinic. A retrospective study of eosinophil count and probable tropical exposure (phase I) followed by a prospective study of parasitological investigation (phase II). Gastroenterology service of an inner London hospital. Adult patients newly attending general gastroenterology and inflammatory bowel disease clinics. In phase I, evidence of undiagnosed helminth infection was sought by analysing patient records for associations between eosinophil count and ethnicity. In phase II, a UK guideline for investigation of eosinophilia in migrants was implemented and diagnostic yield determined. In phase I, prevalence of eosinophilia was determined; in phase II, helminth prevalence and degree of eosinophilia before and after treatment were reported. Information on symptomatic response to treatment was recorded. Ethnicity was used as a proxy measure for tropical exposure. 426 new patients attended in a 12 month period. Eosinophilia was present in 27 (6.3%). 10/27 (37.0%) patients with eosinophilia were of African or Asian ethnicity whereas only 20% (85/426) of patients overall were from these ethnic groups (χ2=5.27, p=0.02). Following implementation of the protocol, 25/36 migrants with eosinophilia attended for parasitological investigations. Helminth infection was diagnosed in 10/25 (40%). Strongyloidiasis (six patients) and schistosomiasis (three patients) were the most common diagnoses. Median eosinophil count was 1.06×109/l in those with helminths and 0.58×109/l in those without (p=0.004). Eosinophil counts normalised in, and symptomatic improvement was reported by, most patients after treatment. Eosinophilia is associated with African or Asian ethnicity in an inner city gastroenterology service. This association is probably explained by imported helminths, which are prevalent in this setting, may be a cause of gastrointestinal symptoms and is easily diagnosed and treated by standard protocols.


Compulsory Licensing of Pharmaceuticals in High-Income Countries: A Comparative Analysis.
Policy Points Pharmaceutical trade organizations and media outlets in the United States regularly point to compulsory licensing-or even its threat-as the mechanism that peer countries use to control the price of prescription drugs. Our comparative analysis shows that compulsory licensing is not frequently employed in high-income countries outside the United States as a direct response to drug prices. When its use is threatened, a license is rarely issued and even less often does it lead to a price discount. Accordingly, compulsory licensing is unlikely to contribute to price discrepancies between the United States and other developed nations. In fact, of the 21 compulsory licensing petitions we identified outside the United States, over one-third were made by pharmaceutical companies themselves and only three were threatened by a government authority. Compulsory licensing is a practice whereby national authorities can license a third party to produce a patented product, such as a pharmaceutical drug, effectively enabling the production of a generic before the original patent expires. The policy was designed-and has historically been used-to improve access to essential medicines in low-income countries and during public health crises. Although it was not intended to impact drug prices directly, the threat of compulsory licensing may indeed contribute to lower drug prices in high-income countries outside the United States. Our study sought to determine the plausibility of this claim. We compiled a comprehensive database of compulsory licensing episodes in the United States and 17 comparator nations over the 20 years following the 2001 Doha Declaration, and we recorded the motivation and outcome of each instance. Our search began with publicly available reports compiled by organizations specializing in pharmaceutical intellectual property, expanded to a query of legal proceedings in Westlaw, and concluded with a comprehensive literature review on PubMed. This strategy yielded 45 unique episodes of compulsory licensing, 24 in the United States and 21 outside. A minority (24%) of petitions outside the United States were motivated by high prices, and in all countries, only three cases were clearly associated with a price discount. We found no evidence to suggest that compulsory licensing is either frequently threatened or successfully implemented by countries outside the United States to secure price discounts for the most expensive pharmaceuticals, those that are newly patented and just entering the market.


Abnormal distribution of sarcoglycan subcomplex in colonic smooth muscle cells of aganglionic bowel.
Hirschsprung's disease (HD) is a development disorder of the enteric nervous system in which the altered innervation explains the inability of the aganglionic segment to relax. Impairment of cytoskeleton in SMC of aganglionic bowel has been shown. Sarcoglycan subcomplex (SG) may support the development and maintenance of muscle cells. We examined the SG subunit expression in colonic aganglionic and ganglionic specimens obtained from patients with HD. Full-thickness bowel specimens were obtained from six patients with HD. Six normal colon specimens were used as controls. Immunofluorescent analysis and reverse transcriptase polymerase chain reaction evaluation were performed for alpha-, beta-, gamma-, delta- and epsilon-SG. In control colon, the indirect immunofluorescence showed a strong staining pattern of beta- gamma- delta- and epsilon-SG while a weak positivity of alpha-SG was recorded. In aganglionic bowel, immunofluorescence intensity values documented a significant lack of epsilon-SG while an enhanced alpha-SG, coupled to a loss of epsilon-SG, was recorded in ganglionic bowel in HD-affected patients. Our observations underscore the assumption that non-neuronal elements of the colon might play a key role in the pathogenesis of HD and loss of epsilon-SG might critically alter the cytoskeleton in the aganglionic bowel segment. Up-regulation of alpha-SG is probably an acquired phenomenon to reinforce the sarcolemma and to perform a forceful contraction in dilated ganglionic HD-affected colon, related to chronic pseudo-obstruction, contributing to the intestinal dysmotility that persists in 20% of patients after resection of the aganglionic bowel.


The curious case of the "inseparable child".
Streptococcal infections in children rarely lead to neuropsychiatric manifestations referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. The common sequelae include tics, Tourette's syndrome or obsessive-compulsive disorder. Rare presentations may include separation anxiety disorder, body dysmorphic disorder and attention deficit hyperactivity disorder. We present a case of a 10-year-old child that presented primarily with abrupt onset of separation anxiety without any other neuropsychiatric manifestations such as tics or obsessive-compulsive symptoms. Streptococcal infections may present with varied neuropsychiatric manifestations in the pediatric age group and one needs to be more vigilant in cases that have an abrupt onset and unusual presentation. A high index of suspicion is important to diagnose such cases and provide them with a timely treatment.


Patient perspectives in the development and use of long-acting antipsychotics in schizophrenia: focus on olanzapine long-acting injection.
Schizophrenia is a chronic mental disorder generally treated with antipsychotic medication. However, non-adherence and partial adherence to antipsychotic medication treatment is common and long-acting injectable "depot" preparations of antipsychotic medications have been used as an alternative to oral medication therapy for patients for whom adherence is a clinically significant problem, as well as for the sake of convenience and in response to patient preference. Olanzapine long-acting injection (OLAI) is a new treatment option and has been approved by several regulatory agencies for the treatment of schizophrenia. OLAI is a crystalline salt formulation of olanzapine and pamoic acid. Efficacy was established in 2 double-blind randomized clinical trials of OLAI for the treatment of acute schizophrenia and for the maintenance of response. The therapeutic OLAI dosages are 150 mg q2 weeks, 210 mg q2 weeks, 300 mg q2 weeks or q4 weeks, and 405 mg q4 weeks, administered by deep intramuscular gluteal injection with a 19-gauge needle. Injection volume ranges from 1 to 2.7 mL. OLAI has essentially the same general tolerability as that of oral olanzapine; however with the depot there is the additional risk of a post-injection delirium sedation syndrome occurring at a rate of 0.07% of injections, requiring a risk management plan that includes observing the patient for 3 hours post injection.


Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial.
This randomized, double-blind, placebo-controlled, dose-finding study assessed efficacy and safety of 1, 5, and 15 mg/h intravenous clazosentan, an endothelin receptor antagonist, in preventing vasospasm after aneurysmal subarachnoid hemorrhage. Patients (n=413) were randomized to placebo or clazosentan beginning within 56 hours and continued up to 14 days after initiation of treatment. The primary end point was moderate or severe angiographic vasospasm based on centrally read, blinded evaluation of digital subtraction angiography at baseline and 7 to 11 days postsubarachnoid hemorrhage. A morbidity/mortality end point, including all-cause mortality, new cerebral infarct from any cause, delayed ischemic neurological deficit due to vasospasm, or use of rescue therapy, was evaluated by local assessment. Clinical outcome was assessed by the extended Glasgow Outcome Scale at 12 weeks. Moderate or severe vasospasm was reduced in a dose-dependent fashion from 66% in the placebo group to 23% in the 15 mg/h clazosentan group (risk reduction, 65%; 95% CI, 47% to 78%; P<0.0001). No significant effects were seen on secondary end points. Post hoc analysis using a centrally assessed morbidity/mortality end point that included death and rescue therapy but only cerebral infarcts and delayed ischemic neurological deficit due to vasospasm on central review showed a trend toward improvement with clazosentan (37%, 28%, and 29% in the 1, 5, and 15 mg/h groups versus 39% in the placebo group, nonsignificant). Clazosentan was associated with increased rates of pulmonary complications, hypotension, and anemia. Clazosentan significantly decreased moderate and severe vasospasm in a dose-dependent manner and showed a trend for reduction in vasospasm-related morbidity/mortality in patients with aneurysmal subarachnoid hemorrhage when centrally assessed. Overall, the adverse effects were manageable and not considered serious.


[Central nervous system mycoses in AIDS with the exception of cryptococcosis. Apropos of 3 anatomo-clinical cases].
Fungal infections of the central nervous system are uncommon in human immunodeficiency virus infected patients. The most frequently encountered is cerebromeningeal cryptococcosis. We report 3 clinicopathological cases of rarer fungal infections of the central nervous system in AIDS patients due to Candida and Aspergillus genders. In most cases, a systemic candida infection or aspergillus pulmonary infection preceded the onset of cerebral granulomas or abscesses. These infections usually occurred at the terminal stage of the disease and were associated with other neuropathologies. Neutropenia associated with lymphopenia represents a frequent risk factor along with intravenous catheter.


Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse.
Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T(+)tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F(1) crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (approximately 29.5 cM) and at 134.5 Mb (approximately 60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.


Language comprehension in schizophrenia: trait or state indicator?
Language comprehension, measured by the Luria-Nebraska Relational Concepts Factor Scale, was evaluated twice in 15 male DSM-III-R schizophrenic patients during a controlled double-blind haloperidol maintenance (without anticholinergics) and placebo replacement protocol. Fifteen male normal controls were tested once. Patients and controls were matched on age and education. Language comprehension was significantly reduced in patients under both pharmacologic conditions, as compared with controls. Patients' comprehension accuracy did not differ significantly between neuroleptic-treatment and placebo replacement conditions. Patients' comprehension accuracy was independent of positive symptoms, anxiety-depression, measures of clinical course, and CSF and plasma monoamines. Comprehension accuracy was also not associated with patients' educational level or WAIS-R measures of their intellectual and short-term memory functioning. Patients' comprehension performance was significantly associated only with the negative symptom anhedonia-asociality during haloperidol maintenance. Thus, language comprehension in schizophrenic patients was independent of changes in pharmacologic treatment and the positive symptoms of psychosis. Results suggest language comprehension may represent a stable or trait characteristic in schizophrenia.


A spontaneous duplication in U6 spliceosomal RNA uncouples the early and late functions of the ACAGA element in vivo.
U6 RNA enters the spliceosome base paired with U4 RNA, but dissociates from U4 RNA before the catalytic steps of splicing. We have identified a cold-sensitive lethal mutation in U4 RNA (U4-cs1) that blocks the splicing pathway after U4/U6 complex formation, but before the first catalytic step of splicing. Remarkably, selection for suppressors of the cold-sensitive growth of the U4-cs1 strain yielded a tandem duplication of the highly conserved ACAGA sequence of U6 RNA (U6-Dup). The ACAGA sequence plays an essential role in spliceosome assembly and in the second catalytic step of pre-mRNA splicing; one or both of these roles involves direct base pairing to the pre-mRNA 5' splice site. In a U4-cs1/U6-Dup double-mutant strain grown at low temperature, the upstream ACAGA sequence of U6 RNA is required for suppression of the U4 mutation, whereas the downstream ACAGA sequence is required for other essential functions. Based on the sequence requirements for function of the upstream ACAGA element of U6-Dup, we propose that it pairs with the pre-mRNA 5' splice site during incorporation of the U4/U6 complex into the spliceosome and that the subsequent dissociation of U4 RNA exposes the downstream ACAGA sequence, which functions in the catalytic steps. The properties of this mutant U4/U6 complex provide compelling in vivo evidence that U6 RNA normally base pairs with the 5' splice site before disruption of its pairing with U4 RNA.


[The long-term depression of the function of the hypothalamo-hypophyseal-adrenocortical system in rats].
Hypothalamo-pituitary-adrenocortical axis reactivity was studied in vivo and in vitro in 7 days after single administration of 30 mg/100 g body weight of hydrocortisone in rats. There were a blockade of stress-induced decrease of CRF-41 content in median eminence, and failure of increase of ACTH and corticosterone levels in the blood to stress in 7 days after hydrocortisone administration. A decrease of reactivity to ACTH was shown during incubation of adrenals from rats treated with hydrocortisone. 300 and 400 mg/100 g body weight of corticosterone s. c. imitates a stress-induced increase of corticosterone in the blood and can be used as replacement therapy. We conclude that high supraphysiological doses of glucocorticoids results in a decrease of reaction of hypothalamus, pituitary and adrenals to stress.


T lymphocytes of young and aged rats. II. Functional defects and the role of interleukin-2.
Splenic T lymphocytes of aged Lewis rats respond to Con A and PHA with diminished 3H-TdR uptake compared with splenic T lymphocytes of young Lewis rats. After immunization with allogeneic tumor cells, uptake of 3H-TdR in mixed lymphocyte-tumor cultures and T cell cytotoxicity against tumor target cells are significantly lower with spleen cells of aged rats compared with those of young rats. The culture of spleen cells of aged rats with Con A results in a diminished conversion of Ia-positive T cells from Ia-negative precursors compared with similar cultures of spleen cells of young rats. Spleen cells of both young and aged rats produce high amounts of IL-2 in response to Con A stimulation. "Old" T cells, however, bind relatively little IL-2, do not utilize it in culture, and do not respond to exogenous IL-2 with enhanced 3H-TdR uptake as do "young" T cells. In allogeneic MLTC, "old" T lymphocytes produce little IL-2 compared with "young" cells, and both "young" and "old" cells respond to exogenous IL-2 with enhanced 3H-TdR uptake and increased cytotoxic activity. The data suggest defects in the synthesis and/or recognition of IL-2 as well as defects in the regulation of Ia antigen expression may be responsible, in part, for the reduced T cell function in aged animals.


Ferroptosis: Cancer Stem Cells Rely on Iron until "to Die for" It.
Cancer stem cells (CSCs) are a distinct subpopulation of tumor cells with stem cell-like features. Able to initiate and sustain tumor growth and mostly resistant to anti-cancer therapies, they are thought responsible for tumor recurrence and metastasis. Recent accumulated evidence supports that iron metabolism with the recent discovery of ferroptosis constitutes a promising new lead in the field of anti-CSC therapeutic strategies. Indeed, iron uptake, efflux, storage and regulation pathways are all over-engaged in the tumor microenvironment suggesting that the reprogramming of iron metabolism is a crucial occurrence in tumor cell survival. In particular, recent studies have highlighted the importance of iron metabolism in the maintenance of CSCs. Furthermore, the high concentration of iron found in CSCs, as compared to non-CSCs, underlines their iron addiction. In line with this, if iron is an essential macronutrient that is nevertheless highly reactive, it represents their Achilles' heel by inducing ferroptosis cell death and therefore providing opportunities to target CSCs. In this review, we first summarize our current understanding of iron metabolism and its regulation in CSCs. Then, we provide an overview of the current knowledge of ferroptosis and discuss the role of autophagy in the (regulation of) ferroptotic pathways. Finally, we discuss the potential therapeutic strategies that could be used for inducing ferroptosis in CSCs to treat cancer.


New insight on the enteric cholinergic innervation of the pig colon by central and peripheral nervous systems: reduction by repeated loperamide administration.
The central and peripheral nervous systems provide cholinergic innervation in the colon. The ability to assess their neuroanatomical distinctions is still a challenge. The pig is regarded as a relevant translational model due to the close similarity of its enteric nervous system (ENS) with that of human. Opioid-induced constipation is one of the most common side effects of opioid therapy. We developed an approach to differentiate the central and peripheral cholinergic innervation of the pig colon using double immunolabeling with a novel mouse anti-human peripheral type of choline acetyltransferase (hpChAT) antibody combined with a rabbit anti-common type of ChAT (cChAT) antibody, a reliable marker of cholinergic neurons in the central nervous system. We examined their spatial configurations in 3D images of the ENS generated from CLARITY-cleared colonic segments. The density was quantitated computationally using Imaris 9.7. We assessed changes in the distal colon induced by daily oral treatment for 4 weeks with the μ opioid receptor agonist, loperamide (0.4 or 3 mg/kg). The double labeling showed strong cChAT immunoreactive (ir) fibers in the cervical vagus nerve and neuronal somata and fibers in the ventral horn of the sacral (S2) cord while hpChAT immunoreactivity was visualized only in the ENS but not in the vagus or sacral neural structures indicating the selectivity of these two antibodies. In the colonic myenteric plexus, dense hpChAT-ir neurons and fibers and varicose cChAT-ir fibers surrounding hpChAT-ir neurons were simultaneously visualized in 3D. The density of cChAT-ir varicose fibers in the outer submucosal plexus of both males and females were higher in the transverse and distal colon than in the proximal colon and in the myenteric plexus compared to the outer submucosal plexus and there was no cChAT innervation in the inner submucosal plexus. The density of hpChAT in the ENS showed no segmental or plexus differences in both sexes. Loperamide at the highest dose significantly decreased the density hpChAT-ir fibers + somata in the myenteric plexus of the distal colon. These data showed the distinct density of central cholinergic innervation between myenteric and submucosal plexuses among colonic segments and the localization of cChAT-ir fibers around peripheral hpChAT neurons in 3D. The reduction of cholinergic myenteric innervation by chronic opiate treatment points to target altered prokinetic cholinergic pathway to counteract opiate constipation.


[Gonococcal surface antigens and their significance for serotyping and vaccines].
Outer membrane components of Neisseria gonorrhoeae play an important role in the initial steps of infection. Precise knowledge about the surface antigens is needed for the development of a serotyping system and of a vaccine against local and systemic gonorrhea. Structure, antigenicity, and function of the best-known membrane components, i.e., lipopolysaccharide, protein I, protein II, protein III, and pili, are discussed. Lipopolysaccharide is a strong immunogen and induces bactericidal antibodies, but is unsuitable for use as a vaccine because of its toxicity. Protein I and protein III are stable proteins, not subject to antigenic variation. Antibodies against protein I, which are able to kill N. gonorrhoeae, are detectable in the serum of patients with disseminated gonococcal infection. Protein II and pili are highly variable antigens with constant, very slightly immunogenic regions. To interrupt the pathomechanism of gonococcal infection at different stages, future vaccines should contain more than one surface antigen.


All-Organic Redox Targeting with a Single Redox Moiety: Combining Organic Radical Batteries and Organic Redox Flow Batteries.
The volumetric capacities and the lifetime of organic redox flow batteries (RFBs) are strongly dependent on the concentrations of the redox-active molecules in the electrolyte. Single-molecule redox targeting represents an efficient approach toward realizing viable organic RFBs with low to moderate electrolyte concentrations. For the first time, an all-organic Nernstian potential-driven redox targeting system is investigated that directly combines a single-electrode material from organic radical batteries (ORBs) with a single redox couple of an aqueous, organic RFB, which are based on the same redox moiety. Namely, poly(TEMPO-methacrylate) (PTMA) is utilized as the redox target ("solid booster") and N,N,N-2,2,6,6-heptamethylpiperidinyloxy-4-ammonium chloride (TMATEMPO) is applied as the sole redox mediator to demonstrate the redox targeting mechanisms between the storage materials of both battery types. The formal potentials of both molecules are investigated, and the targeting mechanism is verified by cyclic voltammetry and state-of-charge measurements. Finally, battery cycling experiments demonstrate that 78-90% of the theoretical capacity of the ORB electrode material can be addressed when this material is present as the redox target in the electrolyte tank of an operating, aqueous organic RFB.


[High expression of snail in mouse cerebral cortex following kainic acid-induced status epilepticus].
Objective To observe the expression of snail in mouse cortex in the model of status epilepticus (SE) induced by kainic acid (KA) and explore the role of snail in SE. Methods Sixty-four adult male C57/BL6 mice were randomly divided into control group and SE group, 32 mice in each group. Intraperitoneal injection of normal saline was performed in control group; instead, KA was injected intraperitoneally in SE group to induce SE. The organs were harvested 3, 8, 24 and 72 hours post the cessation of each group. Reverse transcription-PCR was used to detect the expression of snail mRNA; the expression of snail protein was tested by Western blotting; the distribution of snail was determined using immunohistochemistry; snail expression in cortex was located by immunofluorescence technique. Results Compared with the control group, mRNA and protein expression of snail in SE group were significant higher, and they reached the peak at 24 hours. Immunohistochemistry indicated weak positive expression of snail in control group. In SE group, it was widely distributed in different cortical neurons and glial cells. Immunofluorescence histochemistry further proved that snail was localized in neurons and astrocytes. Conclusion Snail is strongly expressed in neuron and astrocyte of mouse cortex at KA-induced SE, which indicates snail is possibly related to the attack of SE.


All hairstyles are not created equal: What the dermatologist needs to know about black hairstyling practices and the risk of traction alopecia (TA).
Prevalent among black women, traction alopecia (TA) is a type of hair loss that is often attributed to certain hairstyling practices. Although some of the hair care techniques common in the black community can promote ease of everyday hairstyling for black women, many of these practices have been implicated as risk factors for TA. Because of the limited literature on black hairstyling methods, hair loss in this patient population can present a diagnostic and therapeutic challenge for dermatologists. By increasing the knowledge and understanding of these practices and their risk of causing TA, clinicians can better manage this condition and stop the progression of hair loss before it becomes permanent. This information can be used to develop individualized recommendations for safer styling alternatives and improve patient education by identifying high-risk hairstyling habits. This review stratifies these hair care and styling practices into high-, moderate-, and low-risk categories, in addition to outlining a diagnostic approach for TA and detailed guidelines for conservative management.


Subthreshold pharmacological and genetic approaches to analyzing CaV2.1-mediated NMDA receptor signaling in short-term memory.
Ca(V)2.1 is highly expressed in the nervous system and plays an essential role in the presynaptic modulation of neurotransmitter release machinery. Recently, the antiepileptic drug levetiracetam was reported to inhibit presynaptic Ca(V)2.1 functions, reducing glutamate release in the hippocampus, although the precise physiological role of Ca(V)2.1-regulated synaptic functions in cognitive performance at the system level remains unknown. This study examined whether Ca(V)2.1 mediates hippocampus-dependent spatial short-term memory using the object location and Y-maze tests, and perirhinal cortex-dependent nonspatial short-term memory using the object recognition test, via a combined pharmacological and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the Ca(V)2.1alpha(1) mutation had normal spatial and nonspatial short-term memory. A 100mg/kg dose of levetiracetam, which is ineffective in wild-type controls, blocked spatial short-term memory in rol/+ mice. At 5mg/kg, the N-methyl-D-aspartate (NMDA) receptor blocker (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which is ineffective in wild-type controls, also blocked the spatial short-term memory in rol/+ mice. Furthermore, a combination of subthreshold doses of levetiracetam (25 mg/kg) and CPP (2.5mg/kg) triggered a spatial short-term memory deficit in rol/+ mice, but not in wild-type controls. Similar patterns of nonspatial short-term memory were observed in wild-type and rol/+ mice when injected with levetiracetam (0-300 mg/kg). These results indicate that Ca(V)2.1-mediated NMDA receptor signaling is critical in hippocampus-dependent spatial short-term memory and differs in various regions. The combination subthreshold pharmacological and genetic approach presented here is easily performed and can be used to study functional signaling pathways in neuronal circuits.


Regulation of in vivo whole blood aggregation in rats by calcitonin gene related peptide.
The purpose of these experiments was to determine whether calcitonin gene related peptide (CGRP) mediates physiological control of platelet function in vivo. Rat blood pressure was continuously monitored via a femoral arterial cannula, and whole blood aggregation was assessed periodically ex vivo with an impedance aggregometer before and following a 1.4 nmol/kg bolus dose of CGRP8-37, a specific receptor antagonist of CGRP. Mean arterial blood pressure was not significantly affected by CGRP8-37 over a 30-min period (p>0.05). However, whole blood aggregation increased by 38.4+/-18.0% (p<0.01) and 32.0+/-11.2% (p<0.05), at 5 and 15 min post CGRP8-37, respectively, when compared with control. Whole blood aggregation was not significantly different from control at 30 min (p>0.05), suggesting a relatively short duration of action for in vivo CGRP8-37. These data suggest that CGRP contributes to the maintenance of hemostasis, and that this function may be more important than the better known vasodilatatory effects of this neuropeptide.


Compression Behaviors and Mechanical Properties of Modified Face-Centered Cubic Lattice Structures under Quasi-Static and High-Speed Loading.
Our previous work reported a novel lattice structure composed of modified face-centered cubic (modified FCC) cells with crossing rods introduced at the center of each cell. In this work, the proposed modified FCC lattice is further investigated to ascertain its compression behaviors under different loading rates. For this purpose, numerical simulations were carried out for compressing the two-dimensional and three-dimensional modified FCC lattice structures with different loading rates, and to compare their deformation modes and energy absorption capacity under different loading rates. In addition, lattice specimens were fabricated using selective laser melting technology and quasi-static compression experiments were performed to validate the finite element simulations. The results indicate that the proposed modified FCC lattices exhibit better load-bearing capacity and energy absorption than the traditional FCC lattices under different loading rates. Under high-speed loading, the modified FCC structure is less susceptible to buckling, and the length ratio of the central cross-rod corresponding to maximum energy absorption capacity is larger.


Exercise Prescription in Diabetes- S.M.A.R.T.: A Prospective Study.
Exercise prescription has always been a mandatory yet extremely under rated non-pharmacological approach in management of diabetes mellitus. SMART acronym for S - specific, M - measurable, A - attainable, R - realistic, T - time oriented, is a newly proposed idea for implementing the same with supposedly better results. We tried to analyse the results objectively by SMART prescription of individualized exercise regimes to patients along with medicines. Single centred, prospective study conducted over a time span of 3 months, on 75 patients, with biweekly follow-up. At the end of three months, we evaluated the results (of 52 patients who remained) by comparing random blood sugar and glycosylated haemoglobin values of the patients at the beginning and end of the trial. A significant reduction in blood sugar (p-0.023) and A1C levels (p-0.105; ns) was noted after a period of three months; with an average reduction of 31mg/ dl and 0.37% noted in each respectively. Additional benefits of better follow up, reduced financial burden, increased compliance to the said regimen were observed. Recommending exercise and lifestyle changes is as important as pharmacological management in diabetes. A SMART approach, methodical prescription of the exercise routines and drugs- individualized for patients, will likely have better results and patient satisfaction. A practice of switching to precise written suggestions than verbal ideas and reviewing the progress on every follow up visit may improve the outcome.


The relationship between advanced glycation end products and gestational diabetes: A systematic review and meta-analysis.
Gestational Diabetes Mellitus (GDM) is a condition in which women without history of diabetes experience hyperglycemia during pregnancy, especially at the second and third trimesters. In women who have had GDM, an elevated body mass index (BMI) may have a substantial impact for persistent hyperglycemia in their lives after gestation. Beyond hyperglycemia, increased local oxidative stress directly promotes the formation of Advanced Glycation End-products (AGEs). Hence, this systematic review and meta-analysis was aimed to determine the relationship between the level of AGEs and/or related metabolic biomarkers with GDM. Literature search was carried out through visiting electronic databases, indexing services, and directories including PubMed/MEDLINE (Ovid®), EMBASE (Ovid®), google scholar and WorldCat to retrieve studies without time limit. Following screening and eligibility evaluation, relevant data were extracted from included studies and analyzed using Rev-Man 5.3 and STATA 15.0. Inverse variance method with random effects pooling model was used for the analysis of outcome measures at 95% confidence interval. Hedge's adjusted g statistics was applied to calculate the standardized mean difference (SMD) to consider the small sample bias. Besides, meta-regression, meta-influence, and publication bias analyses were conducted. The protocol has been registered on PROSPERO with ID: CRD42020173867. A total of 16 original studies were included for the systematic review and meta-analysis. Compared with women with pregnant controls, the level of AGE was significantly higher in women with GDM (SMD [95% CI] = 2.26 [1.50‒3.02], Z = 5.83, P < 0.00001; I2 = 97%, P< 0.0001). The BMI was also significantly higher in women with GDM (SMD [95% CI] = 0.97 [0.33‒1.62], Z = 2.98, P = 0.003) compared to controls. Regarding specific and related metabolic biomarkers, there was higher level of HOMA-IR (SMD [95% CI] = 0.39 [0.22-0.55], Z = 4.65, P < 0.0001, after sensitivity analysis) and HbA1c (SMD [95% CI] = 0.58 [0.03‒1.12], Z = 2.07, P = 0.04, after sensitivity analysis) in gestational diabetic women. Subgroup analyses indicated that studies conducted in Asia and Europe, at third trimester of pregnancy and blood/plasma AGE samples showed a significant difference in AGE level among women with GDM compared to pregnant controls. What is more, meta-regression with the sample size (regression coefficient (Q) = -0.0092, P = 0.207) and year of publication (Q = 0.0035, P = 0.984) suggested that the covariates had no significant effect on the heterogeneity. The study indicated that there was a strong relationship between AGE and GDM. Besides, the BMI and other specific biomarkers showed a significant difference between the two groups indicating the high risk of developing long-standing type 2 diabetes and its complications in gestational diabetic women. Early detection of these biomarkers may play a pivotal role in controlling postpartum diabetic complications.


The zebrafish embryo as an in vivo model for screening nanoparticle-formulated lipophilic anti-tuberculosis compounds.
With the increasing emergence of drug-resistant Mycobacterium tuberculosis strains, new and effective antibiotics against tuberculosis (TB) are urgently needed. However, the high frequency of poorly water-soluble compounds among hits in high-throughput drug screening campaigns is a major obstacle in drug discovery. Moreover, in vivo testing using conventional animal TB models, such as mice, is time consuming and costly, and represents a major bottleneck in lead compound discovery and development. Here, we report the use of the zebrafish embryo TB model for evaluating the in vivo toxicity and efficacy of five poorly water-soluble nitronaphthofuran derivatives, which were recently identified as possessing anti-TB activity in vitro. To aid solubilization, compounds were formulated in biocompatible polymeric micelles (PMs). Three of the five PM-formulated nitronaphthofuran derivatives showed low toxicity in vivo, significantly reduced bacterial burden and improved survival in infected zebrafish embryos. We propose the zebrafish embryo TB-model as a quick and sensitive tool for evaluating the in vivo toxicity and efficacy of new anti-TB compounds during early stages of drug development. Thus, this model is well suited for pinpointing promising compounds for further development.


Increased expression of human luteinizing hormone/human chorionic gonadotropin receptor mRNA in human endometrial cancer.
Fifty randomly selected endometrial tissue samples were used in this study to determine the existence of LH/hCG receptor. Of these, 6 were matched samples of cancerous and surrounding morphologically normal tissues from the same individuals. Conventional RT-PCR, nested RT-PCR, and relative real-time PCR (TaqMan) methods were used to measure the gene expression on the RNA levels. The results show, (1) Real-time PCR can detect LH/hCG receptor expression in all the RNA samples analyzed when conventional RT-PCR only demonstrates the expression of LH/hCG receptor in 17% of the tested samples. (2) Absolute quantitation of LH/hCG receptor by real-time PCR shows higher expression in cancer tissue. This finding was confirmed by the six matched samples. It suggests that LH/hCG receptor gene expresses in endometrium at very low levels and real-time PCR is the best method to detect the expression. Quantitative real-time PCR also reveals increased expressions of LH/hCG receptor in endometrial cancerous tissues compared with surrounding microscopically normal tissues.


Rapid identification of anterior and posterior root of cauda equina nerves by near-infrared diffuse reflectance spectroscopy.
A new rapid chemometric method has been developed to identify the anterior and posterior roots of cauda equina nerves by near-infrared (NIR) diffuse reflectance spectroscopy. NIR spectra of nerves were measured using a Fourier transform NIR spectrometer equipped with a fiber-optic probe. The result revealed no observable difference in the spectra between the anterior and posterior root samples, but the two roots could be identified by cluster analysis based on the differences of their spectral features. The overall accuracy of the cluster analysis model was 87.5%, and the accuracy for the actual anterior root and actual posterior root were 95% and 80%, respectively. The result suggested that NIR spectroscopy in combination with the chemometrics method (cluster analysis) could be used to classify the anterior and posterior roots of cauda equina nerves. The proposed method required only a few minutes, while classical methods commonly required at least one hour. It was demonstrated that the new method could provide a rapid, correct, nondestructive and low-cost potential means to quickly differentiate anterior and posterior roots in mixed cauda equina nerves, which would be helpful for surgeons to align nerve stumps correctly.


Tunable visual color filter using microfluidic grating.
This paper reports a tunable visual color filter based on a microfluidic transmission grating. The grating lines are formed by the microflows in an array of evenly spaced straight microchannels. In experimental study, the transmission of white light measures a shift of visual color from red to blue in the zeroth order diffraction in response to a change of the refractive index from 1.3290 to 1.3782 in the microflows. The merit of large tunability of transmission peak (Δλ=408 nm) makes this grating potential for various applications in biological and chemical measurements, such as space- and time-resolving micropattern spectrophotometers and separation of the fluorescence from the excitation.


The impact of general/visceral obesity on completion of mesorectum and perioperative outcomes of laparoscopic TME for rectal cancer: A STARD-compliant article.
To evaluate the impact of visceral obesity on laparoscopic total mesorectal excision (TME) and decide the best index to reflect completion of mesorectum and perioperative outcomes.Patients with rectal cancer who underwent laparoscopic TME were enrolled. The data including body mass index (BMI), visceral fat area (VFA), visceral fat area/body surface area (VFA/BSA), mesorectum fat ratio (MFR), pelvic fat area (PFA), pelvic fat ratio (PFR), completion of mesorectum, and other perioperative outcomes were collected. Data were analyzed.A total of 322 patients were enrolled between 2011 and 2014. There was no significantly difference between the BMI groups on completion of mesorectum and other outcomes (P ≥ 0.05). However, in VFA groups, completion of mesorectum (P = 0.002), operative time (P = 0.02), and incision length (P = 0.02) were significantly different. In VFA/BSA groups, completion of mesorectum (P = 0.002) and incision length (P = 0.009) were significantly different. When MFR was equal to 0.48, completion of mesorectum (P = 0.002), operative time (P = 0.001), incision length (P = 0.03), and blood loss (P = 0.04) were significantly different between the 2 groups. In PFA and PFR groups, there was no significantly difference (P ≥ 0.05). After the analysis of logistic regression, only VFA was the risk factor of incomplete mesorectum excision.BMI does not reflect the impact of obesity on laparoscopic rectal surgery. VFA is a better index in predicting the influence of visceral obesity on surgical quality and difficulty of laparoscopic rectal surgery than VFA/BSA and MFR.


[Autotransfusion with acute hemodilution in the surgical treatment of scoliosis (author's transl)].
With the goal to reduce the number and the volume of homologous blood transfusions during surgical treatment of scoliosis and spine deformities, the authors have studied the results of 50 cases treated with immediate acute haemodilutional autotransfusion. In 40 per cent of the case neither per nor post operative homologous blood transfusion was necessary. In addition they have seen a surprising result such as a significant lowering of absolute blood loss during surgery compared to a similar series treated without haemodilutional autotransfusion. Physiopathological principles, precise technique used and limitation of the method are described.


Drug-related problems detected in Australian Community Pharmacies: The PROMISe Trial.
Drug-related problems (DRPs) are a major burden on health care systems. Community pharmacists are ideally placed to detect, prevent, and resolve these DRPs. To determine the number and nature of DRPs detected and clinical interventions performed by Australian community pharmacists, using an electronic system. An electronic documentation system was designed and integrated into the existing dispensing software of 186 pharmacies to allow pharmacists to record details about the clinical interventions they performed to prevent or resolve DRPs. Participating pharmacies were randomly allocated to 3 groups: group 1 had documentation software, group 2 had documentation software plus a timed reminder to document interventions, and group 3 had documentation software, a timed reminder, and an electronic decision support prompt. Pharmacists classified DRPs, entered recommendations they made, and estimated the clinical significance of the intervention. An observational substudy that included pharmacies without any documentation software was completed to verify intervention rates. Over 12 weeks, 531 participating pharmacists recorded 6230 clinical interventions from 2,013,923 prescriptions, with a median intervention rate of 0.23% of prescriptions. No significant differences were seen between the 3 groups that used documentation software; as expected, however, the pharmacies that used this software had a significantly higher documentation rate compared to the pharmacies without documentation software. The most common interventions were related to drug selection problems (30.8%) and educational issues (24.4%). Recommendations were often related to a change in therapy (40.0%), and 41.6% of interventions were self-rated as highly significant. Drug groups most commonly subject to an intervention included antibiotics, glucocorticoids, nonsteroidal antiinflammatory drugs, and opioids. The documentation system allowed for the determination of the frequency and types of DRPs, as well as the recommendations made to resolve them in community pharmacy practice. Use of the software, including its electronic prompts, significantly increased the documentation of interventions by pharmacists.


Structure and function in rhodopsin: further elucidation of the role of the intradiscal cysteines, Cys-110, -185, and -187, in rhodopsin folding and function.
The disulfide bond between Cys-110 and Cys-187 in the intradiscal domain is required for correct folding in vivo and function of mammalian rhodopsin. Misfolding in rhodopsin, characterized by the loss of ability to bind 11-cis-retinal, has been shown to be caused by an intradiscal disulfide bond different from the above native disulfide bond. Further, naturally occurring single mutations of the intradiscal cysteines (C110F, C110Y, and C187Y) are associated with retinitis pigmentosa (RP). To elucidate further the role of every one of the three intradiscal cysteines, mutants containing single-cysteine replacements by alanine residues and the above three RP mutants have been studied. We find that C110A, C110F, and C110Y all form a disulfide bond between C185 and C187 and cause loss of retinal binding. C185A allows the formation of a C110-C187 disulfide bond, with wild-type-like rhodopsin phenotype. C187A forms a disulfide bond between C110 and C185 and binds retinal, and the pigment formed has markedly altered bleaching behavior. However, the opsin from the RP mutant C187Y forms no rhodopsin chromophore.


Substrate analysis and molecular cloning of the extracellular alkaline phosphatase of Streptomyces griseus.
Streptomyces species secrete large amounts of alkaline phosphatase (AP) enzymes that have not been characterized so far. An AP has been purified to homogeneity from cultures of Streptomyces griseus IMRU 3570. The enzyme has a monomer size of 62 kDa and is processed in the culture to a 33 kDa protein as shown by immunoblotting. The enzyme was purified by ammonium sulfate precipitation, CM-Sephadex cationic exchange, chromatofocusing and HPLC Sphaerogel 3000SW filtration. The pure enzyme uses a variety of organic phosphorylated compounds as substrates. The N-terminal end of the mature protein was found to be RLREDPFTLGVASGDPHP. The gene phoA has been cloned using as probe an oligomer based on the N-terminal sequence of the S. griseus AP. phoA encodes a protein of 62678 Da with low homology to the AP of Escherichia coli. The phoA gene was found to be homologous to three alkaline-phosphatase-encoding genes previously identified in the Streptomyces coelicolor genome. On the basis of the optimal pH, substrate specificity and differences in amino acid sequence of motifs defining the active centre of APs, the S. griseus AP uses a wide range of organic phosphate substrates and is different from the phosphatases of Gram-negative bacteria.


[New tools for early detection of multiple sclerosis progression: MSProDiscuss questionnaire].
Diagnosis of secondary progressive multiple sclerosis (SPMS) is based on a history of gradual worsening of neurological symptoms within 6-12 months without exacerbations following an initial relapsing-remitting (RRMS) disease course. In the absence of reliable MRI, immunological and clinical markers, it is hardly possible to achieve objectivity in determining the transition of MS to a progressive stage. This often leads to a long period of diagnostic uncertainty, which prevents timely therapeutic decisions. Physicians expressed an unmet need for a tool that could be used in routine clinical practice to assess the risks of progression to SPMS quickly and reliably, in an easy-to-interpret output for a joint discussion with the patient. From a wide range of disease symptoms and lifestyle factors reflecting the progression to SPMS and obtained by analysis of large clinical data (3294 cases) and a survey of patients and specialists, significant were identified and ranked by categories according to combined expert opinion. A mathematical model was developed and validated, and an electronic version of the MSProDiscuss questionnaire created. Test sensitivity for SPMS diagnosis is 0.82, specificity 0.84, interrater reliability 0.95. Median time for completion of the questionnaire was 2.16 minutes per patient. Physicians of the Russian Federation who used the questionnaire confirmed its high feasibility. Thus, the methodology of the questionnaire development based on the combined opinion of patients and physicians, along with the large clinical data, made it possible to obtain high sensitivity, specificity and reproducibility of the test and takes little time with a clear output. MSProDiscuss may be useful not only in the differential diagnosis of RRMS and SPMS, but also to determine the risks of progression to SPMS, which is of great clinical importance.


Rational design of CH/pi interaction sites in a basic resolving agent.
A novel synthetic basic resolving agent, cis-1-aminobenz[f]indan-2-ol (ABI), was rationally designed by introducing effective CH/pi interaction sites to cis-1-aminoindan-2-ol (AI), whose chiral recognition ability has been reported from our laboratory. ABI was applicable to a wide variety of racemic arylalkanoic acids and showed moderate to excellent chiral recognition ability, which was obviously higher than that of AI. The fundamental and important role of CH/pi interactions, such as tunable CH(sp(2))/pi and CH(sp(3))/pi interactions, in the chiral recognition by ABI was revealed by X-ray crystallographic study.


Relationship between genetic polymorphisms of ALDH2 and ADH1B and esophageal cancer risk: a meta-analysis.
To evaluate the contribution of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) polymorphisms to the risk of esophageal cancer. Nineteen articles were included by searching MEDLINE, EMBASE and the Chinese Biomedical Database, 13 on ADH1B and 18 on ALDH2. We performed a meta-analysis of case-control studies including 13 studies on ADH1B (cases/controls: 2390/7100) and 18 studies on ALDH2 (2631/6030). The crude odds ratio [OR (95% confidence interval)] was 2.91 (2.04-4.14) for ADH1B*1/*1 (vs ADH1B*2/*2) and 1.32 (1.17-1.49) for ADH1B*1/*2. The crude OR for ALDH2*1/*2 (vs ALDH2*1/*1) was 2.52 (1.76-3.61). ADH1B*1/*1 increased the risk of esophageal cancer among never/rare [1.56 (0.93-2.61)], moderate [2.71 (1.37-5.35)], and heavy drinkers [3.22 (2.27-4.57)]. ADH1B*1/*2 was associated with a modest risk among moderate drinkers [1.43 (1.09-1.87)]. ALDH2*1/*2 increased the risk among never/rare [1.28 (0.91-1.80)], moderate [3.12 (1.95-5.01)], and heavy [7.12 (4.67-10.86)] drinkers, and among ex-drinkers [5.64 (1.57-20.25)]. ALDH2*2/*2 increased the risk among drinkers [4.42 (1.72-11.36)]. ADH1B*1/*1 plus ALDH2*1/*2 was associated with the highest risk for heavy drinkers [12.45 (2.9-53.46)]. The results of the meta-regression analysis showed that the effects of ADH1B*1/*1 and ALDH2*1/*2 increased with the level of alcohol consumption. ALDH2*1/*2 was associated with a high risk among Taiwan Chinese and Japanese drinkers, as opposed to a moderate risk among drinkers in high-incidence regions of Mainland China. ADH1B*1/*1 in heavy drinkers and ALDH2*1/*2 in moderate-to-heavy drinkers was associated with similarly high risk among both men and women. ADH1B/ALDH2 genotypes affect the risk of esophageal cancer, and the risk is modified by alcohol consumption, ethnicity, and gender.


Prognostic factors of severe asthma in Puerto Rico.
Asthma in Puerto Rico is a serious Public Health Problem. This study extends our cross-sectional self-reported asthma prevalence survey of 3,000 volunteers. The purpose of the present study was to analyze the importance of known prognostic factors of asthma severity among 486 self-reported participants. Patients with more than one visit to the emergency room in the previous 12 months due to asthma exacerbations were classified as cases of "severe asthma", and those asthmatic patients who did not visit emergency rooms were classified as "non-severe asthmatic subjects". Severe cases and non-severe asthmatic subjects were compared regarding age, sex, family history of asthma, presence of household pets, and in the previous 12 months: history of hospitalization due to asthma, respiratory infections, tobacco smoking, exposure to passive smoking, and avoidance of passive smoking. Crude and logistic regression adjusted odds ratio was used as a measure of association between each prognostic factor, and the outcome namely severe asthma, while adjusting for all confounders simultaneously. The results clearly showed that previous hospitalizations due to asthma (OR = 7.3, p < 0.0001) and frequent of respiratory infection (OR = 2.5, p = 0.0003) were prognostic factors associated with increased asthma severity. A statistically significant, two percent less likelihood to have severe asthma for each year of age was found. Weak associations were found between asthma severity and male gender, family history of asthma, passive smoking, and presence of household pets. Avoidance of environmental tobacco exposure (passive smoking) was found to be an important and statistically significant protective factor associated with a 47% less likelihood for severe asthma. In conclusion, appropriate management of patients with history of hospitalization due to asthma is very important. The correct management of respiratory infection in asthmatic patients may result in a reduction of up to 60 percent of the odds of having asthma severe enough to require emergency treatment, and may reduced by 86.3 percent hospitalizations.


Variations in hepatic lipid species of age-matched male mice fed a methionine-choline-deficient diet and housed in different animal facilities.
Non-alcoholic steatohepatitis (NASH) is a common disease and feeding mice a methionine-choline-deficient (MCD) diet is a frequently used model to study its pathophysiology. Genetic and environmental factors influence NASH development and liver lipid content, which was studied herein using C57BL/6 J mice bred in two different animal facilities. Age-matched male C57BL/6 J mice bred in two different animal facilities (later on referred to as WT1 and WT2) at the University Hospital of Regensburg were fed identical MCD or control chows for 2 weeks. Hepatic gene and protein expression and lipid composition were determined. NASH was associated with increased hepatic triglycerides, which were actually higher in WT1 than WT2 liver in both dietary groups. Cholesterol contributes to hepatic injury but was only elevated in WT2 NASH liver. Ceramides account for insulin resistance and cell death, and ceramide species d18:1/16:0 and d18:1/18:0 were higher in the NASH liver of both groups. Saturated sphingomyelins only declined in WT1 NASH liver. Lysophosphatidylcholine concentrations were quite normal in NASH and only one of the 12 altered phosphatidylcholine species declined in NASH liver of both groups. Very few phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol species were comparably regulated in NASH liver of both animal groups. Seven of these lipid species declined and two increased in NASH. Notably, hepatic mRNA expression of proinflammatory (F4/80, CD68, IL-6, TNF and chemerin) and profibrotic genes (TGF beta and alpha SMA) was comparable in WT1 and WT2 mice. Mice housed and bred in different animal facilities had comparable disease severity of NASH whereas liver lipids varied among the groups. Thus, there was no specific lipid signature for NASH in the MCD model.


An evaluation of cardiopulmonary endurance and muscular strength in adults living with sickle cell disease.
There have been limited investigations into exercise in sickle cell disease (SCD). In the general population, health is reflected in general physical fitness. It is unclear if the same associations are seen in people with SCD. Here, we report a cross-sectional assessment of two important measures of physical fitness, muscle strength and cardiorespiratory endurance, in adults with SCD. A total of 29 adults with SCD (aged 24-62 years; 72% female) completed cardiopulmonary and muscular strength testing using a cycle ergometer and an isokinetic dynamometer. Adults with SCD had lower median values for cardiorespiratory endurance (the median [interquartile range, IQR] peak oxygen uptake [VO2 ] 16.1 [6.3] vs. 42.65 [11.3] ml/kg/min, p < 0.001) and knee strength (median [IQR] flexor torque 26.91[22.5] vs. 55.6 [22.7] Nm, p < 0.001) compared to controls and predicted values. Interestingly, there was a very positive association between muscular strength and peak VO2 values for adults with SCD (r = 0.53, p = 0.003) suggesting these values may be useful in determining cardiopulmonary health.


Inhibition of X-ray- and ultraviolet light-induced transformation in vitro by modifiers of poly(ADP-ribose) synthesis.
Neoplastic transformation in vitro of hamster embryo cells and mouse C3H 10T1/2 cells by X rays and ultraviolet light was suppressed by benzamide or 3-aminobenzamide, agents which inhibit poly(ADP-ribose) polymerization. Suppression was observed under conditions in which the inhibitors reduce poly(ADP-ribose) polymerization by about 75% and increase sister chromatid exchange frequencies, but have no influence on repair of X-ray and uv damage and reportedly have no detectable side effects on nucleotide precursor metabolism. These findings suggest that the mechanisms regulating neoplastic transformation differ from those regulating mutagenesis and sister chromatid exchanges and are mediated via alterations in poly(ADP-ribosylation), causing changes in gene control and expression.


[Preliminary investigation of effect of pyocyanin on common bacteria in burn wound].
Pyocyanin was extracted from culture medium of Ps. aeruginosa by Frank's method. Minimum inhibitory concentration (MIC) & minimum bactericidal concentration (MBC) of pyocyanin for 6 species of bacteria isolated from burn wounds were determined. The results of MIC & MBC: S. aureus 12.5 micrograms/ml, 50 micrograms/ml; E. coli 25 micrograms/ml, 100 micrograms/ml; P. vulgaris 50 micrograms/ml, 200 micrograms/ml; C. freundii 100 micrograms/ml, 400 micrograms/ml; S. epidermidis 12.5 micrograms/ml, 50 micrograms/ml; no inhibitory effect on Ps. aeruginosa. According to the laboratory results and clinical findings, the authors believe that when there is a dominant growth of Ps. aeruginosa in burn wounds there may be pyocyanin production to inhibit or kill other species of bacteria.


Use of solution-IEF-fractionation leads to separation of 2673 mouse brain proteins including 255 hydrophobic structures.
Analyzing complex protein mixtures on a single gel does not allow separation of many extracted proteins. Herein, we tried a prefractionation approach and mouse brain proteins were separated on a narrow pH range ZOOM-IEF Fractionator (MicroSol-IEF device) and run on two-dimensional gel electrophoresis. A total number of 2673 protein spots including 255 hydrophobic structures were successfully analyzed by mass spectrometry. This nonsophisticated approach to increase protein identification of a brain protein extract is a step forward in neurochemistry.


Act of 20 June 1988.
This Missouri Act contains the following provisions with respect to abortions performed with the intent to use fetal organs or tissue for transplantation and experiments: "188.036. 1) No physician shall perform an abortion on a woman if the physician knows that the woman conceived the unborn child for the purpose of providing fetal organs or tissue for medical transplantation to herself or another, and the physician knows that the woman intends to procure that abortion to utilize those organs or tissue for such use for herself or another. 2) No person shall utilize the fetal organs or tissue resulting from an abortion for medical transplantation, if the person knows that the abortion was procured for the purpose of utilizing those organs or tissue for such use. 3) No person shall offer any inducement, monetary or otherwise, to a woman or a prospective father of an unborn child for the purpose of conceiving an unborn child for the medical, scientific, experimental, or therapeutic use of the fetal organs or tissue. 4) No person shall offer any inducement, monetary or otherwise, to the mother or father of an unborn child for the purpose of procuring an abortion for the medical, scientific, experimental, or therapeutic use of the fetal organs or tissue. 5) No person shall knowingly offer or receive any valuable consideration for the fetal organs or tissue resulting form an abortion, provided that nothing in this subsection shall prohibit payment for burial or other final disposition of the fetal remains, or payment for a pathological examination, autopsy or postmortem examination of the fetal remains. 6) If any provision in this section or the application thereof to any person, circumstance, or period of gestation is held invalid, such invalidity shall not affect the provisions or applications which can be given effect without the invalid provision or application, and to this end the provisions of this section are declared severable."


Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model.
Melatonin is a potent scavenger of free radicals and an indirect antioxidant. Recent studies have shown that melatonin possesses beneficial effects in experimental models of brain trauma and global cerebral ischemia. The effects of pretreatment with melatonin on volume of cerebral infarction were investigated in the present study. Adult male Sprague-Dawley rats were anesthetized with sodium pentobarbital to undergo right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hr. A single dose of melatonin (1.5, 5, 15, or 50 mg/kg in 1 mL normal saline) or its vehicle was given via an intraperitoneal injection at 0.5 hr before MCAO. Relative infarction volumes on day 3 after MCAO were significantly reduced in the groups treated with melatonin at 5 (mean +/- S.E.M., 15.7 +/- 2.5%) or 15 (21.4 +/- 3.1 %) mg/kg but not at 1.5 (30.6 +/- 3.5%) or 50 (26.7 +/- 2.8%) mg/ kg when compared with the vehicle group (33.9 +/- 3.5%). There was no significant difference in the arterial blood pressure (BP), heart rate (HR) and relative cerebral blood flow among the experimental groups. These results indicate that pretreatment with melatonin at a dose between 5 and 15 mg/kg protects against focal cerebral ischemia.


[Percutaneous endoscopic discectomy in the treatment of patients with degenerative diseases of the lumbosacral spine].
Modern surgery uses a variety of treatments for spine pathology. Endoscopic techniques have become particularly popular across the world over the past decade. In this article, we summarize our experience and analyze the immediate and long-term results of surgical treatment of lumbar disc herniation using a percutaneous fully endoscopic technique for removing the herniated intervertebral disc, which is new for Russian medical practice. to evaluate the efficacy of percutaneous endoscopic discectomy in the treatment of herniated lumbar discs in patients with radicular pain syndrome. We conducted a cohort retrospective study that included 69 patients who underwent herniated disc removal using the percutaneous endoscopic technique. Surgery was performed through two approaches: the intralaminar approach was used in 44 patients, and the transforaminal approach was used in 25 patients. To assess the efficacy of surgery, we used a visual analogue scale (VAS) of pain: the intensity of local pain (VAS1) and the intensity of radicular pain (VAS2). Changes in the quality of life and ability to work were assessed by using the Oswestry scale; patient satisfaction with treatment was assessed by using the MacNab scale. The mean follow-up period after surgery was 24 months. An analysis of changes in the pain syndrome (VAS1 and VAS2) before surgery and in the early postoperative period demonstrated a significant regression of pain regardless of the approach type (r=0.25). Patients' survey (MacNab scale) in the long-term postoperative period revealed no unsatisfactory results; excellent, good, and satisfactory results were observed in 21 (30%), 32 (46%), and 16 (24%) patients, respectively. Percutaneous endoscopic discectomy is an effective surgical treatment for degenerative diseases of the lumbosacral spine, providing excellent and good treatment outcomes in most operated patients.


Peptide-/Drug-Directed Self-Assembly of Hybrid Polyurethane Hydrogels for Wound Healing.
Drug-loading hydrogels are promising candidates in the bioengineering research field; nevertheless, hydrophobic drug loading into a hydrophilic carrier system remains unsolved and is full of challenges. In this work, following the potential dual interactions between peptides and aromatic drugs, we developed a potent hybrid hydrogel formation method, namely, "peptide-/drug-directed self-assembly". The hybrid hydrogels were synthesized using polyethylene glycol (PEG)-based Fmoc-FF peptide hybrid polyurethane, in which curcumin could be encapsulated through self-assembly with Fmoc-FF peptide via π-π stacking. On the basis of this, curcumin loading capacity could be improved to as high as 3.3 wt % with sustained release. In addition, the curcumin loading enhanced the hydrogel mechanical properties from 4 kPa to over 10 kPa, similar to that of natural soft tissues. Furthermore, the hydrogels were injectable with self-healing properties since the Fmoc-FF peptide/curcumin coassembly was noncovalent and reversible. Spectroscopy results confirmed the existence of the coassembly of Fmoc-FF peptide/curcumin. Further in vivo experiments effectively demonstrated that the hydrogels could improve the cutaneous wound healing in a full-thickness skin defected model. This peptide-/drug-directed self-assembly of hybrid polyurethane hydrogel could be used as a promising platform for tissue-engineering scaffold and biomedical application.


[Peptides derived from the extracellular loop of receptors: structure, mechanisms of action and application in physiology and medicine].
One of the main tasks of the peptide strategy, a new direction in modern biochemistry and physiology, is the creation of selective and effective regulators of hormonal signaling systems on the basis of the peptides corresponding to functionally important regions of signal proteins. At the last years the greatest interest is connected with peptides, derivatives of the extracellular loops of receptors of the serpentine type. With these peptides the molecular basis of interaction between receptors and their ligands are studied, the new approaches for construction and testing of highly selective agonists and antagonists are developed, the etiology and pathogenesis of diseases of human and animals induced by autoimmune reactions to the extracellular loops of receptors are investigated. It is shown that peptides corresponding to the extracellular loops of the receptors and the specific antibodies to them are capable to regulate the activity of hormonal signaling systems in vitro and in vivo and can be considered as functional probes for studying of physiological functions in the norm and pathology. In the review the data obtained during the last years concerning the structures, functions, mechanisms of action and practical application ofpeptides, derivatives of the extracellular loops of serpentine type receptors, are summarized and analyzed. The prospective of their use in fundamental biology and practical medicine are discussed.


Functional effects of the microbiota in chronic respiratory disease.
The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research.


Ultrathin PbS sheets by two-dimensional oriented attachment.
Controlling anisotropy is a key concept in the generation of complex functionality in advanced materials. For this concept, oriented attachment of nanocrystal building blocks, a self-assembly of particles into larger single-crystalline objects, is one of the most promising approaches in nanotechnology. We report here the two-dimensional oriented attachment of lead sulfide (PbS) nanocrystals into ultrathin single-crystal sheets with dimensions on the micrometer scale. We found that this process is initiated by cosolvents, which alter nucleation and growth rates during the primary nanocrystal formation, and is finally driven by dense packing of oleic acid ligands on {100} facets of PbS. The obtained nanosheets can be readily integrated in a photodetector device without further treatment.


Primary carcinoma of the choroid plexus in Li-Fraumeni syndrome: case report.
An 8-month-old female infant with a primary carcinoma of the choroid plexus developed a rhabdomyosarcoma in the anterior chest wall at the age of 1 year and 2 months. Her mother had developed a liposarcoma in her left thigh at the age of 17 years. One of the patient's siblings had a rhabdomyosarcoma of the epipharynx at the age of 1 year. This is the fourth reported case of a choroid plexus carcinoma occurring in Li-Fraumeni syndrome.


Can Speech-Guided Breathing Influence Cardiovascular Regulation and Mood Perception in Hypertensive Patients?
Anthroposophic therapeutic speech (ATS) has been shown to positively influence heart rate variability (HRV) and cardiorespiratory coordination in healthy volunteers. This prospective, exploratory, pre-post study was performed to investigate ATS effects on baroreflex sensitivity (BRS), heart rate (HR), HRV by standard deviation of beat to beat intervals (SDNN), blood pressure (BP), and mood in hypertensive patients. Patients received three ATS treatments, alternating with three sham interventions (control). During the sessions, BP and electrocardiography were continuously recorded. BRS and SDNN were analyzed from those measurements. Changes in mood score were assessed by a questionnaire. All data were compared before and after intervention (ATS and control). Thirty-one patients participated, the majority diagnosed with arterial hypertension (22 out of 31). Pre-post analysis of the data revealed immediate and significant changes in hypertensive patients during control and ATS with respect to BRS (control: 6.57 to 6.92 msec/mmHg, p = 0.0349; ATS: 6.03 to 7.27 msec/mmHg, p < 0.0001), SDNN (control: 39 to 42 msec, p = 0.0058; ATS: 38 to 43 msec, p = 0.0003), and HR (control: 74 to 71 beats per minute [bpm], p < 0.0001; ATS: 74 to 70 bpm, p < 0.0001). In normotensive patients, those changes were generally less pronounced and less significant with respect to BRS (control: 8.13 to 8.56 msec/mmHg, p = 0.1102; ATS: 8.20 to 8.98 msec/mmHg, p = 0.0273), SDNN (control: 36 to 40 msec, p = 0.0002; ATS: 35 to 38 msec, p = 0.0556), and HR (control: 80 to 77 bpm, p < 0.0001; ATS: 80 to 78 bpm, p < 0.0011). Only in hypertensive patients significant long-term changes were observed for BRS (6.6 to 7.7 msec/mmHg, p = 0.0070), SDNN (39.1 to 45.5 msec, p = 0.0074), and HR (75.8 to 67.2 bpm, p = 0.0001). No significant long-term changes were observed in normotensive patients. The mean systolic BP did not change significantly during this study. Both ATS and control also yielded improvements in the mood summary score, which again were more apparent for ATS than for sham interventions, but these were more pronounced among normotensive patients (3.5 to 4.2) than for hypertensive patients (2.9 to 3.9). The results indicate that ATS has the potential to improve cardiovascular parameters which play an important role in BP regulation capability.


Cognitive interventions in behavioral medicine.
In this report an overview is given of the contribution of cognitive approaches to behavioral medicine. The (possible) contribution of cognitive therapy is reviewed in the area of coronary heart disease, obesity, bulimia nervosa, chronic pain, benign headache, cancer, acquired immunodeficiency syndrome/human immunodeficiency virus and asthma. Although the relative contribution of cognitive therapy varies across these various disorders, its positive effects are now well established and new advances undoubtedly will be made in the next few years.


Considerations for Phage Therapy Against Mycobacterium abscessus.
There is a global increasing number of Mycobacterium abscessus infections, especially pulmonary infections. Reduced therapeutic options exist against this opportunistic pathogen due to its high intrinsic and acquired levels of antibiotic resistance. Phage therapy is a promising afresh therapy, which uses viruses to lyse bacteria responsible for the infection. Bacteriophages have been recently administered under compassionate use to a 15-year-old patient infected with M. abscessus in combination with antibiotics with excellent results. This mini review highlights different recommendations for future phage administrations such as where to look for new phages, the use of cocktail of mycobacteriophages to broaden phage specificity and to tackle resistance and phage insensitivity due to temperate phages present in bacterial genomes, the combined use of phages and antibiotics to obtain a synergistic effect, the liposomal administration to reach a prolonged effect, intracellular delivery and protection against neutralizing antibodies, and the convenience of using this strategy in patients suffering from cystic fibrosis (CF) since phages are believed to promote immunomodulatory actions and eliminate biofilms.