Exposure to Environmental Toxicants and Early Language Development for Children Reared in Low-Income Households.
Considerable evidence has highlighted the heightened susceptibility of developmental delay in children from low-income homes; consequently, this study explored whether environmental toxicant exposure may be a contributing factor to disruption in language and cognitive development for children reared in poverty. Using a sample of 190 low-income mothers and their young children, mothers completed questionnaires on toxicant exposure in the home environment. Exposure to toxicants, especially pesticides, was reported by about 20% of mothers at or around pregnancy, and 30% when their children were between 1 and 2 years of age. Toxicant exposure was significantly associated with lags in language and cognition even when controlling for socioeconomic factors. Study findings highlight the importance of the American Academy of Pediatrics' policy statements arguing for pediatricians to take a strong anticipatory guidance role in counseling parents to limit chemical exposure in the home and engage in safe storage practices.


Perceptually stable regions for arbitrary polygons.
Zou and Yan have recently developed a skeletonization algorithm of digital shapes based on a regularity/singularity analysis; they use the polygon whose vertices are the boundary pixels of the image to compute a constrained Delaunay triangulation (CDT) in order to find local symmetries and stable regions. Their method has produced good results but it is slow since its complexity depends on the number of contour pixels. This paper presents an extension of their technique to handle arbitrary polygons, not only polygons of short edges. Consequently, not only can we achieve results as good as theirs for digital images, but we can also compute skeletons of polygons of any number of edges. Since we can handle polygonal approximations of figures, the skeletons are more resilient to noise and faster to process.


[Kinetics of through EDTA-modified calcium channels of the somatic membrane of mollusk neurons].
Kinetics of slow current carried by sodium ions through the potential-dependent calcium channels provided that EDTA is introduced into Ca-free external solution was studied in experiments on isolated internally dialyzed neurons of the mollusc Helix pomatia. Activation kinetics of this current was similar to that of initial calcium current. It can be described using the square power of the activation variable m in the Hodgkin-Huxley equations. Kinetics of decay (inactivation) of the induced sodium current is biexponential during prolonged depolarization of the membrane. On this basis it is suggested that the decay of the sodium current results from two independent processes: voltage-dependent inactivation to some steady-state level hoo with time constant tauh approximately 1 s and a decrease of the current due to accumulation of Na+ ions inside the cell and, consequently, to a change in electrochemical potential for Na+ ions (tau c approximately 10 s). It is concluded that modification of calcium channels resulting in ability for passing sodium ions does not affect gating mechanisms which open or close the channels.


Eravacycline (TP-434) is active in vitro against biofilms formed by uropathogenic Escherichia coli.
Eravacycline (formerly TP-434) was evaluated in vitro against pre-established biofilms formed by a uropathogenic Escherichia coli strain. Biofilms were eradicated by 0.5 μg/ml eravacycline, which was within 2-fold of the MIC for planktonic cells. In contrast, colistin and meropenem disrupted biofilms at 32 and 2 μg/ml, respectively, concentrations well above their respective MICs of 0.5 and 0.03 μg/ml. Gentamicin and levofloxacin eradicated biofilms at concentrations within 2-fold of their MICs.


Micromanipulation of Mechanically Compliant Organic Single-Crystal Optical Microwaveguides.
Flexible organic single crystals are evolving as new materials for optical waveguides that can be used for transfer of information in organic optoelectronic microcircuits. Integration in microelectronics of such crystalline waveguides requires downsizing and precise spatial control over their shape and size at the microscale, however that currently is not possible due to difficulties with manipulation of these small, brittle objects that are prone to cracking and disintegration. Here we demonstrate that atomic force microscopy (AFM) can be used to reshape, resize and relocate single-crystal microwaveguides in order to attain spatial control over their light output. Using an AFM cantilever tip, mechanically compliant acicular microcrystals of three N-benzylideneanilines were bent to an arbitrary angle, sliced out from a bundle into individual crystals, cut into shorter crystals of arbitrary length, and moved across and above a solid surface. When excited by using laser light, such bent microcrystals act as active optical microwaveguides that transduce their fluorescence, with the total intensity of transduced light being dependent on the optical path length. This micromanipulation of the crystal waveguides using AFM is non-invasive, and after bending their emissive spectral output remains unaltered. The approach reported here effectively overcomes the difficulties that are commonly encountered with reshaping and positioning of small delicate objects (the "thick fingers" problem), and can be applied to mechanically reconfigure organic optical waveguides in order to attain spatial control over their output in two and three dimensions in optical microcircuits.


Serum Alkaline Phosphatase Predicts Poor Disease-Free Survival in Patients Receiving Radical Gastrectomy.
BACKGROUND Serum alkaline phosphatase (ALP) has been proved to be a negative prognostic factor for several malignancies, but its clinical significance in gastric cancer (GC) patients has not been sufficiently studied. In the present retrospective study, we investigated the effect of serum ALP on disease-free survival (DFS) after radical gastrectomy. MATERIAL AND METHODS We included 491 GC patients receiving radical gastrectomy at the Chinese People's Liberation Army 309th Hospital. Univariate and multivariate analyses were performed to determine factors influencing serum ALP and DFS. The changes in serum ALP and its clinical relevance were also analyzed using the log-rank test and Cox proportional hazards model. RESULTS There were 491 patients who met our inclusion and exclusion criteria. Pre-treatment serum ALP was elevated in 87 of these patients and was normal in the other 404 patients. Elevation of pre-treatment serum ALP was correlated with the tumor diameter (OR=2.642, P=0.017), TNM stage (OR=4.592, P=0.005), and T classification (OR=1.746, P=0.043). DFS was significantly different between patients with normal or elevated pre-treatment serum ALP (median 42.1 vs. 32.8 months, P=0.001) and multivariate analysis suggested pre-treatment serum ALP is an independent risk factor for poor DFS after radical gastrectomy (HR=2.035, P=0.021). In addition, removal of the primary tumor lesion led to an obvious decline in serum ALP activity (median 262 U/L vs. 152 U/L, P<0.001), and monitoring changes in serum ALP can help evaluate the risk of tumor relapse in GC patients (χ²=17.814, P<0.001). CONCLUSIONS Serum ALP is a good predictor of GC patient DFS after radical gastrectomy, and patients with elevated serum ALP have shorter relapse times.


Adsorption and carbonylation of plasma proteins by dialyser membrane material: in vitro and in vivo proteomics investigations.
Protein carbonylation is an irreversible and not reparable reaction which is caused by the introduction into proteins of carbonyl derivatives such as ketones and aldehydes, generated from direct oxidation processes or from secondary protein reaction with reactive carbonyl compounds. Several studies have demonstrated significantly increased levels of reactive carbonyl compounds, a general increase in plasma protein carbonyls and carbonyl formation on major plasma proteins in blood from uremic patients, particularly those undergoing chronic haemodialysis. In the present preliminary study, we first assessed by an in vitro filtration apparatus the possible effects of different materials used for haemodialysis membranes on protein retention and carbonylation. We employed hollow fiber minidialyzers of identical structural characteristics composed of either polymethylmethacrylate, ethylenevinyl alcohol, or cellulose diacetate materials. Protein Western Blot and SDS-PAGE coupled to mass spectrometry analysis were applied to highlight the carbonylated protein-binding characteristics of the different materials. We also investigated in vivo protein carbonylation and carboxy methyl lisine-modification in plasma obtained before and after a haemodialysis session. Our data underline a different capability on protein adsorption associated with the different properties of the filter materials, highlighting the central buffering and protective role of serum albumin. In particular, polymethylmethacrylate and cellulose diacetate showed, in vitro, the highest capacity of binding plasma proteins on the surface of the hollow fiber minidialyzers. The present study suggests that biomaterials used for fabrication of haemodialysis membrane may affect the carbonyl balance in chronic uremic patients.


Environmental stresses and skeletal deformities in fish from the Willamette River, Oregon.
The Willamette River, one of 14 American Heritage Rivers, flows through the most densely populated and agriculturally productive region of Oregon. Previous biological monitoring of the Willamette River detected elevated frequencies of skeletal deformities in fish from certain areas of the lower (Newberg pool [NP], rivermile [RM] 26 - 55) and middle (Wheatland Ferry [WF], RM 72 - 74) river, relative to those in the upper river (Corvallis [CV], RM 125-138). The objective of this study was to determine the likely cause of these skeletal deformities. In 2002 and 2003, deformity loads in Willamette River fishes were 2-3 times greater at the NP and WF locations than at the CV location. There were some differences in water quality parameters between the NP and CV sites, but they did not readily explain the difference in deformity loads. Concentrations of bioavailable metals were below detection limits (0.6 - 1 microg/ L). Concentrations of bioavailable polychlorinated biphenyls (PCBs) and chlorinated pesticides were generally below 0.25 ng/L. Concentrations of bioavailable polycyclic aromatic hydrocarbons were generally less than 5 ng/L. Concentrations of most persistent organic pollutants were below detection limits in ovary/oocyte tissue samples and sediments, and those that were detected were not significantly different among sites. Bioassay of Willamette River water extracts provided no evidence that unidentified compounds or the complex mixture of compounds present in the extracts could induce skeletal deformities in cyprinid fish. However, metacercariae of a digenean trematode were directly associated with a large percentage of deformities detected in two Willamette River fishes, and similar deformities were reproduced in laboratoryfathead minnows exposed to cercariae extracted from Willamette River snails. Thus, the weight of evidence suggests that parasitic infection, not chemical contaminants, was the primary cause of skeletal deformities observed in Willamette River fish.


New methods for the detection of Chlamydia trachomatis.
The increasing worldwide recognition of the deleterious sequelae of Chlamydia trachomatis urogenital tract infections makes rapid, inexpensive diagnostic tests a high priority. Cell culture, still the standard for all other methods, is only 90% sensitive. Direct fluorescent antibody (FA) tests use highly specific monoclonal fluorescing antibodies directed against the elementary body, permitting direct examination of urethral and endo-cervical smears. These tests are highly sensitive (92% to 95%) and specific (95% to 96%). Major drawbacks are cost, need for a fluorescence microscope, the care required to collect and prepare adequate smears (up to 10% of smears are unacceptable), and the expertise required to interpret slides. By means of enzyme-linked immunoassay (EIA) tests large batches of specimens can be tested in a few hours; they require little technician time and no subjective interpretation, but their sensitivity appears to be less than that of the direct FA tests. Analysis of Gram-stained urethral and endocervical specimens, combined with gonococcal cultures in women, is still the cheapest, most rapid method of establishing a presumptive diagnosis of chlamydial urethritis and endocervicitis. In sexually transmitted disease clinics it is still the method of choice. An EIA test can be used for high-volume screening of women but should be used only in high-risk populations because its predictive value falls sharply as the prevalence of infection decreases.


Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.
Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.


Direct-on-Filter α-Quartz Estimation in Respirable Coal Mine Dust Using Transmission Fourier Transform Infrared Spectrometry and Partial Least Squares Regression.
In order to help reduce silicosis in miners, the National Institute for Occupational Health and Safety (NIOSH) is developing field-portable methods for measuring airborne respirable crystalline silica (RCS), specifically the polymorph α-quartz, in mine dusts. In this study we demonstrate the feasibility of end-of-shift measurement of α-quartz using a direct-on-filter (DoF) method to analyze coal mine dust samples deposited onto polyvinyl chloride filters. The DoF method is potentially amenable for on-site analyses, but deviates from the current regulatory determination of RCS for coal mines by eliminating two sample preparation steps: ashing the sampling filter and redepositing the ash prior to quantification by Fourier transform infrared (FT-IR) spectrometry. In this study, the FT-IR spectra of 66 coal dust samples from active mines were used, and the RCS was quantified by using: (1) an ordinary least squares (OLS) calibration approach that utilizes standard silica material as done in the Mine Safety and Health Administration's P7 method; and (2) a partial least squares (PLS) regression approach. Both were capable of accounting for kaolinite, which can confound the IR analysis of silica. The OLS method utilized analytical standards for silica calibration and kaolin correction, resulting in a good linear correlation with P7 results and minimal bias but with the accuracy limited by the presence of kaolinite. The PLS approach also produced predictions well-correlated to the P7 method, as well as better accuracy in RCS prediction, and no bias due to variable kaolinite mass. Besides decreased sensitivity to mineral or substrate confounders, PLS has the advantage that the analyst is not required to correct for the presence of kaolinite or background interferences related to the substrate, making the method potentially viable for automated RCS prediction in the field. This study demonstrated the efficacy of FT-IR transmission spectrometry for silica determination in coal mine dusts, using both OLS and PLS analyses, when kaolinite was present.


Development of follicular dendritic cells in lymph nodes depends on retinoic acid-mediated signaling.
Specialized stromal cells occupy and help define B- and T-cell domains, which are crucial for proper functioning of our immune system. Signaling through lymphotoxin and TNF receptors is crucial for the development of different stromal subsets, which are thought to arise from a common precursor. However, mechanisms that control the selective generation of the different stromal phenotypes are not known. Using in vitro cultures of embryonic mouse stromal cells, we show that retinoic acid-mediated signaling is important for the differentiation of precursors towards the Cxcl13pos follicular dendritic cell (FDC) lineage, and also blocks lymphotoxin-mediated Ccl19pos fibroblastic reticular cell lineage differentiation. Accordingly, at the day of birth we observe the presence of Cxcl13posCcl19neg/low and Cxcl13neg/lowCcl19pos cells within neonatal lymph nodes. Furthermore, ablation of retinoic acid receptor signaling in stromal precursors early after birth reduces Cxcl13 expression, and complete blockade of retinoic acid signaling prevents the formation of FDC networks in lymph nodes.


Bayesian inference underlies the contraction bias in delayed comparison tasks.
Delayed comparison tasks are widely used in the study of working memory and perception in psychology and neuroscience. It has long been known, however, that decisions in these tasks are biased. When the two stimuli in a delayed comparison trial are small in magnitude, subjects tend to report that the first stimulus is larger than the second stimulus. In contrast, subjects tend to report that the second stimulus is larger than the first when the stimuli are relatively large. Here we study the computational principles underlying this bias, also known as the contraction bias. We propose that the contraction bias results from a Bayesian computation in which a noisy representation of a magnitude is combined with a-priori information about the distribution of magnitudes to optimize performance. We test our hypothesis on choice behavior in a visual delayed comparison experiment by studying the effect of (i) changing the prior distribution and (ii) changing the uncertainty in the memorized stimulus. We show that choice behavior in both manipulations is consistent with the performance of an observer who uses a Bayesian inference in order to improve performance. Moreover, our results suggest that the contraction bias arises during memory retrieval/decision making and not during memory encoding. These results support the notion that the contraction bias illusion can be understood as resulting from optimality considerations.


Pituitary adenylate cyclase activating polypeptide concentrations in the sheep mammary gland, milk, and in the lamb blood plasma after suckling.
Pituitary adenylate cyclase activating polypeptide (PACAP) is involved in development and reproduction. We previously described elevated PACAP levels in the milk compared to the plasma, and the presence of its specific PAC1 receptor in the mammary gland. This study aimed to determine PACAP and vasoactive intestinal peptide (VIP) levels in female suckling lambs compared to ewe plasma and mammary gland, as well as their age-dependent alterations. mRNA expressions of PACAP, VIP, PAC1 receptor and brain-derived neurotrophic factor (BDNF) were quantified in the milk whey and mammary gland. PACAP38-like immunoreactivity (PACAP38-LI) was measured in plasma, milk whey and mammary gland by radioimmunoassay, VIP-LI by enzyme-linked immunoassay. PACAP38-LI was 5, 6 times higher in the milk compared to the plasma of lactating sheep. It significantly increased in the lamb plasma 1 h, but returned to basal level 2 h after suckling. However, VIP mRNA was not present in the mammary gland, we detected the VIP protein in the milk whey. BDNF mRNA significantly decreased with age to approximately 60% and 25% in the 3- and 10-year-old sheep respectively, compared to the 3-month-old lambs. No differences were found between mammary and jugular vein plasma PACAP and VIP concentrations, or during the daily cycle. We propose a rapid absorption of PACAP38 from the milk and/or its release in suckling lambs. PACAP accumulated in the milk might be synthesized in the mammary gland or secreted from the plasma of the mothers. PACAP is suggested to have differentiation/proliferation promoting and immunomodulatory effects in the newborns and/or a local function in the mammary gland.


[Pneumocystis carinii pneumonia].
A study is carried out in 8 infants with a diagnosis of Pneumocystis carinii pneumonia which was established through the study of histologic lung sections, and a microscopic study of protozoas. The following are some of the factors predisposing to this disease: prematurity, significant denutrition, primary immunodeficiencies, extended use of antibiotics, malignancies, and immunosuppressive treatments.


Racial and ethnic disparities in "stop-and-frisk" experience among young sexual minority men in New York City.
Although racial/ethnic disparities in police contact are well documented, less is known about other dimensions of inequity in policing. Sexual minority groups may face disproportionate police contact. We used data from the P18 Cohort Study (Version 2), a study conducted to measure determinants of inequity in STI/HIV risk among young sexual minority men (YSMM) in New York City, to measure across-time trends, racial/ethnic disparities, and correlates of self-reported stop-and-frisk experience over the cohort follow-up (2014-2019). Over the study period, 43% reported stop-and-frisk with higher levels reported among Black (47%) and Hispanic/Latinx (45%) than White (38%) participants. Stop-and-frisk levels declined over follow-up for each racial/ethnic group. The per capita rates among P18 participants calculated based on self-reported stop-and-frisk were much higher than rates calculated based on New York City Police Department official counts. We stratified respondents' ZIP codes of residence into tertiles of per capita stop rates and observed pronounced disparities in Black versus White stop-and-frisk rates, particularly in neighborhoods with low or moderate levels of stop-and-frisk activity. YSMM facing the greatest economic vulnerability and mental disorder symptoms were most likely to report stop-and-frisk. Among White respondents levels of past year stop-and-frisk were markedly higher among those who reported past 30 day marijuana use (41%) versus those reporting no use (17%) while among Black and Hispanic/Latinx respondents stop-and-frisk levels were comparable among those reporting marijuana use (38%) versus those reporting no use (31%). These findings suggest inequity in policing is observed not only among racial/ethnic but also sexual minority groups and that racial/ethnic YSMM, who are at the intersection of multiple minority statuses, face disproportionate risk. Because the most socially vulnerable experience disproportionate stop-and-frisk risk, we need to reach YSMM with community resources to promote health and wellbeing as an alternative to targeting this group with stressful and stigmatizing police exposure.


The blood-ocular barriers under osmotic stress. Studies on the freeze-dried eye.
Regional differences in the response of primate blood-ocular barriers to severe osmotic stress were measured. Marker dyes were localized by fluorescence microscopy in tissues that had been freeze-dried to prevent diffusion. Under severe osmotic stress, the form and the function of the ciliary process are grossly compromised while the iris is spared. Breakdown of the retinal pigment epithelial barrier is widespread, while the retinal blood vessels in large areas retain normal permeability characteristics. The pigment epithelial barrier mechanism is substantially more susceptible to osmotic stress in the region surrounding the optic disc than in the equatorial area.


Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment.
Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.


Post-translational regulation and modifications of flavivirus structural proteins.
Flaviviruses are a group of single-stranded, positive-sense RNA viruses that generally circulate between arthropod vectors and susceptible vertebrate hosts, producing significant human and veterinary disease burdens. Intensive research efforts have broadened our scientific understanding of the replication cycles of these viruses and have revealed several elegant and tightly co-ordinated post-translational modifications that regulate the activity of viral proteins. The three structural proteins in particular - capsid (C), pre-membrane (prM) and envelope (E) - are subjected to strict regulatory modifications as they progress from translation through virus particle assembly and egress. The timing of proteolytic cleavage events at the C-prM junction directly influences the degree of genomic RNA packaging into nascent virions. Proteolytic maturation of prM by host furin during Golgi transit facilitates rearrangement of the E proteins at the virion surface, exposing the fusion loop and thus increasing particle infectivity. Specific interactions between the prM and E proteins are also important for particle assembly, as prM acts as a chaperone, facilitating correct conformational folding of E. It is only once prM/E heterodimers form that these proteins can be secreted efficiently. The addition of branched glycans to the prM and E proteins during virion transit also plays a key role in modulating the rate of secretion, pH sensitivity and infectivity of flavivirus particles. The insights gained from research into post-translational regulation of structural proteins are beginning to be applied in the rational design of improved flavivirus vaccine candidates and make attractive targets for the development of novel therapeutics.


Compensatory neurofuzzy systems with fast learning algorithms.
In this paper, a new adaptive fuzzy reasoning method using compensatory fuzzy operators is proposed to make a fuzzy logic system more adaptive and more effective. Such a compensatory fuzzy logic system is proved to be a universal approximator. The compensatory neural fuzzy networks built by both control-oriented fuzzy neurons and decision-oriented fuzzy neurons cannot only adaptively adjust fuzzy membership functions but also dynamically optimize the adaptive fuzzy reasoning by using a compensatory learning algorithm. The simulation results of a cart-pole balancing system and nonlinear system modeling have shown that: 1) the compensatory neurofuzzy system can effectively learn commonly used fuzzy IF-THEN rules from either well-defined initial data or ill-defined data; 2) the convergence speed of the compensatory learning algorithm is faster than that of the conventional backpropagation algorithm; and 3) the efficiency of the compensatory learning algorithm can be improved by choosing an appropriate compensatory degree.


Microencapsulation: A promising technique for controlled drug delivery.
MICROPARTICLES OFFER VARIOUS SIGNIFICANT ADVANTAGES AS DRUG DELIVERY SYSTEMS, INCLUDING: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed.


Phase II clinical trial of a murine monoclonal antibody cytotoxic for gastrointestinal adenocarcinoma.
A murine monoclonal antibody (MAb) which binds to human metastatic gastrointestinal adenocarcinomas can be administered safely and has tumor effects in some patients. Its therapeutic effect was assessed in 20 patients with measurable advanced colorectal carcinoma that was refractory to prior surgical resection, chemotherapy, and/or radiotherapy. All patients had agreed to receive no other therapy at the time of MAb administration and follow-up evaluation. In one patient, tumor at all known sites responded after a single i.v. injection of antibody. One other patient had a marked reduction in a hepatic metastasis where binding of 131I-labeled F(ab')2 MAb fragments was demonstrated but not in his abdominal wall metastases where no MAb binding could be demonstrated. In a third patient, stabilization persisting for 12 mo of an aggressively growing tumor was observed. The antibody was well tolerated in all patients, although 10 patients mounted an anti-murine immunoglobulin antibody response.


The role of the pro-apoptotic Bcl-2 family member bim in physiological cell death.
Apoptosis, an evolutionarily conserved process for killing unwanted cells in multicellular organisms, is essential for normal development, tissue homeostasis and as a defense against pathogens. The control of apoptosis is of considerable importance for clinical medicine, as its deregulation can lead to cancer, autoimmunity or degenerative diseases. We have disrupted the Bim gene in the mouse and demonstrated that it plays a major and non-redundant role in embryogenesis, in the control of hematopoietic cell death, and as a barrier against autoimmunity.


Outcome of total hip replacement for avascular necrosis in systemic lupus erythematosus.
To describe the short and medium term results of total hip arthroplasty (THA) for avascular necrosis in patients with systemic lupus erythematosus (SLE). Nineteen patients with SLE and avascular necrosis of the femoral head (AVNFH), who underwent 26 THA were retrospectively reviewed with a minimum followup of 2 years. To determine whether these patients had results similar to those of patients with other conditions, we formed a control group of 19 patients who had 29 THA. They were matched for age, sex, and followup to the patients with SLE. Controls had THA for juvenile rheumatoid arthritis (n = 7), osteoarthritis (5), adult onset rheumatoid arthritis (8), developmental dysplasia of the hip (4), and other diagnoses (5). Outcome measures included a 10 point visual analog scale (VAS) for pain, the Harris hip score, and the SF-36 self-administered health outcome questionnaire. We used the methods of Delee, Harris, and Engh for radiological assessment. Mean age at surgery was 46 years (range 21-71 years) and average followup was 4 years, 7 months (range 1 yr 9 mo to 9 yrs 6 mo), similar in both groups. Technical problems, mostly consisting of small, nonpropagating cracks of the calcar in uncemented stems, were encountered in 4 SLE hips and 1 control hip. Six complications were noted in the SLE group, including 2 early, nonrecurrent dislocations, 1 patient with thigh pain for 1 year, 1 pericarditis, 1 sick-sinus syndrome, and 1 urinary tract infection. There was one case of urinary tract infection in the control group. One SLE patient developed a low grade prosthetic infection and underwent successful revision 2 years after primary surgery. Clinical outcome measures had similar scores in the 2 groups: average VAS pain score = 2.00 in SLE hips (maximum 10) and 1.97 in control hips; mean Harris hip score = 86.7 in SLE patients (maximum 100) and 81.9 in controls; average SF-36 score = 63.4 in SLE patients (maximum 100) and 60.5 in controls. There was no radiological evidence of implant loosening in controls; there was 1 asymptomatic cup migration in the SLE group. In the short and medium term, patients with SLE and AVN had good results after THA. Results were similar in patients who had hip replacement for other diagnoses. Less favorable clinical outcomes of hip replacement have been reported in young patients who have AVN of other etiology (e.g., alcoholic, post-traumatic), but this was not the case in our young patients who had AVN and SLE. Thus, AVNFH and SLE should not constitute a contraindication to hip replacement.


Responses of medullary dorsal horn neurons to corneal stimulation by CO(2) pulses in the rat.
Corneal-responsive neurons were recorded extracellularly in two regions of the spinal trigeminal nucleus, subnucleus interpolaris/caudalis (Vi/Vc) and subnucleus caudalis/upper cervical cord (Vc/C1) transition regions, from methohexital-anesthetized male rats. Thirty-nine Vi/Vc and 26 Vc/C1 neurons that responded to mechanical and electrical stimulation of the cornea were examined for convergent cutaneous receptive fields, responses to natural stimulation of the corneal surface by CO(2) pulses (0, 30, 60, 80, and 95%), effects of morphine, and projections to the contralateral thalamus. Forty-six percent of mechanically sensitive Vi/Vc neurons and 58% of Vc/C1 neurons were excited by CO(2) stimulation. The evoked activity of most cells occurred at 60% CO(2) after a delay of 7-22 s. At the Vi/Vc transition three response patterns were seen. Type I cells (n = 11) displayed an increase in activity with increasing CO(2) concentration. Type II cells (n = 7) displayed a biphasic response, an initial inhibition followed by excitation in which the magnitude of the excitatory phase was dependent on CO(2) concentration. A third category of Vi/Vc cells (type III, n = 3) responded to CO(2) pulses only after morphine administration (>1.0 mg/kg). At the Vc/C1 transition, all CO(2)-responsive cells (n = 15) displayed an increase in firing rates with greater CO(2) concentration, similar to the pattern of type I Vi/Vc cells. Comparisons of the effects of CO(2) pulses on Vi/Vc type I units, Vi/Vc type II units, and Vc/C1 corneal units revealed no significant differences in threshold intensity, stimulus encoding, or latency to sustained firing. Morphine (0.5-3.5 mg/kg iv) enhanced the CO(2)-evoked activity of 50% of Vi/Vc neurons tested, whereas all Vc/C1 cells were inhibited in a dose-dependent, naloxone-reversible manner. Stimulation of the contralateral posterior thalamic nucleus antidromically activated 37% of Vc/C1 corneal units; however, no effective sites were found within the ventral posteromedial thalamic nucleus or nucleus submedius. None of the Vi/Vc corneal units tested were antidromically activated from sites within these thalamic regions. Corneal-responsive neurons in the Vi/Vc and Vc/C1 regions likely serve different functions in ocular nociception, a conclusion reflected more by the difference in sensitivity to analgesic drugs and efferent projection targets than by the CO(2) stimulus intensity encoding functions. Collectively, the properties of Vc/C1 corneal neurons were consistent with a role in the sensory-discriminative aspects of ocular pain due to chemical irritation. The unique and heterogeneous properties of Vi/Vc corneal neurons suggested involvement in more specialized ocular functions such as reflex control of tear formation or eye blinks or recruitment of antinociceptive control pathways.


Static and dynamic responses of carotid sinus baroreceptors in dogs with chronic volume overload.
In this study we determined if there are any alterations in carotid sinus baroreceptor discharge in a model of heart failure in the dog. The left carotid sinus was isolated and perfused at 100 mmHg with a modified Krebs-Henseleit solution. Two groups of dogs were used: a normal group and a group with a chronic aorto-caval fistula (a.v.f.) of up to 20 weeks duration. The a.v.f. group had a significantly elevated heart rate and left ventricular end diastolic pressure as well as an increased arterial pulse pressure compared to normals. However, mean arterial pressure measured in the aortic arch was not significantly different. Carotid sinus pressure-discharge curves were constructed during increases in carotid sinus pressure by steps and by ramps of pressure change up to 200 mmHg/s. Carotid sinus diameter was also measured using sonomicrometer crystals. In six dogs from each group the sodium, potassium and water content of the right carotid sinus was measured. Several parameters of second order polynomial curves that were fitted to the data were compared between the two groups for step and ramp increases in pressure. These included maximum baroreceptor gain, threshold pressure and plateau pressure. Baroreceptor gain was significantly lower in the a.v.f. group for the step and lowest ramp rate pressure changes. Threshold pressure was significantly higher for the a.v.f. group for steps and the three slowest ramp rates. Plateau pressures were significantly higher for the steps and lowest ramp rate. The carotid sinus strain that was produced at any given carotid sinus pressure was not significantly different between the two groups. In addition, there was no difference in the sodium, potassium or water content of the carotid sinus between the two groups. It was concluded that there is a depression of the static discharge characteristics in this model of heart failure which is not due to an alteration in electrolyte or water content or to the compliance of the carotid sinus.


Partial interchangeability of Fz3 and Fz6 in tissue polarity signaling for epithelial orientation and axon growth and guidance.
In mammals, a set of anatomically diverse polarity processes - including axon growth and guidance, hair follicle orientation, and stereociliary bundle orientation in inner ear sensory hair cells - appear to be mechanistically related, as judged by their dependence on vertebrate homologues of core tissue polarity/planar cell polarity (PCP) genes in Drosophila. To explore more deeply the mechanistic similarities between different polarity processes, we have determined the extent to which frizzled 3 (Fz3) can rescue the hair follicle and Merkel cell polarity defects in frizzled 6-null (Fz6(-/-)) mice, and, reciprocally, the extent to which Fz6 can rescue the axon growth and guidance defects in Fz3(-/-) mice. These experiments reveal full rescue of the Fz6(-/-) phenotype by Fz3 and partial rescue of the Fz3(-/-) phenotype by Fz6, implying that these two proteins are likely to act in a conserved manner in these two contexts. Stimulated by these observations, we searched for additional anatomical structures that exhibit macroscopic polarity and that might plausibly use Fz3 and/or Fz6 signaling. This search has revealed a hitherto unappreciated pattern of papillae on the dorsal surface of the tongue that depends, at least in part, on redundant signaling by Fz3 and Fz6. Taken together, these experiments provide compelling evidence for a close mechanistic relationship between multiple anatomically diverse polarity processes.


Facial Landmark based BMI Analysis for Pervasive Health Informatics.
Body Mass Index (BMI), calculated based on the ratio between a person's height and weight, is a widely used metric for body weight or fatness. In this paper, we investigate the potential of face image-based BMI estimation using an RGB camera. We proposed a simple yet highly reproducible image processing framework that converts an input face image into a BMI value or obesity class (underweight, normal and overweight). In this framework, we explored the options of using 2D or 3D facial landmark models, view angle correction in 2D and 3D, different choices for facial feature extraction (landmark distances or coordinates), and different prediction models (regression or classification) based on shallow machine learning techniques. Our framework was thoroughly validated on two public datasets. The insights of this measurement are discussed, as well as the challenges and limitations, to increase the understanding for future improvement of camera-based BMI estimation. The source code of this study is available at https://github.com/hxfj/Facial-Landmark-based-BMI-Analysis.git.Clinical relevance- This contributes to simpler and more effective daily health management.


Touching the microworld with force-feedback optical tweezers.
Optical tweezers are a powerful tool for micromanipulation and measurement of picoNewton sized forces. However, conventional interfaces present difficulties as the user cannot feel the forces involved. We present an interface to optical tweezers, based around a low-cost commercial force feedback device. The different dynamics of the micro-world make intuitive force feedback a challenge. We propose a coupling method using an existing optical tweezers system and discuss stability and transparency. Our system allows the user to perceive real Brownian motion and viscosity, as well as forces exerted during manipulation of objects by a trapped bead.


Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse.
Hippocampal plasticity (e.g. neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and 5-bromo-2'-deoxyuridine for older cells born prior to sensitization. Results show that: (i) bHRs exhibited greater psychomotor response to cocaine than bLRs; (ii) acute cocaine did not alter cell proliferation in bLR/bHR rats; (iii) chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence; (iv) neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype; (v) cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine; and (vi) cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR vs. bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs, which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization.


Purpuric Drug Eruptions Caused by Epidermal Growth Factor Receptor Inhibitors for Non-Small Cell Lung Cancer: A Clinicopathologic Study of 32 Cases.
Purpuric skin lesions have only rarely been reported in patients receiving epidermal growth factor receptor inhibitors. However, their clinical and histopathologic presentations have varied considerably. To characterize purpuric skin eruptions caused by epidermal growth factor receptor inhibitors. This prospective study enrolled 32 patients who presented to an integrated dermato-oncologic clinic in a tertiary referral medical center with purpuric skin lesions after using epidermal growth factor receptor inhibitors from January 1, 2013, through December 31, 2015. Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, erlotinib, and afatinib. Clinical presentations, histopathologic features, laboratory examinations, and treatment outcomes of patients with purpuric drug eruptions. Thirty-two patients, 14 with purpuric drug eruptions without pustules (mean [SD] age, 60 [11] years; 12 female and 2 male) and 18 with purpuric drug eruptions with pustules (mean [SD] age, 64 [11] years; 12 female and 6 male), were identified. The median time to development of skin lesions was 3.5 months. The clinical presentations were characterized by purpuric macules, papules, and confluent plaques predominantly on the lower extremities. Pustules in various sizes could be found in 18 patients (56%). Eleven patients (34%) had skin lesions that covered places other than the lower extremities. Eczema craquelé-like features developed in 13 patients (41%). Bacterial pathogens were frequently identified in these skin lesions. Among them, Staphylococcus aureus was the most predominant and was found in 20 patients (63%), commonly in those with cutaneous pustules. Epidermal dysmaturation, neutrophil exocytosis, perivascular infiltration of lymphocytes and neutrophils, red blood cell extravasation, and plumping endothelium were the main histopathologic features. The expressions of filaggrin and human β-defensin 2 in lesional skin of these patients were markedly reduced. All patients improved after receiving at least 1 week of systemic antibiotic treatment; the doses of epidermal growth factor receptor inhibitors were also changed for 14 patients (44%). Purpuric drug eruptions caused by epidermal growth factor receptor inhibitors are uncommon and have characteristic clinical and histopathologic presentations. The role of bacterial pathogens in this reaction is important and requires further exploration.


Ube3a/E6AP is involved in a subset of MeCP2 functions.
Rett syndrome (RTT) and Angelman syndrome (AS) are devastating neurological disorders that share many clinical features. The disease-causing mutations have been identified for both syndromes. Mutations in Methyl-CpG Binding Protein 2 (MECP2) are found in a majority of patients with classical RTT while absence of maternal allele or intragenic mutation in the maternal copy of UBE3A gene encoding the human papilloma virus E6-associated protein (E6AP) cause most cases of AS. Extensive studies have been performed to determine the cause of the neurological problems in each disease. However, the genetic and molecular basis of the overlap in phenotypes between RTT and AS remains largely unknown. Here we present evidence that the phenotypic similarities between the two syndromes might be due to the shared molecular functions between MeCP2 and E6AP in gene expression. Our genetic and biochemical studies suggest that E6AP acts as an essential cofactor for a subset of MeCP2 functions. Specifically, decreased expression of Ube3a was able to rescue the cellular phenotypes induced by MECP2-overexpression in Drosophila. And biochemical assays using mice and cell culture systems show that MeCP2 and E6AP physically interact and regulate the expression of shared target genes. Together these data suggest that MeCP2 and E6AP play a role in the transcriptional control of common target gene expression and provide some insight into why RTT and AS share several neurological phenotypes.


Multimorbidity: will it stand the test of time?
The concept of multimorbidity has risen in popularity over the past few years. Its use has led to, or coincided with, an increased recognition that patients often have more than one health problem which should not be treated in isolation. The motivation for more holistic, person-centred care that lies behind multimorbidity is to be welcomed. The 2016 National Institute for Health and Care Excellence multimorbidity management guideline helpfully makes recommendations in key areas that are important in the care of patients with complicated medical problems.However, we question the sustainability of the term for the following four reasons: (i) it is doctor and researcher centred rather than patient centred, focusing upon the number of diagnoses rather than the patient's lived experience, (ii) it is not a positive term for patients and is at odds with the move towards promoting active and healthy ageing, (iii) its non-specific nature means it holds little value in daily clinical practice and (iv) most definitions apply to a large segment of the population making it of limited use for health care planners. We argue that the complementary concepts of complexity and frailty would fit better with the delivery of patient centred care for people with multiple co-existing health problems and would be more useful to clinicians, commissioners and researchers.


An extremely rare case of adrenocortical cancer with cannon ball pulmonary metastasis.
Multiple pulmonary nodules on chest X-ray, known commonly as cannon ball secondaries, are the classical presentation of hematogenous dissemination of a malignant tumor to the lungs. This almost always indicates an advanced stage of the disease with a very grim outlook in terms of cure or survival. In this case report, we present a patient with very extensive cannon ball lung metastases due to adrenocortical carcinoma with a more favorable prognosis. This is the first case described in the literature of cannonball lung metastases from adrenocortical tumor in a man.


Solution structure of all parallel G-quadruplex formed by the oncogene RET promoter sequence.
RET protein functions as a receptor-type tyrosine kinase and has been found to be aberrantly expressed in a wide range of human diseases. A highly GC-rich region upstream of the promoter plays an important role in the transcriptional regulation of RET. Here, we report the NMR solution structure of the major intramolecular G-quadruplex formed on the G-rich strand of this region in K(+) solution. The overall G-quadruplex is composed of three stacked G-tetrad and four syn guanines, which shows distinct features for all parallel-stranded folding topology. The core structure contains one G-tetrad with all syn guanines and two other with all anti-guanines. There are three double-chain reversal loops: the first and the third loops are made of 3 nt G-C-G segments, while the second one contains only 1 nt C10. These loops interact with the core G-tetrads in a specific way that defines and stabilizes the overall G-quadruplex structure and their conformations are in accord with the experimental mutations. The distinct RET promoter G-quadruplex structure suggests that it can be specifically involved in gene regulation and can be an attractive target for pathway-specific drug design.


Influence of Bacillus subtilis sp. lectin on functional activity of phagocytes.
Intramuscular and intraperitoneal introduction of Bacillus subtilis sp. lectin to mongrel white mice is responsible for the increasing of values of functional activity of peripheral blood phagocytes and peritoneal macrophages of these animals. These results confirmed similar data obtained in vitro. Bactericidal activity of monocytes and neutrophils significantly increased at minimal doses of lectin (0.1-0.5 microgram/animal). But this increase was lower at middle doses (0.5-5.0 micrograms/animal) and again increased at higher ones (5.0-25.0 micrograms/animal). Dose-dependent effect of lectin on macrophages was similar, but it was observed at lower concentrations. Administration of lectin did not give increase of functional reserve of studied cells, but was responsible for the increase of the phagocyte number and phagocytic index of monocytes and neutrophils at relatively middle doses (1.0-5.0 micrograms/animal). Phagocytic activity of macrophages did not increase. Thus, lectin of B. subtilis sp. is the agent non-toxic during studies in vivo, stimulating functional activity of phagocytes and macrophages.


A SN2 reaction that avoids its deep potential energy minimum.
Chemical dynamics trajectory simulations were used to study the atomic-level mechanisms of the OH- + CH3F --> CH3OH + F- SN2 nucleophilic substitution reaction. The reaction dynamics, from the [OH...CH3...F]- central barrier to the reaction products, are simulated by ab initio direct dynamics. The reaction's potential energy surface has a deep minimum in the product exit channel arising from the CH3OH...F- hydrogen-bonded complex. Statistical theories of unimolecular reaction rates assume that the reactive system becomes trapped in this minimum and forms an intermediate, with random redistribution of its vibrational energy, but the majority of the trajectories (90%) avoided this potential energy minimum and instead dissociated directly to products. This finding is discussed in terms of intramolecular vibrational energy redistribution (IVR) and the relation between IVR and molecular structure. The finding of this study may be applicable to other reactive systems where there is a hierarchy of time scales for intramolecular motions and thus inefficient IVR.


The influence of acylation, metal binding and natural antioxidants on the thermal stability of red cabbage anthocyanins in neutral solution.
The main red cabbage anthocyanins (pigments) are cyanidin glycosides bearing one or two acyl groups derived from hydroxycinnamic acids (HCAs). Through π-stacking interactions with the cyanidin chromophore, the HCA residues have a deep influence on the color expressed and its stability. In this work, a series of non-, mono- and diacylated anthocyanins were investigated in neutral solution (pH 7 and 8), where the pigments exhibit purple to blue colors. Under such conditions, the gradual color loss observed is a combination of two distinct processes involving the cyanidin nucleus: reversible water addition and irreversible autoxidation. By acidification to pH < 2, the colorless forms stemming from water addition (hemiketal and chalcones) are converted to the red flavylium ion, thereby permitting the selective monitoring of the irreversible contribution. The kinetics of color loss and of true pigment degradation could thus be recorded for each pigment. The influence of iron - cyanidin binding and of antioxidants (caffeic acid, N-acetylcysteine) was also investigated. A complete kinetic analysis combining the anthocyanin colored and colorless forms and the degradation products is provided. Overall, it appears that acylation is critical to color stability. For instance, the nonacylated pigment is rapidly bleached as a result of fast water addition and its iron complex is too unstable to provide protection. By contrast, the diacylated pigments are efficiently protected against hydration but much more moderately against autoxidation, which on the other hand is inhibited by efficient iron binding and addition of N-acetylcysteine. Finally, the diacylated pigments are much more resistant to bleaching by hydrogen peroxide (possibly produced by cyanidin autoxidation) and bisulfite (a common food preservative).


Interactions between temperature and human leptin physiology in vivo and in vitro.
To investigate the possibility that environmental temperature may exert physiologically significant direct, local effects on subcutaneous adipose tissue temperatures, and its secretion of leptin, we exposed healthy males ( n=12) to repeated cold-water immersion (study 1), and also incubated surgically removed human subcutaneous adipose tissue samples ( n=7) at 27 degrees, 32 degrees and 37 degrees C (study 2). In vivo immersions were conducted over 15 days (60-90 min at 18 degrees C). Regional body temperatures and plasma leptin concentrations were measured before and during immersion. Acute cold exposure suppressed plasma leptin concentration (25 min: -14%, 60 min: -22%, P=0.0001), whilst repeated cold-water immersion was associated with an increase of plasma leptin concentration relative to test day 1 (+19% day 8, +13% day 15, overall P=0.03). Leptin secretion in vitro decreased 3.7-fold as the incubation temperature decreased from 37 degrees to 27 degrees C ( P=0.001). In a compartmental model of leptin turnover in vivo, the measured (local) temperature effect on leptin secretion in vitro was more than able to account for the observed cold-induced decrease in leptin concentration in vivo. We therefore conclude that acute and repeated cold-water immersions have separate and opposing effects on circulating leptin concentrations in humans. Under our experimental conditions, the local effects of reduced subcutaneous adipose tissue temperature may be a more important contributor to the acute effects observed in vivo, than the sympathetically mediated suppression of leptin secretion.


Progesterone prevents estradiol-induced dendritic spine formation in cultured hippocampal neurons.
Estradiol has been shown to cause an increase in dendritic spine density in cultured hippocampal neurons, an effect mediated by downregulation of brain-derived neurotrophic factor (BDNF) and glutamic acid decarboxylase (GAD), and the subsequent phosphorylation of cAMP response element binding protein (CREB) in response to enhanced activity levels. Interestingly, progesterone was shown to counteract the effects of estradiol on dendritic spine density in vivo and in vitro. The present study examined how progesterone may act to block the effects of estradiol in the molecular cascade of cellular events leading to formation of dendritic spines. Progesterone did not affect the estradiol-induced downregulation of BDNF or GAD, but it did block the effect of estradiol on CREB phosphorylation. The latter effects of progesterone on the pCREB response and spine formation were reversed by indomethacin, which prevents the conversion of progesterone to the neurosteroid tetrahydroprogesterone (THP). We therefore examined if the progesterone effects were caused by its active metabolite THP. Progesterone treatment caused a 60-fold increase in THP in the culture medium. THP itself enhanced spontaneous GABAergic activity in patch-clamped cultured neurons. Finally, THP blocked the estradiol-induced increase in spine density. These results suggest that progesterone, through conversion to THP, blocks the effects of estradiol on dendritic spines not via a direct nuclear receptor interaction but by counteracting the enhanced excitability produced by estradiol in the cultured network.


mtDNA and Y-chromosome variation in the Talysh of Iran and Azerbaijan.
The Northern Talysh from Azerbaijan and the Southern Talysh from Iran self-identify as one ethnic group and speak a Northwestern Iranian language. However, the Northern and Southern Talysh dialects are so different that they may actually be separate languages. Does this linguistic differentiation reflect internal change due to isolation, or could contact-induced change have played a role? We analyzed mtDNA HVI sequences, 11 Y-chromosome bi-allelic markers, and 9 Y-STR loci in Northern and Southern Talysh and compared them with their neighboring groups. The mtDNA data show a close relatedness of both groups with each other and with neighboring groups, whereas the Northern Talysh Y-chromosome variation differs from that of neighboring groups, probably as a result of genetic drift. This genetic drift most likely reflects a founder event in the male gene pool of Northern Talysh: either fewer males than females migrated to Azerbaijan, or there was a higher degree of relatedness among the male migrants. Since we find no evidence of substantial genetic contact between either Northern or Southern Talysh and neighboring groups, we conclude that internal change, rather than contact-induced change, most likely explains the linguistic differentiation between Northern and Southern Talysh.


Interferon regulatory factor IRF-7 induces the antiviral alpha interferon response and protects against lethal West Nile virus infection.
Type I interferon (IFN-alpha/beta) comprises a family of immunomodulatory cytokines that are critical for controlling viral infections. In cell culture, many RNA viruses trigger IFN responses through the binding of RNA recognition molecules (RIG-I, MDA5, and TLR-3) and induction of interferon regulatory factor IRF-3-dependent gene transcription. Recent studies with West Nile virus (WNV) have shown that type I IFN is essential for restricting infection and that a deficiency of IRF-3 results in enhanced lethality. However, IRF-3 was not required for optimal systemic IFN production in vivo or in vitro in macrophages. To begin to define the transcriptional factors that regulate type I IFN after WNV infection, we evaluated IFN induction and virus control in IRF-7(-/-) mice. Compared to congenic wild-type mice, IRF-7(-/-) mice showed increased lethality after WNV infection and developed early and elevated WNV burdens in both peripheral and central nervous system tissues. As a correlate, a deficiency of IRF-7 blunted the systemic type I IFN response in mice. Consistent with this, IFN-alpha gene expression and protein production were reduced and viral titers were increased in IRF-7(-/-) primary macrophages, fibroblasts, dendritic cells, and cortical neurons. In contrast, in these cells the IFN-beta response remained largely intact. Our data suggest that the early protective IFN-alpha response against WNV occurs through an IRF-7-dependent transcriptional signal.


Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis.
Previous work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can partially prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation. These changes were associated with a dramatic reduction in the extent of fibrosis induced in 2 mouse models of kidney disease. These effects were not related to changes in circulating leukocytes because bone marrow transplants from miR-33-deficient animals did not have a similar impact on disease progression. Most important, targeted delivery of miR-33 peptide nucleic acid inhibitors to the kidney and other acidic microenvironments was accomplished using pH low insertion peptides as a carrier. This was effective at both increasing the expression of factors involved in FAO and reducing the development of fibrosis. Together, these findings suggest that miR-33 may be an attractive therapeutic target for the treatment of chronic kidney disease.


Dynamics of the Peripheral Membrane Protein P2 from Human Myelin Measured by Neutron Scattering--A Comparison between Wild-Type Protein and a Hinge Mutant.
Myelin protein P2 is a fatty acid-binding structural component of the myelin sheath in the peripheral nervous system, and its function is related to its membrane binding capacity. Here, the link between P2 protein dynamics and structure and function was studied using elastic incoherent neutron scattering (EINS). The P38G mutation, at the hinge between the β barrel and the α-helical lid, increased the lipid stacking capacity of human P2 in vitro, and the mutated protein was also functional in cultured cells. The P38G mutation did not change the overall structure of the protein. For a deeper insight into P2 structure-function relationships, information on protein dynamics in the 10 ps to 1 ns time scale was obtained using EINS. Values of mean square displacements mainly from protein H atoms were extracted for wild-type P2 and the P38G mutant and compared. Our results show that at physiological temperatures, the P38G mutant is more dynamic than the wild-type P2 protein, especially on a slow 1-ns time scale. Molecular dynamics simulations confirmed the enhanced dynamics of the mutant variant, especially within the portal region in the presence of bound fatty acid. The increased softness of the hinge mutant of human myelin P2 protein is likely related to an enhanced flexibility of the portal region of this fatty acid-binding protein, as well as to its interactions with the lipid bilayer surface requiring conformational adaptations.


Quality of life in children with Down syndrome and its association with parent and child demographic characteristics: Parent-reported measures.
This study aims to explore the association between the quality of life (QoL) in children with Down syndrome (DS) and its relationship with demographic characteristics of both parents and children. The investigation encompasses five domains: physical and psychological well-being, autonomy and parental relationship, social well-being, and peers, as well as school and the learning environment. An online questionnaire, the KIDSCREEN-27, was used to measure the QoL of 112 families with DS in Saudi Arabia, referred to as "Parent-Reported Measures." Descriptive statistics were analyzed using the Statistical Package for Social Sciences. The study found that the QoL of children with DS showed high scores in the psychological well-being, autonomy, parental relations, school, and learning environment domains. However, the physical and social well-being and peer domains had lower scores, although still considered "good scores." Family income had a positively significant influence on all QoL domains. Specifically, higher family income was associated with better QoL outcomes, except for social well-being. Parental age was found to influence psychological well-being, while parental education and the relationship between the parent and child influenced social well-being. Lastly, the child's gender was found to have an impact on the school and learning environment domain. The study highlights the importance of understanding the impact of the demographic variability of children with DS and their parents on the QoL of their children. It emphasizes the need to address the needs of families with lower incomes and the importance of parental education and relationships with their children in improving social well-being. The findings could aid policymakers and healthcare providers in improving the QoL for families with children who have DS.


Facile one-pot synthesis of N-difluoromethyl-2-pyridone derivatives.
[reaction: see text] A novel one-pot synthesis of N-difluoromethyl-2-pyridones is described. N-(Pyridin-2-yl)acetamide derivatives were excellent precursors for the preparation of N-difluoromethyl-2-pyridone derivatives. Difluoromethylation of 2-acetaminopyridine derivatives was achieved with sodium chlorodifluoroacetate as a difluorocarbene source in the presence of a catalytic amount of 18-crown-6. Subsequent in situ hydrolysis of resultant 1,2-dihydro-2-acetimino-1-difluoromethylpyridines proceeded under mild acidic conditions to afford the corresponding N-difluoromethyl-2-pyridones in moderate to good yields.


A randomized, placebo-controlled trial of the effects of physical exercises and estrogen therapy on health-related quality of life in postmenopausal women.
The purpose of this study was to evaluate the isolated and associated effects of estrogen therapy (estradiol valerate 1 mg/d orally) and physical exercise (moderate aerobic exercise, 3 h/wk) on health-related quality of life (HRQOL) and menopausal symptoms among women who had undergone hysterectomy. A 6-month, randomized, double-blind, placebo-controlled clinical trial with 44 postmenopausal women who had undergone hysterectomy. The interventions were physical exercise and hormone therapy (n = 9), being sedentary and hormone therapy (n = 14), physical exercise and placebo (n = 11), and being sedentary and placebo (n = 10). HRQOL was assessed by a Brazilian standard version of the Medical Outcome Study Short-Form Health Survey and symptoms by Kupperman Index at baseline and after 6 months. There was a decrease in symptoms in all groups, but only groups who performed physical exercise showed an increase in quality of life. Analysis of variance showed that changes in physical functioning (P = 0.001) and bodily pain (P = 0.012) scores over the 6-month period differed significantly between women who exercised and women who were sedentary, regardless of hormone therapy. Hormone therapy had no effect, and there was also no significant association between physical exercise and hormone therapy in HRQOL. Physical exercises can reduce menopausal symptoms and enhance HRQOL, independent of whether hormone therapy is taken.


Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic worldwide. Currently, however, no effective drug or vaccine is available to treat or prevent the resulting coronavirus disease 2019 (COVID-19). Here, we report our discovery of a promising anti-COVID-19 drug candidate, the lipoglycopeptide antibiotic dalbavancin, based on virtual screening of the FDA-approved peptide drug library combined with in vitro and in vivo functional antiviral assays. Our results showed that dalbavancin directly binds to human angiotensin-converting enzyme 2 (ACE2) with high affinity, thereby blocking its interaction with the SARS-CoV-2 spike protein. Furthermore, dalbavancin effectively prevents SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection are significantly inhibited by dalbavancin administration. Given its high safety and long plasma half-life (8-10 days) shown in previous clinical trials, our data indicate that dalbavancin is a promising anti-COVID-19 drug candidate.


Identifying and managing cow's milk protein allergy.
Cow's milk protein (CMP) is usually one of the first complementary foods to be introduced into the infant's diet and is commonly consumed throughout childhood as part of a balanced diet. CMP is capable of inducing a multitude of adverse reactions in children, which may involve organs like the skin, gastrointestinal (GI) tract or respiratory system. The diagnosis of CMP-induced adverse reactions requires an understanding of their classification and immunological basis as well as the strengths and limitations of diagnostic modalities. In addition to the well-recognised, immediate-onset IgE-mediated allergies, there is increasing evidence to support the role of CMP-induced allergy in a spectrum of delayed-onset disorders ranging from GI symptoms to chronic eczema. The mainstay of treatment is avoidance of CMP; this requires dietetic input to ensure that this does not lead to any nutritional compromise. This review is intended to highlight the broad spectrum of manifestations of CMP allergy and to offer an approach to the diagnosis and treatment thereof.


Expression and high levels of insertional polymorphism of an endogenous gammaretrovirus lineage in dogs.
Despite the absence of a confirmed exogenously replicating retrovirus in Canis lupus familiaris (C. familiaris), past retroviral infections are evident in the genomes of living animals via the presence of endogenous retroviruses (ERVs). Although gammaretrovirus-like transcripts and enzyme activities were previously reported to be present in canine leukemias and lymphomas, those findings were not further explored. Initial analysis of the C. familiaris reference genome revealed a minor subset of one ERV lineage, classified as CfERV-Fc1(a), or Fc1(a) here, with features characteristic of recent integration, including the presence of ORFs and identical or nearly identical LTRs. Our previous analysis of whole genome sequence data belonging to extant Canidae revealed a burst of past infections in Canis ancestors resulting in numerous young, polymorphic, and highly intact loci now segregating in dogs. Here, we demonstrate the expression of full-length Fc1(a) proviruses in tissues collected from healthy animals and from animals with cancer. We observed significantly higher expression in samples of dogs with various cancer diagnoses when compared to samples from healthy dogs. Genotyping of insertionally polymorphic Fc1(a) loci identified candidate expressed proviruses and delineated distributions over sample groups. Collectively, the data show that Fc1(a) proviruses retain biological activity in the domestic dog and provides a means to examine potential genetic links with disease states in this species.


ERK/MAPK Signaling Is Required for Pathway-Specific Striatal Motor Functions.
The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R-MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK-deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity-associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R-MSNs.SIGNIFICANCE STATEMENT Alterations in ERK/MAPK activity are associated with drug abuse, as well as neuropsychiatric and movement disorders. However, genetic evidence defining the functions of ERK/MAPK signaling in striatum-related neurophysiology and behavior is lacking. We show that loss of ERK/MAPK signaling leads to pathway-specific alterations in motor function, reduced neuronal excitability, and the inability of medium spiny neurons to regulate activity-induced gene expression. Our results underscore the potential importance of the ERK/MAPK pathway in human movement disorders.


Measurement of temperature distributions across laser heated samples by multispectral imaging radiometry.
Two-dimensional temperature mapping of laser heated diamond anvil cell samples is performed by processing a set of four simultaneous images of the sample, each obtained at a narrow spectral range in the visible to near infrared. The images are correlated spatially, and each set of four points is fitted to the Planck radiation function to determine the temperature and the emissivity of the sample, using the gray body approximation. The method is tested by measuring the melting point of Pt at 1 bar and measuring laser heated Fe at 20 GPa in the diamond anvil cell. The accuracy and precision are shown to compare well to standard spectroradiometry, and the effect of imaging resolution on the measured distribution is evaluated. The principal advantages of the method are (1) the temperature and emissivity of the sample are mapped in two dimensions; (2) chromatic aberrations are practically eliminated by independent focusing of each spectral band; and (3) all of the spectral images are obtained simultaneously, allowing temporal variations to be studied. This method of measuring temperature distributions can be generalized to other hot objects besides laser heated spots.


Epilepsy and chromosomal rearrangements in Smith-Magenis Syndrome [del(17)(p11.2p11.2)].
Smith-Magenis syndrome is a multiple congenital anomalies/mental retardation syndrome associated with a heterozygous deletion of chromosome 17p11.2. Seizures have not been formally studied in this population. Our objectives were to estimate the prevalence of seizures and electroencephalographic (EEG) epileptiform abnormalities in patients with Smith-Magenis syndrome with defined chromosomal rearrangements and to describe the spectrum of abnormal EEG patterns. Prolonged video-EEGs were obtained in 60 patients. Eighteen percent of patients reported a seizure history; however, abnormal EEGs were identified in 31 of the 60 subjects and 27 of 31 were epileptiform. Generalized epileptiform patterns were the most common (73%). Most patients with either small or large deletions had an abnormal EEG (83%; 75%) in contrast to those with a common deletion (49%). Our results indicate that epileptiform EEG abnormalities are frequent in patients with Smith-Magenis syndrome. Considering that close to one third of individuals with Smith-Magenis syndrome with epileptiform abnormalities also had a history of clinical seizures, cortical hyperexcitability and epilepsy should be considered an important component of the Smith-Magenis syndrome clinical phenotype.


Small molecule inhibitors targeting the PD-1/PD-L1 signaling pathway.
Tumor cells form immune escape and subsequently obtain unlimited proliferation ability due to the abnormal immune surveillance mediated by immune checkpoints. Among this class of immune checkpoints, PD-1/PD-L1 was recognized as an anticancer drug target for many years, and so far, several monoclonal antibodies have achieved encouraging outcome in cancer treatment by targeting the PD-1/PD-L1 signaling pathway. Due to the inherent limitations of antibodies, the development of small molecule inhibitors based on PD-1/PD-L1 signaling pathway is gradually reviving in decades. In this review, we summarized a number of small molecule inhibitors based on three different therapeutic approaches interfering PD-1/PD-L1 signaling pathway: (1) blocking direct interaction between PD-1 and PD-L1; (2) inhibiting transcription and translation of PD-L1; and (3) promoting degradation of PD-L1 protein. The development of these small molecule inhibitors opens a new avenue for tumor immunotherapy based on PD-1/PD-L1 signaling pathway.


Rheumatoid nodulosis. A relatively benign rheumatoid variant.
Subcutaneous nodules and rheumatoid factor (RF) are criteria used to diagnose rheumatoid disease. Their presence correlates with disease severity and poorer prognosis. They have been reported, however, in patients with little arthritis and no systemic disease. We studied four such patients, in whom (1) RF was present in high titer; (2) nodules were often extensive (nodulosis) and involved elbows, hands, and feet, with a predilection for tendons; and (3) roentgenograms showed large, subchondral bone cysts without cortical erosion of correlation with nodule location. The conditions of three of these patients had been previously misdiagnosed as gout or xanthoma. Our findings were similar to those in seven other patients described in earlier reports. We suggest that nodulosis, bone cysts, and elevated RF with little active arthritis constitute a relatively benign variant of rheumatoid disease.


3D axial and circumferential wall shear stress from 4D flow MRI data using a finite element method and a laplacian approach.
To decompose the 3D wall shear stress (WSS) vector field into its axial (WSSA ) and circumferential (WSSC ) components using a Laplacian finite element approach. We validated our method with in silico experiments involving different geometries and a modified Poiseuille flow. We computed 3D maps of the WSS, WSSA , and WSSC using 4D flow MRI data obtained from 10 volunteers and 10 patients with bicuspid aortic valve (BAV). We compared our method with the centerline method. The mean value, standard deviation, root mean-squared error, and Wilcoxon signed rank test are reported. We obtained an error <0.05% processing analytical geometries. We found good agreement between our method and the modified Poiseuille flow for the WSS, WSSA , and WSSC . We found statistically significance differences between our method and a 3D centerline method. In BAV patients, we found a 220% significant increase in the WSSC in the ascending aorta with respect to volunteers. We developed a novel methodology to decompose the WSS vector in WSSA and WSSC in 3D domains, using 4D flow MRI data. Our method provides a more robust quantification of WSSA and WSSC in comparison with other reported methods. Magn Reson Med 79:2816-2823, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Identifying meaningful outcome measures for the intensive care unit.
Despite important progress in measuring the safety of health care delivery in a variety of health care settings, a comprehensive set of metrics for benchmarking is still lacking, especially for patient outcomes. Even in high-risk settings where similar procedures are performed daily, such as hospital intensive care units (ICUs), these measures largely do not exist. Yet we cannot compare safety or quality across institutions or regions, nor can we track whether safety is improving over time. To a large extent, ICU outcome measures deemed valid, important, and preventable by clinicians are unavailable, and abstracting clinical data from the medical record is excessively burdensome. Even if a set of outcomes garnered consensus, ensuring adequate risk adjustment to facilitate fair comparisons across institutions presents another challenge. This study reports on a consensus process to build 5 outcome measures for broad use to evaluate the quality of ICU care and inform quality improvement efforts.


Unilateral isometric muscle fatigue decreases force production and activation of contralateral knee extensors but not elbow flexors.
Nonlocal muscle fatigue occurs when fatiguing 1 muscle alters performance of another rested muscle. The purpose of the study was to investigate if fatiguing 2 separate muscles would affect the same rested muscle, and if fatiguing the same muscle would affect 2 separate muscles. Twenty-one trained males participated in 2 studies (n = 11; n = 10). Subjects performed 2 pre-test maximum voluntary contractions (MVCs) with the nondominant knee extensors. Thereafter they performed two 100-s MVCs with their dominant knee extensors, elbow flexors, or rested. Between and after the sets, a single MVC with the nondominant rested knee extensors was performed. Subsequently, 12 nondominant knee extensors repeated MVCs were completed. Force, quadriceps voluntary activation (VA), and electromyography (EMG) were measured. The same protocol was employed in study 2 except the nondominant elbow-flexors were tested. Study 1: Compared with control conditions, a significant decrease in nondominant knee extensors force, EMG, and VA was found under both fatiguing conditions (P ≤ 0.05; effect size (ES) = 0.91-1.15; 2%-8%). Additionally, decrements in all variables were found from the first post-intervention MVC to the last (P ≤ 0.05; ES = 0.82-2.40; 9%-20%). Study 2: No differences were found between conditions for all variables (P ≥ 0.33; ES ≤ 0.2; ≤3.0%). However, all variables decreased from the first post-intervention MVC to the last (P ≤ 0.05; ES = 0.4-3.0; 7.2%-19.7%). Whereas the rested knee extensors demonstrated nonlocal effects regardless of the muscle being fatigued, the elbow-flexors remained unaffected. This suggests that nonlocal effects are muscle specific, which may hold functional implications for training and performance.


Characterization of a setup to test the impact of high-amplitude pressure waves on living cells.
The impact of pressure waves on cells may provide several possible applications in biology and medicine including the direct killing of tumors, drug delivery or gene transfection. In this study we characterize the physical properties of mechanical pressure waves generated by a nanosecond laser pulse in a setup with well-defined cell culture conditions. To systematically characterize the system on the relevant length and time scales (micrometers and nanoseconds) we use photon Doppler velocimetry (PDV) and obtain velocity profiles of the cell culture vessel at the passage of the pressure wave. These profiles serve as input for numerical pressure wave simulations that help to further quantify the pressure conditions on the cellular length scale. On the biological level we demonstrate killing of glioblastoma cells and quantify experimentally the pressure threshold for cell destruction.


Treacherous Pavements: Paving Slab Patterns Modify Intended Walking Directions.
Current understanding in locomotion research is that, for humans, navigating natural environments relies heavily on visual input; in contrast, walking on even ground in man-made obstacle and hazard-free environments is so highly automated that visual information derived from floor patterns should not affect locomotion and in particular have no impact on the direction of travel. The vision literature on motion perception would suggest otherwise; specifically that oblique floor patterns may induce substantial veering away from the intended direction of travel due to the so-called aperture problem. Here, we tested these contrasting predictions by letting participants walk over commonly encountered floor patterns (paving slabs) and investigating participants' ability to walk "straight ahead" for different pattern orientations. We show that, depending on pattern orientation, participants veered considerably over the measured travel distance (up to 8% across trials), in line with predictions derived from the literature on motion perception. We argue that these findings are important to the study of locomotion, and, if also observed in real world environments, might have implications for architectural design.


Origin of a chloroplast protein importer.
During evolution, chloroplasts have relinquished the majority of their genes to the nucleus. The products of transferred genes are imported into the organelle with the help of an import machinery that is distributed across the inner and outer plastid membranes. The evolutionary origin of this machinery is puzzling because, in the putative predecessors, the cyanobacteria, the outer two membranes, the plasma membrane, and the lipopolysaccharide layer lack a functionally similar protein import system. A 75-kDa protein-conducting channel in the outer envelope of pea chloroplasts, Toc75, shares approximately 22% amino acid identity to a similarly sized protein, designated SynToc75, encoded in the Synechocystis PCC6803 genome. Here we show that SynToc75 is located in the outer membrane (lipopolysaccharide layer) of Synechocystis PCC6803 and that SynToc75 forms a voltage-gated, high conductance channel with a high affinity for polyamines and peptides in reconstituted liposomes. These findings suggest that a component of the chloroplast protein import system, Toc75, was recruited from a preexisting channel-forming protein of the cyanobacterial outer membrane. Furthermore, the presence of a protein in the chloroplastic outer envelope homologous to a cyanobacterial protein provides support for the prokaryotic nature of this chloroplastic membrane.


Spinal cord stimulation for neuropathic pain following idiopathic transverse myelitis: A case report.
We present a patient with intractable neuropathic pain because of idiopathic transverse myelitis unresponsive to medical treatment. After a successful trial of spinal cord stimulation, a permanent stimulator was implanted. Improvement was noted in visual analogue scale, medication usage and daily function. Spinal cord stimulation may offer a therapeutic option for patients with neuropathic pain resulting from transverse myelitis and should be considered when other treatments are failed.


Treatment of dyskeratosis congenita-associated pulmonary fibrosis with danazol.
Individuals with Dyskeratosis Congenita (DC) are at increased risk for complications in variety of systems including pulmonary fibrosis. Idiopathic and DC-associated pulmonary fibrosis are progressive and fatal disorders without known treatment. Here we describe, for the first time, marked improvement in the clinical and laboratory parameters of the pulmonary disease of a child who suffered from TINF2-associated DC and severe pulmonary fibrosis after initiation of therapy with Danazol. We recommend that the clinical efficacy of Danazol in slowing down the progression of pulmonary fibrosis in patients with telomere-related disorders is evaluated in prospective studies.


Norepinephrine increases beta-receptors and adenylate cyclase in canine myocardium.
Norepinephrine, a known inducer of myocardial hypertrophy, was found to have marked effects on the myocardial adrenergic system, which occurred prior to the development of a significant increase in heart weight. The chronic subhypertensive infusion (1.4 microgram/min) in free-roaming dogs produced a threefold increase in plasma norepinephrine (determined by radioimmunoassay). After 3 mo of infusion, right and left ventricular norepinephrine content (ng/mg protein) decreased significantly by twofold (right, 2.50 +/- 0.24; left, 2.08 +/- 0.36) compared with controls (right, 4.76 +/- 1.48; left, 4.65 +/- 1.49), and beta-receptor density (125I-pindolol) increased (right, 0.122 +/- 0.029; left, 0.153 +/- 0.021) over the controls (right, 0.082 +/- 0.015; left, 0.069 +/- 0.008 pmol/mg protein). Accompanying the beta-receptor changes, isoproterenol-stimulated adenylate cyclase activity also increased significantly [right, 29.2 +/- 2.1; left, 29.5 +/- 1.0 vs. controls, right, 13.8 +/- 1.1; left, 20.2 +/- 2.2 pmol adenosine 3',5'-cyclic monophosphate (cAMP) generated X min-1 X mg protein-1]. Because the above changes occurred in the absence of cardiac hypertrophy, it suggests that alterations in the myocardial adrenergic system are dependent on the stimulus (in this case norepinephrine) invoking the change and not the degree of hypertrophy. It also suggests that changes in the adrenergic system may not directly reflect the mechanism involved in the development of hypertrophy.


Sexual practices of People Living with HIV/AIDS attending School of Tropical Medicine, Kolkata.
A hospital-based, cross-sectional, observational study of People Living with HIV/AIDS (PLWHAs) attending the School of Tropical Medicine (STM), Kolkata was carried out for a period of 6 months from May 2006 to October 2006, to assess the sexual practices of PLWHAs. Past sexual practice of PLWHAs revealed that 93.4% males were polygamous, compared to 16.4% females. Of them, 45.7% males and 92.8% females reported sex with a nonregular sex partner (NRSP) in 1 year. Consistent condom use was low in both sexes. Current sexual practice showed that more than four-fifth (87.9%) of the new patients and two-thirds (68.9%) of the indoor patients were currently sexually active in 1 month recall period (P=3.79, Z=0.0000). However, consistent condom use was found only in 35.5% indoor patients and 15.5% of new patients and the difference was statistically significant.


Survivors' perceptions of public health messages during an Ebola crisis in Liberia and Sierra Leone: An exploratory study.
The outbreak of Ebola virus disease in Guinea, Liberia, and Sierra Leone was the largest epidemic of Ebola ever recorded. The healthcare workforce was diminished and exhausted as the region emerged from civil war. Few qualitative, descriptive studies have been conducted to date that concentrate on the voices of Ebola survivors and their perceptions of health messages. In this study, we employed an interpretive, qualitative design to explore participant experiences. Twenty five survivors who had recovered from Ebola were recruited from three villages in Liberia and Sierra Leone in August 2015. Data were collected using semistructured interviews. Data analysis revealed four themes: (i) degrees of mistrust; (ii) messages conflicting with life and culture; (iii) seeing is believing; and (iv) recovery inspires hope. The findings were explored in the context of the relevant literature. The themes highlight the need to develop culturally-appropriate messages, underpinned by a sound understanding of the community and a willingness to work with the culture and trusted leaders.


Machine-Learning-Based Detection of Craving for Gaming Using Multimodal Physiological Signals: Validation of Test-Retest Reliability for Practical Use.
Internet gaming disorder in adolescents and young adults has become an increasing public concern because of its high prevalence rate and potential risk of alteration of brain functions and organizations. Cue exposure therapy is designed for reducing or maintaining craving, a core factor of relapse of addiction, and is extensively employed in addiction treatment. In a previous study, we proposed a machine-learning-based method to detect craving for gaming using multimodal physiological signals including photoplethysmogram, galvanic skin response, and electrooculogram. Our previous study demonstrated that a craving for gaming could be detected with a fairly high accuracy; however, as the feature vectors for the machine-learning-based detection of the craving of a user were selected based on the physiological data of the user that were recorded on the same day, the effectiveness of the reuse of the machine learning model constructed during the previous experiments, without any further calibration sessions, was still questionable. This "high test-retest reliability" characteristic is of importance for the practical use of the craving detection system because the system needs to be repeatedly applied to the treatment processes as a tool to monitor the efficacy of the treatment. We presented short video clips of three addictive games to nine participants, during which various physiological signals were recorded. This experiment was repeated with different video clips on three different days. Initially, we investigated the test-retest reliability of 14 features used in a craving detection system by computing the intraclass correlation coefficient. Then, we classified whether each participant experienced a craving for gaming in the third experiment using various classifiers-the support vector machine, k-nearest neighbors (kNN), centroid displacement-based kNN, linear discriminant analysis, and random forest-trained with the physiological signals recorded during the first or second experiment. Consequently, the craving/non-craving states in the third experiment were classified with an accuracy that was comparable to that achieved using the data of the same day; thus, demonstrating a high test-retest reliability and the practicality of our craving detection method. In addition, the classification performance was further enhanced by using both datasets of the first and second experiments to train the classifiers, suggesting that an individually customized game craving detection system with high accuracy can be implemented by accumulating datasets recorded on different days under different experimental conditions.