All-trans Retinoic Acid-induced Abnormal Hippocampal Expression of Synaptic Genes SynDIG1 and DLG2 is Correlated with Anxiety or Depression-Like Behavior in Mice.
Clinical reports suggest a potential link between excess retinoids and development of depression. Although it has been shown that all-trans retinoic acid (ATRA) administration induces behavioral changes, further insight into how ATRA is involved is lacking. The hippocampus seems to be a major target of retinoids, and abnormal synaptic plasticity of the hippocampus is involved in depression. We examined two genes associated with synaptic function, discs large homolog 2 (DLG2), and synapse differentiation-inducing gene protein 1 (SynDIG1) in terms of hippocampal expression and correlation with behavior. Three different doses of ATRA were injected into young mice and 10 mg/kg ATRA was found to induce depression-like behavior. In the hippocampus, DLG2 mRNA was significantly decreased by ATRA. mRNA levels were positively correlated with central area duration and distance in the open-field test. Increased SynDIG1 mRNA levels were observed. There was a negative correlation between SynDIG1 mRNA levels and mobility time in the forced swimming test. Retinoic acid receptor γ mRNA was significantly positively correlated with DLG2 and negatively correlated with SynDIG1. To summarize, ATRA administration induced anxiety- and depression-like behavior accompanied by a decreased expression of DLG2 and an increased expression of SynDIG1. Moreover, DLG2 was correlated with anxiety-like behavior and SynDIG1 was correlated with depression-like behavior. These results might constitute a novel target underlying ATRA-induced anxiety- and depression-like behavior.


For Whom the Price Escalates: High Price and Uncertain Value of Cancer Drugs.
The price of cancer drugs has skyrocketed, yet it is not clear whether their value is commensurate with their price. More cancer drugs are approved under expedited review, which considers less rigorous clinical evidence, yet only 20% of them show an overall survival gain in the confirmatory trial. Moreover, clinical data are often generated based on small, single-arm studies with surrogate outcomes, challenging economic evaluation. With their high price and uncertain (marginal) clinical value, cancer drugs are frequently rejected by health technology assessment (HTA) bodies. Therefore, agencies, including the UK's National Institute for Health and Care Excellence (NICE), have adopted cancer drug funds (CDF) or risk-sharing schemes to provide extra access for expensive cancer drugs which fail to meet NICE's cost effectiveness threshold. With rising pricing and fewer new cancer medications with novel mechanisms of action, it is unclear if newly marketed cancer therapies address unmet clinical needs or whether we are paying too much. Transparency, equity, innovativeness, and sustainability are all harmed by a "special" approach for cancer medications. If early access is allowed, confirmatory trials within a certain time frame and economic evaluation should be conducted, and label changes or disinvestment should be carried out based on those evaluations.


AtMYB41 activates ectopic suberin synthesis and assembly in multiple plant species and cell types.
Suberin is a lipid and phenolic cell wall heteropolymer found in the roots and other organs of all vascular plants. Suberin plays a critical role in plant water relations and in protecting plants from biotic and abiotic stresses. Here we describe a transcription factor, AtMYB41 (At4g28110), that can activate the steps necessary for aliphatic suberin synthesis and deposition of cell wall-associated suberin-like lamellae in both Arabidopsis thaliana and Nicotiana benthamiana. Overexpression of AtMYB41 increased the abundance of suberin biosynthetic gene transcripts by orders of magnitude and resulted in the accumulation of up to 22 times more suberin-type than cutin-type aliphatic monomers in leaves. Overexpression of AtMYB41 also resulted in elevated amounts of monolignols in leaves and an increase in the accumulation of phenylpropanoid and lignin biosynthetic gene transcripts. Surprisingly, ultrastructural data indicated that overexpression led to the formation of suberin-like lamellae in both epidermal and mesophyll cells of leaves. We further implicate AtMYB41 in the production of aliphatic suberin under abiotic stress conditions. These results provide insight into the molecular-genetic mechanisms of the biosynthesis and deposition of a ubiquitous cell wall-associated plant structure and will serve as a basis for discovering the transcriptional network behind one of the most abundant lipid-based polymers in nature.


Food and Drug Administration proposed testing guidelines for reproduction studies. Revision Committee. FDA Guidelines for Developmental Toxicity and Reproduction, Food and Drug Administration.
In the United States, the Food and Drug Administration (FDA) is the agency responsible for ensuring that the direct food additives and color additives used in food are safe for all consumers. In order to determine the safety of these additives for consumption, appropriate information and results from a series of tests must be made available to the agency. In 1982, in an effort to provide guidance to the food industry concerning the appropriate tests for the determination of safety, the FDA issued the Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Foods, commonly referred to as the Redbook. In 1993, based on the expansion of technology and the use of food additives, as well as the refinement of the scientific criteria for establishing safety, the FDA updated its guidelines and issued the draft Redbook II. Since Redbook II was issued, additional refinements have been made in the procedures for the multigeneration reproduction study and for the assessment of effects on male reproduction. The latest proposed guidelines for multigeneration studies are provided here.


Alternative polyadenylation and the stress response.
The cellular stress response is a universal mechanism necessary for the survival of all organisms. This multifaceted process is primarily driven by regulation of gene expression to produce an intracellular environment suitable for promoting cell survival and recovery. Posttranscriptional regulatory events are considered as critical mechanisms that modulate core characteristics of mRNA transcripts to promote cell adaptation to various assaults. While the impact of processes such as mRNA splicing, turnover, localization, and translation on the cellular stress response has been extensively studied, recent observations highlight the role of alternative polyadenylation (APA) in response to challenges such as oxidative stress, heat shock, and starvation. The role of APA is comprehensive with far reaching effects on mRNA stability, mRNA localization, and protein coding sequences. Nonetheless, APA remains a relatively unappreciated mode of gene regulation despite its role in regulating key mediators of the stress response. The goal of this review is to provide an overview of the recent advances in our understanding of the various ways by which APA affects cell adaptation to its environment and discuss how a defect in APA could have deleterious consequences on cell survival. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Processing > 3' End Processing.


The attenuation of experimental lung metastasis by a bile acid acylated-heparin derivative.
The inhibitory efficacies of new bile acid acylated-heparin derivative (heparin-DOCA) were evaluated on experimental lung metastasis. We evaluated the effect of heparin-DOCA on intercellular interactions including those between B16F10 and thrombin-activated platelets and TNF-alpha-activated HUVECs, and between B16F10 and immobilized mouse P-selectin. In addition, the inhibitory effects of heparin-DOCA on adhesion and invasion of B16F10 to Matrigel were studied. In an animal mouse study, the blood clot formation and the retention of red fluorescence protein (RFP)-B16F10 in lungs were assessed after heparin-DOCA and RFP-B16F10 intravenous administration. Furthermore, we investigated the anti-metastatic effect of heparin-DOCA against lung metastasis induced by B16F10 and SCC7. Heparin-DOCA inhibited intercellular interactions between B16F10 and activated platelets or activated HUVECs by blocking P- and E-selectin-mediated interactions. Moreover, it reduced adhesion and invasion of B16F10 to ECM, thereby affecting the reduction of early retention of B16F10 in the lung. Heparin-DOCA attenuated lung colony formation on the surfaces and in interior of the lung, and attenuated metastasis by B16F10 and SCC7. These results suggest that heparin-DOCA may have potentials as therapeutic agent that prevents tumor metastasis and progression.


Synthetic biology: applying biological circuits beyond novel therapies.
Synthetic biology, an engineering, circuit-driven approach to biology, has developed whole new classes of therapeutics. Unfortunately, these advances have thus far been undercapitalized upon by basic researchers. As discussed herein, using synthetic circuits, one can undertake exhaustive investigations of the endogenous circuitry found in nature, develop novel detectors and better temporally and spatially controlled inducers. One could detect changes in DNA, RNA, protein or even transient signaling events, in cell-based systems, in live mice, and in humans. Synthetic biology has also developed inducible systems that can be induced chemically, optically or using radio waves. This induction has been re-wired to lead to changes in gene expression, RNA stability and splicing, protein stability and splicing, and signaling via endogenous pathways. Beyond simple detectors and inducible systems, one can combine these modalities and develop novel signal integration circuits that can react to a very precise pre-programmed set of conditions or even to multiple sets of precise conditions. In this review, we highlight some tools that were developed in which these circuits were combined such that the detection of a particular event automatically triggered a specific output. Furthermore, using novel circuit-design strategies, circuits have been developed that can integrate multiple inputs together in Boolean logic gates composed of up to 6 inputs. We highlight the tools available and what has been developed thus far, and highlight how some clinical tools can be very useful in basic science. Most of the systems that are presented can be integrated together; and the possibilities far exceed the number of currently developed strategies.


Determining the minimal clinically important differences in activity, fatigue, and sleep quality in patients with rheumatoid arthritis.
To determine the minimal clinically important differences (MCID) in the patient-reported outcomes of activity (0-30, number of days of limitation), fatigue (0 = none, 100 = complete), and sleep quality (0 = no problems, 100 = worst case) for patients with rheumatoid arthritis (RA). Two randomized controlled trials comparing abatacept to placebo in RA patients were considered: ATTAIN (n = 391) and AIM (n = 652). An internal anchor-based approach was used to derive the MCID using the Health Assessment Questionnaire, patient global assessment, and pain as anchors. Minimal important change in activity, fatigue, and sleep were determined by estimating mean changes in these outcomes in patients showing change in a narrow range about the MCID of the internal anchor. Correlation analysis was used to determine the consistency of the changes in the outcomes and anchors, and a Delphi process was used to determine the final MCID values. For the 2 trials, consistent patterns of change for activity, fatigue, and sleep and the internal anchors were found with correlations in the range of 0.5, 0.7, and 0.4, respectively. The mean changes for activity, fatigue, and sleep in a narrow range about the MCID of the 3 internal anchors corresponding to the 2 trials were: 3.4 to 4.3 for activity; 6.7 to 17.0 for fatigue; and 4.1 to 7.3 for sleep. Following the Delphi process the MCID determined were 4 for activity, 10 for fatigue, and 6 for sleep. These MCID for activity limitation, fatigue, and sleep problems can be used in designing clinical trials and providing benchmarks in assessing patient improvement.


Classification of Bartonella strains associated with straw-colored fruit bats (Eidolon helvum) across Africa using a multi-locus sequence typing platform.
Bartonellae are facultative intracellular bacteria and are highly adapted to their mammalian host cell niches. Straw-colored fruit bats (Eidolon helvum) are commonly infected with several bartonella strains. To elucidate the genetic diversity of these bartonella strains, we analyzed 79 bartonella isolates from straw-colored fruit bats in seven countries across Africa (Cameroon, Annobon island of Equatorial Guinea, Ghana, Kenya, Nigeria, Tanzania, and Uganda) using a multi-locus sequencing typing (MLST) approach based on nucleotide sequences of eight loci (ftsZ, gltA, nuoG, ribC, rpoB, ssrA, ITS, and 16S rRNA). The analysis of each locus but ribC demonstrated clustering of the isolates into six genogroups (E1 - E5 and Ew), while ribC was absent in the isolates belonging to the genogroup Ew. In general, grouping of all isolates by each locus was mutually supportive; however, nuoG, gltA, and rpoB showed some incongruity with other loci in several strains, suggesting a possibility of recombination events, which were confirmed by network analyses and recombination/mutation rate ratio (r/m) estimations. The MLST scheme revealed 45 unique sequence types (ST1 - 45) among the analyzed bartonella isolates. Phylogenetic analysis of concatenated sequences supported the discrimination of six phylogenetic lineages (E1 - E5 and Ew) corresponding to separate and unique Bartonella species. One of the defined lineages, Ew, consisted of only two STs (ST1 and ST2), and comprised more than one-quarter of the analyzed isolates, while other lineages contained higher numbers of STs with a smaller number of isolates belonging to each lineage. The low number of allelic polymorphisms of isolates belonging to Ew suggests a more recent origin for this species. Our findings suggest that at least six Bartonella species are associated with straw-colored fruit bats, and that distinct STs can be found across the distribution of this bat species, including in populations of bats which are genetically distinct.


Joint associations of blood plasma proteins with overwinter survival of a large mammal.
In many wild animal populations, hosts are at risk of parasites and malnutrition and resource costs of defence may be difficult to afford. We postulate that proteins, important in homeostasis and immunity, play a complex but central role in condition dependence and resource costs of mammalian immune defence. To test this, we measured plasma concentrations of albumin, total proteins. Self-reactive antibodies and parasite-specific IgG in female Soay sheep. Using a principal component analysis, we found a new metric of condition reflecting individual variation in acquisition, assimilation and/or recycling of plasma proteins that predicted overwinter survival. Controlling for this metric, an age-dependent trade-off between antibody titres and protein reserves emerged, indicating costs of mounting an antibody response: younger individuals survived best when prioritising immunity while older individuals fared better when maintaining high-protein nutritional plane. These findings suggest fascinating roles for protein acquisition and allocation in influencing survival in wild animal populations.


Regulation of trehalase activity during the cell cycle of Saccharomyces cerevisiae.
Synchronous cultures of Saccharomyces cerevisiae prepared by selection of small unbudded cells from an elutriating rotor were used to measure trehalase activity during the cell cycle. After the small cells had been removed from the rotor, the remainder was used to prepare asynchronous control cultures. Both synchronous and control cultures were studied for two cell cycles. In asynchronous cultures the trehalase activity of crude cell lysates rose continuously. In synchronized populations trehalase activity increased from the beginning of budding onwards. However, around the period of cell division the enzyme activity dropped rapidly but transiently by more than 5-fold. The same changes were found during the second budding cycle. Measurements of invertase and glucose-6-phosphate dehydrogenase activities in the same synchronous and asynchronous cultures revealed a continuous increase for both enzymes. Incubation of cell lysates with cAMP-dependent protein kinase before assaying for trehalase resulted in a 2-fold enhancement of enzyme activity in asynchronous control cultures. In synchronized cells this treatment also led to a significant stimulation of trehalase activity, and largely abolished the cell-cycle-dependent oscillatory pattern of enzyme activity. These results suggest that the activity of trehalase during the cell cycle is regulated, presumably at the post-translational level, by a phosphorylation-dephosphorylation mechanism.


Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment.
Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1(+/-)) increased bone resorption, suggesting direct regulation of osteoclast (OC) activity by the Hh pathway. Ptch1(+/-) mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable SMO antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases.


Risk assessment in environmental policy-making.
Environmental policy-making has become more dependent on formal, quantitative risk assessment because of increasing attention to the prevention of human health damage from toxic chemicals. Risk assessment helps set priorities for regulation of the very large numbers of chemicals that are of potential concern and helps direct limited social and government resources against the most significant risks. Although the scientific basis for risk assessment is often uncertain and the public and its representatives have often been confused by its use in regulatory decisions, the U.S. Environmental Protection Agency currently uses a variety of risk assessment techniques to set priorities, tailor regulations, and make decisions at particular sites. The Environmental Protection Agency also attempts to make the practice of risk assessment more consistent throughout the agency and to improve public understanding of the meaning of risk assessment and risk management.


Long-term survival and patterns of care in women with ovarian tumors of low malignant potential.
The objectives of this study were to ascertain long-term survival and patterns of care among women diagnosed with ovarian tumors of low malignant potential (LMP) in a population-based data set. Using the NCI's Surveillance, Epidemiology, and End Results (SEER) database, we identified 2818 women diagnosed with ovarian tumors of low malignant potential between 1988 and 1997. By FIGO stage, 10-year relative survival was as follows: stage I, 99%; stage II, 98%; stage III, 96%; and stage IV 77%. One-quarter of women with stage I disease underwent partial or unilateral oophorectomy only, while women with more advanced disease commonly underwent omentectomy, unilateral or bilateral oophorectomy, and hysterectomy. Adjuvant chemotherapy was given to about 30% of women with stage III and IV disease. Radiation therapy was rarely used. We observed no significant changes in primary surgery or adjuvant treatment over time. The diagnosis of an ovarian tumor of LMP conveys a relatively benign prognosis. Conservative surgery should be considered in younger women with early-stage disease. There are insufficient data to support a role for adjuvant chemotherapy for women with advanced disease.


Post-myocardial infarction left ventricular pseudoaneurysm diagnosed incidentally by echocardiography.
A 54-year-old male developed a left ventricular pseudoaneurysm (Ps) along the lateral wall of the left ventricle (LV), which was diagnosed incidentally by two-dimensional transthoracic echocardiography (2DTTE) 6 months after an acute myocardial infarction. Color flow imaging (CFI) showed blood flow from the LV into the aneurysmal cavity and invasive coronary angiography revealed sub-occlusion of the circumflex artery. A complementary study using cardiovascular magnetic resonance (CMR) confirmed a dilated left ventricle with depressed ejection fraction, thin dyskinetic anterolateral and inferolateral walls, a Ps adjacent to the lateral wall of the LV contained by the pericardium and blood passing in and out through a small defect in the LV mid-anterolateral wall. Late gadolinium-enhanced imaging demonstrated transmural myocardial infarction in the lateral wall and delayed enhancement of the pericardium, which formed the walls of the Ps. A conservative approach was adopted in this case, optimizing the patient's heart failure medications, including cardioselective beta-blocker agents, angiotensin-converting enzyme inhibitors, spironolactone and chronic anticoagulation therapy because of a high risk of ischemic stroke in these patients. At the 13-month follow-up, the patient remained stable with New York Heart Association class II heart failure. In conclusion, 2DTTE and CFI seem to be suitable initial methods for diagnosing Ps of the LV, but CMR is an excellent complementary method for characterizing further this cardiac entity. Furthermore, the long-term outcome of patients with Ps of the LV who are treated medically appears to be relatively benign. Left ventricular pseudoaneurysms are uncommon but severe complications of acute myocardial infarction.Transthoracic two-dimensional echocardiography and CFI are suitable non-invasive diagnostic methods for diagnosing left ventricular pseudoaneurysms.Cardiac magnetic resonance is an excellent complementary method, as it offers additional information for further characterization of this cardiac complication.Despite the fact that surgery is the treatment of choice to avoid a risk of fatal rupture, the long-term outcome of patients with left ventricular pseudoaneurysm who are treated medically appears to be relatively benign.


NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis.
Nuclear factor of activated T cell (NFAT1, NFATC2) is a transcription factor that binds and positively regulates IL2 expression during T-cell activation. NFAT1 has important roles in both innate and adaptive immune responses, but its involvement in cancer is not completely understood. We previously demonstrated that NFAT1 contributes to melanoma growth and metastasis by regulating the autotaxin gene (Enpp2). Here, we report a strong correlation between NFAT1 expression and metastatic potential in melanoma cell lines and tumor specimens. To elucidate the mechanisms underlying NFAT1 overexpression during melanoma progression, we conducted a microarray on a highly metastatic melanoma cell line in which NFAT1 expression was stably silenced. We identified and validated two downstream targets of NFAT1, IL8, and MMP3. Accordingly, NFAT1 depletion in metastatic melanoma cell lines was associated with reduced IL8 and MMP3 expression, whereas NFAT1 overexpression in a weakly metastatic cell line induced expression of these targets. Restoration of NFAT1 expression recovered IL8 and MMP3 expression levels back to baseline, indicating that both are direct targets of NFAT1. Moreover, in vivo studies demonstrated that NFAT1 and MMP3 promoted melanoma tumor growth and lung metastasis. Collectively, our findings assign a new role for NFAT1 in melanoma progression, underscoring the multifaceted functions that immunomodulatory factors may acquire in an unpredictable tumor microenvironment. Cancer Res; 76(11); 3145-55. ©2016 AACR.


Cellular changes and antitumor responses in the plasmacytoma-bearing mouse following cyclophosphamide treatment.
Mice bearing the immunosuppressive plasmacytoma TEPC-183 exhibit a marked splenic hyperplasia. We have characterized these tumor-reactive splenocytes on the basis of cell surface marker expression, nonspecific esterase activity, and morphology. Although splenocyte numbers increased progressively throughout tumor growth, B- and T-lymphocytes, as defined by surface immunoglobulin and Thy-1 antigen expression, respectively, did not increase significantly. Fourteen days after tumor implantation, T-lymphocytes decreased from 70 million to 50 million per spleen. However, cells expressing Mac-1 antigen or nonspecific esterase activity increased from 10 to 65 million. This constituted a 6-fold increase in splenic macrophages. Further studies utilizing the expression of PC.2 antigen in conjunction with morphological examination indicated that metastatic TEPC-183 cells comprise approximately 5% of the tumor-host splenocyte population 14 days after implantation. Ablation of plasmacytoma by cyclophosphamide inhibited the tumor-associated splenocytosis and led to an increase in splenic T-cells (from 70 to 120 million). In addition, macrophage numbers returned to normal. This study also assessed the ability of splenocytes from animals with either actively growing tumors or those from cyclophosphamide-treated tumor-bearing mice to mediate an antitumor response. Splenocytes, when assessed 1 wk following tumor ablation by cyclophosphamide, demonstrated antitumor activity in Winn neutralization assays. This activity was not detectable in splenocytes from animals with progressively growing tumors. Additional studies revealed that the cell population involved in the antitumor effect was glass nonadherent, nylon-wool nonadherent, and expressed Thy-1 antigen. These observations were consistent with the expansion of the splenic T-lymphocyte population following cyclophosphamide treatment. However, the immune response directed against primary TEPC-183 tumor cells was not inhibitory to metastatic tumor cells.


Anti-ulcerogenic effect of Momordica charantia L. fruits on various ulcer models in rats.
The mature fruits of Momordica charantia L. (Cucurbitaceae) are used externally for the rapid healing of wounds and internally for the treatment of peptic ulcers in Turkish folk medicine. For the evaluation of the latter activity, ethanol-induced ulcerogenesis model in rats was employed. The olive oil extract of the material as well as dried-powdered fruits in filtered honey showed significant and dose-dependent anti-ulcerogenic activity against this model. A potent and dose-dependent inhibitory activity was also observed by the administration of ethanol extract of the fruits. For the bioassay-guided fractionation, the material was first extracted with hexane and then by ethanol and both extracts were found active against the same ulcer model. Furthermore, ethanol extract of the fruits showed significant activity against HCl-EtOH induced ulcerogenesis in indomethacin-pretreated rats and diethyldithiocarbamate-induced ulcer models.


Iron deficiency diminishes gallbladder neuronal nitric oxide synthase.
Iron deficiency has been demonstrated in the prairie dog to result in cholesterol crystal formation and altered biliary motility. Gallbladder filling and emptying are influenced by both inhibitory and excitatory stimuli, with nitric oxide (NO) playing a key role in normal relaxation. Iron is a cofactor for nitric oxide synthase. Therefore, we tested the hypothesis that iron deficiency would result in diminished levels of gallbladder neuronal nitric oxide synthase (nNOS) but would not influence the gallbladder's response to excitatory stimuli. Twenty adult female prairie dogs were fed either an iron-supplemented (Fe(+)) (200 ppm) control diet (n = 10) or an iron-deficient (Fe-) (8 ppm) diet (n = 10) for 8 weeks. Fasting gallbladder volume was measured. Gallbladder muscle strips were harvested for response to excitatory stimuli and measurement of nNOS protein levels by Western blotting. Muscle strip response to a spectrum of doses of cholecystokinin, acetylcholine, and electrical field stimuli was determined, and the areas under the response curves were calculated. Gallbladder volume increased in the iron-deficient prairie dogs compared with the iron-supplemented group (1.45 +/- 0.27 mL vs 0.80 +/- 0.13 mL, P < 0.05). Iron deficiency diminished the ratio of gallbladder nNOS to beta-actin protein levels (0.05 +/- 0.01 vs 3.48 +/- 1.02, P < 0.05) but resulted in a normal response to excitatory stimuli. We conclude that diminished gallbladder neuronal nitric oxide synthase contributes to the gallbladder stasis that occurs with iron deficiency. This phenomenon may contribute to the increased incidence of gallstones in premenopausal women.


The prevalence and findings of fibre-optic endoscopic evaluation of swallowing in hospitalised patients with dysphagia.
Swallowing disorder or dysphagia is quite common in hospitalised patients. Using fibre-optic endoscopic evaluation of swallowing (FEES) is one of the clinical standards for evaluating swallowing disorder to prevent serious consequences such as aspiration pneumonia. This study aimed to determine the prevalence and the associated risk of dysphagia in hospitalised patients by using FEES finding. We retrospectively analysed the FEES records from the patients who were screened and suspected of swallowing problems by a certified nurse of dysphagia nursing (CNDN). The FEES findings were compared between dysphagia and without dysphagia to evaluate the associated risk of dysphagia. Six-hundred and nine FEES records were analysed. We found dysphagia 76% in patients who suspected swallowing problems by CNDN. FEES was assessed after the subjects had been admitted for 22 days on average. There was no difference in age between dysphagia and without dysphagia participants. However, the advanced age (age > 85 years old) increased the odd of dysphagia 1.18, P = .03. The primary disease of the subjects was mainly cerebrovascular disease (24%) and pneumonia (22%). Abnormal FEES findings including soft palate elevation, velopharyngeal contraction, whiteout, volitional cough, glottis closure during breath holding, cough reflex and presence of secretion in pharynx were found in hospitalised patients with dysphagia. The prevalence of dysphagia was high in hospitalised patients. Hence, screening the swallowing problem by nurse and FEES evaluation is essential to detect and prevent the complication in the patient who has dysphagia.


The effect of tuning cold plasma composition on glioblastoma cell viability.
Previous research in cold atmospheric plasma (CAP) and cancer cell interaction has repeatedly proven that the cold plasma induced cell death. It is postulated that the reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a major role in the CAP cancer therapy. In this paper, we seek to determine a mechanism of CAP therapy on glioblastoma cells (U87) through an understanding of the composition of the plasma, including treatment time, voltage, flow-rate and plasma-gas composition. In order to determine the threshold of plasma treatment on U87, normal human astrocytes (E6/E7) were used as the comparison cell line. Our data showed that the 30 sec plasma treatment caused 3-fold cell death in the U87 cells compared to the E6/E7 cells. All the other compositions of cold plasma were performed based on this result: plasma treatment time was maintained at 30 s per well while other plasma characteristics such as voltage, flow rate of source gas, and composition of source gas were changed one at a time to vary the intensity of the reactive species composition in the plasma jet, which may finally have various effect on cells reflected by cell viability. We defined a term "plasma dosage" to summarize the relationship of all the characteristics and cell viability.


Technology, Affordances and Occupational Identity Amongst Older Telecommunications Engineers: From Living Machines to Black-Boxes.
This article explores the relationship between technology and occupational identity based on working-life biographical interviews with older telecommunications engineers. In the construction of their own working-life biographical narratives, participants attached great importance to the technology with which they worked. The article contends that workers' relationship with technology can be more nuanced than either the sociology of technology literature or the sociology of work literature accommodates. Adopting the concept of affordances, it is argued that the physical nature of earlier electromechanical technology afforded engineers the opportunity to 'fix' things through the skilled application of tools and act as autonomous custodians of 'living' machines: factors that were inherent to their occupational identity. However, the change to digital technology denied the affordances to apply hands-on skill and undermined key elements of the engineering occupational identity. Rather than simply reflecting the nostalgic romanticizing of the past, the biographies captured deterioration in the material realities of work.


Differences in nasal irritant sensitivity by age, gender, and allergic rhinitis status.
Sensory (eye, nose, and throat) irritation is an important component of non-specific building-related illness ("sick-building syndrome"). Inter-individual variability in susceptibility to upper airway/mucous membrane irritants is suspected epidemiologically, but has been neglected experimentally. We wished to document population variability in nasal irritant sensitivity, as indexed by threshold measurements of sensory acuity. We hypothesized that younger subjects, women, and allergic rhinitis sufferers would display lower sensory thresholds than would older subjects, men, and rhinitis non-sufferers. We evaluated Sixty human subjects (stratified by age, gender, and seasonal allergy status), using two different test systems: (1) carbon dioxide (detection) and (2) n-propanol (localization). We obtained carbon dioxide (CO2) detection thresholds using an ascending concentration series, presenting 3-s pulses of CO2, paired with air in random order, by nasal cannula. Localization thresholds were obtained by the simultaneous presentation of n-propanol vapor (ascending concentrations in air) and blanks (saturated water vapor in air) to opposite nostrils, with laterality randomized. Threshold data were log-transformed to satisfy normality and analyzed by population marker via ANOVA and linear regression. Test-retest variability was greater for volatile organic compound (VOC) localization than for CO2 detection (r=0.50 and 0.75, respectively); the two measurements were, however, positively correlated (r=0.48; P<0.001). Age predicted both (log-transformed) VOC localization thresholds (P<0.0001) and (log-transformed) CO2 thresholds (P<0.01), with younger age predicting lower thresholds. Female gender predicted lower CO2 detection (P<0.05) but not VOC localization thresholds (P=0.10). Nasal allergies predicted lower VOC localization (P<0.05) but not CO2 detection thresholds (P=0.52). Consistent with epidemiological reporting patterns in so-called problem buildings, nasal irritant sensitivity appears to be non-randomly distributed in the population, with significant variability predicted by age, gender, and the presence of allergic rhinitis.


Herceptest: HER2 expression and gene amplification in non-small cell lung cancer.
HER2 is an erbB/HER type 1 tyrosine kinase receptor that is frequently over-expressed in malignant epithelial tumours. Herceptin, a humanised mouse monoclonal antibody to HER2, is proven therapeutically in the management of metastatic breast cancer, significantly prolonging survival when combined with cytotoxic chemotherapeutic agents. Immunohistochemical studies suggest that non-small-cell lung cancer (NSCLC) tumours may over-express HER2. Our aim was to evaluate HER2 gene amplification and semi-quantitative immuno-expression in NSCLC. A total of 344 NSCLC cases were immunostained for HER2 expression in 2 centres using the HercepTest. Fluorescence in situ hybridisation (FISH) analysis for HER2 gene amplification was performed on most positive cases and a subset of negative cases. Fifteen cases (4.3%) demonstrated 2+ or 3+ membranous HER2 immuno-expression. There was no correlation between immuno-expression and tumour histology or grade. Tumours from higher-stage disease were more often HercepTest-positive (p < 0.001). All 4 HercepTest 3+ cases demonstrated gene amplification. One of the 5 2+ cases tested for gene amplification showed areas of borderline amplification and areas of polyploidy. None of the 19 HercepTest-negative cases demonstrated gene amplification or polyploidy (p < 0.001). Gene amplification was demonstrated in all HercepTest 3+ scoring NSCLC cases. Unlike breast cancer, gene amplification and HER2 protein over-expression assessed by the HercepTest appeared to be uncommon in NSCLC. Herceptin may therefore target only a small proportion of NSCLC tumours and be of limited clinical value in this disease, particularly in the adjuvant setting.


Advancing pediatric antimicrobial stewardship: Has pharmacodynamic dosing for gram-negative infections taken effect?
To characterize pharmacodynamic dosing strategies used at children's hospitals using a national survey. Survey. Children's hospitals. Volunteer sample of antimicrobial stewardship program (ASP) respondents. A nationwide survey was conducted to gain greater insight into the current adoption of nontraditional dosing methods and monitoring of select β-lactam and fluoroquinolone antibiotics used to treat serious gram-negative infections in pediatric populations. The survey was performed through the Sharing Antimicrobial Reports for Pediatric Stewardship (SHARPS) Collaborative. Of the 75 children's hospitals that responded, 68% of programs reported adoption of pharmacodynamically optimized dosing using prolonged β-lactam infusions and 35% using continuous β-lactam infusions, although use was infrequent. Factors including routine MIC monitoring and formal postgraduate training and board certification of ASP pharmacists were associated with increased utilization of pharmacodynamic dosing. In addition, 60% of programs reported using pharmacodynamically optimized ciprofloxacin and 14% reported using pharmacodynamically optimized levofloxacin. Only 20% of programs monitored β-lactam levels; they commonly cited lack of published guidance, practitioner experience, and laboratomory support as reasons for lack of utilization. Less physician time dedicated to ASP programs was associated with lower adoption of optimized dosing. Use of pharmacodynamic dosing through prolonged and continuous infusions of β-lactams have not yet been routinely adopted at children's hospitals. Further guidance from trials and literature are needed to continue to guide pediatric pharmacodynamic dosing efforts. Children's hospitals should utilize these data to compare practices and to prioritize further research and education efforts.


Effective one-pot multienzyme (OPME) synthesis of monotreme milk oligosaccharides and other sialosides containing 4-O-acetyl sialic acid.
A facile one-pot two-enzyme chemoenzymatic approach has been established for the gram (Neu4,5Ac2α3Lac, 1.33 g) and preparative scale (Neu4,5Ac2α3LNnT) synthesis of monotreme milk oligosaccharides. Other O-acetyl-5-N-acetylneuraminic acid (Neu4,5Ac2)- or 4-O-acetyl-5-N-glycolylneuraminic acid (Neu4Ac5Gc) -containing α2-3-sialosides have also been synthesized in the preparative scale. Used as an effective probe, Neu4,5Ac2α3GalβpNP was found to be a suitable substrate by human influenza A viruses but not bacterial sialidases.


Comparing treatment with daily and long-acting growth hormone formulations in adults with growth hormone deficiency: Challenging issues, benefits, and risks.
Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies have demonstrated evidence that GH treatment improves body composition, cardiovascular risk factors and quality of life with few side effects. Less frequent GH injections are hypothesized to improve adherence and several long-acting GH (LAGH) formulations have been developed and a few have been approved and marketed. Different pharmacological modifications have been applied and the pharmacokinetics and pharmacodynamics of LAGH are different to each other and to those of daily injections and require different dosing and monitoring specific for each LAGH. Studies have shown improved adherence with LAGH, and short-term efficacy and side effects are comparable between daily GH injections and LAGHs. Long-term treatment with daily GH injections is effective and safe, while long-term studies for LAGHs are awaited. In this review challenges, benefits, and risks of treatment with daily and long-acting GH preparations will be compared.


Scribble is essential for olfactory behavior in Drosophila melanogaster.
The ability to discriminate and respond to chemical signals from the environment is an almost universal prerequisite for survival. Here, we report that the scaffold protein Scribble is essential for odor-guided behavior in Drosophila. Previously, we identified a P-element insert line with generalized sexually dimorphic smell impairment, smi97B. We found that the transposon in this line is located between the predicted promoter region and the transcription initiation site of scrib. A deficiency in this region, Df(3R)Tl-X, and two scrib null alleles fail to complement the smell-impaired phenotype of smi97B. Wild-type behavior is restored by precise excision of the P element, scrib mRNA levels correspond with mutant and wild-type phenotypes, and introduction of a full-length scrib transgene in the smi97B mutant rescues the olfactory deficit. Expression of Scrib is widespread in olfactory organs and the central nervous system. Finally, alternative splicing of scrib generates transcripts that differ in the number of leucine-rich repeats and PDZ domains.


Effect of age on cost-effectiveness of unicompartmental knee arthroplasty compared with total knee arthroplasty in the U.S.
Trade-offs between upfront benefits and later risk of revision of unicompartmental knee arthroplasty compared with those of total knee arthroplasty are poorly understood. The purpose of our study was to compare the cost-effectiveness of unicompartmental knee arthroplasty with that of total knee arthroplasty across the age spectrum of patients undergoing knee replacement. Using a Markov decision analytic model, we compared unicompartmental knee arthroplasty with total knee arthroplasty with regard to lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) from a societal perspective for patients undergoing surgery at forty-five, fifty-five, sixty-five, seventy-five, or eighty-five years of age. Transition probabilities were estimated from the literature; survival, from the Swedish Knee Arthroplasty Register; and costs, from the literature and the Healthcare Cost and Utilization Project (HCUP) database. Costs and QALYs were discounted at 3.0% annually. We conducted sensitivity analyses to test the robustness of model estimates and threshold analyses. For patients sixty-five years of age and older, unicompartmental knee arthroplasty dominated total knee arthroplasty, with lower lifetime costs and higher QALYs. Unicompartmental knee arthroplasty was no longer cost-effective at a $100,000/QALY threshold when total knee arthroplasty rehabilitation costs were reduced by two-thirds or more for these older patients. Lifetime societal savings from utilizing unicompartmental knee arthroplasty in all older patients (sixty-five or older) in 2015 and 2020 were $56 to $336 million and $84 to $544 million, respectively. In the forty-five and fifty-five-year-old age cohorts, total knee arthroplasty had an ICER of $30,300/QALY and $63,000/QALY, respectively. Unicompartmental knee arthroplasty became cost-effective when its twenty-year revision rate dropped from 27.8% to 25.7% for the forty-five-year age group and from 27.9% to 26.7% for the fifty-five-year age group. Unicompartmental knee arthroplasty is an economically attractive alternative in patients sixty-five years of age or older, and modest improvements in implant survivorship could make it a cost-effective alternative in younger patients.


Analysis of neuromonitoring signal loss during retroauricular versus conventional thyroidectomy.
Loss of signal (LOS) during intraoperative neuromonitoring (IONM) of robotic or endoscopic thyroidectomy via a retroauricular approach (RAT) and during conventional open thyroidectomy (COT) was investigated to compare the risk of recurrent laryngeal nerve (RLN) injury between the two groups. Original article. This is a retrospective case series study performed between May 2014 and September 2016. IONM using the NIM 3.0 system (Medtronic Xomed, Inc., Jacksonville, FL) was used for this study. Pre- and postoperative vocal cord functions were assessed using a flexible laryngoscope. LOS types noted intraoperatively and their associations with postoperative vocal cord palsy (VCP) were evaluated. LOS rate and temporary and permanent VCP rates were compared between the two groups. The surgical events associated with LOS were also documented and analyzed in this study. In total, 153 patients were recruited, and 111 patients were enrolled in the RAT group; the remaining 42 patients were enrolled in the COT group. No statistically significant differences in intraoperative LOS (P = 0.812) and postoperative VCP rates (early, permanent; P = 0.259 and P = 0.577, respectively) between the two groups were observed. IONM accuracy of predicting postoperative VCP was 99.1% in our case series. On the basis of IONM findings, the risks of injury to RLN were similar between the two groups. Comparison of LOS was an objective method for verifying the novel RAT approach. We applied our IONM protocol and troubleshooting algorithm during RAT with acceptable accuracy, but the international standardized method of IONM is applicable and recommended for reducing false results using vagal nerve stimulation. 3b Laryngoscope, 129:2199-2204, 2019.


Streptokinase therapy of pulmonary emboli with heparin-associated thrombocytopenia.
A 59-year-old man developed pulmonary emboli with heparin-associated thrombocytopenia. He was treated simultaneously with intravenous streptokinase and oral warfarin sodium. He responded with complete resolution of perfusion defects on lung scan and did not have any hemorrhagic or thrombotic problems. Although optimal therapy for patients with heparin-associated thrombocytopenia and thrombosis is unknown, fibrinolytic therapy may be useful despite thrombocytopenia, provided appropriate resources are available for careful patient monitoring and transfusion therapy.


Autonomous Treatment of Bacterial Infections in Vivo Using Antimicrobial Micro- and Nanomotors.
The increasing resistance of bacteria to existing antibiotics constitutes a major public health threat globally. Most current antibiotic treatments are hindered by poor delivery to the infection site, leading to undesired off-target effects and drug resistance development and spread. Here, we describe micro- and nanomotors that effectively and autonomously deliver antibiotic payloads to the target area. The active motion and antimicrobial activity of the silica-based robots are driven by catalysis of the enzyme urease and antimicrobial peptides, respectively. These antimicrobial motors show micromolar bactericidal activity in vitro against different Gram-positive and Gram-negative pathogenic bacterial strains and act by rapidly depolarizing their membrane. Finally, they demonstrated autonomous anti-infective efficacy in vivo in a clinically relevant abscess infection mouse model. In summary, our motors combine navigation, catalytic conversion, and bactericidal capacity to deliver antimicrobial payloads to specific infection sites. This technology represents a much-needed tool to direct therapeutics to their target to help combat drug-resistant infections.


Evidence for the presence in human plasma of lecithin: cholesterol acyltransferase activity (beta-LCAT) specifically esterifying free cholesterol of combined pre-beta- and beta-lipoproteins. Studies of fish eye disease patients and control subjects.
The present study was undertaken to test our hypothesis that two different lecithin: cholesterol acyltransferase (LCAT) activities exist in normal human plasma, one denoted alpha-LCAT esterifying the free cholesterol of high density lipoproteins (HDL) and the other denoted beta-LCAT acting on the free cholesterol of very low (VLDL) and low (LDL) density lipoproteins. Plasmas depleted of HDL were obtained by means of preparative ultracentrifugation. Incubation at 37 degrees C of these plasma fractions from control subjects and patients with fish eye disease resulted in esterification of the remaining free cholesterol of combined VLDL and LDL (pre-beta- and beta-lipoproteins) in the HDL depleted plasmas. The shapes of the cholesterol esterification rate curves were similar for whole and HDL depleted plasmas from both control subjects and fish eye disease patients. In crosswise mixed incubation experiments with isolated combined VLD and LDL and total lipoprotein depleted plasma from a control subject and a patient with fish eye disease, respectively, esterification of free cholesterol occurred. Incubation of isolated total lipoproteins in plasma from a patient with LCAT deficiency mixed with total lipoprotein depleted plasma from a fish eye disease patient as a source of LCAT caused cholesterol esterification but did not result in normalization of the LCAT deficiency HDL particles, while the amount of normal-sized LDL particles increased. The present results support the hypothesis that a beta-LCAT exists in normal human plasma.


Stakeholder perspectives on primary school pupils and sickness absence - exploring opportunities and challenges.
School absenteeism and its underlying causes can have negative effects on the cognitive, psychosocial and health development of a child. Research in primary education shows high rates of sickness absence. Many stakeholders are involved in addressing school absenteeism, including primary school professionals, child and youth healthcare physicians, school attendance officers and parents. This study explores these stakeholders' perspectives, their approaches and what they envisage to be necessary in order to improve. It also aims to unveil opportunities and challenges in addressing sickness absence among primary school pupils. Qualitative research was performed with six semi-structured focus group interviews and involving 27 participants from the West-Brabant and Amsterdam regions of the Netherlands. Thematic analysis was used. The overarching theme was aiming for the child's wellbeing. Each focus group interview started with low awareness of sickness absence as a threat to this wellbeing, but awareness grew during the interviews. The participating stakeholders regarded problematic sickness absence as complex due to a wide variety of causes, and felt that each other's expertise was necessary to reduce sickness absence. Schools registered absence, but only occasionally used planned steps; they based the identification of problematic sickness on gut feeling rather than any agreed-upon criteria. To be able to systematically address sickness absence and thus improve the wellbeing of children, stakeholders felt the need for a clearly structured approach, including monitoring of sickness absence of all pupils, identifying problematic absence and promoting collaboration with other stakeholders. An approach should allow for tailoring solutions to the individual child.


Response to a third-line mitomycin C (MMC)-based chemotherapy in a patient with metastatic pancreatic adenocarcinoma carrying germline BRCA2 mutation.
Gemcitabine remains the mainstay of palliative chemotherapy for those patients with unresectable or metastatic pancreatic cancer. Objective radiological responses to gemcitabine are rare and reported median survival is only about six months. New therapeutic concepts and strategies are needed in order to improve those dismal statistics. We report here a case of a patient with metastatic pancreatic cancer responding to a third-line therapy with combination of mitomycin C and capecitabine. Interestingly, the patient had a strong family history of breast cancer and tested positive to germline BRCA2 mutation. We feel that this is of interest because of preclinical reports of increased sensitivity of pancreatic cells carrying BRCA2 mutations to DNA-intercalating agents such as mitomycin C. Further research and clinical trials are warranted to support this novel concept.


Variability among institutional review boards' decisions within the context of a multicenter trial.
Institutional review boards (IRBs) are given discretion to interpret and apply the federal regulations governing the protection of human subjects in research. To determine the extent of the variability among different IRBs on their approved research practices and informed consent forms within the context of a multicenter trial that used a common protocol. Descriptive analysis of survey information and informed consent forms. Sixteen IRBs from the institutions participating in a multicenter trial comparing lower vs. traditional tidal volume ventilation in patients with acute lung injury. Analysis of survey information on IRBs' approved research practices. Analysis of informed consent forms for the presence and the adequacy of description of each basic element of informed consent specified in the federal regulations. Reading levels of informed consent forms. Surveys and IRB-approved consent forms were obtained from all of the contacted IRBs (n = 16). Variability was observed among several of the research practices; one IRB waived the requirement for informed consent, five IRBs permitted telephone consent, and three IRBs allowed prisoners to be enrolled. Three consent forms contained all of the basic elements of informed consent outlined in the federal regulations, and 13 forms had varying numbers of these elements absent (six forms without one element, four without two, one without three, and two without four). Reading levels of the consent forms ranged from grades 8.2 to 13.4 (mean +/- sd was 11.6 +/- 1.2 grade level). Within a multicenter trial, IRBs reviewing a common protocol varied in several of their approved research practices and in the extent to which the basic elements of informed consent were included in their consent forms.


Flexible EEG Electrodes with Embedded Pressure Sensors and Customized Interface Towards Comfortable Home EEG Monitoring.
To realize stable and comfortable dry electroencephalography (EEG) recording for home healthcare, a flexible pressure-sensitive electrode (PSE) is proposed, and a dedicated multi-channel pressure sensor interface is developed. The PSE monitors the pressure on the electrode during continuous EEG recording. With the PSE, stable but comfortable electrode-skin contact can be achieved. The analog front-end of the sensor interface is fabricated in 180-nm CMOS, occupying an active area of 0.25 mm2. The flexible sensor exhibited a -2.5 kΩ/kPa sensitivity. The sensor interface enjoyed a large stimulus range of up to 2.65 mApp and showed a resolution of 0.047 - 8.0 mΩ/√Hz. It is digital-compatible, reconfigurable, and area-efficient, which can be migrated into various EEG acquisition integrated circuits and systems.


Sensitive detection of Helicobacter pylori by using polymerase chain reaction.
A polymerase chain reaction (PCR) for the specific detection of Helicobacter pylori was developed with a single primer pair derived from the nucleotide sequence of the urease A gene of H. pylori. We achieved specific amplification of a 411-bp DNA fragment in H. pylori. After 35 cycles of amplification, the product could be detected by agarose gel electrophoresis and contained conserved single HinfI and AluI restriction sites. This fragment was amplified in all 50 strains of H. pylori tested, but it was not detected in other bacterial species, showing the PCR assay to be 100% specific. PCR DNA amplification was able to detect as few as 10 H. pylori cells. PCR detected H. pylori in 15 of 23 clinical human gastric biopsy samples, whereas culturing and microscopy detected H. pylori in only 7 of the samples found to be positive by PCR. Additional primer pairs based on the urease genes enabled the detection of H. pylori in paraffin-embedded human gastric biopsy samples. The detection of H. pylori by PCR will enable both retrospective and prospective analyses of clinical samples, elucidating the role of this organism in gastroduodenal disease.


[Strengths and limitations of the Rio de Janeiro Municipal AIDS Information System as an instrument for epidemiological surveillance].
This study analyzes the Rio de Janeiro Municipal AIDS Information System, specifically the system's strengths and limitations in the epidemic's current context, from a broader perspective of epidemiological surveillance. The objective was to provide a brief description of the system, considering its different components. The authors further analyzed records pertaining to the reporting and investigation of AIDS cases from 1985 to 1995 and an update of the database as a contribution to the system's quality. The results showed improvement in the consistency of the AIDS database, particularly for the following variables: occupation, neighborhood, school, and exposure category, although the study found concrete limitations in the system's design and structure for dealing with the complexity and heterogeneity of AIDS surveillance. The study thus identified the need to construct an efficient HIV/AIDS surveillance system, based on epidemiological indicators aimed at monitoring and evaluating changes in the epidemiological pattern and analysis of the impact on morbidity and mortality resulting from access to more efficient forms of prevention and new treatments.


Primary immunodeficiency in Africa - a review.
Efforts have been made worldwide to improve awareness and treatment of primary immunodeficiency (PID). This has also gained momentum on the African continent albeit at a slower pace. Objective. This review reports on the current status of PID on the African continent regarding its prevalence, distribution, genetic mutations and challenges in diagnosis and treatment of affected patients. Method. We evaluated all studies published from the African continent in the field of PID dealing with prevalence, epidemiology, case reports and genetic findings. Results. The prevalence of PID on the African continent has been estimated to be as high as 902 631 individuals. PID still is mostly underdiagnosed in Africa and although progress has been made in parts of the continent many challenges still remain regarding awareness, diagnosis, registration and care of these patients. Conclusion. Given the unique genetic mutations reported in PID patients on the African continent and the feasibility of hematopoietic stem cell transplantation and gene therapy, increased awareness should be encouraged and new therapeutic options considered.


Regulation of adenylate cyclase by chronic exposure to cannabimimetic drugs.
Previous studies in this laboratory have demonstrated that a cloned neuroblastoma cell line (N18TG2) responds to delta 9-tetrahydrocannabinol (THC), the major psychoactive product of marihuana, with an attenuation of cyclic AMP accumulation that results from an inhibition of adenylate cyclase. The requirement for the Gi regulatory protein, stereoselectivity, pharmacologic specificity and cell selectivity of this response suggest that a receptor for cannabimimetic compounds may be associated with adenylate cyclase in the neuroblastoma cell. Presented here is a comprehensive investigation of cellular effects of chronic exposure to cannabimimetic agents. Short-term exposure to either delta 9-THC or the more potent nantradol analog, desacetyllevonantradol (DALN), at doses up to 100 microM did not compromise the plating efficiency of the cells. Cells that were exposed to 1 microM delta 9-THC (maximally effective for inhibiting cyclic AMP production) for 24 hr in a serum-free medium were shown to accumulate the drug but not to metabolize it. Exposure to 10 microM delta 9-THC or DALN for up to 48 hr failed to significantly affect cell growth rate or protein content per cell. The gross morphology of cannabinoid-treated cells was not altered at the light or the electron microscope level. The cellular organelles and membranes appeared intact, with no remarkable differences from control cells. The inhibition of cyclic AMP accumulation in response to cannabimimetic drugs was diminished in cells treated with delta 9-THC or DALN for 24 hr. This desensitization was homologous because both delta 9-THC and DALN responses were attenuated after exposure to either cannabimimetic drug.(ABSTRACT TRUNCATED AT 250 WORDS)


Temporal trends in asthma mortality over 30 years.
Bronchial asthma is an important cause of morbidity and mortality worldwide. There is limited availability of updated information on asthma mortality trends. In this context, further investigation of asthma mortality trends is necessary. We aimed to assess trends in asthma mortality trends in the Autonomous Community of Andalusia (over 7 million inhabitants), Spain, during the period 1975-2005. Official population estimates and data on asthma deaths were obtained from official authorities. Crude and age-adjusted death rates for different age and gender groups were calculated. Joinpoint regression analysis was used for trend analysis. Age-adjusted death rates for asthma have fallen 2.9% for females and 7.7% for males from 1975 to 2005. This trend has not been constant but has varied during the study period. After a non-significant increase from 1975 to 1981 (4.5% for females and 3.8% for males), adjusted asthma mortality rates have been declining 3.7% for females and 9.6% for males (both p values < 0.05) since 1981. Age-group analysis revealed that the downturn in asthma mortality rates occurred in all age groups above 45 years for males and 35 years for females. During the last decades, significant variation in asthma mortality was found in Andalusia. This variation has not been constant during the study period. Currently, the decreasing trend initiated in 1981 continues.


Determination of the electrostatic potential and electron density of silicon using convergent-beam electron diffraction.
A structure-analysis method using convergent-beam electron diffraction (CBED) developed by Tsuda et al. [Tsuda & Tanaka (1999), Acta Cryst. A55, 939-954; Tsuda, Ogata, Takagi, Hashimoto & Tanaka (2002), Acta Cryst. A58, 514-525] has been applied to the determination of the electrostatic potential and electron density of crystalline silicon. CBED patterns recorded at nine different incidences are simultaneously used to improve the accuracy of the refinement. The Debye-Waller factor and low-order structure factors of silicon have been successfully refined only using CBED data. The electrostatic potential and electron-density distribution have been reconstructed from the refined parameters. The latter clearly shows the bonding electrons between the nearest neighbor atoms. The obtained results are compared with the results of other CBED and recent X-ray diffraction experiments. The influence of the number of refined low-order structure factors on the electron density is discussed. The effect of the reduction of experimental data points on the accuracy of the refined parameters is also examined.


'Less ticking the boxes, more providing support': A qualitative study on health professionals' concerns towards the Liverpool Care of the Dying Pathway.
Despite being widely used, research into the effectiveness of the Liverpool Care of the Dying Pathway (LCP) and associated cases of malpractice does not match dissemination. No study exists focusing on concerns voiced by professionals. To explore the views of professionals who, during the hospital implementation of the Italian version of the Liverpool Care of the Dying Pathway (LCP-I), voiced or showed concerns towards it. A qualitative study nested within the LCP-I randomized cluster trial, with semi-structured interviews analysed using thematic analysis. Six nurses and five physicians from six out of the eight hospital wards who completed the LCP-I implementation were interviewed. Eligibility criteria were having taken part in all steps of the LCP-I Programme, voiced or somehow shown concerns, or failed to fully engage with the implementation process. A total of 12 categories were identified, referring to four topics: the Implementation Programme, the LCP-I clinical documentation, the hospital environment and the educational and professional background of hospital healthcare staff. Issues raised by participants concerned both 'real' characteristics of the LCP-I and a misinterpretation of the LCP-I approach and clinical documentation. Furthermore, difficulties were reported which were not linked to the Programme but rather to end-of-life care. This study provides insights into the experience of professionals with negative opinions of or concerns with the LCP-I. A more comprehensive approach to professional training in palliative care is needed and may envisage the development of new interventions aimed at improving the quality of care throughout the illness trajectory.


Detection of Atrial Fibrillation based on Feature Fusion using Attention-based BiLSTM.
Atrial fibrillation (AF) is a common cardiac arrhythmia, and its early detection is crucial for timely treatment. Conventional methods, such as Electrocardiogram (ECG), can be intrusive and require specialized equipment, whereas Photoplethysmography (PPG) offers a non-invasive alternative. In this study, we present a feature fusion approach for AF detection using attention-based Bidirectional Long Short-Term Memory (BiLSTM) and PPG signals. We extract frequency domain (FD) and time domain (TD) features from PPG signals, combine them with deep learning features generated from an attention-based BiLSTM network, and pass the fusion features through a softmax function. Our approach achieves high accuracy (96.5%) and favorable performance metrics (recall 93.20%, precision 94.50%, and F-score 93.09%), improving AF prediction and diagnosis, and providing support for clinicians in their diagnostic processes.


Pulmonary symptoms measured by the national institutes of health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease.
The 2005 National Institutes of Health (NIH) Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with nonrelapse mortality (NRM), overall survival (OS), and patient-reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter, observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplantation characteristics and nonlung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (P = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM; although, some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0 to 3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality.


An overview of treatment approaches for chronic pain management.
Pain which persists after healing is expected to have taken place, or which exists in the absence of tissue damage, is termed chronic pain. By definition chronic pain cannot be treated and cured in the conventional biomedical sense; rather, the patient who is suffering from the pain must be given the tools with which their long-term pain can be managed to an acceptable level. This article will provide an overview of treatment approaches available for the management of persistent non-malignant pain. As well as attempting to provide relief from the physical aspects of pain through the judicious use of analgesics, interventions, stimulations, and irritations, it is important to pay equal attention to the psychosocial complaints which almost always accompany long-term pain. The pain clinic offers a biopsychosocial approach to treatment with the multidisciplinary pain management programme; encouraging patients to take control of their pain problem and lead a fulfilling life in spite of the pain.


Association of body mass index and waist-to-hip ratio with brain structure: UK Biobank study.
To examine the association of body mass index (BMI) and waist-to-hip ratio (WHR) with brain volume. We used cross-sectional data from the UK Biobank study (n = 9,652, age 55.4 ± 7.5 years, 47.9% men). Measures included BMI, WHR, and total fat mass as ascertained from bioimpedance. Brain images were produced with structural MRI. After adjustment for a range of covariates, higher levels of all obesity measures were related to lower gray matter volume: BMI per 1 SD (β coefficient -4,113, 95% confidence interval [CI] -4,862 to -3,364), WHR (β coefficient -4,272, 95% CI -5,280 to -3,264), and fat mass (β coefficient -4,590, 95% CI -5,386 to -3,793). The combination of overall obesity (BMI ≥30 kg/m2) and central obesity (WHR >0.85 for women, >0.90 for men) was associated with the lowest gray matter compared with that in lean adults. In hypothesis-free testing with a Bonferroni correction, obesity was also related to various regional brain volumes, including caudate, putamen, pallidum, and nucleus accumbens. No associations between obesity and white matter were apparent. The combination of heightened BMI and WHR may be an important risk factor for gray matter atrophy.


Air pollution and atherosclerosis: a cross-sectional analysis of four European cohort studies in the ESCAPE study.
In four European cohorts, we investigated the cross-sectional association between long-term exposure to air pollution and intima-media thickness of the common carotid artery (CIMT), a preclinical marker of atherosclerosis. Individually assigned levels of nitrogen dioxide, nitrogen oxides, particulate matter ≤ 2.5 μm (PM2.5), absorbance of PM2.5 (PM2.5abs), PM10, PMcoarse, and two indicators of residential proximity to highly trafficked roads were obtained under a standard exposure protocol (European Study of Cohorts for Air Pollution Effects-ESCAPE study) in the Stockholm area (Sweden), the Ausburg and Ruhr area (Germany), and the Girona area (Spain). We used linear regression and meta-analyses to examine the association between long-term exposure to air pollution and CIMT. The meta-analysis with 9,183 individuals resulted in an estimated increase in CIMT (geometric mean) of 0.72% (95% CI: -0.65%, 2.10%) per 5-μg/m3 increase in PM2.5 and 0.42% (95% CI: -0.46%, 1.30%) per 10-5/m increase in PM2.5abs. Living in proximity to high traffic was also positively but not significantly associated with CIMT. Meta-analytic estimates for other pollutants were inconsistent. Results were similar across different adjustment sets and sensitivity analyses. In an extended meta-analysis for PM2.5 with three other previously published studies, a 0.78% (95% CI: -0.18%, 1.75%) increase in CIMT was estimated for a 5-μg/m3 contrast in PM2.5. Using a standardized exposure and analytical protocol in four European cohorts, we found that cross-sectional associations between CIMT and the eight ESCAPE markers of long-term residential air pollution exposure did not reach statistical significance. The additional meta-analysis of CIMT and PM2.5 across all published studies also was positive but not significant.


[The protocolization and follow-up of enteral nutrition. 2 years of experience].
The Artificial Nutrition Unit was set up in 1980 in the Pharmacy Service, with the objective of preparing parenteral nutritional units. Different protocols were prepared, approved by the Commission of Pharmacy and Therapeutics. From 1986 onwards, follow-up was commenced and since March 1988, nutritional evaluation of the patients on enteral nutrition has been performed. Encouraged by the results obtained, a proposal for protocolizing enteral nutrition was put to the Commission of Pharmacy and Therapeutics, which was approved in December 1988. The main objective was to select the enteral diets which would be used as a formula for existing hospital diets and, after establishing this formula, protocolize the indications that would assists in selecting from among the diets available, the ones that would best adapt to the individual needs of each patient. As a secondary objective, the Artificial Nutrition Unit took on the responsibility of processing the medical instructions and dispensing enteral diets using the dosage/patient/day distribution system. It also provides information to medical and nursing staff on existing diets, as well as on rules for administration and storage in nursing units, providing when necessary the most suitable containers, equipment and pumps for administering the diets. It also carries out a nutritional evaluation of patients exclusively on enteral nutrition, as well as follow-up of these. Finally, it prepares the monthly actual cost figures generated by each nursing unit, since diets not administered after twenty-four hours are returned to the Nutrition Unit. One problem existing is the non-administration of products or patients who refuse to take their diets.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluating the Efficacy of Therapies in Patients With Coronavirus Disease 2019.
There is a proliferation of clinical trials worldwide to find effective therapies for patients diagnosed with coronavirus disease 2019 (COVID-19). The endpoints that are currently used to evaluate the efficacy of therapeutic agents against COVID-19 are focused on clinical status at a particular day or on time to a specific change of clinical status. To provide a full picture of the clinical course of a patient and make complete use of available data, we consider the trajectory of clinical status over the entire follow-up period. We also show how to combine the evidence of treatment effects on the occurrences of various clinical events. We compare the proposed and existing endpoints through extensive simulation studies. Finally, we provide guidelines on establishing the benefits of treatments.


Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer.
The majority (∼70%) of breast cancers are steroid hormone receptor (SR) positive at the time of diagnosis. Endocrine therapies that target estrogen receptor α (ERα) action (tamoxifen, toremifene, fulvestrant) or estrogen synthesis (aromatase inhibitors: letrozole, anastrozole, exemestane; or ovarian suppression) are a clinical mainstay. However, up to 50% of SR+ breast cancers exhibit de novo or acquired resistance to these clinical interventions. Mechanisms of resistance to endocrine therapies often include upregulation and/or activation of signal transduction pathways that input to cell cycle regulation. Cyclin D1, the regulatory subunit of cyclin-dependent protein kinases four and six (CDK4/6) serves as a convergence point for multiple signaling pathways. In a recent paper entitled 'Therapeutically Activating Retinoblastoma (RB): Reestablishing Cell Cycle Control in Endocrine Therapy-Resistant Breast Cancer', Thangavel et al. reported maintenance of cyclin D1 expression and RB phosphorylation in the face of ER ablation in multiple breast cancer cell line models of endocrine resistance. RB-dysfunction defined a unique gene signature that was associated with luminal B-type breast cancer and predictive of poor response to endocrine therapies. Notably, a new CDK4/6 inhibitor (PD-0332991) was capable of inducing growth arrest by a mechanism that was most consistent with cellular senescence. In this review, these findings are discussed in the context of SRs as important mediators of cell cycle progression, and the frequent loss of cell cycle checkpoint control that typifies breast cancer progression. These studies provide renewed hope of effectively stabilizing endocrine-resistant breast cancers using available complementary (to endocrine-based therapies) cytostatic agents in the form of CDK4/6 inhibitors.


Immunological characterization of honey proteins and identification of MRJP 1 as an IgE-binding protein.
We encountered a fourth case of honey allergy in Japan. We characterized and identified the IgE-binding proteins in honey using the serum of a honey-allergenic patient. Immunoblot analysis revealed that IgE in the patient serum specifically bound to four proteins in each honey sample. At least three of these IgE-binding proteins were N-linked glycoproteins. To identify the 60-kDa IgE-binding protein in dandelion honey, the N-terminal sequences of the fragmented protein were analyzed, revealing the protein to be major royal jelly protein 1 (MRJP 1). Three IgE-binding proteins removed of N-linked oligosaccharide showed a large reduction in IgE-binding activity as compared with the intact protein. This suggests that the carbohydrates in the IgE-binding proteins are a major epitope for patient IgE.


Pharmacokinetics of orally and intravenously administered riboflavin in healthy humans.
The pharmacokinetics and utilization (flavocoenzyme synthesis) of orally and intravenously administered riboflavin in healthy humans were assessed. After the determination of circadian rhythms of riboflavin concentrations in blood plasma and urine of four males and five females (control period), each of these subjects received three different oral riboflavin doses (20, 40, and 60 mg) and one intravenous bolus injection of riboflavin (11.6 mg). Vitamins were administered in a randomized, cross-over design with 2 wk between each administration. Blood plasma and urine specimens were collected repeatedly over a period of 48 h after each administration. Concentrations of flavocoenzymes and riboflavin were analyzed in blood plasma; riboflavin was assayed in urine. During the control period, a small circadian variation was observed: plasma concentrations and urinary excretion of riboflavin were low during the afternoon (P < 0.05). Pharmacokinetics were calculated using a two-compartment open model. The maximal amount of riboflavin that can be absorbed from a single dose was 27 mg per adult. Half-life of absorption was 1.1 h. First-order rate constants describing distribution and elimination of riboflavin were significantly higher after intravenous than after oral administration (P < 0.01). Release of flavocoenzymes into plasma was low compared with the increase of riboflavin concentrations. 7 alpha-Hydroxyriboflavin was identified in plasma. Clearance data indicated that urinary excretion of riboflavin contributes to one-half of the overall removal of riboflavin from plasma. No sex differences were observed for any of the pharmacokinetic variables (P > 0.05).


Socio-demographic inequalities in the diets of mid-aged Australian women.
This study reports on the distributions of food and nutrient intakes by socio-demographic factors for a large population sample of mid-aged Australian women participating in the Australian Longitudinal Study on Women's Health. This cross-sectional population-based study used the Cancer Council of Victoria food frequency questionnaires to derive estimates of food and nutrient intakes. Nationwide community-based survey. A total of 10561 women aged 50-55 y, at the time of the survey in 2001. Analysis showed favourable patterns of food intake, with frequent consumption of many foods that are promoted as components of a healthy diet (eg, fresh fruit, leafy green and other vegetables, bread, cereals, milk and meat). Intakes of both foods and nutrients varied significantly across socio-demographic groups, with unmarried women, and women in 'labouring' occupations (eg, cleaner, factory worker, kitchenhand) having poorer nutrient intake. Although many mid-aged women in this sample had generally healthful diets, women in certain socio-demographic groups (particularly unmarried women and those in labouring occupations) had nutrient intakes of concern. As well as helping to address the dearth of current data on dietary intakes in the Australian population, the results highlight the need for continued targeted public health strategies aimed at improving diet of women from the various socio-economic backgrounds.


Streets, strolls and spots: sex work, drug use and social space in Detroit.
In this paper, we explore social spaces related to street sex work and illicit drug use in Detroit. We consider these spaces as assemblages (Duff, 2011, 2013; Latour, 2005) that reflect the larger moral geography (Hubbard, 2012) of the city and fulfill specific functions in the daily lives of drug using sex workers. We draw on thirty-one in-depth qualitative interviews with former street sex workers who were recruited through a court-based treatment and recovery program, as well as ethnographic field notes from drug treatment and law enforcement settings. Our interview findings reveal highly organized and routine activities that exist in a relatively stable, symbiotic relationship with law enforcement practices, employment and commuter patterns, and built environments. While the daily life of street sex work involves a good deal of individual agency in terms of moving between spaces and negotiating terms of exchange, daily trajectories were also circumscribed by economics, illicit substance use, and the objective risks of the street and the police. We consider the implications of these results for future policy directed at harm reduction in the street setting.


Hybrid nanoparticles with CO2-responsive shells and fluorescence-labelled magnetic cores.
CO2-responsive polymer poly(N,N-diethylaminoethylmethacrylate)-modified magnetic nanoparticles (Fe3O4@dye/SiO2-PDEAEMA) were synthesized by atom transfer radical polymerization from the surfaces of silica coated, dye-labelled iron oxide nanoparticles (Fe3O4@dye/SiO2). TEM, FT-IR, and TGA confirmed and quantified the grafted polymer brushes. The prepared magnetic nanoparticles (MNPs) were fluorescence labelled, as shown by the fluorescence spectra and fluorescence microscopy images. This indicated that the nanoparticles could be utilized as imaging probes to monitor the movement of biological cells or other systems. The PDEAEMA polymer brushes on the surface of MNPs endowed them with a protein adsorption ability. The polymer was also CO2-responsive, so it was a CO2-triggered reversible protein adsorption/release material, which was demonstrated by the bovine serum albumin (BSA) adsorption experiments. The results indicated that the reversible adsorption/release of protein by bubbling CO2 and N2 alternately was easy to achieve.


The prevalence of pre-hypertension and its association to established cardiovascular risk factors in south of Iran.
Pre-hypertension is associated with an increased risk of the development of hypertension and subsequent cardiovascular disease and raises mortality risk. The aim of this study was to determine the prevalence of pre-hypertension and to explore the associations between pre-hypertension and established cardiovascular risk factors in a population-based sample of Iranian adults. In this cross-sectional study a representative sample of 892 participants aged ≥ 30 years was selected using a multistage cluster sampling method. After completion of a detailed demographic and medical questionnaire (gender, age, history of diabetes mellitus and hypertension, taking antihypertensive or hypoglycemic agents and history of smoking), all participants were subjected to physical examination, blood lipid profile, blood glucose, anthropometric and smoking assessments, during the years 2009 and 2010. Variables were considered significant at a p-value ≤ 0.05. Statistical analysis was performed using SPSS version 11.5 software. Pre-hypertension was observed among 300 (33.7%) subjects, 36.4% for men and 31.4% for women (p > 0.05). The pre-hypertensive group had higher levels of blood glucose and triglycerides, higher body mass index and lower percentage of smoking than did the normotensive group. Multivariate logistic regression analysis showed that obesity and overweight were the strongest predictors of pre-hypertension [odds ratio, 2.74: 95% CI (Confidence Interval), 1.62 to 4.62 p < 0.001; odds ratio, 2.56, 95% CI, 1.74 to 3.77, p < 0.001 respectively]. Overweight and obesity are major determinants of the high prevalence rate of pre-hypertension detected in Iranian population. Therefore, primary prevention strategies should concentrate on reducing overweight and obesity if the increased prevalence of pre-hypertension is to be diminished in Iranian adults.


Feces nitrogen release induced by different large herbivores in a dry grassland.
Large herbivores have pronounced effects on nutrient cycling in grasslands. These organisms are known to alter the quality and quantity of plant production as well as the amounts and quality of plant litter and animal wastes. The generalization that the relative quality of detritus inputs is enhanced by herbivores is well known, but how this process is affected by diet selection processing and feces production of different large herbivores remains largely unstudied. Here, we measured how these differences for cattle and sheep on a dry grassland might influence nitrogen (N) mineralization from feces. We found that cattle of larger body size tended to select the low quality grass Stipa grandis as their major food source. In contrast, the subdominant grass Leymus chinensis, with relatively high N content, was a majority in the diet of smaller sheep, when palatable forbs were insufficient in the field. This diverse diet quality resulted in a C:N ratio of cattle feces that was higher than that of sheep feces. Relatively higher labile C availability in the cattle feces, namely relatively higher cellulose/hemicellulose contents, promoted microbial growth and in turn accelerated cattle feces decomposition. A surprise finding was that the feces from cattle mineralized about twice as much N as feces from sheep, despite the latter having slightly higher N content. From a grassland productivity perspective, increasing the proportion of large body-sized species in grazing herbivore assemblages perhaps is beneficial to forage productivity and nutrient recycling by the rapid degradation of feces.


Cleidocranial dysplasia: report of 3 cases and literature review.
Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. It is caused by mutations of the transcription factor RUNX2, which is known as a major regulator of bone differentiation. To report on 3 Chinese pediatric cases of CCD with an emphasis on the clinical presentation and diagnostic modalities. 3 Chinese children were admitted to our hospital because of short stature. All the children had hypoplastic clavicles, absent calvarium, open fontanel, and messy palmprint. Screening laboratory test results for bone mineral density, free thyroxine, and thyroid stimulating hormone were all normal. One child had mental retardation. Two were hereditary, and 1 was sporadic. These results showed that CCD should be suspected in patients with short stature and poor clavicles, calvarium, or teeth. Timely recognition and hereditary tendency counseling is required and useful.


Development and construction of an open-platform, open-source low-cost portable uroflowmeter: The OpenFlow device.
Uroflowmetry is useful to screen for and manage many voiding disorders. Home-based uroflowmetry might better represent the patient's true voiding pattern and be more widely adopted if an accurate low-cost portable device was available. Development and initial evaluation of an open-platform, open-source low-cost portable uroflowmeter. We designed and built an uroflowmeter comprising of a load cell and digital memory card unit connected to a programmable microcontroller board mounted upon a 3D printed frame. It generated date-stamped tables which were processed and plotted. Twenty urologists were recruited to assess the device. Each participant received the equipment that was returned, along with a bladder diary, after at least 24 consecutive hours of homemade uroflowmetry recording. Additionally, were assessed with the International Prostatic Symptom Score (I-PSS) and Peeling diagram, whereas the device's ease of use, robustness, and portability were evaluated with a Likert-type questionnaire. Two experienced urodynamicists independently evaluated the tracings' quality rated with a 3° ordinal scale: (1) Interpretable without artifacts; (2) Interpretable with artifacts; (3) Uninterpretable. Participants' median age was 36.6 years old, none having an I-PSS > 5 or Peeling > 2. Overall 138 voidings were recorded (77 daytime, 61 nightly episodes). The device's ease of use, robustness, and portability obtained maximum score in 80% of evaluations. Most (98%) of the tracings were considered interpretable. Limitations included its small study population and short monitoring times. The construction of a cheap (<50 USD), accurate user-friendly portable uroflowmeter proved feasible, which could facilitate access to portable uroflowmetry.


Reward-related ventral striatum reactivity mediates gender-specific effects of a galanin remote enhancer haplotype on problem drinking.
The neuropeptide galanin has been implicated in the regulation of appetitive and consummatory behaviors. Prior studies have shown that direct injection of galanin into the hypothalamus results in increased release of dopamine (DA) in the nucleus accumbens (NAcc), and parallel increases in food and alcohol consumption. These studies are consistent with a role of hypothalamic galanin in regulating reward system reactivity. In humans, a common functional haplotype (GAL5.1) within a remote enhancer region upstream of the galanin gene (GAL) affects promoter activity and galanin expression in hypothalamic neurons in vitro. Given the effects of hypothalamic galanin on NAcc DA release and the effects of the GAL5.1 haplotype on GAL expression, we examined the impact of this functional genetic variation on human reward-related ventral striatum (VS) reactivity. Using an imaging genetics strategy in Caucasian individuals (N = 138, 72 women) participating in the ongoing Duke Neurogenetics Study, we report a significant gender-by-genotype interaction (right hemisphere: F1,134 = 8.08, P = 0.005; left hemisphere: F1,134 = 5.39, P = 0.022), such that homozygosity for the GG haplotype, which predicts greater GAL expression, is associated with relatively increased VS reactivity in women (n = 50, right hemisphere: P = 0.015; left hemisphere: P = 0.060), but not in men (N = 49, P-values > 0.10). Furthermore, these differences in VS reactivity correlated positively with differences in alcohol use, such that VS reactivity mediated a gender-specific association between GAL5.1 haplotype and problem drinking. Our current results support those in animal models implicating galanin signaling in neural pathways associated with appetitive and consummatory behaviors of relevance for understanding risk for substance use and abuse.


New concepts in relation to urge and detrusor activity.
Investigations of micromotion characteristics of bladder wall strips and pressure wave phenomena in total bladders in vitro and in vivo indicate that micromotion phenomena occur in the bladder wall. Local contractions can occur without an increase in tension or pressure, because other parts are in antiphase. Local contractions stretch surrounding tissues, which can stimulate fast stretch receptors. Synchronisation of these micromotion phenomena appears to be possible. Hence, above threshold levels urge can theoretically occur, even in the absence of a pressure increase. This hypothesis could explain the weak relation between urge and pressure. The distinction between motor and sensory urge could be artifactual based on a misunderstanding of fundamental bladder wall processes.


Single MHC mutation eliminates enthalpy associated with T cell receptor binding.
The keystone of the adaptive immune response is T cell receptor (TCR) recognition of peptide presented by major histocompatibility complex (pMHC) molecules. The crystal structure of AHIII TCR bound to MHC, HLA-A2, showed a large interface with an atypical binding orientation. MHC mutations in the interface of the proteins were tested for changes in TCR recognition. From the range of responses observed, three representative HLA-A2 mutants, T163A, W167A, and K66A, were selected for further study. Binding constants and co-crystal structures of the AHIII TCR and the three mutants were determined. K66 in HLA-A2 makes contacts with both peptide and TCR, and has been identified as a critical residue for recognition by numerous TCR. The K66A mutation resulted in the lowest AHIII T cell response and the lowest binding affinity, which suggests that the T cell response may correlate with affinity. Importantly, the K66A mutation does not affect the conformation of the peptide. The change in affinity appears to be due to a loss in hydrogen bonds in the interface as a result of a conformational change in the TCR complementarity-determining region 3 (CDR3) loop. Isothermal titration calorimetry confirmed the loss of hydrogen bonding by a large loss in enthalpy. Our findings are inconsistent with the notion that the CDR1 and CDR2 loops of the TCR are responsible for MHC restriction, while the CDR3 loops interact solely with the peptide. Instead, we present here an MHC mutation that does not change the conformation of the peptide, yet results in an altered conformation of a CDR3.


Impact of improved neonatal care on the profile of retinopathy of prematurity in rural neonatal centers in India over a 4-year period.
To report the reduction in the incidence and severity of retinopathy of prematurity (ROP) in rural India over a 4-year period following the introduction of improved neonatal care practices. The Karnataka Internet Diagnosis of Retinopathy of Prematurity program (KIDROP), is a tele-medicine network that screens for ROP in different zones of Karnataka state in rural India. North Karnataka is the most underdeveloped and remote zone of this program and did not have any ROP screening programs before the intervention of the KIDROP in 2011. Six government and eleven private neonatal centers in this zone were screened weekly. Specific neonatal guidelines for ROP were developed and introduced in these centers. They included awareness about risk factors, oxygen regulation protocols, use of pulse oxymetry, monitoring postnatal weight gain, nutritional best practices, and management of sepsis. The incidence and severity of ROP were compared before the guidelines were introduced (Jan 2011 to Dec 2012) and after the guidelines were introduced (July 2013 to June 2015). During this 4-year period, 4,167 infants were screened over 11,390 imaging sessions. The number of enrolled infants increased from 1,825 to 2,342 between the two periods (P<0.001). The overall incidence of any stage ROP reduced significantly from 26.8% to 22.4% (P<0.001). The incidence of treatment-requiring ROP reduced from 20.7% to 16% (P=0.06), and of the treated disease, aggressive posterior ROP reduced from 20.8% to 13.1% (P=0.23) following introduction of the guidelines. Rural neonatal centers in middle-income countries have a large, unscreened burden of ROP. Improving neonatal care in these centers can positively impact the incidence and severity of ROP even in a relatively short period. A combined approach of a robust ROP screening program and improved neonatal care practices is required to address the challenge.