Effects of Temperature during Moist Heat Treatment on Ruminal Degradability and Intestinal Digestibility of Protein and Amino Acids in Hempseed Cake.
The objective of this study was to evaluate ruminal degradability and intestinal digestibility of crude protein (CP) and amino acids (AA) in hempseed cake (HC) that were moist heat treated at different temperatures. Samples of cold-pressed HC were autoclaved for 30 min at 110, 120 or 130°C, and a sample of untreated HC was used as the control. Ruminal degradability of CP was estimated, using the in situ Dacron bag technique; intestinal CP digestibility was estimated for the 16 h in situ residue using a three-step in vitro procedure. AA content was determined for the HC samples (heat treated and untreated) of the intact feed, the 16 h in situ residue and the residue after the three-step procedure. There was a linear increase in RUP (p = 0.001) and intestinal digestibility of RUP (p = 0.003) with increasing temperature during heat treatment. The 130°C treatment increased RUP from 259 to 629 g/kg CP, while intestinal digestibility increased from 176 to 730 g/kg RUP, compared to the control. Hence, the intestinal available dietary CP increased more than eight times. Increasing temperatures during heat treatment resulted in linear decreases in ruminal degradability of total AA (p = 0.006) and individual AA (p<0.05) and an increase in intestinal digestibility that could be explained both by a linear and a quadratic model for total AA and most individual AA (p<0.05). The 130°C treatment decreased ruminal degradability of total AA from 837 to 471 g/kg, while intestinal digestibility increased from 267 to 813 g/kg of rumen undegradable AA, compared with the control. There were differences between ruminal AA degradability and between intestinal AA digestibility within all individual HC treatments (p<0.001). It is concluded that moist heat treatment at 130°C did not overprotect the CP of HC and could be used to shift the site of CP and AA digestion from the rumen to the small intestine. This may increase the value of HC as a protein supplement for ruminants.


Text mining of full-text journal articles combined with gene expression analysis reveals a relationship between sphingosine-1-phosphate and invasiveness of a glioblastoma cell line.
Sphingosine 1-phosphate (S1P), a lysophospholipid, is involved in various cellular processes such as migration, proliferation, and survival. To date, the impact of S1P on human glioblastoma is not fully understood. Particularly, the concerted role played by matrix metalloproteinases (MMP) and S1P in aggressive tumor behavior and angiogenesis remains to be elucidated. To gain new insights in the effect of S1P on angiogenesis and invasion of this type of malignant tumor, we used microarrays to investigate the gene expression in glioblastoma as a response to S1P administration in vitro. We compared the expression profiles for the same cell lines under the influence of epidermal growth factor (EGF), an important growth factor. We found a set of 72 genes that are significantly differentially expressed as a unique response to S1P. Based on the result of mining full-text articles from 20 scientific journals in the field of cancer research published over a period of five years, we inferred gene-gene interaction networks for these 72 differentially expressed genes. Among the generated networks, we identified a particularly interesting one. It describes a cascading event, triggered by S1P, leading to the transactivation of MMP-9 via neuregulin-1 (NRG-1), vascular endothelial growth factor (VEGF), and the urokinase-type plasminogen activator (uPA). This interaction network has the potential to shed new light on our understanding of the role played by MMP-9 in invasive glioblastomas. Automated extraction of information from biological literature promises to play an increasingly important role in biological knowledge discovery. This is particularly true for high-throughput approaches, such as microarrays, and for combining and integrating data from different sources. Text mining may hold the key to unraveling previously unknown relationships between biological entities and could develop into an indispensable instrument in the process of formulating novel and potentially promising hypotheses.


Genetic manipulation of the ghrelin signaling system in male mice reveals bone compartment specificity of acylated and unacylated ghrelin in the regulation of bone remodeling.
Ghrelin receptor-deficient (Ghsr-/-) mice that lack acylated ghrelin (AG) signaling retain a metabolic response to unacylated ghrelin (UAG). Recently, we showed that Ghsr-deficiency affects bone metabolism. The aim of this study was to further establish the impact of AG and UAG on bone metabolism. We compared bone metabolism in Ghsr-/- (lacking only AG signaling) and ghrelin-deficient (Ghrl-/-; both AG and UAG deficient) male mice. Ghrl-/- mice had lower cortical bone mass, whereas Ghsr-/- mice had lower trabecular bone mass. This demonstrates bone compartment-specific effects of AG and a role for UAG in bone metabolism. Also, Ghrl-/- but not Ghsr-/- mice had increased bone formation rate and increased osteogenic stem cell numbers in their bone marrow. In ex vivo bone marrow cultures both AG and UAG inhibited osteoblast differentiation. This indicated that bone resorption must be increased in these mice. Accordingly, osteoclastogenesis rate was faster in bone marrow cultures from Ghsr-/- and Ghrl-/- mice, and osteoclast formation was inhibited by AG signaling and partially suppressed by UAG. In osteoblast cultures, AG markedly induced osteoprotegerin gene expression and both peptides reduced RANKL/osteoprotegerin ratio. These data describe unique cell-type specific effects of AG and UAG within a single tissue, supporting a tight and complex control of bone formation and resorption as well as a link between nutrition and bone metabolism. The balance between AG and UAG actions in the bone marrow may lead to bone compartmental-specific effects.


Receptors of glutamate and neurotrophin in vestibular neuronal functions.
The last decade has witnessed advances in understanding the roles of receptors of neurotrophin and glutamate in the vestibular system. In the first section of this review, the biological actions of neurotrophins and their receptors in the peripheral and central vestibular systems are summarized. Emphasis will be placed on the roles of neurotrophins in developmental plasticity and in the maintenance of vestibular function in the adult animal. This is reviewed in relation to the developmental expression pattern of neurotrophins and their receptors within the vestibular nuclei. The second part is focused on the functional role of different glutamate receptors on central vestibular neurons. The developmental expression pattern of glutamate receptor subunits within the vestibular nuclei is reviewed in relation to the potential role of glutamate receptors in regulating the development of vestibular function.


The association between DSM-IV nicotine dependence and stressful life events in the National Epidemiologic Survey on Alcohol and Related Conditions.
Nicotine dependence (ND) is a pervasive public health concern and a leading cause of preventable mortality. Stressful life events (SLEs), which severely disrupt the lives of individuals experiencing such events, have been posited as correlates of persisting ND. While both ND and SLEs have been studied extensively in relation to other variables, there are few instances in which they have been investigated in concert. In this study, we use data on 18,013 smokers from the 2001-2002 data set of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC, N = 43,093) to examine whether experiencing a SLE in the past 12 months was associated with meeting criteria for ND in the same past 12 months. Logistic regression analyses were conducted while accounting for a variety of covariates. A majority of the SLEs were associated with past 12 month ND, even after controlling for poverty, psychiatric and substance use disorders, and a prior history of ND (odds-ratios 1.35-2.20). The rates of past 12 month ND were considerably greater in those experiencing more than one SLE. While these data do not allow us to make causal interpretations, our results suggest an association between SLE and ND. Potentially, individuals experiencing SLEs may find it difficult to quit smoking; alternatively, directly or via correlated risks (e.g., living in a high risk neighborhood), smoking may increase the likelihood of exposure to SLEs.


Specific activation of ERK pathways by chitin oligosaccharides in embryonic zebrafish cell lines.
Chitin oligosaccharides (COs) play a role in plant development and are presumed to affect body plan formation during vertebrate embryogenesis. The mechanisms of COs recognition and cellular processes underlying embryonic development are still not understood. We analyze the possible link with the mitogen-activated protein kinase pathway that is conserved in evolution through the plant and animal kingdom and has been implicated in diverse cellular processes, including cell growth, proliferation, differentiation, survival, and vertebrate development. We show that in vivo stimulation of embryonic zebrafish cells ZF13 and ZF29 with chitin tetrasaccharides at 10-9 M concentration transiently induced activation/phosphorylation of extracellular regulated kinases (ERKs), with a maximum after 15 min. Furthermore the biological specificity of chitin tetrasaccharides and various derivatives was examined. The replacement of one or two GlcNAc residues of the chitin backbone by glucose and fucosylation of chitin tetrasaccharides at the reducing terminus caused a complete loss of their activity. We also tested a chitin tetrasaccharide analogue in which the oxygen atoms in glycosidic linkages were replaced by sulfur atoms. This analog, which could not be enzymatically hydrolyzed, was as potent an inducer as chitin tetrasaccharide. These results suggest that the observed activation of ERKs is chitin tetrasaccharide-specific and does not require further enzymatic processing. We examined possible signaling pathways leading to ERK activation by COs by use of phosphospecific antibodies and inhibitors. We conclude that a high-affinity CO receptor system exists that links to the Raf, MEK, and ERK pathway in zebrafish cells.


Tobacco industry marketing adaptations to Singapore plain packaging.
Singapore has implemented plain packaging, a measure that strips all colours, logos and branding elements from tobacco packs. In other countries, tobacco companies responded to plain packaging with a variety of marketing tactics. Our goal was to describe the tobacco industry's marketing adaptations to Singapore plain packaging. Qualitative analysis of 378 cigarette packs sampled from Singapore retailers in March 2019, March 2020 and January 2021, 12 months prior to, 2 weeks prior to and 6 months after plain packaging phase-in, respectively. For each pack, we collected descriptive information on the brand and variant name, pack and stick dimensions, pack shape, differentiating features and distinctive scents, as well as photographic data of the pack, cigarette sticks and any distinct features. We used the March 2019 collection as our baseline dataset, and March 2020 and January 2021 collections as comparison datasets to examine changes in tobacco marketing strategies just before and after plain packaging phase-in. Around Singapore's plain packaging phase-in, tobacco companies launched variants with flavour capsules, novelty filter features and new flavours and used more descriptive variant names reflecting the variant's colour coding or market positioning. Tobacco companies revamped some existing variants, often with Japanese marketing themes to convey a more premium product image. After plain packaging, tobacco companies used longer packs and variations in stick length, filter length and foil texture to further differentiate products. Following plain packaging in Singapore, tobacco companies rely increasingly on nomenclature and the cigarette stick itself to market and differentiate products.


The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings.
WHO has proposed a public-health approach to antiretroviral therapy (ART) to enable scaling-up access to treatment for HIV-positive people in developing countries, recognising that the western model of specialist physician management and advanced laboratory monitoring is not feasible in resource-poor settings. In this approach, standardised simplified treatment protocols and decentralised service delivery enable treatment to be delivered to large numbers of HIV-positive adults and children through the public and private sector. Simplified tools and approaches to clinical decision-making, centred on the "four Ss"--when to: start drug treatment; substitute for toxicity; switch after treatment failure; and stop--enable lower level health-care workers to deliver care. Simple limited formularies have driven large-scale production of fixed-dose combinations for first-line treatment for adults and lowered prices, but to ensure access to ART in the poorest countries, the care and drugs should be given free at point of service delivery. Population-based surveillance for acquired and transmitted resistance is needed to address concerns that switching regimens on the basis of clinical criteria for failure alone could lead to widespread emergence of drug-resistant virus strains. The integrated management of adult or childhood illness (IMAI/IMCI) facilitates decentralised implementation that is integrated within existing health systems. Simplified operational guidelines, tools, and training materials enable clinical teams in primary-care and second-level facilities to deliver HIV prevention, HIV care, and ART, and to use a standardised patient-tracking system.


Atlantoaxial instability in neck retraction and protrusion positions in patients with rheumatoid arthritis.
Radiographic analysis of the upper cervical spine was performed in patients with rheumatoid arthritis who had C1-C2 instability. To assess whether neck retraction or neck protrusion movements can cause C1-C2 subluxation in patients with C1-C2 instability. Cervical protrusion is the position where the head is maximally translated anteriorly with zero sagittal rotation, and this position has been shown to produce maximal C1-C2 extension. In contrast, cervical retraction is the position where the head is maximally translated posteriorly, and this position produces maximal C1-C2 flexion. To date, there have been no studies evaluating the effects of these two positions on C1-C2 status in patients with C1-C2 instability. Twenty-four patients with rheumatoid arthritis who showed an atlantodental interval of at least 5 mm during neck flexion were evaluated in this study. These patients were instructed to actively hold the neck in protrusion and retraction positions, as well as in flexion and extension positions. Lateral cervical radiographs were taken to measure the C1-C2 angle and the atlantodental interval in the sagittal plane in each position. Retraction produced both maximal C1-C2 flexion and anterior C1-C2 subluxation, of a degree just the same as that produced by cervical flexion. Protrusion reversely produced maximal C1-C2 extension. However, 9 of 24 patients exhibited C1-C2 subluxation even in this protrusion position, in marked contrast to the cervical extension position in which only 2 of 24 patients showed C1-C2 subluxation. The patients who showed C1-C2 subluxation in the protrusion position tended to have more severe C1-C2 instability and less capacity for C1-C2 extension than the other patients who achieved a reduction of C1-C2 in the protrusion position. In patients with C1-C2 instability, not only cervical flexion but also cervical retraction constantly led to both maximal C1-C2 flexion and subluxation. In some patients with severe C1-C2 instability, protrusion also resulted in C1-C2 subluxation, even though the C1-C2 was maximally extended.


Effect of All-trans Retinoic Acid on Panniculus Carnosus Muscle Regeneration in Fetal Mouse Wound Healing.
The dermal panniculus carnosus (PC) muscle is critical for wound contraction in lower mammals and is a useful model of muscle regeneration owing to its high cellular metabolic turnover. During wound healing in mice, skin structures, including PC, are completely regenerated up to embryonic day (E) 13, but PC is only partially regenerated in fetuses or adult animals after E14. Nevertheless, the mechanisms underlying wound repair for complete regeneration in PC have not been fully elucidated. We hypothesized that retinoic acid (RA) signaling, which is involved in muscle differentiation, regulates PC regeneration. Surgical injury was induced in ICR mice on E13 and E14. RA receptor alpha (RARα) expression in tissue samples from embryos was evaluated using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. To evaluate the effects of RA on PC regeneration, beads soaked in all-trans RA (ATRA) were implanted in E13 wounds, and tissues were observed. The effects of RA on myoblast migration were evaluated using a cell migration assay. During wound healing, RARα expression was enhanced at the cut surface in PCs of E13 wounds but was attenuated at the cut edge of E14 PCs. Implantation of ATRA-containing beads inhibited PC regeneration on E13 in a concentration-dependent manner. Treatment of myoblasts with ATRA inhibited cell migration. ATRA inhibits PC regeneration, and decreased RARα expression in wounds after E14 inhibits myoblast migration. Our findings may contribute to the development of therapies to promote complete wound regeneration, even in the muscle.


[Esophageal speech and TE shunt speech--a comparison using the same subjects].
The behaviors of esophageal speech and tracheoesophageal shunt (TE shunt) speech were compared using two laryngectomized subjects who were able to perform both phonation methods. Through X-ray fluorography and fiberscopic observation of the PE segment, it was confirmed that the location and the shape of the vibrating PE segment (pseudoglottis) were consistent during esophageal speech and TE shunt speech in each patient. It was suggested that the mechanism of formation of the pseudoglottis does not differ between the two phonation methods. The aerodynamics were examined using one of the two subjects. There was a positive relationship between subpseudoglottic pressure and vocal pitch and also between subpseudoglottic pressure and pseudoglottic resistance. The vocal pitch and pseudoglottic resistance were significantly higher in esophageal speech than TE shunt speech, when compared within the same subpseudoglottic pressure range. It was suggested that the tension and the effective mass of the pseudoglottis was modulated differently between the two phonation methods.


Vacancy-Driven Gelation Using Defect-Rich Nanoassemblies of 2D Transition Metal Dichalcogenides and Polymeric Binder for Biomedical Applications.
A new approach of vacancy-driven gelation to obtain chemically crosslinked hydrogels from defect-rich 2D molybdenum disulfide (MoS2 ) nanoassemblies and polymeric binder is reported. This approach utilizes the planar and edge atomic defects available on the surface of the 2D MoS2 nanoassemblies to form mechanically resilient and elastomeric nanocomposite hydrogels. The atomic defects present on the lattice plane of 2D MoS2 nanoassemblies are due to atomic vacancies and can act as an active center for vacancy-driven gelation with a thiol-activated terminal such as four-arm poly(ethylene glycol)-thiol (PEG-SH) via chemisorption. By modulating the number of vacancies on the 2D MoS2 nanoassemblies, the physical and chemical properties of the hydrogel network can be controlled. This vacancy-driven gelation process does not require external stimuli such as UV exposure, chemical initiator, or thermal agitation for crosslinking and thus provides a nontoxic and facile approach to encapsulate cells and proteins. 2D MoS2 nanoassemblies are cytocompatible, and encapsulated cells in the nanocomposite hydrogels show high viability. Overall, the nanoengineered hydrogel obtained from vacancy-driven gelation is mechanically resilient and can be used for a range of biomedical applications including tissue engineering, regenerative medicine, and cell and therapeutic delivery.


Risk allocation and competition in foraging groups: reversed effects of competition if group size varies under risk of predation.
Animals often feed more quickly when in larger groups. This group-size effect is often explained by safety advantages for groups but an alternative explanation is that animals feed faster in larger groups because of greater scramble competition for limited food. We show that predation risk enhances the group-size effect if groups vary in size. By contrast, competition leads to the group-size effect only when individuals feed in groups of constant size. When individuals feed in groups that vary in size, the best strategy for dealing with competition is to feed intensely when in smaller groups and feed little when in larger (more competitive) groups. In all situations, the effects of competition interact with the effects of predation risk in a simple multiplicative way. Our results suggest that scramble competition is not a general explanation for the group-size effect on vigilance in situations where group size changes relatively rapidly.


Hyaluronan synthase expression in bovine eyes.
Hyaluronan (HA), a high-molecular-weight linear glycosaminoglycan, is a component of the extracellular matrix (ECM). It is expressed in eyes and plays important roles in many biologic processes, including cell migration, proliferation, and differentiation. Hyaluronan is produced by HA synthase (HAS), which has three isoforms: HAS1, HAS2, and HAS3. In this study, the HAS expression in the anterior segment of bovine eyes was investigated to determine the significance of HA in eyes. To obtain bovine HAS probes, degenerate oligonucleotide primers, based on well-conserved amino acid sequences including the catalytic region of each HAS isoform, were used for reverse transcription-polymerase chain reaction to amplify mRNA from bovine corneal endothelial cells (BCECs). Hyaluronan synthase-1 expression in the anterior segment of bovine eyes at the protein level was investigated by immunohistochemistry. All three HAS isoforms were expressed in BCECs at the mRNA level. Amplified cDNA fragments of HAS1, HAS2, and HAS3 from BCECs can be aligned to human counterparts, showing similarities of 100%, 97.3%, and 100%, respectively, at the amino acid level. Hyaluronan synthase 1 was expressed at the protein level in corneal epithelium, keratocyte, corneal endothelium, conjunctival epithelium, ciliary epithelium, capillary endothelium, and trabecular meshwork. Hyaluronan synthase isoforms were expressed in the ocular anterior segment and are speculated to be involved in HA production in situ.


[Biochemical and histologic changes in patients with chronic hepatitis C under treatment with interferon. a 5-year cohort study].
Since 1989, some schemes of treatment for Chronic hepatitis C (CHC) have been investigated, including alpha and beta interferon (IFN), ribavirin, and amantadine either alone or in combination. These studies have been performed in other countries. In our study, we investigated the outcome of Mexican patients with CHC treated with IFN. Twenty-six patients with five years follow-up treated with IFN in monotherapy were studied. We evaluated three kinds of response: sustained response (SR); non response (NR), and partial response (PR). Patients were evaluated biochemically and histologically by means of aminotransferase levels (pretreatment and serial) and hepatic biopsy (pretreatment and control). The data were obtained from clinical records. Aminotransferase levels at the end of treatment and six months later as well as histologic damage score showed the following results: 16 patients were cataloged as NR (61.5%), four as PR (15.3%), and six as SR (23.1%). Ten patients developed cirrhosis during follow-up, eight from NR group, one from PR group, and one from SR group. CHC patients treated with IFN alone obtained SR in 19% of cases; the patient who developed cirrhosis was not included. A study for longer time, prospective and protocolized to evaluate standardized IFN dose as well as evaluate combined treatment, is necessary.


Genetic confirmation of T2DM meta-analysis variants studied in gestational diabetes mellitus in an Indian population.
Meta-analysis is useful for combining the results of different studies statistically to confirm genuine associations in genetics. Based on earlier reports, we aimed to investigate the association between type 2 diabetes mellitus (T2DM) genetic variants identified in a previous meta-analysis in gestational diabetes mellitus (GDM) in an Indian woman. In this study, 137 pregnant women with GDM and 150 pregnant women were selected on the basis of their serum glucose levels. The six single nucleotide polymorphisms (SNPs) of different genes studied had known involvement in pancreatic β-cell function, particular pathways linked to T2DM, and other biological functions. Genomic DNA was isolated from the 287 women for polymerase chain reaction and restriction fragment length polymorphism analyses. The rs7903146, rs13266634, rs2283228, rs5210 and rs179881 SNPs were found to be positively associated with GDM when calculated for genotype and allele frequencies (p < 0.05), but rs680 (ApaI) variant did not show statistically significant association (p = 0.31). The rs7903146, rs2283228, rs5210 and rs680 variants showed a strong association with oral glucose tolerance test values. The SNPs studied in this GDM had the same role as those identified in a previous T2DM meta-analysis, and showed positive association in the Indian women. Meta-analyses should be implemented to assess the IGF2 gene in GDM subjects.


Comparison of long-term results of dynamic hip screw and AO 130 degrees blade plate in adult trochanteric region fractures.
The aim of this study was to compare the long-term results of two groups of patients with trochanteric fractures of the femur treated with either dynamic hip screw (DHS) or AO angled blade plate (AP) insertions. A total of 157 patients with trochanteric fractures were included in the study, and 82 patients underwent dynamic hip screw insertion, and 75 underwent AO angled blade plate insertion. The mean follow-up period was 8 years (range 2.3-11.7 years) in the DHS group, and 8.5 years (2.4-12.5 years) in the AP group. According to the Boyd and Griffin classification, there were 37 stable fractures (45%) and 45 unstable fractures (55%) in the DHS group, whereas there were 42 stable fractures (56%) and 33 unstable fractures (44%) in the AP group. According to Clawson's functional classification, 64% of patients in the AP group and 81% in the DHS group had good or excellent function (p<0.05). Similarly, according to Foster's classification, 68% of patients in the AP group, and 85% in the DHS group had good to excellent results (p<0.05). DHS yields better long-term results in trochanteric fractures than do AO angled blade plates by providing earlier mobilization of the patient, better stability, and earlier union.


Reversal of prolonged dopamine inhibition of dopaminergic neurons of the ventral tegmental area.
Drug abuse-induced plasticity of putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons may play an important role in changes in the mesocorticolimbic system that lead to the development of addiction. In the present study, extracellular recordings were used to examine time-dependent effects of dopamine (DA) on pDAergic VTA neurons in rat brain slices. Administration of DA (2.5-10 microM) for 40 min resulted in inhibition followed by partial or full reversal of that inhibition. The reduced sensitivity to DA inhibition lasted 30 to 90 min after washout of the long-term dopamine administration. The inhibition reversal was not observed with 40-min administration of the D2 agonist quinpirole (25-200 nM), so this phenomenon was not the result of desensitization induced solely by stimulation of D2 DA receptors. Inhibition reversal could be observed with the coapplication of quinpirole and the D1/D5 agonist SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], suggesting a D1/D5 mechanism for the reversal. Furthermore, D1/D5 antagonists, given in the presence of prolonged DA exposure, prevented the inhibition reversal. Application of 3 microM quinpirole caused desensitization to low quinpirole concentrations that was blocked by a D1/D5 antagonist. These data suggest that coactivation of D1/D5 receptors and D2 receptors in the VTA results in desensitization of autoinhibitory D2 receptors. Prolonged increases in pDAergic tone in the VTA that may occur in vivo with drugs of abuse could reduce the regulation of firing by D2 dopamine receptor activation, producing long-term alteration in information processing related to reward and reinforcement.


Rheumatologists' knowledge and perception of COVID-19 and related vaccines: the vaXurvey2 online survey.
The study aimed to explore the experience of coronavirus disease-2019 (COVID-19) infection and vaccine adverse events (AEs) among rheumatologists. A validated questionnaire was distributed as a Google form to rheumatologists across the country via social networking sites from late December 2021 till early January 2022. The questionnaire included questions regarding participants' socio-demographic details, COVID-19 infection and vaccination details with special emphasis on AEs. Out of 246 responses, 228 were valid. 200 (81.3%) responders had received the vaccine. The mean age of the 228 participants was 37.9 ± 8.5 years, 196 were females and 32 males (F:M 6.1:1) from 18 governorates across the country. Comorbidities were present in 54 subjects (27%). There was a history of highly suspicious or confirmed COVID-19 infection in 66.7% that were all managed at home. The COVID-19 vaccine was received by 200 and a booster dose of 18.5%. Obesity and musculoskeletal involvement co-morbidities were present only in those with AEs (9.1% and 5.5% respectively). AEs were present in 82%; 66.7% had injection-site tenderness, 50% fatigue, 35.5% fever, 15% chills, 42.5% myalgia, 14.5% arthralgia, 8% low back pain, headache 31%, dizziness 10%, sleepliness 16% and 15% developed post-vaccine. There were no differences according to the geolocation regarding the occurrence of COVID-19 infection (p = 0.19) or AEs post-vaccine (p = 0.58). The adverse events were mostly mild to moderate and tolerable which makes this work in agreement with other studies that support the broad safety of the vaccine in favor of the global benefit from mass vaccination.


Sibling support and the educational prospects of young adults in Malawi.
Extended kin networks are an important social and economic resource in Africa. Existing research has focused primarily on intergenerational ties, but much less is known about "lateral" ties, such as those between siblings. In contexts of high adult mortality (i.e., fewer parents and grandparents) sibling interdependencies may assume heightened importance, especially during the transition to adulthood. In this paper, we extend the resource dilution perspective that dominates research on sibling relationships in early childhood and propose an alternate framework in which siblings represent a source of economic support that contributes positively to educational outcomes at later stages of the life course. We draw upon longitudinal data from young adults (age 15-18) in southern Malawi to assess the scope and magnitude of economic transfers among sibship sets. We then explore the relationships between sibship size, net economic transfers between siblings, and four measures of educational progress. First, exchanges of economic support between siblings are pervasive in the Malawian context and patterned, especially by birth order. Second, economic support from siblings is positively associated with educational attainment, as well as with the odds of being at grade level in school, both contemporaneously and prospectively. During young-adulthood, economic support from siblings acts as a buffer against the negative association between sibship size and schooling outcomes that has been documented at earlier ages. We question the established notion that siblings unilaterally subtract from resource pools, and argue that sibling support may be consequential for a wide range of demographic outcomes in a variety of cultural contexts. Our findings point to the need for additional research on the importance of lateral kinship ties across cultural settings and throughout the life course.


Extracorporal Membrane Oxygenation in Nonintubated Patients (Awake ECMO) With COVID-19 Adult Respiratory Distress Syndrome: The Israeli Experience.
In this retrospective multicenter observational study, we describe the Israeli experience with veno-venous extracorporeal membrane oxygenation (VV ECMO) for the treatment of COVID-19-induced severe adult respiratory distress syndrome (ARDS), in which ECMO cannulation was done while the patients were awake and spontaneously breathing without endotracheal tube, namely "awake ECMO." We enrolled all adult patients with severe ARDS due to COVID-19, treated with VV ECMO between March 1, 2020, and November 30, 2021, in which cannulation was done while the patient was awake and spontaneously breathing. During the study period, 365 COVID-19 ARDS patients were treated with VV ECMO. Of these, 25 (6.8%) were treated as awake ECMO. The patient's mean age was 52 years, and 80% were male. Nine of the 25 patients (36%) remained awake throughout their intensive care unit stay and were not sedated and mechanically ventilated at all. Sixteen (64%) were eventually intubated while being on ECMO. Six months survival was 76%. Median mechanical ventilation-free days on ECMO was 8 (interquartile range 5-12) days. This hypothesis-generating study suggests that treating COVID-19 ARDS patients with VV ECMO without sedation and mechanical ventilation is feasible, yet, additional research will be required in order to determine if this modality offers a survival benefit and to identify who are the patients most likely to benefit from it.


Designing UAV Swarm Experiments: A Simulator Selection and Experiment Design Process.
The rapid advancement and increasing number of applications of Unmanned Aerial Vehicle (UAV) swarm systems have garnered significant attention in recent years. These systems offer a multitude of uses and demonstrate great potential in diverse fields, ranging from surveillance and reconnaissance to search and rescue operations. However, the deployment of UAV swarms in dynamic environments necessitates the development of robust experimental designs to ensure their reliability and effectiveness. This study describes the crucial requirement for comprehensive experimental design of UAV swarm systems before their deployment in real-world scenarios. To achieve this, we begin with a concise review of existing simulation platforms, assessing their suitability for various specific needs. Through this evaluation, we identify the most appropriate tools to facilitate one's research objectives. Subsequently, we present an experimental design process tailored for validating the resilience and performance of UAV swarm systems for accomplishing the desired objectives. Furthermore, we explore strategies to simulate various scenarios and challenges that the swarm may encounter in dynamic environments, ensuring comprehensive testing and analysis. Complex multimodal experiments may require system designs that may not be completely satisfied by a single simulation platform; thus, interoperability between simulation platforms is also examined. Overall, this paper serves as a comprehensive guide for designing swarm experiments, enabling the advancement and optimization of UAV swarm systems through validation in simulated controlled environments.


Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy.
Tricyclic antidepressants have been reported to relieve the paresthesiae associated with peripheral neuropathies of many etiologies. We designed a randomized, double-blind, placebo-controlled, crossover trial to establish the efficacy of nortriptyline in the treatment of cis-diamminedichloroplatinum (CDDP)-induced paresthesiae. The study included 51 evaluable patients with CDDP-induced peripheral neuropathy and painful paresthesiae. The study consisted of two 4 week phases, separated by a 1 week 'wash-out' period, in which patients received escalating dosages of either placebo or nortriptyline. The target maximum dose of nortriptyline was 100 mg/day. Each patient filled out pre-randomization and then weekly questionnaires assessing paresthesiae severity, hours of sleep, quality of life, and adverse effects over the 9 week study. No significant differences in paresthesia were observed in the first treatment period between nortriptyline and placebo (means of 49 and 55 respectively on a 0-100 point scale, P=0.78). Although some evidence of a modest effect in favor of nortriptyline was observed during the second treatment period (about one patient in five got a 10-point reduction in pain from drug above placebo effect), this occurred in the presence of a strong carryover effect. Linear models analysis and Bayes methods confirmed that the effect of nortriptyline on paresthesia was modest at best. Hours of sleep increased in the nortriptyline phase (P=0.02). There was no significant difference in measures of quality of life and the effect of paresthesiae on patients' daily activities between nortriptyline and placebo. There was no major toxicity associated with nortriptyline, but dry mouth, dizziness, and constipation were more common with nortriptyline. In summary, nortriptyline failed to demonstrate strong evidence of any effect on paresthesia or pain. The presence of a potential effect which appeared in the second period of the crossover design is questionable due to the observed carryover effect. Cross-validation sensitivity analysis of results support the conclusion that nortriptyline provides modest improvement at best over placebo in terms of chemotherapy-related neuropathy.


Antipsychotic Trials in Schizophrenia from India: A Systematic Review and Meta-analysis.
Ethnic and regional variations have been found in the pharmacological treatment response. Though many efficacy studies have been conducted in India for antipsychotic treatment modalities of schizophrenia, there is a lack meta-analytic data of the existing literature from India. This study aimed to conduct a systematic review and meta-analysis of the antipsychotic treatment trials of schizophrenia in the Indian context. All controlled trials from India evaluating the clinical efficacy of antipsychotics in patients with schizophrenia were evaluated and 28 trials were included in the metanalysis. Effect sizes were computed using Cohen's 'd' and risk of bias was evaluated. Meta analysis revealed superiority of first generation antipsychotics over placebo (mean effect size of 1.387, confidence interval of 1.127 to 1.648). Second generation antipsychotics were marginally better than first generation antipsychotics (effect size 0.106, confidence intervals 0.009 to 0.204). There was improvement in the methodology of the trials over time (Kendall tau=0.289, P=0.049), though no statistically significant increase in trial duration and sample size was noted. There is lack of data on long term efficacy of antipsychotic in schizophrenia from India. First generation antipsychotics have demonstrated benefits over placebo in patients with schizophrenia in the Indian context, though marginally lesser than second generation ones.


Development and validation of the Eating Pathology Symptoms Inventory (EPSI).
Many current measures of eating disorder (ED) symptoms have 1 or more serious limitations, such as inconsistent factor structures or poor discriminant validity. The goal of this study was to overcome these limitations through the development of a comprehensive multidimensional measure of eating pathology. An initial pool of 160 items was developed to assess 20 dimensions of eating pathology. The initial item pool was administered to a student sample (N = 433) and community sample (N = 407) to determine the preliminary structure of the measure using exploratory and confirmatory factor analyses. The revised measure was administered to independent samples of patients recruited from specialty ED treatment centers (N = 158), outpatient psychiatric clinics (N = 303), and students (N = 227). Analyses revealed an 8-factor structure characterized by Body Dissatisfaction, Binge Eating, Cognitive Restraint, Excessive Exercise, Restricting, Purging, Muscle Building, and Negative Attitudes Toward Obesity. Scale scores showed excellent convergent and discriminant validity; other analyses demonstrated that the majority of scales were invariant across sex and weight categories. Eating Pathology Symptoms Inventory scale scores had excellent internal consistency (median coefficient alphas ranged from .84-.89) and reliability over a 2- to 4-week period (mean retest r = .73). The current study represents one of the most comprehensive scale development projects ever conducted in the field of EDs and will enhance future basic and treatment research focused on EDs.


Polycomb-like Protein 3 Induces Proliferation and Drug Resistance in Multiple Myeloma and Is Regulated by miRNA-15a.
Multiple myeloma remains incurable due to the persistence of a minor population of multiple myeloma cells that exhibit drug resistance, which leads to relapsed and/or refractory multiple myeloma. Elucidating the mechanism underlying drug resistance and developing an effective treatment are critical for clinical management of multiple myeloma. Here we showed that promoting expression of the gene for polycomb-like protein 3 (PHF19) induced multiple myeloma cell growth and multidrug resistance in vitro and in vivo. PHF19 was overexpressed in high-risk and drug-resistant primary cells from patients. High levels of PHF19 were correlated with inferior survival of patients with multiple myeloma, in the Total Therapy 2 cohort and in the Intergroup Francophone du Myeloma (IFM) cohort. Enhancing PHF19 expression levels increased Bcl-xL, Mcl-1, and HIF-1a expression in multiple myeloma cells. PHF19 also bound directly with EZH2 and promoted the phosphorylation of EZH2 through PDK1/AKT signaling. miR-15a is a small noncoding RNA that targeted the 3'UTR of PHF19. We found that downregulation of miR-15a led to high levels of PHF19 in multiple myeloma cells. These findings revealed that PHF19 served a crucial role in multiple myeloma proliferation and drug resistance and suggested that the miR-15a/PHF19/EZH2 pathway made a pivotal contribution to multiple myeloma pathogenesis, offering a promising approach to multiple myeloma treatment. IMPLICATIONS: Our findings identify that PHF19 mediates EZH2 phosphorylation as a mechanism of myeloma cell drug resistance, providing a rationale to explore therapeutic potential of targeting PHF19 in relapsed or refractory patients with multiple myeloma.


Spinal column shortening for secondary tethered cord syndrome: radiographic, clinical, patient-reported, and urodynamic short-term outcomes.
Tethered cord syndrome (TCS) is a clinical and radiographic diagnosis of pathological stretching of the spinal cord leading to progressive loss of neurological function. The gold standard treatment for TCS is a tethered cord release. However, detethering involves significant risks of spinal cord injury and high rates of retethering. To mitigate these risks, the concept of spinal column shortening (SCS) to decrease spinal cord tension has become an alternative to detethering. In this study, the authors applied SCS to a pediatric and emerging adult population affected by secondary TCS. A retrospective review of a prospective database at the authors' tertiary pediatric institution was performed. The Pediatric Quality of Life Inventory, patient- and parent-reported outcomes, and urodynamics were used to evaluate the outcomes of TCS treated with SCS. A total of 41 patients with secondary TCS were treated with SCS. The average age at the time of surgery was 15.9 years (range 5-55 years). Preoperative symptoms evaluated included pain (33 patients), weakness (30 patients), and bladder/bowel dysfunction (39 patients). The most common level of spinal column osteotomy was T12, with spinal fusion between T10 and L2. The mean follow-up time was 22.6 months (range 8-45 months). For patients with at least 12 months of follow-up, subjective clinical improvements were reported in 21/23 (91.3%) of those with preoperative pain (p < 0.01); in 16/24 (66.7%) of patients with weakness (p < 0.01), and in 15/29 (51.7%) of those with bladder/bowel dysfunction (p < 0.01). The median differences in initial and most recent Pediatric Quality of Life Inventory results were +5 for patient-reported scores (n = 19, p = 0.04) and +5 for parent-reported scores (n = 19, p = 0.08). Formal urodynamics performed at a median of 3.5 months after surgery documented stable to improved bladder function in 16/17 patients, with a median improvement in one classification category (n = 17, p = 0.01). SCS continues to represent a safe and efficacious alternative to traditional spinal cord untethering for TCS in children and emerging adults, as documented by objective formal urodynamics and patient- and parent-reported outcomes.


Applying lean methodology to improve parenteral chemotherapy and monoclonal antibody documentation processes based on Normalisation Process Theory.
To determine the impact of lean thinking on the original time required to prepare the necessary documentation in relation to the preparation of parenteral chemotherapy/monoclonal antibodies. Four pharmacists and one pharmacy technician from the oncology hospital (Malta) all participated in eight focus groups linked to the different constructs of Normalisation Process Theory (NPT): coherence, cognitive participation, collective action and reflexive monitoring. The value stream documentation process was mapped by analysing all steps in the process where each activity must add value for the patient; tools of lean thinking were applied. Points causing delay in processing were considered critical; possible changes to minimise time waste were discussed and implemented. Time spent on critical points was measured by timing in minutes each step of the process 1 month before and after the changes had been implemented and calculating the mean±SD. An audit was performed comparing the process with standard operating procedures to determine whether any steps required quality improvement. Three critical points were identified: time required to search for pharmacy patient medication records for chemotherapy/monoclonal antibodies required on the day; time to generate preparation labels; and time to generate worksheets. Overall, a total of 122±8.6 min (p=0.06) were saved per day, a 37% decrease from the original documentation time. Five deficiencies were identified in the documentation process audit; corrective action was proposed. By applying lean thinking, non-value-added steps leading to time waste in the documentation process were eliminated. This concept could be implemented by using NPT as part of a strategic system to reduce waste.


The Structure-Activity Relationship between Marine Algae Polysaccharides and Anti-Complement Activity.
In this study, 33 different polysaccharides were prepared to investigate the structure-activity relationships between the polysaccharides, mainly from marine algae, and anti-complement activity in the classical pathway. Factors considered included extraction methods, fractionations, molecular weight, molar ratio of galactose to fucose, sulfate, uronic acid (UA) content, linkage, branching, and the type of monosaccharide. It was shown that the larger the molecular weights, the better the activities. The molar ratio of galactose (Gal) to fucose (Fuc) was a positive factor at a concentration lower than 10 µg/mL, while it had no effect at a concentration more than 10 µg/mL. In addition, sulfate was necessary; however, the sulfate content, the sulfate pattern, linkage and branching had no effect at a concentration of more than 10 µg/mL. Moreover, the type of monosaccharide had no effect. Laminaran and UA fractions had no activity; however, they could reduce the activity by decreasing the effective concentration of the active composition when they were mixed with the active compositions. The effect of the extraction methods could not be determined. Finally, it was observed that sulfated galactofucan showed good anti-complement activity after separation.


UR-1505, a salicylate able to selectively block T-cell activation, shows intestinal anti-inflammatory activity in the chronic phase of the DSS model of rat colitis.
UR-1505 is a novel salicylate derivative compound that has been demonstrated to selectively down-regulate T-cell activation. The aim of the present study was to elucidate the mechanisms involved in the intestinal anti-inflammatory effects of UR-1505 in 2 protocols of a dextran sodium sulfate (DSS) model of rat colitis: acute and established colitis. The first protocol consisted of incorporating DSS into the drinking water at a concentration of 5% (w/v) for 5 days (acute initial colitis). In the second protocol, once the acute colitis had been induced, the concentration of DSS was reduced to 2% (w/v) and maintained for 10 days (established colitis). The results obtained demonstrated that although UR-1505 did not exert a significant intestinal anti-inflammatory effect in ameliorating the initial steps of the intestinal inflammation induced by DSS, it had a beneficial effect on ongoing inflammation, most probably through inhibiting activation of T lymphocytes, thus avoiding perpetuation of the inflammatory process. These results suggest that this compound is a good candidate for inducing remission or maintaining therapies in human inflammatory bowel disease (IBD). Moreover, the different results obtained by UR-1505 in these 2 protocols of colitis induction (acute initial colitis versus established colitis) confirm the importance of selection and optimization of the experimental model to evaluate the drugs to be used in IBD therapy.


Global prediction of chromatin accessibility using small-cell-number and single-cell RNA-seq.
Conventional high-throughput genomic technologies for mapping regulatory element activities in bulk samples such as ChIP-seq, DNase-seq and FAIRE-seq cannot analyze samples with small numbers of cells. The recently developed low-input and single-cell regulome mapping technologies such as ATAC-seq and single-cell ATAC-seq (scATAC-seq) allow analyses of small-cell-number and single-cell samples, but their signals remain highly discrete or noisy. Compared to these regulome mapping technologies, transcriptome profiling by RNA-seq is more widely used. Transcriptome data in single-cell and small-cell-number samples are more continuous and often less noisy. Here, we show that one can globally predict chromatin accessibility and infer regulatory element activities using RNA-seq. Genome-wide chromatin accessibility predicted by RNA-seq from 30 cells can offer better accuracy than ATAC-seq from 500 cells. Predictions based on single-cell RNA-seq (scRNA-seq) can more accurately reconstruct bulk chromatin accessibility than using scATAC-seq. Integrating ATAC-seq with predictions from RNA-seq increases the power and value of both methods. Thus, transcriptome-based prediction provides a new tool for decoding gene regulatory circuitry in samples with limited cell numbers.


Deep Learning Approaches Towards Skin Lesion Segmentation and Classification from Dermoscopic Images - A Review.
Automated intelligent systems for unbiased diagnosis are primary requirement for the pigment lesion analysis. It has gained the attention of researchers in the last few decades. These systems involve multiple phases such as pre-processing, feature extraction, segmentation, classification and post processing. It is crucial to accurately localize and segment the skin lesion. It is observed that recent enhancements in machine learning algorithms and dermoscopic techniques reduced the misclassification rate therefore, the focus towards computer aided systems increased exponentially in recent years. Computer aided diagnostic systems are reliable source for dermatologists to analyze the type of cancer, but it is widely acknowledged that even higher accuracy is needed for computer aided diagnostic systems to be adopted practically in the diagnostic process of life threatening diseases. Skin cancer is one of the most threatening cancers. It occurs by the abnormal multiplication of cells. The core three types of skin cells are: Squamous, Basal and Melanocytes. There are two wide classes of skin cancer; Melanocytic and non-Melanocytic. It is difficult to differentiate between benign and malignant melanoma, therefore dermatologists sometimes misclassify the benign and malignant melanoma. Melanoma is estimated as 19th most frequent cancer, it is riskier than the Basel and Squamous carcinoma because it rapidly spreads throughout the body. Hence, to lower the death risk, it is critical to diagnose the correct type of cancer in early rudimentary phases. It can occur on any part of body, but it has higher probability to occur on chest, back and legs. The paper presents a review of segmentation and classification techniques for skin lesion detection. Dermoscopy and its features are discussed briefly. After that Image pre-processing techniques are described. A thorough review of segmentation and classification phases of skin lesion detection using deep learning techniques is presented Literature is discussed and a comparative analysis of discussed methods is presented. In this paper, we have presented the survey of more than 100 papers and comparative analysis of state of the art techniques, model and methodologies. Malignant melanoma is one of the most threating and deadliest cancers. Since the last few decades, researchers are putting extra attention and effort in accurate diagnosis of melanoma. The main challenges of dermoscopic skin lesion images are: low contrasts, multiple lesions, irregular and fuzzy borders, blood vessels, regression, hairs, bubbles, variegated coloring and other kinds of distortions. The lack of large training dataset makes these problems even more challenging. Due to recent advancement in the paradigm of deep learning, and specially the outstanding performance in medical imaging, it has become important to review the deep learning algorithms performance in skin lesion segmentation. Here, we have discussed the results of different techniques on the basis of different evaluation parameters such as Jaccard coefficient, sensitivity, specificity and accuracy. And the paper listed down the major achievements in this domain with the detailed discussion of the techniques. In future, it is expected to improve results by utilizing the capabilities of deep learning frameworks with other pre and post processing techniques so reliable and accurate diagnostic systems can be built.


Passive Ca transport in human red blood cell ghosts measured with entrapped arsenazo III.
The rate of Ca influx into ghosts containing arsenazo III changes with time, being most rapid during the first 5 min after Ca is added to the outside and declining thereafter. The rate of Ca influx is a nonlinear function of extracellular Ca and plateaus as the latter is increased above 1 mM. The rate of Ca influx was measured as a function of the transmembrane gradients of Na and K and changes in the permeability of the membrane to K and Cl produced by valinomycin and SITS (4-acetamido-4'-isothiocyano-stilbene-2-2'-disulfonic acid), respectively. Changes in the rate of Ca influx are consistent with expected effects of these treatments on the membrane potential. Oligomycin (10 micrograms/ml) and quinidine (1 mM) inhibit the rate of Ca uptake by inhibiting Ca-induced changes in the K permeability. At constant membrane potential, furosemide produced a slight (15%) consistent increase in Ca uptake. Other experiments show that resealed ghosts are heterogeneous in their passive permeability to Ca and that A23187 can be used to effectively eliminate such differences. The results of this paper show that resealed human red cell ghosts containing arsenazo III can be used to continuously monitor intracellular free Ca and to study the factors that influence the permeability of the red cell membrane to Ca.


Erratum: Real-Time Measurements of Calcium and Contractility Parameters in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
An erratum was issued for: Real-Time Measurements of Calcium and Contractility Parameters in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. The Authors section was updated from: Rafeeh Dinani1,2 Emmy Manders1,2,3 Michiel Helmes1,2,3 Lili Wang4 Bjorn Knollmann4 Diederik W. D. Kuster1,2 Jolanda van der Velden1,2 1Division of Physiology, Amsterdam UMC, Vrije University 2Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences 3CytoCypher BV 4Division of Clinical Pharmacology, Vanderbilt School of Medicine to: Rafeeh Dinani1,2 Emmy Manders1,2,3 Michiel Helmes1,2,3 Lili Wang4 Bjorn C. Knollmann4 Diederik W. D. Kuster1,2 Jolanda van der Velden1,2 1Division of Physiology, Amsterdam UMC, Vrije University 2Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences 3CytoCypher BV 4Division of Clinical Pharmacology, Vanderbilt School of Medicine.


Proline rich motifs as drug targets in immune mediated disorders.
The current version of the human immunome network consists of nearly 1400 interactions involving approximately 600 proteins. Intermolecular interactions mediated by proline-rich motifs (PRMs) are observed in many facets of the immune response. The proline-rich regions are known to preferentially adopt a polyproline type II helical conformation, an extended structure that facilitates transient intermolecular interactions such as signal transduction, antigen recognition, cell-cell communication and cytoskeletal organization. The propensity of both the side chain and the backbone carbonyls of the polyproline type II helix to participate in the interface interaction makes it an excellent recognition motif. An advantage of such distinct chemical features is that the interactions can be discriminatory even in the absence of high affinities. Indeed, the immune response is mediated by well-orchestrated low-affinity short-duration intermolecular interactions. The proline-rich regions are predominantly localized in the solvent-exposed regions such as the loops, intrinsically disordered regions, or between domains that constitute the intermolecular interface. Peptide mimics of the PRM have been suggested as potential antagonists of intermolecular interactions. In this paper, we discuss novel PRM-mediated interactions in the human immunome that potentially serve as attractive targets for immunomodulation and drug development for inflammatory and autoimmune pathologies.


The exocytosis regulator synaptotagmin V controls phagocytosis in macrophages.
Synaptotagmins (Syts) play a key role in the regulation of Ca(2+)-triggered exocytosis and membrane fusion events, two crucial events associated to the phagocytic process. In the present study, we investigated the role of Syt V, a regulator of focal exocytosis, in phagocytosis. In macrophages, Syt V is localized on recycling endosomes and on filopodia-like structures and is recruited to the nascent phagosomes independently of the phagocytic receptor engaged. Silencing of Syt V by RNA interference revealed a role for this protein for phagocytosis, particularly under conditions of high membrane demand. In contrast, silencing of Syt V had no effect on the recruitment of the lysosomal marker LAMP1 to phagosomes, indicating that phagosome maturation is not regulated by Syt V. Collectively, these results illustrate the importance of Syt V in the regulation of an important innate function of macrophages. Furthermore, our results are consistent with the concept that focal exocytosis of endocytic organelles is a key event in phagocytosis and suggest that Syt V regulates this process.


Efficient and Effective Context-Based Convolutional Entropy Modeling for Image Compression.
Precise estimation of the probabilistic structure of natural images plays an essential role in image compression. Despite the recent remarkable success of end-to-end optimized image compression, the latent codes are usually assumed to be fully statistically factorized in order to simplify entropy modeling. However, this assumption generally does not hold true and may hinder compression performance. Here we present contextbased convolutional networks (CCNs) for efficient and effective entropy modeling. In particular, a 3D zigzag scanning order and a 3D code dividing technique are introduced to define proper coding contexts for parallel entropy decoding, both of which boil down to place translation-invariant binary masks on convolution filters of CCNs. We demonstrate the promise of CCNs for entropy modeling in both lossless and lossy image compression. For the former, we directly apply a CCN to the binarized representation of an image to compute the Bernoulli distribution of each code for entropy estimation. For the latter, the categorical distribution of each code is represented by a discretized mixture of Gaussian distributions, whose parameters are estimated by three CCNs. We then jointly optimize the CCNbased entropy model along with analysis and synthesis transforms for rate-distortion performance. Experiments on the Kodak and Tecnick datasets show that our methods powered by the proposed CCNs generally achieve comparable compression performance to the state-of-the-art while being much faster.


The anti-endotoxic effect of o-aminobenzoic acid from Radix Isatidis.
To study the anti-endotoxic effect of o-aminobenzoic acid (OABA) isolated from Banlangen(BLG). OABA was extracted and isolated from BLG and diluted into 0.5% solution. The concentration of endotoxin (ET) pretreated with OABA was quantitatively detected using Limulus test. The inhibition of ET-induced fever by OABA was measured in rabbits. The rates of lipopolysaccharides (LPS)-induced death in mice pretreated with or without OABA were then compared. The influence of OABA on the release of TNF-alpha and NO from macrophages induced by LPS was examined in mice. After pretreatment with OABA, 84.4% of ET was destroyed. The ET-induced fever in rabbits decreased significantly and the rate of LPS-induced death in mice dropped from 70% to 20%. The release of TNF-alpha and NO induced by LPS in mice was inhibited dose-dependently when the concentration of OABA was between 0.125% and 0.5%. OABA isolated from BLG has an anti-endotoxic effect.


[Supply and demand of medical specialists in the health facilities of the Ministry of Health: national, regional and by type of specialty gaps].
To characterize the supply, demand and the gap of medical specialists in facilities of the Ministry of Health of Peru (MINSA) at the national, regional and specialty type levels. Observational, descriptive study through which we calculated the supply of medical specialists using secondary sources of MINSA. The analysis of the demand for medical specialists was based on two methodologies: the need for specialists according to the guidelines of classification of the health facilities and according to the epidemiological and demographic profile. The arithmetic difference between the estimated demand and the supply was the procedure used to calculate the gap of medical specialists. The Ministry of Health has a total supply at the national level of 6,074 medical specialists of which 61.5% belong to the clinical specialties, 33.2% to the surgical specialties, 4.9% specialities related to aid to diagnosis and treatment and 0.4% to public health specialties. According to the categorization guideline there is a total demand of 11,176 medical specialists and according to the epidemiological and demographic profile of 11,738. The national estimated gaps found are similar in both methods, although they differ widely across regions and by type of specialty. At the regional level, the gaps are greater in Loreto, Piura, Puno and Madre de Dios when estimating the defficit in relation to the supply. Regarding the speciality, the gap is greater in the four basic specialties: gynecology and obstetrics, pediatrics, internal medicine and general surgery. There is a waid gap between supply and demand of medical specialists at the national and regional levels, as a whole representing approximately 45% of the current offer, regardless of the estimation method.


Spontaneous rupture of solid pseudopapillary neoplasm of the pancreas during pregnancy.
Spontaneous rupture of solid pseudopapillary neoplasm of the pancreas is an unusual complication during pregnancy. At 19 weeks of gestation, a 29-year-old woman presented with a pancreatic mass and upper abdominal pain radiating to the back. On the third day of admission, shock and peritoneal signs developed. Exploratory laparotomy and subsequent subtotal pancreatectomy were performed for a bleeding tumor. Solid pseudopapillary neoplasm was confirmed by pathological examination. The patient delivered a healthy full-term girl vaginally. Eight months postoperatively, the clinical courses of both mother and infant have been uneventful. Ruptured solid pseudopapillary neoplasms can cause an acute abdomen during pregnancy. The expression of progesterone receptors in solid pseudopapillary neoplasm is a possible cause of this potentially devastating event.


How to ensure nutrition security in the global economic crisis to protect and enhance development of young children and our common future.
The global economic crisis, commodity price hikes, and climate change have worsened the position of the poorest and most vulnerable people. These crises are compromising the diet and health of up to 80% of the population in most developing countries and threaten the development of almost an entire generation of children ( approximately 250 million), because the period from conception until 24 mo of age irreversibly shapes people's health and intellectual ability. High food prices reduce diversity and nutritional quality of the diet and for many also reduce food quantity. Poor households are hit hardest, because they already spend 50-80% of expenditures on food, little on medicines, education, transport, or cooking fuel, and cannot afford to pay more. Reduced public spending, declining incomes, increased food and fuel prices, and reduced remittance thus impede and reverse progress made toward Millenium Development Goals 1, 4, and 5. Investments in nutrition are among the most cost-effective development interventions because of very high benefit:cost ratios, for individuals and for sustainable growth of countries, because they protect health, prevent disability, boost economic productivity, and save lives. To bridge the gap between nutrient requirements, particularly for groups with high needs, and the realistic dietary intake under the prevailing circumstances, the use of complementary food supplements to increase a meal's nutrient content is recommended. This can be in the form of, e.g., micronutrient powder or low-dose lipid-based nutrient supplements, which can be provided for free, in return for vouchers, at subsidized, or at commercial prices.


Navigating the Affordance Landscape: Feedback Control as a Process Model of Behavior and Cognition.
We discuss how cybernetic principles of feedback control, used to explain sensorimotor behavior, can be extended to provide a foundation for understanding cognition. In particular, we describe behavior as parallel processes of competition and selection among potential action opportunities ('affordances') expressed at multiple levels of abstraction. Adaptive selection among currently available affordances is biased not only by predictions of their immediate outcomes and payoffs but also by predictions of what new affordances they will make available. This allows animals to purposively create new affordances that they can later exploit to achieve high-level goals, resulting in intentional action that links across multiple levels of control. Finally, we discuss how such a 'hierarchical affordance competition' process can be mapped to brain structure.


Transplacental carcinogenicity of cisplatin: initiation of skin tumors and induction of other preneoplastic and neoplastic lesions in SENCAR mice.
cis-Dichlorodiammineplatinum (cis-DDP), an anticancer agent sometimes used in pregnant women for the treatment of malignant ovarian and uterine tumors, was tested for transplacental carcinogenic and/or tumor-initiating effects in SENCAR mice. Pregnant mice were given a single i.p. injection of either cis-DDP (7.5 mg/kg body weight) in 2.5% NaCl or the same weight-adjusted volume of NaCl (5 ml/kg body weight) on day 17 of gestation. Offspring were delivered and raised by their natural mothers until weaning at 3 weeks of age. Starting at week 4, offspring in experimental groups received topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) in acetone twice a week for 20 weeks while those in control groups received only acetone (0.2 ml/application) for the same duration. The experiment was terminated at 25 weeks of age. A high incidence (18 of 37; 48.7%) of papillomas was observed in offspring exposed transplacentally to cis-DDP and postnatally to TPA, while only 10% (4 of 40) of offspring exposed to TPA alone developed such tumors (P < 0.0002). Although no skin tumors were observed without TPA promotion, transplacental administration of cis-DDP resulted in development of thymic lymphomas, lung tumors, and proliferative kidney lesions in offspring. These results provide the first evidence that cis-DDP can initiate and/or induce preneoplastic and neoplastic lesions in multiple tissues transplacentally.


Republication of "Current Concepts Review: Hallux Rigidus".
Arthritis of the first metatarsophalangeal (MTP) joint, hallux rigid, is a common and disabling source of foot pain in the adult population. Hallux rigidus is characterized by diseased cartilage and large, periarticular osteophytes that result in a stiff, painful joint. Activity modification, sensible shoes, orthotics, anti-inflammatory medications and occasional intra-articular steroid injections can be attempted to alleviate the discomfort associated with hallux rigidus. A number of surgical options exist for the treatment of recalcitrant hallux rigidus. Cheilectomy is a useful treatment for dorsal impingement pain seen in mild hallux rigidus. A new polyvinyl alcohol hemi-arthroplasty implant has shown promising early and midterm results in the treatment of advanced hallux rigidus; however, arthrodesis of the first MTP joint remains the gold standard treatment for advanced hallux rigidus because of unpredictable outcomes after early-generation joint replacement implants.


Enriched CD45RA-CD62L+ central memory T and decreased CD3+CD56+ natural killer T lymphocyte subsets in the rectum of ulcerative colitis patients.
To investigate the distinctive features of lymphocytes promoting inflammation in ulcerative colitis. We performed flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and colorectal mucosa lymphocytes in ulcerative colitis patients (n = 13) and control patients (n = 5). CD62L+/CD3+CD4+ (35.7 ± 14.0% vs. 19.9 ± 6.4%) and CD62L+/CD3+CD4- cells (17.1 ± 17.4% vs. 2.4 ± 3.9%) were higher in the rectum of ulcerative colitis patients than in control patients. Subpopulation analysis revealed that CD45RA-CD62L+/CD3+CD4+, that is, central memory T cell fraction in CD4+ T cells, was significantly increased in the rectum of ulcerative colitis, compared to that in control patients (23.3 ± 10.5% vs. 8.2 ± 4.0%). Comparison of rectum and colon samples in ulcerative colitis patients indicated that CD56+/CD3+ was decreased in the rectum compared to that in the colon (11.3 ± 12.5% vs. 21.3 ± 16.5%). The ratio of CD56+/CD3+ was also decreased in the rectum of active ulcerative colitis patients compared to that in ulcerative colitis patients at the endoscopic remission stages (2.8 ± 1.7% vs. 18.5 ± 13.3%). We demonstrated that CD62L+ T lymphocytes, particularly the CD45RA-CD62L+ T cell subset that represents central memory T cells, were increased in the rectum of patients with ulcerative colitis. In addition, the CD56+/CD3+ subset (natural killer T cells) was decreased in the rectum compared to that of less inflamed colonic mucosa. These results suggest that the enrichment of central memory T lymphocytes and the reduction of natural killer T cells in the gut mucosa are involved in the pathogenesis of ulcerative colitis.


A cadmium-lead-sensing ArsR-SmtB repressor with novel sensory sites. Complementary metal discrimination by NmtR AND CmtR in a common cytosol.
We report a cadmium- and lead-detecting transcriptional repressor from Mycobacterium tuberculosis designated CmtR. Two genes were co-transcribed with cmtR, one encoding a deduced P1 type ATPase. Purified CmtR bound to the cmt operator-promoter, and repression of transcription was lost after introduction of a stop codon into cmtR. Assays of metal-dependent expression from cmt and nmt operator-promoters established that the metal specificity of CmtR in vivo was perfectly inverted relative to the nickel-cobalt sensor NmtR from the same organism, with CmtR totally insensitive to Co(II) or Ni(II) and NmtR totally insensitive to Cd(II) or Pb(II). Absorption spectroscopy of Cd(II)-, Co(II)-, and Ni(II)-substituted CmtR revealed S- to metal-charge-transfer which was absent in NmtR, providing diagnostic metal-difference spectra that discriminated between metal-binding to these two proteins. Ni(II)-binding isothermal titrations of CmtR are complex, with Kapp = 1.8 x 10(4) m(-1) for site1, three orders of magnitude weaker than KNi for NmtR. Mixing equimolar apo-NmtR and apo-CmtR with 0.9 equivalents of Cd(II) gave Cd(II)-dependent difference spectra almost identical to Cd(II)0.9-CmtR. Thus, Cd(II) bound to CmtR in preference to NmtR, whereas the converse was true for Ni(II); this correlates faithfully with and provides a simplistic basis for metal-sensing preferences. In contrast, CmtR and NmtR had similar affinities for Co(II), and alternative explanations for Co(II) sensitivities are invoked. ArsR-SmtB repressors detect metals through derivatives of one or both of two possible allosteric sites at either carboxyl-terminal alpha5 helices or helix alpha3 proximal to the DNA-binding site. Unexpectedly, neither site was required for inducer recognition by CmtR. The mutants in potential metal ligands in, or near, these regions, Cys4, Cys35, Asp79, His81, Asp97, Asp99, Glu105, Glu111, and Glu114, retained both repression and inducer recognition. Crucially, substitution of Cys57, Cys61, and Cys102 with Ser revealed that each of these three residues is obligatory for Cd(II) detection, and this defines completely new sensory sites.


A fully genetically encoded protein architecture for optical control of peptide ligand concentration.
Ion channels are among the most important proteins in biology, regulating the activity of excitable cells and changing in diseases. Ideally it would be possible to actuate endogenous ion channels, in a temporally precise and reversible manner, and without requiring chemical cofactors. Here we present a modular protein architecture for fully genetically encoded, light-modulated control of ligands that modulate ion channels of a targeted cell. Our reagent, which we call a lumitoxin, combines a photoswitch and an ion channel-blocking peptide toxin. Illumination causes the photoswitch to unfold, lowering the toxin's local concentration near the cell surface, and enabling the ion channel to function. We explore lumitoxin modularity by showing operation with peptide toxins that target different voltage-dependent K(+) channels. The lumitoxin architecture may represent a new kind of modular protein-engineering strategy for designing light-activated proteins, and thus may enable development of novel tools for modulating cellular physiology.


Constraints to virus infection in Nicotiana benthamiana plants transformed with a potyvirus amplicon.
Plant genomes have been transformed with full-length cDNA copies of viral genomes, giving rise to what has been called 'amplicon' systems, trying to combine the genetic stability of transgenic plants with the elevated replication rate of plant viruses. However, amplicons' performance has been very variable regardless of the virus on which they are based. This has boosted further interest in understanding the underlying mechanisms that cause this behavior differences, and in developing strategies to control amplicon expression. Nicotiana benthamiana plants were transformed with an amplicon consisting of a full-length cDNA of the potyvirus Plum pox virus (PPV) genome modified to include a GFP reporter gene. Amplicon expression exhibited a great variability among different transgenic lines and even among different plants of the same line. Plants of the line 10.6 initially developed without signs of amplicon expression, but at different times some of them started to display sporadic infection foci in leaves approaching maturity. The infection progressed systemically, but at later times the infected plants recovered and returned to an amplicon-inactive state. The failure to detect virus-specific siRNAs in 10.6 plants before amplicon induction and after recovery suggested that a strong amplicon-specific RNA silencing is not established in these plants. However, the coexpression of extra viral silencing suppressors caused some amplicon activation, suggesting that a low level of RNA silencing could be contributing to maintain amplicon repression in the 10.6 plants. The resistance mechanisms that prevent amplicon-derived virus infection were also active against exogenous PPV introduced by mechanical inoculation or grafting, but did not affect other viruses. Amplicon-derived PPV was able to spread into wild type scions grafted in 10.6 rootstocks that did not display signs of amplicon expression, suggesting that resistance has little effect on virus movement. Our results suggest that amplicon-derived virus infection is limited in this particular transgenic line by a combination of factors, including the presumed low efficiency of the conversion from the transgene transcript to replicable viral RNA, and also by the activation of RNA silencing and other defensive responses of the plant, which are not completely neutralized by viral suppressors.


Simultaneous inference of phylogenetic and transmission trees in infectious disease outbreaks.
Whole-genome sequencing of pathogens from host samples becomes more and more routine during infectious disease outbreaks. These data provide information on possible transmission events which can be used for further epidemiologic analyses, such as identification of risk factors for infectivity and transmission. However, the relationship between transmission events and sequence data is obscured by uncertainty arising from four largely unobserved processes: transmission, case observation, within-host pathogen dynamics and mutation. To properly resolve transmission events, these processes need to be taken into account. Recent years have seen much progress in theory and method development, but existing applications make simplifying assumptions that often break up the dependency between the four processes, or are tailored to specific datasets with matching model assumptions and code. To obtain a method with wider applicability, we have developed a novel approach to reconstruct transmission trees with sequence data. Our approach combines elementary models for transmission, case observation, within-host pathogen dynamics, and mutation, under the assumption that the outbreak is over and all cases have been observed. We use Bayesian inference with MCMC for which we have designed novel proposal steps to efficiently traverse the posterior distribution, taking account of all unobserved processes at once. This allows for efficient sampling of transmission trees from the posterior distribution, and robust estimation of consensus transmission trees. We implemented the proposed method in a new R package phybreak. The method performs well in tests of both new and published simulated data. We apply the model to five datasets on densely sampled infectious disease outbreaks, covering a wide range of epidemiological settings. Using only sampling times and sequences as data, our analyses confirmed the original results or improved on them: the more realistic infection times place more confidence in the inferred transmission trees.


Dietary factors in rheumatic autoimmune diseases: a recipe for therapy?
Today, we are facing a new era of digitization in the health care system, and with increased access to health care information has come a growing demand for safe, cost-effective and easy to administer therapies. Dietary habits have a crucial influence on human health, affecting an individual's risk for hypertension, heart disease and stroke, as well as influencing the risk of developing of cancer. Moreover, an individual's lifestyle choices can greatly influence the progression and manifestation of chronic autoimmune rheumatic diseases. In light of these effects, it makes sense that the search for additional therapies to attenuate such diseases would include investigations into lifestyle modifications. When considering the complex web of factors that influence autoimmunity, it is not surprising to find that several dietary elements are involved in disease progression or prevention. In this Review, several common nutritional components of the human diet are presented, and the evidence for their effects on rheumatic diseases is discussed.


Predictors of new-onset distal neuropathic pain in HIV-infected individuals in the era of combination antiretroviral therapy.
Despite modern combination antiretroviral therapy, distal neuropathic pain (DNP) continues to affect many individuals with HIV infection. We evaluated risk factors for new-onset DNP in the CNS Antiretroviral Therapy Effects Research (CHARTER) study, an observational cohort. Standardized, semiannual clinical evaluations were administered at 6 US sites. Distal neuropathic pain was defined by using a clinician-administered instrument standardized across sites. All participants analyzed were free of DNP at study entry. New-onset DNP was recorded at the first follow-up visit at which it was reported. Mixed-effects logistic regression was used to evaluate potential predictors including HIV disease and treatment factors, demographics, medical comorbidities, and neuropsychiatric factors. Among 493 participants, 131 (27%) reported new DNP over 2306 visits during a median follow-up of 24 months (interquartile range 12-42). In multivariable regression, after adjusting for other covariates, significant entry predictors of new DNP were older age, female sex, current and past antiretroviral treatment, lack of virologic suppression, and lifetime history of opioid use disorder. During follow-up, more severe depression symptoms conferred a significantly elevated risk. The associations with opioid use disorders and depression reinforce the view that the clinical expression of neuropathic pain with peripheral nerve disease is strongly influenced by neuropsychiatric factors. Delineating such risk factors might help target emerging preventive strategies, for example, to individuals with a history of opioid use disorder, or might lead to new treatment approaches such as the use of tools to ameliorate depressed mood.


Non-right-handedness and free serum testosterone levels in detoxified patients with alcohol dependence.
The influence of testosterone on the extent of hemispheric dominance has been discussed not just during the first two trimesters of pregnancy but also later in life. An increase in free serum testosterone levels has been found during and after the detoxification phase of patients with alcohol dependence. In 250 participants (125 men and 125 women) with alcohol dependence immediately after the direct withdrawal phase (Day 21) and in 250 healthy age- and gender-matched participants, free testosterone in the serum was determined and handedness was assessed as a peripheral marker of central hemispheric dominance. Patients with alcohol dependence were 2.7-fold (odds ratio, OR: 2.66; 95% confidence interval, CI: 1.62-4.38) and men 4.1-fold (OR: 4.12; 95% CI: 2.44-6.98) more likely to be non-right-handed (NRH). In addition to male gender, non-right-handedness and alcohol dependence contributed statistically significantly to higher serum testosterone levels. Testosterone values of patients with alcohol dependence differed significantly between the four different Lesch subtypes; in particular, participants with alcohol dependence classified according to Lesch subtype IV were found to have significantly higher serum testosterone levels (F = 20.5; P < 0.001) when compared to participants classified according to Lesch subtypes I-III. An alteration of hemispheric dominance and thus an exogenously modifiable neuronal plasticity may be demonstrated directly on a population at risk.


Tunable Kerr frequency combs and temporal localized states in time-delayed Gires-Tournois interferometers.
In this Letter, we study theoretically a new setup allowing for the generation of temporal localized states (TLSs) and frequency combs. The setup is compact (a few centimeters) and can be implemented using established technologies, while offering tunable repetition rates and potentially high power operation. It consists of a vertically emitting micro-cavity, operated in the Gires-Tournois regime, containing a Kerr medium strong time-delayed optical feedback, and detuned optical injection. We disclose sets of multistable dark and bright TLSs coexisting on their respective bistable homogeneous backgrounds.


[The state of thyroid system in patients with non-traumatic supratentorial hematomas].
Concentrations of thyroid hormones (thyrotrophic - TTG, T3, T4) were measured with radioimmunological assay in the blood serum of 69 operated patients with supratentorial stroke interbrain hematomas. Hematomas were removed using a puncture/ aspiration method with local fibrinolysis. The lethality was 19%. It has been shown that medial hematomas lead to the decrease in TTG secretion while lateral and lobar ones inhibit T4 and T3 synthesis. Replacement therapy with thyroid hormones is needed to improve results of operative treatment of non-traumatic interbrain hematomas.


Leptin is associated with blood pressure and hypertension in women from the National Heart, Lung, and Blood Institute Family Heart Study.
Leptin is a key neuroendocrine hormone regulating food intake, metabolism, and fat accumulation, and it may also affect blood pressure and contribute to hypertension through sympathetic activation in the vasculature or at the renal level. Although previous studies have shown that the distribution of leptin is significantly different between males and females, as is the risk of hypertension between males and females, results regarding the role of leptin in the gender-specific regulation of blood pressure are controversial. Thus, we performed family-based association analyses in the National Heart, Lung, and Blood Institute Family Heart Study to test the hypothesis that LEPTIN gene variants and the plasma leptin level influence variability in blood pressure and the risk of hypertension differently by gender. We identified significant associations between LEPTIN single nucleotide polymorphisms with blood pressure and hypertension, but in postmenopausal women only. We also identified significant associations between plasma leptin levels and both blood pressure and hypertension in women. The current study supports a role for LEPTIN and plasma leptin levels in blood pressure regulation in women. It also provides insight into the gender differences in hypertension, as well as the differential distribution and activity of leptin in men and women.


Cocaine reduces thymic endocrine function: another mechanism for accelerated HIV disease progression.
Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4(+) cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4(+) cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4(+) and CD8(+) cell counts and the CD4(+)/CD8(+) ratio, and the covariate effects of substance use cross-sectionally in 80 HIV(+) active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (β = -0.908,95% CI: -1.704, -0.112; p = 0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR = 0.634, 95% CI: 0.406, 0.989 p = 0.045) and were 75 times more likely to show a decrease in thymulin activity (OR = 74.7, 95% CI: 1.59, 3519.74; p = 0.028) over time. CD4(+) cell count was positively associated with thymulin activity (β = 0.127, 95% CI: 0.048,0.205; p = 0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4 cell count ≥200 cells/μl (RR = 2.324, 95% CI: 1.196, 4.513, p = 0.013), and those with an increase in CD4 cell counts were more likely to show an increase in thymulin activity (OR = 1.02, 95% CI: 1.00, 1.034; p = 0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides opportunities to find alternative strategies to counteract immunosuppression.


The validity of the CAGE scale to screen for heavy drinking and drinking problems in a general population survey.
The CAGE scale is a short test developed in the 1970s to screen for alcoholism or covert drinking problems. The reliability and validity of the scale has been demonstrated in the majority of studies conducted in clinical settings, but the validity of the scale in general population surveys has not yet been shown conclusively. The goal of this study was to assess the criterion validity of the CAGE scale in a general population survey. Data from a large general health survey conducted in 1992 in the province of Quebec (Canada) (N = 23,564) were used to define various measures of heavy drinking and drinking problems and to calculate, for male and female drinkers separately, standard measures of sensitivity, specificity and positive predictive value at different cutoff scores on the CAGE. With respect to both male and female drinkers, with all operational definitions of heavy drinking and useful cutoff scores on the CAGE, the scale was shown to be unable to discriminate between heavy drinkers and non-heavy drinkers. Prevalence of drinking problems among CAGE positive drinkers was also very low. These results do not support the use of the CAGE as a screening tool for heavy drinking and drinking problems in a general population survey or as a tool to estimate the prevalence of drinking problems in the population.


Megalin mediates transepithelial albumin clearance from the alveolar space of intact rabbit lungs.
The alveolo-capillary barrier is effectively impermeable to large solutes such as proteins. A hallmark of acute lung injury/acute respiratory distress syndrome is the accumulation of protein-rich oedema fluid in the distal airspaces. Excess protein must be cleared from the alveolar space for recovery; however, the mechanisms of protein clearance remain incompletely understood. In intact rabbit lungs 29.8 ± 2.2% of the radio-labelled alveolar albumin was transported to the vascular compartment at 37°C within 120 min, as assessed by real-time measurement of 125I-albumin clearance from the alveolar space. At 4°C or 22°C significantly lower albumin clearance (3.7 ± 0.4 or 16.2 ± 1.1%, respectively) was observed. Deposition of a 1000-fold molar excess of unlabelled albumin into the alveolar space or inhibition of cytoskeletal rearrangement or clathrin-dependent endocytosis largely inhibited the transport of 125I-albumin to the vasculature, while administration of unlabelled albumin to the vascular space had no effect on albumin clearance. Furthermore, albumin uptake capacity was measured as about 0.37 mg ml−1 in cultured rat lung epithelial monolayers, further highlighting the (patho)physiological relevance of active alveolar epithelial protein transport. Moreover, gene silencing and pharmacological inhibition of the multi-ligand receptor megalin resulted in significantly decreased albumin binding and uptake in monolayers of primary alveolar type II and type I-like and cultured lung epithelial cells. Our data indicate that clearance of albumin from the distal air spaces is facilitated by an active, high-capacity, megalin-mediated transport process across the alveolar epithelium. Further understanding of this mechanism is of clinical importance, since an inability to clear excess protein from the alveolar space is associated with poor outcome in patients with acute lung injury/acute respiratory distress syndrome.


Dynamic updating of clinical survival prediction models in a changing environment.
Over time, the performance of clinical prediction models may deteriorate due to changes in clinical management, data quality, disease risk and/or patient mix. Such prediction models must be updated in order to remain useful. In this study, we investigate dynamic model updating of clinical survival prediction models. In contrast to discrete or one-time updating, dynamic updating refers to a repeated process for updating a prediction model with new data. We aim to extend previous research which focused largely on binary outcome prediction models by concentrating on time-to-event outcomes. We were motivated by the rapidly changing environment seen during the COVID-19 pandemic where mortality rates changed over time and new treatments and vaccines were introduced. We illustrate three methods for dynamic model updating: Bayesian dynamic updating, recalibration, and full refitting. We use a simulation study to compare performance in a range of scenarios including changing mortality rates, predictors with low prevalence and the introduction of a new treatment. Next, the updating strategies were applied to a model for predicting 70-day COVID-19-related mortality using patient data from QResearch, an electronic health records database from general practices in the UK. In simulated scenarios with mortality rates changing over time, all updating methods resulted in better calibration than not updating. Moreover, dynamic updating outperformed ad hoc updating. In the simulation scenario with a new predictor and a small updating dataset, Bayesian updating improved the C-index over not updating and refitting. In the motivating example with a rare outcome, no single updating method offered the best performance. We found that a dynamic updating process outperformed one-time discrete updating in the simulations. Bayesian updating offered good performance overall, even in scenarios with new predictors and few events. Intercept recalibration was effective in scenarios with smaller sample size and changing baseline hazard. Refitting performance depended on sample size and produced abrupt changes in hazard ratio estimates between periods.


Why is homocysteine toxic for the nervous and immune systems?
Hyperhomocysteinemia is a risk factor for a number of neurodegenerative and cardiovascular diseases. We have shown that homocysteine induces excitotoxic effects in cells expressing glutamate receptors of the NMDA class. These receptors were found not only in neurons but also in immune-competent cells, neutrophils, red blood cells, cardiomyocytes, and osteoblasts. Activation of these cells by homocysteine results in an increase in cytoplasmic calcium ions, accumulation of reactive oxygen species, and activation of MAP kinase. An overload of immune-competent cells activates both necrotic and apoptotic cell death, whereas the neuropeptide carnosine (an antioxidant and immune modulator) protects cells against both processes. In a model of prenatal hyperhomocysteinemia in rats, we have found that carnosine protects animals against homocysteine toxicity with no change of the blood homocysteine levels. The efficiency of carnosine has also been demonstrated in clinical trials of chronic brain ischemia and Parkinson's disease.


Intravascular targets for molecular contrast-enhanced ultrasound imaging.
Molecular targeting of contrast agents for ultrasound imaging is emerging as a new medical imaging modality. It combines advances in ultrasound technology with principles of molecular imaging, thereby allowing non-invasive assessment of biological processes in vivo. Preclinical studies have shown that microbubbles, which provide contrast during ultrasound imaging, can be targeted to specific molecular markers. These microbubbles accumulate in tissue with target (over) expression, thereby significantly increasing the ultrasound signal. This concept offers safe and low-cost imaging with high spatial resolution and sensitivity. It is therefore considered to have great potential in cancer imaging, and early-phase clinical trials are ongoing. In this review, we summarize the current literature on targets that have been successfully imaged in preclinical models using molecularly targeted ultrasound contrast agents. Based on preclinical experience, we discuss the potential clinical utility of targeted microbubbles.