Solution structure of the two N-terminal RNA-binding domains of nucleolin and NMR study of the interaction with its RNA target.
Nucleolin is an abundant 70 kDa nucleolar protein involved in many aspects of ribosomal RNA biogenesis. The central region of nucleolin contains four tandem consensus RNA-binding domains (RBD). The two most N-terminal domains (RBD12) bind with nanomolar affinity to an RNA stem-loop containing the consensus sequence UCCCGA in the loop. We have determined the solution structure of nucleolin RBD12 in its free form and have studied its interaction with a 22 nt RNA stem-loop using multidimensional NMR spectroscopy. The two RBDs adopt the expected beta alpha beta beta alpha beta fold, but the position of the beta 2 strand in both domains differs from what was predicted from sequence alignments. RBD1 and RBD2 are significantly different from each others and this is likely important in their sequence specific recognition of the RNA. RBD1 has a longer alpha-helix 1 and a shorter beta 2-beta 3 loop than RBD2, and differs from most other RBDs in these respects. The two RBDs are separated by a 12 amino acid flexible linker and do not interact with one another in the free protein. This linker becomes ordered when RBD12 binds to the RNA. Analysis of the observed NOEs between the protein and the RNA indicates that both RBDs interact with the RNA loop via their beta-sheet. Each domain binds residues on one side of the loop; specifically, RBD2 contacts the 5' side and RBD1 contacts the 3'.


Evaluation of the efficacy of oral lufenuron combined with topical enilconazole for the management of dermatophytosis in catteries.
The efficacy of oral lufenuron, a chitin synthetase inhibitor, combined with topical enilconazole, was evaluated for the management of Microsporum canis infection in 100 cats housed in two catteries in France. The cats were treated with weekly rinses with enilconazole (0.2 per cent) for four weeks and, in each cattery, one group (A) was also treated with micronised griseofulvin (25 mg/kg administered orally twice a day for five weeks) and a second group (B) was treated with 60 mg/kg lufenuron administered orally once on day 0 and again after 30 days. All the cats were examined individually for cutaneous lesions and mycological cultures were made when the treatment began and after 15, 30, 60 and 90 days. In the first cattery, the cats' clinical scores after 30 and 60 days were significantly lower in group B than in group A. In both catteries and both treatment groups, the mean number of fungal colonies decreased rapidly during the first 15 days of treatment, remained stable for the following 45 days but increased from day 60 to the end of the experiment on day 90.


[Bowen's disease of the palmar region. Apropos of a case].
The authors study a case of Bowen's disease localized on the palm of the right hand, in a patient of the female sex, 63 years old. At the studied case the patient had presented squamous carcinoma in situ of the cervix which appeared about 7 years before the appearance of the cutaneous lesion. A literature revision was done, and the authors verified the rarity of the palm localization of the Bowen's disease.


Accuracy of routinely collected clinical data on acute medical admissions to one hospital.
Despite the rapid growth in routine computerized data collection within the National Health Service (NHS), and the increased use of such data for generating hospital statistics and doctor activity rates, few validation studies exist. During a study of 158 acute medical admissions, and examination of hospital data revealed numerous and systematic inaccuracies. If general practitioner (GP) performance statistics are to be reliably based on such sources, data validation, staff training, and protocols for data entry should form a routine part of NHS practice.


Appropriateness of hospital use: an overview of Italian studies.
This paper reports on the general features and findings of 11 studies conducted in Italy on appropriateness of hospital admission and days of stay using the Appropriateness Evaluation Protocol (AEP). Studies have been grouped for presentation in two categories. The first comprises six heterogeneous studies illustrating different ways of targeting the use of the AEP: two used it to assess appropriateness of admission in an emergency room setting, two measured appropriateness of days of stay in patients with AIDS and nosocomial infections and finally two others evaluated hospital days in a group of elderly patients and "before and after" the institution of a domiciliary nursing service, respectively. The second group comprises five more homogeneous utilization review studies aimed at assessing inappropriateness of admissions and days of stay in medical/surgical departments of large hospitals in northern Italy. Besides detecting a substantial amount of inappropriateness in admission (range = 25-38%) and days of stay (range = 28-49%) this latter group of studies suggests that delays in execution and reporting of laboratory investigations, unavailability of operating rooms and delays due to difficulties in transferring patients to long-term care facilities are the most common causes of inappropriate days of stay. Despite the differences in their objectives, design and methods of sampling, these studies indicate that an explicit, diagnosis-independent and standardized instrument such as the AEP can help to uncover a substantial amount of the potentially avoidable use of hospital resources in the Italian context.


Altered 11 beta-hydroxylase activity in glucocorticoid-suppressible hyperaldosteronism.
Corticosteroid 11 beta-hydroxylation is catalyzed by 11 beta-hydroxylase and aldosterone synthase. Using plasma steroid ratios, the level of this process in patients with glucocorticoid-suppressible hyperaldosteronism (GSH) was compared with that in unaffected control subjects and patients with Conn's syndrome. Based on both 11-deoxycortisol/cortisol (S:F) and 11-deoxycorticosterone/corticosterone (DOC:B) ratios, patients with GSH showed impaired resting 11 beta-hydroxylase activity. In GSH, but not in the other groups, the S:F ratio was significantly correlated with the basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all of these patient groups, suggesting a common partial deficiency. The results also indicate that 11 beta-hydroxylation may be rate limiting in normal subjects. In control subjects and patients with Conn's syndrome, the DOC:B ratio was not affected by ACTH. However, in GSH patients, this ratio fell markedly, indicating an increased efficiency of 11 beta-hydroxylation of DOC (but not S). This may be due to the activation by ACTH of the zona fasciculata chimeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone, and DOC concentrations appeared to be more sensitive to ACTH in GSH than in the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in this condition and may contribute to the phenotype variability.


The use of pNJ5000 as an intermediate vector for the genetic manipulation of Agrobacterium Ti-plasmids.
The use of broad-host-range plasmids derived from RP4 as intermediate vectors for the transfer of narrow-host-range recombinant plasmids from Escherichia coli to Agrobacterium tumefaciens as a preliminary to marker exchange is described. Recombinant plasmids having a ColE1 type origin were linked to the RP4 derivative. Cointegrate formation appeared to take place by RecA-independent, homologous recombination within a short piece of DNA derived from the beta-lactamase gene of Tn1/Tn3 carried by both vector components, so that it never disrupted the recombinant portion of the construction. pNJ5000 provides an unstable intermediate vector for use in marker exchange experiments, while its stable relative pNJ1020 provides a carrier for use in binary vector systems.


In vivo recordings of brain activity using organic transistors.
In vivo electrophysiological recordings of neuronal circuits are necessary for diagnostic purposes and for brain-machine interfaces. Organic electronic devices constitute a promising candidate because of their mechanical flexibility and biocompatibility. Here we demonstrate the engineering of an organic electrochemical transistor embedded in an ultrathin organic film designed to record electrophysiological signals on the surface of the brain. The device, tested in vivo on epileptiform discharges, displayed superior signal-to-noise ratio due to local amplification compared with surface electrodes. The organic transistor was able to record on the surface low-amplitude brain activities, which were poorly resolved with surface electrodes. This study introduces a new class of biocompatible, highly flexible devices for recording brain activity with superior signal-to-noise ratio that hold great promise for medical applications.


Analgesic Effects of Regional Analgesic Techniques in Pediatric Inguinal Surgeries: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.
Various regional analgesic techniques have been used in pediatric inguinal surgery to facilitate postoperative recovery. However, each technique's relative performance was undetermined owing to the lack of quantitative analysis. We systematically searched MEDLINE, Cochrane Library, EMBASE, and Web of Science for randomized controlled trials that compared regional analgesia in pediatric inguinal surgeries. After critical study screening and selection, a random-effects network meta-analysis was performed. The primary outcome was the time to the first rescue analgesic after surgery, and the secondary outcomes were the number of patients requiring rescue analgesics after surgery, postoperative pain scores, incidence of postoperative nausea and vomiting, and other adverse events. This network meta-analysis included 69 randomized controlled trials (4636 patients) that compared 10 regional analgesic techniques. Our study revealed that the quadratus lumborum and transversus abdominis plane blocks had the longest time to the first rescue analgesic after pediatric inguinal surgeries, by 7.7 hours (95% confidence interval [CI], 5.0-10.3) and 6.0 hours (95% CI, 3.9-8.2) when compared with the control group, respectively. In the subgroup involving only inguinal hernia repair, the quadratus lumborum block significantly prolonged the time to the first rescue analgesic than all other regional analgesics. In contrast, in the subgroup involving orchidopexies, only the caudal block significantly prolonged the time to the first rescue analgesic when compared with the control group (4.1 hours; 95% CI, 0.7-7.5). Wound infiltration and landmark-based ilioinguinal-iliohypogastric block had relatively poor analgesic effects than other regional analgesics. No serious adverse effects related to the regional analgesic techniques were reported in any of the included studies. The quadratus lumborum and transversus abdominis plane blocks had the longest time to the first rescue analgesic and the least rescue analgesic requirement for pediatric inguinal surgeries. Specifically, the quadratus lumborum block had the longest analgesic duration in inguinal hernia repair, and the caudal block was found to be the only regional analgesia that extended the time to the first rescue analgesic in pediatric orchidopexy. Most included randomized controlled trials had some concern or a high risk of bias, and future studies should focus on providing high-quality evidence to further clarify the analgesic effects of regional analgesia for pediatric inguinal surgeries.


Intracranial Pressure Evaluation in Swine During Full-Endoscopic Lumbar Spine Surgery.
Neurological complications during full-endoscopic spine surgery (FESS) might be attributed to intracranial pressure (ICP) increase due to continuous saline infusion (CSI). Understanding CSI and ICP correlation might modify irrigation pump usage. This study aimed to evaluate invasive ICP during interlaminar FESS; correlate ICP with irrigation pump parameters (IPPs); evaluate ICP during saline outflow occlusion, commonly used to control bleeding and improve the surgeon's view; and, after durotomy, simulate accidental dural tear. Five swine were monitored, submitted to total intravenous anesthesia, and positioned ventrally. A parenchymal catheter was installed through a skull burr for ICP monitoring. Lumbar interlaminar FESS was performed until exposure of neural structures. CSI was used within progressively higher IPPs (A [60 mm Hg, 350 mL/minute] to D [150 mm Hg, 700 mL/minute]), and ICP was documented. During each IPP, different situations were grouped: intact dura with open channels (A1-D1) or occlusion test (A2-D2); dural tear with open channels (Ax1-Dx1) or occlusion test (Ax2-Dx2). ICP <20 mm Hg was defined as safe. Basal average ICP was 8.1 mm Hg. Adjustment in total intravenous anesthesia or suspension of tests was necessary due to critical ICP or animal discomfort. It was safe to operate with all IPPs with opened drainage channels (A1-D1) even with dural tear (Ax1-Dx1). Several occlusion tests (A2-D2, Ax2-Dx2) caused ICP increase (e.g., 86.1 mm Hg) influenced by anesthetic state and hemodynamics. During FESS, CSI might critically raise ICP. Keeping drainage channels open, with ideal anesthetic state, ICP remains safe even with high IPPs, despite dural tear. Drainage occlusions can quickly raise ICP, being even more severe with higher IPPs. Total intravenous anesthesia may protect from ICP increase and may allow longer drainage occlusion or higher IPPs.


A transient role for ciliary neurotrophic factor in chick photoreceptor development.
Previous studies suggest that ciliary neurotrophic factor (CNTF) may represent one of the extrinsic signals controlling the development of vertebrate retinal photoreceptors. In dissociated cultures from embryonic chick retina, exogenously applied CNTF has been shown to act on postmitotic rod precursor cells, resulting in an two- to fourfold increase in the number of cells acquiring an opsin-positive phenotype. We now demonstrate that the responsiveness of photoreceptor precursors to CNTF is confined to a brief phase between their final mitosis and their terminal differentiation owing to the temporally restricted expression of the CNTF receptor (CNTFR alpha). As shown immunocytochemically, CNTFR alpha expression in the presumptive photoreceptor layer of the chick retina starts at embryonic day 8 (E8) and is rapidly down-regulated a few days later prior to the differentiation of opsin-positive photoreceptors, both in vivo and in dissociated cultures from E8. We further show that the CNTF-dependent in vitro differentiation of rods is followed by a phase of photoreceptor-specific apoptotic cell death. The loss of differentiated rods during this apoptotic phase can be prevented by micromolar concentrations of retinol. Our results provide evidence that photoreceptor development depends on the sequential action of different extrinsic signals. The time course of CNTFR alpha expression and the in vitro effects suggest that CNTF or a related molecule is required during early stages of rod differentiation, while differentiated rods depend on additional protective factors for survival.


Processing and secretion by Escherichia coli of a recombinant form of the immunogenic protein MPB70 of Mycobacterium bovis.
The gene encoding an immunodominant secreted antigen, MPB70, of Mycobacterium bovis was cloned into the plasmid vector pBluescript II KS+ along with its native ribosome-binding site. In this construct translation of the protein in Escherichia coli was from the native AUG initiation codon and was directed by the mycobacterial ribosome-binding site. Two different molecular mass forms (26 kDa and 22 kDa) of MPB70 were observed in whole-cell pellets of recombinant E. coli. The difference in size indicates cleavage of the signal peptide of MPB70 by an endopeptidase of E. coli. MPB70 was secreted into the periplasm of recombinant E. coli, where the 22 kDa form of the protein was predominant. The culture filtrate contained only the 22 kDa form of the protein, which was soluble. The passage of MPB70 from the periplasm into the growth medium was found to be due, at least in part, to non-specific leakage of periplasmic proteins across the outer membrane associated with the expression of recombinant MPB70.


[Recruitment of immunocompetent cells in a transplanted lung is not impaired despite incompletel reinnervation].
It is not clear whether surgical intervention during lung transplantation which includes cutting vegetative nerves, lymphatic vessels and bronchial arteries, leads to alterations in immune responses. Thus, it was studied in an animal model whether an induced pulmonary immune reaction after syngenic lung transplantation was impaired without the influence of immunosuppression and rejection. The recruitment of leukocytes and the status of reinnervation was examined. Syngenic transplantation of the left lung was performed in Lewis rats without rejection and therefore without immunosuppressive therapy. In a subgroup of animals host and donor leukocytes were distinguished. An ovalbumin (OVA)-specific pulmonary immune response was induced four months after transplantation. Bronchoalveolar lavage (BAL) and interstitial leukocytes were examined using flow cytometry and immunocytology, comparing the right lung and the grafted left lung. Immunohistology was performed to detect nerve fibers on cryostat sections. An induced cellular inflammation was observed in the right host lung as well as in the grafted left lung. However, the CD4 T cell numbers in the BAL were increased in the left lung. Single donor-type leukocytes could still be observed four months after transplantation. A partial reinnervation was found. The recruitment of immune cells into the lung interstitium and bronchoalveolar space of grafted lungs is not impaired. The incomplete reinnervation has no influence on leukocyte recruitment.


[A telemedical consultation system based on multicast].
That the multicast technology is fit for telemedical consultation application has been developed on the basis of the features analysis of medical consultation action. A scheme of the telemedical consultation application based on the multicast technology has been designed. The features of this scheme are: unrestrained joining in and quitting, simultaneous control over the transport information of doctor and patient, extending, and simulating consultation scene. And the implementation of this scheme is discussed.


Releasing of hexabromocyclododecanes from expanded polystyrenes in seawater -field and laboratory experiments.
Expanded polystyrene (EPS) is a major component of marine debris globally. Recently, hazardous hexabromocyclododecanes (HBCDDs) were detected in EPS buoys used for aquaculture farming. Subsequently, enrichment of HBCDDs was found in nearby marine sediments and mussels growing on EPS buoys. It was suspected that EPS buoys and their debris might be sources of HBCDDs. To confirm this, the release of HBCDDs from EPS spherules detached from a buoy to seawater was investigated under field (open sea surface and closed outdoor chambers with sun exposure and in the dark) and laboratory (particle-size) conditions. In all exposure groups, initial rapid leaching of HBCDDs was followed by slow desorption over time. Abundant release of HBCDDs was observed from EPS spherules exposed to the open sea surface (natural) and on exposure to sunlight irradiation or in the dark in controlled saline water. Water leaching and UV-light/temperature along with possibly biodegradation were responsible for about 37% and 12% of HBCDDs flux, respectively. Crumbled EPS particles (≤1 mm) in samples deployed on the sea surface for 6 months showed a high degree of weathering. This implies that surface erosion and further fragmentation of EPS via environmental weathering could enhance the leaching of HBCDDs from the surface of EPS. Overall, in the marine environment, HBCDDs could be released to a great extent from EPS products and their debris due to the cumulative effects of the movement of large volumes of water (dilution), biodegradation, UV-light/temperature, wave action (shaking), salinity and further fragmentation of EPS spherules.


Cultural influence of social information use in pedestrian road-crossing behaviours.
Social information use is common in a wide range of group-living animals, notably in humans. The role it plays in decision-making could be a key to understanding how social groups make collective decisions. The observation of road-crossing behaviours in the presence of other individuals is an ideal means to study the influence of social information on decision-making. This study investigated the influence of culture on social information used by pedestrians in a potentially dangerous scenario, namely road crossing. We scored the collective crossing of pedestrians at four locations in Nagoya (Japan) and three locations in Strasbourg (France). French pedestrians cross against the lights much more often (41.9%) than Japanese ones (2.1%). Individuals deciding to cross the road were strongly influenced by the behaviour and the presence of other pedestrians, especially in Japan, where a stronger conformism was noted. However, Japanese pedestrians were half as likely to be influenced by social information as their French counterparts when crossing at the red light, as they were more respectful of rules. Men show riskier behaviour than women (40.6% versus 25.7% of rule-breaking, respectively), deciding quickly and setting off earlier than women. Further related studies could help target specific preventive, culture-specific solutions for pedestrian safety.


Establishment and maintenance of parasegmental compartments.
Embryos of higher metazoans are divided into repeating units early in development. In Drosophila, the earliest segmental units to form are the parasegments. Parasegments are initially defined by alternating stripes of expression of the fushi-tarazu and even-skipped genes. How fushi-tarazu and even-skipped define the parasegment boundaries, and how parasegments are lost when fushi-tarazu or even-skipped fail to function correctly, have never been fully or properly explained. Here we show that parasegment widths are defined early by the relative levels of fushi-tarazu and even-skipped at stripe junctions. Changing these levels results in alternating wide and narrow parasegments. When shifted by 30% or more, the enlarged parasegments remain enlarged and the reduced parasegments are lost. Loss of the reduced parasegments occurs in three steps; delamination of cells from the epithelial layer, apoptosis of the delaminated cells and finally apoptosis of inappropriate cells remaining at the surface. The establishment and maintenance of vertebrate metameres may be governed by similar processes and properties.


Identification of NOX4 as a New Biomarker in Hepatocellular Carcinoma and Its Effect on Sorafenib Therapy.
To improve the survival of patients with hepatocellular carcinoma (HCC), new biomarkers and therapeutic targets are urgently needed. In this study, the GEO and TCGA dataset were used to explore the differential co-expressed genes and their prognostic correlation between HCC and normal samples. The mRNA levels of these genes were validated by qRT-PCR in 20 paired fresh HCC samples. The results demonstrated that the eight-gene model was effective in predicting the prognosis of HCC patients in the validation cohorts. Based on qRT-PCR results, NOX4 was selected to further explore biological functions within the model and 150 cases of paraffin-embedded HCC tissues were scored for NOX4 immunohistochemical staining. We found that the NOX4 expression was significantly upregulated in HCC and was associated with poor survival. In terms of function, the knockdown of NOX4 markedly inhibited the progression of HCC in vivo and in vitro. Mechanistic studies suggested that NOX4 promotes HCC progression through the activation of the epithelial-mesenchymal transition. In addition, the sensitivity of HCC cells to sorafenib treatment was obviously decreased after NOX4 overexpression. Taken together, this study reveals NOX4 as a potential therapeutic target for HCC and a biomarker for predicting the sorafenib treatment response.


Aortic Root Surgery in Marfan Syndrome: Medium-Term Outcome in a Single-Center Experience.
The study aim was to analyze the authors' experience with aortic root surgery in Marfan syndrome (MFS), and to expand the surgical outcome data of patients meeting the Ghent criteria (Marfan registry). Analyses were performed of data acquired from MFS patients (who met the Ghent criteria), including an aortic root surgery and Kaplan-Meier survival. Between April 2004 and February 2012, a total of 59 MFS patients (mean age at surgery 36 ± 13 years) underwent 67 operations for aortic root aneurysm (n = 52), aortic valve (AV) regurgitation (n = 15), acute aortic dissection (n = 2), and/or mitral valve (MV) regurgitation resulting from MV prolapse (n = 7). Of 59 initial operations, 21 (36%) involved AV-replacing root surgery, 38 (64%) AV-sparing root surgery, seven (12%) aortic arch or hemi-arch repair, and five (8%) simultaneous MV surgery. There were no early mortalities. The mean follow up was 6.8 ± 1.2 years, with five deaths (8%) and a relatively low reoperation rate (10 reoperations in nine patients; 14%). Seven reoperations involved AV or aortic root surgery (including four for AV regurgitation following failed AV-sparing surgery), two MV repair/replacements, and one coronary artery bypass graft. Eight patients (21%) with AV-sparing surgery had moderate/severe AV regurgitation at the last follow up before re-intervention. The mean five-year freedom from postoperative death was 91.2 ± 8.8%, from cardiac reoperation 86.3 ± 4.5%, and more-than-moderate AV regurgitation 90.3 ± 4.8%. Prophylactic aortic surgery in MFS patients with AV-replacing root or AV-sparing root surgery carries a low risk of operative morbidity and death when performed at an experienced center. AV-sparing root surgery increases the risk of AV regurgitation and, possibly, of re-intervention. Regular clinical follow up is important after any aortic root surgery in MFS patients, with a delineation of risk factors for AV regurgitation after AV rootsparing surgery.


On-chip fabrication to add temperature control to a microfluidic solution exchange system.
We present a concept for the post production modification of commercially available microfluidic devices to incorporate local temperature control, thus allowing for the exact alignment of heating structures with the existing features, e.g. wells, channels or valves, of a system. Specifically, we demonstrate the application of programmable local heating, controlled by computerized PI regulation, to a rapid solution exchanger. Characterisation of the system to show that both uniform temperature distributions and temperature gradients can be established, and to confirm that the solution exchange properties are undisturbed by heating, was achieved using in situ thermometry and amperometry.


Effectiveness of functional ankle taping for judo athletes: a comparison between judo bandaging and taping.
This study was conducted to compare the effectiveness of the traditional method of ankle bandaging and the new method of ankle taping for judo athletes in Japan, and to introduce a functionally effective taping method for judo players. Four university judo athletes with ankle instability were selected to undertake radiography of the ankles before and after exercise, with bandaging at one time and taping at the other. Talar tilt (TT) angles were measured in order to compare the ankle-supporting effects. The results showed that the old ankle bandaging method had no role in eliminating the talar tilt during judo practice. In contrast, the new taping method was more effective in eliminating the talar tilt and supporting the involved ankles both mechanically and functionally.


Risk attitudes to treatment among patients with severe intermittent claudication.
To determine claudication patients' risk attitude to invasive treatment and whether this treatment is cost effective. Quality of life and health state utility status of 50 consecutive patients with severe intermittent claudication was assessed and compared with ankle-brachial pressure index values (ABPI) and results from treadmill tests before and after endovascular or open revascularization. Health utility scores were then calculated and used in a cost-utility analysis. Before surgery, patients were assigned a utility score of 0.51 (EQ-5D index) for their disease, and the standard gamble (SG) and time trade-off (TTO) median scores were 0.88 and 0.70, respectively. Before treatment, a weak correlation (r = 0.43, P < .001) between having a high risk perception of treatment and patients' walking distance were observed, where patients able to walk short distances accepted a higher risk. After treatment, ABI (P = .003) and walking distance (P = .002) improved significantly as well the physical components of the quality of life instruments (P < .001). The surgical treatment generated an improvement in quality of life expressed in QALYs equivalent to 0.17. With an estimated survival of 5 years, it adds up to a value of 0.85, corresponding to a sum of 51,000 US dollars gained. Patients with severe intermittent claudication are risk-seeking when it comes to surgical treatment and their risk attitude is correlated to their walking ability and quality of life. The incremental QALYs gained by treatment are achieved at a reasonable cost and revascularization appears to be cost effective.


Two regularizers for recursive least squared algorithms in feedforward multilayered neural networks.
Recursive least squares (RLS)-based algorithms are a class of fast online training algorithms for feedforward multilayered neural networks (FMNNs). Though the standard RLS algorithm has an implicit weight decay term in its energy function, the weight decay effect decreases linearly as the number of learning epochs increases, thus rendering a diminishing weight decay effect as training progresses. In this paper, we derive two modified RLS algorithms to tackle this problem. In the first algorithm, namely, the true weight decay RLS (TWDRLS) algorithm, we consider a modified energy function whereby the weight decay effect remains constant, irrespective of the number of learning epochs. The second version, the input perturbation RLS (IPRLS) algorithm, is derived by requiring robustness in its prediction performance to input perturbations. Simulation results show that both algorithms improve the generalization capability of the trained network.


Understanding hypothyroidism in Unani medicine.
Hypothyroidism (Qillat-e-Ifraz-e-Darqiyya) is a condition where the thyroid gland is underactive and unable to produce enough thyroid hormone. The description of hypothyroidism as a disease is not directly found in Unani texts. However, the signs and symptom of hypothyroidism resemble the clinical manifestation associated with Su-e-Mizaj Barid Maddi (derangement in cold temperament), such as plethora (Imtila), excessive salivation (Kasrat-e-Luabe-e-Dahan), tiredness (Aa'yan), loss of appetite (Zoaf-e-Ishteha), excessive sleeping (Kasrat-e-Naum) and cold skin (Baroodat-e-Jildia). These signs and symptoms are the result of an excess in abnormal phlegm (Ghair Tabayi Balgham) in the body. This review article identifies the observations from Unani literature that describe derangement in cold temperament and relate them to the clinical presentation of primary hypothyroidism in conventional medicine. We also discuss management of these symptoms in Unani medicine.


A collaborative approach to control hypertension in diabetes: outcomes of a pilot intervention.
We sought to develop and pilot an intervention to improve blood pressure (BP) and other intermediate outcomes (hemoglobin A1c, low-density lipoprotein cholesterol) of diabetes in a low-income, ethnically diverse population. English- or Spanish-speaking primary care patients with BP ≥ 140/90 on 2 visits in the past 12 months and any level of A1c were randomized to usual care (n = 24) or intervention (n = 31). Home health nurses assessed self-management and medication adherence, and they performed health behavior counseling. Participants transmitted daily BP and glucose results using simple home telemetry units to the nurse coordinator; these results were then aggregated and transmitted weekly to primary care providers to facilitate intensified treatment. After controlling for baseline levels, a significantly larger proportion of the intervention group was at goal for BP (adjusted OR = 9.3, P = .006) and A1c (AOR = 4.3, P = .049), but not for low-density lipoprotein cholesterol (AOR = 1.1, P =.86). Clinicians made more BP medication changes in the intervention group compared to the control group (8.3 vs 3.8, approaching significance at P = .06). Self-reported medication adherence and self-care behaviors were not significantly improved. We successfully developed a telephone- and email-based collaboration between home health nurses and primary care clinicians to address poorly controlled hypertension in an ethnically diverse population. The intervention, combining enhanced feedback to patients and their primary care providers and individualized behavior change support by home health nurses, is effective for improving BP and glucose in this setting.


Structural basis for the inhibition of the essential Plasmodium falciparum M1 neutral aminopeptidase.
Plasmodium falciparum parasites are responsible for the major global disease malaria, which results in >2 million deaths each year. With the rise of drug-resistant malarial parasites, novel drug targets and lead compounds are urgently required for the development of new therapeutic strategies. Here, we address this important problem by targeting the malarial neutral aminopeptidases that are involved in the terminal stages of hemoglobin digestion and essential for the provision of amino acids used for parasite growth and development within the erythrocyte. We characterize the structure and substrate specificity of one such aminopeptidase, PfA-M1, a validated drug target. The X-ray crystal structure of PfA-M1 alone and in complex with the generic inhibitor, bestatin, and a phosphinate dipeptide analogue with potent in vitro and in vivo antimalarial activity, hPheP[CH(2)]Phe, reveals features within the protease active site that are critical to its function as an aminopeptidase and can be exploited for drug development. These results set the groundwork for the development of antimalarial therapeutics that target the neutral aminopeptidases of the parasite.


Pathogenesis of aleutian disease of mink: identification of nonpersistent infections.
Aleutian disease virus usually produces a persistent infection and progressive immune comples disease in mink of the Aleutian genotype. Study of Aleutian disease virus infection in non-Aleutian mink showed that about one-quarter developed nonpersistent infections by the virus, and that the nonpersistence was not genetically determined by the host. The nonpersistently infected mink developed only a transient elevation of serum gamma globulin, and much lower specific Aleutian disease virus antibody titers than persistently infected mink. No lesions were found in the nonpersistently infected mink.


Therapies with emerging evidence of efficacy: avotermin for the improvement of scarring.
Many patients are dissatisfied with scars on both visible and non-visible body sites and would value any opportunity to improve or minimise scarring following surgery. Approximately 44 million procedures in the US and 42 million procedures in the EU per annum could benefit from scar reduction therapy. A wide range of non-invasive and invasive techniques have been used in an attempt to improve scarring although robust, prospective clinical trials to support the efficacy of these therapies are lacking. Differences in wound healing and scar outcome between early fetal and adult wounds led to interest in the role of the TGFbeta family of cytokines in scar formation and the identification of TGFbeta3 (avotermin) as a potential therapeutic agent for the improvement of scar appearance. Extensive pre-clinical and human Phase I and II clinical trial programmes have confirmed the scar improving efficacy of avotermin which produces macroscopic and histological improvements in scar architecture, with improved restitution of the epidermis and an organisation of dermal extracellular matrix that more closely resembles normal skin. Avotermin is safe and well tolerated and is currently in Phase III of clinical development, with the first study, in patients undergoing scar revision surgery, fully recruited.


Migration, mitochondria, and the yellow-rumped warbler.
Discordance between mitochondrial and nuclear DNA has been noted in many systems. Asymmetric introgression of mitochondria is a common cause of such discordances, although in most cases the drivers of introgression are unknown. In the yellow-rumped warbler, evidence suggests that mtDNA from the eastern, myrtle warbler, has introgressed across much of the range of the western form, the Audubon's warbler. Within the southwestern United States myrtle mtDNA comes into contact with another clade that occurs in the Mexican black-fronted warbler. Both northern forms exhibit seasonal migration, whereas black-fronted warblers are nonmigratory. We investigated the link between mitochondrial introgression, mitochondrial function, and migration using novel genetic, isotopic, biochemical, and phenotypic data obtained from populations in the transition zone. Isotopes suggest the zone is coincident with a shift in migration, with individuals in the south being resident and populations further north becoming increasingly more migratory. Mitochondrial respiration in flight muscles demonstrates that myrtle-type individuals have a significantly greater acceptor control ratio of mitochondria, suggesting it may be more metabolically efficient. To our knowledge this is the first time this type of intraspecific variation in mitochondrial respiration has been measured in wild birds and we discuss how such mitochondrial adaptations may have facilitated introgression.


Risk factors for PICU admission and death among children and young people hospitalized with COVID-19 and PIMS-TS in England during the first pandemic year.
Identifying which children and young people (CYP) are most vulnerable to serious infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important to guide protective interventions. To address this question, we used data for all hospitalizations in England among 0-17 year olds from 1 February 2019 to 31 January 2021. We examined how sociodemographic factors and comorbidities might be risk factors for pediatric intensive care unit (PICU) admission among hospitalizations due to the following causes: Coronavirus Disease 2019 (COVID-19) and pediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the first pandemic year (2020-2021); hospitalizations due to all other non-traumatic causes in 2020-2021; hospitalizations due to all non-traumatic causes in 2019-2020; and hospitalizations due to influenza in 2019-2020. Risk of PICU admission and death from COVID-19 or PIMS-TS in CYP was very low. We identified 6,338 hospitalizations with COVID-19, of which 259 were admitted to a PICU and eight CYP died. We identified 712 hospitalizations with PIMS-TS, of which 312 were admitted to a PICU and fewer than five CYP died. Hospitalizations with COVID-19 and PIMS-TS were more common among males, older CYP, those from socioeconomically deprived neighborhoods and those who were of non-White ethnicity (Black, Asian, Mixed or Other). The odds of PICU admission were increased in CYP younger than 1 month old and decreased among 15-17 year olds compared to 1-4 year olds with COVID-19; increased in older CYP and females with PIMS-TS; and increased for Black compared to White ethnicity in patients with COVID-19 and PIMS-TS. Odds of PICU admission in COVID-19 were increased for CYP with comorbidities and highest for CYP with multiple medical problems. Increases in odds of PICU admission associated with different comorbidities in COVID-19 showed a similar pattern to other causes of hospitalization examined and, thus, likely reflect background vulnerabilities. These findings identify distinct risk factors associated with PICU admission among CYP with COVID-19 or PIMS-TS that might aid treatment and prevention strategies.


[Peculiarities of clinical course and approaches to surgical treatment of patients with epidural hematoma in isolated cranio-cerebral trauma].
Peculiarities of clinical course and approaches to surgical treatment were studied in patients, suffering isolated cranio-cerebral trauma (CCT); new approaches were elaborated, permitting to improve outcome of epidural hematoma (EG) in surgical treatment of the patients. For isolated CCT 188 patients there were operated on, EG was revealed in 83 (44.1%) of them. The majority of patients were admitted to the hospital in subcompensated stage of clinical course of CCT. EG occurrs in the injured persons in indented cranial fracture, it is diagnosed by KT of the brain. Unfavorable impact on the surgical treatment results causes admittance to the hospital in a rude decompensation stage, in case of preoperative treatment absence, while diagnostic mistake committ- ment, late conduction of the operation, and admittance to the hospital more than 1 day after the trauma. The intensive therapy conduction postoperatively permits to reduce significantly the rate of cerebral and extracerebral complications.


Adherence of mucoid and nonmucoid Pseudomonas aeruginosa to acid-injured tracheal epithelium.
A model of the adherence of Pseudomonas aeruginosa to injured lower respiratory tract cells is described. Mouse tracheas were injured by exposure to 0.1 N HCl for 15 min, cut into pieces of 2 to 4 rings, and placed in petri dishes for adherence studies. Adherence was quantitated by direct count of the number of bacteria attached to a fixed surface area as viewed by scanning electron microscopy. Optimal conditions for study were 1 h of incubation with an inoculum of 10(7) to 10(8) CFU/ml. Both mucoid and nonmucoid P. aeruginosa adhered to the injured cells in this system, and no major differences in adherence between these strains was apparent. Adherence to injured tracheal cells was a phenomenon limited to P. aeruginosa and did not occur with Escherichia coli and Klebsiella pneumoniae. Besides adherence to injured cells, this model allowed the demonstration of adherence of mucoid P. aeruginosa and K. pneumoniae to mucin strands of uninjured control tracheas. This model is an alternative to the buccal cell model and has the advantage of allowing the study of the adherence of both mucoid and nonmucoid strains of P. aeruginosa.


Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding.
The crystal structure of an inactive chiral analogue of insulin containing nonstandard substitution allo-Ile(A2) is described at 2.0 A resolution. In native insulin, the invariant Ile(A2) side chain anchors the N-terminal alpha-helix of the A-chain to the hydrophobic core. The structure of the variant protein was determined by molecular replacement as a T(3)R(3) zinc hexamer. Whereas respective T- and R-state main-chain structures are similar to those of native insulin (main-chain root-mean-square deviations (RMSD) of 0.45 and 0.54 A, respectively), differences in core packing are observed near the variant side chain. The R-state core resembles that of the native R-state with a local inversion of A2 orientation (core side chain RMSD 0.75 A excluding A2); in the T-state, allo-Ile(A2) exhibits an altered conformation in association with the reorganization of the surrounding side chains (RMSD 0.98 A). Surprisingly, the core of the R-state is similar to that observed in solution nuclear magnetic resonance (NMR) studies of an engineered T-like monomer containing the same chiral substitution (allo-Ile(A2)-DKP-insulin; Xu, B., Hua, Q. X., Nakagawa, S. H., Jia, W., Chu, Y. C., Katsoyannis, P. G., and Weiss, M. A. (2002) J. Mol. Biol. 316, 435-441). Simulation of NOESY spectra based on crystallographic protomers enables the analysis of similarities and differences in solution. The different responses of the T- and R-state cores to chiral perturbation illustrates both their intrinsic plasticity and constraints imposed by hexamer assembly. Although variant T- and R-protomers retain nativelike protein surfaces, the receptor-binding activity of allo-Ile(A2)-insulin is low (2% relative to native insulin). This seeming paradox suggests that insulin undergoes a change in conformation to expose Ile(A2) at the hormone-receptor interface.


Clinical trials with glycoprotein IIb/IIIa receptor antagonists in acute coronary syndromes.
Glycoprotein IIb/IIIa receptor antagonists are more potent platelet inhibitors than aspirin. Although important reductions in ischemic/thrombotic complications have been observed with these agents following coronary interventions, their potential value for the medical treatment of acute coronary syndromes is at present uncertain. The final results of large randomized studies in patients with acute coronary syndromes are eagerly awaited.


Regulation of the Escherichia coli methylgalactoside transport system by gene mglD.
Constitutive activity of the methylgalactoside transport system of Escherichia coli K-12 is shown to result from mutation of a genetic locus distinct from the two previously described regulatory loci for this permease. Employing an autoradiographic procedure whereby constitutive and inducible cells can be differentiated, it is demonstrated that this locus, termed mglD, is 20% cotransducible with ptsF by bacteriophage P1. Selection for constitutive mutants among an inducible population yielded cells who mutations mapped in mglD. Cotransduction of mglD with mglB, minus C, and minus A, three genes required for activity of the methylgalactoside transport system, is 95, 88, and 81%, respectively. The results of recombination studies employing three and four factors indicate that the order of genes in this region is ptsF, mglD, B, C, A.


Regulating the architectures of hydrogen-bonded frameworks through topological enforcement.
The role of conformational flexibility in topological enforcement of several crystalline materials based on hydrogen-bonded two-dimensional guanidinium-sulfonate (GS) networks is demonstrated by using a series of organopolysulfonates that prompt the formation of either lamellar or cylindrical architectures. Whereas flexible organopolysulfonate linkers decorated with flexible arms self-assemble into lamellar architectures, rigid organopolysulfonates linkers enforce the formation of hydrogen-bonded cylinders with intercylinder spacing governed by the size of the linker. Specifically, hexagonal cylindrical structures generated from trisulfonates with three-fold molecular symmetry are the topological equivalent of the cylindrical hexagonal phases reported previously for guanidinium organomonosulfonate inclusion compounds, but neighboring cylinders are now connected through covalent nodes provided by the trisulfonates rather than dispersive interactions between the arene rings of the organomonosulfonates. Organopolysulfonates with moderate conformational freedom, however, can generate both lamellar and cylindrical structures, depending on the guest molecules encapsulated by the host framework. These observations illustrate that the crystal architecture (i.e., lamellar vs cylindrical) and the shape of GS cylinders can be regulated in a predictable way by the molecular symmetries and conformational constraints of the organopolysulfonates building blocks.


Disruption of the MreB Elongasome Is Overcome by Mutations in the Tricarboxylic Acid Cycle.
The bacterial actin homolog, MreB, is highly conserved among rod-shaped bacteria and essential for growth under normal growth conditions. MreB directs the localization of cell wall synthesis and loss of MreB results in round cells and death. Using the MreB depolymerizing drug, A22, we show that changes to central metabolism through deletion of malate dehydrogenase from the tricarboxylic acid (TCA) cycle results in cells with an increased tolerance to A22. We hypothesize that deletion of malate dehydrogenase leads to the upregulation of gluconeogenesis resulting in an increase in cell wall precursors. Consistent with this idea, metabolite analysis revealed that malate dehydrogenase (mdh) deletion cells possess elevated levels of several glycolysis/gluconeogenesis compounds and the cell wall precursor, uridine diphosphate N-acetylglucosamine (UDP-NAG). In agreement with these results, the increased A22 resistance phenotype can be recapitulated through the addition of glucose to the media. Finally, we show that this increase in antibiotic tolerance is not specific to A22 but also applies to the cell wall-targeting antibiotic, mecillinam.


The correlation between heart failure and the risk of ischemic colitis: a systematic review and meta-analysis.
Ischemic colitis is a relatively common gastrointestinal disease caused by hypoperfusion of the colon. Recently, studies have suggested an association between heart failure (HF) and ischemic colitis, even though the magnitude of the reported association varied considerably across the studies. This systematic review and meta-analysis were performed to comprehensively explore whether patients with HF are at a higher risk of ischemic colitis compared with individuals without HF by combining the results of all available observational studies. Systematic literature review was performed using EMBASE, MEDLINE and Google Scholar database up to May 2020. Eligible studies could be any observational ones that evaluated whether patients with HF have a higher risk of ischemic colitis than individuals without HF. Point estimates and standard errors from each eligible study were combined together using the generic inverse variance method of DerSimonian and Laird. The systematic review identified 7 case-control studies and 1 cross-sectional study. The pooled analysis found that patients with HF had a significantly higher risk of ischemic colitis with the pooled odds ratio of 3.42 (95% confidence interval 1.49-7.82; I2 96%). Funnel plot was relatively symmetric and was not suggestive of presence of publication bias. A significantly increased risk of ischemic colitis among patients with HF was demonstrated in this systematic review and meta-analysis.


Nanosized particles in bone and dissolution insensitivity of bone mineral.
Most of the mineral crystals in bone are platelets of carbonated apatite with thicknesses of a few nanometers embedded in a collagen matrix. We report that spherical to cylindrical shaped nanosized particles are also an integral part of bone structure observed by high resolution scanning electron microscopy. High resolution back scattered electron imaging reveals that the spherical particles have a contrast similar to the crystal platelets, suggesting that they are thus likely to have similar mineral properties. By means of constant composition (CC) dissolution of bone, similar sized nanoparticles are shown to be insensitive to demineralization and are thought to be dynamically stabilized due to the absence of active pits/defects on the crystallite surfaces. Similar reproducible self-inhibited dissolution was observed with these nanoparticles during CC dissolution of synthetic carbonated apatite. This result rules out the possible influence of complicating biological factors such as the possible presence of organic matrix components and other impurities. This phenomenon can be explained by a unique dissolution model involving size considerations at the nanoscale. The unexpected presence of nanoparticles in mature bone may also be due to the stabilization of some nanosized particles during the formation process in a fluctuating biological milieux.


The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy.
TRPML3 is an inward rectifying Ca(2+) channel that is regulated by extracytosolic H(+). Although gain-of-function mutation in TRPML3 causes the varitint-waddler phenotype, the role of TRPML3 in cellular physiology is not known. In this study, we report that TRPML3 is a prominent regulator of endocytosis, membrane trafficking and autophagy. Gradient fractionation and confocal localization reveal that TRPML3 is expressed in the plasma membrane and multiple intracellular compartments. However, expression of TRPML3 is dynamic, with accumulation of TRPML3 in the plasma membrane upon inhibition of endocytosis, and recruitment of TRPML3 to autophagosomes upon induction of autophagy. Accordingly, overexpression of TRPML3 leads to reduced constitutive and regulated endocytosis, increased autophagy and marked exacerbation of autophagy evoked by various cell stressors with nearly complete recruitment of TRPML3 into the autophagosomes. Importantly, both knockdown of TRPML3 by siRNA and expression of the channel-dead dominant negative TRPML3(D458K) have a reciprocal effect, reducing endocytosis and autophagy. These findings reveal a prominent role for TRPML3 in regulating endocytosis, membrane trafficking and autophagy, perhaps by controlling the Ca(2+) in the vicinity of cellular organelles that is necessary to regulate these cellular events.


Protein 2A is not required for Theiler's virus replication.
Nonpolar mutations were introduced into all 12 regions of the genome of Theiler's murine encephalomyelitis virus. In agreement with data previously reported for other picornaviruses, mutations in regions 2B, 2C, 3A, 3B, 3C, and 3D totally abrogated viral RNA replication. Viruses with deletions in each of the capsid proteins retained RNA replication proficiency, although they were unable to propagate from cell to cell. As reported previously, mutations in the leader protein did not impair RNA replication or virus production in BHK-21 cells. Surprisingly, region 2A also appeared to be dispensable for the replication process. Indeed, up to 77 of the 133 amino acids of 2A could be deleted without significantly affecting RNA replication. 2A mutant viruses had only a slow cytopathic effect for BHK-21 cells and were totally avirulent for mice. As was the case for mutants lacking the leader protein, viruses with deletions in 2A propagated in BHK-21 cells, but their propagation was highly restricted in L929 cells.


The mechanics behind DNA sequence-dependent properties of the nucleosome.
Chromatin organization and composition impart sophisticated regulatory features critical to eukaryotic genomic function. Although DNA sequence-dependent histone octamer binding is important for nucleosome activity, many aspects of this phenomenon have remained elusive. We studied nucleosome structure and stability with diverse DNA sequences, including Widom 601 derivatives with the highest known octamer affinities, to establish a simple model behind the mechanics of sequence dependency. This uncovers the unique but unexpected role of TA dinucleotides and a propensity for G|C-rich sequence elements to conform energetically favourably at most locations around the histone octamer, which rationalizes G|C% as the most predictive factor for nucleosome occupancy in vivo. In addition, our findings reveal dominant constraints on double helix conformation by H3-H4 relative to H2A-H2B binding and DNA sequence context-dependency underlying nucleosome structure, positioning and stability. This provides a basis for improved prediction of nucleosomal properties and the design of tailored DNA constructs for chromatin investigations.


Small-animal whole-body photoacoustic tomography: a review.
With the wide use of small animals for biomedical studies, in vivo small-animal whole-body imaging plays an increasingly important role. Photoacoustic tomography (PAT) is an emerging whole-body imaging modality that shows great potential for preclinical research. As a hybrid technique, PAT is based on the acoustic detection of optical absorption from either endogenous tissue chromophores, such as oxyhemoglobin and deoxyhemoglobin, or exogenous contrast agents. Because ultrasound scatters much less than light in tissue, PAT generates high-resolution images in both the optical ballistic and diffusive regimes. Using near-infrared light, which has relatively low blood absorption, PAT can image through the whole body of small animals with acoustically defined spatial resolution. Anatomical and vascular structures are imaged with endogenous hemoglobin contrast, while functional and molecular images are enabled by the wide choice of exogenous optical contrasts. This paper reviews the rapidly growing field of small-animal whole-body PAT and highlights studies done in the past decade.


Saccadic fatigability in the oculomotor system.
Fatigue is one of the most common and disabling symptoms in multiple sclerosis (MS), but challenging to quantify. This prospective study investigated if repeated saccadic eye movements enable measurement of oculomotor fatigability and can reflect on perceived fatigue in MS. A standardized infrared oculography protocol (DEMoNS) was used for quantifying saccades in MS patients and healthy controls which included a first and a repeated pro-saccadic task (FPT and RPT). Saccadic peak velocity, latency, gain, area under the curve (AUC) and peak velocity divided by amplitude (Pv/Am) were calculated in both tasks. Perception based fatigue was assessed using the Checklist Individual Strength and the Neurological Fatigue Index (NFI). Linear regression models were used for assessing the relation between saccadic parameters and perceived fatigue. This study included 181 MS patients and 58 healthy controls subjects. From FPT to RPT, there were significant changes in saccadic parameters. Latency of both tasks was significantly related to NFI summary score (FPT: β = 0.022, p = .049, RPT: β 0.023, p = .021). These relationships were weakened after adjustment for Expanded Disability Status score (p > .05). There was however no significant group difference in changes in saccadic parameters. This study presents an objective and reproducible method for measuring saccadic fatigability. Saccadic fatigability was found to be of limited use in MS, and should be tested in conditions affecting ocular muscles or the neuromuscular junction.


Concepts in psoriasis: psoriasis and the extracellular matrix.
Post-streptococcal guttate psoriasis only sometimes progresses to the persistent plaque psoriasis. We have previously proposed that psoriasis is driven by multiple extradomain A+ fibronectin (EDA+ FN) 'feedback loops'. The psoriasis-specific loop, the 'keratinocyte loop', depends upon expression by keratinocytes of α5β1 integrin. In normal skin, α5β1 expression is minimal or absent in resting epithelial cells, where basal cells are anchored to the laminin component of the basement membrane (via integrins α6β4 and α3β1). However, when the laminin layer is disrupted, due to wounding for instance, α5β1 is then strongly expressed by basal cells as a means for anchoring. At uninvolved skin sites in patients with psoriasis the laminin layer within the basement membrane is disrupted, with a consequential increase in the expression by basal keratinocytes of EDA+ FN and α5β1. We are postulating that in guttate psoriasis streptococcal lytic enzymes, and in particular streptokinase, may - via plasminogen activation - initiate a disruption of the laminin layer in the basement membrane. It is also possible that the expression by proliferating keratinocytes of plasminogen-activating factor might result in additional laminin digestion. The suggestion is that progression of guttate psoriasis to full-blown plaque psoriasis, or to its spontaneous resolution, is governed largely by the triggering of humoral immune responses. Thus, if streptococcal lytic enzymes are neutralized by host antibodies in advance of irreversible and lasting damage to the basement membrane of the dermal papillae, then guttate psoriasis will resolve spontaneously. In contrast, if permanent damage is induced prior to effective neutralization of the relevant bacterial toxins, then keratinocytes will become chronically destabilized. The consequence will be to liberate keratinocytes to proliferate in response to various stimuli, and to continue to elaborate plasminogen activation enzymes; the combined effect being, in concert with immunological priming, to precipitate and sustain plaque psoriasis.


Activation of the heat shock transcription factor Hsf1 is essential for the full virulence of the fungal pathogen Candida albicans.
The evolutionarily conserved heat shock transcription factor Hsf1 plays a central role in thermal adaptation in the major fungal pathogen of humans, Candida albicans. Hsf1 becomes hyperphosphorylated in response to heat shock and activates the transcription of genes with heat shock elements (HSEs) in their promoters, these genes contributing to thermal adaptation. However, the relevance of Hsf1 activation to C. albicans virulence is not clear as this pathogen is thought to be obligately associated with warm blooded animals, and this issue has not been tested because HSF1 is essential for viability in C. albicans. In this study, we demonstrate that the HSE regulon is active in C. albicans cells infecting the kidney. We also show the CE2 region of Hsf1 is required for activation and that the phosphorylation of specific residues in this domain contributes to Hsf1 activation. C. albicans HSF1 mutants that lack this CE2 region are viable. However, they are unable to activate HSE-containing genes in response to heat shock, and they are thermosensitive. Using this HSF1 CE2 deletion mutant we demonstrate that Hsf1 activation, and hence thermal adaptation, contributes significantly to the virulence of C. albicans.


Design, synthesis and evaluation of novel indole-2-carboxamides for growth inhibition of Mycobacterium tuberculosis and paediatric brain tumour cells.
The omnipresent threat of tuberculosis (TB) and the scant treatment options thereof necessitate the development of new antitubercular agents, preferably working via a novel mechanism of action distinct from the current drugs. Various studies identified the mycobacterial membrane protein large 3 transporter (MmpL3) as the target of several classes of compounds, including the indole-2-caboxamides. Herein, several indoleamide analogues were rationally designed, synthesised, and evaluated for their antitubercular and antitumour activities. Compound 8g displayed the highest activity (MIC = 0.32 μM) against the drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) H37Rv strain. This compound also exhibited high selective activity towards M. tb over mammalian cells [IC50 (Vero cells) = 40.9 μM, SI = 128], suggesting its minimal cytotoxicity. In addition, when docked into the MmpL3 active site, 8g adopted a binding profile similar to the indoleamide ligand ICA38. A related compound 8f showed dual antitubercular (MIC = 0.62 μM) and cytotoxic activities against paediatric glioblastoma multiforme (GBM) cell line KNS42 [IC50 (viability) = 0.84 μM]. Compound 8f also showed poor cytotoxic activity against healthy Vero cells (IC50 = 39.9 μM). Compounds 9a and 15, which were inactive against M. tb, showed potent cytotoxic (IC50 = 8.25 and 5.04 μM, respectively) and antiproliferative activities (IC50 = 9.85 and 6.62 μM, respectively) against KNS42 cells. Transcriptional analysis of KNS42 cells treated with compound 15 revealed a significant downregulation in the expression of the carbonic anhydrase 9 (CA9) and the spleen tyrosine kinase (SYK) genes. The expression levels of these genes in GBM tumours were previously shown to contribute to tumour progression, suggesting their involvement in our observed antitumour activities. Compounds 9a and 15 were selected for further evaluations against three different paediatric brain tumour cell lines (BT12, BT16 and DAOY) and non-neoplastic human fibroblast cells HFF1. Compound 9a showed remarkable cytotoxic (IC50 = 0.89 and 1.81 μM, respectively) and antiproliferative activities (IC50 = 7.44 and 6.06 μM, respectively) against the two tested atypical teratoid/rhabdoid tumour (AT/RT) cells BT12 and BT16. Interestingly, compound 9a was not cytotoxic when tested against non-neoplastic HFF1 cells [IC50 (viability) = 119 μM]. This suggests that an indoleamide scaffold can be fine-tuned to confer a set of derivatives with selective antitubercular and/or antitumour activities.


Anomalous Stagewise Lithiation of Gold-Coated Silicon Nanowires: A Combined In Situ Characterization and First-Principles Study.
Through a combined density functional theory and in situ scanning electron microscopy study, the effects of presence of gold (Au) spreading on the lithiation process of silicon nanowire (SiNW) were systematically examined. Different from a pristine SiNW, an Au-coated SiNW (Au-SiNW) is lithiated in three distinct stages; Li atoms are found to be incorporated preferentially in the Au shell, whereas the thin AuSi interface layer may serve as a facile diffusion path along the nanowire axial direction, followed by the prompt lithiation of the Si core in the radial direction. The underlying mechanism of the intriguing stagewise lithiation behavior is explained through our theoretical analysis, which appears well-aligned with the experimental evidence.


Subjective expansion of extended time-spans in experienced meditators.
Experienced meditators typically report that they experience time slowing down in meditation practice as well as in everyday life. Conceptually this phenomenon may be understood through functional states of mindfulness, i.e., by attention regulation, body awareness, emotion regulation, and enhanced memory. However, hardly any systematic empirical work exists regarding the experience of time in meditators. In the current cross-sectional study, we investigated whether 42 experienced mindfulness meditation practitioners (with on average 10 years of experience) showed differences in the experience of time as compared to 42 controls without any meditation experience matched for age, sex, and education. The perception of time was assessed with a battery of psychophysical tasks assessing the accuracy of prospective time judgments in duration discrimination, duration reproduction, and time estimation in the milliseconds to minutes range as well with several psychometric instruments related to subjective time such as the Zimbardo Time Perspective Inventory, the Barratt Impulsivity Scale and the Freiburg Mindfulness Inventory. In addition, subjective time judgments on the current passage of time and retrospective time ranges were assessed. While subjective judgements of time were found to be significantly different between the two groups on several scales, no differences in duration estimates in the psychophysical tasks were detected. Regarding subjective time, mindfulness meditators experienced less time pressure, more time dilation, and a general slower passage of time. Moreover, they felt that the last week and the last month passed more slowly. Overall, although no intergroup differences in psychophysical tasks were detected, the reported findings demonstrate a close association between mindfulness meditation and the subjective feeling of the passage of time captured by psychometric instruments.


Accelerated wound repair, cell proliferation, and collagen accumulation are produced by a cartilage-derived growth factor.
Cartilage-derived growth factor (CDGF), a cationic polypeptide of approximately 18,000 mol wt, was prepared from bovine articular cartilage; other sources were bovine and human scapular and costal cartilage. Previous studies have shown that CDGF stimulates the proliferation of cultured mouse fibroblasts as well as chondrocytes and endothelial cells from various sources. In this study, CDGF was shown to stimulate dose-dependently the accumulation of DNA and collagen by rat embryo fibroblasts and a population of fibroblasts derived from granulation tissue. CDGF also stimulated the proliferation of cultured bovine capillary endothelial cells dose-dependently. To evaluate the effects of CDGF in vivo, we implanted polyvinyl alcohol sponges subcutaneously in rats. 6 d postimplantation, sponges were injected with 300 micrograms of partially purified CDGF, a dose which takes into account the cell numbers in the sponges as compared with cell cultures. CDGF rapidly disappeared from the sponges and only approximately 10% of the initial dose was present at 4 h. Despite its transient presence, CDGF caused a relative increase in sponge DNA content of 2.6-fold at 48 h and 2.4-fold at 72 h. We repeated the sponge experiment by using 500-ng injections of CDGF purified to near homogeneity by heparin-Sepharose chromatography. Purified CDGF caused significant increases in sponge collagen, protein, and DNA content at 48 and 72 h after a single injection. The effects of CDGF were abolished by heat and unaffected by reduction of disulfide linkages. Morphologically, CDGF did not evoke an inflammatory response, and its effect on proliferating endothelial cells and fibroblasts was, therefore, probably direct. However, increases in DNA content of sponges could not be fully accounted for by increased DNA synthesis, which suggests that recruitment may be an important component of the in vivo response. Taken together, the effects of CDGF on cultured cells and granulation tissue suggest that the sustained presence of CDGF in vivo may greatly enhance its effects upon wound repair.


Groshong PICC and home care: an opportunity. Clinical experience after the first 200 implants.
Peripherally Inserted Central Catheters (PICC) represent an alternative for critical patient care, and are safer to implant in home patients. The authors report on their experience with the first 200 4 Fr Groshong PICC implanted during the last 18 months. The procedure can be easily applied at home (98% successful implant rate), without the need for fluoroscopic or ultrasound guidance. Moreover, the authors believe that the X-ray control after implant is not strictly necessary. After 11,570 days/catheters, only 5 devices were explanted because of complications: 4 because of sepsis and peripheral phlebitis, and the last was explanted by another medical staff for unclear reasons. The complications needing no explanation were a total of 32: for 12 of them the external portion of tube was damaged during use, while for the other 20 the internal clots were resolved with forced flushing. The authors conclude that Groshong PICC can be considered the gold standard for home care management of critical patients, taking into account the quality of pure silicon, the presence of a valve and the specially-made closed-tip.


Gender specific pattern of left ventricular cardiac adaptation to hypertension and obesity in a tertiary health facility in Nigeria.
Cardiac adaptation to hypertension and obesity may be related to many factors such as race, gender and haemodynamic status. Some gender specific associations with left ventricular structure and function have been described among Caucasians. To describe the sex specific pattern of left ventricular adaptations to obesity and hypertension among Nigerians. It was a cross sectional study carried out at LAUTECH Teaching Hospital, Osogbo, Nigeria. 313 subjects had full echocardiography performed. Participants were divided into four groups: normal, obese, hypertensives and obese-hypertensives. Indices of LV adaptation were compared between the groups. SPSS 16.0 was used for analysis. Relative to normal subjects, LV mass (LVM), LV mass index (LVMI) and wall thickness were significantly higher among hypertensive men and obese hypertensive men. They were similar between normal and obese men. However, LVM, LVMI and wall thickness were increased among obese women compared to normal women while they were similar among obese, hypertensive and obese-hypertensive women. Men with concurrent obesity and hypertension presented with a further increase of LVM and wall thickness above values in the merely obese or hypertensive subjects. Female obese-hypertensive seem to present more with eccentric hypertrophy than male obese-hypertensive subjects (17.2% vs. 9.1% respectively, p<0.05) while male obese-hypertensive seem to present more with concentric hypertrophy (54.5% vs. 43.1% respectively, p>0.05) than female obese-hypertensive subjects. Structural, functional and geometric LV adaptation to obesity and hypertension varies between the two genders among Nigerians. The impact of isolated obesity on LV adaptation in women appears very significant.


C11ORF24 is a novel type I membrane protein that cycles between the Golgi apparatus and the plasma membrane in Rab6-positive vesicles.
The Golgi apparatus is an intracellular compartment necessary for post-translational modification, sorting and transport of proteins. It plays a key role in mitotic entry through the Golgi mitotic checkpoint. In order to identify new proteins involved in the Golgi mitotic checkpoint, we combine the results of a knockdown screen for mitotic phenotypes and a localization screen. Using this approach, we identify a new Golgi protein C11ORF24 (NP_071733.1). We show that C11ORF24 has a signal peptide at the N-terminus and a transmembrane domain in the C-terminal region. C11ORF24 is localized on the Golgi apparatus and on the trans-Golgi network. A large part of the protein is present in the lumen of the Golgi apparatus whereas only a short tail extends into the cytosol. This cytosolic tail is well conserved in evolution. By FRAP experiments we show that the dynamics of C11ORF24 in the Golgi membrane are coherent with the presence of a transmembrane domain in the protein. C11ORF24 is not only present on the Golgi apparatus but also cycles to the plasma membrane via endosomes in a pH sensitive manner. Moreover, via video-microscopy studies we show that C11ORF24 is found on transport intermediates and is colocalized with the small GTPase RAB6, a GTPase involved in anterograde transport from the Golgi to the plasma membrane. Knocking down C11ORF24 does not lead to a mitotic phenotype or an intracellular transport defect in our hands. All together, these data suggest that C11ORF24 is present on the Golgi apparatus, transported to the plasma membrane and cycles back through the endosomes by way of RAB6 positive carriers.


Anticancer and antitumor potential of fucoidan and fucoxanthin, two main metabolites isolated from brown algae.
Seaweed is one of the largest producers of biomass in marine environment and is a rich arsenal of active metabolites and functional ingredients with valuable beneficial health effects. Being a staple part of Asian cuisine, investigations on the crude extracts of Phaeophyceae or brown algae revealed marked antitumor activity, eliciting a variety of research to determine the active ingredients involved in this potential. The sulfated polysaccharide of fucoidan and carotenoid of fucoxanthin were found to be the most important active metabolites of brown algae as potential chemotherapeutic or chemopreventive agents. This review strives to provide detailed account of all current knowledge on the anticancer and antitumor activity of fucoidan and fucoxanthin as the two major metabolites isolated from brown algae.


Liver transient elastography (Fibroscan): a place in the management algorithms of chronic viral hepatitis.
Treatment guidelines are continuously evolving in chronic viral hepatitis, taking into consideration our greater understanding of natural history and therapeutic efficacy and safety. Key in the decision making process is an assessment of liver injury. Traditionally, liver biopsy has provided this information; however, this is an invasive procedure and not completely reliable. Liver transient elastography (Fibroscan) is exciting new technology that allows estimation of hepatic fibrosis through measurement of liver stiffness. It is acceptably accurate, safe, cheap, quick and widely applicable, and can reduce the need for liver biopsy in chronic hepatitis. In chronic hepatitis C, it can identify those most likely to benefit from treatment, as well as those with cirrhosis who require more specific care. In chronic hepatitis B, it could screen groups previously excluded from treatment (normal alanine aminotransferase and low DNA) to identify the subgroup that would benefit from therapy. It cannot replace biopsy in all settings, but it will narrow the group who do require biopsy, and provide information on liver damage in patients for whom biopsy would probably not have been considered.


C2orf37 mutational spectrum in Woodhouse-Sakati syndrome patients.
Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder that encompasses hypogonadism, deafness, alopecia, mental retardation, diabetes mellitus and progressive extrapyramidal defects. The syndrome is caused by mutation of the C2orf37 gene. Here we studied a cohort of seven new cases from three ethnic backgrounds, presenting with the hallmarks of WSS, in an effort to extend the mutational spectrum of this disorder. Genetic analysis revealed a novel mutation in each of the four families investigated, of which three were nonsense mutations and the fourth was a splice site ablation. We also examined a separate collection of 11 cases presenting with deafness and dystonia, two constituents of WSS, but found no pathogenic changes. This study doubles the number of known mutations for this disorder, confirms that truncating mutations in C2orf37 are the only known cause of WSS, and suggests that mutations in this gene do not contribute significantly to cases presenting with isolated elements of WSS such as deafness and dystonia. The lack of correlation between clinically expressivity of WSS and the site of the eight truncating mutations strongly supports that they are equally null, while the intrafamilial variability argues for an important role of modifiers in this disease.


Evaluation of medical supplies essential for the care of survivors of sex- and gender-based violence in post-conflict Eastern Democratic Republic of Congo.
The fundamental concepts set forth in the formal Post-Conflict Needs Assessment (PCNA) initiative created by the United Nations Development Group have the potential to be adapted to assist local groups in documenting the needs of and the provision of health care to survivors of sex- and gender-based violence (SGBV) in Eastern Democratic Republic of Congo (DRC). In partnership with Congolese health care providers, we took the first step in advocating for a locally-adapted and focused needs assessment through the development and administration of surveys to providers in the South Kivu Province, DRC. The content of the surveys was largely based on lists of medical supplies deemed essential for reproductive health and for the care of survivors by the Reproductive Health Response in Crises Consortium. The providers in both urban and rural settings considered many of the supplies identified on the surveys necessary for the care of survivors (84%; p < 0.05) but considered few accessible (26%; p < 0.05) in their particular clinical settings. Providers also felt that the existing list of supplies was inadequate to meet the needs of survivors, and also that providers needed ongoing training to improve supply procurement and management, more knowledge of the needs of male survivors of SGBV, and more educational opportunities to improve the quality of care to survivors. Given the deficiencies expressed by providers in the surveys, this study demonstrated a critical need for a locally-adapted and focused needs assessment to improve health services to survivors.


Home-measured blood pressure is more strongly associated with electrocardiographic left ventricular hypertrophy than is clinic blood pressure: the Finn-HOME study.
Electrocardiographic evidence of left ventricular hypertrophy (ECG-LVH) has a grave prognostic significance in hypertensive patients. The purpose of our study was to assess whether ECG-LVH is more strongly associated with home-measured blood pressure (BP) than with clinic BP, and whether the correlation between home BP and ECG-LVH increases with the number of home measurements performed. We studied a representative sample of the general adult population (1989 subjects 45-74 years of age) in Finland. Subjects included in the study underwent a clinical interview, electrocardiography and measurement of clinic BP (mean of two clinic measurements) and home BP (mean of 14 duplicate home measurements performed during 1 week). Home BP correlated significantly better than clinic BP with the Sokolow-Lyon voltage (home/clinic systolic: r=0.23/0.22, P=0.60; diastolic: r=0.17/0.12, P=0.009), Cornell voltage (systolic: r=0.30/0.25, P=0.004; diastolic: r=0.21/0.12, P<0.001) and Cornell product (systolic: r=0.30/0.24, P=0.001; diastolic r=0.22/0.14, P<0.001) criteria of ECG-LVH. The correlation between home BP and ECG-LVH increased slightly with the number of home measurements, but even the mean of the initial two home BP measurements correlated equally well (systolic BP), or better (diastolic BP) with ECG-LVH than did clinic BP. In conclusion, home BP measurement allows us to obtain a large number of measurements that have a strong association with ECG-LVH. Our data support the application of home BP measurement in clinical practice.


COPD patients hospitalized with exacerbations have greater cognitive impairment than patients hospitalized with decompensated heart failure.
People with COPD have cognitive dysfunction, which is greater in those hospitalized for exacerbations than in stable outpatients. We tested the hypothesis that cognitive dysfunction at exacerbation is a disease-specific feature of COPD, rather than a nonspecific feature of hospitalization for acute illness, by comparing cognition between patients hospitalized for acute COPD exacerbations and those with worsening heart failure (HF). A total of 40 hospital inpatients were recruited, 20 patients with COPD exacerbations and 20 patients with congestive or left-sided HF. Exclusion criteria included previous stroke, known neurological disease, and marked alcohol excess. Participants completed the Montreal cognitive assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) and underwent spirometry and review of clinical records. Age (mean±SD, COPD 73±10; HF 76±11 years), acute illness severity (Acute Physiology and Chronic Health Evaluation [APACHE]-II, COPD 15.4±3.5; HF 15.9±3.0), comorbidities (Charlson index, COPD 1.3±1.9; HF 1.6±1.5), and educational background were similar between COPD and HF groups. MoCA total was significantly lower in COPD than in HF (COPD 20.6±5.6; HF 24.8±3.5, P=0.007); however, significance was lost after correction for age, sex, and pack year smoking history. When compared with HF patients, the COPD cohort performed worse on the following domains of the MoCA: visuospatial function (median [IQR], COPD 0 [1]; HF 2 [1], P=0.003), executive function (COPD 2 [1]; HF 3 [1], P=0.035), and attention (COPD 4 [3]; HF 6 [2], P=0.020). Age (P=0.012) and random glucose concentration (P=0.041) were associated with cognitive function in whole group analysis, with pack year smoking history reaching borderline significance (P=0.050). Total MoCA score for COPD and HF indicated that both groups had mild cognitive impairment, although this was greater in people with COPD. Mechanisms underlying the observed cognitive dysfunction in COPD remain unclear but appear related to blood glucose concentrations and greater lifetime smoking load.


Displaced Physeal and Metaphyseal Fractures of Distal Radius in Children. Can Wire Fixation Achieve Better Outcome at Skeletal Maturity than Cast Alone?
Redisplacement following fracture reduction is a known sequela during the casting period in children treated for distal radius fracture. Kirschner wire pinning can be alternatively used to maintain the reduction during fracture healing. This study was conducted to compare the outcomes at skeletal maturity of distal radius fractures in children treated with a cast alone or together with a Kirschner wire transfixation. This was a retrospective study involving 57 children with metaphyseal and physeal fractures of the distal radius. There were 30 patients with metaphyseal fractures, 19 were casted, and 11 were wire transfixed. There were 27 patients with physeal fractures, 19 were treated with a cast alone, and the remaining eight underwent pinning with Kirschner wires. All were evaluated clinically, and radiologically, and their overall outcome assessed according to the scoring system, at or after skeletal maturity, at the mean follow-up of 6.5 years (3.0 to 9.0 years). In the metaphysis group, patients treated with wire fixation had a restriction in wrist palmar flexion (p=0.04) compared with patients treated with a cast. There was no radiological difference between cast and wire fixation in the metaphysis group. In the physis group, restriction of motion was found in both dorsiflexion (p=0.04) and palmar flexion (p=0.01) in patients treated with wire fixation. There was a statistically significant difference in radial inclination (p=0.01) and dorsal tilt (p=0.03) between cast and wire fixation in physis group with a more increased radial inclination in wire fixation and a more dorsal tilt in patients treated with a cast. All patients were pain-free except one (5.3%) in the physis group who had only mild pain. Overall outcomes at skeletal maturity were excellent and good in all patients. Grip strength showed no statistical difference in all groups. Complications of wire fixation included radial physeal arrests, pin site infection and numbness. Cast and wire fixation showed excellent and good outcomes at skeletal maturity in children with previous distal radius fracture involving both metaphysis and physis. We would recommend that children who are still having at least two years of growth remaining be treated with a cast alone following a reduction unless there is a persistent unacceptable reduction warranting a wire fixation. The site of the fracture and the type of treatment have no influence on the grip strength at skeletal maturity.


Increased interleukin-4 and decreased interferon-gamma in exhaled breath condensate of children with asthma.
Exhaled breath condensate analysis for noninvasive quantification of airway inflammation in asthma is a potentially useful research tool in children. There is an imbalance between T-helper (Th)-2 cells, which secrete interleukin (IL)-4, and Th1 cells, which secrete interferon (IFN)-gamma, in asthma. We measured concentrations of IL-4 and IFN-gamma in breath condensates of 37 children (11 normal, 12 steroid-naive, and 14 steroid-treated children with asthma). Exhaled IFN-gamma was significantly lower in steroid-naive and steroid-treated children with asthma compared with normal control subjects (3.7 +/- 0.2 versus 5.1 +/- 0.4 pg/ml, p < 0.01 and 4.1 versus 5.1 pg/ml, p < 0.05). By contrast, mean exhaled IL-4 was elevated in asthma (53.7 +/- 4.2 pg/ml) compared with normal children (35.7 +/- 6.2 pg/ml, p < 0.05) and concentrations were lower with steroid treatment (37.5 +/- 5.6 pg/ml, p < 0.05). Exhaled IL-4 was significantly lower in children with asthma on more than 600 microg inhaled steroid/day. The IL-4/IFN-gamma ratio was significantly greater in children with asthma compared with control children and the children with asthma on inhaled steroid therapy. We have shown for the first time that IFN-gamma and IL-4 can be assayed in exhaled breath condensate and shows an increased ratio of IL-4/IFN-gamma, consistent with predominance of Th2 cells in airways of children with asthma. Exhaled breath condensate analysis may have a useful role in studying allergic inflammation in childhood asthma.


Enhancing cue salience improves aspects of naturalistic time-based prospective memory in older adults with HIV disease.
Older persons living with HIV (PLWH) disease commonly experience failures of time-based prospective memory (PM) in their daily lives. This study examined the benefits of providing strategic supports at encoding, monitoring, and cue detection for naturalistic time-based PM among older PLWH. Participants included 116 older PLWH and 48 seronegatives who completed a baseline neuropsychological evaluation (see Woods et al., 2020), including a laboratory PM experiment that paralleled the design of the current naturalistic study. The naturalistic time-based PM task required participants to press a button on a portable PM response box 4 times per day for 1 month. PLWH were randomly assigned to an unsupported control condition or to an experimental group in which strategic processing was supported at encoding (implementation intentions and visualization), monitoring (content-free cuing), and/or cue detection (auditory alarm). The seronegative participants were all assigned to the unsupported control group. In a model adjusting for age and affective disorders, PLWH who received all three supports in combination demonstrated moderately better naturalistic time-based PM accuracy as compared with PLWH controls. Both the cue detection and combination conditions were associated with markedly more precise response timing on the naturalistic time-based PM task. Supported PM accuracy as measured in the laboratory was positively associated with naturalistic PM accuracy among PLWH in the experimental groups. Providing strategic supports to enhance the cue salience of naturalistic time-based PM tasks may improve both the accuracy and timing with which older PLWH remember to perform time-based intentions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Frequent methylation silencing of p15(INK4b) (MTS2) and p16(INK4a) (MTS1) in B-cell and T-cell lymphomas.
The methylation status of p15(INK4b) (MTS2), p16(INK4a) (MTS1) and p14(ARF) (p16beta) was analyzed in 56 lymphomas by restriction-enzyme related polymerase chain reaction (PCR) (REP), methylation-specific PCR (MSP), and bisulfite genomic sequencing (BGS). Methylation of the p15 and p16 genes was detected, respectively, in 64% and 32% of the B-cell lymphomas, in 44% and 22% of the T-cell lymphomas, and in none of the 5 reactive lymph nodes analyzed. Both p15 and p16 genes were methylated more often in the high-grade (78% and 50%, respectively) than in the low-grade B-cell lymphomas (55% and 21%, respectively). For 5 cases, mapping of the methylated CpGs of the p16 promoter region confirmed the results of REP and MSP. In addition, a large variation in the methylation patterns of p16 exon 1 was observed, not only from one lymphoma to another, but also within a given tumor. Methylation of p15 and p16 was associated with an absence of gene expression, as assessed by reverse transcription-PCR. The p14 gene was unmethylated and normally expressed in all 56 tumors. We found no mutations of p15, p16, or p14 in any of the 56 lymphomas. Our results suggest a role for p15 and p16 gene methylation during lymphomagenesis and a possible association between p15 and p16 inactivation and aggressive transformation in B-cell and T-cell lymphomas.


Tissue cytokine responses in canine visceral leishmaniasis.
To elucidate the local tissue cytokine response of dogs infected with Leishmania chagasi, cytokine mRNA levels were measured in bone marrow aspirates from 27 naturally infected dogs from Brazil and were compared with those from 5 uninfected control animals. Interferon-gamma mRNA accumulation was enhanced in infected dogs and was positively correlated with humoral (IgG1) but not with lymphoproliferative responses to Leishmania antigen in infected dogs. Increased accumulation of mRNA for interleukin (IL)-4, IL-10, and IL-18 was not observed in infected dogs, and mRNA for these cytokines did not correlate with antibody or proliferative responses. However, infected dogs with detectable IL-4 mRNA had significantly more severe symptoms. IL-13 mRNA was not detectable in either control or infected dogs. These data suggest that clinical symptoms are not due to a deficiency in interferon-gamma production. However, in contrast to its role in human visceral leishmaniasis, IL-10 may not play a key immunosuppressive role in dogs.


Topical hexylaminolevulinate and aminolevulinic acid photodynamic therapy: complete arteriole vasoconstriction occurs frequently and depends on protoporphyrin IX concentration in vessel wall.
Vascular responses to photodynamic therapy (PDT) may influence the availability of oxygen during PDT and the extent of tumor destruction after PDT. However, for topical PDT vascular effects are largely unknown. Arteriole and venule diameters were measured before and after hexylaminolevulinate (HAL) and aminolevulinic acid (ALA) PDT and related to the protoporphyrin IX (PpIX) concentration in the vessel wall. A mouse skin fold chamber model and an intravital confocal microscope allowed direct imaging of the subcutaneous vessels underlying the treated area. In both HAL and ALA groups over 60% of arterioles constricted completely, while venules generally did not respond, except for two larger veins that constricted partially. Arteriole vasoconstriction strongly correlated with PpIX fluorescence intensity in the arteriole wall. Total PpIX fluorescence intensity was significantly higher for HAL than ALA for the whole area that was imaged but not for the arteriole walls. In conclusion, complete arteriole vasoconstriction occurs frequently in both HAL and ALA based topical PDT, especially when relatively high PpIX concentrations in arteriole walls are reached. Vasoconstriction will likely influence PDT effect and should be considered in studies on topical HAL and ALA-PDT. Also, our results may redefine the vasculature as a potential secondary target for topical PDT.


A novel targeted therapy of Leydig and granulosa cell tumors through the luteinizing hormone receptor using a hecate-chorionic gonadotropin beta conjugate in transgenic mice.
We investigated the antitumoral efficacy, endocrine consequences, and molecular mechanisms underlying cell death induced by the Hecate-chorionic gonadotropin (CG)beta conjugate, a fusion protein of a 23-amino acid lytic peptide Hecate with a 15-amino acid (81-95) fragment of the human CGbeta chain. Transgenic (TG) mice expressing the inhibin alpha-subunit promoter (inhalpha)/Simian Virus 40 T-antigen (Tag) transgene, developing luteinizing hormone (LH) receptor (R) expressing Leydig and granulosa cell tumors, and wild-type control littermates were treated either with vehicle, Hecate, or Hecate-CGbeta conjugate for 3 weeks. Hecate-CGbeta conjugate treatment reduced the testicular and ovarian tumor burden (P < .05), whereas a concomitant increase (testis; P < .05) or no change (ovary) in tumor volumes occured with Hectate treatment. A drop in serum progesterone, produced by the tumors, and an increase in LH levels occured in Hecate-CGbeta treated mice, in comparison with vehicle and Hecate groups, providing further support for the positive treatment response. Hecate-CGbeta conjugate induced a rapid and cell-specific membrane permeabilization of LHR-expressing cells in vitro, suggesting a necrotic mode of cell death without activation of apoptosis. These results prove the principle that the Hecate-CGbeta conjugate provides a novel specific lead into gonadal somatic cell cancer therapy by targeted destruction of LHR-expressing tumor cells.


IL-15 sustains IL-7R-independent ILC2 and ILC3 development.
The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra-/- mice. Il7ra-/- ILC2 primarily express an ST2- phenotype, but are not inflammatory ILC2. CCR6+ ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra-/- siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra-/- ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling.