Text Messaging for Improving Antiretroviral Therapy Adherence: No Effects After 1 Year in a Randomized Controlled Trial Among Adolescents and Young Adults.
To assess the effectiveness of Short Message Service (SMS) reminder messages on antiretroviral and cotrimoxazole prophylaxis adherence among HIV-positive youths as well as the relative effectiveness of SMS with and without a response option. Eligible HIV-positive patients aged 15 to 22 years at 2 HIV clinics in Kampala, Uganda, participated in a year-long parallel individual-randomized controlled trial and were assigned in a 1-to-1-to-1 ratio to a weekly SMS message group, weekly SMS message with response option group, or a usual-care control group. We enrolled 332 participants. Electronically measured mean adherence was 67% in the control group, 64% in the 1-way SMS group (95% confidence interval [CI] = 0.77, 1.14), and 61% in the 2-way SMS group (95% CI = 0.75, 1.12) in an intent-to-treat analysis. Results for secondary outcomes and complete-case analysis were similarly statistically insignificant across groups. Despite previous evidence that interventions using SMS reminders can promote antiretroviral therapy adherence, this study shows that they are not always effective in achieving behavior change. More research is needed to find out for whom, and under what conditions, they can be beneficial. ClinicalTrials.gov identifier: NCT00830622.


Highly Expandable Foam for Lithographic 3D Printing.
In modern manufacturing, it is a widely accepted limitation that the parts patterned by an additive or subtractive manufacturing process (i.e., a lathe, mill, or 3D printer) must be smaller than the machine itself that produced them. Once such parts are manufactured, they can be postprocessed, fastened together, welded, or adhesively bonded to form larger structures. We have developed a foaming prepolymer resin for lithographic additive manufacturing, which can be expanded after printing to produce parts up to 40× larger than their original volume. This allows for the fabrication of structures significantly larger than the build volume of the 3D printer that produced them. Complex geometries comprised of porous foams have implications in technologically demanding fields such as architecture, aerospace, energy, and biomedicine. This manuscript presents a comprehensive screening process for resin formulations, detailed analysis of printing parameters, and observed mechanical properties of the 3D-printed foams.


Anti-hypertensive drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies and clinical trials.
Current treatment for Parkinson's disease (PD) is focused on relieving symptoms, at present there is nothing that is widely accepted to halt or slow disease progression. Potential neuroprotective or disease modifying agents have been identified from preclinical studies. One such group of compounds are anti-hypertensive drugs. 1) Do anti-hypertensive drugs prevent the onset of PD? (primary prevention)2) Are anti-hypertensive drugs disease modifying agents in PD, do they slow the progression of disease once PD is established? (secondary prevention)3) What are the adverse effects of taking anti-hypertensive drugs for patients with PD? Electronic databases including trial registers were searched, complemented with handsearching of conference proceedings and searching the citations of key articles (updated May 2011). Authors were contacted, to provide additional information, where necessary. For the primary prevention review, primary prevention trials and observational studies (cohort and case control studies) were sought. Participants were free of PD when exposure to anti-hypertensive drugs was assessed. For the secondary prevention review, clinical trials in patients with well defined PD were sought. Two people independently selected studies for inclusion using predetermined criteria. Data were abstracted from the source papers and methodological quality was assessed independently by two review authors. Results for both reviews were dealt with descriptively. Two cohort studies and four case control studies met the inclusion criteria for the primary prevention review. The two cohort studies found no effect of exposure to calcium channel blockers on the risk of developing PD. Three case control studies looked at the effects of exposure to calcium channel blockers and beta blockers on the risk of developing PD but the assessment periods of exposure were markedly different prior to PD onset, and different subclasses of drugs were examined, so results were not comparable. A protective effect of centrally acting calcium channel blockers was found in one study.Two trials and one ongoing trial met the inclusion criteria for the secondary prevention review. Each completed trial examined a different class of anti-hypertensive drug. The ongoing trial is examining the effects of the calcium channel blocker isradipine on motor symptoms and disease progression. It follows an earlier tolerability study. The results are due in the year 2012.Adverse effects were noted in all included trials and included intolerability to the drugs and worsening PD symptoms. There is currently a lack of evidence for the use of antihypertensive drugs for either the primary or secondary prevention of PD. More observational studies are required to identify potential drugs to go forward for safety and tolerability studies in people with early PD. The results of the ongoing trial will help inform further research.


A Critical Assessment of Diagnostic Criteria for the Tall Cell Subtype of Papillary Thyroid Carcinoma-How Much? How Tall? And When Is It Relevant?
Tall cell papillary thyroid carcinoma (TC-PTC) is considered adverse histology. However, previous studies are confounded by inconsistent criteria and strong associations with other adverse features. It is therefore still unclear if TC-PTC represents an independent prognostic factor in multivariate analysis and, if it does, what criteria should be employed for the diagnosis. We retrospectively reviewed 487 PTCs from our institution (where we have historically avoided the prospective diagnosis of TC-PTC) for both the height of tall cells (that is if the cells were two, or three, times as tall as wide) and the percentage of tall cells. On univariate analysis, there was significantly better disease free survival (DFS) in PTCs with no significant tall cell component (< 30%) compared to PTCs with cells two times tall as wide (p = 0.005). The proportion of tall cells (30-50% and > 50%) was significantly associated with DFS (p = 0.012). In a multivariate model including age, size, vascular space invasion, and lymph node metastasis, the current WHO tall cell criteria, met by 7.8% of PTCs, lacked statistical significance for DFS (p = 0.519). However, in the subset of tumours otherwise similar to the American Thyroid Association (ATA) guidelines low-risk category, WHO TC-PTC demonstrated a highly significant reduction in DFS (p = 0.004). In contrast, in intermediate to high-risk tumours, TC-PTC by WHO criteria lacked statistical significance (p = 0.384). We conclude that it may be simplistic to think of tall cell features as being present or absent, as both the height of the cells (two times versus three times) and the percentage of cells that are tall have different clinical significances in different contexts. Most importantly, the primary clinical significance of TC-PTC is restricted to PTCs that are otherwise low risk by ATA guidelines.


Continuous Reassortment of Clade 22.214.171.124 H5N6 Highly Pathogenetic Avian Influenza Viruses Demonstrating High Risk to Public Health.
Since it firstly emerged in China in 2013, clade 220.127.116.11 H5N6 highly pathogenic avian influenza viruses (HPAIVs) has rapidly replaced predominant H5N1 to become the dominant H5 subtype in China, especially in ducks. Not only endemic in China, it also crossed the geographical barrier and emerged in South Korea, Japan, and Europe. Here, we analyzed the genetic properties of the clade 126.96.36.199 H5N6 HPAIVs with full genome sequences available online together with our own isolates. Phylogenetic analysis showed that clade 18.104.22.168 H5N6 HPAIVs continuously reassorted with local H5, H6, and H7N9/H9N2. Species analysis reveals that aquatic poultry and migratory birds became the dominant hosts of H5N6. Adaption to aquatic poultry might help clade 188.8.131.52 H5N6 better adapt to migratory birds, thus enabling it to become endemic in China. Besides, migratory birds might help clade 188.8.131.52 H5N6 transmit all over the world. Clade 184.108.40.206 H5N6 HPAIVs also showed a preference for α2,6-SA receptors when compared to other avian origin influenza viruses. Experiments in vitro and in vivo revealed that clade 220.127.116.11 H5N6 HPAIVs exhibited high replication efficiency in both avian and mammal cells, and it also showed high pathogenicity in both mice and chickens, demonstrating high risk to public health. Considering all the factors together, adaption to aquatic poultry and migratory birds helps clade 184.108.40.206 H5N6 overcome the geographical isolation, and it has potential to be the next influenza pandemic in the world, making it worthy of our attention.


[Intracerebral pressure and the EEG following graded changes in cerebrospinal fluid volume].
The effect of graded change of the CSF amount on the clinical status, intracerebral pressure and brain bioelectrical activity was studied in 31 patients operated on for brain tumors of various sites. Normally, the graded change in the CSF amount made with an object of examining the biophysical characteristics of the intracranial system did not produce the impairment of the patients status. Discomfort sensation that occurred in rare cases was not a consequence of either hypo- or hypertension as such but of the absence of CNS ability to adapt rapidly to the changes of the pressure in the cranium. The graded change in the CSF amount and thus in the CSF pressure caused minimum transitory changes in the intracerebral pressure of interstitial liquid and in brain bioelectrical activity. The data obtained indicate the feasibility of studying the biophysic characteristics of the intracranial system by means of graded changes of the CSF amount in neurosurgical patients undergoing acute postoperative period.


Drug safety aspects of herbal medicinal products.
There are numerous statements in the literature suggesting that the safety of herbal products or herbal medicinal products is inadequately considered. Despite the presence of risk, the potential is commonly underestimated as herbals are considered to be natural substances. It is necessary to consider the different categories of herbal products in the market. On one hand there are authorised herbal medicinal products (HMPs) which have adhered to the requirements to present data on quality, efficacy and safety. On the other hand there are products falling outside the use of marketing authorisations as for remedies. In the European Union (EU), HMPs are subject to an ambitious and comprehensive risk management system as for chemically defined drugs, which react effectively to risk concerns with scientific methods, as has been shown in the past. The established methods of pharmacovigilance and risk management favour the authorisation of herbal preparations for medicinal purposes as proprietary medicinal drugs.


Epigenetic Drugs for Cancer and microRNAs: A Focus on Histone Deacetylase Inhibitors.
Over recent decades, it has become clear that epigenetic abnormalities are involved in the hallmarks of cancer. Histone modifications, such as acetylation, play a crucial role in cancer development and progression, by regulating gene expression, such as for oncogenes or tumor suppressor genes. Therefore, histone deacetylase inhibitors (HDACi) have recently shown efficacy against both hematological and solid cancers. Designed to target histone deacetylases (HDAC), these drugs can modify the expression pattern of numerous genes including those coding for micro-RNAs (miRNA). miRNAs are small non-coding RNAs that regulate gene expression by targeting messenger RNA. Current research has found that miRNAs from a tumor can be investigated in the tumor itself, as well as in patient body fluids. In this review, we summarized current knowledge about HDAC and HDACi in several cancers, and described their impact on miRNA expression. We discuss briefly how circulating miRNAs may be used as biomarkers of HDACi response and used to investigate response to treatment.


NTP Toxicology and Carcinogenesis Studies of a-Methylbenzyl Alcohol (CAS No. 98-85-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
NTP Toxicology and Carcinogenesis studies of a-methylbenzyl alcohol (greater than 99% pure), a cosmetic ingredient and food flavoring agent, were conducted by administering the chemical in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. a-Methylbenzyl alcohol was nominated for study by the National Cancer Institute because of the potential for widespread human exposure. Sixteen-Day and Thirteen-Week Studies: The doses used in the 16-day studies for rats and mice ranged between 125 and 2,000 mg/kg. Six of 10 rats and all mice dosed at 2,000 mg/kg died. In addition, because 7/9 mice dosed at 1,000 mg/kg died, the doses selected for the 13-week studies for mice (47-750 mg/kg) were half those used for rats (93-1,500 mg/kg). In the 13-week studies, deaths of 1/10 male and 3/10 female rats dosed at 1,500 mg/kg were compound related; none of the mice died. Body weight gain was reduced in rats at 1,500 mg/kg; there were no significant histopathologic lesions in either rats or mice. The only compound-related effects were ataxia, labored breathing, and lethargy for up to 30 minutes after dosing in rats and mice given the two highest doses and increases in liver weight to body weight ratios for male rats given the three highest doses and for female rats at all doses. Based on the pattern of mortality and the effects on body weight gain in the short-term studies, doses of 375 and 750 mg/kg a-methylbenzyl alcohol were administered in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats and 50 mice of each sex. Two-Year Studies: Significant reduction in body weight gain commenced at weeks 20-30 in high dose male and female rats, and body weights were 20%-30% below those of vehicle controls at study termination. In the low dose groups, body weight reduction occurred only in male rats during the last 10 weeks of the study. After 80 weeks, 60% of the high dose rats and 80%-100% of the low dose and vehicle control rats were alive; thereafter, the number of deaths in the chemically exposed groups increased sharply so that, at the end of 2 years, final survival for vehicle control, low dose, and high dose rats was 35/50; 8/50; and 1/50 for males and 34/50, 25/50, and 11/50 for females. There were a large number of gavage accidents in these studies (1, 9, and 8 for male rats and 1, 4, and 14 for female rats), but these accidents did not contribute to the increase in mortality after week 80, as all but 4 of these occurred earlier. Mortality in the last quarter of the study was thought to be due to the effects of cumulative toxicity of a-methylbenzyl alcohol on a renal excretory system already compromised by aging. Renal nephropathy that commonly occurs during aging was found in all groups of rats, but the severity was greater in male rats dosed with a-methylbenzyl alcohol. In addition, a collection of nonneoplastic lesions (parathyroid hyperplasia, calcification of the heart and glandular stomach, and fibrous osteodystrophy of bone) was found in the dosed male rats; these lesions were probably secondary to mineral imbalance arising from renal dysfunction. Since survival was poor in low and high dose male and high dose female rats, the sensitivity of the study for detecting a carcinogenic effect in these groups was reduced. Despite this limitation, there were dose-related increases in the incidences of renal tubular cell adenomas or adenocarcinomas (combined) in male rats (vehicle control, 0/50; low dose, 2/50; high dose, 5/50). In addition, transitional cell papillomas of the urinary bladder were observed in one high dose male and two high dose female rats. In mice, a reduction in body weight gain was apparent in the high dose groups of males and females. Final survival rates in mice were similar among groups (male: 39/49; 40/50; 28/50; female: 41/50; 41/50; 38/50). No neoplastic or nonneoplastic lesions were attributed to a-methylbenzyl lesions were attributed to a-methylbenzyl alcohol administration in mice of either sex. Genetic Toxicology: a-Methylbenzyl alcohol was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation. a-Methylbenzyl alcohol produced a positive response without activation in the mouse L5178Y/TK+/- lymphoma assay for induction of trifluorothymidine resistance; it was not tested with activation. In cytogenetic tests with CHO cells, a-methylbenzyl alcohol induced chromosomal aberrations in the presence, but not the absence, of metabolic activation; no induction of sister chromatid exchanges was observed in CHO cells after exposure to a-methylbenzyl alcohol. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activityof a-methylbenzyl alcohol for male F344/N rats, as shown by increased incidences of renal tubular cell adenomas and adenomas or adenocarcinomas (combined). There was no evidence of carcinogenic activity for female F344/N rats administered 375 or 750 mg/kg. Renal toxicity characterized by severe nephropathy and related secondary lesions was observed in the dosed rats, and excessive mortality occurred during the last quarter of the studies. Poor survival reduced the sensitivity of the studies for detecting the presence of a carcinogenic response both in chemically exposed groups of male rats and in the high dose group of female rats. There was no evidence of carcinogenic activity of a-methylbenzyl alcohol for male or female B6C3F1 mice administered 375 or 750 mg/kg for 2 years. Synonyms: styrallyl alcohol; styralyl alcohol; a-methylbenzenemethanol; phenylmethylcarbinol; 1-phenethyl alcohol


Experimental murine candidiasis: cell-mediated immunity after cutaneous challenge.
Attempts were made to isolate an antigen(s) from Candida albicans suitable for detecting hypersensitivity in a murine model of candidiasis. Using footpad reactivity in cutaneously infected animals as the assay, comparisons were made of two commercial extracts and cell wall and cytoplasmic preparations made in the laboratory. An extract of the cell wall, a glycoprotein (GP) removed with ethylenediamine, and an extract prepared from the membrane fraction of disrupted C. albicans blastospores proved most useful in demonstrating delayed hypersensitivity in the murine model. The activity of the GP fraction was considerably reduced by oxidation with periodate and was abrogated entirely by digestion with proteolytic enzymes. The extract from the membrane fraction was obtained by incubating the insoluble membrane fraction with phosphate-buffered saline, pH 7.4, at 50 degrees C, and the proteins in the extract were subsequently precipitated with ammonium sulfate to yield a test preparation that was approximately 75% protein and 25% carbohydrate. The precipitated extract was designated ppt-HEX. Footpad reactivity to ppt-HEX could be transferred with cells and not with serum if the cells were taken from animals at the appropriate time after sensitization. Since the membrane and GP fractions appear to elicit true delayed hypersensitivity reactions, further investigations into their specificity and biochemistry seem warranted.


Cloning and expression of the imipenem-hydrolyzing beta-lactamase operon from Pseudomonas maltophilia in Escherichia coli.
The L-1 penicillinase structural gene, blaS, from Pseudomonas maltophilia has been cloned into the vector pACYC184. The pMON01 recombinant plasmid selected by ampicillin resistance carried a 2.6-kilobase Sau3A fragment of P. maltophilia DNA and was confirmed to express L-1 beta-lactamase by comparative isoelectric focusing. A detailed physical map was constructed, and the blaS structural gene was localized with a 17-mer oligonucleotide mixed probe encoding the L-1 N-terminal amino acid sequence. Induction studies confirmed constitutive expression. Isolation of a complete beta-lactamase operon was attempted by construction of a P. maltophilia genomic library into phage lambda 2001. A recombinant phage was selected by DNA hybridization, and the 13.4-kilobase DNA insert was physically mapped and subcloned into plasmid vectors. Expression and L-1 beta-lactamase synthesis were studied in Escherichia coli.


[The communicative skills of physicians in ambulatory practice].
The effectiveness of medical care in most cases depends on the quality of information exchange between patient and physician. The knowledge of communicative skills makes it possible for physician to settle more effectively the curative diagnostic and organizational issues in the process of providing medical care to patients. The information support and fundamental theoretical training of physicians not always correspond to modern considerations on patient-physician relationship. The long-standing traditions and profound development of theoretical issues of effective exchange of information between patient and physician provide researchers, practical physicians and teachers large possibilities in significant progressing in the field of development of communication technologies in the system of national public health system.


Flocculation of Clay-Based Tailings: Differences of Kaolin and Sodium Montmorillonite in Salt Medium.
Complex gangues and low-quality waters are a concern for the mining industries, particularly in water shortage areas, where the closure of hydric circuits and reduction in water use are essential to maintain the economic and environmental sustainability of mineral processing. This study analyzes the phenomena involved in the water recovery stage, such as sedimentation of clay-based tailings flocculated with anionic polyelectrolyte in industrial water and seawater. Flocculation-sedimentation batch tests were performed to ascertain the aggregate size distribution, the hindered settling rate, and the structure of flocs expressed through their fractal dimension and density. The aggregates' properties were characterized by the Focused Beam Reflectance Measurement (FBRM) and Particle Vision Microscope (PVM) techniques. The impact of the type of water depends on the type of clay that constitutes the suspension. For quartz/kaolin, the highest performance was obtained in industrial water, with bigger aggregates and faster settling rates. However, the tailings composed of quartz/Na-montmorillonite reversed this trend. The type of water impacted the efficiency of primary-particle aggregation. The trials in industrial water generated a portion of non-flocculated particles, which was observed through a bimodal distribution in the unweighted chord-length distribution. This behavior was not observed in seawater, where a perceptible fraction of non-flocculated particles was not found. The additional cationic bonds that offer seawater favor finer primary-particle agglomeration for all tailings types.


Selenium and the course of mild Graves' orbitopathy.
Oxygen free radicals and cytokines play a pathogenic role in Graves' orbitopathy. We carried out a randomized, double-blind, placebo-controlled trial to determine the effect of selenium (an antioxidant agent) or pentoxifylline (an antiinflammatory agent) in 159 patients with mild Graves' orbitopathy. The patients were given selenium (100 μg twice daily), pentoxifylline (600 mg twice daily), or placebo (twice daily) orally for 6 months and were then followed for 6 months after treatment was withdrawn. Primary outcomes at 6 months were evaluated by means of an overall ophthalmic assessment, conducted by an ophthalmologist who was unaware of the treatment assignments, and a Graves' orbitopathy-specific quality-of-life questionnaire, completed by the patient. Secondary outcomes were evaluated with the use of a Clinical Activity Score and a diplopia score. At the 6-month evaluation, treatment with selenium, but not with pentoxifylline, was associated with an improved quality of life (P<0.001) and less eye involvement (P=0.01) and slowed the progression of Graves' orbitopathy (P=0.01), as compared with placebo. The Clinical Activity Score decreased in all groups, but the change was significantly greater in the selenium-treated patients. Exploratory evaluations at 12 months confirmed the results seen at 6 months. Two patients assigned to placebo and one assigned to pentoxifylline required immunosuppressive therapy for deterioration in their condition. No adverse events were evident with selenium, whereas pentoxifylline was associated with frequent gastrointestinal problems. Selenium administration significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild Graves' orbitopathy. (Funded by the University of Pisa and the Italian Ministry for Education, University and Research; EUGOGO Netherlands Trial Register number, NTR524.).


A multifaceted analysis of HIV-1 protease multidrug resistance phenotypes.
Great strides have been made in the effective treatment of HIV-1 with the development of second-generation protease inhibitors (PIs) that are effective against historically multi-PI-resistant HIV-1 variants. Nevertheless, mutation patterns that confer decreasing susceptibility to available PIs continue to arise within the population. Understanding the phenotypic and genotypic patterns responsible for multi-PI resistance is necessary for developing PIs that are active against clinically-relevant PI-resistant HIV-1 variants. In this work, we use globally optimal integer programming-based clustering techniques to elucidate multi-PI phenotypic resistance patterns using a data set of 398 HIV-1 protease sequences that have each been phenotyped for susceptibility toward the nine clinically-approved HIV-1 PIs. We validate the information content of the clusters by evaluating their ability to predict the level of decreased susceptibility to each of the available PIs using a cross validation procedure. We demonstrate the finding that as a result of phenotypic cross resistance, the considered clinical HIV-1 protease isolates are confined to ~6% or less of the clinically-relevant phenotypic space. Clustering and feature selection methods are used to find representative sequences and mutations for major resistance phenotypes to elucidate their genotypic signatures. We show that phenotypic similarity does not imply genotypic similarity, that different PI-resistance mutation patterns can give rise to HIV-1 isolates with similar phenotypic profiles. Rather than characterizing HIV-1 susceptibility toward each PI individually, our study offers a unique perspective on the phenomenon of PI class resistance by uncovering major multidrug-resistant phenotypic patterns and their often diverse genotypic determinants, providing a methodology that can be applied to understand clinically-relevant phenotypic patterns to aid in the design of novel inhibitors that target other rapidly evolving molecular targets as well.


Pseudogout of the cervical and thoracic spine mimicking infection after lumbar fusion: case report.
Pseudogout is a form of acute calcium pyrophosphate deposition (CPPD) disease that typically afflicts the elderly. CPPD commonly involves larger joints, such as the knees, wrists, shoulders, and hips, and has been known to involve the spine. The authors report the case of a 66-year-old woman with a recent history of lumbar laminectomy and fusion who presented 5 weeks postprocedure with a clinical and radiographic picture consistent with multilevel skip lesions involving the cervical and thoracic spine, thoracic discitis, and epidural abscess. Serial blood cultures and repeat biopsy samples were sterile. Subsequent wrist and ankle erythema, pain, and swelling led to synovial fluid analysis, and pseudogout was diagnosed. She was treated with an interleukin-1 inhibitor with immediate symptom relief. To the authors' knowledge, this is only the second report of spinal pseudogout presenting with a clinical and radiographic picture consistent with discitis and epidural abscess. This report is the first to report skip lesions of pseudogout occurring throughout the spine that are uniquely remote from a recent lumbar surgery.


A receptor/cytoskeletal movement triggered by costimulation during T cell activation.
During T cell activation, the engagement of costimulatory molecules is often crucial to the development of an effective immune response, but the mechanism by which this is achieved is not known. Here, it is shown that beads attached to the surface of a T cell translocate toward the interface shortly after the start of T cell activation. This movement appears to depend on myosin motor proteins and requires the engagement of the major costimulatory receptor pairs, B7-CD28 and ICAM-1-LFA-1. This suggests that the engagement of costimulatory receptors triggers an active accumulation of molecules at the interface of the T cell and the antigen-presenting cell, which then increases the overall amplitude and duration of T cell signaling.


Focal shift, optical transfer function, and phase-space representations.
The focal shift for a lens of finite value of Fresnel number can be defined in terms of the second moment of the intensity distribution in transverse planes. The connection with the optical transfer function is described. The specification of the focused amplitude in terms of the fractional Fourier transform is discussed, and the connections among the fractional Fourier transform, the Wigner distribution, and the ambiguity function are described, leading to a model for effects of Fresnel number in terms of a rotation in phase space. The uncertainty principle is discussed, including the significance of the beam propagation factor M2 and the width of optical fiber beam modes. Calculation of the moments in terms of the modulus and the phase of the illuminating wave is presented, and the use of the Kaiser-Teager energy operator is also described.


Fast Multilevel Functional Principal Component Analysis.
We introduce fast multilevel functional principal component analysis (fast MFPCA), which scales up to high dimensional functional data measured at multiple visits. The new approach is orders of magnitude faster than and achieves comparable estimation accuracy with the original MFPCA (Di et al., 2009). Methods are motivated by the National Health and Nutritional Examination Survey (NHANES), which contains minute-level physical activity information of more than 10000 participants over multiple days and 1440 observations per day. While MFPCA takes more than five days to analyze these data, fast MFPCA takes less than five minutes. A theoretical study of the proposed method is also provided. The associated function mfpca.face() is available in the R package refund.


µ-TRTX-Ca1a: a novel neurotoxin from Cyriopagopus albostriatus with analgesic effects.
Human genetic and pharmacological studies have demonstrated that voltage-gated sodium channels (VGSCs) are promising therapeutic targets for the treatment of pain. Spider venom contains many toxins that modulate the activity of VGSCs. To date, only 0.01% of such spider toxins has been explored, and thus there is a great potential for discovery of novel VGSC modulators as useful pharmacological tools or potential therapeutics. In the current study, we identified a novel peptide, µ-TRTX-Ca1a (Ca1a), in the venom of the tarantula Cyriopagopus albostriatus. This peptide consisted of 38 residues, including 6 cysteines, i.e. IFECSISCEIEKEGNGKKCKPKKCKGGWKCKFNICVKV. In HEK293T or ND7/23 cells expressing mammalian VGSCs, this peptide exhibited the strongest inhibitory activity on Nav1.7 (IC50 378 nM), followed by Nav1.6 (IC50 547 nM), Nav1.2 (IC50 728 nM), Nav1.3 (IC50 2.2 µM) and Nav1.4 (IC50 3.2 µM), and produced negligible inhibitory effect on Nav1.5, Nav1.8, and Nav1.9, even at high concentrations of up to 10 µM. Furthermore, this peptide did not significantly affect the activation and inactivation of Nav1.7. Using site-directed mutagenesis of Nav1.7 and Nav1.4, we revealed that its binding site was localized to the DIIS3-S4 linker region involving the D816 and E818 residues. In three different mouse models of pain, pretreatment with Cala (100, 200, 500 µg/kg) dose-dependently suppressed the nociceptive responses induced by formalin, acetic acid or heat. These results suggest that Ca1a is a novel neurotoxin against VGSCs and has a potential to be developed as a novel analgesic.


Role of Helicobacter pylori infection on nutrition and metabolism.
Helicobacter pylori (H. pylori) is a gram-negative pathogen that is widespread all over the world, infecting more than 50% of the world's population. It is etiologically associated with non-atrophic and atrophic gastritis, peptic ulcer and shows a deep association with primary gastric B-cell lymphoma and gastric adenocarcinoma. Recently, the medical research focused on the modification of the gastric environment induced by H. pylori infection, possibly affecting the absorption of nutrients and drugs as well as the production of hormones strongly implicated in the regulation of appetite and growth. Interestingly, the absorption of iron and vitamin B12 is impaired by H. pylori infection, while infected subjects have lower basal and fasting serum levels of ghrelin and higher concentration of leptin compared to controls. Since leptin is an anorexigenic hormone, and ghrelin stimulates powerfully the release of growth hormone in humans, H. pylori infection may finally induce growth retardation if acquired very early in the childhood and in malnourished children. This review is focused on the nutritional effects of H. pylori infection, such as the reduced bioavailability or the malabsorbption of essential nutrients, and of gastrointestinal hormones, as well as on the relationship between H. pylori and the metabolic syndrome.


Guidance for Studies Evaluating the Accuracy of Rapid Tuberculosis Drug-Susceptibility Tests.
The development and implementation of rapid molecular diagnostics for tuberculosis (TB) drug-susceptibility testing is critical to inform treatment of patients and to prevent the emergence and spread of resistance. Optimal trial planning for existing tests and those in development will be critical to rapidly gather the evidence necessary to inform World Health Organization review and to support potential policy recommendations. The evidence necessary includes an assessment of the performance for TB and resistance detection as well as an assessment of the operational characteristics of these platforms. The performance assessment should include analytical studies to confirm the limit of detection and assay ability to detect mutations conferring resistance across globally representative strains. The analytical evaluation is typically followed by multisite clinical evaluation studies to confirm diagnostic performance in sites and populations of intended use. This paper summarizes the considerations for the design of these analytical and clinical studies.


Prevalence of apathy following head injury.
Although several studies have examined the demographics of mood disorders and personality changes following closed head injury (CHI), there are no studies that address the prevalence of apathy after CHI. Utilizing standardized evaluation tools, this study examines the prevalence of apathy in 83 consecutive patients seen in a neuropsychiatric clinic. A total of 10.84% had apathy without depression while an equal number were depressed without apathy; another 60% of patients exhibited both apathy and depression. Younger patients were more likely to be apathetic than older patients who were more likely to be depressed and apathetic. Patients with severe injury were more likely to exhibit apathy alone. Family members rated the patients higher on apathy scale. These findings suggest that apathy is a frequent symptom after head injury and may occur either alone or in association with depression.


Integrating SNVs and CNAs on a phylogenetic tree from single-cell DNA sequencing data.
Single-cell DNA sequencing enables the construction of evolutionary trees that can reveal how tumors gain mutations and grow. Different whole-genome amplification procedures render genomic materials of different characteristics, often suitable for the detection of either single-nucleotide variation or copy number aberration, but not ideally for both. Consequently, this hinders the inference of a comprehensive phylogenetic tree and limits opportunities to investigate the interplay of SNVs and CNAs. Existing methods such as SCARLET and COMPASS require that the SNVs and CNAs are detected from the same sets of cells, which is technically challenging. Here we present a novel computational tool, SCsnvcna, that places SNVs on a tree inferred from CNA signals, whereas the sets of cells rendering the SNVs and CNAs are independent, offering a more practical solution in terms of the technical challenges. SCsnvcna is a Bayesian probabilistic model using both the genotype constraints on the tree and the cellular prevalence to search the optimal solution. Comprehensive simulations and comparison with seven state-of-the-art methods show that SCsnvcna is robust and accurate in a variety of circumstances. Particularly, SCsnvcna most frequently produces the lowest error rates, with ability to scale to a wide range of numerical values for leaf nodes in the tree, SNVs, and SNV cells. The application of SCsnvcna to two published colorectal cancer data sets shows highly consistent placement of SNV cells and SNVs with the original study while also supporting a refined placement of ATP7B, illustrating SCsnvcna's value in analyzing complex multitumor samples.


[Clinical study on treatment of internal derangement of the T.M. joint].
The author has studied on treatment of internal derangement of the temporomandibular joint induced by incision of the retrodiscal ligament, and on an extracapsular surgical treatment method composed of lower repositioning of the mandibular condyle with oblique osteotomy of the ramus on the animals and 5 patients with internal derangement of the T.M. joint. To induce internal derangement on experimental animals, 5 Malaysian monkeys aging around 2 years and weighing about 3kg. were used, the retrodiscal ligament of the left temporomandibular joint was incised, and 1mm lower repositioning surgery of the condyle was performed 3 weeks after. The animals were observed and sacrificed on the 1st, 2nd, 3rd, 4th and 5th weeks thereafter, and the temporomandibular joints and their surrounding tissues were obtained to make microscopic specimens stained with Hematoxylin-Eosin and with Van Gieson method and patient treated by means of lower reposition surgery and 5 patients treated have been observed clinically. And 5 patients treated have been observed clinically. The results obtained were as follows: 1. Internal derangement of the T.M. joint occurred in by resecting retrodiscal ligament. 2. A lots of bone resorption on articular eminence was shown, 1-2 weeks after lower repositioning surgery. 3. Bone healing on articular eminence was shown, 3-5 weeks after lower repositioning surgery. 4. Displased articular disks came back to normal positions by lower repositioning surgery. 5. 5 patients with internal derangement completely treated by application of lower repositioning surgery.


Chemotactic migration of leucocytes through corneal layers: an in vitro study.
The ability of polymorphonuclear leucocytes (PMNs) to migrate into the different corneal layers in the presence or absence of a chemotactic stimulus was investigated in rabbits. The epithelial and/or endothelial surfaces were damaged in some corneas and in others they were intact. One side of the cornea was kept in contact with a viable population of rabbit PMNs and the other side with a chemotactic agent (zymosan activated human serum). The migration of PMNs into the cornea was traced histologically. The PMNs could not penetrate intact epithelium and Descemet's membrane even under the influence of a chemotactic stimulus. The stroma allowed PMN migration only when the chemotactic agent was present. The endothelium offered no resistance to PMN invasion whether the chemotactic stimulus was present or not.


Plasminogen activator inhibitor-1 activity is independently related to both insulin sensitivity and serum triglycerides in 70-year-old men.
Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been discussed as a part of the insulin resistance syndrome. However, it is not clear whether the relationship between PAI-1 and insulin resistance is independent of or mediated by increased triglycerides levels. The aim of this study was to investigate whether PAI-1 activity is associated with insulin sensitivity independently of serum triglycerides (sTG) and of other potential confounders. Seventy-year-old men (n=871), participating in a cohort study undergoing extensive metabolic investigations, had blood samples taken for determination of PAI-1 activity. Insulin sensitivity was determined by the euglycemic hyperinsulinemic clamp. In multivariate correlation and regression analyses, insulin sensitivity was a statistically significant determinant of PAI-1 activity (partial r=-.12; P<.001), independent of sTG, body mass index, waist-hip ratio, and other potential confounders. The levels of sTG were also independently related to PAI-1 activity (partial r=.18; P<.001). The relationships between PAI-1 and insulin sensitivity and sTG were independent of fasting glucose levels. Aggregation of risk factors of the insulin resistance syndrome was associated with increased activity of PAI-1 in men with normal glucose tolerance. We conclude that PAI-1 activity is related to insulin sensitivity and sTG, independently of each other and of other potential confounders, and that increased levels of PAI-1 should be regarded as a component of the insulin resistance syndrome.


In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism.
This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.


Application of various power densities of ultrasound in the treatment of leg ulcers.
The objective of our study was to determine which ultrasound power density (0.5 W/cm(2) or 1 W/cm(2)) is more effective at reducing the area and volume of leg ulceration. A total of 65 patients with venous ulcers were randomly divided into three groups: A, B and C. In group A, 22 patients were treated with ultrasound rated at 1 W/cm(2) and with compressive therapy. In group B, 21 patients were treated with ultrasound rated at 0.5 W/cm(2) and with compressive therapy. In both groups the patients were treated with a pulsed wave of a duty cycle of 1/5 (impulse time=2 ms, pause time=8 ms) and frequency of 1 MHz. The 22 patients in group C (control group) were subjected to topical pharmacological treatment. We found a statistically significant reduction of the ulcer area, volume and linear dimensions in all three groups of patients. The ulcer area reduction rate was highest in group B. The volume reduction rate in group B was higher than in group A only. The rate of reduction of suppurate area was highest in group B. We have demonstrated that ultrasound rated at 0.5 W/cm(2) causes greater and faster changes in the healing process than ultrasound rated at 1 W/cm(2).


[The activity of alpha2-macroglobulin and its forms in patients with destructive pulmonary tuberculosis].
A hundred and three patients with destructive pulmonary tuberculosis were examined. These patients had heterodirectional changes in the serum levels of alpha2-macroglobulin (MG) and its forms. The lowering of the level of the F-form of the inhibitor outstripped the decrease in the activity of total alpha2-MG and it was detectable in the lobar processes with moderate symptoms of intoxication and with the inoculation of adjacent segments. The preservation of the low total activity of the inhibitor and its forms during antituberculous therapy characterize a diminished process. The high content of the S form of alpha2-MG is a feature in patients showing positive changes before and 2 months after treatment whereas the changes in total alpha2-MG and its F form may vary. Whether it is expedient to study the fractional composition of alpha2-MG is determined by the heterodirectionality of changes in its S and F forms depending on the pattern of a process.


Anaesthetic management of two different cases of mediastinal mass.
We report the management of two paediatric cases undergoing median sternotomy and right lateral thoracotomy for mediastinal mass. An 8-year-old boy presented with a history of intermittent fever and episodes of respiratory illness since 3 years and a 16-year-old girl presented with dyspnoea, cough, fever and dysphagia for solid foods. Radiological investigation confirmed the diagnoses. Absence of pressure symptoms pointed towards a compressible mass in the boy and indicated a non-compressible mass in the girl. We discuss the anaesthetic management of the younger patient with an uneventful course as opposed to the older patient where airway obstruction ensued soon after induction and led to near-cardiopulmonary arrest necessitating rescue measures. Swift measures at securing airway while simultaneously resuscitating the patient served to successfully revert an otherwise fateful eventuality.


Musical obsessions.
Obsessive-compulsive disorder (OCD) is a common psychiatric illness. A case of OCD is presented, in which the chief symptom was recurrent imagery of musical sounds of different instruments experienced by the person. Patient was a musician who played various musical instruments. Such obsessions with predominant musical themes, lyrics, and tunes have not been described in detail in standard textbooks of psychiatry or phenomenology, nor are they considered in the various diagnostic procedures for OCD. These symptoms are rare and may, at times, go unnoticed because of low clinical awareness.


Physical examination instead of laboratory tests for most infants born to mothers colonized with group B Streptococcus: support for the Centers for Disease Control and Prevention's 2010 recommendations.
To compare 2 approaches in the management of neonates at risk for group B Streptococcus early-onset sepsis: laboratory tests plus standardized physical examination and standardized physical examination alone. Prospective, sequential study over 2 consecutive 12-month periods, carried out in the maternity hospitals of the region Friuli-Venezia Giulia (north-eastern Italy). All term infants were included (7628 in the first period, 7611 in the second). In the first period, complete blood count and blood culture were required for all infants at risk, followed by a 48-hour period of observation with a standardized physical examination. In the second period, only standardized physical examination was performed. Study outcomes were: (1) number of neonates treated with antibiotics; and (2) time between onset of signs of possible sepsis and beginning of treatment. There was no difference between the 2 periods in the rate of maternal colonization (19.7% vs 19.8%, P = .8), or in other risk factors. The interval between onset of signs of sepsis and starting of antibiotics was not different in the 2 periods. Significantly fewer infants were treated with antibiotics in the second period (0.5% vs 1.2%, P < .001). Laboratory tests together with standardized physical examination seem to offer no advantage over standardized physical examination alone; the latter was associated with fewer antibiotic treatments. Our results are in agreement with the Center for Disease Control and Prevention's 2010 recommendations.


Dynamic Optical Contrast Imaging.
The variable location and indistinct features of parathyroid glands can make their intraoperative identification challenging. Currently, there exists no routine use of localization methods during surgery. Dynamic optical contrast imaging (DOCI) leverages a novel realization of temporally dependent measurements of tissue autofluorescence that allows the acquisition of specific tissue properties. A prospective series of patients with primary hyperparathyroidism was examined. Parathyroid lesions and surrounding tissues were collected; fluorescence decay images were acquired via DOCI. Ex vivo samples (81 patients) were processed for histologic assessment. DOCI extracts relative fluorescence decay information in a surgically relevant field of view with a clinically accessible acquisition time <2 minutes. Analysis of DOCI revealed microscopic characterization sufficient for tissue type identification consistent with histology ( P < .05). DOCI is capable of efficiently distinguishing parathyroid tissue from adjacent tissues. Such an intraoperative tool would be transformative, helping surgeons to identify lesions, preserve healthy tissue, and improve patient outcomes.


Identification of human plasma metabolites exhibiting time-of-day variation using an untargeted liquid chromatography-mass spectrometry metabolomic approach.
Although daily rhythms regulate multiple aspects of human physiology, rhythmic control of the metabolome remains poorly understood. The primary objective of this proof-of-concept study was identification of metabolites in human plasma that exhibit significant 24-h variation. This was assessed via an untargeted metabolomic approach using liquid chromatography-mass spectrometry (LC-MS). Eight lean, healthy, and unmedicated men, mean age 53.6 (SD ± 6.0) yrs, maintained a fixed sleep/wake schedule and dietary regime for 1 wk at home prior to an adaptation night and followed by a 25-h experimental session in the laboratory where the light/dark cycle, sleep/wake, posture, and calorific intake were strictly controlled. Plasma samples from each individual at selected time points were prepared using liquid-phase extraction followed by reverse-phase LC coupled to quadrupole time-of-flight MS analysis in positive ionization mode. Time-of-day variation in the metabolites was screened for using orthogonal partial least square discrimination between selected time points of 10:00 vs. 22:00 h, 16:00 vs. 04:00 h, and 07:00 (d 1) vs. 16:00 h, as well as repeated-measures analysis of variance with time as an independent variable. Subsequently, cosinor analysis was performed on all the sampled time points across the 24-h day to assess for significant daily variation. In this study, analytical variability, assessed using known internal standards, was low with coefficients of variation <10%. A total of 1069 metabolite features were detected and 203 (19%) showed significant time-of-day variation. Of these, 34 metabolites were identified using a combination of accurate mass, tandem MS, and online database searches. These metabolites include corticosteroids, bilirubin, amino acids, acylcarnitines, and phospholipids; of note, the magnitude of the 24-h variation of these identified metabolites was large, with the mean ratio of oscillation range over MESOR (24-h time series mean) of 65% (95% confidence interval [CI]: 49-81%). Importantly, several of these human plasma metabolites, including specific acylcarnitines and phospholipids, were hitherto not known to be 24-h variant. These findings represent an important baseline and will be useful in guiding the design and interpretation of future metabolite-based studies.


Clinical pharmacology of deoxycoformycin.
Deoxycoformycin (DCF) is an inhibitor of adenosine deaminase (ADA). Twenty-one courses of DCF were administered to 13 patients ranging in age from 15 to 78 yr. Eight patients had T-cell disorders, and five patients had non-T-cell malignancies. The i.v. bolus dose was escalated from 5 to 30 mg/sq m/day, and the duration of the courses ranged from 1 to 5 days. The DCF plasma half-life ranged from 4.9 to 6.2 hr and was independent of dose. The dose-limiting toxicities involved the central nervous system (CNS) and the kidneys. Other toxicities included bronchitis, decreases in hematocrit, arthralgias, and myalgias. Mortality was encountered in three patients. These toxic effects may have been secondary to the accumulation of the metabolites adenosine and deoxyadenosine. Deoxyadenosine and adenosine were both detectable in plasma (10(-6) M) and in urine (10(-3) M). Two partial remissions were observed: one in a patient with T-cell ALL and another in a patient with mycosis fungoides. Minimal responses characterized by either declines in peripheral blast counts or partial resolution of adenopathy were observed in five other patients. No responses were observed in six patients. These observations suggest that DCF is effective in the treatment of T-cell lymphoid malignancies.


The future of clinical engineering: technology that enables improved patient care.
Speakers at this year's ACCE Symposium will describe in detail the scope and depth of technological and other factors that are at work changing the healthcare delivery paradigm. Other presenters will explore the impact the changes will likely have on the clinical engineering profession. Still others will outline the steps necessary for clinical engineers to take to effectively prepare for the challenges facing them. The experts agree: clinical engineering is at a critical crossroads. No one who intends to pursue clinical engineering or healthcare technology management over the next 10 years can afford to miss this year's meeting.


Icodextrin improves the serum potassium profile with the enhancement of nutritional status in continuous ambulatory peritoneal dialysis patients.
The impact of glucose-free icodextrin (ID) for overnight dwell as compared to conventional glucose-containing dialysate (GD) on potassium (K(+)) metabolism in continuous ambulatory peritoneal dialysis (CAPD) patients has not yet been investigated. Serum K(+) in a total of 255 stable patients (116 on GD and 139 on ID) on CAPD for more than 6 months and in 139 patients on ID before and after ID use (Pre-ID and Post-ID) were observed along with nutritional markers in a 2-year study period (Jan. 2006 to Dec. 2007). The prevalence of hypokalemia was similar between patients on GD and ID (16.7% vs 17.3%), but was lower on Post-ID than Pre-ID (17.3% vs 20.5%) without statistic significance. The mean serum K(+) level was higher on ID than on GD (P<0.05) as well as Post-ID than Pre-ID (P<0.001). In the multivariate analysis, serum K(+) levels were positively correlated with serum albumin, and creatinine in all patients (P<0.05), and ID-use in younger patients (age≤56, P<0.001). Serum albumin, creatinine, total CO(2), and body mass index were significantly higher on Post-ID than Pre-ID. Icodextrin dialysate for chronic overnight dwell could increase serum K(+) levels and lower the prevalence of hypokalemia compared to conventional glucose-containing dialysate. The improved chronic K(+) balance in CAPD patients on icodextrin could be related to enhanced nutritional status rather than its impact on acute intracellular K(+) redistribution.


A multi-level memristor based on atomic layer deposition of iron oxide.
This work reports the fabrication of memristive devices based on iron oxide (Fe2O3) thin films grown by atomic layer deposition (ALD) using ferrocene as iron precursor and ozone as oxidant. An excellent control of the ALD process was achieved by using an experimental procedure based on a sequence of micro-pulses, which provided long residence time and homogeneous diffusion of precursors, allowing ALD of thin films with smooth morphology and crystallinity which was found to increase with layer thickness, at temperatures as low as 250 °C. The resistive switching of symmetric Pt/Fe2O3/Pt thin film devices exhibited bipolar mode with good stability and endurance. Multi-level switching was achieved via current and voltage control. It was proved that the ON state regime can be tuned by changing the current compliance while the OFF state can be changed to intermediate levels by decreasing the maximum voltage during RESET. The structural analysis of the switched oxide layer revealed the presence of nano-sized crystalline domains corresponding to different iron oxide phases, suggesting that Joule heating effects during I-V cycling are responsible for a crystallization process of the pristine amorphous layer.


Enantiomers of 4-amino-3-fluorobutanoic acid as substrates for gamma-aminobutyric acid aminotransferase. Conformational probes for GABA binding.
Gamma-aminobutyric acid aminotransferase (GABA-AT), a pyridoxal 5'-phosphate dependent enzyme, catalyzes the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to succinic semialdehyde with concomitant conversion of pyridoxal 5'-phosphate (PLP) to pyridoxamine 5'-phosphate (PMP). The enzyme then catalyzes the conversion of alpha-ketoglutarate to the excitatory neurotransmitter L-glutamate. Racemic 4-amino-3-fluorobutanoic acid (3-F-GABA) was shown previously to act as a substrate for GABA-AT, not for transamination, but for HF elimination. Here we report studies of the reaction catalyzed by GABA-AT on (R)- and (S)-3-F-GABA. Neither enantiomer is a substrate for transamination. Very little elimination from the (S)-enantiomer was detected using a coupled enzyme assay; The rate of elimination of HF from the (R)-enantiomer is at least 10 times greater than that for the (S)-enantiomer. The (R)-enantiomer is about 20 times more efficient as a substrate for GABA-AT catalyzed HF elimination than GABA is a substrate for transamination. The (R)-enantiomer also inhibits the transamination of GABA 10 times more effectively than the (S)-enantiomer. Using a combination of computer modeling and the knowledge that vicinal C-F and C-NH3+ bonds have a strong preference to align gauche rather than anti to each other, it is concluded that on binding of free 3-F-GABA to GABA-AT the optimal conformation places the C-NH3+ and C-F bonds gauche in the (R)-enantiomer but anti in the (S)-enantiomer. Furthermore, the dynamic binding process and the bioactive conformation of GABA bound to GABA-AT have been inferred on the basis of the different biological behavior of the two enantiomers of 3-F-GABA when they bind to the enzyme. The present study suggests that the C-F bond can be utilized as a conformational probe to explore the dynamic binding process and provide insight into the bioactive conformation of substrates, which cannot be easily determined by other biophysical approaches.


Combining Physiology-Based Modeling and Evolutionary Algorithms for Personalized, Noninvasive Cardiovascular Assessment Based on Electrocardiography and Ballistocardiography.
Purpose: This study proposes a novel approach to obtain personalized estimates of cardiovascular parameters by combining (i) electrocardiography and ballistocardiography for noninvasive cardiovascular monitoring, (ii) a physiology-based mathematical model for predicting personalized cardiovascular variables, and (iii) an evolutionary algorithm (EA) for searching optimal model parameters. Methods: Electrocardiogram (ECG), ballistocardiogram (BCG), and a total of six blood pressure measurements are recorded on three healthy subjects. The R peaks in the ECG are used to segment the BCG signal into single BCG curves for each heart beat. The time distance between R peaks is used as an input for a validated physiology-based mathematical model that predicts distributions of pressures and volumes in the cardiovascular system, along with the associated BCG curve. An EA is designed to search the generation of parameter values of the cardiovascular model that optimizes the match between model-predicted and experimentally-measured BCG curves. The physiological relevance of the optimal EA solution is evaluated a posteriori by comparing the model-predicted blood pressure with a cuff placed on the arm of the subjects to measure the blood pressure. Results: The proposed approach successfully captures amplitudes and timings of the most prominent peak and valley in the BCG curve, also known as the J peak and K valley. The values of cardiovascular parameters pertaining to ventricular function can be estimated by the EA in a consistent manner when the search is performed over five different BCG curves corresponding to five different heart-beats of the same subject. Notably, the blood pressure predicted by the physiology-based model with the personalized parameter values provided by the EA search exhibits a very good agreement with the cuff-based blood pressure measurement. Conclusion: The combination of EA with physiology-based modeling proved capable of providing personalized estimates of cardiovascular parameters and physiological variables of great interest, such as blood pressure. This novel approach opens the possibility for developing quantitative devices for noninvasive cardiovascular monitoring based on BCG sensing.


Psychotherapies for borderline personality disorder: a focused systematic review and meta-analysis.
A recently updated Cochrane review supports the efficacy of psychotherapy for borderline personality disorder (BPD). To evaluate the effects of standalone and add-on psychotherapeutic treatments more concisely. We applied the same methods as the 2020 Cochrane review, but focused on adult samples and comparisons of active treatments and unspecific control conditions. Standalone treatments (i.e. necessarily including individual psychotherapy as either the sole or one of several treatment components) and add-on interventions (i.e. complementing any ongoing individual BPD treatment) were analysed separately. Primary outcomes were BPD severity, self-harm, suicide-related outcomes and psychosocial functioning. Secondary outcomes were remaining BPD diagnostic criteria, depression and attrition. Thirty-one randomised controlled trials totalling 1870 participants were identified. Among standalone treatments, statistically significant effects of low overall certainty were observed for dialectical behaviour therapy (self-harm: standardised mean difference (SMD) -0.54, P = 0.006; psychosocial functioning: SMD -0.51, P = 0.01) and mentalisation-based treatment (self-harm: risk ratio 0.51, P < 0.0007; suicide-related outcomes: risk ratio 0.10, P < 0.0001). For adjunctive interventions, moderate-quality evidence of beneficial effects was observed for DBT skills training (BPD severity: SMD -0.66, P = 0.002; psychosocial functioning: SMD -0.45, P = 0.002), and statistically significant low-certainty evidence was observed for the emotion regulation group (BPD severity: mean difference -8.49, P < 0.00001), manual-assisted cognitive therapy (self-harm: mean difference -3.03, P = 0.03; suicide-related outcomes: SMD -0.96, P = 0.005) and the systems training for emotional predictability and problem-solving (BPD severity: SMD -0.48, P = 0.002). There is reasonable evidence to conclude that psychotherapeutic interventions are helpful for individuals with BPD. Replication studies are needed to enhance the certainty of findings.


Anti-inflammatory effects of intravenous anesthetics on endotoxemia.
Endotoxemia and endotoxin shock are common problems in the intensive care unit and carry a very high mortality rate. Endotoxemia increases production of endogenous cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, and IL-8. Not only endotoxin but also cytokines have been implicated as important factors in the pathophysiology of endotoxic shock and the development of cardiovascular dysfunction in endotoxemia. Recently, it has been shown both in vitro and in vivo that several intravenous anesthetics have anti-inflammatory effects. Thiopental and ketamine inhibit the endotoxin-induced TNF-alpha, IL-1 and IL-8 responses and increase IL-10 release in vitro. Ketamine prevent the pro-inflammatory cytokine (TNF-alpha, IL-1, and IL-6) responses to endotoxemia in vivo. Moreover, thiopental and ketamine suppress the activation of nuclear factor-kappa B induced by endotoxin. Propofol have been proven its anti-inflammatory effects on endotoxemia both in vitro and in vivo, but several studies have shown that propofol does not have any anti-inflammatory effects and deteriorates the inflammatory response to endotoxemia. This article reviews the anti-inflammatory effects of intravenous anesthetics on endotoxemia and endotoxic shock.


Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes of HSD3B2 c.35G>A Homozygotes.
3-β-hydroxysteroid dehydrogenase (HSD3B2) deficiency accounts for less than 5% of congenital adrenal hyperplasia worldwide, but is relatively common among the Old Order Amish of North America due to a HSD3B2 c.35G>A founder mutation. We review clinical presentation, disease course, treatment, and outcomes of a genetically homogenous population of HSD3B2-deficient patients. This was a retrospective case series: anthropometric, biochemical, and clinical data from 16 (six male) affected subjects (age, 7.2 ± 6.4 y) were compared to reference data from 12 age-matched unaffected siblings. The setting was the Clinic for Special Children, a nonprofit rural community health center in Lancaster, Pennsylvania. The main outcome measures were growth, skeletal maturation, sexual development, blood pressure, glucocorticoid dose, pituitary-adrenal homeostasis, and long-term morbidity. Exogenous glucocorticoid requirement was dichotomous: a standard-dose group (n = 9) required 15.4 ± 4.9 mg/m(2)/d hydrocortisone equivalent, whereas a high-dose group required much larger and more variable doses (hydrocortisone equivalent, 37.8 ± 15.4 mg/m(2)/d) (P < .0001). Despite glucocorticoid doses 2-fold higher than the standard-dose group, high-dose patients: 1) had ACTH, 17-hydroxypregnenolone, and dehydroepiandrosterone levels that were 10-fold, 20-fold, and 20-fold higher, respectively; 2) were exclusively affected by signs of sex steroid excess; and 3) tended to have more iatrogenic complications. Patients with HSD3B2 deficiency and 21-hydroxylase deficiency suffer similar morbid complications from under- and overtreatment, but HSD3B2 deficiency is associated with a distinctive pattern of sex steroid dysmetabolism. Disease- and treatment-related morbidities are almost exclusively observed among subjects who have a high exogenous glucocorticoid requirement.


Focal segmental glomerulosclerosis in association with Cushing's disease.
Focal segmental glomerulosclerosis (FSGS) may be idiopathic or secondary to a variety of causes. Clinical distinction between primary and secondary forms of FSGS has crucial therapeutic consequences. Whereas the former may respond to immunosuppressive therapy, treatment of secondary forms of FSGS must aim to resolve the underlying diseases. Although the combination of nephrotic syndrome and Cushing's syndrome has been described anecdotally, the causal relationship between these two diseases remains controversial. We report herein a 37-year-old man who presented with lower extremity pitting edema. Heavy proteinuria and mild renal insufficiency prompted to perform a kidney biopsy and the specimen showed FSGS. On the other hand, admission physical examination was notable for a Cushingoid appearance. After endocrinological investigations, the patient was diagnosed as having Cushing's disease caused by pituitary adrenocorticotropic hormone-producing microadenoma. Immunosuppressive therapy for the treatment of FSGS was not carried out and we treated his Cushing's disease with transsphenoidal resection of the pituitary microadenoma. Surprisingly, resolution of heavy proteinuria occurred when the patient's physical features characteristic of Cushing's disease were gradually resolved 3 months later. This case suggests a possible association of Cushing's disease with FSGS.


Stimulation of extracellular matrix remodeling by the first type III repeat in fibronectin.
The fibronectin matrix contains cryptic sites which are thought to modulate cellular biological responses. One of these sites, located in fibronectin's first type III repeat (III1c), influences signaling pathways that are relevant to cytoskeletal organization and cell cycle progression. The purpose of this study was to identify possible mechanisms responsible for the effects of III1c on cell behavior. Recombinant peptides representing various type III repeats of fibronectin were compared for their effects on fibronectin matrix organization and activation of intracellular signaling pathways. III1c and III13 but not III11c or III10 bound to monolayers of human skin fibroblasts in a dose- and time-dependent manner and were localized to the extracellular matrix. Binding of III13, but not III1c, to matrix was sensitive to heparitinase, suggesting that the association of III1c with the matrix was not dependent on heparan sulfate proteoglycans. Quantitative and morphological assessment indicated that, in contrast to previously published reports, the binding of III1c to cell layers did not result in the loss or disruption of matrix fibronectin. Binding of III1c but not III13 to the extracellular matrix did result in the loss of a conformationally sensitive epitope present within the EDA type III module of cellular fibronectin. III1c-induced loss of the EDA epitope did not require the presence of cells, occurred within 1 hour and was associated with the activation of p38 mitogen-activated protein kinase (MAPK) followed by the formation of filopodia. Maximal phosphorylation of p38 MAPK occurred within 1 hour, whereas cytoskeletal changes did not appear until 12 hours later. These findings are consistent with a model in which the binding of III1c to the extracellular matrix results in a conformational remodeling of the fibronectin matrix, which has both short- and long-term effects on cell physiology.


Epicardial and Pericoronary Adipose Tissue, Coronary Inflammation, and Acute Coronary Syndromes.
Vascular inflammation is recognized as the primary trigger of acute coronary syndrome (ACS). However, current noninvasive methods are not capable of accurately detecting coronary inflammation. Epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT), in addition to their role as an energy reserve system, have been found to contribute to the development and progression of coronary artery calcification, inflammation, and plaque vulnerability. They also participate in the vascular response during ischemia, sympathetic stimuli, and arrhythmia. As a result, the evaluation of EAT and PCAT using imaging techniques such as computed tomography (CT), cardiac magnetic resonance (CMR), and nuclear imaging has gained significant attention. PCAT-CT attenuation, which measures the average CT attenuation in Hounsfield units (HU) of the adipose tissue, reflects adipocyte differentiation/size and leukocyte infiltration. It is emerging as a marker of tissue inflammation and has shown prognostic value in coronary artery disease (CAD), being associated with plaque development, vulnerability, and rupture. In patients with acute myocardial infarction (AMI), an inflammatory pericoronary microenvironment promoted by dysfunctional EAT/PCAT has been demonstrated, and more recently, it has been associated with plaque rupture in non-ST-segment elevation myocardial infarction (NSTEMI). Endothelial dysfunction, known for its detrimental effects on coronary vessels and its association with plaque progression, is bidirectionally linked to PCAT. PCAT modulates the secretory profile of endothelial cells in response to inflammation and also plays a crucial role in regulating vascular tone in the coronary district. Consequently, dysregulated PCAT has been hypothesized to contribute to type 2 myocardial infarction with non-obstructive coronary arteries (MINOCA) and coronary vasculitis. Recently, quantitative measures of EAT derived from coronary CT angiography (CCTA) have been included in artificial intelligence (AI) models for cardiovascular risk stratification. These models have shown incremental utility in predicting major adverse cardiovascular events (MACEs) compared to plaque characteristics alone. Therefore, the analysis of PCAT and EAT, particularly through PCAT-CT attenuation, appears to be a safe, valuable, and sufficiently specific noninvasive method for accurately identifying coronary inflammation and subsequent high-risk plaque. These findings are supported by biopsy and in vivo evidence. Although speculative, these pieces of evidence open the door for a fascinating new strategy in cardiovascular risk stratification. The incorporation of PCAT and EAT analysis, mainly through PCAT-CT attenuation, could potentially lead to improved risk stratification and guide early targeted primary prevention and intensive secondary prevention in patients at higher risk of cardiac events.


Searching for the holy grail of a staphylococcal vaccine.
The pursuit of an effective staphylococcal vaccine has never been more critical, as community-associated MRSA has become the most common bacterial infection in the US. In this commentary, we will highlight new discoveries in the host response to colonization and infection with S. aureus, discuss potential antigens that might be used as vaccines, and make recommendations as to how the field can move forward towards discovering the "holy grail" of an effective staphylococcal vaccine.


To See or Not to See: How Does Seeing Spellings Support Vocabulary Learning?
Purpose The aim of this study was to determine when, why, and how the presence of a word's written form during instruction aids vocabulary learning (a process known as orthographic facilitation). Method A systematic review of the research on orthographic facilitation was carried out. PsycInfo, Web of Science, ProQuest, and OpenGrey databases were searched. The search returned 3,529 results, and 23 of these met inclusion criteria. Studies were included in the review if they were written in English, published in a peer-reviewed journal, and compared vocabulary learning outcomes when words were taught with and without their written forms. Conclusions There is strong evidence that the presence of a word's written form leads to improved learning of its spelling and spoken form. There is also some evidence that it may lead to better learning of a word's meaning. A small number of studies have also shown that the presence of a word's written form benefits vocabulary learning in children with developmental language disorder, autism, Down syndrome, and reading difficulties. However, further research into the effects of orthographic facilitation in special populations is needed. In particular, ecologically valid experiments in clinical and educational settings are required in order to better understand how exposure to a word's written form can aid naturalistic vocabulary learning.


Mechanistic aspects of dinitrogen cleavage and hydrogenation to produce ammonia in catalysis and organometallic chemistry: relevance of metal hydride bonds and dihydrogen.
Dinitrogen cleavage and hydrogenation by transition-metal centers to produce ammonia is central in industry and in Nature. After an introductory section on the thermodynamic and kinetic challenges linked to N2 splitting, this tutorial review discusses three major classes of transition-metal systems (homogeneous, heterogeneous and biological) capable of achieving dissociation and hydrogenation of dinitrogen. Molecular complexes, solid-state Haber-Bosch catalytic systems, silica-supported tantalum hydrides and nitrogenase will be discussed. Emphasis is focused on the reaction mechanisms operating in the process of dissociation and hydrogenation of dinitrogen, and in particular on the key role played by metal hydride bonds and by dihydrogen in such reactions.


Substrate specificity of human protein arginine methyltransferase 7 (PRMT7): the importance of acidic residues in the double E loop.
Protein arginine methyltransferase 7 (PRMT7) methylates arginine residues on various protein substrates and is involved in DNA transcription, RNA splicing, DNA repair, cell differentiation, and metastasis. The substrate sequences it recognizes in vivo and the enzymatic mechanism behind it, however, remain to be explored. Here we characterize methylation catalyzed by a bacterially expressed GST-tagged human PRMT7 fusion protein with a broad range of peptide and protein substrates. After confirming its type III activity generating only ω-N(G)-monomethylarginine and its distinct substrate specificity for RXR motifs surrounded by basic residues, we performed site-directed mutagenesis studies on this enzyme, revealing that two acidic residues within the double E loop, Asp-147 and Glu-149, modulate the substrate preference. Furthermore, altering a single acidic residue, Glu-478, on the C-terminal domain to glutamine nearly abolished the activity of the enzyme. Additionally, we demonstrate that PRMT7 has unusual temperature dependence and salt tolerance. These results provide a biochemical foundation to understanding the broad biological functions of PRMT7 in health and disease.


[Degeneration and regeneration of the peripheral nervous system with aging].
Clinical and experimental studies have shown that with aging there appear neurological changes which affect both the Central Nervous System (CNS) as well as the Peripheral Nervous System (PNS), bringing about a series of cognitive, sensory and physical disabilities in older people. Nerve lesions also cause disability. The basic mechanisms which begin with lesioned neurons have proved an interesting field of study for many neuroscientists since as far back as the mid-nineteenth century. However the influence of age on these postlesion neuronal processes has not aroused the same level of interest even though many authors have, out of curiosity, published reports of changes which take place in regenerative neurons as a result of age. The progressive increase in the aged population in industrialised nations warrants a detailed study into the influence of age on such neuronal processes. The PNS, due to its accessibility and greater regenerative potential vis-à-vis the CNS, may be a good model for this purpose. From results obtained by both other authors and ourselves it is clear that aging causes a decline in the regenerative abilities of peripheral nerve fibres. Functional recovery is not only slowed down but also decreases with age. The number of regenerative axons and their capacity for end sprouting, together with the biosynthesis and transport of new materials in the regenerative neurons, as well as the proliferation and synthesis of trophic factors by Schwann cells also decay. All of this leads to the fact that the regenerative capacity of nerve fibres is lesser with age, and that functional disabilities after a lesion are greater in older than in younger people.


Predictors of successful cancer prevention programs.
Finding the optimal use of health-care resources requires the reliable estimation of costs and consequences. Acquiring these estimates may not be difficult for some common treatments. More difficult is the optimization of resources in the area of diagnostics. Only a few attempts have been made to optimize the use of resources in the area of prevention. Several aspects have to be considered when optimizing the resources for prevention: (1) participation rates in structured prevention programs are low, (2), acquiring data on follow-up and outcomes is difficult, (3) there are concerns about the quality of information available to public, and (4), the public is often unaware of scientific assessments of prevention programs. As prevention programs are costly long-term projects, a strategy to select these programs according to possible predictors of success might be useful. The few analyses of cancer prevention in the literature have been directed towards the most common malignant diseases (as assessed by incidence) such as cancer of the breast, colon, lung and prostate. We argue that incidence is a poor marker for selecting secondary prevention programs. Incidence may be a misleading indicator for two reasons: incidence of disease does not predict efficiency of management or good health outcomes, and incidence does not separate clinically significant from non-significant disease. The traditional strategy is based on the assumption that more screening increases the chance of cure. We propose an alternative outcomes model that suggests better disease management justifies new prevention programs. Indicators for better disease management are effective and efficient treatments as well as high-quality screening (sensitivity and specificity) techniques and possibly "side-effects of prevention programs," which provide early signs of success to motivate the patient's participation, to keep up with the program and finally to succeed.


The unpredictable character of congenital cystic lung lesions.
The spectrum of congenital cystic disease of the lung ranges from hydrops and neonatal respiratory distress to asymptomatic lesions. Surgical management is dictated by the presence of symptoms, recurrent infection, and the potential risk of malignant transformation. Since 1995, all consecutive patients with congenital cystic lung lesions underwent follow-up for symptoms, treatment, and correlation of presumptive with pathological diagnosis. Twelve cystic lung lesions were identified. Seven were diagnosed with mediastinal shift in utero; in 6 of 7, the shift subsequently resolved. Overall, 6 of 7 lesions that were followed up serially decreased in size. Two patients were symptomatic in utero; 1 underwent thoracoamniotic shunting, 1 pleurocentesis for impending hydrops. Postnatally, these 2, and 2 other newborns required urgent surgery. Five of 8 asymptomatic patients had elective resection by 16 months, and 4 await operation. In 6 of the 9 surgical cases (67%), there was a discrepancy between preoperative and pathological diagnosis. There were 4 hybrid congenital cystic adenomatoid malformation (CCAM)/sequestrations. At least 6 of 7 congenital cystic lung lesions decreased in size regardless of gestational age or presence of mediastinal shift. Antenatal intervention is therefore rarely indicated. Hybrid morphology may necessitate resection of stable, asymptomatic lesions to prevent the theoretical concern for associated malignancies as well as other complications of CCAM.


[Long-term study following panretinal argon laser coagulation in proliferative diabetic retinopathy].
Fifty-eight Type I diabetics were followed up for a minimum of 5 years after panretinal argon laser coagulation in both eyes for proliferative diabetic retinopathy. During the course of this study, 18 patients were excluded because thorough follow-up examinations according to our systematic approach had become impossible. The results of this study indicate that successful photocoagulation depends essentially on the initial findings, on the type and extent of treatment as well as on regular and thorough follow-up examinations.


Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients.
Deep brain stimulation (DBS) has been advocated as a more highly effective and less morbidity-producing alternative to ablative stereotactic surgery in the treatment of medically intractable movement disorders. Nevertheless, the exact incidence of morbidity and mortality associated with the procedure is not well known. In this study the authors reviewed the surgical morbidity and mortality rates in a large series of DBS operations. The authors retrospectively analyzed surgical complications in their consecutive series of 179 DBS implantations in 109 patients performed by a single surgical team at one center between July 1998 and April 2002. The mean follow-up period was 20 months. There were 16 serious adverse events related to surgery in 14 patients (12.8%). There were two perioperative deaths (1.8%), one caused by pulmonary embolism and the second due to aspiration pneumonia. The other adverse events were two pulmonary embolisms, two subcortical hemorrhages, two chronic subdural hematomas, one venous infarction, one seizure, four infections, one cerebrospinal fluid leak, and one skin erosion. The incidence of permanent sequelae was 4.6% (five of 109 patients). The incidence of device-related complications, such as infection or skin erosion, was also 4.6% (five of 109 patients). There is a significant incidence of adverse events associated with the DBS procedure. Nevertheless, DBS is clinically effective in well-selected patients and should be seriously considered as a treatment option for patients with medically refractory movement disorders.


High-efficiency zone-plate optics for multi-keV X-ray focusing.
High-efficiency nanofocusing of hard X-rays using stacked multilevel Fresnel zone plates with a smallest zone width of 200 nm is demonstrated. The approach is to approximate the ideal parabolic lens profile with two-, three-, four- and six-level zone plates. By stacking binary and three-level zone plates with an additional binary zone plate, the number of levels in the optical transmission function was doubled, resulting in four- and six-level profiles, respectively. Efficiencies up to 53.7% focusing were experimentally obtained with 6.5 keV photons using a compact alignment apparatus based on piezoelectric actuators. The measurements have also been compared with numerical simulations to study the misalignment of the two zone plates.


The cannabinoid CB1 receptor inverse agonist AM 251 and antagonist AM 4113 produce similar effects on the behavioral satiety sequence in rats.
Cannabinoid CB1 inverse agonists such as rimonabant and AM 251 hold therapeutic promise as appetite suppressants, but the extent to which non-motivational factors contribute to their anorectic effects is not fully known. Examination of the behavioral satiety sequence (BSS) in rats, the orderly progression from eating to post-prandial grooming and then resting, has revealed that these compounds preserve the order of events but differ markedly from natural satiation. The most notable difference is that grooming (particularly scratching) is profoundly enhanced at anorectic doses, while eating and resting are diminished, raising the possibility that the anorectic effect is simply secondary to the grooming effect. In the current design, the neutral CB1 antagonist AM 4113, which has been found to lack some of the undesirable effects of AM 251, produced nearly identical effects on the BSS as AM 251. The possibility that competition from enhanced grooming could account for the anorectic effect of AM 4113 was examined by yoking the pattern of disruptions caused by grooming in the AM 4113-treated group to forced locomotion in a different group fed in a modified running wheel. This response competition did not significantly reduce food intake. It was concluded that AM 4113, a CB1 neutral antagonist, produces the same effects on the BSS as AM 251, but that response competition from enhanced grooming may not be a sufficient explanation for the anorectic effects of CB1 antagonists/inverse agonists.


Hydrolysis of the amyloid beta-peptide (A beta) 1-40 between Asp23-Val24 produces non-aggregating fragments. An electrospray mass spectrometric study.
The aggregation of full-length (residues 1-40) amyloid beta-peptide (A beta) and fragments corresponding to residues 1-23 and 24-40 was studied by electrospray mass spectrometry, using gramicidin as a non-aggregating reference. Following a lag period, A beta(1-40) at 140 microM concentration aggregates with apparent first-order kinetics. Under acidic conditions A beta(1-40) undergoes spontaneous cleavage between Asp23-Val24 and to a lesser extent also at two other Asp-X motifs. Incubation in acidic H(2)18O showed incorporation of 18O in fragment A beta(1-23), confirming that the Asp23-Val24 peptide bond had been hydrolyzed. Incubation of synthetic A beta(1-23) and A beta(24-40) peptides with A beta(1-40) showed that A beta(24-40) remained in solution for several months, that A beta(1-23) partly disappeared from solution, whereas A beta(1-40) completely disappeared. Further, treatment of sedimentable aggregates formed after co-incubation of the three peptides with hexafluoro-2-propanol or formic acid recovered the intensity of A beta(1-40). These data support previous studies showing that the region of A beta encompassing residues 16-24 is necessary for aggregation into amyloid fibrils.


[Effect of diamide derivatives of imidazole- and pyrazoledicarboxylic acids on glyolysis indices depending on their structural characteristics].
A study was made of the effect of diamide derivatives of imidazole- and pyrazole-dicarboxylic acids on blood glycolysis in rabbits depending on structural and conformational features of the molecules. It was shown that glycolysis is affected by the position and magnitude of an alkyl substituent in the heterocyclic part of the molecule. An essential role in the manifestation of metabolic activity is played by structural similarity of the test compounds to the adenine molecule.


[Listeria monocytogenes and Listeria sp in heat-processed products].
Presence of Listeria monocytogenes in thermoprocessed food which is vacuum packaged, refrigerated stored and eaten uncooked or minimally heated was investigated. Thirty samples including sausage, large sausage with ham, spring large sausage, liverwurst and bologna were examined. Listeria monocytogenes was isolated and identified according to USDA-FSIS method for meat products, simultaneously with McBride agar. Seven out of 30 samples were found to contain listeriae. Five isolates were identified as Listeria monocytogenes through Gram coloration, culture appearance, biochemical test and serotyping. This product results potentially risky for the susceptible population. The presence of this microorganism in this kind of product suggests environmental post-process contamination or insufficient thermal process.


Multiwavelength anomalous solvent contrast (MASC): derivation of envelope structure-factor amplitudes and comparison with model values.
A previous article [Fourme et al. (1995). J. Synchrotron Rad. 2, 36-48] presented the theoretical foundations of MASC, a new contrast-variation method using multiwavelength anomalous scattering, and reported the first experimental results. New experiments have been conducted both at the ESRF (Grenoble, France) and at LURE-DCI (Orsay, France), using cryocooled crystals of three proteins of known structures and very different molecular weights. Amplitudes of {GammaT(h)}, the 'normal' structure factors of the anomalously scattering part of the crystal including the solvent zone and the ordered anomalous scattering sites (if any), have been extracted from multiwavelength data. In the very low resolution range (d >/= 20 A), the agreement between experimental {GammaT(h)} and model values calculated from the bulk solvent is all the more satisfactory since the molecular weight of the protein is high. For spacings between 10 and 20 A, the agreement between experimental {GammaT(h)} and model values is also satisfactory if one takes into account ordered anomalous scatterer sites. Such sites have been found in the three cases.


Testing for risk and protective trends in genetic analyses of HIV acquisition.
Host genetics studies of HIV-1 acquisition are critically important for the identification of new targets for drug and vaccine development. Analyses of such studies typically focus on pairwise comparisons of three different groups: HIV-1 positive individuals, HIV-1 high-risk seronegative individuals, and population controls. Because there is a clear expectation of how gene frequencies of risk or protective alleles would be ordered in the three groups, we are able to construct a statistical framework that offers a consistent increase in power over a wide-range of the magnitude of risk/protective effects. In this paper, we develop tests that constrain the alternative hypothesis to appropriately reflect risk or protective trends jointly across the three groups and show that they lead to a substantial increase in power over the naive pairwise approach. We develop both likelihood-ratio and score statistics that test for genetic effects across the three groups while constraining the alternative hypothesis to reflect biologically motivated trends of risk or protection. The asymptotic distribution of both statistics (likelihood ratio and score) is derived. We investigate the performance of our approach via extensive simulation studies using a biologically motivated model of HIV-1 acquisition, and find that our proposed approach leads to an increase in power of roughly 10-28%. We illustrate our approach with an analysis of the effect of the CCR5Δ32 mutation on HIV acquisition.


Adaptive homogeneity-directed demosaicing algorithm.
A cost-effective digital camera uses a single-image sensor, applying alternating patterns of red, green, and blue color filters to each pixel location. A way to reconstruct a full three-color representation of color images by estimating the missing pixel components in each color plane is called a demosaicing algorithm. This paper presents three inherent problems often associated with demosaicing algorithms that incorporate two-dimensional (2-D) directional interpolation: misguidance color artifacts, interpolation color artifacts, and aliasing. The level of misguidance color artifacts present in two images can be compared using metric neighborhood modeling. The proposed demosaicing algorithm estimates missing pixels by interpolating in the direction with fewer color artifacts. The aliasing problem is addressed by applying filterbank techniques to 2-D directional interpolation. The interpolation artifacts are reduced using a nonlinear iterative procedure. Experimental results using digital images confirm the effectiveness of this approach.


Experimental evidence that brighter males sire more extra-pair young in tree swallows.
Across taxa, extra-pair mating is widespread among socially monogamous species, but few studies have identified male ornamental traits associated with extra-pair mating success, and even fewer studies have experimentally manipulated male traits to determine whether they are related directly to paternity. As a consequence, there is little experimental evidence to support the widespread hypothesis that females choose more ornamented males as extra-pair mates. Here, we conducted an experimental study of the relationship between male plumage colour and fertilization success in tree swallows (Tachycineta bicolor), which have one of the highest levels of extra-pair mating in birds. In this study, we experimentally dulled the bright blue plumage on the back of males (with nontoxic ink markers) early in the breeding season prior to most mating. Compared with control males, dulled males sired fewer extra-pair young, and, as a result, fewer young overall. Among untreated males, brighter blue males also sired more extra-pair young, and in paired comparisons, extra-pair sires had brighter blue plumage than the within-pair male they cuckolded. These results, together with previous work on tree swallows, suggest that extra-pair mating behaviour is driven by benefits to both males and females.


Effect of Professional CGM (pCGM) on Glucose Management in Type 2 Diabetes Patients in Primary Care.
Little data exists regarding the impact of continuous glucose monitoring (CGM) in the primary care management of type 2 diabetes (T2D). We initiated a quality improvement (QI) project in a large healthcare system to determine the effect of professional CGM (pCGM) on glucose management. We evaluated both an MD and RN/Certified Diabetes Care and Education Specialist (CDCES) Care Model. Participants with T2D for >1 yr., A1C ≥7.0% to <11.0%, managed with any T2D regimen and willing to use pCGM were included. Baseline A1C was collected and participants wore a pCGM (Libre Pro) for up to 2 weeks, followed by a visit with an MD or RN/CDCES to review CGM data including Ambulatory Glucose Profile (AGP) Report. Shared-decision making was used to modify lifestyle and medications. Clinic follow-up in 3 to 6 months included an A1C and, in a subset, a repeat pCGM. Sixty-eight participants average age 61.6 years, average duration of T2D 15 years, mean A1C 8.8%, were identified. Pre to post pCGM lowered A1C from 8.8% ± 1.2% to 8.2% ± 1.3% (n=68, P=0.006). The time in range (TIR) and time in hyperglycemia improved along with more hypoglycemia in the subset of 37 participants who wore a second pCGM. Glycemic improvement was due to lifestyle counseling (68% of participants) and intensification of therapy (65% of participants), rather than addition of medications. Using pCGM in primary care, with an MD or RN/CDCES Care Model, is effective at lowering A1C, increasing TIR and reducing time in hyperglycemia without necessarily requiring additional medications.