A broader view: microbial enzymes and their relevance in industries, medicine, and beyond.
Enzymes are the large biomolecules that are required for the numerous chemical interconversions that sustain life. They accelerate all the metabolic processes in the body and carry out a specific task. Enzymes are highly efficient, which can increase reaction rates by 100 million to 10 billion times faster than any normal chemical reaction. Due to development in recombinant technology and protein engineering, enzymes have evolved as an important molecule that has been widely used in different industrial and therapeutical purposes. Microbial enzymes are currently acquiring much attention with rapid development of enzyme technology. Microbial enzymes are preferred due to their economic feasibility, high yields, consistency, ease of product modification and optimization, regular supply due to absence of seasonal fluctuations, rapid growth of microbes on inexpensive media, stability, and greater catalytic activity. Microbial enzymes play a major role in the diagnosis, treatment, biochemical investigation, and monitoring of various dreaded diseases. Amylase and lipase are two very important enzymes that have been vastly studied and have great importance in different industries and therapeutic industry. In this review, an approach has been made to highlight the importance of different enzymes with special emphasis on amylase and lipase in the different industrial and medical fields.


Impact of asian race on response to combination therapy with peginterferon alfa-2a and ribavirin in chronic hepatitis C.
Prior investigation has identified factors associated with response to treatment in hepatitis C including viral genotype and titre, body weight, hepatic fibrosis, and adherence to therapy. The lower response rate of African-Americans relative to whites has been previously described, but studies of other racial or ethnic groups remain limited. To determine whether Asian race is an independent marker for response to antiviral therapy in hepatitis C. Data on treatment-naïve patients from a large multicenter study of combination therapy with peginterferon alfa-2a (180 mug SC each week) and ribavirin (800 mg daily) were analyzed retrospectively to identify factors associated with an SVR, defined as an undetectable serum HCV RNA at least 24 wk after completion of therapy. SVR occurred in 45% of 384 whites and 65% of 52 Asians (P= 0.0047) who were treatment naïve. In a multivariate logistic regression analysis that adjusted for all the aforementioned factors known to be associated with treatment response, Asian race was shown to be an independent predictor of achieving an SVR (OR 2.22, 95% CI 1.11-4.46). Other independent predictors of SVR include viral genotype, body mass index, degree of hepatic fibrosis, and adherence with ribavirin. Asians are more likely to achieve an SVR to treatment with peginterferon alfa-2a and ribavirin than whites with chronic hepatitis C, suggesting a genetic influence on the antiviral response.


Effect of Ki-67 assessment in the distribution of breast cancer subtypes: Evaluation in a cohort of Latin American patients.
Breast cancer (BC) is a heterogeneous disease composed of four main subtypes with distinct clinical and epidemiological features. Although several reports have described the distribution of BC subtypes in Latin America, the majority of them have not included the cellular marker, Ki-67, in the immunohistochemical (IHC) panel. The aim of the present study was to describe the distribution of BC subtypes in a cohort of Latin American women using an IHC panel with Ki-67. A prospective cohort of 580 patients in three centers of Peru (the Hospital Nacional Edgardo Rebagliatti Martins, the Hospital Nacional Guillermo Almenara Irigoyen, the Hospital Nacional Alberto Sabogal, Lima) and one in Uruguay (Instituto Nacional del Cáncer, Montevideo) were evaluated. BC phenotypes were classified according to an IHC panel: Estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki-67. Silver in situ hybridization was used when the HER2 status, as determined by IHC, was equivocal. The associations between the BC phenotypes and their clinicopathological features were evaluated. ER was positive in 65% of the cases (n=377), and PgR in 50% (n=203). In total, 79.1% (n=459) were HER2-negative, 19.8% (n=115) were HER2-positive and 1% (n=6) had an equivocal status. With respect to Ki-67, 44.7% of the patients exhibited staining in >14% of the tumor cells (n=259). The distribution of subtypes was as follows: Luminal A, 31.9% (n=183); luminal B, 35% (n=201); HER2, 12.1% (n=70); and triple-negative, 20.9% (n=120). When Ki-67 was not included in the panel, the frequency of luminal A was 41.1% and luminal B, 25.8% (9.2% of the cases were misclassified). Ki-67 was most highly expressed in triple-negative and HER2 tumors. Inclusion of Ki-67 in the IHC panel to assign subtypes revealed a higher frequency of luminal B tumors than was reported previously for Latin American women with BC, whereas the distribution of triple-negative and HER2 tumors were similar to that previously reported. In conclusion, these results demonstrated that excluding Ki-67 from the panel of IHC markers may lead to an underestimation of the rates of luminal B tumors.


The transcriptional repression of the human Cu/Zn superoxide dismutase(sod1) gene by the anticancer drug, mitomycin C(MMC).
The Cu/Zn superoxide dismutase(sod1) is one of the key enzymes that protects cells against oxidative stress. In order to investigate the effects of mitomycin C(MMC) on the induction of apoptotic cell death and on the sod1 transcription level, the CATs activity of HepG2 cells transfected with sod1 promoter-CAT(chloramphenicol acetyl transferase) fusion reporter was measured after MMC treatment. The CAT assay showed that exposure of HepG2 cells to MMC decreased the transcription level of the sod1 gene. The accumulation of p53 tumor suppressor protein by MMC treatment of HepG2 cells was noted. In order to investigate the p53-negative response element in its promoter region, a p53 cotransfection experiment with serially deleted sod1 promoter/CAT reporter constructs was performed. The results show a significant reduction of CAT activity in all deletion reporter constructs. The results show that MMC treatment inhibited sod1 gene transcription through p53-mediated transcriptional repression.


Withaferin A induces cell death and differentiation in multiple myeloma cancer stem cells.
Multiple myeloma (MM) remains an incurable malignancy despite the development of novel therapeutics. This is believed to be due to a subset of rare chemotherapy-resistant cancer stem cells (CSCs). Differentiation therapy represents one strategy aimed at reducing the stemness of CSCs. The anticancer effect of withaferin A (WFA) was studied in MM-CSCs and RPMI 8226 MM tumoral plasma cells (RPMIs). WFA exhibited growth inhibitory effects in both MM-CSCs and RPMIs, with IC50 values of 649 and 224 nM, respectively. WFA also induced a G2 cell cycle arrest, as well as cell death and apoptosis. Although, WFA did not exhibit a direct anti-migratory effect, a remarkable morphological change was observed in MM-CSCs in response to WFA treatment. Using qPCR gene expression analyses, WFA caused a reduction in stemness markers, and a promotion of differentiation markers in MM-CSCs. These results warrant further investigation of WFA in relevant MM animal models.


Phnomibacter ginsenosidimutans gen. nov., sp. nov., a novel glycoside hydrolase positive bacterial strain with ginsenoside hydrolysing activity.
The conversion of major ginsenosides into minor ginsenosides attracts a lot of interest because of their biological and pharmaceutical activities. Therefore, for the conversion of ginsenosides, finding a novel competent glycoside hydrolase-producing bacterial strain is useful for future research studies and the mass production of minor ginsenosides. Wastewater samples were collected and screened for novel glycoside hydrolase bacterial strains using Reasoner's 2A+aesculin agar medium. As a result, a novel glycoside hydrolase positive bacterial strain (SB-02T) was identified and subjected to a polyphasic taxonomic analysis. Based on genome analysis, strain SB-02T was found to be affiliated with the family Chitinophagaceae and have less than 92.8 % sequence similarity to other members of the same family. Functional analysis indicated that SB-02T was able to hydrolyse the ginsenosides Rb1, Rc and Rd to F2 and C-K. Due to the conversion of ginsenosides, the strain's genome was sequenced and the genes were annotated by the NCBI. The average amino acid identity and average nucleotide identity values between SB-02T and the available reference genomes were 65.7 and 65.9 %, respectively. The novel isolate contained MK-7 as the predominant menaquinone, the major polyamine putrescine, and iso-C15 : 0, iso-C15 : 1 G and iso-C17 : 0 3-OH as major fatty acids. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Thus, based on the data presented here, strain SB-02T represents a novel species within a new genus in the family Chitinophagaceae, for which the name Phnomibacter ginsenosidimutans gen. nov., sp. nov. is proposed. The type strain of Phnomibacter ginsenosidimutans is SB-02T (=KACC 21266T=LMG 31707T). The genome annotation of SB-02T shows many glycoside hydrolase genes, which may be responsible for the efficient production of many kinds of minor ginsenosides and will be very helpful for future research (target gene cloning) and mass production of either F2 or C-K.


MRF energy minimization and beyond via dual decomposition.
This paper introduces a new rigorous theoretical framework to address discrete MRF-based optimization in computer vision. Such a framework exploits the powerful technique of Dual Decomposition. It is based on a projected subgradient scheme that attempts to solve an MRF optimization problem by first decomposing it into a set of appropriately chosen subproblems, and then combining their solutions in a principled way. In order to determine the limits of this method, we analyze the conditions that these subproblems have to satisfy and demonstrate the extreme generality and flexibility of such an approach. We thus show that by appropriately choosing what subproblems to use, one can design novel and very powerful MRF optimization algorithms. For instance, in this manner we are able to derive algorithms that: 1) generalize and extend state-of-the-art message-passing methods, 2) optimize very tight LP-relaxations to MRF optimization, and 3) take full advantage of the special structure that may exist in particular MRFs, allowing the use of efficient inference techniques such as, e.g., graph-cut-based methods. Theoretical analysis on the bounds related with the different algorithms derived from our framework and experimental results/comparisons using synthetic and real data for a variety of tasks in computer vision demonstrate the extreme potentials of our approach.


miTALOS v2: Analyzing Tissue Specific microRNA Function.
MicroRNAs are involved in almost all biological processes and have emerged as regulators of signaling pathways. We show that miRNA target genes and pathway genes are not uniformly expressed across human tissues. To capture tissue specific effects, we developed a novel methodology for tissue specific pathway analysis of miRNAs. We incorporated the most recent and highest quality miRNA targeting data (TargetScan and StarBase), RNA-seq based gene expression data (EBI Expression Atlas) and multiple new pathway data sources to increase the biological relevance of the predicted miRNA-pathway associations. We identified new potential roles of miR-199a-3p, miR-199b-3p and the miR-200 family in hepatocellular carcinoma, involving the regulation of metastasis through MAPK and Wnt signaling. Also, an association of miR-571 and Notch signaling in liver fibrosis was proposed. To facilitate data update and future extensions of our tool, we developed a flexible database backend using the graph database neo4j. The new backend as well as the novel methodology were included in the updated miTALOS v2, a tool that provides insights into tissue specific miRNA regulation of biological pathways. miTALOS v2 is available at http://mips.helmholtz-muenchen.de/mitalos.


Simplified method to quantify valve back-leak uncovers severe mesenteric lymphatic valve dysfunction in mice deficient in connexins 43 and 37.
Lymphatic valve defects are one of the major causes of lymph transport dysfunction; however, there are no accessible methods for quantitatively assessing valve function. This report describes a novel technique for quantifying lymphatic valve back-leak. Postnatal endothelial-specific deletion of connexin 43 (Cx43) in connexin 37 null (Cx37-/- ) mice results in rapid regression of valve leaflets and severe valve dysfunction. This method can also be used for assessing the function of venous and lymphatic valves from various species, including humans. The lymphatic system relies on robust, spontaneous contractions of collecting lymphatic vessels and one-way secondary lymphatic valves to efficiently move lymph forward. Secondary valves prevent reflux and allow for the generation of propulsive pressure during each contraction cycle. Lymphatic valve defects are one of the major causes of lymph transport dysfunction. Genetic mutations in multiple genes have been associated with the development of primary lymphoedema in humans; and many of the same mutations in mice result in valve defects that subsequently lead to chylous ascites or chylothorax. At present the only experimental technique for the quantitative assessment of lymphatic valve function utilizes the servo-null micropressure system, which is highly accurate and precise, but relatively inaccessible and difficult to use. We developed a novel, simplified alternative method for quantifying valve function and determining the degree of pressure back-leak through an intact valve in pressurized, single-valve segments of isolated lymphatic vessels. With this diameter-based method, the competence of each lymphatic valve is challenged over a physiological range of pressures (e.g. 0.5-10cmH2 O) and pressure back-leak is extrapolated from calibrated, pressure-driven changes in diameter upstream from the valve. Using mesenteric lymphatic vessels from C57BL/6J, Ub-CreERT2 ;Rasa1fx/fx , Foxc2Cre/+ , Lyve1-Cre;Cx43fx/fx , and Prox1-CreERT2 ;Cx43fx/fx ;Cx37-/- mice, we tested our method on lymphatic valves displaying a wide range of dysfunction, from fully competent to completely incompetent. Our results were validated by simultaneous direct measurement of pressure back-leak using a servo-null micropressure system. Our diameter-based technique can be used to quantify valve function in isolated lymphatic valves from a variety of species. This method also revealed that haplodeficiency in Foxc2 (Foxc2Cre/+ ) is not sufficient to cause significant valve dysfunction; however, postnatal endothelial-specific deletion of Cx43 in Cx37-/- mice results in rapid regression of valve leaflets and severe valve dysfunction.


In vivo study of halothane hepatotoxicity in the rat using magnetic resonance imaging and 31P spectroscopy.
Using magnetic resonance imaging (MRI) and spectroscopy (MRS), in vivo halothane hepatotoxicity was assessed in male Wistar rats. With 1.5% halothane in 100 or 20% O2, an edematous region, characterized by increased intensity on T2 weighted images and an increase in regional tissue water content (rho water), was seen proximal to the hepatic portal vein in the liver. Both spin-lattice relaxation (T1) and spin-spin relaxation (T2) increased in this region, relative to distal regions of the liver. Similarly, a high signal intensity on proton density weighted images was observed in this area. As halothane anaesthesia progressed, a decrease in the adenosine triphosphate-inorganic phosphate ratio (ATP/Pi) and an increase in the phosphomonoester-phosphodiester (PME/PDE) ratio was detected in the liver. In addition, intracellular pH decreased and intracellular free magnesium concentration [Mg2+] increased with time of exposure. Excessive vacuolation, ribosomal disappearance from rough endoplasmic reticulum, mitochondrial swelling and fragmentation of smooth endoplasmic reticulum were observed by transmission electron microscopy (TEM) in samples from the edematous region of the liver.


Design, analysis, and implementation of a telemedicine remote consultation and diagnosis session playback using discrete event system specification.
Telemedicine remote consultation and diagnosis (RCD) software is a complex and distributed system. RCD allows physicians to collaborate on radiology or pathology cases from distributed geographic locations. It is very important to simplify design, construction, and maintenance of such a system. Currently, object-oriented design methodology is used to design and develop a software system in a modular fashion. Object-oriented software is made of various objects that work together. From the design of the software system, we get information about object methods and inheritance. We also get information about which objects are contained in a particular object and which objects are used by another object. One important element that the traditional object-oriented design misses is time. We propose the use of discrete event system specification (DEVS) in the design and analysis of a software system, such as RCD. With DEVS, coupling between objects can be specified explicitly and an object behavior can be shown in time. We introduce DEVS, show the time-line analysis of Remote Consultation and Diagnosis session playback using DEVS, and then describe its implementation.


Complete Genome Sequence of a Vancomycin-Resistant Sequence Type 203 Enterococcus faecium Strain with vanA Belonging to Complex Type 859.
In 2014, the first vancomycin-resistant (encoded by vanA) Enterococcus faecium isolate belonging to sequence type 203 (ST203) and complex type 859 (CT859) was detected in Denmark. In 2016, 64% of the Danish clinical vanA E. faecium isolates belonged to ST203 and CT859. Using Pacific Biosciences (PacBio) RS II sequencing, we describe the genome of ST203 CT859 vanA E. faecium.


Sarcoidosis of the spinal cord. Report of an autopsy case and review of the literature.
The authors report a female elderly patient with quadriplegia, hypesthesia below the neck, and rectourinary dysfunction, which were found at autopsy to have been caused by involvement of the lower cervical and upper thoracic segments of the spinal cord in systemic sarcoidosis. Sixty cases of spinal cord sarcoidosis reported in the literature are also reviewed. Most patients had clinical signs which mimicked those of a spinal cord tumor or meningomyelitis. Only in less than one-third of the cases had sarcoidosis been diagnosed before neurological symptoms occurred. Macroscopically, most intramedullary lesions formed a mass, whereas extramedullary lesions usually manifested as meningitis. Histologically, perivascular distribution of sarcoid granulomas was noted in our patient as well as in many cases reported in the literature. The clinical course of the patients with spinal sarcoidosis was usually poor when early diagnosis was not made.


Evaluation of trace metals in tobacco of local and imported cigarette brands used in Pakistan by spectrophotometer through microwave digestion.
Uncontrolled exposure of active and passive smokers to trace metals causes increase in health risks. The primary objective of this study was to determine whether local and imported cigarette brands used in Pakistan, have elevated levels of metals or not. Six metals manganese (Mn), cobalt (Co), copper (Cu), cadmium (Cd), lead (Pb) and zinc (Zn) were determined in tobacco of twenty cigarette brands (local and imported) used in Pakistan by flame atomic absorption Spectrophotometry. To overcome contamination chances and for complete digestion of analytes a microwave digester was used. The analytical results showed highest concentration of Mn (84.78 microg/g dry weight), Cd (0.525 microg/g dry weight) and Zn (14.34 microg/g dry weight) metals in imported brands in relation to counterparts from the local brands. Certain elevated levels were observed for Co (3.344 microg/g dry weight), Pb (14.16 microg/g dry weight) and Cu (7.889 microg/g dry weight) metals in local brands. The inter-metal relationships in the tobacco of local and imported cigarette brands showed some integrated variation in the selected metal levels. In view of health risk associated with the above metals, there should be a strict quality control over monitoring of heavy metals during growing, processing and smoking of tobacco. Therefore, it is prudent to minimize exposure to toxic substances whenever possible because smoking and exposure to cigarette smoke is a confounder to be taken into account when carrying out epidemiological studies on human exposure to metals.


Vascular Smooth Muscle Cells in Atherosclerosis.
The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis.


Serum creatine phosphokinase activity and histological changes in the multifidus muscle: a prospective randomized controlled comparative study of discectomy with or without retraction.
The aim of this study was to determine the extent of muscle injury caused by continuous or intermittent muscle retraction during macro- and microdiscectomy in lumbar disc surgery. Pain scores, serum creatine phosphokinase (CPK) levels, and histological findings obtained in muscle specimens were compared. Sixty patients who underwent surgery for a one-level disc herniation during a 1-year period (January 2004-January 2005) and who had similar demographic characteristics were randomly assigned to one of four groups, each consisting of 15 patients: Group A, microdiscectomy in which the retractor was never released; Group B, microdiscectomy in which the retractor was released every 15 minutes; Group C, macrodiscectomy in which the retractor was never released; and Group D, macrodiscectomy in which the retractor was released every 15 minutes. Muscle biopsy samples were acquired in each group, and biochemical studies were conducted to determine serum CPK levels. The duration of muscle retraction was 15 minutes followed by 3 minutes of relaxation in Groups B and D. In all groups, muscle degeneration and elevation in serum CPK levels were observed immediately after surgery. The overall results, however, were different. The decline of serum CPK levels started 1 week after surgery. The smallest degree of muscle injury (reflected by the lowest serum CPK level) was observed in Group B. When the pre- and postoperative CPK values were compared in all groups, the patients in Groups B and D reported the least amount of back pain (p < 0.001). No significant differences in serum CPK levels were observed between Groups A and C or between Groups B and D. The extent of back pain was evaluated using a visual analog scale, and the consumption of analgesics was also assessed. The groups exhibited significantly different responses: the lowest analgesic consumption and the lowest pain scores were demonstrated in Groups B and D. In this prospective randomized clinical trial, the authors determined that muscle injury during lumbar disc surgery was closely related to muscle retraction and relaxation times whereas the size of the paravertebral skin incision had no effect on postoperative back pain and disability. There was no significant difference among the groups in terms of back pain during the long-term follow-up period (18-19 months).


Cross-sectional relations of arterial stiffness, pressure pulsatility, wave reflection, and arterial calcification.
Arterial hemodynamics and vascular calcification are associated with increased risk for cardiovascular disease, but their inter-relations remain unclear. We sought to examine the associations of arterial stiffness, pressure pulsatility, and wave reflection with arterial calcification in individuals free of prevalent cardiovascular disease. Framingham Heart Study Third Generation and Offspring Cohort participants free of cardiovascular disease underwent applanation tonometry to measure arterial stiffness, pressure pulsatility, and wave reflection, including carotid-femoral pulse wave velocity, central pulse pressure, forward wave amplitude, and augmentation index. Participants in each cohort (n=1905, 45±6 years and n=1015, 65±9 years, respectively) underwent multidetector computed tomography to assess the presence and quantity of thoracic aortic calcification, abdominal aortic calcification, and coronary artery calcification. In multivariable-adjusted models, both higher carotid-femoral pulse wave velocity and central pulse pressure were associated with greater thoracic aortic calcification and abdominal aortic calcification, whereas higher augmentation index was associated with abdominal aortic calcification. Among the tonometry measures, carotid-femoral pulse wave velocity was the strongest correlate of all calcification measures in multivariable-adjusted models (odds ratio per SD for thoracic aortic calcification, 2.69 [95% confidence interval, 2.17-3.35]; abdominal aortic calcification, 1.47 [95% confidence interval, 1.26-1.73]; and coronary artery calcification, 1.48 [95% confidence interval, 1.28-1.72]; all P<0.001, respectively). We observed stronger relations of carotid-femoral pulse wave velocity, central pulse pressure, and forward wave amplitude with nearly all continuous calcification measures in the younger Third Generation Cohort as compared with the Offspring Cohort. In community-dwelling individuals without prevalent cardiovascular disease, abnormal central arterial hemodynamics were positively associated with vascular calcification and were observed at younger ages than previously recognized. The mechanisms of these associations may be bidirectional and deserve further study.


Investigation of genetic susceptibility factors for human longevity - a targeted nonsynonymous SNP study.
Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25-32%. Experimental model organisms point to the existence of core survival and anti-ageing pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger control subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity research conducted to-date. The three top-ranking markers, which are located in the genes DUSP6, NALP1 and PERP, revealed p-values≤0.01 in the allelic case-control comparisons. Although the association signals in Germans were not replicated in an independent French sample, the large number of analysis results is deemed a valuable reference point for further genetic studies.


[Mechanism of bacterial resistance to tetracyclines and the importance of structural elements of tetracycline molecule for induction of resistance].
The resistance of Staphylococcus aureus P-282 and E. coli E-107 to chlorotetracycline is based on the acquired ability of energy-dependent "counteraction" with regard to penetration of the antibiotic in to the cells. Thus, inhibitors of energy processes stimulate chlorotetracycline absorption by resistant strains and increase their sensitivity to the antibiotic. The studied bacterial hospital strains absorb chlorotetracycline by means of oxalacetic acid transport system similar to resistant strains obtained in the laboratory. The transport system of chlorotetracycline is stereospecific and is involved in absorption of analogues of the antibiotic with the intact phenoldiketone or diphenol structure of the molecule. These analogues, like the natural antibiotic, induce an increase in the resistance to the antibiotic. No changes in the nature of the antibiotic transport system occur during induction. The increased resistance caused by induction is due entirely to a decrease in absorption of the antibiotic by the cells.


Random main effects of treatment: A case study with a network meta-analysis.
If the number of treatments in a network meta-analysis is large, it may be possible and useful to model the main effect of treatment as random, that is to say as random realizations from a normal distribution of possible treatment effects. This then constitutes a third sort of random effect that may be considered in connection with such analyses. The first and most common models treatment-by-trial interaction as being random and the second, rather rarer, models the main effects of trial as being random and thus permits the recovery of intertrial information. Taking the example of a network meta-analysis of 44 similar treatments in 10 trials, we illustrate how a hierarchical approach to modeling a random main effect of treatment can be used to produce shrunk (toward the overall mean) estimates of effects for individual treatments. As a related problem, we also consider the issue of using a random-effect model for the within-trial variances from trial to trial. We provide a number of possible graphical representations of the results and discuss the advantages and disadvantages of such an approach.


Evaluation of MR imaging compatibility of a new intracranial pressure monitoring device.
We report our observations on MR imaging quality and functionality of a recently introduced intracranial pressure monitoring device. The device was tested at two different field strengths in a pig brain specimen to investigate MR imaging artifacts, probe function during and after MR data acquisition, and device-related temperature changes in the brain tissue. Image reading was not impaired, and probe function, although reduced, was not fully interrupted during data acquisition.


[Nearly total thyroidectomy: versus total thyroidectomy: our experience].
Generally, the classification of thyroidectomy as benign pathology is: multinodular toxic goitre, simple goitre, toxic adenoma, Base-dow disease, Hashimoto's tyroiditis Subtotal thyroidectomy provides for the removal of the gland except for a bilateral residue of about 6-10 g, near total thyroidectomy provides for the near total removal of the gland except for a residue inferior to 5 grams. Near total thyroidectomy has taken the place of the subtotal thyroidectomy. In two years, in our institute, there have been exeuted: 96 near total thyrodectomies, 96 total thyroidetomies, 8 lobectomies ad two revues for recurrencies. In 2 cases there have been haemorrhagies after nearly total thyroidetomy. Only in 1 case we practiced tracheotomy for follicular carcinoma infiltering thiroidic cartilage. In 2 cases treated with nearly total thyroidetomy and in 4 cases treated with total thyroidetomy, there has been temporary hypoparathyroidism. In no case treared wih nearly total thyroidetomy and in 2 cases treated with total thyroidetomy, there has been permanent hypo-parathyroidism. In 5 cases treated with total thyroidetomy and in no case treated with nearly total thyroidetomy, there has been, monolateral, temporary paralysis of the inferior laryngeal nerve that solved in 6 months for 3 patients and in 2 months for 2 patients. There has not been permanent paralysis of the mono or bilateral inferior laryngeal nerve. Even if the surgical approach to the benign disease is now orientated to the total thyroidectomy, a more conservative surgery is, in our opinion, justified when a malignant pathology is excluded and considering also the low effect of recurrencies and hypothyroidism.


Validation of the Brief Coping Orientation to Problem Experienced (Brief COPE) inventory in people living with HIV/AIDS in Vietnam.
The Brief Coping Orientation to Problem Experienced (Brief COPE) inventory is one of the most widely used instruments in coping research; however, no study has evaluated the psychometric properties of the Brief COPE in the Vietnamese population. This study aimed to validate a culturally appropriate Vietnamese version of the Brief COPE for the evaluation of coping strategies in people living with HIV/AIDS in Vietnam. We translated the Brief COPE into Vietnamese, and it was self-administered among 1,164 HIV-infected patients receiving antiretroviral therapy at a large HIV outpatient clinic in Hanoi between January 2019 and March 2020. Data on demographics and HIV-related information, depression and social support were also collected. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were conducted to assess construct validity. Content validity, internal consistency, and convergent validity were also assessed. The CFA of a 14-factor structure of the original Brief COPE revealed acceptable model fitness, but poor internal consistency for some subscales. In the subsequent EFA, we found a revised 26-item version which had a six-factor structure consisting of problem-solving, avoidance, humor, social support, religion, and substance use. The final CFA found that the model fitness of the revised scale with fewer factor structures was comparable to that of the original Brief COPE; the internal consistency of the revised scale was even better than that of the original scale. Furthermore, six factors of the revised scale showed anticipated associations with depression and social support.


Experiences of South Asian patients in early inflammatory arthritis clinic: a qualitative interview study.
The aim was to explore how UK South Asian patients living with RA interact with health care professionals and experience receiving health information in an early inflammatory arthritis clinic. A semi-structured interview schedule, designed in conjunction with a patient partner, was used for face-to-face interviews. South Asian participants with RA were recruited from Central Manchester University Hospitals National Health Service Foundation Trust. Data were recorded and transcribed by an independent company. Data were analysed using inductive thematic analysis. Fifteen participants were interviewed. Three predominant themes emerged around participants' experiences and interaction with health care professionals in early inflammatory arthritis clinic. First, 'the personal experiences of RA and cultural link to early inflammatory arthritis clinic', where participants described the impact of RA as individuals and their altered roles within their cultural setting. Second, 'experiences of interacting and receiving information in the early inflammatory arthritis clinic', where participants described their limited engagement with health care professionals and the quality of information discussed in the clinic. Third, 'views on future content for early inflammatory arthritis clinics', where participants highlighted new innovative ideas to build on current practice. We believe this to be the first study to generate insight into the experiences of South Asian patients of interacting with health care professionals while attending an early inflammatory arthritis clinic. Policy directives aimed at improving access to services and delivery of information for ethnic minority groups in early inflammatory arthritis clinics should include consideration of the different roles of cultures. Professionals should be cognizant of the factors that drive health inequalities and focus on improving service delivery.


Online Training of an Opto-Electronic Reservoir Computer Applied to Real-Time Channel Equalization.
Reservoir computing is a bioinspired computing paradigm for processing time-dependent signals. The performance of its analog implementation is comparable to other state-of-the-art algorithms for tasks such as speech recognition or chaotic time series prediction, but these are often constrained by the offline training methods commonly employed. Here, we investigated the online learning approach by training an optoelectronic reservoir computer using a simple gradient descent algorithm, programmed on a field-programmable gate array chip. Our system was applied to wireless communications, a quickly growing domain with an increasing demand for fast analog devices to equalize the nonlinear distorted channels. We report error rates up to two orders of magnitude lower than previous implementations on this task. We show that our system is particularly well suited for realistic channel equalization by testing it on a drifting and a switching channel and obtaining good performances.


Perceived discrimination in health care and health status in a racially diverse sample.
Despite the surge of recent research on the association between perceived discrimination and health-related outcomes, few studies have focused on race-based discrimination encountered in health care settings. This study examined the prevalence of such discrimination, and its association with health status, for the 3 largest race/ethnic groups in the United States. Data were drawn from the 2004 Behavioral Risk Factor Surveillance System survey. The primary variables were perceived racial discrimination in health care and self-reported health status. Multivariable logistic regression was used to compare the prevalence of perceived discrimination for whites, African Americans, and Hispanics, and to examine the association between perceived discrimination and health status, controlling for sex, age, income, education, health care coverage, affordability of medical care, racial salience, and state. Perceived discrimination was reported by 2%, 5.2%, and 10.9% of whites, Hispanics, and African Americans, respectively. Only the difference between African Americans and whites remained significant in adjusted analyses [odds ratio (OR) = 3.22, 95% confidence interval (CI) = 2.46-4.21]. Racial/ethnic differences in perceived discrimination depended on income, education, health care coverage, and affordability of medical care. Perceived discrimination was associated with worse health status for the overall sample (OR = 1.71, 95% CI = 1.35-2.16). Stratified analyses revealed that this relationship was significant for whites (OR = 2.00, 95% CI = 1.45-2.77) and African Americans (OR = 1.95, 95% CI = 1.39-2.73), but not for Hispanics (OR = 0.55, 95% CI = 0.24-1.22). Perceived racial discrimination in health care is much more prevalent for African Americans than for whites or Hispanics. Furthermore, such discrimination is associated with worse health both for African Americans and for whites.


A bicarbonate-alkaline mineral water protects from ethanol-induced hemorrhagic gastric lesions in mice.
Ingestion of elevated amounts of ethanol in humans and rodents induces hemorrhagic gastric lesions, at least in part by increasing oxidative stress. The present study was undertaken in order to evaluate the influence of a bicarbonate-alkaline mineral water (Uliveto on ethanol-induced hemorrhagic gastric lesions in mice. Lesions were evaluated by both macroscopic and microscopic analysis. In a first set of experiments, mice were allowed to drink Uliveto or reference water ad libitum until 3 h prior to intragastric (i.g.) ethanol (23 ml/kg) administration. Neither Uliveto nor reference water did afford any protection. In a second set of experiments, acute exposure to reference water (35 ml/kg, i.g.), given 30 min before ethanol, did not inhibit gastric lesions. However, administration of the same amount of Uliveto caused a remarkable reduction in ethanol-evoked gastric lesions. Ethanol administration increased 4-hydroxy-2-nonenal levels, a byproduct of oxidative stress, in the luminal part of the gastric mucosa. This response was substantially reduced by about 70% by Uliveto, but not by reference water. Reference water, added with the bicarbonate content, present in the Uliveto water, protected against ethanol-induced lesions. Thus, acute pre-exposure to bicarbonate-alkaline mineral water (Uliveto) protects from both oxidative stress and hemorrhagic gastric lesions caused by ethanol. The elevated bicarbonate content of Uliveto likely accounts for the protection against ethanol-induced gastric injury.


Release and endogenous actions of the gastrin/cholecystokinin (CCK) family in the chicken.
The regulation of cholecystokinin (CCK) and gastrin release in the chicken and their endogenous actions are summarized. Both dietary protein and amino acids stimulated CCK releases. Among dietary fat sources, medium-chain triacylglycerol (MCT) was a potent stimulator of CCK release compared with long-chain triacylglycerol (LCT). However, it is difficult to explain that endogenous CCK released by those stimulators has an important role in the avian gastrointestinal physiology. Luminal acids may be an important regulator in pancreatic enzyme and fluid secretion. Gastrin (a regulator of luminal acid secretion) release was stimulated by food components, strongly by MCT, but not by LCT, and weakly by some amino acids, and was inhibited by luminal acids. Luminal acids controlled food passage from the crop. In conclusion, gastrointestinal physiology may be directly regulated by luminal acid rather than by the gastrin/CCK family in the chicken.


Nanosecond laser pulse stimulation of spiral ganglion neurons and model cells.
Optical stimulation of the inner ear has recently attracted attention, suggesting a higher frequency resolution compared to electrical cochlear implants due to its high spatial stimulation selectivity. Although the feasibility of the effect is shown in multiple in vivo experiments, the stimulation mechanism remains open to discussion. Here we investigate in single-cell measurements the reaction of spiral ganglion neurons and model cells to irradiation with a nanosecond-pulsed laser beam over a broad wavelength range from 420 nm up to 1950 nm using the patch clamp technique. Cell reactions were wavelength- and pulse-energy-dependent but too small to elicit action potentials in the investigated spiral ganglion neurons. As the applied radiant exposure was much higher than the reported threshold for in vivo experiments in the same laser regime, we conclude that in a stimulation paradigm with nanosecond-pulses, direct neuronal stimulation is not the main cause of optical cochlea stimulation.


Templated assembly of albumin-based nanoparticles for simultaneous gene silencing and magnetic resonance imaging.
In this article, we address the design of innovative human serum albumin (HSA)-based nanoparticles loaded with silencing RNA and grafted with gadolinium complexes having average sizes ranging from ca. 50 to 150 nm according to the siRNA/HSA composition. The non-covalent siRNA/HSA assembly is formed on isobutyramide-modified mesoporous silica and the self-supported HSA-based nanoparticles are obtained following the silica template dissolution. These original protein particles provide simultaneous magnetic resonance imaging contrast enhancement and cellular in vitro gene silencing.


Secondary Organic Aerosol Formation via 2-Methyl-3-buten-2-ol Photooxidation: Evidence of Acid-Catalyzed Reactive Uptake of Epoxides.
Secondary organic aerosol (SOA) formation from 2-methyl-3-buten-2-ol (MBO) photooxidation has recently been observed in both field and laboratory studies. Similar to the level of isoprene, the level of MBO-derived SOA increases with elevated aerosol acidity in the absence of nitric oxide; therefore, an epoxide intermediate, (3,3-dimethyloxiran-2-yl)methanol (MBO epoxide), was synthesized and tentatively proposed to explain this enhancement. In this study, the potential of the synthetic MBO epoxide to form SOA via reactive uptake was systematically examined. SOA was observed only in the presence of acidic aerosol. Major SOA constituents, 2,3-dihydroxyisopentanol and MBO-derived organosulfate isomers, were chemically characterized in both laboratory-generated SOA and in ambient fine aerosol collected from the BEACHON-RoMBAS field campaign during the summer of 2011, where MBO emissions are substantial. Our results support the idea that epoxides are potential products of MBO photooxidation leading to the formation of atmospheric SOA and suggest that reactive uptake of epoxides may explain acid enhancement of SOA observed from other biogenic hydrocarbons.


Major trauma presentations and patient outcomes in English hospitals during the COVID-19 pandemic: An observational cohort study.
Single-centre studies suggest that successive Coronavirus Disease 2019 (COVID-19)-related "lockdown" restrictions in England may have led to significant changes in the characteristics of major trauma patients. There is also evidence from other countries that diversion of intensive care capacity and other healthcare resources to treating patients with COVID-19 may have impacted on outcomes for major trauma patients. We aimed to assess the impact of the COVID-19 pandemic on the number, characteristics, care pathways, and outcomes of major trauma patients presenting to hospitals in England. We completed an observational cohort study and interrupted time series analysis including all patients eligible for inclusion in England in the national clinical audit for major trauma presenting between 1 January 2017 and 31 of August 2021 (354,202 patients). Demographic characteristics (age, sex, physiology, and injury severity) and clinical pathways of major trauma patients in the first lockdown (17,510 patients) and second lockdown (38,262 patients) were compared to pre-COVID-19 periods in 2018 to 2019 (comparator period 1: 22,243 patients; comparator period 2: 18,099 patients). Discontinuities in trends for weekly estimated excess survival rate were estimated when lockdown measures were introduced using segmented linear regression. The first lockdown had a larger associated reduction in numbers of major trauma patients (-4,733 (21%)) compared to the pre-COVID period than the second lockdown (-2,754 (6.7%)). The largest reductions observed were in numbers of people injured in road traffic collisions excepting cyclists where numbers increased. During the second lockdown, there were increases in the numbers of people injured aged 65 and over (665 (3%)) and 85 and over (828 (9.3%)). In the second week of March 2020, there was a reduction in level of major trauma excess survival rate (-1.71%; 95% CI: -2.76% to -0.66%) associated with the first lockdown. This was followed by a weekly trend of improving survival until the lifting of restrictions in July 2020 (0.25; 95% CI: 0.14 to 0.35). Limitations include eligibility criteria for inclusion to the audit and COVID status of patients not being recorded. This national evaluation of the impact of COVID on major trauma presentations to English hospitals has observed important public health findings: The large reduction in overall numbers injured has been primarily driven by reductions in road traffic collisions, while numbers of older people injured at home increased over the second lockdown. Future research is needed to better understand the initial reduction in likelihood of survival after major trauma observed with the implementation of the first lockdown.


Impact of screening versus symptomatic measurement of deep vein thrombosis in a national quality improvement registry.
Deep vein thrombosis (DVT) is a quality measure recorded by initiatives such as the National Surgical Quality Improvement Program (NSQIP). However, because surveillance-detected DVT rates may be higher than symptomatic DVT rates, we examined how differences in the method of DVT detection may affect the use of this quality measure. Using the NSQIP database (2007-2009), we compared DVT rates of vascular (amputation, open aortic procedures, and lower extremity bypass) and nonvascular (prostatectomy, gastric bypass [GBP], and hip arthroplasty) operations. Using a predefined literature search strategy, we compared the incidence of DVT in NSQIP to the incidence of DVT reported in published literature, diagnosed by symptomatic status or by surveillance studies. Within NSQIP, the overall incidence of postoperative DVT was 0.7%. This varied from 0.3% after GBP to 1.8% after open aortic surgery. Across all procedures except amputation, the incidence of DVT in NSQIP was similar to the incidence of DVT reported in our literature survey of "symptomatic" DVTs. The relative rate (RR) of literature-derived symptomatic DVTs to NSQIP ranged from 0.7 for aortic cases (95% confidence interval [CI], 0.3-1.7) to 1.4 (95% CI, .7-3.1) for GBP. Overall, surveillance studies had 11.6 higher RR of DVT compared to NSQIP (95% CI, 10.5-13), ranging from 2.6 for GBP (95% CI, 1.4-5) to 14 .5 for hip arthroplasty (95% CI, 10.5-20). The incidence of DVT reported in NSQIP is similar to the reported incidence of symptomatic DVT for many high-risk procedures but is much lower than rates of DVT reported in surveillance studies. Clear delineation of symptomatic vs surveillance detection of DVT would improve the usefulness of this measurement in quality improvement registries.


Harnessing social media in mental health practice in Kenya: a community case study report.
The use of social media to increase awareness on mental health is rapidly gaining momentum globally. However, despite evidence of a growing trend in social media use in sub Saharan Africa, little has been reported on tapping the potential of social media within a mental health practice to not only increase awareness but also facilitate linkage to specialist care. We describe one such mental health practice and its process of integration of the different social media platforms to promote mental health and increase linkage to specialist care. We further highlight the challenges and practical implication of social media use in the Kenyan setting. We conclude by advocating for this integration to raise awareness and also encourage peer support for persons with mental health problems and recommend research that measures the impact of such interventions in sub-Saharan Africa.


A multiparameter optimization of digital mammography.
Multiparameter optimizations have been carried out for a wide range of digital mammography system configurations and requirements, with the aim of optimizing the image quality for a given patient dose. These conditions include a range of slot widths for scanning mammography systems, exposure times from 1 to 10 s, focal spot sizes from 80 to 800 microns, a range of detector resolutions and noise levels, dose restrictions, patient thicknesses and targets, and x-ray tube targets. The influences of these on the optimum system configuration in terms of tube potential, filtration, source to patient distance and target magnification are discussed. It is demonstrated that x-ray tube power constraints can significantly restrict the optimum magnification for slot scanning systems, with the result that poor-resolution detectors are not suited for use in a scanning configuration, and that large-focal-spot-good-detector resolution combinations are more suitable. The use of a detector with increased width, raised tube potential and reduced amount of added filtration is shown to be helpful in reducing x-ray tube power limitations. It is shown that, in many cases, correct optimization can bring the detail SNR for an examination using a given detector-x-ray tube configuration to within 10-15% of the SNR achieved with the optimum combination. This gives the designer some scope to consider other factors such as cost and the implications of image size on storage space.


Mediation Analysis using Semi-parametric Shape-Restricted Regression with Applications.
Often linear regression is used to perform mediation analysis. However, in many instances, the underlying relationships may not be linear, as in the case of placental-fetal hormones and fetal development. Although, the exact functional form of the relationship may be unknown, one may hypothesize the general shape of the relationship. For these reasons, we develop a novel shape-restricted inference-based methodology for conducting mediation analysis. This work is motivated by an application in fetal endocrinology where researchers are interested in understanding the effects of pesticide application on birth weight, with human chorionic gonadotropin (hCG) as the mediator. We assume a practically plausible set of nonlinear effects of hCG on the birth weight and a linear relationship between pesticide exposure and hCG, with both exposure-outcome and exposure-mediator models being linear in the confounding factors. Using the proposed methodology on a population-level prenatal screening program data, with hCG as the mediator, we discovered that, while the natural direct effects suggest a positive association between pesticide application and birth weight, the natural indirect effects were negative.


Specific tyrosine phosphorylations mediate signal-dependent stimulation of SHIP2 inositol phosphatase activity, while the SH2 domain confers an inhibitory effect to maintain the basal activity.
SH2 domain-containing 5-inositol phosphatase (SHIP2) is implicated in the development of type 2 diabetes and cancer. Tyrosine phosphorylation of SHIP2 is shown to enhance its phosphatase activity. Using IP4 as a substrate, we show here that tyrosines 986, 987, and 1135 are critical for EGF-induced stimulation of SHIP2 activity. SHIP2 with a disrupted SH2 domain (R47G mutation) displays higher constitutive activity than wild-type SHIP2. Deletion of the C-terminus region similarly activates SHIP2. Thus, the SH2 domain of SHIP2, in conjunction with the C-terminus, confers an inhibitory effect to maintain a low basal activity, and signal-induced tyrosine phosphorylations overcome this effect to activate SHIP2.


Coronary blood flow during exercise following nonselective and selective alpha 1-adrenergic blockade with indoramin.
Studies were performed to compare the effects of alpha 1-adrenergic blockade with indoramin and nonselective alpha-adrenergic blockade with phentolamine on coronary blood flow and myocardial oxygen consumption during exercise. Nine dogs trained to run on a motor-driven treadmill were instrumented with electromagnetic flowmeter probes on the left circumflex coronary artery, and aortic and coronary sinus catheters for determination of myocardial arteriovenous oxygen difference. During control conditions, myocardial oxygen consumption and coronary blood flow increased as a direct function of heart rate during exercise. Phentolamine caused a significant decrease in blood pressure, while heart rate, coronary blood flow, and myocardial oxygen consumption were significantly increased at rest and during all exercise stages. Although alpha 1-adrenergic blockade with indoramin caused a similar reduction of arterial pressure, heart rate was unaltered both at rest and during exercise. Coronary blood flow and myocardial oxygen consumption were unchanged by alpha 1-adrenergic blockade at rest and during light exercise: however, during the heaviest exercise stages alpha 1-blockade caused a significant decrease in myocardial oxygen consumption. These findings are in agreement with the concept that phentolamine, by blocking presynaptic alpha 2-adrenoceptors which normally modulate norepinephrine release, increases sympathetic activity during exercise while indoramin, by acting as a selective alpha 1-adrenergic blocker, does not produce this effect.


A retrospective analysis on the natural history of incidental small paraclinoid unruptured aneurysm.
The optimal consensus concerning treatment of incidental small paraclinoid unruptured intracranial aneurysms (UIAs) remains controversial. The aim of this retrospective study was to reveal the natural history of small paraclinoid UIAs with the goal of informing the treatment plan. 524 patients harbouring 568 paraclinoid UIAs (≤5 mm) were retrospectively evaluated during the mean follow-up of 35.4 months. The aneurysms were divided into two groups with respect to arterial branch: related (ophthalmic and superior hypophyseal artery), and non-related. Medical records were reviewed concerning multiple variables, such as sex, age, hypertension (HTN), diabetes mellitus, smoking and aneurysmal factors (size, arterial relationship, multiplicity and the occurrence of rupture and growth). The cumulative risk and the risk factors of aneurysmal rupture and growth were analysed. Two aneurysmal (0.35%) ruptures and 17 growths (3.0%) were observed during the follow-up of 1675.5 aneurysm-years with an annual rupture of 0.12% and an annual growth of 1.01%. The cumulative survival without aneurysmal growth reached a significant difference in aneurysms ≥4 mm (p=0.001), HTN (p=0.002), and arterial branch-related location (p=0.001). Multivariate analysis disclosed that aneurysm ≥4 mm (HR, 4.41; p=0.003), HTN (HR, 5.74; p=0.003), arterial branch-related location (HR, 6.04; p=0.002), and multiplicity (HR, 0.27; p=0.042) were significant predictive factors for aneurysm growth. Although incidental small paraclinoid UIAs have a relatively lower rupture and growth risk, patients with high-risk factors, including aneurysm ≥4 mm, HTN, arterial branch-related aneurysms, and multiple aneurysms must be monitored closely. The limitation of the retrospective nature of this study should be taken into consideration.


Nano-infrared analysis of amyloid β1-42 fibrils formed in the presence of lipids with unsaturated fatty acids.
Alzheimer's disease (AD) is characterized by progressive memory loss and serious impairment of cognitive abilities. AD is the most common cause of dementia, affecting more than 44 million people around the world. The hallmark of AD is amyloid plaques, extracellular deposits primarily found in the frontal lobe, that are composed of amyloid β (Aβ) aggregates. In this study, we utilized nano-infrared spectroscopy, also known as Atomic Force Microscopy Infrared (AFM-IR) spectroscopy to investigate the effect of unsaturated phospholipids on the rate of Aβ1-42 aggregation. We found that unsaturated phosphatidylcholine, phosphatidylserine, and cardiolipin strongly suppressed aggregation of Aβ1-42. Furthermore, Aβ1-42 fibrils formed in the presence of such lipids exerted significantly lower cell toxicity compared to the protein aggregates formed in the lipid-free environment. These findings suggest that dietary changes linked to the increased consumption of unsaturated phospholipids could be considered as a potential therapeutic approach that can decelerate the progression of AD. These results also suggest that large unilamellar vesicles with unsaturated lipids can be used as potential therapeutics to delay the onset and decelerate the progression of AD.


Patient satisfaction with PAs in the Netherlands.
Physician assistants (PAs) were introduced in the Netherlands in 2002 and are now widely deployed. However, little is known about patient satisfaction with Dutch PAs. A comparative study of patient satisfaction was undertaken in the primary care setting. Patients seen by general practitioners (GPs) and PAs were surveyed using the Consumer Quality Index, a European quality survey instrument. Quality of performance indicators included patient satisfaction, effectiveness of treatment, and safety of treatment. The results found that few differences emerged, and Dutch patients appear to be as satisfied with the care received by PAs as with GPs.


Ultra-wideband communication system prototype using orthogonal frequency coded SAW correlators.
This paper presents preliminary ultra-wideband (UWB) communication system results utilizing orthogonal frequency coded SAW correlators. Orthogonal frequency coding (OFC) and pseudo-noise (PN) coding provides a means for spread-spectrum UWB. The use of OFC spectrally spreads a PN sequence beyond that of CDMA; allowing for improved correlation gain. The transceiver approach is still very similar to that of the CDMA approach, but provides greater code diversity. Use of SAW correlators eliminates many of the costly components that are typically needed in the intermediate frequency (IF) section in the transmitter and receiver, and greatly reduces the signal processing requirements. Development and results of an experimental prototype system with center frequency of 250 MHz are presented. The prototype system is configured using modular RF components and benchtop pulse generator and frequency source. The SAW correlation filters used in the test setup were designed using 7 chip frequencies within the transducer. The fractional bandwidth of approximately 29% was implemented to exceed the defined UWB specification. Discussion of the filter design and results are presented and are compared with packaged device measurements. A prototype UWB system using OFC SAW correlators is demonstrated in wired and wireless configurations. OFC-coded SAW filters are used for generation of a transmitted spread-spectrum UWB and matched filter correlated reception. Autocorrelation and cross-correlation system outputs are compared. The results demonstrate the feasibility of UWB SAW correlators for use in UWB communication transceivers.


WHOLE-BODY VIBRATION EXERCISE IS WELL TOLERATED IN PATIENTS WITH DUCHENNE MUSCULAR DYSTROPHY: A SYSTEMATIC REVIEW.
Duchenne muscular dystrophy (DMD) is caused by a defective gene located on the X-chromosome, responsible for the production of the dystrophin protein. Complications in the musculoskeletal system have been previously described in DMD patients. Whole body vibration exercise (WBVE) is a treatment that improves musculoskeletal function in movement disorders. The aim of this study was to review the effects of WBVE on functional mobility, bone and muscle in DMD patients. Four databases were searched. Three eligible studies were found; all three conclude the management of DMD patients with WBV was clinically well tolerated. The studies used a side-alternating WBV system, frequencies 7 - 24 Hz; and amplitudes 2 - 4 mm. A work indicates that a temporary increase in creatine kinase in DMD during the first days of WBV was observed, but other authors did not find changes. No significant changes in bone mass, muscle strength or bone markers. Some patients reported subjective functional improvement during training. Interpretation. It is concluded that WBV seems to be a feasible and well tolerated exercise modality in DMD patients.


Use of computed tomography and mechanical CPR in cardiac arrest to confirm pulmonary embolism: a case study.
Precise therapeutic decision-making is vital in managing out-of-hospital cardiac arrest. We present an interesting approach where suspected pulmonary embolism could be confirmed by early computed tomography in cardiac arrest. Chest compressions were performed automatically by mechanical devices also during the acquisition of computed tomography data and subsequent thrombolysis.


Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation.
Most patients who undergo kidney or kidney-pancreas transplantation have renal osteodystrophy, and immediately after transplantation bone mineral density (BMD) commonly falls. Together, these abnormalities predispose to an increased fracture incidence. Bisphosphonate or calcitriol therapy can preserve BMD after transplantation, but although bisphosphonates may be more effective, they pose potential risks for adynamic bone. A total of 153 kidney (61%) and kidney-pancreas (39%) transplant recipients were allocated to bisphosphonate (62%) or calcitriol (38%) therapy using an algorithm that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment. Patients received cholecalciferol and calcium as appropriate and were followed for 12 mo. Patients who were treated with bisphosphonates had lower BMD at the lumbar spine and femoral neck and longer time on dialysis. Age and gender were similar between the groups. At 12 mo, bisphosphonate-treated patients had significant BMD increases at the lumber spine and femoral neck and a negative trend at the wrist. Patients who were allocated to calcitriol, who were assessed to have lower baseline fracture risk, had no significant change in BMD at any site. At 1 yr, mean levels of bone turnover marker and intact parathyroid hormone normalized in both groups. Incident fracture rates did not differ significantly. With targeted treatment, BMD levels were stable or improved and bone turnover markers normalized. This algorithm provides a guide to targeting therapy after transplantation that avoids BMD loss and may reduce suppression of bone turnover.


Low-adhesive superhydrophobic surface-enhanced Raman spectroscopy substrate fabricated by femtosecond laser ablation for ultratrace molecular detection.
Ultratrace molecular detections from a limited amount of highly diluted solutions can offer unprecedented benefits in the biomedical/analytical fields, such as in precancer diagnosis, forensic analysis, and food safety. However, huge difficulties exist in completely concentrating the target molecules within a sensitive area and thereby enhancing the detection sensitivity. Herein, we report the ultratrace molecular detection using a low-adhesive superhydrophobic surface-enhanced Raman spectroscopy (LAS-SERS) substrate fabricated by femtosecond laser ablation. The LAS-SERS substrate has good characteristics, including a contact angle as high as 154°, a contact angle hysteresis below 5°, and a simulated Raman signal enhancement factor of up to 6 × 106. Compared to the previously developed superhydrophobic SERS (S-SERS) methods, the low-adhesive nature of the LAS-SERS method can greatly reduce the final contact area, thus significantly enhancing the detection limit. In our experiments, the final contact area of the LAS-SERS substrate was reduced by 19.5 times, corresponding to an 88.1 times increase in the concentration effect, as compared to the highly adhesive S-SERS substrates fabricated using the same technique. The enhanced condensation effect led to a detection limit as low as 10-14 M, which shows an obvious improvement compared to that of the other non-photolithography methods. The method reported herein offers a facile and efficient approach to the cost-effective fabrication of a high-performance LAS-SERS substrate for ultratrace molecular detection.


No evidence of asymptomatic monkeypox infection in a highly sexually active MSM population in Austria.
The 2022 outbreak of monkeypox virus (MPXV) revealed new transmission routes. Incidence declined sharply in September 2022, and it remains unclear whether MPXV is circulating in asymptomatic individuals because of increased immunity. Our study aimed to assesss the number of asymtomatic MPXV carriers in individuals at high risk for STI. We analysed anal samples from asymptomatic highly sexually active men who have sex with men for the presence of MPXV. We detected a high number of concomitant sexually transmitted infections but did not find a single sample with MPXV. Our results indicate that the general recommendation to implement screening for MPXV is not currently justified.


Theory-driven formative research to inform the design of a national sanitation campaign in Tanzania.
There are gaps in global understanding about how to design and implement interventions to improve sanitation. This formative study provided insights for the subsequent redesign of a government-led national sanitation campaign targeting rural populations in Tanzania. The Behaviour Centred Design approach was used to investigate the determinants of toilet building, improvement and use. Varied, novel, and interactive research tools were employed in fifty-five households in two regions of rural Tanzania. Results were analysed to articulate a Theory of Change, which then informed intervention design. Participants valued hard work, enterprise, and improving their lives over many years. They wanted better toilets but felt no urgency to act quickly. A common emotional motivator for improving toilets was to protect children from disease (Nurture) but this was insufficient to drive rapid change. Disgust with traditional toilets meant they were built at a distance from the house: an 'out of sight, out of mind' attitude. Other powerful motives included the desire to improve living conditions (Create), and to become a modern Tanzanian (Status), albeit without 'showing off'. Construction costs and water scarcity were the main stated barriers. Receiving information about realistic costs, support accessing materials, and visiting better latrines elsewhere were commonly reported reasons for improving latrines. The resulting Theory of Change recommended that the intervention should surprise people with a novel conversation about toilets, promote toilets as a means of conferring status, and introduce a perceived urgency to 'act now'. It should suggest that modest improvements would lead to a better life. Feelings of disgust and fear with poor quality toilets should be amplified, and barriers lessened through promoting transformational toilet improvements, and improving access to modern toilet products. This research provided considerable insight into sanitation behaviours in rural Tanzania, which informed creative intervention design.


Biodegradable Hollow MoSe2/Fe3O4 Nanospheres as the Photodynamic Therapy-Enhanced Agent for Multimode CT/MR/IR Imaging and Synergistic Antitumor Therapy.
Photodynamic therapy (PDT) is considered as one of the most effective cancer treatment strategies because of its minimally invasive and high efficiency. On account of the correlation between PDT and photocatalytic oxidation, the hollow MoSe2/Fe3O4 (MF-2) nanoheterostructure was constructed to enhance PDT as shown in this paper. The size and the hollow structure can be well controlled by the addition of F-127. MoSe2/Fe3O4 reveals the twofold reactive oxygen species (ROS) generation in contrast to the pure MoSe2, which is ascribed to the effective separation of photogenic charges. The novel hollow structure also supplies a lot of cavities for perfluorocarbon (PFC) and O2 loading, and O2@PFC@MF-2 can effectively overcome the hypoxic microenvironment to further cause more than 3 times ROS production. Moreover, the narrow band gap and hollow structure also make sure that the strong near-infrared (NIR) light absorption and high photothermal conversion efficiency is as high as 66.2%. Furthermore, the combination of Fe3O4 can further accelerate the effective biodegradation capacity of MF-2 because of the repeated endogenous redox reaction to form water-soluble MoVI-oxide species. Meanwhile, doxorubicin (Dox, anticancer drug) was assembled onto the MF-2@PEG nanomaterials through π-π staking and electrostatic interaction for chemotherapy. O2@PFC@MF-2@PEG/Dox possesses the potential application in triple-model computed tomography, magnetic resonance, and infrared (CT/MR/IR) imaging-guided photothermal/photodynamic/chemotherapy (PTT/PDT/chemotherapy) nanodiagnosis platforms.


Evidence for the load-dependent mechanical efficiency of individual myosin heads in skeletal muscle fibers activated by laser flash photolysis of caged calcium in the presence of a limited amount of ATP.
Although a contracting muscle regulates its energy output depending on the load imposed on it ("Fenn effect"), the mechanism underlying the load-dependent energy output remains obscure. To explore the possibility that the mechanical efficiency, with which chemical energy derived from ATP hydrolysis is converted into mechanical work, of individual myosin heads changes in a load-dependent manner, we examined the auxotonic shortening of glycerinated rabbit psoas muscle fibers, containing ATP molecules almost equal in number to the myosin heads, after laser-flash photolysis of caged calcium. Immediately before laser-flash activation, almost all of the myosin heads in the fiber are in the state M.ADP.Pi, and can undergo only one ATP hydrolysis cycle after activation. When the fibers were activated to shorten under various auxotonic loads, the length, force, and power output changes were found to be scaled according to the auxotonic load. Both the power and energy outputs were maximal under a moderate auxotonic load. The amount of M.ADP.Pi utilized at a time after activation was estimated from the amount of isometric force developed after interruption of fiber shortening. This amount was minimal in the isometric condition and increased nearly in proportion to the distance of fiber shortening. These results are taken as evidence that the efficiency of chemomechanical energy conversion in individual myosin heads changes in a load-dependent manner.


Bariatric surgery in patients with cirrhosis with and without portal hypertension: a single-center experience.
To assess safety and outcomes (metabolic and liver) of bariatric surgery in patients with cirrhosis with or without portal hypertension. This study is a retrospective review of 14 patients with Child's A cirrhosis with or without portal hypertension who were prospectively enrolled from February 23, 2009, through November 9, 2011, with 6- to 24-month follow-up after bariatric surgery (11 patients underwent sleeve gastrectomy [78.6%] and 3 gastric bypass [21.4%]). Four patients had portal hypertension detected by esophagogastroduodenoscopy. The mean patient age was 55.5 years, and 10 of 14 patients were women. The mean weight decreased from 125±18 to 94±17 at 1 year (P<.001) and 93±17 kg at 2 years (P<.001) postsurgery. The prevalence of diabetes decreased from 10 of 14 patients to 4 of 12 (P=.01) and 1 of 6 (P=.02) at 1 and 2 years postsurgery. The frequency of dyslipidemia and hypertension decreased but was not statistically significant; however, the number of medications required to control them decreased. Hepatic steatosis was detected by perioperative liver biopsy in 13 of 14 patients (5%-30% steatosis in 6 patients, 31%-60% in 6, and >60% in 1). At 1 year postsurgery, only 1 of 8 patients who underwent follow-up ultrasound imaging showed evidence of steatosis. The bilirubin level was above 2 mg/dL in 1 patient at 1 year postsurgery. One patient had encephalopathy at 2 years postsurgery. None of the patients developed peri- or postoperative bleeding or surgical complications. Bariatric surgery in patients with compensated cirrhosis even with mild portal hypertension is well tolerated and safe with minimal risk of postoperative complications if performed in a large referral center. This population can experience the beneficial effects of weight loss and improved metabolic syndrome, as well as reduced hepatic steatosis.


Speaking rates of American and New Zealand varieties of English.
Various acoustic measures of speaking rate were calculated for 40 adult speakers of New Zealand English (NZE). These measures were then compared to a group of 40 adult speakers of American English (AE). Results of the analysis identified significantly faster overall speaking rate and articulation rate for the NZE group compared to the AE group. No gender differences in speaking rate or articulation rate were found for either variety of English. The observed differences in rate between AE and NZE are interpreted with regard to diverse vowel production patterns between the varieties, as well as possible differences in rhythmic timing patterns. The impact of differences in speaking rate between varieties of English on the assessment and treatment of speech timing disorders is discussed.


Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer.
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.


School time is associated with cardiorespiratory fitness in adolescents: The HELENA study.
We assessed the association between school time and physical fitness in adolescents. The study included 2,024 adolescents, aged 12.5-17.5 years, who participated in the Healthy Lifestyle in Europe by Nutrition in Adolescence study. Health-related physical fitness components were assessed using the physical fitness tests battery. Cardiovascular risk was categorized using the sex-specific cut-offs for a healthy cardiorespiratory fitness level in adolescents proposed by FitnessGram®. School time was classified as short or long. Multivariate analysis accounted for confounding factors such age, sex, body mass index, time spent in moderate to vigorous physical activity, pubertal status, and parents' educational level. Cardiorespiratory fitness was higher in adolescents with a long school time than in those with a short school time (42.0 ± 7.6 vs 40.7 ± 7.2 mL.kg-1.min-1, respectively; p < 0.05). The percentage of adolescents at cardiovascular risk in adulthood was higher in the short than in the long time group (45.2% vs 31.7%, respectively) (p < 0.05). These findings suggest that a long school day is associated with higher cardiorespiratory fitness in adolescents and that school time should be considered in interventions and health promotion strategies.


Expression of brain-derived neurotrophic factor and its cognate receptor, TrkB, in the rat suprachiasmatic nucleus.
Photic entrainment of mammalian circadian rhythms occurs because the pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus is endowed with a rhythmic sensitivity to photic signals conveyed by the retinohypothalamic tract. Since brain-derived neurotrophic factor (BDNF) has been implicated in the functional modulation of other retinal targets, the rat SCN was examined for expression and cellular distribution of this neurotrophin and TrkB, the tyrosine kinase receptor that preferentially binds BDNF. The rat SCN was found to express the mature BDNF peptide and mRNA by Western blotting, enzyme-linked immunosorbent assay (ELISA), and reverse transcription-polymerase chain reaction (RT-PCR) analyses. BDNF-immunoreactivity and hybridization signal for its mRNA were coextensively localized within a number of SCN cells throughout the rostrocaudal axis of each nucleus. In addition, some cells intercalated within the optic chiasm were distinguished by expression of BDNF immunoreactivity or mRNA. Immunostaining for the TrkB receptor was also evident in the SCN within terminals or fibers predominantly located along the SCN/optic chiasm interface and within scattered perikarya near the medial border of each nucleus. Combined in situ hybridization and immunocytochemical analysis revealed that BDNF mRNA-expressing cells within the ventrolateral SCN were often closely apposed to TrkB-positive fibers extending from the optic chiasm. These findings raise the possibility that target-derived interactions between BDNF and TrkB receptors could play a role in the circadian modulation of SCN pacemaker sensitivity to photic input transmitted by the retinohypothalamic tract.


Degeneration and regeneration of chloroplasts in Euglena gracilis grown in the presence of acetate: ultrastructural evidence.
When green cells of Euglena gracilis, strain Z, were light-grown for several months on a solid medium containing an excess of sodium acetate (1.0% instead of the normal 0.1%), some 30% of the cells were colourless. The 'acetate-bleached' organisms, isolated by plating methods and subsequently incubated in the light in a liquid medium, regained the capacity to form chlorophyll in a few days in the absence of any organic carbon source, and within 1-2 weeks in the presence of 0.1% acetate. A number of bleached colonies, however, gave rise to populations in which the delay in pigment synthesis initiation was at least 2 months. Besides numerous paramylum granules and lipid inclusions, the acetate-bleached cells exhibited variably shaped and sized plastids, apparently lacking in ribosomes and showing a deeply disorganized membrane system. In the alga greened in the presence of 0.1% acetate, the pattern of plastidome reorganization was altered; the thylakoids were often unpaired and vesiculated in different degrees, owing primarily to the swelling of the lumen. A complete recovery of normal chloroplast structure occurred only after several weeks of exponential growth. The entire population greened in the absence of acetate constantly showed normal chloroplasts with perfectly reassociated thylakoids and clear partitions.


Comparison of charge movement components in intact and cut twitch fibers of the frog. Effects of stretch and temperature.
Charge movements were measured in frog intact fibers with the three-microelectrode technique and in cut fibers with the double Vaseline gap technique. At 13-14 degrees C, the ON segments of charge movement records from both preparations showed an early I beta component and a late I gamma hump component. When an intact fiber was cooled to 4-7 degrees C, the time-to-peak of I gamma (tp,gamma) was prolonged, but I gamma still appeared as a hump. Q-V plots from intact fibers at 4-7 degrees C were fitted with a sum of two Boltzmann distribution functions (method 1). The more steeply voltage-dependent component, identified with Q gamma, accounted for 32.1% (SEM 2.2%) of the total charge. This fraction was larger than the 22.6% (SEM 1.5%) obtained by separating the ON currents with a sum of two kinetic functions (method 2). The total charge in cut fibers stretched to a sarcomere length of 3.5 microns at 13-14 degrees C was separated into Q beta and Q gamma by methods 1 and 2. The fraction of Q gamma in the total charge was 51.3% (SEM 1.7%) and 53.7% (SEM 1.8%), respectively, suggesting that cut fibers have a larger proportion of Q gamma:Q beta than intact fibers. When cut fibers were stretched to a sarcomere length of 4 microns, the proportion of Q gamma:Q beta was unchanged. Between 4 and 13 degrees C, the Q10 of l/tp,gamma in intact fibers was 2.33 (SEM 0.33) and that of 1/tau beta was less than 1.44 (SEM 0.04), implying that the kinetics of I gamma has a steeper temperature dependence than the kinetics of I beta. When cut fibers were cooled from 14 to 6 degrees C, I gamma in the ON segment generally became too broad to be manifested as a hump. In a cut fiber in which I gamma was manifested as a hump, the Q10 of l/tp,gamma was 2.08 and that of l/tau beta was less than 1.47. Separating the Q-V plots from cut fibers at different temperatures by method 1 showed that the proportion of Q gamma:Q beta was unaffected by temperature change. The appearance of I gamma humps at low temperatures in intact fibers but generally not in cut fibers suggests an intrinsic difference between the two fiber preparations.


Stroke prenotification is associated with shorter treatment times for warfarin-associated intracerebral hemorrhage.
Warfarin-associated intracerebral hemorrhage (WAICH) is a devastating disease with increasing incidence. In this setting, treatment with prothrombin complex concentrates (PCC) is essential to correct coagulopathy. Yet despite the availability of coagulopathy correction strategies, significant treatment delays can occur in emergency departments (EDs), which may be overcome using stroke prenotification strategies. To explore this, we compared arrival-to-treatment times with PCC for WAICH between two different stroke response systems that used the same international normalized ratio (INR) correction protocol. We established a registry of consecutive patients presenting with WAICH and treated with PCC presenting to two Canadian tertiary-care academic stroke centers: one with a stroke prenotification system, and one with a traditional ED assessment, treatment and referral system. In this comparative cohort design, we defined the WAICH diagnosis time as the earliest time point where both INR and CT were available. We compared median times from arrival to treatment, as well as arrival to diagnosis, and diagnosis to treatment. Between 2008 and 2010, we collected data from 123 consecutive patients with intracranial hemorrhage who received PCC for INR correction (79 from ED referral, and 44 prenotification). Onset-to-arrival times, demographics, Glasgow Coma Scale scores, and baseline INR were similar between the two systems. Arrival-to-treatment times were significantly shorter in the prenotification system as compared to the traditional ED referral system (135 vs. 267 min; p = 0.001), which was driven by both decreased arrival-to-diagnosis time (49 vs. 117 min; p = 0.006), as well as decreased diagnosis-to-treatment time (56 vs. 112 min; p < 0.001). Arrival-to-scan times and arrival-to-INR times were similarly shorter in the prenotification system (68 vs. 118 min and 20.5 vs. 47 min, respectively). Stroke prenotification was associated with shorter arrival-to-treatment times for emergent INR correction in patients with WAICH, which was driven by both faster diagnosis and treatment. Our results are consistent with those seen in ischemic stroke, suggesting that prenotification systems present an opportunity to optimize acute intracerebral hemorrhage therapy.


[Respiration mechanics in tetraplegia].
Patients with quadriplegia due to transection of the lower cervical cord show, on spirographic examination, a marked decrease in vital capacity and its two components, i.e. inspiratory capacity (i.c.) and expiratory reserve volume (ERV). The loss of IC results partly from the decreased inspiratory muscle strength consecutive to the intercostal muscle paralysis but mostly from a reduction in the distensibility of the lungs and the rib cage. The reduction in ERV is related to the paralysis of all the well-recognized muscles of expiration (abdominals, interosseous internal intercostals); however, the clavicular portion of the pectoralis major allows these patients to maintain a small ERV.


Developing and Testing Methylated Nano-Structured Dipeptides that Inhibit Src Kinase Activity In Vitro for Anti-Cancer Applications.
Here, with the aim of developing a novel anti-cancer treatment, seven dipeptides were designed that contained methylated tryptophan and/or methylated arginine and were produced using Fmoc solid-phase peptide synthesis. Overexpression of the Src tyrosine kinase enzyme has been implicated in the development of different cancers. Dipeptides containing unnatural amino acids such as methylated arginine (RCH3), dimethylated arginine (R(CH3)2), and/or methylated tryptophan (WCH3) residues have earlier been shown to inhibit Src kinase. In this study, three such dipeptides, W-RCH3, WCH3-RCH3, and W-R(CH3)2, were tested using acellular assays and were found to have IC50 values (the concentration at which 50% inhibition occurs) of 510 nM, 916 nM, and 1 µM, respectively. These values were comparable to those obtained for cyclic penta- to nano-W-R peptides ([W-R]5-[W-R]9) synthesized in previous studies. However, the unmethylated versions of the dipeptides did not show any inhibitory activity against Src kinase. All of these dipeptides (50 µM) did not show any cytotoxicity after incubation up to 72 h with three different cancer cell lines, including leukemia (CCRF-CEM), breast adenocarcinoma (MDA-MB-231), and ovarian adenocarcinoma (SK-OV-3) cell lines, indicating the limited permeability of the peptides through the cell membrane. Therefore, further study is needed to improve the permeability of these peptides for anticancer applications, such as by using a peptide carrier or additional peptide functionalization. In summary, this study provides a protocol to synthesize and test peptides that inhibit Src kinase activity, and thus possess promising anticancer ability, as demonstrated using acellular and cellular assays.


[Peruvian newborn fetal growing curves].
Fetal grow evaluation is decisive to predict some grow problems and to consider high-risk pregnancies attention outcomes. To obtain fetal grow curves of a selected group of Peruvian newborns. Prospective and transversal study with successive enrolment of living newborns. Weighing and measurement techniques standardization in newborns was made by Centro Latinoamericano de Perinatologia's guidelines, as gestational age determination alike, based in date of last menstruation. Patients with some maternal-fetal condition that changes fetal grow were excluded, and smokers and undernourished too. Mean, standard deviation, 10, 50 and 90-weight percentile, height, and cephalic perimeter were used. Curves were traced and smoothed by third grade polynomial adjustment in Excel software. During 2005 there were born 99,439 Peruvians, in 29 hospitals of Ministerio de Salud de Perú. Dates from 50,568 (50.8%) newborns were used to trace curves of fetal grow from 24 to 43 weeks of gestation. Weeks 39 and 40 of gestation were the most representative (55.8%), with a weigh average of 3,295 g +/- 407 g, and 3,400 +/- 421 g, respectively (10, 50, and 90-percentile were: 2,750; 3,275; 3,810, and 2,875; 3,385, and 3,930 g, respectively). Average birth size was: 49.7 cm +/- 2.3, and 50.1 +/- 2.3, respectively. Cephalic perimeter was: 342 +/- 16, and 345 +/- 13 mm, respectively. Fetal grow curves according to weight, size, and cephalic perimeter from a selected group of Peruvian newborns were reported.


Prognosis of early hepatocellular carcinoma after hepatic resection.
Clinicopathologic characteristics and postoperative prognosis of early hepatocellular carcinoma (eHCC) have not been clarified. Early HCC was designated as tumor purely composed of well-differentiated HCC not containing moderately or poorly differentiated component. Twenty seven patients with early HCC among 515 patients underwent hepatic resection for HCC were analyzed. The survival rate at 5 years after hepatic resection of the patients with early HCC was 76%. No clinicopathologic factors correlated with the survival. The postoperative recurrence occurred in 19 (70%) patients, and nine patients survived more than five years free of recurrence. The levels of aspartate aminotransferase and alanine aminotransferase of the patients with recurrence within five years (n = 9) were much higher than those of the patients without recurrence (n = 18). The prognosis after recurrence of the patients with more than three tumors was significantly worse than that of the patients with one or two tumors (P < 0.01). The survival rate of early HCC after hepatic resection is favorable, however, recurrence is considerably frequent and it depends on the degree of inflammation of underling liver disease. Therefore, the control of inflammation of liver parenchyma and the preservation of liver function may be most important in patients with early HCC.


Improved least squares topology testing and estimation.
Generalized least squares (GLS) methods provide a relatively fast means of constructing a confidence set of topologies. Because they utilize information about the covariances between distances, it is reasonable to expect additional efficiency in estimation and confidence set construction relative to other least squares (LS) methods. Difficulties have been found to arise in a number of practical settings due to estimates of covariance matrices being ill conditioned or even noninvertible. We present here new ways of estimating the covariance matrices for distances that are much more likely to be positive definite, as the actual covariance matrices are. A thorough investigation of performance is also conducted. An alternative to GLS that has been proposed for constructing confidence sets of topologies is weighted least squares (WLS). As currently implemented, this approach is equivalent to the use of GLS but with covariances set to zero rather than being estimated. In effect, this approach assumes normality of the estimated distances and zero covariances. As the results here illustrate, this assumption leads to poor performance. A 95% confidence set is almost certain to contain the true topology but will contain many more topologies than are needed. On the other hand, the results here also indicate that, among LS methods, WLS performs quite well at estimating the correct topology. It turns out to be possible to improve the performance of WLS for confidence set construction through a relatively inexpensive normal parametric bootstrap that utilizes the same variances and covariances of GLS. The resulting procedure is shown to perform at least as well as GLS and thus provides a reasonable alternative in cases where covariance matrices are ill conditioned.


[Interhemispheric asymmetry of ipsilateral interzonal evoked potentials in the parietal and sensorimotor cortex of the cat].
EPs recorded in response to electrical stimulation of ipsilateral visual or auditory cortex, revealed mostly a positive-negative configuration on the surface of parietal and sensomotor cortex in 66 immobilized cats. The positive phase amplitude of the EPs was higher in the parietal area. The latency of audio-parietal and audio-motor EPs was longer than that of visual-parietal or visual-motor EPs. The distribution of the EPs over the parietal cortex revealed a mirror effect for audio-parietal responses. Interzonal EPs were asymmetrical in parietal cortex of the two hemispheres. The right hemisphere dominated, at that. Some individual interhemispheric asymmetry was also revealed between sensomotor interzonal EPs, their latency dominating in the left hemisphere for both zones. The interhemispheric asymmetry of the parietal EPs was associated to some extent with the sex of the animals.


Beyond metformin: safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: reflections from a diabetes care editors' expert forum.
The trend toward personalized management of diabetes has focused attention on the differences among available pharmacological agents in terms of mechanisms of action, efficacy, and, most important, safety. Clinicians must select from these features to develop individualized therapy regimens. In June 2013, a nine-member Diabetes Care Editors' Expert Forum convened to review safety evidence for six major diabetes drug classes: insulin, sulfonylureas (SUs), thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter 2 inhibitors. This article, an outgrowth of the forum, summarizes well-delineated and theoretical safety concerns related to these drug classes, as well as the panelists' opinions regarding their best use in patients with type 2 diabetes. All of the options appear to have reasonably wide safety margins when used appropriately. Those about which we know the most-metformin, SUs, insulin, and perhaps now also TZDs-are efficacious in most patients and can be placed into a basic initial algorithm. However, these agents leave some clinical needs unmet. Selecting next steps is a more formidable process involving newer agents that are understood less well and for which there are unresolved questions regarding risk versus benefit in certain populations. Choosing a specific agent is not as important as implementing some form of early intervention and advancing rapidly to some form of combination therapy as needed. When all options are relatively safe given the benefits they confer, therapeutic decision making must rely on a personalized approach, taking into account patients' clinical circumstances, phenotype, pathophysiological defects, preferences, abilities, and costs.