Venom-related transcripts from Bothrops jararaca tissues provide novel molecular insights into the production and evolution of snake venom.
Attempts to reconstruct the evolutionary history of snake toxins in the context of their co-option to the venom gland rarely account for nonvenom snake genes that are paralogous to toxins, and which therefore represent important connectors to ancestral genes. In order to reevaluate this process, we conducted a comparative transcriptomic survey on body tissues from a venomous snake. A nonredundant set of 33,000 unigenes (assembled transcripts of reference genes) was independently assembled from six organs of the medically important viperid snake Bothrops jararaca, providing a reference list of 82 full-length toxins from the venom gland and specific products from other tissues, such as pancreatic digestive enzymes. Unigenes were then screened for nontoxin transcripts paralogous to toxins revealing 1) low level coexpression of approximately 20% of toxin genes (e.g., bradykinin-potentiating peptide, C-type lectin, snake venom metalloproteinase, snake venom nerve growth factor) in body tissues, 2) the identity of the closest paralogs to toxin genes in eight classes of toxins, 3) the location and level of paralog expression, indicating that, in general, co-expression occurs in a higher number of tissues and at lower levels than observed for toxin genes, and 4) strong evidence of a toxin gene reverting back to selective expression in a body tissue. In addition, our differential gene expression analyses identify specific cellular processes that make the venom gland a highly specialized secretory tissue. Our results demonstrate that the evolution and production of venom in snakes is a complex process that can only be understood in the context of comparative data from other snake tissues, including the identification of genes paralogous to venom toxins.


Current Insights to Regulation and Role of Telomerase in Human Diseases.
The telomerase ribonucleoprotein complex has a pivotal role in regulating the proliferation and senescence of normal somatic cells as well as cancer cells. This complex is comprised mainly of telomerase reverse transcriptase (TERT), telomerase RNA component (TERC) and other associated proteins that function to elongate telomeres localized at the end of the chromosomes. While reactivation of telomerase is a major hallmark of most cancers, together with the synergistic activation of other oncogenic signals, deficiency in telomerase and telomeric proteins might lead to aging and senescence-associated disorders. Therefore, it is critically important to understand the canonical as well as non-canonical functions of telomerase through TERT to develop a therapeutic strategy against telomerase-related diseases. In this review, we shed light on the regulation and function of telomerase, and current therapeutic strategies against telomerase in cancer and age-related diseases.


[Video-assisted mammary harvest technique with harmonic scalpel].
We have developed a video-assisted mammary harvest technique using the Harmonic Scalpel. The clinical method and results are reported here. Since Nov. 1995, 70 left and 5 right internal mammary arteries (L/RIMAs) were taken down thoracoscopically and utilized for minimally invasive coronary artery bypass grafting. Each of the IMAs was harvested up to the upper margin of the first rib or higher and down to the bifurcation. Coagulation and cutting of the branches were achieved with excellent hemostasis using only the Harmonic Scalpel with a hook dissector. A CO2 insufflation technique with 8-10 mmHg of intrathoracic pressure safely improved visualization of the IMA in each case. The mean operative time was 65 minutes (range 45-95) for the left and 35 minutes (range 25-45) for the right. All the pedicled IMAs but one which was lost due to intimal dissection had satisfactory free flows. Video-assisted mammary harvest can be accomplished with insufflation technique and facilitated by using the Harmonic Scalpel with a hook dissector.


Atypical hemolytic-uremic syndrome: recurrent phenotypic expression of a patient with MCP gene mutation combined with risk haplotypes.
: We bring the case of a 38-year-old man who was presented to the emergency department with nausea, fever, and choluria, 4 days after the ingestion of raw oysters. Analytical study revealed thrombocytopenia and acute kidney injury that were associated to a possible thrombotic microangiopathy. Therapeutic plasma exchange was started and resolution of the manifestations was obtained. To identify the cause of the thrombotic microangiopathy a molecular study was performed and a pathogenic variant in the MCP gene, c.287-2A>G (splice acceptor) in heterozygous state with a concomitant presence of both risk haplotypes, MCPggaac and Complement factor H (CFH)-H3 were identified. These findings make the diagnosis of atypical hemolytic-uremic syndrome (aHUS), and despite a relatively benign course with a positive response to plasma exchange without an evolution to renal failure was evident a recurrent profile of aHUS when associated with an infectious trigger.


Nutritional assessment of patients with schizophrenia: a preliminary study.
The prevalence of obesity in the United States population is increasing, and similar trends can be observed among schizophrenia patients. No thorough examination of the actual nutritional composition of the diet of schizophrenia patients in the United States has been carried out. We therefore employed a 24-hour diet recall in 146 schizophrenia outpatients to gather information on different nutritional variables, such as total caloric intake and total fat, protein, carbohydrate, cholesterol, and fiber content. Data were subsequently compared to data for the general population collected in the Third National Health and Nutrition Examination Survey (NHANES III). Schizophrenia patients as a group ate more food when compared to NHANES III subjects, but the relative percentages of calories derived from fat, protein, and carbohydrates were not found to be different. Therefore, it is unlikely that schizophrenia patients make dietary choices different from those of people in the general population. Instead, schizophrenia patients seem to eat more of the same food.


Religious coping and religiosity in patients with COPD following pulmonary rehabilitation.
Religious coping (RC) is defined as the use of behavioral and cognitive techniques in stressful life events in a multidimensional construct with positive and negative effects on outcomes, while religiosity is considered a use of individual beliefs, values, practices, and rituals related to faith. There is no evidence for the effects of pulmonary rehabilitation (PR) in RC and religiosity in patients with COPD. The aims of this study were 1) to compare RC and religiosity in patients with COPD following PR and 2) to investigate associations between changes in RC, religiosity and exercise capacity, quality of life (QoL), anxiety, depression, and dyspnea. Seventy-four patients were enrolled in this study including 38 patients in the PR group and 36 patients in the control group. PR protocol was composed of a 12-week (three sessions per week, 60 min per day) outpatient comprehensive program, and the control group was composed of patients in a waiting list for admission to PR program. RC, religiosity, exercise capacity, QoL, anxiety, depression, and dyspnea were measured before and after the study protocol. Positive religious coping and organizational religious activities increased (p=0.01; p<0.001, respectively), while negative religious coping decreased (p=0.03) after 12 weeks in the PR group (p<0.001). Significant associations were observed between changes in RC, organizational religiosity with exercise capacity, and QoL following PR. No differences were found in the control group. PR improves RC and organizational religiosity in patients with COPD, and these improvements are related to increases in exercise capacity and QoL.


[Diagnosis and treatment of obstructive jaundice].
The analysis of diagnosis and treatment of 76 patients with obstructive jaundice of different genesis was carried out. In 20 cases, an unloading diagnostic laparoscopic cholecystostomy was created, direct roentgenologic examination of the bile ducts conducted, removal of concrements from the gallbladder by means of a choledochoscope performed. Twenty four patients with choledocholithiasis underwent the radical operation, 23 with jaundice of oncologic genesis-the palliative one. All the patients are alive.


Intramuscular ceftriaxone versus ampicillin-chloramphenicol in childhood bacterial meningitis.
70 children aged 4 months-12 years, with bacteriologically proven bacterial meningitis were treated with either intramuscular (IM) ceftriaxone (CFT) 100 mg/kg given once daily, or with combined IM ampicillin 160 mg/kg/day and IM chloramphenicol 100 mg/kg/day (AMC) given every 6 h. There were 35 children in each of the treatment groups. The children in both groups were comparable with regard to age, sex, duration of illness, and state of consciousness. 29 children in the CFT group and 26 in the AMC group recovered without any permanent complications or sequelae. Of the 15 children who died 10 (3 in the CFT and 7 in the AMC group) were in deep coma when treatment was started. Intramuscular CFT given once daily proved effective and much easier to administer than our standard hospital therapy with combined AMC given every 6 h IM.


Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy.
This is an updated version of the original Cochrane review published in Issue 11, 2013.Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for which stiripentol (STP) has been recently licensed as add-on therapy. To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) for patients with SMEI. We searched the Cochrane Epilepsy Group Specialised Register (27 April 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 27 April 2015) and MEDLINE (1946 to 27 April 2015). We systematically searched the online trials registry ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform and the bibliographies of identified studies for additional references. We handsearched selected journals and conference proceedings and imposed no language restrictions. Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment. Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. We assessed the following outcomes: 50% or greater seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. We assessed outcomes by using a Mantel-Haenszel meta-analysis to calculate risk ratios (RRs) with 95% confidence intervals (95% CIs). In the updated search, we identified no additional studies suitable for inclusion. We found no RCTs assessing drugs other than STP. The previous version of this review included two RCTs evaluating use of STP (total of 64 children). Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 vs 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 vs 1/31; RR 7.93, 95% CI 1.52 to 41.21). Investigators found no significant differences in proportions of dropouts from the STP group compared with the placebo group (2/33 vs 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects, noting that higher proportions of participants in the STP group experienced side effects than in the placebo group (100% vs 25%; RR 3.73, 95% CI 1.81 to 7.67). Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Additional adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of patients with SMEI.


The potential for successful family foster care: conceptualizing competency domains for foster parents.
The potential to foster successfully starts with developing and supporting competency in 12 domains: providing a safe and secure environment, providing a nurturing environment, promoting educational attainment and success, meeting physical and mental healthcare needs, promoting social and emotional development, supporting diversity and children's cultural needs, supporting permanency planning, managing ambiguity and loss for the foster child and family, growing as a foster parent, managing the demands of fostering on personal and familial well-being, supporting relationships between children and their families, and working as a team member. This article describes each domain and reviews relevant research to help guide the assessment of practicing and future foster parents.


Putative osmosensor--OsHK3b--a histidine kinase protein from rice shows high structural conservation with its ortholog AtHK1 from Arabidopsis.
Prokaryotes and eukaryotes respond to various environmental stimuli using the two-component system (TCS). Essentially, it consists of membrane-bound histidine kinase (HK) which senses the stimuli and further transfers the signal to the response regulator, which in turn, regulates expression of various target genes. Recently, sequence-based genome wide analysis has been carried out in Arabidopsis and rice to identify all the putative members of TCS family. One of the members of this family i.e. AtHK1, (a putative osmosensor, hybrid-type sensory histidine kinase) is known to interact with AtHPt1 (phosphotransfer proteins) in Arabidopsis. Based on predicted rice interactome network (PRIN), the ortholog of AtHK1 in rice, OsHK3b, was found to be interacting with OsHPt2. The analysis of amino acid sequence of AtHK1 showed the presence of transmitter domain (TD) and receiver domain (RD), while OsHK3b showed presence of three conserved domains namely CHASE (signaling domain), TD, and RD. In order to elaborate on structural details of functional domains of hybrid-type HK and phosphotransfer proteins in both these genera, we have modeled them using homology modeling approach. The structural motifs present in various functional domains of the orthologous proteins were found to be highly conserved. Binding analysis of the RD domain of these sensory proteins in Arabidopsis and rice revealed the role of various residues such as histidine in HPt protein which are essential for their interaction.


Accuracy of mammography in an Australian community setting.
The records of three surgeons in a Sydney suburban practice have been reviewed to compare the histopathological data from breast biopsies with the clinical assessment, and the mammographic and ultrasound reports, and to assess the extent of the delay before presentation to a surgeon to determine the diagnostic accuracy of the three modalities, and whether mammography contributed to this delay. Two hundred and nineteen breast biopsies that were performed in the years 1984 to 1986 inclusive were reviewed. Of these, 72 were cancerous lesions and 147 were benign lesions. The accuracy (true-positive rate) of mammography for the detection of cancer was 83% with a false-negative rate of 11%. We found no evidence that mammography contributed significantly to the delay before patients presented to specialist surgeons, nor to any delay before they underwent a biopsy.


Hearing improvement after stapedotomy using teflon loop prosthesis.
To assess hearing improvement after stapedotomy for otosclerosis using teflon loop prosthesis. Quasy experimental study. January 2001 to May 2003 in the Otorhinolaryngology Department, CMH, Rawalpindi. Thirty diagnosed cases of otosclerosis were included in the study. Ear with greater air-bone gap was selected and stapedotomy was done using teflon loop prosthesis (size 4 - 4.5 mm). Mild vertigo occurred during immediate postoperative period, which subsided with Inj. Prochlorperazine. Patients were followed-up postsurgically at one month, two months, four months, six months and one year and postoperative air-bone gap was calculated. Out of 30 cases, there were 24 males and 06 females. The age ranged from 18 to 50 years. Twenty-one (70%) patients had bilateral hearing loss and 09 (30%) had tinnitis also. Pre-operative audiograms showed conductive deafness. Carhart's notch was present in 10 (33.3%) cases. Tympanogram revealed loss of stapedial reflex. Postoperatively good hearing improvement was seen in 56.7% (postoperative air-bone gap closure upto 10 dB), fair improvement in 30% (postoperative air bone gap closure from 11 to 20 dB) and poor results in 10% (postoperative air-bone gap more than 21 dB) cases. One patient developed dead ear. Stapedotomy using teflon loop prosthesis for otosclerosis is an effective method to restore hearing. Complications are uncommon.


Self-assembly of fiber-forming collagen mimetic peptides controlled by triple-helical nucleation.
Mimicking the multistep self-assembly of the fibrillar protein collagen is an important design challenge in biomimetic supramolecular chemistry. Utilizing the complementarity of oppositely charged domains in short collagen-like peptides, we have devised a strategy for the self-assembly of these peptides into fibers. The strategy depends on the formation of a staggered triple helical species facilitated by interchain charged pairs, and is inspired by similar sticky-ended fibrillation designs applied in DNA and coiled coil fibers. We compare two classes of collagen mimetic peptides with the same composition but different domain arrangements, and show that differences in their proposed nucleation events differentiates their fibrillation capabilities. Larger nucleation domains result in rapid fiber formation and eventual precipitation or gelation while short nucleation domains leave the peptide soluble for long periods of time. For one of the fiber-forming peptides, we elucidate the packing parameters by X-ray diffraction.


Legal background of aviation medicine in Europe and its future development.
European aviation is moving into an exciting phase now, the administrative structure is changing. Aviation rules and aviation medicine will get a new structure as well. The nature of air traffic required an international scope in rulemaking--especially in such a confined continent as Europe with 41 countries, about 380 Million inhabitants and 317 billion person kilometres flown each year. For economic reasons it became necessary to develop common standards for certification of aircraft in the beginning of the 1970ies, maintenance followed later on. The Cyprus arrangement of 01 July 1990 created the JAA (Joint Aviation Authorities). Joint Aviation Requirements were drafted to replace existing national provisions and have been implemented from the end of the 1990s. The areas of air operations and pilot licensing have been covered as well. The latter comprises of aviation medicine as well. The implementation of JAR-FCL 3, which covers the medical requirements for pilots, started from 1999 on in the several JAA member states. A detailed overview about development and structure of JAA, tools for harmonisation, rulemaking and amendment of requirements, medical standards, review procedures for contentious or marginal cases is described. Shortcomings were the fact that implementation was left to the discretion of the member states and that JAA had no executive power. This resulted in differences in safety and the EU commission concluded that aviation safety had to be regulated by the EU commission. After adoption of EU regulation 1592/2002 in 2002 common and binding requirements were to be drafted and a European aviation agency to be founded. EASA (European Aviation Safety Agency) started its work in September 2003. Finally it will take over the role of JAA completely. Whereas Certification and Maintenance were in the focus first, Flight Operations and Licensing are going to be covered as well in the near future. Essential Requirements have been drafted, outlining - inter alia - the scope of Licensing and of aeromedical aspects. However, the legislative process will most probably last at least until the end of 2007. Implementing Rules - being based on existing JAR-FCLs will be drafted soon and are going to be implemented as soon as EASA is operative for Licensing. JAR-FCL 3 will be the basis for the Implementing Rules concerning aeromedical fitness. An overview about the structure of the Agency, rulemaking procedures, philosophy of medical provisions and the transition from JAA to EASA is described.


Transient characteristics of chaos synchronization in a semiconductor laser subject to optical feedback.
We have investigated the transient characteristics of two types of chaos synchronization in a semiconductor laser subject to optical feedback: complete synchronization and strong injection locking-type synchronization. We have calculated the statistical distribution of the transient response time of synchronization when the initial position in the starting attractor is varied. For complete synchronization, the distribution of the transient response time has much larger average and variance than the average period of the chaotic oscillations. Conversely, a short transient response time is obtained for strong injection locking-type synchronization. We found that the transient response time is dependent upon the maximum Lyapunov exponent of the chaotic temporal waveform for complete synchronization, whereas it is almost constant for strong injection locking-type synchronization.


Syndecan 1 represses cell growth and FSH responsiveness in human granulosa cells.
Albeit devoid of intrinsic catalytic activity, the transmembrane heparan sulphate proteoglycan syndecan 1 plays critical roles in cellular processes such as extracellular matrix crosstalk, cytoskeletal organization, cell spreading, proliferation and differentiation. During the ovarian cycle, the expression of syndecan 1 in granulosa cells shows cyclic variation suggesting that it might fulfil specific roles in follicle development. To investigate its physiological roles on granulosa cells, syndecan 1 was overexpressed in human granulosa cell line KGN which retains features of granulosa cells from small antral follicle such as estradiol (E2) synthesis and low expression of functional FSH receptor (FSHR). We demonstrated that overexpression of syndecan 1 in immature granulosa cells (KGN-SDC1) induces a profound alteration in their intrinsic characteristics including enhanced spreading and attachment, both associated with a reduced growth rate. Flow cytometry analysis revealed that syndecan 1 overexpression increases the percentage of KGN cells in quiescent phase. This partial cell cycle exit is concordant with downregulated levels of CCND1 and CDK4 and upregulated expression of CDK inhibitor CDKN1A In parallel both unstimulated and FSH-induced E2 synthesis are reduced in KGN-SDC1 through both repression of CYP19A1 and FSHR mRNA associated with decreased levels of potential regulators NR5A1 and ESR2 Additionally, we provide evidence that transient cAMP accumulation reduction in cells overexpressing syndecan 1 is accompanied by an increase in cAMP-hydrolysing PDE activity. Our results demonstrated that syndecan 1 might regulate differentiation of granulosa cells and follicular development by means of various mechanisms involving morphological changes, control of signalling pathways and alterations in gene expressions.Free French abstract: A French translation of this abstract is freely available at http://www.reproduction-online.org/content/153/6/797/suppl/DC1.Reproduction.


Postpartum family planning: missed opportunities across the continuum of care
Postpartum family planning is defined as the prevention of unintended pregnancies and closely spaced pregnancies during the first 12 months following childbirth. To assess the practice of family planning (FP) by postpartum mothers in the Regional Director of Health Services (RDHS) division, Kalutara, Sri Lanka. A community-based, descriptive, cross sectional study was carried out among mothers, 8 to 12 weeks postpartum, in the RDHS division, Kalutara in 2014. Calculated sample size was 1200 and the participants were recruited using cluster sampling method. They were interviewed at their residence about their practice of FP methods using an interviewer administered questionnaire. The response rate was 93.7% (n=1112) of which 730 (65.6%) were practicing a FP method at 8-12 weeks after delivery. Condoms were the most popular modern FP method (30.4%, n=222) followed by intrauterine device (26.7%, n=195) and depot medroxyprogesterone acetate (DMPA) injections (22.9%, n=167). Approximately 80% had utilized government sector FP services. Women with higher level of education (p< 0.05), lower family income (p< 0.01), parity more than 3 (p< 0.001) and more than three living children (p<0.01) were significantly more likely to use a FP method. Prevalence of postpartum FP is not satisfactory. Therefore, FP services should consider reaching postpartum mothers with unmet needs as a priority and ensure that a wide range of contraceptive options are available to them. Postpartum FP should be considered as a continuum of maternal care.


Donor/Acceptor Photovoltaic Cells Fabricated on p-Doped Organic Single-Crystal Substrates.
In this study, the operation of donor/acceptor photovoltaic cells fabricated on homoepitaxially grown p-doped rubrene single-crystal substrates is demonstrated. The photocurrent density is dominated by the sheet conductivity (σ□) of the p-type single-crystal layer doped to 100 ppm with an iron chloride (Fe2Cl6) acceptor. A 65 mm thick p-type rubrene single-crystal substrate is expected to be required for a photocurrent density of 20 mA·cm-2. An entire bulk doping technique for rubrene single crystals is indispensable for the fabrication of practical organic single-crystal solar cells.


A case study of race differences among late abortion patients.
The majority of women who terminate an unwanted pregnancy do so in the first trimester of their pregnancy. A much smaller population postpones their decision into the second trimester. Abortion delays greatly increase the health risks and mental stress experienced by women. We examine 240 women who underwent abortions in the second trimester of their pregnancy. The analysis focuses on characteristics that distinguish between black and white women. A discriminant analysis of the data identifies a number of variables that differentiate blacks from whites. Variables that are associated with black and white women who delay their abortion decision include attitudes toward legal abortion, religiosity, household income, the presence of other children, residence patterns, an unwillingness to disclose the pregnancy, and social support for their decision. Discussion of the findings focuses on the role played by cultural experiences.


Solvation dynamics of tryptophan in water-dimethyl sulfoxide binary mixture: in search of molecular origin of composition dependent multiple anomalies.
Experimental and simulation studies have uncovered at least two anomalous concentration regimes in water-dimethyl sulfoxide (DMSO) binary mixture whose precise origin has remained a subject of debate. In order to facilitate time domain experimental investigation of the dynamics of such binary mixtures, we explore strength or extent of influence of these anomalies in dipolar solvation dynamics by carrying out long molecular dynamics simulations over a wide range of DMSO concentration. The solvation time correlation function so calculated indeed displays strong composition dependent anomalies, reflected in pronounced non-exponential kinetics and non-monotonous composition dependence of the average solvation time constant. In particular, we find remarkable slow-down in the solvation dynamics around 10%-20% and 35%-50% mole percentage. We investigate microscopic origin of these two anomalies. The population distribution analyses of different structural morphology elucidate that these two slowing down are reflections of intriguing structural transformations in water-DMSO mixture. The structural transformations themselves can be explained in terms of a change in the relative coordination number of DMSO and water molecules, from 1DMSO:2H2O to 1H2O:1DMSO and 1H2O:2DMSO complex formation. Thus, while the emergence of first slow down (at 15% DMSO mole percentage) is due to the percolation among DMSO molecules supported by the water molecules (whose percolating network remains largely unaffected), the 2nd anomaly (centered on 40%-50%) is due to the formation of the network structure where the unit of 1DMSO:1H2O and 2DMSO:1H2O dominates to give rise to rich dynamical features. Through an analysis of partial solvation dynamics an interesting negative cross-correlation between water and DMSO is observed that makes an important contribution to relaxation at intermediate to longer times.


Blood biomarkers for cognitive decline and clinical progression in a Mexican American cohort.
Introduction: The clinical translation of biofluid markers for dementia requires validation in diverse cohorts. The study goal was to evaluate if blood biomarkers reflecting diverse pathophysiological processes predict disease progression in Mexican American adults. Methods: Mexican American adults (n = 745), 50 years of age and older, completed annual assessments over a mean of 4 years. Serum collected at baseline was assayed for total tau, neurofilament light (NFL), ubiquitin carboxyl-terminal hydrolase LI, glial fibrillary acidic protein (GFAP), soluble cluster of differentiation 14 (sCD14), and chitinase-3-like protein 1 (YKL-40). Results: Higher GFAP and NFL were associated with global cognitive decline. Only GFAP was associated with increased incident dementia risk (hazard ratio: 1.611 (95% confidence interval: 1.204-2.155)) and inclusion of additional biomarkers did not improve model fit. Discussion: Among a panel of six blood biomarkers previously associated with neurodegenerative disease, only GFAP predicted incident dementia in our cohort. The findings suggest that blood GFAP levels may aid dementia-risk prediction among Mexican American adults.


[Mechanisms favoring and triggering atrial fibrillation].
Many experimental and clinical studies have demonstrated that it is possible to trigger atrial fibrillation (AF) by vagal stimulation which reduces and disperses the atrial refractory periods and decreases the threshold of fibrillation. In order to induce fibrillation, it is necessary to deliver a stimulation near to the refractory period. It has also been shown that, in these conditions, there is a delay in atrial conduction. A temporal relationship between the preceding diastole and the coupling interval increases atrial vulnerability and plays an equally important role. The decrease in the effective atrial refractory period, especially when the values are widely dispersed, and the delay in conduction predisposing to atrial reentry, may be considered to be the two most important electrophysiological mechanisms of AF. However, in order to maintain AF, the atrium must be dilated, especially when there is a concurrent cardiac disease. The presence of a shorter "wave length" of activation allowing multiple reentry circuits is an essential condition for sustaining AF. All conductions of induction and maintenance of AF may be observed without participation of S.N.A.. When no cause of AF (atrial pathology, etc.) is apparent, a short atrial refractory period with dispersion of its values and slowing of atrial conduction in presence of an extrastimulus are the probable inducing factors.


ADAD2 interacts with RNF17 in P-bodies to repress the Ping-pong cycle in pachytene piRNA biogenesis.
Pachytene piRNA biogenesis is a hallmark of the germline, distinct from another wave of pre-pachytene piRNA biogenesis with regard to the lack of a secondary amplification process known as the Ping-pong cycle. However, the underlying molecular mechanism and the venue for the suppression of the Ping-pong cycle remain elusive. Here, we showed that a testis-specific protein, ADAD2, interacts with a TDRD family member protein RNF17 and is associated with P-bodies. Importantly, ADAD2 directs RNF17 to repress Ping-pong activity in pachytene piRNA biogenesis. The P-body localization of RNF17 requires the intrinsically disordered domain of ADAD2. Deletion of Adad2 or Rnf17 causes the mislocalization of each other and subsequent Ping-pong activity derepression, secondary piRNAs overproduced, and disruption of P-body integrity at the meiotic stage, thereby leading to spermatogenesis arrested at the round spermatid stage. Collectively, by identifying the ADAD2-dependent mechanism, our study reveals a novel function of P-bodies in suppressing Ping-pong activity in pachytene piRNA biogenesis.


Bioinspired Nanofeatured Substrates: Suitable Environment for Bone Regeneration.
Bone mimicking coatings provide a complex microenvironment in which material, through its inherent properties (such as nanostructure and composition), affects the commitment of stem cells into bone lineage and the production of bone tissue regulating factors required for bone healing and regeneration. Herein, a bioactive mineral/biopolymer composite made of calcium phosphate/chitosan and hyaluronic acid (CaP-CHI-HA) was elaborated using a versatile simultaneous spray coating of interacting species. The resulting CaP-CHI-HA coating was mainly constituted of bioactive, carbonated and crystalline hydroxyapatite with 277 ± 98 nm of roughness, 1 μm of thickness, and 2.3 ± 1 GPa of stiffness. After five days of culture, CaP-CHI-HA suggested a synergistic effect of intrinsic biophysical features and biopolymers on stem cell mechanobiology and nuclear organization, leading to the expression of an early osteoblast-like phenotype and the production of bone tissue regulating factors such as osteoprotegerin and vascular endothelial growth factor. More interestingly, amalgamation with biopolymers conferred to the mineral a bacterial antiadhesive property. These significant data shed light on the potential regenerative application of CaP-CHI-HA bioinspired coating in providing a suitable environment for stem cell bone regeneration and an ideal strategy to prevent implant-associated infections.


Effect of inorganic carbon on the completely autotrophic nitrogen removal over nitrite (CANON) process in a sequencing batch biofilm reactor.
Ammonia-oxidizing bacteria (AOB) and anaerobic ammonia-oxidizing bacteria (AnAOB) are autotrophic microorganisms. Inorganic carbon (IC) is their main carbon source. The effects of IC limitation on AOB and AnAOB in the completely autotrophic nitrogen removal over nitrite (CANON) process in a sequencing batch biofilm reactor (SBBR) were examined. The optimal IC concentration in the influent was investigated. The start-up time of the CANON process from the activated sludge in the SBBR was 80 d under controlled free ammonia (FA) conditions and sufficient IC source. The AOB and AnAOB activities were limited by an IC concentration of 50 mg-C-L(-1) in the influent, whilst the nitrogen loading rate (NLR) was 200 mg-N x L(-1) x d(-1). The experiment on recovering the influent IC showed that AOB and AnAOB activities were affected by the IC limitation, and not by the pH or FA, at 200mg-N x L(-1) x d(-1) NLR and 50mg-C x L(-1) IC in the CANON process. The activities were recovered by increasing the IC concentration in the influent. From an economic point of view, the optimal IC concentration in the influent was 250mg-C x L(-1) at 200mg-N x L(-1) x d(-1) NLR in this CANON system.


The analysis of incontinence episodes and other count data in patients with overactive bladder by Poisson and negative binomial regression.
Clinical studies in overactive bladder have traditionally used analysis of covariance or nonparametric methods to analyse the number of incontinence episodes and other count data. It is known that if the underlying distributional assumptions of a particular parametric method do not hold, an alternative parametric method may be more efficient than a nonparametric one, which makes no assumptions regarding the underlying distribution of the data. Therefore, there are advantages in using methods based on the Poisson distribution or extensions of that method, which incorporate specific features that provide a modelling framework for count data. One challenge with count data is overdispersion, but methods are available that can account for this through the introduction of random effect terms in the modelling, and it is this modelling framework that leads to the negative binomial distribution. These models can also provide clinicians with a clearer and more appropriate interpretation of treatment effects in terms of rate ratios. In this paper, the previously used parametric and non-parametric approaches are contrasted with those based on Poisson regression and various extensions in trials evaluating solifenacin and mirabegron in patients with overactive bladder. In these applications, negative binomial models are seen to fit the data well.


[Tryptic hydrolysis extended to the level of aspartyl bonds].
A quantitative modification of free carboxyl groups in peptides and proteins can be obtained, under mild conditions, by reacting them with ethylenediamine in the presence of N-ethyl-N'-(3-dimethylaminopropyl)-Carbodimide. Aminoethylasparagine and aminoethylglutamine side chains are thus generated in place of the corresponding carboxylic ones. The first kind of residue because of its structure closer to that of lysine, is a point of greater potential trypsic cleavage than the second one. The specificity and yields of this enzymatic cleavage reaction and its possible application in sequence studies are discussed.


Platanus pollen season in Andalusia (southern Spain): trends and modeling.
Platanus is a major cause of pollen allergy in many Spanish cities. The present paper reports an analysis of Platanus pollen season throughout the Andalusia region (southern Spain), which has among the highest pollen counts and the highest incidence of Platanus-related allergies in Europe. The main aim was to analyze pollen season trends from 1992 to 2010 in Andalusia; models were also constructed to forecast the start of the season. Daily pollen counts were recorded using Hirst-type volumetric spore-traps. Pollen season start-dates were very similar at all sites, usually occurring in March. The pollen season was delayed over the study period. The Pollen-season duration and Pollen index generally increased throughout the study period. The starting date for temperature accumulation was around the 10th February, although the threshold temperatures varied by site. The regional model for Andalusia failed to provide sufficiently accurate results compared with sub-regional or local models. For modeling purposes, three sub-regions are recommended: Inland, East Coast and West Coast.


The combination of targeted vaccination and ring vaccination.
Complex networks have become an important tool for investigating epidemic dynamics. A widely concerned research field for epidemics is to develop and study mitigation strategies or control measures. In this paper, we devote our attention to ring vaccination and targeted vaccination and consider the combination of them. Based on the different roles ring vaccination plays in the mixed strategy, the whole parameter space can be roughly divided into two regimes. In one regime, the mixed strategy performs poorly compared with targeted vaccination alone, while in the other regime, the addition of ring vaccination can improve the performance of targeted vaccination. This result gives us the more general and overall comparison between targeted and ring vaccination. In addition, we construct a susceptible-infected-recovered epidemic model coupled with the immunization dynamics on random networks. The comparison between stochastic simulations and numerical simulations confirms the validity of the model we propose.


Depression of fractional sodium reabsorption by the proximal tubule of the dog without sodium diuresis.
The effect of infusions of hyperoncotic solutions on fractional sodium reabsorption by the proximal tubule of the dog was studied by the recollection micropuncture method. Tubule fluid to plasma inulin concentration ratios were measured for identified proximal tubule segments before and after infusion of 25% albumin or dextran solutions. Results were compared with changes in fractional reabsorption during saline diuresis. Plasma volume increased 66% +/- SE 5.8 after infusion of albumin solution and 94% +/- SE 8.2 after infusion of dextran solution. Fractional sodium reabosorption by the proximal tubule was depressed after infusion of both of these hyperoncotic solutions. Nevertheless, changes in sodium excretion after infusion of albumin and dextran were small. In contrast, after infusions of isotonic sodium chloride solution, which increased plasma volume 61% +/- SE 5.8, a decrease in fractional reabsorption of 50.7% +/- SE 7.2 was associated with large changes in sodium excretion.


State-of-the-art treatment of chronic leg ulcers: A randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings.
Current treatment modalities for chronic leg ulcers are time consuming, expensive, and only moderately successful. Recent data suggest that creating a subatmospheric pressure by vacuum-assisted closure (V.A.C., KCI Concepts, San Antonio, Texas) therapy supports the wound healing process. The efficacy of vacuum-assisted closure in the treatment of chronic leg ulcers was prospectively studied in a randomized controlled trial in which 60 hospitalized patients with chronic leg ulcers were randomly assigned to either treatment by V.A.C. or therapy with conventional wound care techniques. The primary outcome measure was the time to complete healing (days). Statistical analysis was performed on the intention-to-treat basis. The median time to complete healing was 29 days (95% confidence interval [CI], 25.5 to 32.5) in the V.A.C. group compared with 45 days (95% CI, 36.2 to 53.8) in the control group (P = .0001). Further, wound bed preparation during V.A.C. therapy was also significantly shorter at 7 days (95% CI 5.7 to 8.3) than during conventional wound care at 17 days (95% CI, 10 to 24, P = .005). The costs of conventional wound care were higher than those of V.A.C. Both groups showed a significant increase in quality of life at the end of therapy and a significant decrease in pain scores at the end of follow-up. V.A.C. therapy should be considered as the treatment of choice for chronic leg ulcers owing to its significant advantages in the time to complete healing and wound bed preparation time compared with conventional wound care. Particularly during the preparation stage, V.A.C. therapy appears to be superior to conventional wound care techniques.


Asymmetric catecholimidazolines and catecholamidines: affinity and efficacy relationships at the alpha adrenoreceptor in rat aorta.
The epinephrine (EPI) stereoisomers interact with the alpha adrenoreceptor according to the Easson-Stedman model with an order of potency of (-)-EPI greater than (+)-EPI = Epinine. A series of catecholimidazolines (CI) and catecholamidines (CA) were compared with the EPI series for the relationship of stereoisomerism to potency, affinity and efficacy. Within each group of desoxy compound and stereoisomers obtained by -OH substitution at the benzylic position, differences in potency were found to be due solely to differences in affinity; differences in efficacy were not significant. The stereoisomers of the CI and CA series followed the order of potency predicted by the Easson-Stedman model: (-)-isomer greater than (+)-isomer. The desoxy analogs, in contrast to the prediction based on the Easson-Stedman hypothesis, were equal (CI) or greater (CA) in potency than the more potent (-)-isomer of each series. Possible explanations for this include differences in physical properties in the desoxy analogs of CI and CA compared with the corresponding enantiomers. Methyl or benzyl substitution at C-4 of the imidazoline ring decreased potency over 100-fold; potency differences between enantiomers were negligible. Thus, the Easson-Stedman model cannot be extended to either the CI or CA series of alpha adrenoreceptor agonists.


[Diagnosis and treatment of cornual obstruction by transcervical fallopian tube cannulation under hysteroscopy].
Transcervical cannulation of the proximal oviduct was performed with a tube catheter and flexible guidewire under hysteroscopic guidance to evaluate and treat intramural fallopian tube obstruction in 37 patients. Hysteroscopic cannulation with direct visualization by laparoscopy was successful in 69.2% of the obstructed tubes, 77.4% of the cases. 74% of the obstructed tubes diagnosed by HSG and/or laparoscopy was patent after hydrotubation and cannulation by hysteroscopy. Transcervical cannulation of the proximal oviduct is an effective method for evaluation and treatment of cornual obstruction.


Assessment and management of acute spinal cord injury: From point of injury to rehabilitation.
Spinal cord injury (SCI) is a devastating condition that can lead to significant neurological impairment and reduced quality of life. Despite advancements in our understanding of the pathophysiology and secondary injury mechanisms involved in SCI, there are currently very few effective treatments for this condition. The field, however, is rapidly changing as new treatments are developed and key discoveries are made. In this review, we outline the pathophysiology, management, and long-term rehabilitation of individuals with traumatic SCI. We also provide an in-depth overview of emerging therapies along the spectrum of the translational pipeline. The concept of "time is spine" refers to the concept which emphasizes the importance of early transfer to specialized centers, early decompressive surgery, and early delivery of other treatments (e.g. blood pressure augmentation, methylprednisolone) to affect long-term outcomes. Another important evolution in management has been the recognition and prevention of the chronic complications of SCI including respiratory compromise, bladder dysfunction, Charcot joints, and pressure sores through directed interventions along with early integration of physical rehabilitation and mobilization. There have also been significant advances in neuroprotective and neuroregenerative strategies for SCI, many of which are actively in clinical trial including riluzole, Cethrin, stem cell transplantation, and the use of functional electrical stimulation. Pharmacologic treatments, cell-based therapies, and other technology-driven interventions will likely play a combinatorial role in the evolving management of SCI as the field continues to evolve.


Functional restoration of cultured mouse pancreatic islets after in vitro exposure to alloxan.
The molecular mechanisms behind the functional responses of the beta-cells after cytotoxic damage are still largely unknown. The aim of this study was to investigate to what extent the islet beta-cells are capable of repairing cellular injuries after acute treatment with increasing doses of alloxan. Isolated mouse pancreatic islets were exposed for 30 min. at 37 degrees to alloxan (1.0, 1.5 and 2.0 mM) or vehicle alone (controls). Immediately after alloxan exposure the islet glucose-stimulated insulin release was severely decreased, and there were morphological evidences of partial necrosis of the islets. After further six days in culture, there was a marked decrease in islet number in the groups of islets treated with 1.5 or 2.0 mM alloxan. However, the DNA and insulin contents of the remaining islets were similar to the values observed in cultured control islets. Furthermore, the insulin secretory response to glucose and the light microscopical appearance of these islets were largely restored on day 6. It is concluded that beta-cells surviving after an injury induced by alloxan may recover their functional capacity after an initial period of inhibited function.


Cadherin-6 in the developing mouse brain: expression along restricted connection systems and synaptic localization suggest a potential role in neuronal circuitry.
Multiple subtypes of the cadherin homophilic cell-cell adhesion molecule are expressed differentially in developing and mature brains, each being expressed in restricted neuronal groups. Cadherin-6 (cad6) is one of such cadherins. Recent studies of cad6 mRNA expression in the postnatal mouse forebrain showed that it occurs in neurons constituting a specific subset of thalamocortical connections. Here we analyzed the localization of cad6 mRNA as well as its protein in the entire central nervous system and also in cranial ganglia of mice at late embryonic to postnatal stages. Our results showed that cad6 is expressed by a limited population of neurons or their precursors, which are synaptically connected to one another, throughout the perinatal stages, and that this expression delineates restricted neuronal circuits from the central to peripheral nervous systems, which include subpathways of the auditory, somatosensory, solitary, vestibular, and olivocerebellar systems. cad6 proteins were detected in these cad6 mRNA-positive neurons on the surface of their cell bodies or dendrites as well as in the cytoplasm. Confocal microscopic analysis revealed that the cad6 protein distribution overlapped that of synaptotagmin in synapse forming areas, suggesting that homotypic cad6 interactions are involved in synaptic connections between neurons expressing this protein. These findings support the idea that cadherin-mediated cell-cell adhesions take part in specific interneuronal connections.


Integrated multicomponent interventions to support healthy aging of the whole person.
Healthy aging is an integrated "whole person" process that involves an individual's biology, behavior, and social/physical environment. With the recent development of antiaging drugs, careful consideration of the respective roles of pharmacologic and nonpharmacologic approaches to both health and aging is in order. Recent advances in understanding the cellular and molecular mechanisms of aging are providing new measures that can be used as clinical outcomes in studying the impact of antiaging interventions in humans. This paper outlines the strategic interest of the National Center for Complementary and Integrative Health (NCCIH) in supporting the development, testing, and implementation of effective, scalable, and integrated multicomponent interventions to support healthy aging of the whole person.


A study of the auditory evoked magnetic field of the human brain.
Small but reproducible and consistent auditory evoked magnetic fields have been obtained for 6 male subjects. These fields exhibit features with a clear spatial symmetry which can be accounted for by assuming that their source consists of two vertically oriented neuronal complexes symmetrically located deep in the temporal lobes. This assignment, which is also consistent with the available electrical data, places the sources within the auditory cortex near the sylvian fissure. Our results suggest that auditory evoked magnetic fields may provide assistance in unravelling the source structure that produces the auditory evoked response, both electrical and magnetic.


MS-282a and MS-282b, new inhibitors of calmodulin-activated myosin light chain kinase from Streptomyces tauricus ATCC 27470.
MS-282a and MS-282b were isolated from the culture broth of Streptomyces tauricus ATCC 27470 as inhibitors of smooth muscle myosin light chain kinase (MLCK). MS-282a and MS-282b inhibited the activity of chicken gizzard MLCK with IC50 values of 3.8 microM and 5.2 microM, respectively. Cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase and protein kinase C were not inhibited by 150 microM MS-282a at all. It is likely that MS-282a blocks MLCK activity by antagonizing calmodulin since 1) the compound inhibited calmodulin-dependent but not calmodulin-independent activity of MLCK; 2) the inhibition of MLCK was antagonized by increasing concentrations of calmodulin, and 3) the compound inhibited calmodulin-dependent cyclic nucleotide phosphodiesterase.


Influenza A Virus Virulence Depends on Two Amino Acids in the N-Terminal Domain of Its NS1 Protein To Facilitate Inhibition of the RNA-Dependent Protein Kinase PKR.
The RNA-dependent protein kinase (PKR) has broad antiviral activity inducing translational shutdown of viral and cellular genes and is therefore targeted by various viral proteins to facilitate pathogen propagation. The pleiotropic NS1 protein of influenza A virus acts as silencer of PKR activation and ensures high-level viral replication and virulence. However, the exact manner of this inhibition remains controversial. To elucidate the structural requirements within the NS1 protein for PKR inhibition, we generated a set of mutant viruses, identifying highly conserved arginine residues 35 and 46 within the NS1 N terminus as being most critical not only for binding to and blocking activation of PKR but also for efficient virus propagation. Biochemical and Förster resonance energy transfer (FRET)-based interaction studies showed that mutation of R35 or R46 allowed formation of NS1 dimers but eliminated any detectable binding to PKR as well as to double-stranded RNA (dsRNA). Using in vitro and in vivo approaches to phenotypic restoration, we demonstrated the essential role of the NS1 N terminus for blocking PKR. The strong attenuation conferred by NS1 mutation R35A or R46A was substantially alleviated by stable knockdown of PKR in human cells. Intriguingly, both NS1 mutant viruses did not trigger any signs of disease in PKR+/+ mice, but replicated to high titers in lungs of PKR-/- mice and caused lethal infections. These data not only establish the NS1 N terminus as highly critical for neutralization of PKR's antiviral activity but also identify this blockade as an indispensable contribution of NS1 to the viral life cycle.IMPORTANCE Influenza A virus inhibits activation of the RNA-dependent protein kinase (PKR) by means of its nonstructural NS1 protein, but the underlying mode of inhibition is debated. Using mutational analysis, we identified arginine residues 35 and 46 within the N-terminal NS1 domain as highly critical for binding to and functional silencing of PKR. In addition, our data show that this is a main activity of amino acids 35 and 46, as the strong attenuation of corresponding mutant viruses in human cells was rescued to a large extent by lowering of PKR expression levels. Significantly, this corresponded with restoration of viral virulence for NS1 R35A and R46A mutant viruses in PKR-/- mice. Therefore, our data establish a model in which the NS1 N-terminal domain engages in a binding interaction to inhibit activation of PKR and ensure efficient viral propagation and virulence.


Defect Dynamics at a Single Pt Nanoparticle during Catalytic Oxidation.
Defects can affect all aspects of a material by altering its electronic properties and controlling its chemical reactivity. At defect sites, preferential adsorption of reactants and/or formation of chemical species at active sites are observed in heterogeneous catalysis. Understanding the structural response at defect sites during catalytic reactions provides a unique opportunity to exploit defect control of nanoparticle-based catalysts. However, it remains difficult to characterize the strain and defect evolution for a single nanocrystal catalyst in situ. Here, we report Bragg coherent X-ray diffraction imaging of defect dynamics in an individual Pt nanoparticle during catalytic methane oxidation. We observed that the initially tensile strained regions of the crystal became seed points for the development of further strain and subsequent disappearance of diffraction density during oxidation reactions. Our detailed understanding of the catalytically induced deformation at the defect sites and observed reversibility during the relevant steps of the catalytic oxidation process provide important insights of defect control and engineering of heterogeneous catalysts.


Overcoming Hypoxia-Restrained Radiotherapy Using an Erythrocyte-Inspired and Glucose-Activatable Platform.
Radiotherapy (RT) as one of the most powerful cancer treatment strategies has been greatly restricted by tumor hypoxia. A mounting effort has been devoted to develop oxygen delivery systems for boosting the RT effect. Unluckily, those systems only supplied modest oxygen, which could not afford more than once and long-time RT. Herein, we describe the development of a glucose-regulated drug release platform, allowing for a long-term tumor normoxic microenvironment and repeated RT for a long time. The repeated cycles resulted in sustained high Endostar plasma levels, which dramatically normalized the tumor vasculature and chronically reversed tumor hypoxia. Taking advantage of the inexhaustible supply of oxygen, Endo@GOx-ER enabled RT achieved an impressive cancer treatment output. To the best of our knowledge, our strategy is the initial attempt to overcome tumor-hypoxia-limited RT through the normalization of tumor vasculature by using an erythrocyte-inspired and glucose-activatable platform and it visually casts a light on the clinical development.


Expression and Prognosis Value of the KLF Family Members in Colorectal Cancer.
Krüppel-like factors (KLFs) are some kind of transcriptional regulator that regulates a broad range of cellular functions and has been linked to the development of certain malignancies. KLF expression patterns and prognostic values in colorectal cancer (CRC) have, however, been investigated rarely. To investigate the differential expression, predictive value, and gene mutations of KLFs in CRC patients, we used various online analytic tools, including ONCOMINE, TCGA, cBioPortal, and the TIMER database. KLF2-6, KLF8-10, KLF12-15, and KLF17 mRNA expression levels were dramatically downregulated in CRC tissues, but KLF1, KLF7, and KLF16 mRNA expression levels were significantly elevated in CRC tissues. According to the findings of Cox regression analysis, upregulation of KLF3, KLF5, and KLF6 and downregulation of KLF15 were linked with a better prognosis in CRC. For functional enrichment, our findings revealed that KLF members are involved in a variety of cancer-related biological processes. In colon cancer and rectal cancer, KLFs were also shown to be associated with a variety of immune cells. The findings of this research reveal that KLF family members' mRNA expression levels are possible prognostic indicators for patients with CRC.


Reliability and Versatility of Reverse Sural Island Neurofasciocutaneous Leg Flaps.
Distally based sural neurofasciocutaneous (NFC) flaps are a commonly used method for foot and ankle reconstruction given that they are much simpler and, at the same time, still efficient alternative to perforator flaps and free style free flaps. This study aims to evaluate the reliability and versatility of reverse sural island NFC flaps as a powerful and efficient method that can be used for repair of lower leg skin defects. This method does not require microsurgical facilities or extensive training. Patients with soft tissue defects of the distal third of the leg and ankle region received reverse sural island NFC flaps. Inclusion criteria included an absence of damage to the sural neurovascular axis or communicating perforators, absence of peripheral vascular disease, and the presence of soft tissue defects deep enough to expose tendon or bone. Patients were assessed for flap (defect) size, pedicle length and location of defects, postoperative flap survival rates, and complications. Donor sites were closed directly or skin grafted. Of 24 consecutive patient (20 male; 4 female), all flaps except 1 (4.16%), survived, although partial necrosis was observed in 2 patients (8.33%). The overall major complication rate was 12.50%. Epidermolysis was noted in 1 patient (4.16%). Three cases of transient venous congestion resolved without additional complications. The overall minor complication rate was 16.66%. Minimal complications were associated with healing of donor sites. Reverse sural island NFC flaps provide adequate and aesthetically very acceptable coverage of soft tissue defects of the distal lower leg and proximal foot with no functional impairment.


[Extensions of the Reformation of Martin Luther to public health in his time].
The reformation as the decisive social change during the first half of the 16th century influenced directly also the organisational forms of the contemporary social welfare and indirectly the development of public health of that time. By evaluation of still existing account health of that time. By evaluation of still existing account-books of the Gemeinen Kasten the changes in the provision of the poor and the development of the old hospitals caused by reformation were investigated. Here the personal influence of Martin Luther is shown.


Combination of thresholding and fitting methods for measuring nanoparticle sizes and size distributions in (S)TEM.
The practical need for a simple and reliable tool for routine size analysis of nanoparticles with diameters down to a few nm embedded in a polymer matrix motivated the development of a new approach. The idea underlying the method proposed in this work is to combine intensity thresholding and contrast fitting procedures in the same software for particle recognition and measurements of sizes and size distributions of nanoparticles in transmission and scanning transmission electron microscopy images. Particle recognition in images is performed in an interactive process of manual setting the numerical threshold level after image preprocessing. We show that fitting the calculated gray level distribution to the real images is able to provide a maximum accuracy in measurements of the particle diameters in contrast to thresholding approaches. The fitting procedure is applied in the vicinity of nanoparticle images with the mass-thickness, diffraction, and chemical contrast. The grayscale function associated to the nanoparticle thickness is described using polynomial gt=g0+g1t+g2t2+g3t3… with degree ⩾ 2 and undetermined coefficients. The program for particle detection and size measurement-Analyzer of Nanoparticles (AnNa)-has been written and is described here. It was successfully tested on systems containing Ag nanoparticles grown and stabilized in aqueous solutions of different polymers for biomedical use and is available from the authors.


Electrodeposition of Nanotwin Cu by Pulse Current for Through-Si-Via (TSV) Process.
Recently, the through-Si-via (TSV) had been focused as an optimal solution for interconnecting the 3-dimensionaly stacked semiconductor devices. One of core processes in the TSV technology is the Cu filling process which electrochemically forms the Cu in the via with high aspect ratio. The nanotwin Cu is effective candidate for replacing the conventional electrodeposited Cu due to its ultrahigh mechanical strength and good electrical conductivity. In this work, the formation of the nanotwin Cu in the TSV by applying pulse current was systematically studied. Also, TSV filling behavior by electrodeposition with pulse current was compared with direct current. The variation of mechanical properties as well as the electrical resistivity of electrodeposited Cu by the pulse current also investigated.


[Dosimetry fundamentals of endovascular therapy using Re-188 for the prevention of restenosis after angioplasty].
Various radionuclides can be used for endovascular brachytherapy. A new concept is to inflate the balloon of a dilatation catheter with a radioactive solution. Re-188 can be eluted from a generator system and is available daily. The aim of this study was to obtain dosimetric data for this radionuclide. The dose decrease of Re-188 was calculated and measured with a TLD-system radial to a balloon catheter typically used in cardiology (diameter: 3 mm, length: 20 mm). Using a specific activity of 370 MBq/ml a dose of 0.3 Gy could be achieved within 1 min in a TLD in contact with the balloon. Paired TLDs differed about 3%. A fast dose reduction of 50% and 10% were stated within 0.5 mm and 2.5 mm, respectively. Calculated and measured values were in good agreement. The data are comparable to those known for Y-90. Calculations of dose distribution are consistent with TLD measurements of Re-188. Using a specific activity of 1.85 GBq/ml, a dose of 10-15 Gy at the coronary artery wall can be achieved within 2-3 min. Compared to radioactive stents or wires the use of this liquid beta-emitter is a simple alternative for prevention of the restenosis following the angioplasty.


[A Case of Locally Advanced Rectal Cancer Successfully Treated by Conversion Surgery after Multidisciplinary Treatment].
A 70-year-old woman who complained of abdominal pain and a prolapsed tumor from the anus was diagnosed with an intestinal obstruction resulting from anal canal cancer. Computed tomography (CT) and magnetic resonance imaging revealed a huge tumor (11×5×12 cm) invading the vagina and levator ani muscle. Enlarged inguinal lymph nodes on both sides indicated metastasis. The clinical stage was T4b (vagina, levator ani muscle, and pudenda) N0H0M1a (LYM), stage IV (Japanese Classification of Colorectal Carcinoma: 8th edition). As curative resection was not possible, a transvers colostomy was performed to relieve the intestinal obstruction. This was followed by chemoradiotherapy (45 Gy/1.8 Gy×25; TS-1, 80 mg/body for 2 weeks and a 1-week interval, for 2 courses) and up to 10 courses of Bev+mFOLFOX6 continuously. After this regimen, there was a remarkable reduction in tumor size. Positron emission tomography-CT revealed no FDG uptake in the primary rectal site or inguinal lymph nodes, but a maximum standardized uptake value (SUVmax) of 6.3 was detected in the vagina. Six weeks after chemotherapy, the patient underwent a pelvic exenteration including resection of the vagina, bladder, and pudenda. The pathological stage was yp T4b (vagina) N0H0M0, stageⅡ. Curative resection was performed, and the patient had a Grade 2 pathological response after chemoradiotherapy.


Evolution and Development of Ilizarov Technique in the Treatment of Infected Long Bone Nonunion with or without Bone Defects.
The treatment of infected bone nonunion and bone defects is a considerable challenge in the orthopedics field. The standard clinical therapy methods include local free bone transplantation, vascularized bone graft, and the Ilizarov technique; the first two are controversial due to the iatrogenic self-injury. The Ilizarov bone transport technique has been widely used to treat infected bone nonunion and bone defects, and good clinical effect has been demonstrated. Yet, it brings many related complications, which exerts additional suffering to the patient. The best treatment is to combine bone defect rehabilitation with infection control, intramedullary nail fixation, appropriate time for bone grafts, beaded type scaffold slippage and new Taylor fixation, reducing the external fixation time and the incidence of complications, thereby reducing the occurrence of patients' physical and psychological problems. This review focuses on the induction, summary and analysis of the Ilizarov bone transport technique in the treatment of infected long bone nonunion with or without bone defects, providing new ideas and methods for orthopedic disease prevention and treatment by the Ilizarov technique, which is following the development direction of digital orthopedics.


Investigating ebullition in a sand column using dissolved gas analysis and reactive transport modeling.
Ebullition of gas bubbles through saturated sediments can enhance the migration of gases through the subsurface, affect the rate of biogeochemical processes, and potentially enhance the emission of important greenhouse gases to the atmosphere. To better understand the parameters controlling ebullition, methanogenic conditions were produced in a column experiment and ebullition through the column was monitored and quantified through dissolved gas analysis and reactive transport modeling. Dissolved gas analysis showed rapid transport of CH4 vertically through the column at rates several times faster than the bromide tracer and the more soluble gas CO2, indicating that ebullition was the main transport mechanism for CH4. An empirically derived formulation describing ebullition was integrated into the reactive transport code MIN3P allowing this process to be investigated on the REV scale in a complex geochemical framework. The simulations provided insights into the parameters controlling ebullition and show that, over the duration of the experiment, 36% of the CH4 and 19% of the CO2 produced were transported to the top of the column through ebullition.


Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer.
The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer. DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established. Overall genomic alteration rates in the younger (<40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53 (FDR < 0.01) and CTNNB1 (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and APC (FDR < 0.01), KRAS (FDR < 0.01), BRAF (FDR < 0.01), and FAM123B (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR < 0.01), BRAF (FDR < 0.01), and KRAS (FDR < 0.01). Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.


Predicting return to work after traumatic brain injury using machine learning and administrative data.
Accurate patient-specific predictions on return-to-work after traumatic brain injury (TBI) can support both clinical practice and policymaking. The use of machine learning on large administrative data provides interesting opportunities to create such prognostic models. The current study assesses whether return-to-work one year after TBI can be predicted accurately from administrative data. Additionally, this study explores how model performance and feature importance change depending on whether a distinction is made between mild and moderate-to-severe TBI. This study used a population-based dataset that combined discharge, claims and social security data of patients hospitalized with a TBI in Belgium during the year 2016. The prediction of TBI was attempted with three algorithms, elastic net logistic regression, random forest and gradient boosting and compared in their performance by their accuracy, sensitivity, specificity and area under the receiver operator curve (ROC AUC). The distinct modelling algorithms resulted in similar results, with 83% accuracy (ROC AUC 85%) for a binary classification of employed vs. not employed and up to 76% (ROC AUC 82%) for a multiclass operationalization of employment outcome. Modelling mild and moderate-to-severe TBI separately did not result in considerable differences in model performance and feature importance. The features of main importance for return-to-work prediction were related to pre-injury employment. While clearly offering some information beneficial for predicting return-to-work, administrative data needs to be supplemented with additional information to allow further improvement of patient-specific prognose.


Enhancement of erythrocyte antioxidants by green and black tea polyphenols during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.
We evaluated the comparative chemopreventive efficacy of green tea polyphenols (polyphenon-E) and black tea polyphenols (polyphenon-B) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Lipid peroxidation, reduced and oxidized glutathione (GSH and GSSG, respectively), and the GSH-dependent enzymes glutathione peroxidase and glutathione S-transferase in the erythrocytes were used as biomarkers of chemoprevention. Enhanced lipid peroxidation in erythrocytes of DMBA-treated animals was accompanied by a significant decrease in the antioxidant status. Dietary administration of polyphenon-E and -B to DMBA-treated animals significantly decreased the extent of lipid peroxidation and enhanced the levels of GSH, GSH/GSSG ratio, and activities of GSH-dependent enzymes. Our study provides evidence that polyphenon-B is more effective in inhibiting HBP carcinogenesis than polyphenon-E by enhancing the antioxidant status, suggesting that polyphenon-B may have a major impact in the chemoprevention of oral cancer.


Chromatin insulator bodies are nuclear structures that form in response to osmotic stress and cell death.
Chromatin insulators assist in the formation of higher-order chromatin structures by mediating long-range contacts between distant genomic sites. It has been suggested that insulators accomplish this task by forming dense nuclear foci termed insulator bodies that result from the coalescence of multiple protein-bound insulators. However, these structures remain poorly understood, particularly the mechanisms triggering body formation and their role in nuclear function. In this paper, we show that insulator proteins undergo a dramatic and dynamic spatial reorganization into insulator bodies during osmostress and cell death in a high osmolarity glycerol-p38 mitogen-activated protein kinase-independent manner, leading to a large reduction in DNA-bound insulator proteins that rapidly repopulate chromatin as the bodies disassemble upon return to isotonicity. These bodies occupy distinct nuclear territories and contain a defined structural arrangement of insulator proteins. Our findings suggest insulator bodies are novel nuclear stress foci that can be used as a proxy to monitor the chromatin-bound state of insulator proteins and provide new insights into the effects of osmostress on nuclear and genome organization.


Population health and the economy: Mortality and the Great Recession in Europe.
We analyze the evolution of mortality-based health indicators in 27 European countries before and after the start of the Great Recession. We find that in the countries where the crisis has been particularly severe, mortality reductions in 2007-2010 were considerably bigger than in 2004-2007. Panel models adjusted for space-invariant and time-invariant factors show that an increase of 1 percentage point in the national unemployment rate is associated with a reduction of 0.5% (p < .001) in the rate of age-adjusted mortality. The pattern of mortality oscillating procyclically is found for total and sex-specific mortality, cause-specific mortality due to major causes of death, and mortality for ages 30-44 and 75 and over, but not for ages 0-14. Suicides appear increasing when the economy decelerates-countercyclically-but the evidence is weak. Results are robust to using different weights in the regression, applying nonlinear methods for detrending, expanding the sample, and using as business cycle indicator gross domestic product per capita or employment-to-population ratios rather than the unemployment rate. We conclude that in the European experience of the past 20 years, recessions, on average, have beneficial short-term effects on mortality of the adult population.


Long-term results of simple enucleation for the treatment of small renal cell carcinoma.
We have analyzed our institutional experience with simple enucleation for the treatment of small renal tumors for elective indications. A total of 30 patients underwent elective nephron-sparing surgery (NSS) from May 1997 to January 2001. All patients underwent NSS by means of enucleation. The tumor bed was coagulated carefully for haemostatic and partly for oncological reasons. Median follow-up was 71 months (range: 49-91 months). Pathological review according to the 2002 TNM classification showed that 70 % (21 of 30) of tumors were pT1a, 26.7 % (8 of 30) pT1b and 3.3 % (1 of 30) pT3a. Median tumor size was 3.7 cm. (range: 3.0 - 5.5 cm). There was no perioperative mortality (within the first 30 days). Bleeding had not been recorded during perioperative period. Urinary leakage was observed in 1 patient (3.3%). No case of local recurrence was observed. Five and 7-year cumulative survival was 96.6% and 93.3%, respectively. Five and 7-year cancer specific survival was 100% and 96.5%, respectively. Simple tumor enucleation is a safe and acceptable approach for elective NSS. It provides excellent long-term progression-free and cancer specific survival rates, and is not associated with an increased risk of local recurrence compared to partial nephrectomy.


Active and passive immunization for cancer.
Vaccination started around the 10th century AD as a means of preventing smallpox. By the end of the 19th century such therapeutic vaccines were well established with both active and passive preparations being used in clinical practice. Active immunization involved administering an immunogen that might be live/ attenuated, killed/ inactivated, toxoid or subunit in origin. Passive immunization involved giving pre-formed antibodies, usually to very recently exposed individuals. At about the same time such approaches were also tried to treat a variety of cancers - proof of principle for the protective role of the immune response against malignancy was established by the observation that tumors transplanted into syngeneic hosts were rejected by the host innate and adaptive responses. The impact of these therapeutic vaccination has taken a considerable time to become established - in part because target antigens against which an adaptive response can be directed do not appear to be uniquely expressed on malignant transformed cells; and also because tumor cells are able to manipulate their environment to downregulate the host immune response. Therapeutic cancer vaccines are also divided into active and passive types - the latter being subdivided into specific and non-specific vaccines. Active immunization utilizes an immunogen to generate a host response designed to eliminate the malignant cells, whereas in passive immunization preformed antibodies or cells are administered to directly eliminate the transformed cells - examples of each are considered in this review.


EHAI: Enhanced Human Microbe-Disease Association Identification.
Recently, an increasing number of biological and clinical reports have demonstrated that imbalance of microbial community has the ability to play important roles among several complex diseases concerning human health. Having a good knowledge of discovering potential of microbe-disease relationships, which provides the ability to having a better understanding of some issues, including disease pathology, further boosts disease diagnostics and prognostics, has been taken into account. Nevertheless, a few computational approaches can meet the need of huge scale of microbe-disease association discovery. In this work, we proposed the EHAI model, which is Enhanced Human microbe- disease Association Identification. EHAI employed the microbe-disease associations, and then Gaussian interaction profile kernel similarity has been utilized to enhance the basic microbe-disease association. Actually, some known microbe-disease associations and a large amount of associations are still unavailable among the datasets. The 'super-microbe' and 'super-disease' were employed to enhance the model. Computational results demonstrated that such super-classes have the ability to be helpful to the performance of EHAI. Therefore, it is anticipated that EHAI can be treated as an important biological tool in this field.


Chemical Composition and Antifungal Activity of Ocimum basilicum L. Essential Oil.
The leaves of Ocimum basilicum L. (basil) are used in traditional cuisine as spices; its essential oil has found a wide application in perfumery, dental products as well as antifungal agents. To assess the chemical composition as well as the in vitro antifungal activity of O. basilicum L. essential oil against Aspergillus flavus fungal growth and aflatoxin B1 production. The essential oil of O. basilicum was obtained by hydrodistillation and analysed using gas chromatography (GC) and GC coupled with mass spectrometry (GC/MS). The essential oil was tested for its effects on Aspergillus flavus (A. flavus) mycelial growth and aflatoxin B1 production in Yeast Extract Sucrose (YES) growth media. Aflatoxin B1 production was determined by high performance liquid chromatography (HPLC). Nineteen compounds, representing 96.7% of the total oil were identified. The main components were as follows: linalool (48.4%), 1,8-cineol (12.2%), eugenol (6.6%), methyl cinnamate (6.2%), α-cubebene (5.7%), caryophyllene (2.5%), β-ocimene (2.1%) and α-farnesene (2.0%). The tested oil showed significant antifungal activity that was dependent on the used oil concentration. The complete inhibition of A. flavus growth was observed at 1000 ppm oil concentration, while marked inhibition of aflatoxin B1 production was observed at all oil concentrations tested (500, 750 and 1000 ppm). These results confirm the antifungal activities of O. basilicum L. oil and its potential use to cure mycotic infections and act as pharmaceutical preservative against A. flavus growth and aflatoxin B1 production.


Palmitate increases Nur77 expression by modulating ZBP89 and Sp1 binding to the Nur77 proximal promoter in pancreatic β-cells.
Nur77 is a stress sensor in pancreatic β-cells, which negatively regulates glucose-stimulated insulin secretion. We recently showed that a lipotoxic shock caused by exposure of β-cells to the saturated fatty acid palmitate strongly increases Nur77 expression. Here, using dual luciferase reporter assays and Nur77 promoter deletion constructs, we identified a regulatory cassette between -1534 and -1512 bp upstream from the translational start site mediating Nur77 promoter activation in response to palmitate exposure. Chromatin immunoprecipitation, transient transfection and siRNA-mediated knockdown assays revealed that palmitate induced Nur77 promoter activation involves Sp1 recruitment and ZBP89 release from the gene promoter.


[Clinical application and effectiveness of patellar tunnel locator in medial patellofemoral ligament reconstruction surgery].
To evaluate the operability and effectiveness of a self-developed patellar bone canal locator (hereinafter referred to as "locator") in the reconstruction of the medial patellofemoral ligament (MPFL). A total of 38 patients with recurrent patellar dislocation who met the selection criteria admitted between January 2022 and December 2022 were randomly divided into study group (the patellar canal was established with a locator during MPFL reconstruction) and control group (no locator was used in MPFL reconstruction), with 19 cases in each group. There was no significant difference in baseline data between the two groups ( P>0.05), such as gender, age, body mass index, disease duration, patella Wiberg classification, constituent ratio of cartilage injury, Caton index, tibia tubercle-trochlear groove, and preoperative Lysholm score, Kujal score, Tegner score, visual analogue scale (VAS) score, and so on. The Lysholm score, Kujal score, Tegner score, and VAS score were used to evaluate knee joint function before operation and at 3 days,1 month, 3 months, and 6 months after operation. The ideal prepatellar cortical thickness and canal length were measured before operation, and the actual prepatellar cortical thickness and canal length after operation were also measured, and D1 (the distance between the ideal entrance and the actual entrance), D2 (the ideal canal length minus the actual canal length), D3 (the ideal prepatellar cortical thickness minus the actual prepatellar cortical thickness) were calculated. Patients in both groups were followed up 6-8 months (mean, 6.7 months). The incision length and intraoperative blood loss in the study group were smaller than those in the control group, but the operation time was longer than that in the control group, the differences were significant ( P<0.05). There was no complication such as incision infection, effusion, and delayed healing in both groups, and no further dislocation occurred during follow-up. One patient in the study group had persistent pain in the anserine area after operation, and the symptoms were relieved after physiotherapy. The VAS score of the two groups increased significantly at 3 days after operation, and gradually decreased with the extension of time; the change trends of Lysholm score, Kujal score, and Tegner score were opposite to VAS score. Except that the Lysholm score and Kujal score of the study group were higher than those of the control group at 3 days after operation, and the VAS score of the study group was lower than that of the control group at 3 days and 1 month after operation, the differences were significant ( P<0.05), there was no significant difference in the scores between the two groups at other time points ( P>0.05). Patellar bone canal evaluation showed that there was no significant difference in preoperative simulated ideal canal length, prepatellar cortical thickness, and postoperative actual canal length between the two groups ( P>0.05). The postoperative actual prepatellar cortical thickness of the study group was significantly smaller than that of the control group ( P<0.05). D1 and D3 in the study group were significantly higher than those in control group ( P<0.05), but there was no significant difference in D2 between the two groups ( P>0.05). The locator can improve the accuracy of MPFL reconstruction surgery, reduce the possibility of intraoperative damage to the articular surface of patella and postoperative patellar fractures.


Simultaneous analysis of nine aromatic amines in mainstream cigarette smoke using online solid-phase extraction combined with liquid chromatography-tandem mass spectrometry.
A fully automated analytical method was developed and validated by this present study. The method was based on two-dimensional (2D) online solid-phase extraction liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) to determine nine aromatic amines (AAs) in mainstream smoke (MSS) simultaneously. As a part of validation process, AAs yields for 16 top-selling commercial cigarettes from China market were evaluated by the developed method under both Health Canada Intensive (HCI) and ISO machine smoking regimes. The gas phase of MSS was trapped by 25 mL 0.6 M hydrochloric acid solution, while the particulate phase was collected on a glass fiber filter. Then, the glass fiber pad was extracted with hydrochloric acid solution in an ultrasonic bath. The extract was analyzed with 2D online SPE-LC-MS/MS. In order to minimize the matrix effects of sample on each analyte, two cartridges with different extraction mechanisms were utilized to cleanup disturbances of different polarity, which were performed by the 2D SPE. A phenyl-hexyl analytical column was used to achieve a chromatographic separation. Under the optimized conditions, the isomers of p-toluidine, m-toluidine and o-toluidine, 3-aminobiphenyl and 4-aminobiphenyl, and 1-naphthylamine and 2-naphthylamine were baseline separated with good peak shapes for the first time. The limits of detection for nine AAs ranged from 0.03 to 0.24 ng cig-1. The recovery of the measurement of nine AAs was from 84.82 to 118.47%. The intra-day and inter-day precisions of nine AAs were less than 10 and 16%, respectively. Compared with ISO machine smoking regime, the AAs yields in MSS were 1.17 to 3.41 times higher under HCI machine smoking regime. Graphical abstract New method using online SPE-LC/MS/MS for analysis of aromatic amines in mainstream cigarette smoke.


Burden of gastrointestinal and liver diseases in India, 1990-2016.
There is no comprehensive report on the burden of gastrointestinal (GI) and liver diseases in India. In this study, we estimated the age-standardized prevalence, mortality, and disability adjusted life years (DALY) rates of GI and liver diseases in India from 1990 to 2016 using data from the Global Burden of Disease (GBD) Study, which systematically reviews literature and reports for international disease burden trends. Despite a decrease in the overall burden from GI infectious disorders since 1990, they still accounted for the majority of DALYs in 2016. Among noncommunicable disorders (NCDs), there were increases in the prevalence and mortality rates for pancreatitis, liver cancer, paralytic ileus and intestinal obstruction, gallbladder and biliary tract cancer, vascular intestinal disorders, colorectal cancer, and inflammatory bowel disease. Prevalence and mortality rates decreased for peptic ulcer disease, hernias, appendicitis, and stomach and esophageal cancer. For gastritis and duodenitis, cirrhosis and other chronic liver diseases, and gallbladder and biliary tract diseases, there was an increase in prevalence but a decrease in mortality while the opposite was true for pancreatic cancer (decreased prevalence, increased mortality). Indian gastroenterologists and hepatologists must continue to attend to the large majority of patients with infectious diseases while also managing the increasing number of GI and liver diseases, noncommunicable nonmalignant and malignant.


Effects on muscle activity from microstimuli applied to somatosensory and motor cortex during voluntary movement in the monkey.
It is well known that electrical stimulation of primary somatosensory cortex (SI) evokes movements that resemble those evoked from primary motor cortex. These findings have led to the concept that SI may possess motor capabilities paralleling those of motor cortex and speculation that SI could function as a robust relay mediating motor responses from central and peripheral inputs. The purpose of this study was to rigorously examine the motor output capabilities of SI areas with the use of the techniques of spike- and stimulus-triggered averaging of electromyographic (EMG) activity in awake monkeys. Unit recordings were obtained from primary motor cortex and SI areas 3a, 3b, 1, and 2 in three rhesus monkeys. Spike-triggered averaging was used to assess the output linkage between individual cells and motoneurons of the recorded muscles. Cells in motor cortex producing postspike facilitation (PSpF) in spike-triggered averages of rectified EMG activity were designated corticomotoneuronal (CM) cells. Motor output efficacy was also assessed by applying stimuli through the microelectrode and computing stimulus-triggered averages of rectified EMG activity. One hundred seventy-one sites in motor cortex and 68 sites in SI were characterized functionally and tested for motor output effects on muscle activity. The incidence, character, and magnitude of motor output effects from SI areas were in sharp contrast to effects from CM cell sites in primary motor cortex. Of 68 SI cells tested with spike-triggered averaging, only one area 3a cell produced significant PSpF in spike-triggered averages of EMG activity. In comparison, 20 of 171 (12%) motor cortex cells tested produced significant postspike effects. Single-pulse intracortical microstimulation produced effects at all CM cell sites in motor cortex but at only 14% of SI sites. The large fraction of SI effects that was inhibitory represented yet another marked difference between CM cell sites in motor cortex and SI sites (25% vs 93%). The fact that motor output effects from SI were frequently absent or very weak and predominantly inhibitory emphasizes the differing motor capabilities of SI compared with primary motor cortex.


[Direct Coombs' test in the aged].
Blood samples from 431 persons (age: 78 to 99 years) were examined by the direct anti-human-globulin test (d. AHGT ) with polyspecific and monospecific antisera. Three antibody-mediated positive d. AHGT were found. There was no increase in non antibody-mediated positive complement Coombs reactions in healthy persons of high age.


Tonic pain: a SPET study in normal subjects and cluster headache patients.
Whether the pathogenesis of cluster headache (CH) is peripheral or central is still matter of debate. An involvement of central structures related to pain perception and modulation, which also causes an alteration of the physiological pattern of pain perception in CH, has been hypothesized. We investigated the pattern of brain response to pain in normal subjects and CH patients by evaluating the cerebral blood flow (CBF) changes using an experimental model of tonic aching pain stimulation, the cold water pressor test (CWPT). CBF was assessed quantitatively by the Xe-133 inhalation method and single photon emission tomography (SPET), at rest and during CWPT, as previously described (Di Piero et al., 1994). CWPT was performed in 12 volunteers and in seven patients with CH. All the CH patients had a left-sided headache and were studied in a headache-free phase out of the cluster period. During CWPT, volunteers showed a significant CBF increase in the contralateral primary sensorimotor (P < 0.001), frontal (P < 0.01) and temporal (P < 0.002) regions and thalamus (P < 0.01) and in the ipsilateral temporal (P < 0.005) and anterior cingulate (P < 0.01) regions. During left-hand stimulation (ipsilateral to the headache side) by CWPT in CH patients, CBF changes were significantly lower than those observed in volunteers in the contralateral primary sensorimotor region (P < 0.0005) and thalamus region (P < 0.01). There were no significant differences in the brain response observed during the stimulation of the hand contralateral to the headache side. In conclusion, in a headache-free phase out of the cluster period, the pattern of cerebral activation during tonic pain stimulation of the hand ipsilateral to the headache side is critically modified in CH patients in areas which are probably involved in the detection of the stimulus intensity. This modification may reflect a marker of a biological modification of the pain conveyance system. The fact that it is also present out of the active period of the disease, suggests a possible involvement of central tonic pain mechanisms in the pathogenesis of CH.


Missing data in clinical trials for weight management.
In 2014, the US FDA approved liraglutide for weight management. The statistical review of the application presented various challenges related to the handling of missing data. The ability of the drug to cause weight loss was not in question. The challenge centered on obtaining a reliable estimate of the intention-to-treat effect to support the risk-benefit evaluation. Subjects in the trials that stopped treatment prior to the endpoint were encouraged to attend the primary endpoint visit. Data from the subjects that returned for a primary efficacy assessment played a significant role in the statistical review. They were used to illustrate shortcomings of the applicant's primary efficacy analysis and sensitivity analyses. They were also used in the FDA analyses to address missing data. The goal of this article is to illustrate challenges and considerations associated with the handling of missing data in clinical trials.


Application of 3D visualization and 3D printing technology on ERCP for patients with hilar cholangiocarcinoma.
Endoscopic retrograde cholangiopancreatography (ERCP) is an important treatment for inoperable hilar cholangiocarcinoma (HCC). The aim of the present study as to evaluate the clinical value of three-dimensional visualization (3DV) and 3D printing (3DP) technologies for ERCP in patients with HCC. The clinical data of 15 patients with HCC admitted for ERCP were analyzed retrospectively, including 9 males and 6 females. Thin-sliced data of computed tomography and magnetic resonance cholangiopancreatography (MRCP) were acquired and imported into Mimics Innovation Suite v17.0 software for 3D reconstruction. Standard Template Library files were exported for 3D printing. The target bile duct and Bismuth-Corlette (BC) classification were selected and performed respectively with the aid of Mimics Innovation Suite v17.0 software. The results were compared with the selected ones in ERCP. 3DV and 3DP models were successfully constructed for all patients, which presented the tumor, bile duct and the spatial relationship between them from multiple perspectives. The ERCP of all patients in the present study were performed successfully. The target bile duct screened by them had a high concordance rate of 86.7% with that in ERCP. The diagnostic accuracy of BC type results by 3DV and 3DP models was 93.3%. 3DV and 3DP technologies can accurately show the tumor and its associations with the surrounding bile duct, and it can be used to guide ERCP in HCC patients and improve the success rate of the operation.