[Inequalities in mortality in the Italian longitudinal studies].
The article presents some of the most relevant results on inequalities in mortality, obtained by the two Italian longitudinal studies carried out in Turin, and Tuscany (in Leghorn and Florence). The two studies share the same methodology. Each database contains census data, information from population register and from death certificates. The authors approach this issue not in an analytical way (as they did in the works cited in the reference list), but answering some questions, relevant both from a scientific and a political point of view. How big are the health inequalities in Italy? Are the health inequalities in Italy increasing or decreasing? Are the health inequalities due to absolute or to relative deprivation? Does the mortality profile of the Italian population express the presence of old or new health inequalities? Can the health inequalities be reduced? The study's results prove that the health inequalities in Italy are deep and strictly related to individuals' position in the social fabric. Facing the other questions the authors focus only in the Turin data. From the 1970's to the 1990's the health inequalities in Turin have increased, despite of general improvement of population's health condition and the progressive reduction of the size of deprived groups. Turin data support both the hypotheses on the source of health inequalities, using long term unemployment as absolute deprivation's indicator, and status' inconsistency as (a row) indicator of relative deprivation. The growth of drug-related causes of death (AIDS and overdose) shows that in the Turin and--quite reasonably--Italian population old and new health inequalities live together. The essay closes offering evidence on the possibility to reduce health inequalities. For this purpose the authors analyses the Turin trend of avoidable deaths and infant and adolescent mortality.


Paradoxical effects of interatrial conduction delay in a hypertrophic cardiomyopathy patient in the long-term: time is a great healer.
We present a unique case where early proarrhythmic and late antiarrhythmic characteristics of interatrial conduction delay were observed during the long-term progression of HCM. Occurrence of AT constantly increased as the interatrial conduction delay became more prominent, while the P-wave width in sinus rhythm and the AT cycle length both showed an instantaneous increase in parallel. As the interatrial delay reached a critical point, the right and left atrial P-wave became virtually separated, as demonstrated by the findings of ECGs and echocardiography. This phenomenon resulted in the complete cessation of tachycardias.


Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo controlled trial.
Uterine leiomyomas are widely prevalent and frequently cause menorrhagia. The major therapeutic option today is hysterectomy. Medical options are of highest interest. A total of 30 women with uterine leiomyomas scheduled for surgical intervention were randomized to receive either 50 mg mifepristone or placebo every other day during 3 months prior to surgery. Uterine blood flow and leiomyoma volume were evaluated once a month until surgery. Endometrial biopsies were obtained prior to and at end of treatment. Relevant biochemistry, symptoms and bleeding were recorded. Primary outcome was reduction in uterine leiomyoma size. There was a significant percentual decrease (P = 0.021) in the total leiomyoma volume in the mifepristone-treated group, -28 (-48, -8) % (mean +/- 0, 95 confidence interval), compared with the control group values 6 (-13, 25) %. Mifepristone treatment significantly reduced the bleeding days (P = 0.001) and increased serum haemoglobin values (P = 0.046). Serum cortisol levels remained unchanged, while a mild increase in serum androgens was noted. Endometrial biopsies showed no premalignant changes or changes in mitotic indices. Mifepristone may offer an effective treatment option for women with uterine leiomyoma and the associated pronounced uterovaginal bleeding. Clinical Trials identifier: www.clinicaltrials.gov: NCT00579475.


Heat shock protein 27 modification is increased in the human diabetic failing heart.
Chronic conditions like diabetes mellitus (DM) leading to altered metabolism might cause cardiac dysfunction. Hyperglycemia plays an important role in the pathogenesis of diabetic complications including accumulation of methylglyoxal (MG), a highly reactive alpha-dicarbonyl metabolite of glucose degradation pathways and increased generation of advanced glycation endproducts (AGEs). The aim of this investigation was to study the extent of the MG-modification argpyrimidine in human diabetic heart and in rat cardiomyoblasts grown under hyperglycemic conditions. Left ventricular myocardial samples from explanted hearts of patients with cardiomyopathy with (n=8) or without DM (n=8) as well as nonfailing donor organs (n=6), and rat cardiac myoblasts H9c2 treated with glucose were screened for the MG-modification argpyrimidine. The small heat shock protein 27 (Hsp27) revealed to be the major argpyrimidine containing protein in cardiac tissue. Additionally, the modification of arginine leading to argpyrimidine and the phosphorylation of Hsp27 are increased in the myocardium of patients with DM. In H9c2 cells hyperglycemia leads to a decrease of the Hsp27-expression and an increase in argpyrimidine content and phosphorylation of Hsp27, which was accompanied by the induction of oxidative stress and apoptosis. This study shows an association between diabetes and increased argpyrimidine-modification of myocardial Hsp27, a protein which is involved in apoptosis, oxidative stress, and cytoskeleton stabilization.


Naturally Acquired Rift Valley Fever Virus Neutralizing Antibodies Predominantly Target the Gn Glycoprotein.
Rift Valley fever (RVF) is a viral hemorrhagic disease first discovered in Kenya in 1930. Numerous animal studies have demonstrated that protective immunity is acquired following RVF virus (RVFV) infection and that this correlates with acquisition of virus-neutralizing antibodies (nAbs) that target the viral envelope glycoproteins. However, naturally acquired immunity to RVF in humans is poorly described. Here, we characterized the immune response to the viral envelope glycoproteins, Gn and Gc, in RVFV-exposed Kenyan adults. Long-lived IgG (dominated by IgG1 subclass) and T cell responses were detected against both Gn and Gc. However, antigen-specific antibody depletion experiments showed that Gn-specific antibodies dominate the RVFV nAb response. IgG avidity against Gn, but not Gc, correlated with nAb titers. These data are consistent with the greater level of immune accessibility of Gn on the viral envelope surface and confirm the importance of Gn as an integral component for RVF vaccine development.


The impact of preterm birth <37 weeks on parents and families: a cross-sectional study in the 2 years after discharge from the neonatal intensive care unit.
Little is known about the quality of life of parents and families of preterm infants after discharge from the neonatal intensive care unit (NICU). Our aims were (1) to describe the impact of preterm birth on parents and families and (2) and to identify potentially modifiable determinants of parent and family impact. We surveyed 196 parents of preterm infants <24 months corrected age in 3 specialty clinics (82% response rate). Primary outcomes were: (1) the Impact on Family Scale total score; and (2) the Infant Toddler Quality of Life parent emotion and (3) time limitations scores. Potentially modifiable factors were use of community-based services, financial burdens, and health-related social problems. We estimated associations of potentially modifiable factors with outcomes, adjusting for socio-demographic and infant characteristics using linear regression. Median (inter-quartile range) infant gestational age was 28 (26-31) weeks. Higher Impact on Family scores (indicating worse effects on family functioning) were associated with taking ≥3 unpaid hours/week off from work, increased debt, financial worry, unsafe home environment and social isolation. Lower parent emotion scores (indicating greater impact on the parent) were also associated with social isolation and unpaid time off from work. Lower parent time limitations scores were associated with social isolation, unpaid time off from work, financial worry, and an unsafe home environment. In contrast, higher parent time limitations scores (indicating less impact) were associated with enrollment in early intervention and Medicaid. Interventions to reduce social isolation, lessen financial burden, improve home safety, and increase enrollment in early intervention and Medicaid all have the potential to lessen the impact of preterm birth on parents and families.


Palladium-catalyzed intramolecular C-H activation/C-C bond formation: a straightforward synthesis of phenanthridines.
The palladium-catalyzed intramolecular C-H activation/C-C cross-coupling has been developed for a straightforward and efficient synthesis of phenanthridines. With Pd(OAc)(2) (4 mol %) as the catalyst, PCy(3) (8 mol %) as the ligand, and Cs(2)CO(3) as the base, this protocol was applied to synthesize a small library of phenanthridine derivatives in good yields in THF.


From disk devices to transcatheter patches: the evolution of wireless heart defect occlusion.
Since 1988, we have been using double-disk devices with several device generations and improving results. Our current disk device, "The ButtonSeal Centering on Demand Device," is a multipurpose device made of stainless steel and polyurethane. It has shown high occlusion rates and no significant complications in atrial septal defects (ASDs) up to 30 mm in diameter. It can be used according to the ASD anatomy both in large, single defects (centering) and in multiple fenestrations (noncentering). The ButtonSeal shares the same limitations as other disk devices, namely, the possibility of wire-related problems and the need for significant septal rim. The development of wireless balloon-delivered devices and patches addresses these problems and limitations. Both detachable balloon devices and patches were used experimentally in animals and in feasibility studies in humans. The results showed good occlusion rates and lack of wire-related complications. Both methods required a minimal rim and occluded more defects than the disk devices. The transcatheter patch method was safer and had only one disadvantage, which was the need for 48-hour balloon support.


[Influence of burying testis in inguinal region on spermatogenesis in rabbit to repair scrotum defect].
To explore the effect of burying testis in inguinal pocket on spermatogenesis. Sixty New Zealand rabbits of 6-8 months old included 36 males and 24 females, weighing 2.5-2.7 kg. The male rabbits were randomly divided into the experimental group (n=18) and the control group (n=18). The model of repairing skin defect of scrotum were established by burying testes in inguinal region subcutaneously in the experimental group. The rabbits were not treated in the control group. The sperms were collected and the surface temperature of testis was measured in both groups after 8 weeks. Testes biopsies were harvested from 6 rabbits of 2 groups randomly respectively. The apoptosis of spermatogenic cells was detected with TUNEL. The other 12 male rabbits in two groups were fed respectively with female rabbits to observe the fertility. The semen density and the spermid activity ratio were (237.3 +/- 39.7) x 10(9)/L and 76.9% +/- 3.8% in the control group, and were (4.7 +/- 2.7) x 10(9)/L and 0 in the experimental group respectively; showing statistically significant difference between two groups (P< 0.05). The average superficial temperature of testes was (38.02 +/- 0.36) degrees C in the experimental group and (36.15 +/- 0.64) degrees C in the control group (P < 0.05). TUNEL results showed: The spermatogenic epithelium became thin and obvious apoptotic spermatogenic cells were found in experimental group; the spermatogenic epithelium was normal and few apoptotic spermatogenic cells were found in the control group. The apoptotic index (A1) was 89.69% +/- 3.76% in the experimental group and 7.73% +/- 4.95% in the control group (P < 0.05). The Pairing results showed that the female rabbits pairing with male rabbits of the experimental group were all not pregnant, and those of the control group were all pregnant (P < 0.05). As the same as the scrotum was reconstructed with skin flaps, it will induce the rabbit infertility that the testes were buried in inguinal region subcutaneously to repair defect of scrotum skin. The main reason is the excessive apoptosis of spermatogenic cell by the high testes environmental temperature.


Characterization of a new mouse model of empyema and the mechanisms of pleural invasion by Streptococcus pneumoniae.
Although empyema affects more than 65,000 people each year in the United States and in the United Kingdom, there are limited data on the pathogenesis of pleural infection. We investigated the pathogenesis of empyema using animal and cell culture models of Streptococcus pneumoniae infection. The pathological processes during the development of empyema associated with murine pneumonia due to S. pneumoniae (strain D39) were investigated. Lungs were examined using histology, and pleural fluid and blood bacterial colony-forming units, cytokine levels, and cellular infiltrate were determined over time. Bacterial migration across mesothelial monolayers was investigated using cell culture techniques, flow cytometry, and confocal microscopy. After intranasal inoculation with 10(7) S. pneumoniae D39 strain, mice developed pneumonia associated with rapid bacterial invasion of the pleural space; raised intrapleural IL-8, VEGF, MCP-1, and TNF-α levels; and caused significant intrapleural neutrophilia followed by the development of fibrinous pleural adhesions. Bacterial clearance from the pleural space was poor, and in vitro assays demonstrated that S. pneumoniae crossed mesothelial layers by translocation through cells rather than by a paracellular route. This study describes key events during the development of S. pneumoniae empyema using a novel murine model of pneumonia-associated empyema that closely mimics human disease. The model allows for future assessment of molecular mechanisms involved in the development of empyema and evaluation of potential new therapies. The data suggest that transmigration of bacteria through mesothelial cells could be important in empyema development. Furthermore, upon entry the pleural cavity offers a protected compartment for the bacteria.


Cloning and characterization of a p53 and DNA damage down-regulated gene PIQ that codes for a novel calmodulin-binding IQ motif protein and is up-regulated in gastrointestinal cancers.
We have identified a p53 and DNA damage-regulated gene that encodes a novel IQ motif protein, which we have named p53 and DNA damage-regulated IQ motif protein (PIQ). PIQ has two isoforms, long (PIQ-L) and short (PIQ-S), and both bind to calmodulin in the presence and absence of calcium. PIQ expression is down-regulated by p53 and DNA damage-inducing agents, whereas PIQ itself represses the expression of p53 up-regulated modulator of apoptosis that is a key mediator of p53-induced apoptosis. Thus, PIQ is a novel protein that may function to bridge a crosstalk between p53 and calmodulin-regulated cellular processes. We further show that PIQ expression is up-regulated in a number of primary colorectal and gastric tumors when compared with matching normal tissues, suggesting that PIQ may be involved in tumorigenesis and could serve as a valuable diagnostic/prognostic marker for gastrointestinal tumors.


Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis.
The indolylmaleimide (IM) derivative IM-17 shows inhibitory activity against oxidative-stress-induced necrotic cell death and cardioprotective activity in rat ischemia-reperfusion injury models. In order to develop a more potent derivative, we conducted a detailed structure-activity relationship study of IM derivatives and identified IM-93 as the most potent derivative with good water solubility. IM-93 inhibited ferroptosis and NETosis, but not necroptosis or pyroptosis. In contrast, ferrostatin-1 (Fer-1), a ferroptosis inhibitor, did not inhibit NETosis, although the accompanying lipid peroxidation was partially inhibited by Fer-1, as well as by IM-93. Thus, IM derivatives have a unique activity profile and appear to be promising candidates for in vivo application.


Blood markers of endothelial dysfunction and their correlation to cerebrovascular reactivity in patients with chronic hepatitis C infection.
Although liver cirrhosis and hepatocellular carcinoma are major consequences of hepatitis C (HCV), there has been an increasing number of studies examining extrahepatic manifestations, especially those caused by systemic chronic inflammation and metabolic complications that might predispose HCV patients to atherosclerosis and ischemic cerebrovascular disease (CVD). The aim of our study was to assess E-selectin, VCAM-1, ICAM-1 and VEGF-A serum levels in patients with chronic HCV infection and to correlate them with cerebrovascular reactivity. A blood sample was taken from eighteen patients with chronic hepatitis C infection and from the same number of healthy blood donors in the control group. The aim was to analyse markers of endothelial dysfunction and to correlate them with cerebrovascular reactivity expressed as breath-holding index (BHI) determined using transcranial color Doppler. The obtained results revealed significant differences between the groups in all endothelial markers except for the E selectin. While the ICAM-1 and sVCAM-1 were significantly increased in the hepatitis group, VEGF-A was significantly decreased. A significant reduction of 0.5 (95% CI 0.2, 0.8) in the mean BHI was found in the hepatitis group (mean BHI 0.64) compared to controls (mean BHI 1.10). No significant association between the BHI and any of the endothelial markers was found in the control group, while in the hepatitis group, the scatter plot of ICAM-1 vs BHI suggested that the association might be present. In conclusion, the results of this study confirm an association between a chronic HCV infection and altered cerebrovascular reactivity as well as higher levels of markers of endothelial activation (ICAM-1, VCAM-1) as possible indicators of an increased CVD risk.


[Artificial nutrition in surgery: status, current problems and perspectives].
Parenteral and enteral nutrition are safe and efficacious substitutes of normal oral intake even for prolonged periods of time and offer adequate treatment of protein-calorie malnutrition and effective palliation of cancer cachexia. Perioperative nutritional support reduces operative morbidity and mortality in malnourished patients. Furthermore, parenteral and enteral nutrition are an effective primary treatment for acute inflammatory bowel disease, short bowel syndrome and small bowel fistulae. Enteral nutrients specifically support structure and function of both the intestinal mucosa and the mucosa-associated lymphatic tissues: Recent clinical data emphasize the need to feed enterally whenever possible, especially in critically ill patients. Continuing efforts to include new substrates and to create more balanced and disease-adapted solutions of parenteral and enteral nutrition will improve the available systems. In addition, parenteral and enteral nutrition as a component of new complex treatment modalities including growth factors and cytokines will improve treatment and patient care in general surgery, oncology and traumatology.


Growth performance and apparent total tract nutrient digestibility of limit-fed diets containing wet brewer's grains to Holstein heifers.
The objective of this study was to evaluate the growth performance and apparent total tract nutrient digestibility of Holstein heifers limit-fed diets containing different amounts of wet brewer's grains (WBG). A 12-wk randomized complete block study was conducted using 30 yearling Holstein heifers [378 ± 27 d of age, and body weight (BW) of 357.8 ± 27.6 kg (mean ± SD)]. Treatments were 0%, 10% and 20% of WBG on a dry matter (DM) basis and diets were formulated to be limit-fed for dry matter intake (DMI) at 2.35% of BW and provided 15% crude protein (CP) and 2.27 Mcal metabolizable energy/kg of DM. Dry matter intake was recorded daily, while BW and skeletal measurements were measured every 2 wk. During week 12, fecal samples were collected directly from the rectum over four consecutive days and composited by heifer to determine apparent total tract nutrient digestibility using acid detergent insoluble ash as a marker. Data were analyzed using the MIXED procedure of SAS. Dry matter intakes, BW, and average daily gain were not different among treatments (P = 0.2, P = 0.4, and P = 0.6, respectively). Dry matter intakes ranged from 8.6 to 9.0 kg/d. Average BW were 404.4, 411.5, and 409.3 kg for heifers fed the 0%, 10%, and 20% WBG diets, respectively. Average daily gains were 1.03, 1.04, and 0.96 kg/d for heifers fed the 0%, 10%, and 20% WBG diets respectively. Skeletal measurements and body condition scores (BCS) were not different among treatments except for the change in heart girth (P < 0.01) and initial BCS (P < 0.01). Apparent total tract digestibilities of DM, organic matter, CP, fat, and hemicellulose were greater or tended to be greater in heifers fed 0% and 20% WBG treatments than heifers fed 10 % WBG (P = 0.04, P = 0.04, P = 0.06, P = 0.06, and P = 0.01, respectively). Neutral detergent fiber, acid detergent fiber, and fat digestibilities were similar among treatments (P = 0.2, P = 0.3, and P = 0.3, respectively). During the digestibility phase, DMI tended to be greater (P = 0.08) for the 10% WBG treatment. These results demonstrate that limit-feeding heifers with diets containing up to 20% WBG could replace soybean- and corn-based concentrates in diets without adverse consequences to the heifer growth performance.


Whole genome sequencing-based classification of human-related Haemophilus species and detection of antimicrobial resistance genes.
Bacteria belonging to the genus Haemophilus cause a wide range of diseases in humans. Recently, H. influenzae was classified by the WHO as priority pathogen due to the wide spread of ampicillin resistant strains. However, other Haemophilus spp. are often misclassified as H. influenzae. Therefore, we established an accurate and rapid whole genome sequencing (WGS) based classification and serotyping algorithm and combined it with the detection of resistance genes. A gene presence/absence-based classification algorithm was developed, which employs the open-source gene-detection tool SRST2 and a new classification database comprising 36 genes, including capsule loci for serotyping. These genes were identified using a comparative genome analysis of 215 strains belonging to ten human-related Haemophilus (sub)species (training dataset). The algorithm was evaluated on 1329 public short read datasets (evaluation dataset) and used to reclassify 262 clinical Haemophilus spp. isolates from 250 patients (German cohort). In addition, the presence of antibiotic resistance genes within the German dataset was evaluated with SRST2 and correlated with results of traditional phenotyping assays. The newly developed algorithm can differentiate between clinically relevant Haemophilus species including, but not limited to, H. influenzae, H. haemolyticus, and H. parainfluenzae. It can also identify putative haemin-independent H. haemolyticus strains and determine the serotype of typeable Haemophilus strains. The algorithm performed excellently in the evaluation dataset (99.6% concordance with reported species classification and 99.5% with reported serotype) and revealed several misclassifications. Additionally, 83 out of 262 (31.7%) suspected H. influenzae strains from the German cohort were in fact H. haemolyticus strains, some of which associated with mouth abscesses and lower respiratory tract infections. Resistance genes were detected in 16 out of 262 datasets from the German cohort. Prediction of ampicillin resistance, associated with blaTEM-1D, and tetracycline resistance, associated with tetB, correlated well with available phenotypic data. Our new classification database and algorithm have the potential to improve diagnosis and surveillance of Haemophilus spp. and can easily be coupled with other public genotyping and antimicrobial resistance databases. Our data also point towards a possible pathogenic role of H. haemolyticus strains, which needs to be further investigated.


Kubo conductivity tensor for two- and three-dimensional magnetic nulls.
The complete Kubo conductivity tensor is computed in two- and three-dimensional linear magnetic null systems using collisionless single-particle simulations. Regions of chaotic charged-particle dynamics are constructed for each case. It is found that stochastic frequency mixing of particle bounce motion, as well as gyromotion, contribute significantly to the conductivity. The conductivity curves are well approximated by power laws over a certain frequency range and the ac conductivity is found to be an order of magnitude smaller than the dc value, leading to enhanced resistivity, particularly near the cyclotron frequency. The ac conductivities must be accounted for in computation of the total dissipation.


Pain, pills, and possibilities: drug therapy in peripheral vascular disease.
Currently, pharmacologic therapy offers no cures for the patient with vascular disease. Drugs are available, however, to prevent or delay the end organ damage of vascular disease, to keep vessels patent as long as possible, and to provide some relief from the pain associated with vascular disease and cell damage. In this article, the author reviews the drugs used to manage hypertension--diuretics, beta blockers, alpha adrenergic blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, antiadrenergic drugs, and nitroprusside; and drugs used to maintain vessel patency in peripheral vascular disease--peripheral vasodilators and anticoagulants; and reviews one regimen for dealing with the chronic pain of vascular disease--narcotics and tricyclic antidepressants.


Predominance of CTX-M genotype among extended spectrum beta lactamase isolates in a tertiary hospital in Saudi Arabia.
To determine the molecular characterization of extended-spectrum beta-lactamases (ESBL) isolates from a tertiary center in Saudi Arabia using multiplex polymerase chain reaction (PCR) technique and assess their antibiotic susceptibility pattern. Prospective study conducted at the Saudi Aramco Dhahran Health Center, Dhahran, Saudi Arabia between April-December 2006. Extended-spectrum beta-lactamases phenotype of isolates identified by automated methods was confirmed using E-test. Multiplex PCR for the detection of blaTEM, blaSHV and blaCTX-M was performed. Susceptibility to a panel of antibiotics was determined. One hundred isolates (Escherichia coli [E.coli] n=84; Klebsiella pneumoniae [K. pneumoniae] n=16) were studied and 71% harbored the blaCTX-M gene. For E.coli isolates 43 (51%) harbored CTX-M+TEM combination and 21 (25%) had CTX-M alone. In contrast, only one K. pneumoniae isolate (6.2%) harbored the CTX-M+TEM combination and 3 (18.8%) isolates had CTX-M only. One E.coli and 7 K. pneumoniae isolates were blaSHV positive. The blaCTX-M gene was found predominantly in urinary isolates (n=63/71; 88.7%). The presence of blaCTX-M was significantly higher in isolates from outpatients compared to inpatient (p<0.05). Sensitivity to imipenem was 100% and 78% to nitrofurantoin. Resistance to amoxicillin-sulbactam was significantly higher in blaCTX-M positive isolates (p<0.05). The findings indicate a high-level of blaCTX-M positive ESBL isolates circulating in our setting with the dissemination of these in the community. The trend of multidrug resistance profile associated with carriage of blaCTX-M gene is cause for concern.


Standard practice of presacral exposure during transvaginal natural orifice transluminal endoscopic surgery for sacrocolpopexy.
We describe the standard practice of presacral exposure during transvaginal natural orifice transluminal endoscopic surgery (vNOTES) for sacrocolpopexy in women with uterine prolapse. In this video, we demonstrate the key techniques: identifying the right hypogastric nerve (rHN) before opening the pelvic peritoneum; removing the fat and loose connective tissue along the rHN to expose the presacral fascia; incising the presacral fascia to reach the presacral space to expose the middle sacral vasculature and the anterior longitudinal ligament (ALL) of the first sacral vertebra (S1) below the promontory; attaching the mesh to the ALL to avoid vessel injury; and completing the peritonealisation.


The muscles of mastication in the caspian seal (Phoca caspica).
The muscles of mastication and their related skull characters in the Caspian seal (Phoca caspica) were anatomically examined and compared with those of the Baikal (Phoca sibirica) and ringed (Phoca hispida) seals. A well-developed masseter muscle was observed in the Caspian seal, whereas the temporal muscle consisted of thin bundles. The skull of the Caspian seal possessed the same thin frontal bone and the dorso-ventrally developed zygomatic arch found in the Baikal seal that are required to install the enlarged eyeball into the orbit. The temporal bone was not robust, and the digastric muscle was well-developed in the ventral space of the auditory bulla. The present results suggest that the skull form of the Caspian seal has changed morphologically from its ringed seal-like ancestors, and suggest that the evolutionary strategy of the muscles of mastication in the Caspian seal is principally consistent with that of the Baikal seal.


Detection and validation of stay-green QTL in post-rainy sorghum involving widely adapted cultivar, M35-1 and a popular stay-green genotype B35.
Sorghum [Sorghum bicolor (L.) Moench] is an important dry-land cereal of the world providing food, fodder, feed and fuel. Stay-green (delayed-leaf senescence) is a key attribute in sorghum determining its adaptation to terminal drought stress. The objective of this study was to validate sorghum stay-green quantitative trait loci (QTL) identified in the past, and to identify new QTL in the genetic background of a post-rainy adapted genotype M35-1. A genetic linkage map based on 245 F9 Recombinant Inbred Lines (RILs) derived from a cross between M35-1 (more senescent) and B35 (less senescent) with 237 markers consisting of 174 genomic, 60 genic and 3 morphological markers was used. The phenotypic data collected for three consecutive post-rainy crop seasons on the RIL population (M35-1 × B35) was used for QTL analysis. Sixty-one QTL were identified for various measures of stay-green trait and each trait was controlled by one to ten QTL. The phenotypic variation explained by each QTL ranged from 3.8 to 18.7%. Co-localization of QTL for more than five traits was observed on two linkage groups i.e. on SBI-09-3 flanked by S18 and Xgap206 markers and, on SBI-03 flanked by XnhsbSFCILP67 and Xtxp31. QTL identified in this study were stable across environments and corresponded to sorghum stay-green and grain yield QTL reported previously. Of the 60 genic SSRs mapped, 14 were closely linked with QTL for ten traits. A genic marker, XnhsbSFCILP67 (Sb03g028240) encoding Indole-3-acetic acid-amido synthetase GH3.5, was co-located with QTL for GLB, GLM, PGLM and GLAM on SBI-03. Genes underlying key enzymes of chlorophyll metabolism were also found in the stay-green QTL regions. We validated important stay-green QTL reported in the past in sorghum and detected new QTL influencing the stay-green related traits consistently. Stg2, Stg3 and StgB were prominent in their expression. Collectively, the QTL/markers identified are likely candidates for subsequent verification for their involvement in stay-green phenotype using NILs and to develop drought tolerant sorghum varieties through marker-assisted breeding for terminal drought tolerance in sorghum.


Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically.
Differentiation-inducing therapy for tumors is a strategy that aims to induce the differentiation and maturation of cancer stem cells (CSCs). The differentiation-inducing capacity of arsenic trioxide (ATO) in hepatocellular carcinoma (HCC) and the underlying mechanism were previously unknown. In the present study, we explored the ATO-induced differentiation of CSCs in HCC by detecting the expression of CSC-related markers and tumorigenicity variation in vivo and in vitro. We developed a combined chemotherapeutic approach to HCC by characterizing the effects of combinatorial treatment with 5-fluorouracil (5-FU)/cisplatin and ATO in vitro and in patient-derived xenograft models. Changes in gene expression patterns were investigated by gene microarray analysis. ATO effectively induced differentiation of CSCs by downregulation of CSC-related genes and suppression of tumorigenicity capability. Combinatorial treatment with ATO and 5-FU/cisplatin significantly enhanced therapeutic effects in HCC cells compared with the treatment with 5-FU/cisplatin alone. Synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways by ATO and 5-FU/cisplatin is a potential molecular mechanism underlying the differentiation effect. ATO induced the differentiation of HCC CSCs and potentiated the cytotoxic effects of 5-FU/cisplatin through synergistic inhibition of the LIF/JAK1/STAT3 and NF-kB signaling pathways. These results offer new insights for the clinical treatment of HCC.


Fibrinolysis is a reasonable alternative for STEMI care during the COVID-19 pandemic.
No data are available to develop uniform recommendations for reperfusion therapies in ST-segment elevation myocardial infarction (STEMI) during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to fill the evidence gap regarding STEMI reperfusion strategy during the COVID-19 era. Clinical characteristics and outcomes for 17 patients with STEMI who received fibrinolysis during the COVID-19 pandemic were compared with 20 patients who received primary percutaneous coronary intervention (PPCI), and were further compared with another 41 patients who received PPCI in the pre-COVID-19 period. In patients with STEMI, fibrinolysis achieved a comparable in-hospital and 30-day primary composite end point, as compared with those who received PPCI during the COVID-19 pandemic. No major bleeding was detected in either group. Compared patients with STEMI who received PPCI in the pre-COVID-19 period, we found a remarkable extension of chest pain onset-to-first medical contact (FMC) and FMC-to-wire crossing times, significantly increased number and length of stents, and much worse thrombolysis in myocardial infarction flow in patients with STEMI who received PPCI during the COVID-19 pandemic. Owing to its considerable efficacy and safety and advantages in conserving medical resources, we recommend fibrinolysis as a reasonable alternative for STEMI care during the COVID-19 pandemic.


[Antitumor mechanism of 3-bromopropionylamino benzoylurea on leukemia and lymphoma].
To study the antitumor mechanism of 3-bromopropionylamino benzoylurea (JIMB01) on leukemia and lymphoma. The antitumor effects of JIMB01 in cell culture was detected by MTT staining. JIMB01-induced apoptosis in leukemia and lymphoma cells was tested by Giemsa staining, fluorescent Hoechst33258 staining, as well as DNA gel electrophoresis. Cell cycle was analyzed by flow cytometry. JIMB01-induced Bcl-2 phosphorylation in CEM cell lines was detected by Western blot methods. The activities of caspase-3 and caspase-8 were determined by colorimetric protease assay and that of caspase-9 was determined by fluorescent intensity. This compound showed antiproliferative activities in a panel of nine human leukemia and lymphoma cell lines with IC50 values in the range of 0.25 micromol x L(-10 to 0. 51 micromol x L(-1). Morphological observation and cell cycle analysis indicated that CEM cells were blocked at mitosis phase by JIMB01. The fluorescent Hoechst33258 staining showed apoptotic nuclear degradation dispersed in the cytoplasm of CEM cells exposed to JIMB01 at 0. 80 micromol x L(-1) for 24 h. DNA degradation in the form of a multiple-unit DNA ladder was clearly demonstrated in CEM leukemia cells treated with JIMB01 at 0.15 micromol x L(-1) or higher for 24 h using agarose gel electrophoresis. Bcl-2 phosphorylation became visible, in Western blot, within 6 h in CEM cells treated with JIMB01 at 0.15 micromol x L(-1) or higher for 24 h. JIMB01 increased the activities of caspase-3, -8 and -9 in CEM cells; DEVD-fmk, a caspase-3 inhibitor, inhibited the cytotoxicity of JIMB01 in CEM leukemia cells. The antitumor mechanism of JIMB01 is that JIMB01 may induce tumor cell apoptosis through Bcl-2 phosphorylation and then caspase passway.


Dual detection approach to a more accurate measure of relative purity in high-throughput characterization of compound collections.
The accurate determination of compound purity is crucial for characterizing library purity, monitoring the stability of storage compounds, and obtaining meaningful high-throughput screening results. However, current high-throughput techniques for the determination of compound purity are inadequate. We evaluated on-line chromatography detectors, including UV(TWC), UV(214), and ELSD detectors, in a series of studies of 233 compound mixtures prepared with known compositions. Results indicate that both UV(TWC) and UV(214) overestimate the minor component in a mixture whereas ELSD underestimates the minor component. An average of UV(TWC) and ELSD purities gives a more accurate measure of the relative purity for a wide range of compounds in various purity ranges. This technique was applied to 959 compounds from our compound collection to more accurately determine their relative purity.


Foam front propagation in anisotropic oil reservoirs.
The pressure-driven growth model is considered, describing the motion of a foam front through an oil reservoir during foam improved oil recovery, foam being formed as gas advances into an initially liquid-filled reservoir. In the model, the foam front is represented by a set of so-called "material points" that track the advance of gas into the liquid-filled region. According to the model, the shape of the foam front is prone to develop concave sharply curved concavities, where the orientation of the front changes rapidly over a small spatial distance: these are referred to as "concave corners". These concave corners need to be propagated differently from the material points on the foam front itself. Typically the corner must move faster than those material points, otherwise spurious numerical artifacts develop in the computed shape of the front. A propagation rule or "speed up" rule is derived for the concave corners, which is shown to be sensitive to the level of anisotropy in the permeability of the reservoir and also sensitive to the orientation of the corners themselves. In particular if a corner in an anisotropic reservoir were to be propagated according to an isotropic speed up rule, this might not be sufficient to suppress spurious numerical artifacts, at least for certain orientations of the corner. On the other hand, systems that are both heterogeneous and anisotropic tend to be well behaved numerically, regardless of whether one uses the isotropic or anisotropic speed up rule for corners. This comes about because, in the heterogeneous and anisotropic case, the orientation of the corner is such that the "correct" anisotropic speed is just very slightly less than the "incorrect" isotropic one. The anisotropic rule does however manage to keep the corner very slightly sharper than the isotropic rule does.


Asthma management.
The UK is considered to have the highest rates of morbidity and mortality among children and adults with asthma in Europe. According to the National Review of Asthma Deaths (NRAD), 28 children died in the UK between February 2012 and January 2013 because of asthma. Most of these deaths would be considered preventable by respiratory specialists.


Calculation of movement direction from firing activities of neurons in intrinsic co-ordinate systems defined by their preferred directions.
In this work we carried out computer simulations to compare different coding algorithms (the tensor network theoretical approach of Pellionisz & Llinas, 1979; and the weighted average population coding model of Georgopoulos et al., 1986) that were originally devised to recompute vectors of the external world from firing rate responses of neurons of the central nervous system. Georgopoulos and his colleagues (1986, 1988) observed, in electrophysiological experiments, that certain neurons of the primate motor cortex are selective to the direction of arm movement in a three-dimensional space (directional neurons). The discharge rate of a cell is highest with movement in a certain direction (the cell's "preferred direction") and decreases as a linear function of the cosine of the angle between the direction of movement and the cell's preferred direction. They calculated a population vector to predict the direction of arm movement from neuronal responses as a weighted linear combination of the preferred direction vectors using several sets of weighting coefficients. It was implicitly assumed in this approach that if the brain uses such coding, the calculations are carried out by a further layer of neurons. The tensor network theory also gives an algorithm to calculate an external vector in an intrinsic co-ordinate system whose basis vectors are distinguished vectors assigned to the individual neurons based on results of physiological observations. However, it goes beyond providing a simple mathematical formula to recompute an external vector (Pellionisz & Llinas, 1979). It is a promising theoretical solution for the problem faced by sensorimotor systems; how to transform information about the environment, measured by a diverse set of sensors, into appropriate responses executed by multiple muscles acting in concert. As the weighting coefficients used by Georgopoulos et al. in their calculations differed from those used by Pellionisz & Llinas, we show here how they are related. We compared the exactness and robustness of the two approaches in computer simulations assuming that the firing rate responses of individual neurons would change from trial to trial even when the movement direction is the same. We also allowed that different sets of preferred directions were used in different trials mimicking the case when different movement-related directional neurons would be active from trial to trial. In our computer simulations the outcome of the different algorithms were fairly similar. No experimental protocol can be devised in which the activity of all the possible active motor cortex neurons taking part in coding the direction of movement could be simultaneously monitored.(ABSTRACT TRUNCATED AT 400 WORDS)


[Frontal lobe syndromes in (pre-)senile dementias of the Alzheimer type: a correlative statistical study].
A group of gerontopsychiatric patients suffering from mild to severe dementia was studied. Clinical instruments were a psychological assessment system and a battery of tests. Structural changes of the brain were detected by computerized tomography. A number of correlations between clinical and morphological variables was found. The statistical analysis of most of the variables correlating with the CT determinants of the frontal lobe (Huckman-number, width of the frontal interhemispheric fissure) revealed plausibility consistent with the classical frontal lobe syndrome. The relations of the remaining items with the symptomatology of normal pressure hydrocephalus are critically discussed.


Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage.
Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABAA receptors, and GABAA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing. We used fast-scan cyclic voltammetry in anesthetized female and male rats to measure dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area, before and after administration of allopregnanolone. Allopregnanolone (7.5-25 mg/kg, IP) reduced evoked dopamine release in both male and female rats, compared to β-cyclodextrin vehicle. In males, all doses of allopregnanolone decreased dopamine transmission, with stronger effects at 15 and 25 mg/kg allopregnanolone. In females, 15 and 25 mg/kg allopregnanolone reduced dopamine release, while 7.5 mg/kg allopregnanolone was no different from vehicle. Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Consistent with this, females in proestrus (high progesterone levels) were less responsive to allopregnanolone than females in other estrous cycle stages. Furthermore, 30 mg/kg progesterone reduced evoked dopamine release in males, similar to allopregnanolone. Our findings confirm that allopregnanolone reduces evoked dopamine release in both male and female rats. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects.


Prevalence of gastrointestinal parasitic infection in cows and buffaloes in Lower Dir, Khyber Pakhtunkhwa, Pakistan.
Gastrointestinal (GI) Parasitic infection is a hot issue for cattle management. There is variation of GI parasites effects in sex, age of cattle, drinking water condition, nutrition, and severity of infection. Studies on prevalence of GI parasites among cattle population in Dir Lower are lacking. A total of 40 farms were selected randomly in six tehsil namely Tehsil Adenzai, Tehsil Timergara, Tehsil Balambat, Tehsil Munda ,Tehsil Lalqala, Tehsil Khall. Freshly cattle fecal samples were collected randomly from the selected farms during March 2018 till December 2018. Out of 314 buffaloes and cattle examined 58.59% (184/314) were positive for eggs, cyst/oocyst of one or more species of GI Parasites. The prevalence of parasitic infection was higher in Buffaloes 63.55% (75/118) as compared to Cow 55.61% (109/196) but the difference was not significant (p>0.05) Entamoeba,spp, Moniezia spp, Haemonchus spp and Coccidian spp were found in this study. The non-treated animals indicated the highest percentage of infection in cow 57.71% (101/175) and buffalo 68.13% (62/91).GI parasite prevalence in female animal were higher female cow 62.58% (87/139) and female buffalo 77.33% (58/75) as compared to male. But the difference is non-significant (p> 0.05) Yearling calves had the lower rate of GI parasitic infection than adults. Future investigations are necessary to evaluate the economic loss due to GI parasites in cattle's.


Target Exposome for Characterizing Early Gestational Exposure to Contaminants of Emerging Concern and Association with Gestational Diabetes Mellitus.
Characterization of gestational exposure to complex contaminants of emerging concern (CECs) is critical to the identification of environmental risk factors for pregnancy complications. However, determination of various CECs with diverse physicochemical properties in biological fluids is technically challenging. In the present study, we developed a target exposome protocol, consisting of simple liquid-liquid extraction-based sample preparation and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, to determine 325 CECs covering 11 subclasses, including poly- and perfluoroalkyl substances, organophosphate esters, ultraviolet (UV) stabilizers, synthetic antioxidants, phthalate esters, and several others. The protocol exhibits exceptional advantages over traditional approaches in the coverage of chemicals, sample volume demand, and time and financial cost. The protocol was applied in a prospective nested gestational diabetes mellitus (GDM) study including 120 cases and 240 matched healthy controls. Thirty-three CECs were detected in >70% of the samples, with a combined concentration of 17.0-484.7 ng/mL. Bayesian kernel machine regression analysis showed that exposure to the CEC mixture was significantly associated with a higher GDM risk. For example, when increasing all CECs in the mixture from 50th percentile to 75th percentile, the estimated probit of GDM incidence had an increase of 92% (95% CI: 56%, 127%). Meanwhile, perfluorohexanesulfonic acid, 1,3-diphenylguanidine, and dibutyl fumarate were identified as the key CECs driving the joint effect. This work demonstrates great potential of our target exposome protocol for environmental risk factor identification in large-scale epidemiology or biomonitoring studies.


Magnitudes of decline on Automated Neuropsychological Assessment Metrics subtest scores relative to predeployment baseline performance among service members evaluated for traumatic brain injury in Iraq.
: Identify the proportion of service members demonstrating declines in Automated Neuropsychological Assessment Metrics (ANAM) scores as part of a traumatic brain injury (TBI) evaluation conducted while deployed to Iraq. : Although TBI has been associated with poorer performance on cognitive test in the general population and military combatants, little is known about the proportion of service members demonstrating declines in ANAM scores after TBI. : Military personnel (N = 116) referred to a combat support hospital for TBI evaluation in Iraq underwent a standardized intake evaluation including computerized neurocognitive testing, psychological and physical health questionnaires, a clinical interview, and a physical examination by a physician. Predeployment and postinjury cognitive performance among service members with and without a TBI diagnosis was compared. : A significantly larger proportion of patients with TBI demonstrated greater declines in speed across all ANAM subtests compared with patients with no TBI. Differences in accuracy scores among patients with TBI relative to patients without TBI were nonsignificant. Patients with TBI also demonstrated greater than minimal declines on throughput Simple Reaction Time, Procedural Reaction Time, Code Substitution-Learning, and Spatial Memory scores, with no significant differences on Code Substitution-Delayed or Mathematical Processing (MATH). A similar pattern was seen among individuals examined within 72 hours of index injury. : Assessment of cognitive impairment following TBI in a combat zone may assist providers in making treatment recommendations for service members with mild TBI.


Aggregation of methacrylate-based ternary biomimetic antimicrobial polymers in solution.
Using detailed atomistic simulations, we explore the morphological characteristics of aggregates formed in solution phase by ternary biomimetic antimicrobial (AM) methacrylate polymers, composed of hydrophobic, charged cationic and polar functional groups and compare it with aggregate morphologies of binary methacrylate polymers, composed only of hydrophobic and charged cationic functional groups. The effect of sequence of the constituent functional groups on aggregate conformation is also studied by considering random and block sequences along the polymer backbone. Our results show that while binary polymers tend to form robust aggregates, replacing some of the hydrophobic groups with overall charge neutral polar groups weakens the aggregate considerably, leading to increased conformational fluctuations and formation of loose-packed, open aggregates, particularly in the case of random ternary polymers. Interaction energy calculations clearly suggest that the role of inclusion of polar groups in ternary polymers is two-fold: (1) to reduce possible strong local concentration of hydrophobic groups and 'smear' the overall hydrophobicity along the polymer backbone to increase the solubility of the polymers (2) to compensate the loss of attractive hydrophobic interactions by forming attractive electrostatic interactions with the charged groups and contribute to aggregation formation, albeit weak. Given that most of the naturally occurring AM peptides have contributions from all the three functional groups, this study elucidates the functionally tuneable role of inclusion of polar groups in the way AM agents interact with each other in solution phase, which can eventually dictate their partitioning behaviour into bacterial and mammalian membranes.


Endoscopic retrograde cholangiopancreatography-related perforation: Management and prevention.
Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure that can result in serious complications, and thus should be handled by a skilled endoscopist to minimize the risk of complications and to enhance the success rate. The incidence of ERCP-related complications is 5%-10%, most commonly involving post-ERCP pancreatitis and clinically significant post-endoscopic sphincterotomy bleeding. Although ERCP-related perforation has a relatively lower incidence of 0.14%-1.6%, this complication is associated with a high mortality rate of 4.2%-29.6%. A classification of perforation type based on the instrument that caused the perforation was recently described that we postulated could affect the implementation of perforation management. In the present article, an algorithm for management and prevention of ERCP-related perforations is proposed that is based on the perforation type and delay of diagnosis. Available evidence demonstrates that a delayed diagnosis and/or treatment of perforation results in a poorer prognosis, and thus should be at the forefront of procedural consideration. Furthermore, this review provides steps and recommendations from the pre-procedural stage through the post-procedural evaluation with consideration of contributing factors in order to minimize ERCP-related complication risk and improve patient outcome. To avoid perforation, endoscopists must evaluate the risks related to the individual patient and the procedure and perform the procedure gently. Once a perforation occurs, immediate diagnosis and early management are key factors to minimize mortality.


Left Ventricular Pseudo-pseudoaneurysm with Hemopericardium.
We report a case of pseudo-pseudoaneurysm, which is a very rare complication of myocardial infarction. A 69-year-old man was admitted to our clinic with chest tightness and dyspnea. He had undergone aortic valve replacement with a pericardial bioprosthetic valve, ring mitral annuloplasty, and reconstruction of an aortic annular defect due to infective endocarditis with bovine pericardium 4 years prior. Echocardiography and computed tomography showed pericardial effusion and a 16-mm cavity at the anterolateral wall of the left ventricle. Magnetic resonance imaging suggested either pseudo-pseudoaneurysm or myocardial abscess. We successfully repaired the myocardial defect using a patch made from a vascular graft with pledgeted horizontal mattress sutures under cardiopulmonary bypass.


Tumor necrosis factor alpha is a promising circulating biomarker for the development of obstructive sleep apnea syndrome: a meta-analysis.
Obstructive sleep apnea syndrome (OSAS) is a chronic inflammatory disorder. The relationship between tumor necrosis factor alpha (TNF-alpha) and OSAS has been widely evaluated, but the results thus far remain inconclusive. We thereby decided to quantify the changes of TNF-alpha between OSAS patients and controls by a meta-analysis. This study complies with the MOOSE guidelines. Two reviewers independently searched articles and abstracted relevant data. In total, 47 articles (59 studies) were analyzed, including 2857 OSAS patients and 2115 controls. Overall, OSAS patients had a significantly higher level of circulating TNF-alpha than controls (weighted mean difference [WMD]: 9.66 pg/mL, 95% confidence interval [CI]: 8.66 to 11.24, P<0.001), but with significant heterogeneity (I2: 99.7%). After adjusting for potential missing studies, the overall estimate was weakened but still significant (filled WMD: 2.63 pg/mL, 95% CI: 2.56 to 2.70, P<0.001). When studies were stratified by OSAS severity, the changes in circulating TNF-alpha between patients and controls increased gradually with the more severe grades of OSAS. In patients with mild, mild-to-moderate, moderate, moderate-to-severe and severe OSAS, circulating TNF-alpha was higher than respective controls by 0.99, 1.48. 7.79, 10.08 and 8.85 pg/mL, with significant heterogeneity (I2: 91.2%, 74.5%, 97.6%, 99.0% and 98.1%). In conclusion, our findings demonstrated that circulating TNF-alpha was significantly higher in OSAS patients than in controls, and this difference became more pronounced with the more severe grades of OSAS, indicating that TNF-alpha might be a promising circulating biomarker for the development of OSAS.


Hepatitis C virus-like particle morphogenesis.
Although much is known about the hepatitis C virus (HCV) genome, first cloned in 1989, little is known about HCV structure and assembly due to the lack of an efficient in vitro culture system for HCV. Using a recombinant Semliki forest virus replicon expressing genes encoding HCV structural proteins, we observed for the first time the assembly of these proteins into HCV-like particles in mammalian cells. This system opens up new possibilities for the investigation of viral morphogenesis and virus-host cell interactions.


Modulation of synchrony between single motor units during precision grip tasks in humans.
During precision grip, coherence between motor cortex and hand muscle EMG oscillatory activity in the 15-30 Hz range covaries with the compliance of the manipulated object. The current study investigated whether short-term synchrony and coherence between discharges of single motor units (SMUs) in the first dorsal interosseous (1DI) muscle were similarly modulated by object compliance during precision grip. Eight subjects used index finger and thumb to grip two levers that were under robotic control. Guided by visual feedback of the lever force levels, subjects held the levers against a steady force of 1.3 N for 8 s; they then linearly increased the force to 1.6 N over a 2 s period and held for a further 8 s before linearly decreasing the force back to the 1.3 N level over another 2 s period. Subjects performed the task at two different levels of compliance, each with identical grip force levels. Both surface EMG and SMU activity were recorded from the 1DI muscle. Short-term synchrony between the discharges of pairs of SMUs was assessed in the time domain by cross-correlation and in the frequency domain by coherence analysis. Coherence was seen in two frequency ranges: 6-12 Hz and 15-30 Hz. The compliance of the gripped object had a significant effect on both short-term synchronisation and coherence in the 15-30 Hz range between SMUs; both were greater for the more compliant condition. There was no change in the 6-12 Hz coherence.


Structure and Thermal Expansion of Cu-90 vol. % Graphite Composites.
Copper-graphite composites are promising functional materials exhibiting application potential in electrical equipment and heat exchangers, due to their lower expansion coefficient and high electrical and thermal conductivities. Here, copper-graphite composites with 10-90 vol. % graphite were prepared by hot isostatic pressing, and their microstructure and coefficient of thermal expansion (CTE) were experimentally examined. The CTE decreased with increasing graphite volume fraction, from 17.8 × 10-6 K-1 for HIPed pure copper to 4.9 × 10-6 K-1 for 90 vol. % graphite. In the HIPed pure copper, the presence of cuprous oxide was detected by SEM-EDS. In contrast, Cu-graphite composites contained only a very small amount of oxygen (OHN analysis). There was only one exception, the composite with 90 vol. % graphite contained around 1.8 wt. % water absorbed inside the structure. The internal stresses in the composites were released during the first heating cycle of the CTE measurement. The permanent prolongation and shape of CTE curves were strongly affected by composition. After the release of internal stresses, the CTE curves of composites did not change any further. Finally, the modified Schapery model, including anisotropy and the clustering of graphite, was used to model the dependence of CTE on graphite volume fraction. Modeling suggested that the clustering of graphite via van der Waals bonds (out of hexagonal plane) is the most critical parameter and significantly affects the microstructure and CTE of the Cu-graphite composites when more than 30 vol. % graphite is present.


MicroRNA networks alter to conform to transcription factor networks adding redundancy and reducing the repertoire of target genes for coordinated regulation.
Transcription factors (TFs) and microRNAs (miRNAs) comprise two major layers of gene regulatory networks (GRNs). TFs and miRNAs function coordinately, but they have distinct molecular mechanisms and evolutionary backgrounds. Therefore, we aimed to systematically reveal the difference in contribution between TF and miRNA networks to the evolution of their coordinated regulations by focusing on composite feedforward circuits (cFFCs) that each comprises a TF and an miRNA. We compiled 124,736 human-mouse conserved TF regulatory connections and 34,298 conserved miRNA regulatory connections into two distinct connection matrices. To differentially assess the contributions to cFFC formation of TFs and miRNAs, we randomized one matrix and kept the other unchanged and subsequently examined the number of cFFCs, the number of cFFC-targeted genes, and the redundancy formed by cFFCs in comparison with those of the real GRNs. Because the matrices represent selectively constrained networks, if selection has been operating on the networks for or against cFFC formation, the values of cFFC network properties would deviate significantly from the expectation of the randomized networks. As the cFFC includes both TF and miRNA connections, the partial randomizations indicate the extent of influence of selection on cFFC formation differentially between TF and miRNA networks. Thus, we adopted the deviation of each cFFC network property value as a measure to estimate the extent of influence of selection on cFFCs and to compare the contribution between TF and miRNA networks. We found that miRNA regulatory networks changed their configuration such that they conformed to the stable TF regulatory networks with an increased circuit redundancy and a marked reduction in the repertoire of cFFC-targeted genes. We also revealed that this redundancy-adding role is preferentially attributable to miRNA network alterations. The results indicate that the redundancy-adding role might serve as a niche for many miRNA connections to survive, avoiding conflicts with the stable TF regulatory networks.


Trinorsesquiterpenoids from the root extract of Pentalinon andrieuxii.
Two unusual trinorsesquiterpenoids, urechitols A (1) and B (2), were isolated from the root extract of Pentalinon andrieuxii, a plant used commonly in Yucatecan traditional medicine to treat leishmaniasis. The structures of 1 and 2 were identified by interpretation of their spectroscopic data and chemical correlation reactions. The relative stereochemistry of 1 was confirmed through an X-ray crystallographic study.


Eagle's Syndrome Managed Successfully by Pulsed Radiofrequency Treatment.
Eagle's syndrome is a rare cause of craniofacial pain caused by impingement of adjacent neurovascular elements by an elongated styloid process or by a calcified stylohyoid ligament. There is a wide spectrum of clinical presentations, which encompasses craniofacial pain, oropharyngeal pain, otalgia, headache, and vertigo. Typically, the glossopharyngeal nerve gets entrapped, giving rise to characteristic orofacial pain. The diagnosis of Eagle's syndrome is confirmed radiologically, and the management includes pharmacotherapy and surgical removal of the styloid process. Moreover, minimally invasive interventions in the form of glossopharyngeal nerve block and radiofrequency treatment can also be effective in providing pain relief. We report a case of an elderly male who presented with features of glossopharyngeal neuralgia secondary to an elongated styloid process and was managed successfully with pulsed radiofrequency treatment of the glossopharyngeal nerve.


Yb- and Mn-Doped Lead-Free Double Perovskite Cs2AgBiX6 (X = Cl-, Br-) Nanocrystals.
Lead-free double perovskite nanocrystals (NCs) have emerged as a new category of materials that hold the potential for overcoming the instability and toxicity issues of lead-based counterparts. Doping chemistry represents a unique avenue toward tuning and optimizing the intrinsic optical and electronic properties of semiconductor materials. In this study, we report the first example of doping Yb3+ ions into lead-free double perovskite Cs2AgBiX6 (X = Cl-, Br-) NCs via a hot injection method. The doping of Yb3+ endows the double perovskite NCs with a newly emerged near-infrared emission band (sensitized from the NC hosts) in addition to their intrinsic trap-related visible photoluminescence. By controlling the Yb-doping concentration, the dual emission profiles and photon relaxation dynamics of the double perovskite NCs can be systematically tuned. Furthermore, we have successfully inserted divalent Mn2+ ions in Cs2AgBiCl6 NCs and observed emergence of dopant emission. Our work illustrates an effective and facile route toward modifying and optimizing optical properties of double perovskite Cs2AgBiX6 (X = Cl-, Br-) NCs with an indirect bandgap nature, which can broaden a range of their potential applications in optoelectronic devices.


Glucocerebrosidase in Parkinson's disease: Insights into pathogenesis and prospects for treatment.
PD involves several converging pathogenetic pathways to neurodegeneration; highlighted in specific cases by genetic mutations causing familial PD. Numerically, the most important genetic mutations associated with PD are those of the glucocerebrosidase gene. Approximately 10% of PD patients carry glucocerebrosidase mutations. This observation has enhanced focus on the autophagy-lysosome system as important in pathogenesis. The relationship of the glucocerebrosidase pathway to the cause and progression of PD highlights the potential to use abnormalities identified as biomarkers and modify glucocerebrosidase activity or substrate accumulation as neuroprotection. Biomarkers relevant to the glucocerebrosidase pathway, for example, enzyme activity and substrate levels, may be identified in blood, urine, and CSF. These may be combined with clinical features to help identify mutation carriers that are at increased risk of PD. The molecular mechanisms by which glucocerebrosidase mutations may result in PD are not fully understood. There is evidence accumulating that there is a reciprocal interaction between glucocerebrosidase and alpha-synuclein levels. This interaction may potentially be used to increase glucocerebrosidase enzyme activities and therefore reduce alpha-synuclein levels to modify the course of PD. Substrate reduction therapy may be an alternative strategy, particularly if membrane abnormalities underlie the organellar dysfunction in PD neurodegeneration. © 2016 International Parkinson and Movement Disorder Society.


Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis and DMBA-DNA adduct formation by curcumin.
Curcumin, a constituent of the traditional Indian spice and medicine turmeric, was evaluated for its capacity to inhibit the mammary tumor initiating activity of 7,12-dimethylbenz[a]anthracene (DMBA) and the in vivo formation of mammary DMBA-DNA adducts in the female rat. Administration (i.p.) of curcumin at 100 mg/kg and 200 mg/kg doses was associated with a significant decrease in the number of palpable mammary tumors and mammary adenocarcinomas. The in vivo formation of mammary DMBA-DNA adducts also was depressed for animals administered curcumin doses from 50 mg/kg to 200 mg/kg. There was, however, no significant enhancement of liver glutathione-S-transferase activity following curcumin administration. Therefore, curcumin when administered i.p. can act as an effective chemopreventative agent towards DMBA-induced rat mammary tumorigenesis and mammary adduct formation.


New endourologic technology for simultaneous holmium:YAG laser lithotripsy and fragment evacuation for PCNL: ex-vivo comparison to standard ultrasonic lithotripsy.
Percutaneous nephrolithotomy (PCNL) is a well established procedure and accepted as the standard of care for the treatment of large renal calculi. Since the introduction of the holmium:yttrium-aluminum-garnet (Ho:YAG) laser into clinical practice in 1990, it has been used successfully to treat various urologic conditions. Today it is the modality of choice for retrograde intracorporeal stone disintegration ureteroscopically, and has also been used successfully for PCNL. One disadvantage when using the Ho:YAG laser for disintegration of renal calculi is the need for graspers to extract fragments and the mobilization of fragments due to the lack of simultaneous suction. We present our experience with a Ho:YAG laser in combination with simultaneous suction in an in-vitro model using a new endourologic technique in comparison to conventional ultrasonic lithotripsy.


Autocrine stimulation of interleukin-1 in the growth of human thyroid carcinoma cell line NIM 1.
We reported first in this study that human thyroid cell line NIM 1 established from a patient with papillary adenocarcinoma of the thyroid associated with hypercalcemia and peripheral neutrocytosis produced interleukin (IL)-1 alpha and IL-1 beta in the culture supernatant and cell lysate as detected by murine thymocyte proliferative response and enzyme-linked immunosorbent assay. Production of IL-1 alpha and IL-1 beta was further confirmed by the demonstration of IL-1 alpha and IL-1 beta messenger ribonucleic acid expression with Northern blot hybridization analysis. The in vitro growth of NIM 1 cells was inhibited by the addition of anti-IL-1 alpha and IL-1 beta antibody. The growth of NIM 1 cells was further enhanced by the addition of recombinant human IL-1 alpha and IL-1 beta, whereas this enhancement was also inhibited by the addition of anti-IL-1 antibody. IL-1 receptors were expressed on NIM 1 cells. These results suggest that IL-1 plays a regulatory role in the growth of NIM 1 cells by an autocrine mechanism.


Twinning across the Developing World.
Until now, little was known about the variation in incidence of twin births across developing countries, because national representative data was lacking. This study provides the first comprehensive overview of national twinning rates across the developing world on the basis of reliable survey data. Data on incidence of twinning was extracted from birth histories of women aged 15-49 interviewed in 150 Demographic and Health Surveys, held between 1987 and 2010 in 75 low and middle income countries. During the interview, information on all live births experienced by the women was recorded, including whether it was a singleton or multiple birth. Information was available for 2.47 million births experienced by 1.38 million women in a period of ten years before the interview. Twinning incidence was measured as the number of twin births per thousand births. Data for China were computed on the basis of published figures from the 1990 census. Both natural and age-standardized twinning rates are presented. The very low natural twinning rates of 6-9 per thousand births previously observed in some East Asian countries turn out to be the dominant pattern in the whole South and South-East Asian region. Very high twinning rates of above 18 per thousand are not restricted to Nigeria (until now seen as the world's twinning champion) but found in most Central-African countries. Twinning rates in Latin America turn out to be as low as those in Asia. Changes over time are small and not in a specific direction. We provide the most complete and comparable overview of twinning rates across the developing world currently possible.


Reslizumab in the management of poorly controlled asthma: the data so far.
Interleukin-5, an important cytokine in the pathophysiology of asthma, participates in terminal maturation and increases chemotaxis, endothelial adhesion, and activation of eosinophils. Blockade of interleukin-5 activity with monoclonal antibodies have been successful in decreasing eosinophil counts. Reslizumab, a monoclonal antibody that targets interleukin-5, has been studied for the treatment of severe asthma. Several studies have shown that reslizumab can effectively treat severe asthma with an eosinophilic phenotype. Compared to placebo, patients treated with reslizumab had a reduction in the rates of asthma exacerbations and experienced improvement in FEV1 and asthma control questionnaires scores as early as 4 weeks after the therapy was initiated. Reslizumab was not effective in various asthma outcomes in patients without eosinophilia. The adverse events reported were similar in both treatment and placebo groups. Patients should be observed immediately after treatment because anaphylaxis may occur rarely (0.3%) after exposure to reslizumab. Future surveillance studies are still needed to establish the risks of malignancy and safety during pregnancy.


Concurrent ruptured spontaneous heterotopic pregnancy and ruptured appendix with delayed presentation in the first trimester: a case report.
Acute appendicitis is the commonest non-gynaecological surgical emergency in pregnancy. However, the concurrent occurrence of acute appendicitis with a heterotopic pregnancy is a rare event and presents diagnostic challenges to unsuspecting clinicians and sonographers. We present a case of a woman who had a heterotopic pregnancy and was noted to have a gangrenous appendicitis at laparotomy, illustrating how a diagnosis of acute appendicitis could easily be missed in pregnancy. We report the case of a 34-year-old woman in the first trimester of pregnancy who had a missed diagnosis of acute appendicitis after she had complained of vague abdominal symptoms for three weeks. She presented to a gynaecologist with vaginal bleeding for three days and was noted to have a heterotopic pregnancy on ultrasound scan. At laparotomy, she was noted to have a gangrenous appendicitis with pyoperitoneum concurrent with a ruptured left fimbrial ectopic pregnancy. Left salpingectomy and saline lavage were done and she had uneventful post-operative recovery. Unsuspecting clinicians, in patients without risk factors, can miss both heterotopic pregnancy and acute appendicitis. As assisted reproductive techniques become widespread, the possibility of heterotopic pregnancies must always be considered and any patient who presents with vague abdominal symptoms must be suspected to have the possibility of acute appendicitis. Because of the unreliability of laboratory investigations and clinical predictive scores in pregnancy, sonographers must be specifically asked to scan for heterotopic pregnancy and appendicitis in suspected cases.


Stress- and treatment-induced elevations of cortisol levels associated with impaired declarative memory in healthy adults.
Two studies investigated the association between cortisol levels and memory performance in healthy adults. In a first study, 13 subjects were exposed to a brief psychosocial laboratory stress ("Trier Social Stress Test") with a subsequent test of declarative memory performance. Results indicated a significant negative relationship between stress-induced cortisol levels and performance in the memory task, i.e. subjects with high cortisol response to the stressor showed poorer memory performance. In a second experiment it was investigated if cortisol, alone, i.e. independent of psychological stress, would also impair memory function. In this study, 40 healthy subjects received either 10 mg cortisol or placebo orally. One hour later they were tested for procedural and declarative memory and spatial thinking. Subjects who received cortisol showed impaired performance in the declarative memory and spatial thinking tasks but not in the procedural memory task. From these results we conclude that in healthy adults elevated free cortisol levels are associated with impaired memory function.


Introduction of an implant surgical selective into a predoctoral dental curriculum.
This article describes the introduction of an implant surgical selective into a predoctoral dental curriculum. It outlines the various challenges encountered in developing the program and the methods used to overcome those challenges. The article also discusses the outcomes of the first year of the program.


Generation of Wheat Transcription Factor FOX Rice Lines and Systematic Screening for Salt and Osmotic Stress Tolerance.
Transcription factors (TFs) play important roles in plant growth, development, and responses to environmental stress. In this study, we collected 1,455 full-length (FL) cDNAs of TFs, representing 45 families, from wheat and its relatives Triticum urartu, Aegilops speltoides, Aegilops tauschii, Triticum carthlicum, and Triticum aestivum. More than 15,000 T0 TF FOX (Full-length cDNA Over-eXpressing) rice lines were generated; of these, 10,496 lines set seeds. About 14.88% of the T0 plants showed obvious phenotypic changes. T1 lines (5,232 lines) were screened for salt and osmotic stress tolerance using 150 mM NaCl and 20% (v/v) PEG-4000, respectively. Among them, five lines (591, 746, 1647, 1812, and J4065) showed enhanced salt stress tolerance, five lines (591, 746, 898, 1078, and 1647) showed enhanced osmotic stress tolerance, and three lines (591, 746, and 1647) showed both salt and osmotic stress tolerance. Further analysis of the T-DNA flanking sequences showed that line 746 over-expressed TaEREB1, line 898 over-expressed TabZIPD, and lines 1812 and J4065 over-expressed TaOBF1a and TaOBF1b, respectively. The enhanced salt and osmotic stress tolerance of lines 898 and 1812 was confirmed by retransformation of the respective genes. Our results demonstrate that a heterologous FOX system may be used as an alternative genetic resource for the systematic functional analysis of the wheat genome.


Analysis and localization of blue whale vocalizations in the Solomon Sea using waveform amplitude data.
During the Woodlark Basin seismic experiment in eastern Papua New Guinea (1999-2000), an ocean-bottom seismic array recorded marine mammal vocalizations along with target earthquake signals. The array consisted of 14 instruments, 7 of which were three-component seismometers with a fourth component hydrophone. They were deployed at 2.0-3.2 km water depth and operated from September 1999 through February 2000. While whale vocalizations were recorded throughout the deployment, this study focuses on 3 h from December 21, 1999 during which the signals are particularly clear. The recordings show a blue whale song composed of a three-unit phrase. That song does not match vocalization characteristics of other known Pacific subpopulations and may represent a previously undocumented blue whale song. Animal tracking and source level estimates are obtained with a Bayesian inversion method that generates probabilistic source locations. The Bayesian method is augmented to include travel time estimates from seismometers and hydrophones and acoustic signal amplitude. Tracking results show the whale traveled northeasterly over the course of 3 h, covering approximately 27 km. The path followed the edge of the Woodlark Basin along a shelf that separates the shallow waters of the Trobriand platform from the deep waters of the basin.


Developmental instability of ano-genital distance index: Implications for assessment of prenatal masculinization.
Prenatal androgens are generally assumed to permanently affect the morphology of external genitalia. In laboratory rodents, the ano-genital distance index (AGDI) has become widely used as a marker of natural prenatal masculinization. A greater value should indicate a greater masculinization. The aim of this study was to assess the developmental stability of the AGDI in female mice during pre- (Days 1-21) and postweaning (Days 21-61) periods. Presuming that the AGDI reflects a permanent effect of prenatal masculinization, we hypothesized that the AGDI will be a developmentally stable morphometric measurement (interindividual differences in the AGDI measurement should persist over time). In contrast to our prediction, the AGDI showed poor repeatability both during pre- (.15) and postweaning (.22) periods, indicating developmental instability. (A value of 1 indicates perfect repeatability and a value of 0 indicates no repeatability.) The AGDI thus does not seem to be a reliable marker of prenatal female masculinization.


[Streptococcal gangrene. A report on 9 cases (author's transl)].
The authors have treated 9 cases of streptococcal gangrene of the limbs. They describe the clinical features:local oedema, erythema, and cyanotic spots. In 7 of the cases the infected general condition was very severe. At operation, the subcutaneous soft tissues were grey-green without pus. The authors have reviewed the literature and consider that treatment should be based on early excision of the skin and subcutaneous tissues. Antibiotics are of great help but are not sufficient by themselves. Nine patients reached a stable state but sequelae have been severe with one disarticulation of the shoulder, one ankylosis of the wrist, one ankylosis of the knee and one generalised stiffness of the hand. Only five patients have been completely cured.


CPSTF: A lesser known, but valuable, resource for FPs.
The Community Preventive Services Task Force provides evidence-based practice interventions and related practical tools to assist in achieving health-promotion and disease-prevention goals.


Susceptibility to Bismuth(III) of Aquaculture Bacterial Pathogens: Effectiveness of Bismuth-Deferiprone Therapy against Vibrio anguillarum Infection in Fish.
Bismuth is a heavy metal with antibacterial properties that has a long history of medicinal use. The results reported here suggest that bismuth(III) (chelated with deferiprone) could be used in aquaculture systems to treat bacterial disease outbreaks, greatly reducing antibiotic use. We tested bismuth susceptibility in a collection of aquaculture bacterial pathogens. In the presence of bismuth concentrations ranging from 1.3 to 13 µM, most bacteria started showing a drastic decrease in their growth ability, although with high inter- and intraspecific variability. The minimal inhibitory concentrations of bismuth ranged from 13 to more than 780 µM, depending on bacterial species and strain. The results of in vivo assays suggest that low concentrations of bismuth could be especially effective to treat vibriosis caused by Vibrio anguillarum, since bismuth greatly reduced mortality in experimentally infected fish without any observable side effects. A bismuth therapy, alone or combined with other antimicrobials, could contribute to reduce the use of antibiotics in aquaculture.


Contemporary perspectives on pediatric diffuse lung disease.
It is much more challenging in children than in adults to obtain computed tomography images of the lung parenchyma at optimal lung volumes without motion artifact. Some of the more common forms of diffuse lung disease in adults rarely occur in children, and several forms of diffuse lung disease are unique to children. Recognition of these differences has led to the development of a new classification scheme for pediatric diffuse lung disease. Knowledge of this classification and recognition of characteristic imaging findings of specific disorders will lead to accurate diagnosis and guide appropriate treatment of children with diffuse lung disease.


Distractor strength and selective attention in picture-naming performance.
Whereas it has long been assumed that competition plays a role in lexical selection in word production (e.g., Levelt, Roelofs, & Meyer, 1999), recently Finkbeiner and Caramazza (2006) argued against the competition assumption on the basis of their observation that visible distractors yield semantic interference in picture naming, whereas masked distractors yield semantic facilitation. We examined an alternative account of these findings that preserves the competition assumption. According to this account, the interference and facilitation effects of distractor words reflect whether or not distractors are strong enough to exceed a threshold for entering the competition process. We report two experiments in which distractor strength was manipulated by means of coactivation and visibility. Naming performance was assessed in terms of mean response time (RT) and RT distributions. In Experiment 1, with low coactivation, semantic facilitation was obtained from clearly visible distractors, whereas poorly visible distractors yielded no semantic effect. In Experiment 2, with high coactivation, semantic interference was obtained from both clearly and poorly visible distractors. These findings support the competition threshold account of the polarity of semantic effects in naming.


Quaternary Heusler compounds Co(2-x)Rh(x)MnZ (Z = Ga, Sn, Sb): crystal structure, electronic structure, and magnetic properties.
Within the huge family of Heusler compounds only a few quaternary derivatives are known that crystallize in the F43m space group. In this work, the yet unreported compounds CoRhMnZ (Z = Ga, Sn, Sb) and the alloy Co(0.5)Rh(1.5)MnSb were investigated in detail by experimental techniques and theoretical methods. The ab initio calculations predict the CoRhMnZ compounds to be half-metallic ferromagnets or to be close to the half-metallic ferromagnetic state. Calculations of the elastic constants show that the cubic structure is stable in compounds containing Mn. Both calculations and experiment reveal that Mn cannot be exchanged by Fe (CoRhFeGa). The low temperature magnetization of the compounds is in the range of 3.4-5.5 μ(B) depending on the composition. The best agreement between experiment and calculation has been achieved for CoRhMnSn (5 μ(B)). The other compounds are also cubic but tend to anti-site disorder. Compared to Co(2)MnSn it is interesting to note that the magnetic properties and half-metallicity are preserved when replacing one of the 'magnetic' Co atoms by a 'non-magnetic' Rh atom. This allows us to increase the spin-orbit interaction at one of the lattice sites while keeping the properties as a precondition for applications and physical effects relying on a large spin-orbit interaction. The Curie temperatures were determined from measurements in induction fields of up to 1 T by applying molecular field fits respecting the applied field. The highest Curie temperature was found for CoRhMnSn (620 K) that makes it, together with the other well defined properties, attractive for above room temperature spintronic applications.


Polyomavirus early-late switch is not regulated at the level of transcription initiation and is associated with changes in RNA processing.
Polyoma gene expression is temporally regulated during productive infection of mouse cells. Early genes are expressed throughout the viral life cycle, but late mRNAs are not detected until after the onset of DNA replication. At late times, late-strand transcripts represent the great majority of viral-specific RNA in the cell. To learn more about the mechanism by which the early-late switch is regulated, we have carried out a detailed analysis of polyomavirus transcription in mouse NIH 3T6 cells. Nuclei were isolated from cells infected for 6, 12, 18, or 24 hr, and run-on assays were performed. The resulting RNAs were then hybridized to a number of immobilized early- and late-strand-specific probes, which represent the entire polyoma genome. Results indicate that the late promoter is always on, even in the absence of DNA replication. Even though the early-late switch is characterized by a greater than 300-fold difference in the ratio of steady-state early- and late-strand RNAs, there is only a 2-fold effect at the level of transcription initiation. Furthermore, the efficiency of termination for late transcripts is very high at early times during infection (greater than 90%) but drops drastically at late times (less than 40%). In other experiments, we have found an increase in splicing efficiency of late pre-mRNA molecules that parallels the decrease in termination efficiency. These results, taken together with other studies from our laboratory, have led us to propose two possible models for the temporal control of polyomavirus late gene expression.


A framework for the design, conduct and interpretation of randomised controlled trials in the presence of treatment changes.
When a randomised trial is subject to deviations from randomised treatment, analysis according to intention-to-treat does not estimate two important quantities: relative treatment efficacy and effectiveness in a setting different from that in the trial. Even in trials of a predominantly pragmatic nature, there may be numerous reasons to consider the extent, and impact on analysis, of such deviations from protocol. Simple methods such as per-protocol or as-treated analyses, which exclude or censor patients on the basis of their adherence, usually introduce selection and confounding biases. However, there exist appropriate causal estimation methods which seek to overcome these inherent biases, but these methods remain relatively unfamiliar and are rarely implemented in trials. This paper demonstrates when it may be of interest to look beyond intention-to-treat analysis for answers to alternative causal research questions through illustrative case studies. We seek to guide trialists on how to handle treatment changes in the design, conduct and planning the analysis of a trial; these changes may be planned or unplanned, and may or may not be permitted in the protocol. We highlight issues that must be considered at the trial planning stage relating to: the definition of nonadherence and the causal research question of interest, trial design, data collection, monitoring, statistical analysis and sample size. During trial planning, trialists should define their causal research questions of interest, anticipate the likely extent of treatment changes and use these to inform trial design, including the extent of data collection and data monitoring. A series of concise recommendations is presented to guide trialists when considering undertaking causal analyses.


[Identification of infectious agents in cases suspicious of Hantavirus infection but with negative serology].
The diagnosis of acute respiratory illness caused by Hantavirus is based in the rapid and progressive clinical course, epidemiological background and the serological confirmation of the virus. When the presence of the virus is not confirmed a differential diagnosis must be made with other infections. Between 1999 and 2001, the Chilean Public Health Institute received 1063 blood samples from patients with a suspicious clinical picture, to study the presence of Andes strain of Hantavirus. In 134 of these samples, the presence of the virus was confirmed. To study the presence of other infections in sera from patients with suspected Hantavirus acute respiratory illness but serologically negative for Hantavirus. A retrospective study of 98 serum samples, received at the National Public Health Institute, of patients with negative serology for Hantavirus. The presence of antibodies against influenza virus, Mycoplasma pneumoniae, Leptospira and Streptococcus pneumoniae was determined using Latex techniques. Leptospira was detected in 23 patients, influenza virus in 13, Streptococcus pneumoniae in six and Mycoplasma pneumoniae in one case. Leptospira infections were confirmed in four cases by ELISA determination of IgM antibodies. Influenza virus infection was confirmed in three cases by Hemmaglutation Inhibition Assay. In suspected cases of Hantavirus acute respiratory infection, but with negative serology, other infectious agents such as Leptospira, influenza virus and Streptococcus pneumoniae, must be sought.


Low-temperature-induced desaturation of fatty acids and expression of desaturase genes in the cyanobacterium Synechococcus sp. PCC 7002.
Changes in response to temperature of lipid classes, fatty acid composition and mRNA levels for acyl-lipid desaturase genes were studied in the marine unicellular cyanobacterium, Synechococcus sp. PCC 7002. The degree of unsaturation of C18 fatty acids increased in cells grown at lower temperature for all lipid classes, and omega 3 desaturation occurred specifically in cells grown at low temperature. While the level of 18:1(9) fatty acids declined, desaturation at the omega 3 position of C18 fatty acids increased gradually during a 12-h period after a temperature shift-down to 22 degrees C. However, the mRNA levels of the desA (delta 12 desaturase), desB (omega 3 desaturase) and desC (delta 9 desaturase) genes increased within 15 min after a temperature shift-down to 22 degrees C; the desaturase gene mRNA levels also rapidly declined within 15 min after a temperature shift-up to 38 degrees C. Therefore, the elevation of mRNA levels for the desaturase genes is not the rate-limiting event for the increased desaturation of membrane lipids after a temperature shift-down. The rapid, low-temperature-induced changes in mRNA levels occurred even when cells were grown under light-limiting conditions for which the growth rates at 22 degrees C and 38 degrees C were identical. These studies indicate that the ambient growth temperature, and not some other growth rate-related process, regulates the expression of acyl lipid desaturation in this cyanobacterium.


[What is possible for us to corroborate developing countries in the leprosy field?].
Developing countries have their own unique characteristics, histories, and situation. There are great differences from country to country. From the experiences worked in both Bangladesh and Myanmar which share their border, some similarities and dissimilarities among these two greatly different countries are discussed. Considering this, common problems on leprosy in the developing countries are analyzed. The needs of developing countries in the field of leprosy are studied, and the possible way of corroboration for us, Japanese leprosy workers, are suggested.


SB-T-121205, a next-generation taxane, enhances apoptosis and inhibits migration/invasion in MCF-7/PTX cells.
Breast cancer is the leading cause of cancer death among women. Paclitaxel, a mitotic inhibitor, is highly effective in the treatment of breast cancer. However, development of resistance to paclitaxel limits its clinical use. Identifying new compounds and new strategies that are effective against breast cancer, in particular drug-resistant cancer, is of great importance. the aim of the present study was to explore the potential of a next-generation taxoid, SB-T-121205, in modulating the proliferation, migration and invasion of paclitaxel-resistant human breast cancer cells (MCF-7/PTX) and further evaluate the underlying molecular mechanisms. The results of MTT assay showed that SB-T-121205 has much higher potency to human breast cancer cells (MCF-7/S, MCF-7/PTX and MDA-MB-453 cells) than paclitaxel, while that the non-tumorigenic human bronchial epithelial cells (BEAS-2B) were slightly less sensitive to SB-T-121205 than paclitaxel. Flow cytometry and western blot methods revealed that SB-T-121205 induced cell cycle arrest at the G2/M phase and apoptosis in MCF-7/PTX cells through accelerating mitochondrial apoptotic pathway, resulting in reduction of Bcl-2/Bax ratio, as well as elevation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) levels. Moreover, SB-T-121205 changed epithelial-mesenchymal transition (EMT) property, and suppressed migration and invasion abilities of MCF-7/PTX cells. Additionally, SB-T-121205 exerted antitumor activity by inhibiting the transgelin 2 and PI3K/Akt pathway. These findings indicate that SB-T-121205 is a potent antitumor agent that promotes apoptosis and also recedes migration/invasion abilities of MCF-7/PTX cells by restraining the activity of transgelin 2 and PI3K/Akt, as well as mitochondrial apoptotic pathway. Such results suggest a potential clinical value of SB-T-121205 in breast cancer treatment.


Antisense inhibition of group II phospholipase A2 expression blocks the production of prostaglandin E2 by P388D1 cells.
Macrophage-like P388D1 cells release [3H]arachidonic acid and produce prostaglandin E2 (PGE2) upon stimulation with bacterial lipopolysaccharide (LPS) and platelet-activating factor (PAF). To determine whether group II phospholipase A2 (PLA2) is involved in this release, we treated P388D1 cells with antisense inhibitors specific for group II PLA2 RNA. Treatment with oligonucleotide ASGII decreased PLA2 activity in P388D1 cell homogenates by approximately 60% and reduced the release of [3H]arachidonic acid and PGE2 from activated cells to nearly resting cell levels. The inhibition by antisense oligonucleotide ASGII was blocked when its sense complement, SGII, was included in the incubation mixture. Stably transfected P388D1 cells expressing an antisense construct for group II PLA2 also produced reduced quantities of PGE2 in response to LPS and PAF. These data suggest that prostaglandin production by activated P388D1 cells involves phospholipid hydrolysis by group II PLA2. Oligonucleotide ASGII also blocked the appearance of a heparin-releasable group II PLA2 in the culture supernatants of P388D1 cells. The disappearance of this protein correlated with reduced PGE2 production by activated cells, indicating that an extracellular heparin-associated pool of group II PLA2 is involved in prostaglandin production by P388D1 cells.