The attenuation of vasospasm by using a sod mimetic after experimental subarachnoidal haemorrhage in rats.
Delayed cerebral vasoconstriction and brain ischemia, are critical problems in the management of a patient affected by rupture of an intracranial aneurysm. Overexpression of Cu-Zn superoxide dismutase (Cu-Zn SOD) can reduce the extent of cerebral vasospasm. We, therefore investigated if vasospasm, can be prevented by a novel, stable, and cell permeable SOD mimetic, MnTBAP [Mn(III) tetrakis (4-benzoic acid) porphyrin] which permeates the biological membranes and scavenges superoxide anions and peroxynitrite. 28 rats (225-250 g) were divided equally into four groups: group 1: control; group 2: SAH only; group 3: SAH plus placebo; and group 4: SAH plus MnTBAP. We used a double haemorrhage method to produce SAH. Starting six hours after SAH, 5 mg/kg MnTBAP (Calbiochem, Darmstadt-Germany; Cat. No 475870)) or an equal volume of 0.9% saline (37 degrees C) was administered by intraperitoneal injection twice daily for 5 days to groups 4 and 3 respectively. MnTBAP or 0.9% saline injections were continued up to fifth day after SAH and rats were sacrificed on the fifth day. Brain sections at the level of the pons were examined by light microscopy. Planimetric measurements were made for the cross-sectional areas of the lumen and the vessel wall (intima plus media) of the basilar artery by a micrometer. Administration of MnTBAP significantly attenuated the vasoconstriction of the basilar artery in group 4 compared with the groups 2 and 3 (p<0.001). These results suggest that this SOD mimetic (MnTBAP) attenuates delayed cerebral vasoconstriction following experimental SAH and that superoxide anions have a role in the pathogenesis of vasospasm after SAH.


The pollen tube journey in the pistil and imaging the in vivo process by two-photon microscopy.
The process of pollen germination and tube growth in the pistil involves a series of cell-cell interactions, some facilitating fertilization while others prohibiting pollen tube access to the female gametophyte, either because of incompatibility or as a result of mechanisms to avert polyspermy and to ensure reproductive success. Understanding pollen tube growth and guidance to the female gametophyte has long been a pursuit among plant biologists, and observations indicate that diverse strategies may be adopted by different plant species. Recent studies in Arabidopsis, maize, and Torenia fournieri suggest that low molecular weight secretory molecules probably play major roles in the short-range attraction of pollen tubes to the female gametophyte. The process of pollen tube growth in the pistil occurs beneath several cell layers so much of the information that conveys the intimate partnership between penetrating pollen tubes and the female tissues has come from fixed samples and observations of in vitro pollen tube growth responses to female factors. A unique glimpse of the in vivo pollen germination and tube growth process is provided here by intra-vital two-photon excitation (TPE) microscopy of pollinated Arabidopsis pistils that remained on intact plants. Further discoveries of critical factors of male or female origins and how they control the pollen tube growth and fertilization process will broaden our understanding of the common themes and diverse strategies that plants have evolved to ensure reproductive success. The advancement of imaging technology to monitor pollination and fertilization and the development of probes to monitor various aspects of the pollen tube growth process, including pollen intracellular dynamics, will allow us to superimpose details obtained from studying pollen tube growth in culture conditions to interpret and understand the in vivo events.


Thirty-day postoperative death rate at an academic medical center.
To improve understanding of perioperative deaths at an academic medical center. Because published data have typically focused on specific patient populations, diagnoses, or procedures, there are few data regarding surgical deaths and complications in institutional or regional studies. Specifically, surgical adverse events and errors are generally not studied comprehensively. This limits the overall understanding of complications and deaths. Data from all operations performed in the main operating suite of the University of Virginia Health Sciences Center from January 1 to June 30, 1999, were compared with state death records to gain a dataset of patients dying within 30 days of surgery. All clinical records from patients who died were screened for adverse events and subsequently reviewed by three surgeons who identified adverse events and errors and performed comparisons with survivors. One hundred nineteen deaths followed 7,379 operations performed on 6,296 patients, yielding a patient death rate of 1.9%. Patients dying within 30 days of surgery were older and had higher American Society of Anesthesiologists scores. Of 119 deaths, 86 (72.3%) were attributable to the patient's primary disease. Twenty-three patient deaths (19.3% of all deaths, 0.37% of all patients) could not be attributed to the patient's primary disease and thus were suspicious for an adverse event (AE) as the cause of the death. Of the 23 deaths suspicious for AE, 15 (12.6% of all deaths, and 65.2% of AE deaths) followed an error in care and thus were classified as potentially preventable, affecting 0.24% of the study population. Overall, the 30-day postoperative death rate was low in the total surgical population at an academic medical center. Errors and AEs were associated with 12.6% and 19.3% of deaths, respectively. Retrospective review inadequately characterized the nature of AEs and failed to determine causality. Prospective audits of outcomes will enhance our understanding of surgical AEs.


A tyrosine-specific protein kinase from Ehrlich ascites tumor cells.
A protein tyrosine kinase that phosphorylates both alpha and beta subunits of inactivated (Na+,K+)-ATPase from dog kidney was purified about 500-fold from Ehrlich ascites tumor cell membranes. The enzyme required divalent cations Mn2+, Mg2+, or Fe2+ but was inhibited by Cu2+ or Zn2+. The purified enzyme phosphorylated the beta subunit about five times faster than the alpha subunit of the (Na+,K+)-ATPase. The random polymer poly(Glu80Tyr20) was an excellent substrate while casein was only marginally phosphorylated. In contrast, the purified transforming gene product of Rous sarcoma virus phosphorylated all three substrates and the (Na+,K+)-ATPase was preferentially phosphorylated on the alpha subunit. The transforming gene product of Fujinami sarcoma visue and EGF receptor kinase from A431 cells phosphorylated (Na+,K+)-ATPase poorly whereas casein was an excellent substrate. The molecular weight of the partially purified protein tyrosine kinase from Ehrlich ascites tumor cells determined by gel filtration was about 60,000. One of two major phosphorylated phosphopeptides resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis had an Mr of 60 kDa, thus suggesting that it might be the autophosphorylated protein tyrosine kinase. A phosphatase that hydrolyzes phosphorylated histones or poly(Glu80Tyr20) was partially purified from the same membrane.


[Observe effect of treating C-IBS by Tongyouqing].
To explore the effect of Tongyouqing treating the C-IBS. According to rome standard II, fifty-eithy C-IBS patients were randomly divided into two groups. Control group (28 cases) were given tijiaseluo (6 mg, qd). Treatment group (30 cases) were given Tongyouqing. After treatment for 4 weeks, observing and comparing the two groups IBS symptom between treatment before and later (Bristol score, abdominal distention, abdominal angina, constipation, partial defecation, belch, mind). To understand the condition of the colonic dynamic by colonic transit trial. Comparing the effective rate of the two group and the proportion of patients still choosing the medicine which they were given. The symptom score of the two groups patients, there were signifi-cant differences between the two groups before treatment and after treatment (P <0.05). After treatment, treatment group is prefer to control group in the improvement of the colonic dynamic (P <0.05). The effective rate and the proportion of patients still choosing the medicine which they were given of treatment group is also more higher than control group. Tongyouqing can relieve the gastrointestinal symptom, improve the fecal character, lessen abdominal distention and abdominal angina, increase the defecating times, improve the colonic dynamic, improve the mind state quilkly and manifestly. Tongyouqing is an effective method to treat C-IBS. It deserves clinical spreading, its mechnism needs further study.


Anal canal duplication and triplication: a rare entity with different presentations.
Anal canal duplication (ACD) is the rarest of gastrointestinal duplications. Few cases have been reported. Most cases present as an opening in the midline, posterior to the normal anus. The aim of our revision is to contribute with eight new cases, some of them with unusual presentations: five presented as the typical form, one with a perianal nodule, and two presented as two separate orifices (anal canal triplication). Complete excision was performed in all patients with no complications. ACD is the most distal and the least frequent digestive duplication. Its treatment should be surgical excision, to avoid complications such as abscess, fistulization, or malignization. Anal canal triplication has never been described before.


Postoperative spinal deep wound infection: a six-year review of 3230 selective procedures.
Postoperative wound infection remains a troublesome but common complication after spinal surgery. This study presents the 6-year experience of our surgical team with post-operative deep wound infection in Taipei Veterans General Hospital. Of 3230 selected operations, 72 cases of wound infection were identified. Thirty patients with deep wound infection were reviewed, including 17 men and 13 women at a mean age of 32 years. The pre-operative diagnoses included spondylolisthesis, scoliosis, spinal stenosis, herniated inter-vertebral disc, spinal fracture and adjacent syndrome. In this report, different deep wound infection rates were compared between different operative procedures including (1) posterior decompression with fixation and fusion, 1.15%. (2) simple decompression (laminectomy) and disectomy, 0.37%, (3) revision fixation with decompression, 4.4%, and (4) removal of implant. 0.33%. The onset of infection sign was divided into 3 groups: (1) acute (< 2 weeks), 43.3%, (2) subacute (2-4 weeks), 40%, and (3) chronic (> 4 weeks), 16.6%. In 11 patients with deep wound infection, no bacteria was cultured, while 14 patients had Methicillin-resistant Staphylococcus aureus and another 3 patients had lower-grade toxic Staphylococcus aureus. All patients received debridement followed by delayed wound closure with effective antibiotics. Instruments were removed in only 8 patients. Twenty seven cases were cured after treatment but 3 patients expired in poor condition. In this series, total deep wound infection was 0.9% in our 6-year experience. The incidence of postoperative spinal infection increased with the complexity of the procedure. Most patients got completely disease free with antibiotics and surgical treatment.


Acupuncture points & use of moxibustion, found in the popular literature & paintings of 17th century Japan.
Acupuncture and moxibustion have long been an integral part of Far Eastern oriental medicine. Moxibustion and acupuncture cannot be discussed without each other since both use the same acupuncture point locations and nomenclatures. In the late 17th century, the famous travel diary of Basho, a Japanese master of haiku poetry, made reference to personal use of moxibustion on one of the well-known acupuncture points, stomach 36. Recently, the author found 2 paintings of a 17th century Kyoto geisha house and its surroundings in the Boston Museum of Fine Arts, painted in realistic color by Moronobu, the originator of the Ukiyoe style and a contemporary of Basho. Part of the scene depicts some professional porters at work; on their legs are white scars at some of the well-known acupuncture points, including stomach 36 and spleen 6. The scars appear to be the result of moxibustion. This may indicate the common use of moxibustion on well-known acupuncture points of the lower extremities in late 17th century Japan for professional porters and for people making extensive journeys. Further support of the relatively widespread use of acupuncture and moxibustion is even found in the popular, non-medical literature of late 17th century Japan. In one of the short stories about the life of average people, written by the novelist Saikaku, the details of a young woman giving moxibustion on the back of a young man is realistically described with illustrations. Reports written by some of the foreign physicians who visited Japan during this period were published, describing these methods with illustrations.(ABSTRACT TRUNCATED AT 250 WORDS)


[Benefits and disadvantages of telemedicine].
Telemedicine is used more and more frequently worldwide. It is increasingly popular in North America, Australia, South Africa, as well as the Scandinavian countries. However, it is not commonly used in Hungary despite various attempts, which is presumably due to earlier dismissive governmental attitude. In this paper the authors analyze ethical, legal and financial aspects of telemedicine from the viewpoints of physicians and patients, too. The results indicate that it cannot be clearly decided whether telemedicine is worth to apply at present. Further, introduction of telemedicine should be based on experience gained in local application.


Clinical and MRI Outcomes of Repaired Peripheral Longitudinal Tears of the Posterior Horn of the Medial Meniscus With ACL Reconstruction: Results According to Tear Size.
Arthroscopic repair of longitudinal tears in the medial meniscal posterior horn (MMPH) has been reported to result in high rates of meniscal healing when performed alongside anterior cruciate ligament reconstruction (ACLR). However, studies that have focused on longitudinal tears and their impact on clinical outcomes after arthroscopic repair are insufficient. To investigate the clinical outcome and healing status after concomitant arthroscopic ACLR and repair of MMPH peripheral longitudinal tears, with respect to the tear length. Cohort study; Level of evidence, 3. A total of 263 patients who underwent concurrent arthroscopic suture repair of longitudinal tears of the MMPH and ACLR were enrolled. All patients had 2-year postoperative magnetic resonance imaging (MRI) evaluations, and 61% of patients underwent a second-look arthroscopy. The exclusion criteria were partial meniscectomies and multiligament injuries. Patients were assessed pre- and postoperatively for clinical scores, amount of anterior translation, grade of pivot shift, and presence of meniscal tear extension. According to the length of longitudinal tears, patients were classified into 2 groups: (1) patients with tears that were located in the posterior compartment and (2) patients with tears that extended to the midbody of the meniscus. Binary stepwise logistic regression analysis was used to evaluate the risk factors for unhealed menisci as identified by MRI. A total of 83 patients were included in this study-52 patients (group 1) had MMPH tears without tear extension and 31 patients (group 2) had MMPH tears with tear extension. There were no differences in outcomes between the groups, including the healing rate after meniscal repair (P > .05). Based on postoperative MRI scans, 67 patients (80.7%) were categorized as completely healed and 16 patients (19.3%) as unhealed. There were no significant differences between the completely healed and unhealed groups in outcomes or the rate of preoperative midbody tear extension. Higher body mass index and lower preoperative Lysholm scores were identified as risk factors for unhealed menisci. Overall, the rate of complete healing of MMPH tears repaired concomitantly with ACLR was 80.7% (67/83), and midbody tear extension did not affect the healing rate of the repaired meniscus. Results indicate that suture repair for unstable MMPH tears should be considered regardless of tear size.


Somatostatin inhibition of phospholipase C activity in isolated rat pancreatic islets.
We have assessed the effect of somatostatin on the phospholipase C activity in isolated rat pancreatic islets. The phospholipase C activity was measured as the generation of inositol 1,4,5-trisphosphate and its metabolite inositol 1,3,4-trisphosphate from the hydrolysis of polyphosphoinositides. Inositol phosphates were measured using anion-exchange fast protein liquid chromatography analysis of extracts from islets prelabelled with myo-[3H]inositol. Somatostatin (1-1000 nmol l-1) significantly inhibited the glucose-induced (12 mmol l-1) phospholipase C activity in a concentration-dependent manner. The Ca2+ channel blocker verapamil (25 mumol l-1) also inhibited the glucose-induced (12 mmol l-1) phospholipase C, whereas the combination of somatostatin and verapamil did not induce any additional inhibition. At 3.3 mmol l-1 glucose, the hypoglycaemic sulphonylurea, tolbutamide (1 mmol l-1), increased the phospholipase C activity. This effect was reversed by somatostatin (100 nmol l-1). Tolbutamide did not further increase the glucose-induced (12 mmol l-1) phospholipase C activity. However, the somatostatin inhibition of glucose-induced (12 mmol l-1) phospholipase C was reversed by tolbutamide. The activator of adenylyl cyclase, forskolin (20 mumol l-1), did not exert any effect on the PLC-inhibition of somatostatin, whereas forskolin alone inhibited the phospholipase C activation at 12 mmol l-1 glucose. Our study demonstrates that somatostatin inhibits the hydrolysis of polyphosphoinositides in pancreatic islets, apparently via a mechanism dependent on Ca2+ and not on cAMP.


Altered sphingolipid metabolism in multidrug-resistant ovarian cancer cells is due to uncoupling of glycolipid biosynthesis in the Golgi apparatus.
Multidrug-resistant tumor cells display enhanced levels of glucosylceramide. In this study, we investigated how this relates to the overall sphingolipid composition of multidrug-resistant ovarian carcinoma cells and which mechanisms are responsible for adapted sphingolipid metabolism. We found in multidrug-resistant cells substantially lower levels of lactosylceramide and gangliosides in sharp contrast to glucosylceramide, galactosylceramide, and sphingomyelin levels. This indicates a block in the glycolipid biosynthetic pathway at the level of lactosylceramide formation, with concomitant accumulation of glucosylceramide. A series of observations exclude regulation at the enzyme level as the underlying mechanism. First, reduced lactosylceramide formation occurred only in intact resistant cells whereas cell-free activity of lactosylceramide synthase was higher compared with the parental cells. Second, the level of lactosylceramide synthase gene expression was equal in both phenotypes. Third, glucosylceramide synthase (mRNA and protein) expression and activity were equal or lower in resistant cells. Based on the kinetics of sphingolipid metabolism, the observation that brefeldin A does not restore lactosylceramide synthesis, and altered localization of lactosylceramide synthase fused to green fluorescent protein, we conclude that lactosylceramide biosynthesis is highly uncoupled from glucosylceramide biosynthesis in the Golgi apparatus of resistant cells.


Timing and risk factors of maternal complications of cesarean section.
To investigate the timing and risk factors of maternal complications of cesarean section (CS). Review of the files of all women who underwent CS at a tertiary medical center between September 2007 and December 2008 yielded 100 patients with postpartum complications. Their clinical and surgery-related characteristics were compared with 100 women with uncomplicated CS operated in January 2009. Complications were analyzed by prevalence and time of occurrence. The only between-group difference in background factors was a higher rate of obesity (BMI > 30) in the controls. The complication rate was 5.7%. The most common complication was endomyometritis (3.6%), followed by wound infection (1.8%) and wound hematoma (1.2%). In most cases, endomyometritis was diagnosed on postoperative days 2-3 and wound complications on days 2-5; 7 of the 9 readmissions occurred on postoperative days 5-6. On multivariate analysis, significant independent predictors of postoperative complications were surgeon experience (OR = 2.4, 95% CI 1.2-4.8) and intra-partum CS (OR = 2.1, 95% CI 1.1-4.3). Cesarean section performed by a resident or during active labor is associated with an increased risk of postpartum complications. Medical teams should be alert to morbidity in women at risk, particularly during the first 4 days after CS.


Muscle relaxants--the current position in the treatment of spasticity in orthopedics.
Muscle tone often exists concomitantly with pain symptoms in different neurological and orthopaedic disease entities. In order to overcome that painful symptom, it is crucial to integrate painkillers with adjunctive therapy using muscle relaxants which decrease the muscle tone. Muscle relaxants available in pharmaceutical trade suppress motor outflow through different mechanisms of action, these include drugs such as: Tizanidine, botulinum toxin, Baclofen, Tolperisone, Methocarbamol. Combining muscle relaxants with analgesics significantly improves the effectiveness of the treatment and allows to reduce drugs doses.


Evaluation of carbamazepine pharmacokinetic profiles in mice with kainic acid-induced acute seizures.
The purpose of the present study was to evaluate the effect of kainic acid (KA)-induced acute seizures on the pharmacokinetic profiles of antiepileptic drug, carbamazepine (CBZ) in mice. Experimental acute seizure in mice was induced by intraperitoneal injection of KA (30 mg/kg), and mice were provided for experiments after 48 h of KA treatment. The portal plasma concentrations of CBZ and its metabolite carbamazepine-10,11-epoxide (CBZ-epo) had trends to decrease as compared to the control mice, whereas the brain CBZ and CBZ-epo concentrations was actually lower in KA treated mice. On the other hand, the exsorption of CBZ from blood to the intestinal lumen via P-glycoprotein (P-gp) in KA treated-mice was significantly increased in parallel with that of Rhodamine-123 (Rho123), a P-gp substrate. Western blotting analysis for intestinal and cerebral P-gp showed that the P-gp expression was induced in the KA-treated mice. The apparent brain-to-plasma concentration ratio (Kp) of CBZ in the KA-treated mice showed significant decrease but that of CBZ-epo did not. Moreover, in the KA-treated mice, the percentage of protein binding was significantly increased, and found to be an inverse proportion in the relationship between the Kp and protein binding of CBZ. In conclusion, the mechanism responsible for a decreased brain CBZ concentration in the KA-induced seizure mice is based on the up-regulation of P-gp function in tissues and plasma protein binding of CBZ.


Determinants of breastfeeding initiation and cessation among employed mothers: a prospective cohort study.
The U.S. continues to have one of the lowest breastfeeding rates in the industrialized world. Studies have shown that full-time employment and early return to work decreased breastfeeding duration, but little is known about the relationship between leave policies and breastfeeding initiation and cessation. This study aimed to identify workplace-related barriers and facilitators associated with breastfeeding initiation and cessation in the first 6 months postpartum. A prospective cohort study design was utilized to recruit 817 Minnesota women aged 18 and older while hospitalized for childbirth. Selection criteria included English-speaking, employed mothers with a healthy, singleton birth. These women were followed up using telephone interviews at 6 weeks, 12 weeks, and 6 months after childbirth. The main study outcomes were breastfeeding initiation, measured during hospital enrollment, and breastfeeding cessation by 6 months postpartum. Women were 30 years old; 86 % were White, and 73 % were married. Breastfeeding rates were 81 % at childbirth, 67 % at 6 weeks, 49 % at 12 weeks, and 33 % at 6 months postpartum. Logistic regression revealed the odds of breastfeeding initiation were higher for women who: held professional jobs, were primiparae, had graduate degree, did not smoke prenatally, had no breastfeeding problems, and had family or friends who breastfeed. Survival analyses showed the hazard for breastfeeding cessation by 6 months was: higher for women who returned to work at any time during the 6 months postpartum versus those who did not return, lower for professional workers, higher among single than married women, higher for every educational category compared to graduate school, and higher for those with no family or friends who breastfeed. While employer paid leave policy did not affect breastfeeding initiation or cessation, women who took shorter leaves were more likely to stop breastfeeding in the first 6 months postpartum. Future research should examine women's awareness of employer policies regarding paid and unpaid leave.


Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.
Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification.


Preliminary study on alleviation of heat-induced intestinal inflammation through compensatory effects of glucose oxidase.
1. The influence of glucose oxidase (GOD) supplementation on growth, gut inflammation and its compensatory effects in broilers was investigated before and after heat stress.2. Before heat stress, one-day-old broilers were divided into two groups: the control (CON) and GOD (100 g/t complete feed) groups. On d 21, the CON group was equally divided into CON1 and CON2 groups, and heat stress (35°C) was applied to the CON2 and GOD groups for 8 h/day to the end of the study, d 27 of age. The chickens were either killed before heat stress and 2 d after heat stress for the determination of cytokines in the liver and ileum, serum antioxidant enzymes and ileal microbiota. Growth performance was determined before and 7 d after heat stress.3. The GOD decreased Clostridiales and Enterobacteriaceae families of bacteria and increased ileal nuclear factor-κB, interleukin-1β, and interferon-γ (P < 0.05) before heat stress. The broilers exhibited compensatory effects, including increases in ileal sirtuin-1, heat shock protein 70 expression, liver nuclear factor erythroid 2-related factor 2 content, serum total antioxidant capacity and glutathione peroxidase level (P < 0.05). At 2 d after heat stress, inflammatory factors were increased in both the CON2 and GOD groups, but the levels were lower in the GOD than CON2 (P < 0.05). On d 7 after heat stress, GOS alleviated heat stress induced growth retardation (P < 0.05).4. These data suggested that GOD supplementation in broiler diets before heat stress stimulated intestinal oxidative stress and produced a compensatory response, which prevented a rapid increase in intestinal inflammatory factors and helped to maintain growth performance under heat stress.


Laboratory measurements of the heterogeneous oxidation of condensed-phase organic molecular makers for motor vehicle exhaust.
Triterpanoid hopanes and steranes are petroleum biomarkers used to apportion fine particulate matter to motor vehicle emissions. To investigate the chemical stability of these compounds, aerosolized motor oil was exposed to the hydroxyl radical (OH) in a smog chamber and the reaction rate constants of hopanes, steranes, and n-alkanes were measured. The experiments were conducted across a range of atmospheric conditions including low and high relative humidity (RH) and with mixtures of lubricating oil and secondary organic aerosol. Hopanes and steranes were found to react at atmospherically significant rates across the entire range of experimental conditions; they are estimated to have lifetimes on the order of several days at average summertime OH levels. The one experimental parameter that strongly influenced the effective rate constants was RH; oxidization of hopanes and steranes was about a factor of 4 slower at 75% RH than at 10% RH. Chemical mass balance (CMB) analysis was performed to illustrate the effects of oxidation on source apportionment estimates. As the extent of oxidation increases, traditional CMB analysis increasingly underestimates the contribution of gasoline vehicles butthe diesel estimates are largely unaffected. The results demonstrate that even modest levels of oxidation can alter policy-relevant conclusions about the total and relative contribution of gasoline and diesel vehicle emissions to ambient fine particle concentrations.


Effects of peripheral high energy missile trauma on the oxygenation of lung tissue in the pig.
The purpose of this paper was to study the effect of peripheral high energy missile trauma on oxygenation of the lung tissue. Eleven pigs were randomised to either high energy gunshot wound of the soft tissues of the thigh or sham exposure. Under anaesthesia and controlled ventilation, the carotid artery and the jugular vein were catheterised and a thoracotomy was performed. A Clark-type multiwire electrode was placed on the surface of the middle lung lobe for registration of the oxygen pressure fields of the lung tissue (PtO2). In animals subjected to missile trauma, an increased heterogeneity was seen in PtO2 1 and 2 hours after exposure, specially under hypoventilatory provocation. Furthermore, PtO2 values did not return to baseline when hypoventilation was followed by normoventilation, in contrast to what was seen in the sham exposed animals. No differences between groups were found in arterial PO2, O2-saturation, PCO2, pH or in pulse frequency. These findings of disturbance in oxygenation of pulmonary tissue, may represent an early phase in the development of a lung injury resembling the post-traumatic adult respiratory distress syndrome seen in man. The initiating events could be release of mediators from traumatised tissue and/or direct effects of the shock waves from missile impact, passing through the body.


Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA.
In Machado-Joseph disease (MJD) gene, there is a C/G polymorphism immediately after the CAG repeat; the expanded CAG repeat tract is exclusively followed by C, whereas about half of wild-type alleles are followed by G. Using this C/G polymorphism, we have engineered the small interfering RNA (siRNA) which decreased the expression of mutant ataxin-3, Q79C, by 96.0%, whereas there was minimal reduction on that of the wild type, Q22G (5.9%). Furthermore, unexpectedly, the expression of another wild-type allele, Q22C, was also much less suppressed (22.5%) by this siRNA possibly due to difference of the secondary structure of the target RNA. This is the first report of sequence-independent discrimination of mutant and wild-type alleles by siRNA.


Magnetic resonance imaging (MRI) in evaluation of left atrial masses: an in vitro and in vivo study.
Thirty patients, 15 each of suspected of left atrial myxoma and clot were studied in a prospective study to assess the role of magnetic resonance imaging (MRI) in evaluation of left atrial masses. Upon clinical and echocardiographic suspicion of a left atrial mass, patients were subjected to ECG-gated MRI (in vivo study) and subsequently all of them underwent surgery for the removal of mass and/or mitral valve replacement/repair. Within 6 hours of its removal the mass was subjected to in vitro MRI study and subsequently to histopathological examination. During the study T1, T2 gated images were obtained and tissue characterization was done. A magnetic dye Gd-DTPA was used for contrast enhancement. Cine-display of the images was obtained to demonstrate dynamic movement of the mass across the mitral valve. MRI was found to be highly useful in delineating the exact anatomical details of left atrial masses. Results of MRI diagnosis with illustrations are discussed.


Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population-based cohort study.
To explore the association between administration-to-birth interval of antenatal corticosteroids (ACS) and survival in extremely preterm infants. Population-based prospective cohort study. All obstetric and neonatal units in Sweden from 1 April 2004 to 31 March 2007. All live-born infants (n = 707) born at 22-26 completed weeks of gestation. The relationship between time from first administration of ACS to delivery and survival was investigated using Cox proportional hazards regression analysis. Neonatal (0-27 days) and infant (0-365 days) survival, and infant survival without major neonatal morbidity (intraventricular haemorrhage grade ≥ 3, retinopathy of prematurity stage ≥ 3, periventricular leukomalacia, necrotising enterocolitis, or severe bronchopulmonary dysplasia). Five-hundred and ninety-one (84%) infants were exposed to ACS. In the final adjusted model, infant survival was lower in infants unexposed to ACS [hazard ratio (HR) = 0.26; 95% confidence interval 0.15-0.43], in infants born <24 h [HR = 0.53 (0.33-0.87)] and >7 days after ACS [HR = 0.56 (0.32-0.97)], but not in infants born 24-47 h after ACS [HR = 1.60 (0.73-3.50)], as compared with infants born 48 h to 7 days after administration. The findings were similar for neonatal survival. Survival without major neonatal morbidity among live-born infants was 14% in unexposed infants and 30-39% in steroid-exposed groups, indicating that any ACS exposure was valuable. Administration of ACS 24 h to 7 days before extremely preterm birth was associated with significantly higher survival than in unexposed infants and in infants exposed to ACS at shorter or longer administration-to-birth intervals. Timing of antenatal corticosteroids is important for extremely preterm infants' survival.


Rhinogobius maculagenys, A new species of freshwater goby (Teleostei: Gobiidae) from Hunan, China.
A new freshwater goby, Rhinogobius maculagenys sp. nov., was collected from Hunan Province in Southern China. This species can be distinguished from all congeners by a combination of the following features: first dorsal fin with 6 spines; second dorsal fin with a single spine and 7-9 segmented rays; anal fin with a single spine and 6-8 segmented rays; pectoral fin with 16 segmented rays; 32-34 longitudinal scales; 9-13 transverse scales; 11+16=27 vertebrae; pore ω1 missing; head and body yellowish brown; cheek and opercle yellowish brown with over 30 small orange spots, branchiostegal membrane yellow with over 10 small orange spots in males and white and spotless in females; first dorsal fin trapezoidal in males and nearly semicircular in females, with large bright blue blotch in front of second spine; spines 4 and 5 longest, rear tip extending to base of second branched ray of second dorsal fin in males when adpressed, but just reaching or not reaching anterior margin of second dorsal fin in females; caudal fin with 5-6 vertical rows of brown spots; flank with several longitudinal rows of blackish-brown spots; and belly pale white.


Properties of overlapping EREs: synergistic activation of transcription and cooperative binding of ER.
We have designed a novel estrogen-responsive unit, overERE, which consists of two overlapping ERE separated by 5 bp (center-to-center). In gel retardation assays, this sequence forms a low-mobility complex that migrates like an estrogen receptor tetramer. The receptor-overERE complex was specific and was supershifted by anti-ER H222 antibodies. Dose response studies showed that the formation of the receptor tetramer-overERE complex was cooperative. Truncated receptors were used to assess the contribution of the receptor domains. Deletion of the E domain of the ER prevented the formation of an ER-tetramer complex, which reflects a novel function of this receptor domain. In transfection experiments, 17-beta-estradiol activated transcription from an overERE-containing promoter 4-6 times better than from an ERE-containing promoter. This synergistic effect was observed using either the natural hormone (17-beta-estradiol) or xenoestrogens (phenol red, chlordane). We conclude that two overlapping estrogen-responsive elements can elicit synergistic induction of transcription.


Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure.
Understanding the tubular location of diuretic resistance (DR) in heart failure (HF) is critical to developing targeted treatment strategies. Rodents chronically administered loop diuretics develop DR due to compensatory distal tubular sodium reabsorption, but whether this translates to human DR is unknown. We studied consecutive patients with HF (n=128) receiving treatment with loop diuretics at the Yale Transitional Care Center. We measured the fractional excretion of lithium (FELi), the gold standard for in vivo assessment of proximal tubular and loop of Henle sodium handling, to assess sodium exit after loop diuretic administration and FENa to assess the net sodium excreted into the urine. The mean±SD prediuretic FELi was 16.2%±9.5%, similar to that in a control cohort without HF not receiving diuretics (n=52; 16.6%±9.2%; P=0.82). Administration of a median of 160 (interquartile range, 40-270) mg intravenous furosemide equivalents increased FELi by 12.6%±10.8% (P<0.001) but increased FENa by only 4.8%±3.3%. Thus, only 34% (interquartile range, 15.6%-75.7%) of the estimated diuretic-induced sodium release did not undergo distal reabsorption. After controlling for urine diuretic levels, the increase in FELi explained only 6.4% of the increase in FENa (P=0.002). These data suggest that administration of high-dose loop diuretics to patients with HF yields meaningful increases in sodium exit from the proximal tubule/loop of Henle. However, little of this sodium seems to reach the urine, consistent with findings from animal models that indicate that distal tubular compensatory sodium reabsorption is a primary driver of DR.


No evidence for a specific role of IgM in mesangial proliferation of idiopathic nephrotic syndrome.
To define the relationship of mesangial IgM to various morphologic categories of idiopathic nephrotic syndrome (INS), an analysis of 100 patients was carried out in which five morphologic subgroups were evaluated: group 1, minimal glomerular change (38 patients); group 2, minimal change with focal global sclerosis (18 patients); group 3, focal segmental glomerulosclerosis ( FSG ) (23 patients); group 4, mesangial proliferation (12 patients); group 5, focal segmental glomerulosclerosis with mesangial proliferation (9 patients). Immunohistochemical studies failed to demonstrate any differences between these five groups. The intensities of immunofluorescence and the percentage of tissue samples demonstrating IgM and/or C3 in the glomerular mesangium and subendothelial regions were similar. In addition, the presence or intensity of mesangial IgM did not predict the patients' current status or responsiveness to steroid therapy. Morphologic transitions were observed in patients who had more than one biopsy: one of five in group 2 and two of eight in group 3 developed mesangial proliferation; and nine of ten patients with mesangial proliferation in the first biopsy continued to show this finding in the second. In general, a complete response to steroid therapy and a favorable outcome is less likely in patients with this morphologic abnormality. In nine of the 27 repeat biopsies, there was lack of agreement between the first and second tissue samples with respect to the presence or absence of mesangial IgM. Although mesangial proliferation is a consistent feature of the morphology of certain patients with INS, these studies do not support a unique association with mesangial IgM.


Intrafusal effects of botulinum toxin injections for spasticity: revisiting a previous paper.
Botulinum toxin, frequently used to manage focal limb spasticity, has been reported to affect both extrafusal and intrafusal fibers of the injected muscle. Since most studies have used spinal reflexes, it is difficult to isolate the intrafusal effects from extrafusal and central effects. In a paper by On et al. [7], both stretch and H-reflexes were used to examine the intrafusal effects of botulinum toxin injections. Revisiting the data from On et al. [7] presented a unique opportunity to describe a novel method of measuring the effect of botulinum toxin-A on muscle spindle activity in patients with spasticity. H-reflex, maximum M-wave, and Achilles tendon reflex were serially assessed in ten patients with stroke pre-, 2, 4, and 12 weeks post-botulinum. In order to assess the intrafusal effects, we subtracted the %change in H-reflex amplitude from baseline (representing extrafusal and central effects) from the %change in Achilles tendon reflex amplitude from baseline (representing intrafusal, extrafusal and central effects). Using this formula, our results suggest that botulinum induces significant chemodenervation of the intrafusal muscle fibers (33% decreases). Intrafusal effects were greatest at 2 weeks, but tapered off by 12 weeks post-botulinum (p<0.017). We found a significant positive correlation between the intrafusal effects of botulinum toxin and changes in modified Ashworth scale. Our method of assessing the effects of botulinum toxin shows significant effect on intrafusal fibers, which correlates with clinical manifestation of spasticity. Future studies need to investigate ways to maximize intrafusal effects and minimize extrafusal effects of botulinum therapy.


Metabolic Profile and Inflammatory Responses in Dairy Cows with Left Displaced Abomasum Kept under Small-Scaled Farm Conditions.
Left displaced abomasum (LDA) is a severe metabolic disease of cattle with a strong negative impact on production efficiency of dairy farms. Metabolic and inflammatory alterations associated with this disease have been reported in earlier studies, conducted mostly in large dairy farms. This research aimed to: (1) evaluate metabolic and inflammatory responses in dairy cows affected by LDA in small-scaled dairy farms; and (2) establish an Animals 2015, 5 1022 association between lactation number and milk production with the outcome of metabolic variables. The cows with LDA had lower serum calcium (Ca), but greater concentrations of non-esterified fatty acids (NEFA) and beta-hydroxy-butyrate (BHBA), in particular when lactation number was >2. Cows with LDA showed elevated levels of aspartate aminotransferase, glutamate dehydrogenase, and serum amyloid A (SAA), regardless of lactation number. In addition, this study revealed strong associations between milk yield and the alteration of metabolic profile but not with inflammation in the sick cows. Results indicate metabolic alterations, liver damage, and inflammation in LDA cows kept under small-scale farm conditions. Furthermore, the data suggest exacerbation of metabolic profile and Ca metabolism but not of inflammation and liver health with increasing lactation number and milk yield in cows affected by LDA.


Experience of gastrostomy using a quality care framework: the example of rett syndrome.
Rett syndrome is one of many severe neurodevelopmental disorders with feeding difficulties. In this study, associations between feeding difficulties, age, MECP2 genotype, and utilization of gastrostomy were investigated. Weight change and family satisfaction following gastrostomy were explored. Data from the longitudinal Australian Rett Syndrome Database whose parents provided data in the 2011 family questionnaire (n=229) were interrogated. We used logistic regression to model relationships between feeding difficulties, age group, and genotype. Content analysis was used to analyze data on satisfaction following gastrostomy. In those who had never had gastrostomy and who fed orally (n=166/229), parents of girls<7 years were more concerned about food intake compared with their adult peers (odds ratio [OR] 4.26; 95% confidence interval [CI] 1.29, 14.10). Those with a p.Arg168 mutation were often perceived as eating poorly with nearly a 6-fold increased odds of choking compared to the p.Arg133Cys mutation (OR 5.88; 95% CI 1.27, 27.24). Coughing, choking, or gagging during meals was associated with increased likelihood of later gastrostomy. Sixty-six females (28.8%) had a gastrostomy, and in those, large MECP2 deletions and p.Arg168 mutations were common. Weight-for-age z-scores increased by 0.86 (95% CI 0.41, 1.31) approximately 2 years after surgery. Families were satisfied with gastrostomy and felt less anxious about the care of their child. Mutation type provided some explanation for feeding difficulties. Gastrostomy assisted the management of feeding difficulties and poor weight gain, and was acceptable to families. Our findings are likely applicable to the broader community of children with severe disability.


Parameter Estimation and Species Tree Rooting Using ALE and GeneRax.
ALE and GeneRax are tools for probabilistic gene tree-species tree reconciliation. Based on a common underlying statistical model of how gene trees evolve along species trees, these methods rely on gene vs. species tree discordance to infer gene duplication, transfer, and loss events, map gene family origins, and root species trees. Published analyses have used these methods to root species trees of Archaea, Bacteria, and several eukaryotic groups, as well as to infer ancestral gene repertoires. However, it was recently suggested that reconciliation-based estimates of duplication and transfer events using the ALE/GeneRax model were unreliable, with potential implications for species tree rooting. Here, we assess these criticisms and find that the methods are accurate when applied to simulated data and in generally good agreement with alternative methodological approaches on empirical data. In particular, ALE recovers variation in gene duplication and transfer frequencies across lineages that is consistent with the known biology of studied clades. In plants and opisthokonts, ALE recovers the consensus species tree root; in Bacteria-where there is less certainty about the root position-ALE agrees with alternative approaches on the most likely root region. Overall, ALE and related approaches are promising tools for studying genome evolution.


Health Benefits and Cost-Effectiveness From Promoting Smartphone Apps for Weight Loss: Multistate Life Table Modeling.
Obesity is an important risk factor for many chronic diseases. Mobile health interventions such as smartphone apps can potentially provide a convenient low-cost addition to other obesity reduction strategies. This study aimed to estimate the impacts on quality-adjusted life-years (QALYs) gained and health system costs over the remainder of the life span of the New Zealand population (N=4.4 million) for a smartphone app promotion intervention in 1 calendar year (2011) using currently available apps for weight loss. The intervention was a national mass media promotion of selected smartphone apps for weight loss compared with no dedicated promotion. A multistate life table model including 14 body mass index-related diseases was used to estimate QALYs gained and health systems costs. A lifetime horizon, 3% discount rate, and health system perspective were used. The proportion of the target population receiving the intervention (1.36%) was calculated using the best evidence for the proportion who have access to smartphones, are likely to see the mass media campaign promoting the app, are likely to download a weight loss app, and are likely to continue using this app. In the base-case model, the smartphone app promotion intervention generated 29 QALYs (95% uncertainty interval, UI: 14-52) and cost the health system US $1.6 million (95% UI: 1.1-2.0 million) with the standard download rate. Under plausible assumptions, QALYs increased to 59 (95% UI: 27-107) and costs decreased to US $1.2 million (95% UI: 0.5-1.8) when standard download rates were doubled. Costs per QALY gained were US $53,600 for the standard download rate and US $20,100 when download rates were doubled. On the basis of a threshold of US $30,000 per QALY, this intervention was cost-effective for Māori when the standard download rates were increased by 50% and also for the total population when download rates were doubled. In this modeling study, the mass media promotion of a smartphone app for weight loss produced relatively small health gains on a population level and was of borderline cost-effectiveness for the total population. Nevertheless, the scope for this type of intervention may expand with increasing smartphone use, more easy-to-use and effective apps becoming available, and with recommendations to use such apps being integrated into dietary counseling by health workers.


Infectivity of secondary dapsone-resistant cases.
The incidence rate of leprosy among 517 household contacts of 113 cases of secondary dapsone resistance with 5074 person years at risk were studied. The incidence rate of leprosy was 4.3 per 1000 person years at risk, which is very similar to the incidence rate (4.8) among household contacts of lepromatous cases. Two, possibly three, cases of primary dapsone resistance were detected among the 27 contacts who developed multibacillary leprosy. There was no evidence of dapsone resistance among 48 paucibacillary leprosy cases assessed when treated with dapsone monotherapy. The possibility that secondary dapsone-resistant cases will infect and will result in an increase in the number of primary dapsone-resistant cases needs to be investigated further.


Paradoxical recovery in a bilingual patient with aphasia after right capsuloputaminal infarction.
We report the case of a bilingual dextral patient, who presented with an uncommon pattern of aphasic deficit following a right capsulo-putaminal infarction. In this patient, the linguistic deficit concerned the use of her mother tongue (Galician, L1) much more than the lesser practised second language (Spanish, L2). Our patient presented spontaneous fluent speech in L2 but not in L1, automatic translation into L2, and impaired repetition in L1, whereas comprehension was spared in both L1 and L2. Reading and writing were less valuable due to educational interference (reduced schooling). Spontaneous speech 16 months after the stroke showed the stability of the impairment. This is the first reporting of a crossed subcortical aphasia in a bilingual patient.


The Arabidopsis unannotated secreted peptide database, a resource for plant peptidomics.
In the era of genomics, if a gene is not annotated, it is not investigated. Due to their small size, genes encoding peptides are often missed in genome annotations. Secreted peptides are important regulators of plant growth, development, and physiology. Identification of additional peptide signals by sequence homology searches has had limited success due to sequence heterogeneity. A bioinformatics approach was taken to find unannotated Arabidopsis (Arabidopsis thaliana) peptides. Arabidopsis chromosome sequences were searched for all open reading frames (ORFs) encoding peptides and small proteins between 25 and 250 amino acids in length. The translated ORFs were then sequentially queried for the presence of an amino-terminal cleavable signal peptide, the absence of transmembrane domains, and the absence of endoplasmic reticulum lumenal retention sequences. Next, the ORFs were filtered against the The Arabidopsis Information Resource 6.0 annotated Arabidopsis genes to remove those ORFs overlapping known genes. The remaining 33,809 ORFs were placed in a relational database to which additional annotation data were deposited. Genome-wide tiling array data were compared with the coordinates of the ORFs, supporting the possibility that many of the ORFs may be expressed. In addition, clustering and sequence similarity analyses revealed that many of the putative peptides are in gene families and/or appear to be present in the rice (Oryza sativa) genome. A subset of the ORFs was evaluated by reverse transcription-PCR and, for one-fifth of those, expression was detected. These results support the idea that the number and diversity of plant peptides is broader than currently assumed. The peptides identified and their annotation data may be viewed or downloaded through a searchable Web interface at peptidome.missouri.edu.


Effective waist circumference reduction rate necessary to avoid the development of type 2 diabetes in Japanese men with abdominal obesity.
The aim of this study was to determine the effective waist circumference (WC) reduction rate in avoiding the development of type 2 diabetes mellitus (T2DM) in <55 years and ≥55 years Japanese men with abdominal obesity. The study subjects were 795 men with WC ≥85 cm, fasting plasma glucose <126 mg/dL, 2-hr plasma glucose on 75 g of oral glucose tolerance test <200 mg/dL, and HbA1c 5.6-6.4 % (38-40 mmol/mol) at baseline who underwent general health checkups more than twice between April 2007 and May 2015. They were divided into 5 groups based on the change in WC during the observation period (WC gain group, and four groups stratified according the rate of WC loss). The subjects were also divided into the <55 years and ≥55 years (at baseline) subgroups. The cumulative incidence rate of T2DM was analyzed and compared among the groups. The cumulative incidence rates of the largest WC loss quartile (≥5.45 %) in all age, of the largest WC loss quartile (≥5.60 %) and second largest WC loss quartile (3.44-5.59 %) in the <55 years subgroup, and of the largest WC loss quartile (≥5.37 %) in the ≥55 years subgroup were significantly lower than that of the gain group (p<0.001, p=0.009, 0.012, and 0.012, respectively). WC reduction rate of at least about 3 % in the younger (<55 years) and at least about 5 % in the older (≥55 years) non-diabetic Japanese men with abdominal obesity can effectively reduce the chance of development of T2DM.


Expression of hypoxia-inducible angiogenic proteins (hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and E26 transformation-specific-1) and plaque hemorrhage in human carotid atherosclerosis.
Plaque hemorrhage in carotid atherosclerosis promotes plaque progression, resulting in cerebrovascular disease. Hypoxia inducible factor-1alpha (HIF-1alpha) induces angiogenesis via the expression of vascular endothelial growth factor (VEGF) and E26 transformation-specific-1 (Ets-1). The authors investigated human carotid plaques to determine whether these hypoxia-inducible angiogenic proteins play a major role in intraplaque angiogenesis and hemorrhage. The expression of HIF-1alpha, VEGF, and Ets-1 was analyzed using immunohistochemistry and Western blotting in 29 human carotid plaques obtained at carotid endarterectomy. The authors investigated the relationship between plaque characteristics and clinical symptoms. A higher incidence of plaque hemorrhage was observed in plaques associated with symptoms than in those without symptoms (p = 0.03). Hypoxia-inducible factor-1alpha, VEGF, and Ets-1 coexisted in the deep layer of plaque, where angiogenesis was remarkably developed; the expression levels of HIF-1alpha, VEGF, and Ets-1 were significantly enhanced in the main lesion of the plaque (p < 0.01). Symptomatic plaques showed higher expression of VEGF (p = 0.04) than asymptomatic plaques. Plaques with hemorrhage showed a higher incidence of plaque ulcer (p = 0.001) and higher expression of Ets-1 (p = 0.03) than those without hemorrhage. Moreover, significantly increased expressions of VEGF (p = 0.01) and Ets-1 (p = 0.006) were observed in plaques with not only hemorrhages but also ulcers and severe stenosis. The findings in this study suggest that hypoxia-inducible angiogenic proteins in human carotid atherosclerosis promote intraplaque angiogenesis, which can induce plaque hemorrhage and progression.


Atypical sites of twin atrioventricular nodes in a rare form of univentricular heart.
Twin atrioventricular nodes (AVNs) associated with complex tachycardias has been described in a heart with discordant atrioventricular (AV) connection. The present case had twin AVNs (approximately 3 o'clock and 8 o'clock position) of sole AV annulus with absent right AV connection. It is a first report demonstrated the twin AVNs identified at atypical sites associated with a univentricular heart with single inlet connection.


Effect of tigecycline on normal oropharyngeal and intestinal microflora.
Antibacterial agents disrupt the ecological balance of the normal human microflora. Tigecycline, a member of a new class of antibiotics (glycylcyclines), has been shown to have a potent broad-spectrum activity against most gram-positive and gram-negative aerobic and anaerobic bacteria. The aim of the study was to investigate the ecological effects of tigecycline on the normal oropharyngeal and intestinal microflora of healthy subjects. Thirteen healthy white subjects (six females and seven males) between 20 and 31 years of age received 100 mg of tigecycline in the morning on day 1 as a 30-min intravenous infusion followed by a 50-mg dose of tigecycline every 12 h as a 30-minute infusion for 10 days. One subject was withdrawn on day 2 because of an adverse event (urticaria). Serum, saliva, and fecal samples were collected before, during, and after administration for microbiological cultivation and for assays of tigecycline. All new colonizing bacteria were tested for susceptibility (resistance of > or =8 mg/liter) during the investigation period. The fecal concentrations on day 8 were from 3.0 to 14.1 mg/kg, with a mean value of 6.0 mg/kg and a median value of 5.6 mg/kg. The saliva concentrations were generally low (0 to 0.12 mg/liter). A minor effect on the oropharyngeal microflora was observed. The numbers of enterococci and Escherichia coli cells in the intestinal microflora were reduced at day 8 (P < 0.05), while those of other enterobacteria and yeasts increased. There was a marked reduction of lactobacilli and bifidobacteria (P < 0.05) but no impact on bacteroides. No Clostridium difficile strains were isolated. Two Klebsiella pneumoniae strains and five Enterobacter cloacae strains resistant to tigecycline were found on day 8.


Access to Healthcare Services among Thai Immigrants in Japan: A Study of the Areas Surrounding Tokyo.
Numerous undocumented and uninsured foreigners living in Japan have faced barriers when trying to obtain appropriate healthcare services, which have occasionally led to issues with unpaid medical bills to medical institutions. Although information on health and socioeconomic status is essential to tackle such issues, relevant data has been unavailable due to difficulties in contacting this population. This study involved a cross-sectional survey using questionnaires concerning the general demographic characteristics, socioeconomic status, health profiles, information access, and knowledge/attitude/practice of health insurance of Thai nationals living in Japan. The study participants included Thai nationals who lived in Tokyo and the surrounding prefectures. The survey was conducted mainly at public religious events from September 2022 to December 2022. Overall, the questionnaires were obtained from 84 participants, though 67 participants were included in the final analysis after excluding missing variables. There were participants with unspecified visa status (32.8%) and uninsured status (40.3%). Among them, 86.4% expressed positive attitudes towards health insurance. However, multivariate multivariable regression analyses revealed the low insurance practice status among the unspecified visa group (aOR, 0.02; 95% CI, 0.00-0.13). Overall, the results reveal limited access to healthcare services in subgroups of Thai immigrants in Japan.


Mollisianitrile, a new antibiotic from Mollisia sp. A59-96.
Mollisianitrile (1), a new antibiotic was isolated from the fermentation broth of Mollisa sp. A59-96 together with the two known isocoumarins 2 and 3. 1 exhibited antimicrobial, cytotoxic, and phytotoxic activities. 1 contains a reactive propiolonitrile moiety which is believed to be responsible for its antibiotic activities. Upon incubation with L-cysteine the biological activity was lost.


Overutilization of Endoscopic Surveillance in Barrett's Esophagus: The Perils of Too Much of a Good Thing.
A cost-utility analysis in the current issue of AJG examines the ramifications of the overuse of surveillance endoscopy in Barrett's esophagus (BE). This study suggests that excess surveillance is expensive, increasing costs by 50% or more, with only nominal increases in quality-adjusted life expectancy. This study joins a growing literature of cost-utility analyses that suggest that more is not likely better when it comes to surveillance endoscopy. Given the plentiful literature showing overutilization of surveillance endoscopy in BE, the authors argue for a focus on the quality of endoscopy rather than increased frequency of surveillance to improve returns on our healthcare investment.


Beyond Household Walls: The Spatial Structure of American Extended Kinship Networks.
How far do Americans live from their close and extended kin? The answer is likely to structure the types of social, instrumental, and financial support that they are able to provide to one another. Based on the Panel Study of Income Dynamics, kin pairs vary widely in odds of household co-residence, co-residence in the same administrative units, and inter-tract distances if they do not live in the same census tract. Multivariate regression tests show that family structure, educational attainment, and age are closely associated with kin proximity. Fixed effects models demonstrate that fam ily formation shapes spatial relations between kin.


Antithrombotic therapy for patients with cardiac disease.
The use and type of antithrombotic therapy for patients with cardiac disease are described based on an understanding of the pathophysiologic mechanisms involved, the risk of thromboembolism, and the evidence from prospective and, if necessary, retrospective clinical trials. The indications and intensity of anticoagulant therapy in patients with valvular heart disease and prosthetic valves are first discussed. We recommend that the prothrombin time be reported as a ratio and standardized using the International Normalized Ratio. The pivotal role of platelets and the clotting system in the initiation and progression of atherosclerosis and the acute coronary syndromes is described. There is no evidence to date that antiplatelet therapy is of value in primary prevention or in patients with stable angina, but the value of aspirin in patients with unstable angina was clearly shown in two well-designed studies. Adequate prophylactic therapy to prevent the thrombotic complications of acute myocardial infarction (i.e., venous thrombosis and intracardiac thrombosis) is described, and the available data on the prevention of coronary reocclusion after thrombolysis reviewed. There is now convincing evidence from studies in animals and in patients that vascular injury during aortocoronary vein bypass graft surgery requires antitihrombotic therapy starting before the procedure to minimize acute platelet thrombus deposition and prevent occlusion. Restenosis after arterial angioplasty appears to be related to acute platelet thrombus deposition on the site of deep arterial injury. Therapeutic interventions should probably involve both anticoagulants and platelet inhibitor therapy. Implications derived from recent animal studies are discussed.


DFT coupled with NEGF study of the electronic properties and ballistic transport performances of 2D SbSiTe3.
Identifying novel 2D semiconductors with promising electronic properties and transport performances for the development of electronic and optoelectronic applications is of utmost importance. Here, we show a detailed study of the electronic properties and ballistic quantum transport performance of a new 2D semiconductor, SbSiTe3, based on density functional theory (DFT) and non-equilibrium Green's function (NEGF) formalism. Promisingly, monolayer SbSiTe3 owns an indirect band gap of 1.61 eV with a light electron effective mass (0.13m0) and an anisotropic hole effective mass (0.49m0 and 1.34m0). The ballistic performance simulations indicate that the 10 nm monolayer SbSiTe3 n- and p-MOSFETs display a steep subthreshold swing of about 80 mV dec-1 and a high on/off ratio (106), which indicate a good gate-controlling capability. As the channel length of SbSiTe3 decreases to 5 nm, its p-MOSFET also effectively suppresses the intra-band tunneling. Therefore, 2D SbSiTe3 is a potential semiconductor for future nanoelectronics.


The impact of TP53 activation and apoptosis in primary hereditary microcephaly.
Autosomal recessive primary microcephaly (MCPH) is a constellation of disorders that share significant brain size reduction and mild to moderate intellectual disability, which may be accompanied by a large variety of more invalidating clinical signs. Extensive neural progenitor cells (NPC) proliferation and differentiation are essential to determine brain final size. Accordingly, the 30 MCPH loci mapped so far (MCPH1-MCPH30) encode for proteins involved in microtubule and spindle organization, centriole biogenesis, nuclear envelope, DNA replication and repair, underscoring that a wide variety of cellular processes is required for sustaining NPC expansion during development. Current models propose that altered balance between symmetric and asymmetric division, as well as premature differentiation, are the main mechanisms leading to MCPH. Although studies of cellular alterations in microcephaly models have constantly shown the co-existence of high DNA damage and apoptosis levels, these mechanisms are less considered as primary factors. In this review we highlight how the molecular and cellular events produced by mutation of the majority of MCPH genes may converge on apoptotic death of NPCs and neurons, via TP53 activation. We propose that these mechanisms should be more carefully considered in the alterations of the sophisticated equilibrium between proliferation, differentiation and death produced by MCPH gene mutations. In consideration of the potential druggability of cell apoptotic pathways, a better understanding of their role in MCPH may significantly facilitate the development of translational approaches.


Ecological effects of scrubber water discharge on coastal plankton: Potential synergistic effects of contaminants reduce survival and feeding of the copepod Acartia tonsa.
To meet the oncoming requirements for lower sulphur emissions, shipping companies can install scrubbers where the exhaust is sprayed with seawater and subsequently discharged to the sea. The discharge water has a pH around 3 and contains elevated concentrations of vanadium, nickel, lead and hydrocarbons. We investigated 1) the threshold concentrations of scrubber discharge water for survival, feeding and reproduction of the copepod Acartia tonsa, 2) whether the effects depend on the exposure route and 3) whether exposure to discharge water can be detected in field-collected organisms. A direct exposure to discharge water increased adult copepod mortality and reduced feeding at metal concentrations which were orders of magnitude lower than the lethal concentrations in previous single-metal studies. In contrast, reproduction was not influenced by dietary uptake of contaminants. Scrubber water constituents could have synergistic effects on plankton productivity and bioaccumulation of metals, although the effects will depend on their dilution in the marine environment.


Life satisfaction: The role of domain-specific reference points.
In the evaluation of well-being, it is not only important what people have in absolute terms, but also how this compares to reference points in relative terms. We explore the relevance of relative comparisons by testing the effect of people's self-rated position on potential reference points for income and health on their subjective well-being. We used Multiple Discrepancies Theory as a framework to identify seven potentially relevant reference points for income and health. A representative sample (N = 550) of the Netherlands assessed their income and health relative to these reference points. In addition, we elicited monthly household income, health status (EQ-5D-5L), and subjective well-being (SWLS). In line with the literature, we found a negative convex relationship between subjective well-being and age and a positive relationship with being employed, income, and health. For income, subjective well-being was also associated with how current income compared to respondents' needs and progression over time, and for health especially with how current health compared to what they felt they deserved. Our findings suggest that income and health are important for subjective well-being both in absolute and relative terms. We found negative effects on life satisfaction if some of the domain specific reference points were not met.


Cold Flow as Versatile Approach for Stable and Highly Luminescent Quantum Dot-Salt Composites.
Since the beginning of the 1980s, colloidally synthesized quantum dots (QDs) have been in the focus of interest due to their possible implementation for color conversion, luminescent light concentrators, and lasing. For all these applications, the QDs benefit from being embedded into a host matrix to ensure stability and usability. Many different host materials used for this purpose still have their individual shortcomings. Here, we present a universal, fast, and flexible approach for the direct incorporation of a wide range of QDs into inorganic ionic crystals using cold flow. The QD solution is mixed with a finely milled salt, followed by the removal of the solvent under vacuum. Under high pressure (GPa), the salt powder loaded with QDs transforms into transparent pellets. This effect is well-known for many inorganic salts (e.g., KCl, KBr, KI, NaCl, CsI, AgCl) from, e.g., sample preparation for IR spectroscopy. With this approach, we are able to obtain strongly luminescent QD-salt composites, have precise control over the loading, and provide a chemically robust matrix ensuring long-term stability of the embedded QDs. Furthermore, we show the photo-, chemical, and thermal stability of the composite materials and their use as color conversion layers for a white light-emitting diode (w-LED). The method presented can potentially be used for all kinds of nanoparticles synthesized in organic as well as in aqueous media.


Stress: a risk factor for serious illness.
The body's principal adaptive responses to stress stimuli are mediated by an intricate stress system, which includes the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathoadrenal system (SAS). Dysregulation of the system, caused by the cumulative burden of repetitive or chronic environmental stress challenges (allostatic load) contributes to the development of a variety of illnesses including hypertension, atherosclerosis, and the insulin-resistance-dyslipidemia syndrome, as well as certain disorders of immune function. The brain's limbic system, particularly the hippocampus and amygdala, is also intimately involved in the stress response. Chronically elevated corticosteroid levels induced by persisting stress may adversely affect hippocampal structure and function, producing deficits of both memory and cognition. The ability of stress to cause illness in humans is most clearly exemplified by post-traumatic stress disorder (PTSD), which consists of a predictable constellation of distressing behavioral symptoms and physiological features. An appreciable proportion of the observed variance in vulnerability to PTSD is attributable to genetic factors. The relationship of this disorder to its precipitating cause-a recent, severely traumatic event-is unambiguous. The neuroendocrinology of PTSD is noteworthy, being characterized in many adult victims by enhanced negative feedback sensitivity of glucocorticoid receptors in the stress response system, and lower than normal urinary and plasma cortisol levels. Adult patients with PTSD also have been shown to exhibit exaggerated catecholamine responses to trauma-related stimuli. On the other hand, severely maltreated prepubertal children with PTSD continue to excrete greater than normal urinary cortisol, catecholamines, and dopamine years after disclosure of the causative abuse.


Micro-CT studies on 3-D bioactive glass-ceramic scaffolds for bone regeneration.
The aim of this study was the preparation and characterization of bioactive glass-ceramic scaffolds for bone tissue engineering. For this purpose, a glass belonging to the system SiO2-P2O5-CaO-MgO-Na2O-K2O (CEL2) was used. The sponge-replication method was adopted to prepare the scaffolds; specifically, a polymeric skeleton was impregnated with a slurry containing CEL2 powder, polyvinyl alcohol (PVA) as a binding agent and distilled water. The impregnated sponge was then thermally treated to remove the polymeric phase and to sinter the inorganic one. The obtained scaffolds possessed an open and interconnected porosity, analogous to cancellous bone texture, and with a mechanical strength above 2 MPa. Moreover, the scaffolds underwent partial bioresorption due to ion-leaching phenomena. This feature was investigated by X-ray computed microcomputed tomography (micro-CT). Micro-CT is a three-dimensional (3-D) radiographic imaging technique, able to achieve a spatial resolution close to 1 microm(3). The use of synchrotron radiation allows the selected photon energy to be tuned to optimize the contrast among the different phases in the investigated samples. The 3-D scaffolds were soaked in a simulated body fluid (SBF) to study the formation of hydroxyapatite microcrystals on the scaffold struts and on the internal pore walls. The 3-D scaffolds were also soaked in a buffer solution (Tris-HCl) for different times to assess the scaffold bioresorption according to the ISO standard. A gradual resorption of the pores walls was observed during the soakings both in SBF and in Tris-HCl.


Effects of glucose deprivation, chemical hypoxia, and simulated ischemia on Na+ homeostasis in rat spinal cord astrocytes.
A steep inwardly directed Na+ gradient is essential for glial functions such as glutamate reuptake and regulation of intracellular ion concentrations. We investigated the effects of glucose deprivation, chemical hypoxia, and simulated ischemia on intracellular Na+ concentration ([Na+]i) in cultured spinal cord astrocytes using fluorescence ratio imaging with sodium-binding benzofuran isophthalate (SBFI) AM. Glucose removal or chemical hypoxia (induced by 10 mM NaN3) for 60 min increased [Na+]i from a baseline of 8.3 to 11 mM. Combined glycolytic and respiratory blockage by NaN3 and 0 glucose saline caused [Na+]i to increase by 20 mM, similar to the [Na+]i increases elicited by blocking the Na+/K+-ATPase with ouabain. Recovery from large [Na+]i increases (>15 mM) induced by the glutamatergic agonist kainate was attenuated during glucose deprivation or NaN3 application and was blocked in NaN3 and 0 glucose. To mimic in vivo ischemia, we exposed astrocytes to NaN3 and 0 glucose saline containing L-lactate and glutamate with increased [K+] and decreased [Na+], [Ca2+], and pH. This induced an [Na+]i decrease followed by an [Na+]i rise and a further [Na+]i increase after reperfusion with standard saline. Similar multiphasic [Na+]i changes were observed after NaN3 and 0 glucose saline with only reduced [Na+]e. Our results suggest that the ability to maintain a low [Na+]i enables spinal cord astrocytes to continue uptake of K+ and/or glutamate at the onset of energy failure. With prolonged energy failure, however, astrocytic [Na+]i rises; with loss of their steep transmembrane Na+ gradient, astrocytes may aggravate metabolic insults by carrier reversal and release of acid, K+, and/or glutamate into the extracellular space.


Hominid exploitation of the environment and cave bear populations. The case of Ursus spelaeus Rosenmüller-Heinroth in Amutxate cave (Aralar, Navarra-Spain).
Cave bears (Ursus deningeri and U. spelaeus) and hominids (Homo heidelbergensis, H. neanderthalensis, and H. sapiens) were potential competitors for environmental resources (subterranean and open air). Here, we examined the age at death of cave bear (Ursus spelaeus Rosenmüller-Heinroth) specimens from Amutxate cave in order to shed light on the effect of resource sharing between cave bears and hominids. After studying dental wear of the deciduous and permanent dentitions, the ontogenetic development of mandibles, and incremental layers of cement (annuli), we defined five age groups differentiated by marked development and size gaps. Our findings indicate that after hibernating, bears abandoned the den, thereby leaving the subterranean environment (caves) free for temporary hominid occupation-this would explain the subtle traces of hominid presence in many dens. However, a simple calculation based on age at death of subadult and adult cave bear specimens in Amutxate cave, extrapolated to the whole cave area, showed that the area surrounding this cave hosted bears for at least 9,000 years. This length of habitation, quite similar to the time-span derived from amino acid racemization and electron spin resonance, indicates that bear populations in the Amutxate cave constituted a serious constraint for hominid exploitation of the environment.


A Morphometric and Cellular Analysis Method for the Murine Mandibular Condyle.
The temporomandibular joint (TMJ) has the capacity to adapt to external stimuli, and loading changes can affect the position of condyles, as well as the structural and cellular components of the mandibular condylar cartilage (MCC). This manuscript describes methods for analyzing these changes and a method for altering the loading of the TMJ in mice (i.e., compressive static TMJ loading). The structural evaluation illustrated here is a simple morphometric approach that uses the Digimizer software and is performed in radiographs of small bones. In addition, the analysis of cellular changes leading to alterations in collagen expression, bone remodeling, cell division, and proteoglycan distribution in the MCC is described. The quantification of these changes in histological sections - by counting the positive fluorescent pixels using image software and measuring the distance mapping and stained area with Digimizer - is also demonstrated. The methods shown here are not limited to the murine TMJ, but could be used on additional bones of small experimental animals and in other regions of endochondral ossification.


The influence of body mass index obesity status on vascular surgery 30-day morbidity and mortality.
Mild obesity may have a protective effect against some diseases, termed an "obesity paradox." This study examined the effect of body mass index (Kg/m(2) BMI) on surgical 30-day morbidity and mortality in patients undergoing vascular surgical procedures. As part of the National Surgical Quality Improvement Program (NSQIP), demographic and clinical risk variables, mortality, and 22 defined complications (morbidity) were obtained over three years from vascular services at 14 medical centers. At each medical center, patients from the operative schedule were prospectively and systematically enrolled according to NSQIP protocols. Outcomes and risk variables were compared across NIH-defined obesity classes (underweight [BMI<or=18.5], normal [18.5<BMI<25], overweight [25<BMI<or=30], obese I [30<BMI<or=35], obese II [35<BMI<or=40], and obese III [BMI>40]) using analysis of variance and means comparisons. Logistic regression was used to control for other risk factors. Vascular procedures in 7,543 patients included lower extremity revascularization (24.6%), aneurysm repair (17.4%), cerebrovascular procedures (17.3%), amputations (9.4%), and "other" procedures (31.3%). In the entire cohort, there were 1,659 (22.0%) patients with complications and 295 (3.9%) deaths. Risk factors of hypertension and diabetes increased with BMI (analysis of variance [ANOVA] P < .05) as expected; smoking, disseminated cancer, and stroke decreased (ANOVA P < .01). Twenty other risk factors, as well as mortality and morbidity, had "U" or "J"-shaped distributions with the highest incidence in underweight and/or obese class III extremes but reduced minimums in overweight or obese I classes (ANOVA P < .05). After controlling for age, gender, and operation type, mortality risk remained lowest in obese class I patients (Odds ratio [OR] 0.63, P = .023) while morbidity risk was highest in obese class III patients (OR 1.70, P = .0003), due to wound infection, thromboembolism, and renal complications. Underweight patients have poorer outcomes and class III obesity is associated with increased morbidity. Mildly obese patients have reduced co-morbid illness, surprisingly even less than normal-class patients, with correspondingly reduced mortality. Mild obesity is not a risk factor for 30-day outcomes after vascular surgery and confers an advantage.


Influence of material viscoelasticity on the scattering of guided waves by defects.
Guided waves are potential candidates for the nondestructive evaluation of viscoelastic structures due to their relatively long range of propagation. The major drawback is the difficulty in interpreting the scattered waves especially at high frequency-thickness values since many modes then exist. Moreover, in damping material waveguides, each mode of the scattered field has its own attenuation. Viscoelastic material characterization has been widely investigated by many authors in the past, but very few are treating multimodal scattering by discontinuities in viscoelastic guide. The scattering of a pure fundamental mode incident on a trough in a viscoelastic plate is investigated in this paper, over a relatively large frequency range, with up to five scattered modes. A hybrid two-dimensional finite element and modal projection method is used, based on modal orthogonality, to obtain the relative energy fluxes of each mode. Experiments are also made to validate the numerical predictions.


CKIP-1 ameliorates high glucose-induced expression of fibronectin and intercellular cell adhesion molecule-1 by activating the Nrf2/ARE pathway in glomerular mesangial cells.
Glucose and lipid metabolism disorders as well as oxidative stress (OSS) play important roles in diabetic nephropathy (DN). Glucose and lipid metabolic dysfunctions are the basic pathological changes of chronic microvascular complications of diabetes mellitus, such as DN. OSS can lead to the accumulation of extracellular matrix and inflammatory factors which will accelerate the progress of DN. Casein kinase 2 interacting protein-1 (CKIP-1) mediates adipogenesis, cell proliferation and inflammation under many circumstances. However, whether CKIP-1 is involved in the development of DN remains unknown. Here, we show that CKIP-1 is a novel regulator of resisting the development of DN and the underlying molecular mechanism is related to activating the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidative stress pathway. The following findings were obtained: (1) The treatment of glomerular mesangial cells (GMCs) with high glucose (HG) decreased CKIP-1 levels in a time-dependent manner; (2) CKIP-1 overexpression dramatically reduced fibronectin (FN) and intercellular adhesionmolecule-1 (ICAM-1) expression. Depletion of CKIP-1 further induced the production of FN and ICAM-1; (3) CKIP-1 promoted the nuclear accumulation, DNA binding, and transcriptional activity of Nrf2. Moreover, CKIP-1 upregulated the expression of Nrf2 downstream genes, heme oxygenase (HO-1) and superoxide dismutase 1 (SOD1); and ultimately decreased the levels of reactive oxygen species (ROS). The molecular mechanisms clarify that the advantageous effect of CKIP-1 on DN are well connected with the activation of the Nrf2/ARE antioxidative stress pathway.


Evidence that enteric cholinergic neurones project orally in the intestinal nerve of the chicken.
The intestinal nerve of the chicken, which runs almost the whole length of the small and large intestine, was studied in vitro, using suction electrodes for stimulation and recording. Lengths of nerve with side branches intact in the region of the ileum and rectum were used. The spike discharges that were evoked by supramaximal stimulation of a side branch were recorded at oral and aboral ends of the main nerve trunk. Exposure of the preparation to hexamethonium (550 microM) reversibly abolished or greatly reduced the amplitude of the largest component of the evoked oral response in eighteen experiments, but was without effect on the evoked aboral response in ten experiments. No evidence of a nicotinic cholinergic component to the evoked aboral response was obtained at distances up to 12.5 mm along the nerve. There was also no evidence for a projection of post-ganglionic neurones along the stimulated side branch. The mean conduction velocity of the preganglionic nerve fibres was 0.25 +/- 0.02 m. s-1 while that for the post-ganglionic nerve fibres was 0.66 +/- 0.11 m.s-1. These results suggest that both groups of nerve fibres are non-myelinated. 8-16 d after side branch transection, stimulation of the side branch evoked no oral response in five experiments and a hexamethonium-insensitive response in seven others. In a further four experiments a hexamethonium-sensitive component was seen, but it constituted only a small part of the evoked oral response. It is postulated that transection results in the degeneration of cholinergic nerves in the intestinal nerve. The results suggest that enteric cholinergic nerves form part of a pathway which projects orally along the ileal and rectal segments of the intestinal nerve.


X-linked bulbo-spinal neuronopathy: a family study of three patients.
The clinical features of two brothers and one nephew with X-linked recessive bulbo-spinal neuronopathy are described. The neurophysiological investigations and sural nerve biopsy, previously unreported, confirmed that both motor and sensory nerves are affected. Because of the genetic implications, the importance is stressed of recognising this disorder as a separate entity which should not be classified with the spinal muscular atrophies.


Statins for women with polycystic ovary syndrome not actively trying to conceive.
Statins are lipid-lowering agents with pleiotropic actions. Experts have proposed that in addition to improving the dyslipidaemia associated with polycystic ovary syndrome (PCOS), statins may also exert other beneficial metabolic and endocrine effects, such as reducing testosterone levels. This is an update of a Cochrane Review first published in 2011. To assess the efficacy and safety of statin therapy in women with PCOS who are not actively trying to conceive. We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHLs, and four ongoing trials registers on 7 November 2022. We also handsearched relevant conference proceedings and the reference lists of relevant trials for any additional studies, and we contacted experts in the field for any further ongoing studies. We included randomised controlled trials (RCTs) that evaluated the effects of statin therapy in women with PCOS not actively trying to conceive. Eligible comparisons were statin versus placebo or no treatment, statin plus another agent versus the other agent alone, and statin versus another agent. We performed statistical analysis using Review Manager 5, and we assessed the certainty of the evidence using GRADE methods. We used standard Cochrane methodology. Our primary outcomes were resumption of menstrual regularity and resumption of spontaneous ovulation. Our secondary outcomes were clinical and physiological measures including hirsutism, acne severity, testosterone levels, and adverse events. Six RCTs fulfilled the criteria for inclusion. They included 396 women with PCOS who received six weeks, three months, or six months of treatment; 374 women completed the studies. Three studies evaluated the effects of simvastatin and three studies evaluated the effects of atorvastatin. We summarised the results of the studies under the following comparisons. Statins versus placebo (3 RCTs) One trial measured resumption of menstrual regularity as menstrual cycle length in days. We are uncertain if statins compared with placebo shorten the mean length of the menstrual cycle (mean difference (MD) -2.00 days, 95% confidence interval (CI) -24.86 to 20.86; 37 participants; very low-certainty evidence). No studies reported resumption of spontaneous ovulation, improvement in hirsutism, or improvement in acne. We are uncertain if statins compared with placebo reduce testosterone levels after six weeks (MD 0.06, 95% CI -0.72 to 0.84; 1 RCT, 20 participants; very low-certainty evidence), after 3 months (MD -0.53, 95% CI -1.61 to 0.54; 2 RCTs, 64 participants; very low-certainty evidence), or after 6 months (MD 0.10, 95% CI -0.43 to 0.63; 1 RCT, 28 participants; very low-certainty evidence) Two studies recorded adverse events, and neither reported significant differences between the groups. Statins plus metformin versus metformin alone (1 RCT) The single RCT included in this comparison measured resumption of menstrual regularity as the number of spontaneous menses per six months. We are uncertain if statins plus metformin compared with metformin improves resumption of menstrual regularity (MD 0.60 menses, 95% CI 0.08 to 1.12; 69 participants; very low-certainty evidence). The study did not report resumption of spontaneous ovulation. We are uncertain if statins plus metformin compared with metformin alone improves hirsutism measured using the Ferriman-Gallwey score (MD -0.16, 95% CI -0.91 to 0.59; 69 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.31, 95% CI -0.67 to 0.05; 69 participants; very low-certainty evidence), or testosterone levels (MD -0.03, 95% CI -0.37 to 0.31; 69 participants; very low-certainty evidence). The study reported that no significant adverse events occurred. Statins plus oral contraceptive pill versus oral contraceptive pill alone (1 RCT) The single RCT included in this comparison did not report resumption of menstrual regularity or spontaneous ovulation. We are uncertain if statins plus the oral contraceptive pill (OCP) improves hirsutism compared with OCP alone (MD -0.12, 95% CI -0.41 to 0.17; 48 participants; very low-certainty evidence). The study did not report improvement in acne severity. We are also uncertain if statins plus OCP compared with OCP alone reduces testosterone levels, because the certainty of the evidence was very low (MD -0.82, 95% CI -1.38 to -0.26; 48 participants). The study reported that no participants experienced significant side effects. Statins versus metformin (2 RCTs) We are uncertain if statins improve menstrual regularity compared with metformin (number of spontaneous menses per six months) compared to metformin (MD 0.50 menses, 95% CI -0.05 to 1.05; 1 RCT, 61 participants, very low-certainty evidence). No studies reported resumption of spontaneous ovulation. We are uncertain if statins compared with metformin reduce hirsutism measured using the Ferriman-Gallwey score (MD -0.26, 95% CI -0.97 to 0.45; 1 RCT, 61 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.18, 95% CI -0.53 to 0.17; 1 RCT, 61 participants; very low-certainty evidence), or testosterone levels (MD -0.24, 95% CI -0.58 to 0.10; 1 RCT, 61 participants; very low-certainty evidence). Both trials reported that no significant adverse events had occurred. Statins versus oral contraceptive pill plus flutamide (1 RCT) According to the study report, no participants experienced any significant side effects. There were no available data for any other main outcomes. The evidence for all main outcomes of this review was of very low certainty. Due to the limited evidence, we are uncertain if statins compared with placebo, or statins plus metformin compared with metformin alone, improve resumption of menstrual regularity. The trial evaluating statin plus OCP versus OCP alone reported neither of our primary outcomes. No other studies reported resumption of spontaneous ovulation. We are uncertain if statins improve hirsutism, acne severity, or testosterone. All trials that measured adverse events reported no significant differences between the groups.


Prioritization of Outcomes in Efficacy and Effectiveness of Alcohol Brief Intervention Trials: International Multi-Stakeholder e-Delphi Consensus Study to Inform a Core Outcome Set.
Outcomes used in alcohol brief intervention trials vary considerably. Achieving consensus about key outcomes can enhance evidence synthesis and improve healthcare guidelines. This international, e-Delphi study sought to prioritize outcomes for alcohol brief intervention trials as part of a larger program of work develop an alcohol brief intervention core outcome set. In total, 150 registrants from 19 countries, representing researchers, policymakers, and patients, participated in a two-round e-Delphi study. In Round 1, participants (n = 137) rated 86 outcomes, derived from a review of the literature and a patient and public involvement panel, by importance. In Round 2, participants (n = 114) received feedback on importance ratings for each outcome, and a reminder of their personal rating, before rating the outcomes for importance a second time. Seven additional outcomes suggested in Round 1 were added to the Round 2 questionnaire. We defined consensus a priori as 70% agreement across all stakeholder groups. Seven consumption outcomes met inclusion criteria: typical frequency, typical quantity, frequency of heavy drinking, alcohol-related problems, weekly drinks, at-risk drinking, and combined consumption measures. Others meeting the threshold were alcohol-related injury, quality of life, readiness to change, and intervention fidelity. This is the first international e-Delphi study to identify and prioritize outcomes for use in alcohol brief intervention trials. The use and reporting of outcomes in future alcohol brief intervention trials should improve evidence synthesis in systematic reviews and meta-analyses. Further work is required to refine these outcomes into a core outcome set that includes guidance for measurement of outcomes.


[Morphological aspects of acute intoxication with azaleptin].
Clinico-anatomical analysis, chemico-toxicological and histological examination of material from 54 deceased from intoxication with azaleptin both in urgent toxicology department and pre-admission stage, were performed. Morphology of intoxication with azaleptin was studied, structural base of genopathy at these intoxications was developed.


Induction of parkin expression in the presence of oxidative stress.
Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Gene mutations have been found in rare familial forms of PD, with mutations in parkin being the most common cause. Oxidative stresses have also been implicated as an important contributing factor in the pathogenesis of PD. Currently, there is accumulating evidence that parkin may play a role in maintaining mitochondrial function and preventing oxidative stress. We demonstrated here that parkin is up-regulated when SH-SY5Y dopaminergic neuroblastoma cells are exposed to the oxidant dopamine. The up-regulation of parkin appeared to be due to transcriptional activation as luciferase assays confirmed that specific parkin promoter constructs could confer enhanced transcriptional activation in response to dopamine. Moreover, this effect was also seen when SH-SY5Y cells were subjected to another oxidative stress, 1-methyl-4-phenylpyridinium. In parallel with these studies, we also observed similar transcriptional activation of the parkin coregulated gene by oxidative stress. This is the first demonstration that parkin expression is up-regulated by oxidative stresses and may suggest that this might be a general neuroprotective response of parkin to oxidative stresses.


Properties of an epithelial cell type in culture: the epidermal keratinocyte and its dependence on products of the fibroblast.
Keratinocytes of stratified squamous epithelium can be grown serially in culture and retain the various markers typical of their form of differentiation. In order to form colonies at each transfer, the keratinocytes must be suitably supported by fibroblasts. Established keratinocyte lines of teratomal origin show this dependence, as do diploid strains of finite culture life derived from human skin. For at least some keratinocyte lines, this requirement can be satisfied by soluble products elaborated by the fibroblasts. It is suggested that epithelial cells in general may not be independent cell types and that their poor cultivability may be due to failure to provide suitable fibroblast support. The existence of a number of established lines of epithelial origin that can grow without such support and of lines of fibroblastic origin which cannot support keratinocytes suggests that both epithelial dependence and the fibroblast supporting function can sometimes be lost in established cell lines.