Application of dipole analysis for the diagnosis of myocardial infarction in the presence of left bundle branch block.
The residue value on dipole analysis (the ratio of non-dipolar component to the measured body surface potentials) was estimated mathematically in 16 patients with left bundle branch block. Patients were classified into those with (group A, nine patients) and those without (group B, seven patients) a perfusion defect on thallium-201 myocardial scintigraphy. For the entire QRS complex the residue of group B was smaller than that of normal subjects (20.0 +/- 4.1% versus 24.6 +/- 3.5%, p less than 0.05). Group A showed a greater mean residue value than group B (27.4 +/- 4.4% versus 20.3 +/- 2.4%, p less than 0.01) only during the initial one-third of the QRS complex. All but one patient of group A and only one patient in group B showed a high peak on the residue curve during the initial stage of the QRS complex. The maximal residue value of group A during the initial QRS complex was significantly greater than that of group B (40.9 +/- 10.9% versus 23.4 +/- 5.4%, p less than 0.01). An arbitrarily selected criterion of the maximal residue value greater than or equal to 30% during the initial QRS complex showed a sensitivity of 89% with a specificity of 86% for the diagnosis of myocardial infarction in the presence of left bundle branch block. These results might be related to the complex ventricular activation around the infarcted area even in the presence of left bundle branch block in which intramyocardial conduction with a simple activation front predominates. Dipole analysis appeared to be a valuable method of diagnosing myocardial infarction in the presence of left bundle branch block.


Reduction in 2-year recurrent risk score and improved behavioral outcomes after participation in the "Beating Heart Problems" self-management program: results of a randomized controlled trial.
While behavior change can improve risk factor profiles and prognosis after an acute cardiac event, patients need assistance to achieve sustained lifestyle changes. We developed the "Beating Heart Problems" cognitive-behavioral therapy and motivational interviewing program to support patients to develop behavioral and cognitive self-management skills. We report the results of a randomized controlled trial of the program. Patients (n = 275) consecutively admitted to 2 Melbourne hospitals after acute myocardial infarction (32%), coronary artery bypass graft surgery (40%), or percutaneous coronary intervention (28%) were randomized to treatment (T; n = 139) or control (C; n = 136). T group patients were invited to participate in the 8-week group-based program. Patients underwent risk factor screening 6 weeks after hospital discharge (before randomization) and again 4 and 12 months later. At both the followups, T and C groups were compared on 2-year risk of a recurrent cardiac event and key behavioral outcomes, using both intention-to-treat and "completers only" analyses. Patients ranged in age from 32 to 75 years (mean = 59.0 years; SD - 9.1 years). Most patients (86%) were men. Compared with the C group patients, T group patients tended toward greater reduction in 2-year risk, at both the 4- and 12-month followups. Significant benefits in dietary fat intake and functional capacity were also evident. The "Beating Heart Problems" program showed modest but important benefit over usual care at 4 and, to a lesser extent, 12 months. Modifications to the program such as the inclusion of booster sessions and translation to online delivery are likely to improve outcomes.


Anti-ulcer action of Panax japonicus rhizome.
Using HCl/ethanol-induced ulcer in rats as a screening model, an anti-ulcer effect was observed for a methanol extract of Panax japonicus rhizome, saponin fractions and chikusetsusaponin III. Results suggest that the gastric mucous membrane-protective effect of the methanol extract is likely to be due to the crude saponin fraction and chikusetsusaponin III.


Oncological outcomes of early glottic carcinoma treated with transoral robotic surgery.
Although glottic level is an off-label use of da Vinci system, the feasibility and early-term outcomes of transoral robotic surgery (TORS) for the treatment of early-stage (Tis, T1, T2) glottic carcinoma have been documented. But little is known about the oncological outcomes. We investigated the oncological outcomes of TORS in patients followed at least three years and mean follow-up time was over five years. We retrospectively investigated patients with early glottic carcinoma (Tis, T1, T2) who underwent TORS cordectomy in a tertiary hospital between January 2010 and June 2018. Forty-eight patients were enrolled in the study. Mean follow-up time was 65.6±16.6months. Only one patient died and overall survival rate was found 97.9%. Local recurrence occurred in five patients and disease free survival rate was found 89.6%. Anterior commissure involvement was occurred in 6 (12.5%) patients and local recurrence was seen two of them (33.3%). Synechia complication was occurred in 8 (16.7%) patients and local recurrence was seen three of them (36.7%). Although local recurrence rate was high in both anterior commissure involvement and synechia, only synechia reached to statistical significance for local recurrence (p: 0.027). The recurrences of four patients were treated with radiation therapy (RT) and the remaining one patient underwent total laryngectomy. Laryngeal preservation rate was found 97.9%. Our investigation of the oncological outcomes of TORS on early-stage glottic carcinoma revealed that TORS has similar results when compared with transoral laser microsurgery and RT in terms of recurrence, laryngeal preservation and survival rates. Synechia is also a cautionary complication for recurrence and must be followed closely. We expect that TORS usage will be wider if robotic technology works on innovative developments oriented to glottic area.


Longitudinal analysis for the risk of depression according to the consumption of sugar-sweetened carbonated beverage in non-diabetic and diabetic population.
Studies have presented that high intake of sugar-sweetened carbonated beverage (SSCB) was more associated with the prevalence of depression. However, longitudinal evidence is still insufficient to identify whether the effect of SSCB on incident depression is independent of metabolic factors. Therefore, to evaluate the effect of SSCB consumption on the risk of depression, we analyzed the risk of depression according to the consumption of SSCB in 87,115 working aged Koreans who responded to Center for Epidemiologic Studies Depression (CES-D) scale. They were categorized into 5 groups by SSCB consumption based on one serving dose (200 ml) with never/almost never, < 1 serving/week, 1 ≤ serving/week < 3, 3 ≤ serving/week < 5, and 5 ≤ serving/week. During follow-up, CES-D ≥ 16 was determined as incident depressive symptom. Cox proportional hazards model was used to calculate the multivariable-adjusted hazard ratio (HR) and 95% confidence intervals (CI) for depressive symptom. In analysis for all study participants, the risk of depressive symptom significantly increased proportionally to SSCB consumption (never/almost never: reference, < 1 serving/week: 1.12 [1.07-1.17], 1 ≤ ~ < 3 serving/week: 1.26 [1.19-1.33], 3 ≤ ~ < 5 serving/week: 1.32 [1.23-1.42], and ≥ 5 serving/week: 1.45 [1.33-1.59]). This association was identically observed in men, women, normal glycemic subgroup and prediabetes subgroup.


Outcomes of AO/OTA C-type fractures of the distal humerus after open reduction and internal fixation with locking plate constructs in patients at least 65 years old.
Modern treatment options of distal humerus fractures of active elderly patients are osteosynthesis and total elbow arthroplasty. The evidence of outcomes of ORIF after AO/OTA C-type fractures mostly predates the adoption of locking plates. We evaluated the results of open reduction and internal fixation of these fractures treated exclusively with anatomic locking plates. A retrospective cohort of 39 patients aged 65 years or above with ORIF for AO/OTA C-type distal humerus fracture using locking plates was analysed. 23 provided follow-up data and 14 attended a follow-up visit. Primary outcome was the Oxford Elbow Score. Secondary outcomes were Mayo Elbow Performance Score, quickDASH, satisfaction, range of motion, complications and revision surgeries. Mean Oxford Elbow Score pain was 83 (SD 17), Oxford Elbow Score function 83 (17) and Oxford Elbow Score social-psychological 79 (20). Mean total Oxford Elbow Score was 81 (15). Among the 14 patients who attended a follow-up visit, Mayo Elbow Performance Score was 85 (17), qDASH 19 (16), active arc of motion 119 (19) degrees. Mayo Elbow Performance Score and arc of motion were worse than on the healthy side. One patient had a serious deep infection. Eleven patients had at least one revision surgery, of which 6 were implant removals and 2 subsequent total elbow arthroplasties. Distal AO/OTA C-type distal humerus fractures in older adults can be treated reliably and with good outcomes with ORIF using modern locking plates. The mean qDASH scores are similar to population normal values, but when compared to the healthy arm, single-arm outcomes indicated somewhat impaired function. About 1 in 4 patients had at least one revision surgery.


High expression levels of FANCI correlate with worse prognosis and promote tumor growth of lung adenocarcinoma partly via suppression of M1 macrophages.
FANCI, a member of the Fanconi anemia (FA) complementation group, normally associates with FANCD2 to play an important role in ribosome biogenesis and DNA repair. However, the correlation of FANCI with prognostic value and the molecular mechanism in patients with lung adenocarcinoma (LUAD) remains unclear. In the present study, bioinformatics analysis was performed on LUAD data from TCGA and GEO databases, and further confirmed by in vitro experiments. We found that a high level of FANCI was significantly correlated with a worse survival probability in patients with LUAD. Moreover, the results from in vitro experiments revealed high levels of FANCI in LUAD specimens and cell lines. Knockdown of FANCI expression in A549 and H460 cells significantly inhibited cell viability and clone formation of LUAD cells in vitro and in vivo. Furthermore, high FANCI levels were negatively correlated with a variety of tumor-infiltrating immune cells. Importantly, the overexpression of FANCI significantly inhibited the activation of M1 macrophages. All the data demonstrated that FANCI was a useful prognostic biomarker in patients with LUAD, and knockdown of FANCI inhibited tumor growth of LUAD cells in vitro and in vivo, partly by suppressing the activation of M1 macrophages.


Colorimetric reverse transcriptase assay for HIV-1.
A colorimetric assay for reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) was developed using a double labelled (biotin and digoxigenin) deoxyuridine triphosphate mixture instead of tritiated thymidine triphosphate. After the RT reaction, the newly polymerized strand from oligodeoxythymidylic acid (oligo-dT) contained both biotin and digoxigenin labels. This nucleotide was bound to streptavidin-magnetic beads by the reaction to biotin. At the detection step, an alkaline phosphatase conjugated antibody to digoxigenin was added, followed by the reaction of a colorimetric substrate for this enzyme. This RT assay was comparable to the isotopic RT assay using purified AMV-RT and two strains of HIV grown in cell lines. In addition it was equivalent to the isotopic RT assay for analysis of the time course of in vitro infection of human peripheral blood lymphocytes by HIV-1. The total assay time after the RT reaction step was less than one hour.


Robot-assisted Radical Nephrectomy: A Systematic Review and Meta-analysis of Comparative Studies.
Radical nephrectomy (RN) is the gold standard treatment for large and locally advanced renal tumors. Although robot-assisted radical nephrectomy (RRN) is being increasingly adopted, it remains unclear whether it offers benefits over standard laparoscopic radical nephrectomy (LRN) or open radical nephrectomy (ORN). To compare the outcomes of robotic surgery to those of laparoscopic and open surgery in patients undergoing RN for renal cell carcinoma (RCC). A systematic search was performed across MEDLINE, EMBASE, and Web of Science for retrospective and prospective studies comparing RRN to LRN or ORN. A meta-analysis evaluated perioperative safety, effectiveness, survival, and cost-effectiveness outcomes. The weighted mean difference (WMD) and odds ratio (OR) were used to compare continuous and dichotomous variables, respectively. Quality was assessed using the Newcastle-Ottawa scale. Sensitivity analyses were performed to assess the robustness of the estimates. Twelve studies involving 64 221 patients were identified and included in the analysis. Compared to LRN, RRN was associated with statistically significant longer operative time (WMD 37.44 min; p = 0.03), shorter length of stay (WMD -0.84 days; p = 0.02) and higher total costs (WMD US$4700; p < 0.001). Compared to ORN, RRN was associated with shorter length of stay (WMD -3.06 days; p = 0.002), fewer overall complications (OR 0.56; p < 0.001), lower estimated blood loss (WMD -702 ml; p = 0.01), and higher total hospital costs (WMD US$4520; p = 0.004). There was high heterogeneity across all analyses. In patients undergoing RN for RCC, RRN seems to offer some key advantages compared to ORN, including shorter hospitalization and fewer complications. Compared to LRN, RRN provides similar surgical outcomes but at higher total costs. These findings should be interpreted within the limitations of this type of analysis, given high heterogeneity between studies and poor robustness for most outcomes. Randomized clinical studies with long-term follow-up are needed to obtain more definitive results. In patients with renal cell carcinoma, robot-assisted radical nephrectomy shows perioperative advantages compared to open radical nephrectomy, but not compared to laparoscopic radical nephrectomy.


Longitudinal comparison of preterm pain responses to repeated heelsticks.
Preterm infants receive repeated heelsticks over their hospitalization, yet contradictions exist regarding the influence of prior heelsticks, prior painful procedures, and severity of illness on assessment of the pain responses. Compare pain responses to repeated heelsticks in infants of varying gestational age groups, and determine the influence of number of prior heelsticks, total number of prior painful procedures, and severity of illness on pain responses over time. The descriptive longitudinal design utilized a convenience sample of 81 preterm infants from a Midwestern Level III newborn intensive care unit (NICU). Significant differences in Preterm Infant Pain Profile (PIPP) scores were found between age groups. Both the severity of illness and the total number of prior painful procedures had a significant influence on pain scores. Nurses' use of developmental care and the QuickHeel device may result in lower pain scores. Higher severity of illness and number of prior heelsticks may lower pain scores.


Understanding the effect of gender-based violence on uptake and utilisation of HIV prevention, treatment, and care services among transgender women: a qualitative study in the greater Kampala metropolitan area, Uganda.
Transwomen (also known as transgender women) are disproportionately affected by all forms of gender-based violence (GBV). The high prevalence of physical, sexual and emotional violence not only predisposes transwomen to HIV infection but also limits the uptake/access to HIV prevention, care, and treatment services. Despite the high prevalence of HIV infection and GBV among transwomen, there is limited evidence on how GBV affects the uptake and utilisation of HIV prevention, care, and treatment services. Therefore, this qualitative study explored how GBV affects uptake and utilisation of HIV prevention, treatment, and care services among transwomen in the Greater Kampala Metropolitan Area (GKMA), Uganda. This participatory qualitative study was conducted among transwomen in the GKMA. A total of 20 in-depth interviews, 6 focus group discussions, and 10 key informant interviews were conducted to explore how GBV affects the uptake and utilisation of HIV prevention, treatment, and care services among transwomen. Data were analysed using a thematic content analysis framework. Data were transcribed verbatim, and NVivo version 12 was used for coding. At the individual level, emotional violence suffered by transwomen led to fear of disclosing their HIV status and other health conditions to intimate partners and healthcare providers respectively; inability to negotiate condom use; and non-adherence to antiretroviral therapy (ART). Sexual violence compromised the ability of transwomen to negotiate condom use with intimate partners, clients, and employers. Physical and emotional violence at the community level led to fear among transwomen traveling to healthcare facilities. Emotional violence suffered by transwomen in healthcare settings led to the limited use of pre-exposure prophylaxis and HIV testing services, denial of healthcare services, and delays in receiving appropriate care. The fear of emotional violence also made it difficult for transwomen to approach healthcare providers. Fear of physical violence such as being beaten while in healthcare settings made transwomen shun healthcare facilities. The effects of GBV on the uptake and utilisation of HIV prevention, care, and treatment services were observed in individual, community, and healthcare settings. Across all levels, physical, emotional, and sexual violence suffered by transwomen led to the shunning of healthcare facilities, denial of healthcare services, delays in receiving appropriate care, and the low utilisation of post-exposure prophylaxis, and HIV testing services. Given its effects on HIV transmission, there is a need to develop and implement strategies/ interventions targeting a reduction in GBV. Interventions should include strategies to sensitize communities to accept transwomen. Healthcare settings should provide an enabling environment for transwomen to approach any healthcare provider of their choice without fear of experiencing GBV.


Clinical case definitions for malaria: clinical malaria associated with very low parasite densities in African infants.
In areas endemic for Plasmodium falciparum, clinical malaria is believed to be less common in infants than in older children, but specific case definitions have rarely been determined for this age group. As malaria case definitions are known to be both age- and site-specific, assessment of the risk of disease in infancy requires the development of appropriate diagnostic criteria. In southern Ghana, 154 children were recruited at birth and monitored for fever and malaria infection until 2 years of age. Logistic regression was used to model fever risk as a continuous function of parasite density to determine case definitions for the diagnosis of clinical malaria, and to determine age- and season-specific estimates of the fraction of fevers attributable to malaria (AF); 2360 observations were made on 154 children. For fevers defined by a measured temperature > or = 37.5 degrees C, the estimated population AF was 44% (95% confidence interval 34-53). Estimates of AF varied with age and season. For infants, AF was 51% during the wet season and 22% during the dry season; for children over one year of age, AF was 89% during the wet season and 36% during the dry season. The estimated parasite density threshold for initiation of a febrile episode was 100 parasites per microL of blood in infants, compared with 3500 parasites per microL for children over one year of age. Using these case definitions, the incidence of clinical malaria was estimated at 0.09 cases per child-year at risk for children less than 6 months of age, 0.40 for children aged 6-11 months, and 0.69 for children aged 12-23 months. Of 66 cases of clinical malaria, only 3 were observed in children under 5 months of age. We concluded that, although most fevers in infants are not due to malaria, infant clinical malaria may occur at extremely low parasite densities. This may be indicative of a lack of anti-disease immunity in this age group. In southern Ghana, an infant with axillary temperature > or = 37.5 degrees C and parasitaemia > or = 100/microL should be considered to have clinical malaria. Nevertheless, the incidence of clinical malaria is very low in children under 6 months of age, confirming that they are significantly protected from clinical malaria compared to older children.


Heat shock induces the nuclear accumulation of YAP1 via SRC.
Yes-associated protein 1 (YAP1), a co-transcription activator, shuttles between the cytoplasm and the nucleus. Phosphorylation by large tumor suppressor kinases (LATS1/2) is the major determinant of YAP1 subcellular localization. Unphosphorylated YAP1 interacts with transcription factors in the nucleus and regulates gene transcription, while phosphorylated YAP1 is trapped in the cytoplasm and is degraded. We found that when U2OS and HeLa cells are exposed to 42 °C, YAP1 enters the nucleus within 30 min and returns to the cytoplasm at 4 h. SRC and HSP90 are involved in nuclear accumulation and return to the cytoplasm, respectively. Upon heat shock, LATS2 forms aggregates including protein phosphatase 1 and is dephosphorylated and inactivated. SRC activation is necessary for the formation of aggregates, while HSP90 is required for their dissociation. YAP1 is involved in heat shock-induced NF-κB signaling. Mechanistically, YAP1 is implicated in strengthening the interaction between RELA and DPF3, a component of SWI/SNF chromatin remodeling complex, in response to heat shock. Thus, YAP1 plays a role as a thermosensor.


Transcatheter aortic valve replacement with Evolut R versus Sapien 3 in Japanese patients with a small aortic annulus: The OCEAN-TAVI registry.
To compare safety, efficacy, and hemodynamics of transfemoral transcatheter aortic valve replacement (TAVR) using self-expanding and balloon-expandable transcatheter heart valves (THVs) in patients with a small aortic annulus. Few studies have directly compared TAVR outcomes using third-generation THVs, focusing on patients with small aortic annuli. In a multicenter TAVR registry, we analyzed data from 576 patients with a small annulus and who underwent transfemoral TAVR using third-generation THVs. Propensity score matching was used to adjust baseline clinical characteristics. The device success rate in the overall cohort was 92.0% (Evolut R: 92.1% vs. Sapien 3:92.0%, p = 0.96). One year after TAVR, patients treated with Evolut R maintained a lower mean pressure gradient (mPG) and a higher indexed effective orifice area (iEOA) in the matched cohort {mPG: 9.0 [interquartile range (IQR): 6.0-11.9] vs. 12.0 [IQR: 9.9-16.3] mmHg, p < .001; iEOA: 1.20 [IQR: 1.01-1.46] vs. 1.08 [IQR: 0.90-1.28] cm2 /m2 , p < .001}. However, no significant differences were reported in the incidence of severe prosthesis-patient mismatch and aortic regurgitation at 1 year. Furthermore, both groups showed comparable outcomes with no differences in terms of all-cause mortality (log-lank test, p = .81). TAVR for patients with a small annulus using third-generation THVs was associated with high device success. Evolut R seems to be superior to Sapien 3 in hemodynamic performance for patients with a small annulus and body surface area up to 1 year after TAVR. Nevertheless, all-cause mortality at 1 year was similar between both groups.


Expression of nitric oxide synthase in the spinal cord in amyotrophic lateral sclerosis.
The expression of nitric oxide synthase was studied in human postmortem cervical spinal cord from four individuals with amyotrophic lateral sclerosis (ALS) and four individuals who had died from non-neurological causes. A novel autoradiographic method employing [3H]nitro-L-arginine, a potent inhibitor of the enzyme, as the binding ligand, was used. The expression was quantified in four discrete subregions of the grey matter, and in the dorsal and ventral white matter. The maximum density of binding in the superficial dorsal, deeper dorsal horn, and intermediate subregions of the grey matter was similar in ALS and control tissue, but it was higher in the ALS tissue, in the ventral horn, and in the dorsal and ventral white matter, compared to the corresponding regions in the control tissue. Saturation analysis of the binding indicated a single population of high affinity binding sites in all subregions in the control tissue. However, in the ALS tissue, in all subregions, the presence of two populations of binding sites with different ligand binding affinities were indicated. It is possible therefore that the expression of an inducible isotype of nitric oxide synthase may contribute to the neuropathic changes seen in ALS.


Glial influences on BBB functions and molecular players in immune cell trafficking.
The blood-brain barrier (BBB) constitutes an elaborate structure formed by specialized capillary endothelial cells, which together with pericytes and perivascular glial cells regulates the exchanges between the central nervous system (CNS) and the periphery. Intricate interactions between the different cellular constituents of the BBB are crucial in establishing a functional BBB and maintaining the delicate homeostasis of the CNS microenvironment. In this review, we discuss the role of astrocytes and microglia in inducing and maintaining barrier properties under physiological conditions as well as their involvement during neuroinflammatory pathologies. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.


[Cancers in children in the Auvergne area: retrospective study from 1986 to 1991].
The specificity of childhood cancers led to the creation of regional childhood cancer registries. An epidemiological study of childhood cancers in the Auvergne area was carried out over a 6 year-period (1986-1991) in order to create a registry. The population of our study was 252,820 children (0-15 years old), living in the Auvergne region. All malignant neoplasms were included together with brain tumours (whatever grading). Data were collected from medical and administrative sources. The data of 153 cases were collected during this period. World age standardized overall incidence rate was 120.5 cases/milion/year. Age standardized incidence rates were: leukemias 37.6 (ALL 28.01), central nervous system tumours 18.34 (medulloblastomas 4.6, astrocytomas 4.6, ependymomas 3.8), lymphomas 10.0, neuroblastomas 18.6, soft tissue tumors 8.3, bone tumours 6.1 (Ewing's sarcomas 4.1, osteosarcomas 2.0), nephroblastomas 5.5, retinoblastomas 3.1, liver tumours 0.5 and others 0.5. Our data base in the Auvergne area might be a source of information for epidemiological studies on the role of etiological factors, the survival, the sequelae and the incidence trends.


Two helping alliance methods for predicting outcomes of psychotherapy. A counting signs vs. a global rating method.
This paper reports on the development of measures of helping alliances in psychotherapy, i.e., the patient's experience of the treatment or relationship with the therapist as helpful, or potentially helpful. The helping alliance counting signs measure, which is the special focus of this paper, entails the counting of certain types of patient statements (signs) which are identified in a manual. The main findings were: a) these types of statements were found to be "scorable" with moderate interjudge agreement; b) scores based on the manual showed moderate agreement with a similar helping alliance manual based upon global ratings; c) scores were fairly to moderately consistent from early to late in treatment; d) scores predicted outcome significantly, e.g., early positive signs of helping alliance correlated .57 (p less than .01) with rated benefits, and .59 (p less than .01) with change in the first target complaint (Battle, C., Imber, S., Hoehn-Saric, R., et al. Target complaints as criteria of improvement. Am. J. Psychother., 20: 184-192, 1966); and e) basic background similarities between patient and therapist, such as in age and religious activity, attained highest correlations with the helping alliance measure, e.g., the sum of 10 similarities correlated .60 (p less than .01) with early positive helping alliance counting signs.


No game, more pain - Examining possible long term effects and underlying mechanisms of habitual violent video gaming on the acquired capability for suicide.
According to Joiner`s interpersonal-psychological theory of suicide repeated engagement in suicidal behavior or so-called painful and provocative events constitutes the acquired capability for suicide (ACS) comprising two facets: enhanced pain tolerance and fearlessness about death (FAD). Recent research showed that single bouts of violent-video-gaming (VVG) increase pain tolerance. It is unknown whether individuals who habitually play VVGs at a high frequency rate show higher signs of ACS in terms of low pain sensitivity, high tolerance and lowered FAD compared to non-gamers. In a cross-sectional case-control study, we compared pain sensitivity and tolerance during a 5-min Cold-Pressor-Test (CPT) besides FAD in young males, playing VVGs highly frequent (n = 18) vs. non-gamers (n = 17). Mood was rated before and after the CPT. We found higher CPT-pain tolerance, lower intensity ratings and higher FAD scores among gamers compared to non-gamers. A significant time x group interaction of pain ratings indicated a process of habituation in the gamers. An increase of positive mood in the gamers emphasizes the role of opponent processes. The results suggest that habitual VVG might reflect a repetitive behavior enhancing the ACS.


Neonatal and infant outcome in boys and girls born very prematurely.
Although important new strategies have improved outcomes for very preterm infants, males have greater mortality/morbidity than females. We investigated whether the excess of adverse later effects in males operated through poorer neonatal profile or if there was an intrinsic male effect. Male sex was significantly associated with higher birth weight, death or oxygen dependency (72% vs. 61%, boys vs. girls), hospital stay (97 vs. 86 days), pulmonary hemorrhage (15% vs. 10%), postnatal steroids (37% vs. 21%), and major cranial ultrasound abnormality (20% vs. 12%). Differences remained significant after adjusting for birth weight and gestation. At follow-up, disability, cognitive delay, and use of inhalers remained significant after further adjustment. We conclude that in very preterm infants, male sex is an important risk factor for poor neonatal outcome and poor neurological and respiratory outcome at follow-up. The increased risks at follow-up are not explained by neonatal factors and lend support to the concept of male vulnerability following preterm birth. Data came from the United Kingdom Oscillation Study, with 797 infants (428 boys) born at 23-28 wk gestational age. Thirteen maternal factors, 8 infant factors, 11 acute outcomes, and neurological and respiratory outcomes at follow-up were analyzed. Follow-up outcomes were adjusted for birth and neonatal factors sequentially to explore mechanisms for differences by sex.


Control of cell volume in oocytes and eggs from Xenopus laevis.
The mechanism by which Xenopus laevis oocytes and eggs survive in hypotonic media was investigated by measuring cell volume (Vc) and intracellular pressure (P(ic)) during osmotic swelling. After 2 hr in 10 mOsm buffer, eggs remained intact, while 60.2 +/- 7.0% of oocytes had burst. Water uptake was proportional to buffer osmolarity in oocytes, but not in eggs. We did not see a regulatory volume decrease in the cells, nor was there any evidence for osmolyte efflux. Oocyte P(ic) increased from 0.27 cm H2O (range 0.14-0.61 cm H2O) to 5.92 cm H2O (range 2.52-7.18 cm H2O, P < 0.001) after 70 min in 20 mOsm buffer. Egg P(ic) in 20 mOsm buffer (0.04 cm H2O, range -0.07 to 0.014 cm H2O) was not significantly different from the value in isotonic (200 mOsm) buffer (0.14 cm H2O, range 0-0.16 cm H2O). The data indicate that Vc in oocytes and eggs is not regulated by either plasma membrane ion transport or the mechanical properties of the vitelline envelope. While oocytes appear to behave as passive osmometers, we speculate that the ability of eggs to maintain volume is determined, in part, by the cytoplasm, in particular by its gel-like nature.


Failure of streptozotocin tetraacetate to undergo extensive hydrolysis and to inhibit D-glucose metabolism and insulinotropic action in rat pancreatic islets.
The esterification of several monosaccharides, such as D-glucose, D-mannoheptulose and 2-deoxy-D-glucose was recently reported to increase their biological efficiency as either nutrient or antimetabolic agent. In the present study, however, the tetraacetate ester of streptozotocin was unexpectedly found to be less potent than unesterified streptozotocin in inhibiting D-glucose metabolism and insulinotropic action in isolated rat pancreatic islets. This coincided with a much lower rate for the hydrolysis of streptozotocin tetraacetate than D-glucose pentaacetate in islet homogenates. These findings document that the esterification of single sugars is not always a successful procedure to enhance their biological potency, for instance because of too low a rate for the intracellular hydrolysis of the ester. To the extent that the activity of the concerned esterase(s) may differ in distinct cell types, as suggested by a prior observation, advantage could be taken of such a situation to target selected esters towards specific, e.g. tumoural cells.


The use of antidepressants in patients with advanced cancer--results from an international multicentre study.
Depression is common in patients with advanced cancer; however, it is not often recognized and therefore not treated. The aims of this study were to examine the prevalence of the use of antidepressants (ADs) in an international cross-sectional study sample and to identify sociodemographic and medical variables associated with their use. The study was conducted in patients with advanced cancer from 17 centres across eight countries. Healthcare professionals registered patient and disease-related characteristics. A dichotomous score (no/yes) was used to assess the use of ADs other than as adjuvant for pain. Self-report questionnaires from patients were used for the assessment of functioning and symptom intensity. Of 1051 patient records with complete data on ADs, 1048 were included (M:540/F:508, mean age 62 years, standard deviation [SD] 12). The majority were inpatients, and 85% had metastatic disease. The prevalence of AD use was 14%. Multivariate logistic regression analyses showed that younger age (odds ratio [OR] 2.46; confidence interval [CI] 1.32-4.55), female gender (OR 1.59; CI 1.09-2.33), current medication for pain (OR 2.68; CI 1.65-4.33) and presence of three or more co-morbidities (OR 4.74; CI 2.27-9.91) were associated with AD use for reasons other than pain. Disease-related variables (diagnoses, stage, Karnofsky Performance Status and survival) were not associated with the use of ADs. Female gender, younger age, analgesic use and multiple co-morbidities were associated with the use of ADs. However, information is still limited on which variables guide physicians in prescribing AD medication. Further longitudinal studies including details on psychiatric and medication history are needed to improve the identification of patients in need of ADs.


Salidroside attenuates sepsis-associated acute lung injury through PPP1R15A mediated endoplasmic reticulum stress inhibition.
This study explored the role and mechanism of salidroside in sepsis-associated acute lung injury (ALI). Sepsis-associated ALI in rats was induced by cecal ligation and perforation method, while lipopolysaccharide (LPS) was used to stimulate cell model. After the treatment of salidroside and dexamethasone (DEX), hematoxylin and eosin staining was applied to evaluate the rat lung injury. Next, the number of total cells and neutrophils in rat bronchoalveolar lavage fluid (BALF) was counted, and the lung wet/dry (W/D) ratio and water content were measured. The neutrophil elastase activity and inflammatory factor levels in BALF were detected by Elastase Assay kit and ELISA. The expressions of PPP1R15A and endoplasmic reticulum (ER) stress-related genes were detected by quantitative reverse transcription polymerase chain reaction and western blot. And the effects of silenced PPP1R15A and tauroursodeoxycholic acid (TUDCA) on cell viability, apoptosis and endoplasmic reticulum (ER) stress were determined by cell counting kit-8 assay, flow cytometry and western blot. The lung injury, inflammation and edema in sepsis model rats were alleviated by salidroside and DEX, meanwhile salidroside increased the viability and inhibited apoptosis in LPS-treated cells. The expression of PPP1R15A was decreased in sepsis models and increased by salidroside, and salidroside down-regulated the ER stress-related protein expressions in vitro and in vivo. Silenced PPP1R15A reversed the effect of salidroside on cell viability, apoptosis and ER stress, whereas TUDCA could counteract the above effect of silenced PPP1R15A. Salidroside targeted PPP1R15A to ameliorate lung injury in sepsis through inhibiting ER stress.


Complete Genome Sequence of a Very Virulent Porcine Epidemic Diarrhea Virus Strain, CH/GDGZ/2012, Isolated in Southern China.
The classical symptoms of porcine epidemic diarrhea (PED) are acute diarrhea and dehydration. The isolated porcine epidemic diarrhea virus (PEDV) CH/GDGZ/2012 strain was obtained from the feces of diseased pigs in 2012 in southern China. We report the complete genome sequence of strain CH/GDGZ/2012, which might be useful for better understanding the molecular characteristics of this virus.


The role of carotenoids in the prevention of human pathologies.
Reactive oxygen species (ROS) and oxidative damage to biomolecules have been postulated to be involved in the causation and progression of several chronic diseases, including cancer and cardiovascular diseases, the two major causes of morbidity and mortality in Western world. Consequently dietary antioxidants, which inactivate ROS and provide protection from oxidative damage are being considered as important preventive strategic molecules. Carotenoids have been implicated as important dietary nutrients having antioxidant potential, being involved in the scavenging of two of the ROS, singlet molecular oxygen (1O2) and peroxyl radicals generated in the process of lipid peroxidation. Carotenoids are lipophilic molecules which tend to accumulate in lipophilic compartments like membranes or lipoproteins. Chronic ethanol consumption significantly increases hydrogen peroxide and decreases mitochondrial glutathione (GSH) in cells overexpressing CYP2E1. The depletion of mitochondrial GSH and the rise of hydrogen peroxide are responsible for the ethanol-induced apoptosis. Increased intake of lycopene, a major carotenoid in tomatoes, consumed as the all-trans-isomer attenuates alcohol induced apoptosis in 2E1 cells and reduces risk of prostate, lung and digestive cancers. Cancer-preventive activities of carotenoids have been associated as well as with their antioxidant properties and the induction and stimulation of intercellular communication via gap junctions which play a role in the regulation of cell growth, differentiation and apoptosis. Gap junctional communication between cells which may be a basis for protection against cancer development is independent of the antioxidant property.


Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release.
To evaluate the effect of strict glycemic control of insulin-dependent diabetes mellitus (IDDM) on the plasma glucose threshold initiating counterregulatory hormone responses to hypoglycemia, we used the glucose clamp technique to produce a standardized gradual glucose decline from 90 to 40 mg/dl in seven young IDDM patients before and after 2-6 mo of intensified insulin therapy. Before intensive therapy [hemoglobin A1 (HbA1) 9.6 +/- 1.1%], epinephrine responses were triggered at a higher plasma glucose level (67 +/- 4 mg/dl) than in normal control subjects (56 +/- 1 mg/dl, P less than .05), and clinical symptoms of hypoglycemia appeared at glucose levels of 50-60 mg/dl. After intensive therapy (HbA1 7.1 +/- 0.7%), the glucose threshold for epinephrine release consistently declined to values (46 +/- 2 mg/dl) below normal (P less than .01). Furthermore, epinephrine concentrations were markedly reduced at each hypoglycemic level, and a greater hypoglycemic stimulus was required to elicit symptoms. The glucose threshold stimulating release of growth hormone also significantly declined after intensive therapy. We conclude that strict glycemic control of IDDM lowers the plasma glucose level required to generate epinephrine release during hypoglycemia. This may diminish patient recognition of moderate hypoglycemia and increase the risk of severe hypoglycemia in intensively treated IDDM.


Structural and functional dynamics of an integral membrane protein complex modulated by lipid headgroup charge.
We have used membrane surface charge to modulate the structural dynamics of an integral membrane protein, phospholamban (PLB), and thereby its functional inhibition of the sarcoplasmic reticulum Ca-ATPase (SERCA). It was previously shown by electron paramagnetic resonance, in vesicles of neutral lipids, that the PLB cytoplasmic domain is in equilibrium between an ordered T state and a dynamically disordered R state and that phosphorylation of PLB increases the R state and relieves SERCA inhibition, suggesting that R is less inhibitory. Here, we sought to control the T/R equilibrium by an alternative means-varying the lipid headgroup charge, thus perturbing the electrostatic interaction of PLB's cationic cytoplasmic domain with the membrane surface. We resolved the T and R states not only by electron paramagnetic resonance in the absence of SERCA but also by time-resolved fluorescence resonance energy transfer from SERCA to PLB, thus probing directly the SERCA-PLB complex. Compared to neutral lipids, anionic lipids increased both the T population and SERCA inhibition, while cationic lipids had the opposite effects. In contrast to conventional models, decreased inhibition was not accompanied by decreased binding. We conclude that PLB binds to SERCA in two distinct structural states of the cytoplasmic domain: an inhibitory T state that interacts strongly with the membrane surface and a less inhibitory R state that interacts more strongly with the anionic SERCA cytoplasmic domain. Modulating membrane surface charge provides an effective way of investigating the correlation between structural dynamics and function of integral membrane proteins.


Functional organization of the corticofugal system from visual cortex to lateral geniculate nucleus in the cat (with an appendix on geniculo-cortical mono-synaptic connections).
1. In the cat visual cortex (VC), electrophoretic glutamate application at a depth corresponding to layer VI may have excitatory or inhibitory effects on relay cells of the lateral geniculate nucleus (LGN). Corticofugal excitation was seen, if the receptive field centers (RFCs) of the VC neurons recorded at the application site were within 2.3 degrees of the RFCs of the LGN neurons under test. Inhibitory effects were seen if the RFCs of both cells were further apart up to 3.1 degrees. Glutamate application at more superficial cortical sites had no effect on LGN-neuron activity. 2. Cross-correlation analysis between spontaneous activities of simultaneously recorded VC and LGN neurons revealed excitatory cortico-geniculate connections in 18 pairs with RFCs separated by less than 1.7 degrees. In 15 pairs the peak latency of the excitation was 2--5 msec (3.4 msec in the average), 3 pairs showed long cortico-geniculate latencies (13--18 msec). The existence of a fast and slow cortico-geniculate system is suggested. 3. Inhibitory cortico-geniculate interaction was demonstrated with cross-correlation analysis in 8 pairs of which 4 had RFCs separated by more than 1.7 degrees. The onset latency of the inhibition was 2--7 msec except for 2 pairs with about 20 msec latency. 4. Most of the LGN neurons which were affected by cortical glutamate application or which showed an excitatory or inhibitory connection with a VC neurons were sustained cells, while the majority of VC neurons which were recorded in the effective glutamate application sites or which showed a significant interaction with LGN neurons in the cross-correlogram were binocularly driven and complex, with mostly large RFCs (mean diameter 3.5 degrees). They responded briskly to moving small spots as well as to moving slits. 5. It is concluded that the corticofugal excitatory effect is transmitted through monosynaptic links from VC neurons located in layer VI (complex cell) to LGN relay neurons (mostly sustained-cell) and this system is organized in a precise topographical manner. 6. In an Appendix neuron pairs which showed a positive correlation in the geniculo-cortical direction were described. The findings may support the view that complex as well as simple cells are drive monosynaptically from geniculo-cortical afferents of the sustained or transient type.


Synthesis and biological evaluation of a novel artesunate-podophyllotoxin conjugate as anticancer agent.
A novel conjugate of artesunate-podophyllotoxin was prepared and evaluated for its cytotoxicity against diverse normal and multidrug resistance human cancer cell lines by CCK-8 assay. The conjugate exhibited good cytotoxicity on all the cell lines with IC50 values of 0.453±0.156-3.011±0.272μM and reduced the resistant factor. The conjugate was further found to disrupt the microtubule network and induce G2/M cell cycle arrest in multidrug resistance K562/ADR cells. Meanwhile, Hoechst staining analysis suggested that conjugate induced cell death by apoptosis. Furthermore, conjugate could downregulate the levels of P-glycoprotein (P-gp) in P-gp overexpressing K562/ADR cells.


Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population.
Histamine plays a major role in allergic disorders, including asthma. A major pathway of histamine biotransformation in the lungs is mediated by histamine N-methyltransferase (HNMT). We investigated the association of a functional SNP C314T; a SNP A929G, a (CA)n repeat in intron 5, and a novel (CA)n repeat (BV677277), 7.5 kb downstream of the HNMT gene with asthma and its associated traits such as total serum IgE levels in a case-control as well as in a family-based study design. In contrast to a previous study, no association was observed for the polymorphisms investigated with asthma (P>0.05). When haplotypes were constructed for these loci and compared, no significant difference was observed in the distribution between cases and controls. In the family-based design, no biased transmission was observed for any of the polymorphisms and haplotypes with asthma using the additive model of inheritance in family-based association test (FBAT). Thus, consistent with the case-control findings, the polymorphisms and haplotypes in the HNMT gene are not associated with asthma in the Indian population.


Echocardiographic evaluation of the left atrium and left atrial appendage function in patients with atrial septum aneurysm: implications for thromboembolic complications.
Our study aimed to assess left atrium (LA) and left atrial appendage (LAA) function in patients with atrial septum aneurysm (ASA) and to relate it to thromboembolic complications. The study group comprised 25 patients with isolated ASA (group I) and 17 clinically healthy subjects (control group = group II). Transthoracic and transesophageal echocardiography were performed in all investigated patients. In group I, the following parameters were significantly higher than in the controls: LA minimal dimension (LA (min)) was 2.13 vs. 1.7 cm; LA presystolic dimension (LA (a)) was 2.66 vs. 2.29 cm and LA pre-ejection period/LA ejection time index (PEP/ETLA) was 1.26 vs. 0.41 ( P < 0.05). There were no statistically significant differences between groups as to P wave and PR-interval duration, which were 69 vs. 72 ms and 167 vs. 173 ms, respectively. All LAA parameters were investigated, but LAA minimal areas (LAA (area min)) were higher in the study group than in controls: LAA transversal dimension (LAA (trans)) was 1.89 vs. 1.32 cm; LAA longitudinal dimension (LAA (long)) was 4.24 vs. 3.11 cm; LAA maximal area (LAA (area max)) was 4.35 vs. 3.1 cm (2); LAA ejection fraction (EFLAA) was 56 vs. 33 %; LAA peak emptying (LAAE) was 0.64 vs. 0.41 m/s, and filling velocities (LAAF) was 0.55 vs. 0.42 m/s ( P < 0.05). The results indicate a depression of LA systolic and an enhancement of LAA function in patients with ASA compared with clinically healthy subjects. (1) Atrial septum aneurysm impairs left atrium systolic function. (2) In patients with atrial septum aneurysm, left atrium appendage function changes; its systolic as well as a reservoir function improve. (3) The enhancement of LAA function in ASA may be a compensatory mechanism for LA systolic function deterioration. (4) As LAA systolic function is enhanced, it is rather unlikely that LAA is the place of origin of thrombi, which occur relatively frequently (according to the literature) in patients with ASA. The thrombi seem to be formed in the bulging sack of ASA, i.e., in the part of the LA whose systolic function is depressed.


Family planning practices among currently married women in Khairpur District, Sindh, Pakistan.
To determine the prevalence and sociodemographic factors associated with family planning practices among currently married women in Khairpur District, Sindh, Pakistan. Cross-sectional community-based survey. From May to June 2000 in Khairpur District, Sindh. A pre-tested structured questionnaire was used to interview 300 subjects from the study area. Stratified cluster sampling was done to collect information on knowledge and use of family planning methods and other sociodemographic factors from the respondents. In this series 62% of the women were illiterate. Nearly 45% of the women were in the age group of 25-34 years. Exposure to family planning messages was greater by television (66%) than by radio (55%). The prevalence of family planning methods among married women was 27%. Oral contraceptive pills were the predominant method used (32%). Regarding sociodemographic factors, more than four living children, exposure to family planning messages on TV, and husband's approval were the main factors associated with the use of family planning methods. Prevalence of family planning is still low in upper Sindh area. In addition to continued use of mass media (television and radio), involvement of males should be incorporated in future family planning initiatives.


A recent advancement on nanomaterials for electrochemical sensing of sulfamethaoxole and its futuristic approach.
Sulfamethoxazole (SMX) forms the high harmfulness and causing negative health impacts to well-being human and environment that found to be major drastic concern. It is subsequently important to keep in track for monitoring of SMX through convenient detecting devices which include the requirement of being minimal expense and potential for on location environmental applications. Nanomaterials based design has been proposed to determine the SMX antibiotic which in turn provides the solution for this issue. In spite of the critical advancement accomplished in research, further endeavors are yet to foster the progress on electrochemical sensors with the guide of various functional nanomaterials and guarantee the effective transportability for such sensors with improved coherence. Moreover, it has been noticed that, only few reports on electrochemical sensing of SMX detection using nanomaterials was observed. Hence an in-depth evaluation of electrochemical sensing systems using various nanomaterials for SMX detection was summarized in this review. Additionally this current review centers with brief presentation around SMX hazard evaluation followed by study on the current logical techniques to feature the importance for SMX detection. This review will provide the sum up view towards the future ideas of this field which assists in improving the detecting strategies for SMX detection.


Flexible enzyme cascade sensing platform based on a G-quadruplex nanofiber biohydrogel for target colorimetric sensing.
Enzyme cascade reactions can greatly improve catalytic efficiency and achieve selective and sensitive detection of targets. This paper presents a novel strategy for colorimetric sensing of targets by loading natural enzymes into a hemin-doped G-quadruplex (G4-hemin) biohydrogel to form a flexible enzyme cascade sensing (FECS) platform. The biohydrogel has advantages of biocompatibility, printability and flexibility. The biohydrogel not only participates in the cascade reaction as the mimic enzyme but also provides a mild microenvironment for the natural enzyme. The FECS platform has a linear range from 0.4 μM to 120 μM and a detection limit of 3.6 × 10-6 M for hydrogen peroxide detection. Additionally, the FECS platform has a low detection limit and wide linear range for glucose and xanthine by loading xanthine oxidase (XOD) and glucose oxidase (GOD) into the biohydrogel, respectively. These results indicate that the novel FECS platform is an effective detection platform that can detect multiple targets and is expected to be widely used in flexible sensing.


Development of a simple measurement method for GluR2 protein expression as an index of neuronal vulnerability.
In vitro estimating strategies for potential neurotoxicity are required to screen multiple substances. In a previous study, we showed that exposure to low-concentrations of some chemicals, such as organotin, decreased the expression of GluR2 protein, which is a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors, and led to neuronal vulnerability. This result suggested that GluR2 decreases as an index of neuronal cell sensitivity and vulnerability to various toxic insults. Accordingly, we developed a versatile method that is a large scale determination of GluR2 protein expression in the presence of environmental chemicals by means of AlphaLISA technology. Various analytical conditions were optimized, and then GluR2 protein amount was measured by the method using AlphaLISA. The GluR2 amounts were strongly correlated with that of measured by western blotting, which is currently used to determine GluR2 expression. An ideal standard curve could be written with the authentic GluR2 protein from 0 ng to 100 ng. Subsequently, twenty environmental chemicals were screened and nitenpyram was identified as a chemical which lead to decrease in GluR2 protein expression. This assay may provide a tool for detecting neurotoxic chemicals according to decreases in GluR2 protein expression.


Triiodothyronine reverses depressed contractile performance after excessive catecholamine stimulation.
Conflicting results have been reported regarding the acute effects of triiodothyronine (T3) on myocardial contractile performance. The present study analyzes the role of T3 in reversing the depressant effect of excessive catecholamine stimulation in isolated porcine left ventricular myocardium. Thirty-six left ventricular trabeculae (0.4 x 6.0 mm) obtained from 6 pigs were used for measurements of isometric force development, isotonic shortening, and intracellular calcium in three experimental series (measurement conditions: 37 degrees C; optimal length; supramaximal electrical stimulation, 1 Hz; calcium measurement, fura-2 ratio method; frequency, 225 Hz). In series 1, isometric force development was measured before and after a 60-minute incubation with 10(-7) mol/L epinephrine in preparations with (n = 6) and without (n = 6) preceding fura-2 loading for calcium measurements. In series 2, the acute effects of a 30-minute administration of T3 (10(-9) mol/L) on isometric force and intracellular calcium were analyzed (n = 6). In series 3, after simultaneous fura-2 loading and a 6-hour 10(-7) mol/L epinephrine exposure the effects of T3 (10(-9) mol/L, 30 minutes) on force development, shortening, and intracellular calcium transient were analyzed. Long-term and high-dose epinephrine exposure induced a severe contractile depression with a significant reduction of isometric force development (p < 0.05) and increased diastolic (p < 0.001) and systolic calcium (p < 0.001). In normal porcine myocardium T3 had no effect on the extent of isometric force generation but accelerated the time course of force development (p < 0.05) and increased the calcium transient (p < 0.001). After induction of myocardial depression by epinephrine exposure T3 accelerated the intracellular calcium transients and reduced diastolic calcium. Triiodothyronine increased the shortening amplitude and the force amplitude (p < 0.01). Triiodothyronine reverses depressed contractile performance after preceding high-dose epinephrine exposure in isolated porcine myocardium. Increased force amplitudes and unaltered or even reduced intracellular calcium transients argue in favor of a resensitization of the contractile apparatus for calcium by T3. The study supports a potential role for T3 treatment in depressed myocardium after previous excessive catecholamine exposure (eg, brain death, catecholamine treatment, ischemia).


Surgical treatment of female stress urinary incontinence with a transobturator tape (Monarc): short-term results of a prospective multicenter study.
Transobturator tape (TOT) kits approved as medical instruments are still not available in Japan. This study aimed to: (1) assess the outcomes of TOT using Monarc (American Medical Systems; AMS Inc, Minnetonka, MN, USA) in women with stress urinary incontinence (SUI); (2) evaluate possible different surgical outcomes in women with urethral hypermobility (UH) and/or intrinsic urethral deficiency (ISD); and (3) evaluate the possibility of improvement of preoperative urgency and urge urinary incontinence after TOT in mixed urinary incontinence (MUI). Data from 140 women with SUI in a prospective multicenter study were examined at 3-6 months follow-up. 82.1% of the patients were cured and 10.7% showed improvement. The surgical outcome was significantly better in UH than in UH combined with ISD or ISD. In 44 MUI patients, 79.6% were cured and 15.9% showed improvement. Urgency improved in about 75% of patients after TOT. TOT is effective for both SUI and MUI, with urgency improving.


Postoperative drift and dose-response of strabismus surgery in thyroid eye disease: predicting desired outcomes with intraoperative adjustable sutures.
To report outcomes of strabismus surgery in thyroid eye disease using intraoperative bow-knot adjustable sutures under topical anaesthesia and calculate prediction models for surgical correction and postoperative drift depending on surgical dose-response. We retrospectively reviewed patients operated on from 2016 to 2021. A satisfactory outcome was defined as no diplopia with maintenance of vertical (<5 PD) and horizontal (<10 PD) stable alignment at primary gaze. Subjective diplopia corrected with prisms within successful motor alignment was defined as a fair result. Otherwise, the result was considered to be poor. A total of 73 patients were included (60 females, 82%). Mean preoperative horizontal and vertical deviations were 26.9 PD (19.1 SD), and 11.8 PD (7.6 SD), respectively. Mean horizontal drift was -3.2 PD (5.2 SD), whereas mean vertical drift was -3.4 PD (3.3 SD). A linear regression established a dose-response of 2.37 PD/mm for each medial rectus recession (p < 0.0001; r2 = 0.777) and 3.75 PD/mm for unilateral inferior rectus recession (p < 0.0001; r2 = 0.922). Final success rate was satisfactory in 62 patients (85%), fair in 7 patients (10%), and poor in 4 patients (5%). Muscle recession with intraoperative adjustable sutures is effective for the treatment of thyroid eye disease strabismus. Predictable dose-responses could be achieved with a drift toward overcorrection. Undercorrection proportional to the planned surgical dose should be the immediate postoperative target of choice. Other variables such as orbital decompression and concurrent vertical and horizontal surgery do not correlate with dose-response and postoperative drift. However, further studies are necessary to validate our findings.


Ocular and biochemical abnormalities in gyrate atrophy of the choroid and retina.
Patients with gyrate atrophy of the choroid and retina have myopia, constricted visual fields, elevated dark adaptation thresholds, small or nondetectable ERGs, and chorioretinal atrophy. Biochemical abnormalities include hyperornithinemia, hypolysinemia, hyperornithinuria, an unknown amino compound in the urine, and virtual absence of OKT activity in extracts of cultured skin fibroblasts. Extracts of cultured skin fibroblasts from one patient studied in our laboratory showed an increase in OKT activity with increasing concentrations of vitamin B6 in the assay medium; this patient also showed some biochemical responsiveness within three weeks to 300 mg/day or orally administered vitamin B6. Three patients whose fibroblasts did not show increased OKT activity in vitro with increasing vitamin B6 did not respond in vivo to 300 mg/day of vitamin B6 over the same period. All four patients continue to be evaluated with larger doses of this vitamin. It remains to be established if long-term treatment with vitamin B6 will stabilize the course of the chorioretinal degeneration for at least some patients with this disease.


Evaluation of anti-infective potential of a tribal folklore Odina wodier Roxb against some selected microbes and herpes simplex virus associated with skin infection.
To evaluate the in vitro antimicrobial activity of aqueous and methanol extracts of Odina wodier bark (OWB), a folk medicine, against representative bacteria, fungi and herpes simplex virus (HSV) associated with skin infections. The OWB extract(s) was found to inhibit the isolates of Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli at an MIC of 256-5000 μg ml(-1) and Candida albicans at and above 4000 μg ml(-1) by agar and broth dilution assays. The growth curve of Staph. aureus revealed the highest activity within 2-6 h of methanol extract (ME) exposure. Interestingly, the MTT and plaque reduction assay showed that the extracts can inhibit HSV-1 and HSV-2 at EC50 of 22·4 and 28·8 μg ml(-1) , with Selectivity index of 11·7-15. While the time kinetic and binding assays demonstrated that the ME at 50 μg ml(-1) prevents viral attachment into Vero cells. Phytochemical and HPLC analysis of ME revealed the presence of flavonoids, phytosterols, saponins and tannins including the pseudotannin chlorogenic acid. The traditional use of OWB for the management of skin infections has scientific basis. This study demonstrated the antimicrobial potential of OWB on selected isolates of bacteria, fungi and HSV, associated with skin infections.


Kissing balloon or sequential dilation of the side branch and main vessel for provisional stenting of bifurcations: lessons from micro-computed tomography and computational simulations.
This study sought to evaluate post-dilation strategies in bifurcation stenting. In bifurcation stenting practice, it is still controversial how post-dilation should be performed and whether the kissing balloon (KB) technique is mandatory when only the main vessel (MV) receives a stent. A series of drug-eluting stents (DES) (n = 26) were deployed in a coronary bifurcation model following a provisional approach. After the deployment of the stent in the MV, post-dilation with the KB technique was compared with a 2-step, sequential post-dilation of the side branch (SB) and MV without kissing. The percentage of the SB lumen area free of stent struts was similar after KB (79.1 ± 8.7%) and after the 2-step sequence (74.4 ± 11.6%, p = 0.25), a considerable improvement compared with MV stenting only without dilation of the stent at the SB ostium (30.8 ± 7.8%, p < 0.0001). The rate of strut malapposition in the ostium was 21.3 ± 9.2% after KB and 24.9 ± 10.4% after the 2-step sequence, respectively, a significant reduction compared with a simple SB dilation (55.3 ± 16.8%, p < 0.0001) or MV stenting only (47.0 ± 8.5%, p < 0.0005). KB created a significant elliptical overexpansion of the MV lumen, inducing higher stress concentration proximal to the SB. KB also led to a higher risk of incomplete stent apposition at the proximal stent edge (30.7 ± 26.4% vs. 2.8 ± 9.6% for 2-step, p = 0.0016). Sequential 2-step post-dilation of the SB and MV may offer a simpler and more efficient alternative to final KB technique for provisional stenting of bifurcations.


Biochemical and immunocytochemical characterization of GRIP, a putative AMPA receptor anchoring protein, in rat brain.
The mechanisms by which glutamate receptors are concentrated in brain excitatory synapses are believed to involve interactions between receptor subunits and postsynaptic anchoring or scaffolding proteins. Recently GRIP, a protein containing seven PDZ domains, was identified as an AMPA receptor binding protein and implicated in the synaptic targeting of AMPA receptors. Here we show that GRIP mRNA is also expressed in some tissues outside of the brain, including testis and kidney. Specific antibodies were raised to study GRIP protein. On Western blots, GRIP protein appears as a heterogeneous band (approximately 130 kilodaltons) which is expressed in widespread brain regions and throughout postnatal development. Biochemical studies reveal that GRIP is largely membrane associated and enriched in the postsynaptic density (PSD), though not as highly concentrated in the PSD as is PSD-95. By immunohistochemistry, GRIP is distributed in a somatodendritic pattern in neurons of adult rat brain, with especially prominent expression in a subset of interneurons.


Adherence to support pessary in the treatment of pelvic organ prolapse: a retrospective study conducted among 1,371 women.
The objective was to investigate the adherence to pessary treatment in women with pelvic organ prolapse (POP) who were found eligible for this treatment by the urogynecologist, at the first visit at the Department of Gynecology and Obstetrics, Odense University Hospital. Data were extracted from the women's medical records. Frequency tabulations were performed to describe the women's reasons for pessary discontinuation by age group. Binominal logistic regression analysis was conducted to investigate how women's age, POP characteristics, urogynecological history, and their pessary experience and management were associated with continued pessary use. This study included 1,371 women treated with support pessary. Of these, 850 women continued pessary treatment and 521 women underwent surgical treatment. A history of hysterectomy (OR: 0.68, 95% CI: 0.51-0.90, p = 0.008), urinary incontinence (OR: 0.71, 95% CI: 0.56-0.89, p = 0.003), and previous pessary use (OR: 0.75, 95% CI: 0.56-0.99, p = 0.047) were significant factors associated with discontinuation. Further, women aged 81-99 years were significantly more likely to continue pessary treatment (OR: 1.77, 95% CI: 1.15-2.74, p = 0.009). "POP surgery," "prolapse stage," and "prolapse predominant compartment" were not associated with discontinuation. Approximately 38% of women aged 26-54 years discontinued owing to personal preference. Hysterectomy, incontinence, and previous pessary use are significant predictors of pessary discontinuation. Increasing age is significantly associated with pessary continuation.


Ultrasound-based liver elastography: current results and future perspectives.
Chronic liver disease affects 185 million population worldwide. It encompasses a heterogenous disease spectrum, but all can lead to the development of liver fibrosis. The degree of liver fibrosis is not only a prognosticator, but has also been used to guide the treatment strategy and to evaluate treatment response. Traditionally, staging of liver fibrosis is determined on histological analysis using samples obtained from an invasive liver biopsy. Ultrasound-based liver elastography is a non-invasive method of assessing diffuse liver disease in patients with known chronic liver disease. The use of liver elastography has led to a significant reduction in the number of liver biopsies performed to assess the severity of liver fibrosis and a liver biopsy is now reserved for only select sub-groups of patients. The aim of this review article is to discuss the key findings and current evidence for ultrasound-based elastography in diffuse liver disease as well as the technical challenges and to evaluate the potential research direction.


Low lumbar multifidus muscle status and bone mineral density are important risk factors for adjacent segment disease after lumbar fusion: a case-control study.
The quantity and quality of the paraspinal muscles are important factors that lead to spinal diseases. However, the role of paraspinal muscles in the pathogenesis of adjacent segment disease (ASD) after lumbar fusion surgery is rarely studied. The purpose of the research is to investigate the relationship between paraspinal muscles and ASD. Thirty-three patients with ASD were included, and 33 controls without ASD were matched according to the basic demographic information. Cross-sectional images of the paraspinal muscles at each intervertebral disk level (L1-S1) before the first operation were analyzed, and the cross-sectional area (CSA) and degree of fat infiltration (FI) of the multifidus (MF) muscle and the erector spinae muscle were compared. There was no significant difference in demographic characteristics (P > 0.05) except for the bone mineral density (BMD) (P = 0.037) between the two groups. There were significant differences in the CSA and FI of the lower lumbar multifidus (P < 0.05). The CSA of the MF muscle at L3-L4, FI of the MF muscle at L4-L5 and L5-S1 and BMD were important risk factors for ASD. Among patients who received two-segment fusion for the first time, significant difference was observed in the degree of FI of the MF muscle in the lower lumbar segment (P < 0.05). The CSA, FI and BMD of the lower lumbar MF muscle were closely related to the occurrence of ASD. The CSA of the MF muscle at L3-L4, the degree of FI of the MF muscle at L4-L5 and L5-S1 and BMD were important risk factors for ASD. The number of fusion segments in the first operation has a certain impact on the above-mentioned conclusions.


A heat shock protein gene, CsHsp45.9, involved in the response to diverse stresses in cucumber.
Heat shock proteins (Hsps) are a family of highly conserved proteins present in all organisms. They mediate a range of cytoprotective functions as molecular chaperones and are recently reported to regulate the immune response. Using suppression subtractive hybridization, we isolated and characterized a cucumber cDNA, designated CsHsp45.9, which encodes a putative heat shock protein of 45.9 kDa protein, containing three conserved DnaJ domains belonging to the Type I Hsp40 family. Real-time quantitative RT-PCR analysis revealed that CsHsp45.9 was significantly induced in cucumber leaves inoculated with downy mildew (Pseudoperonospora cubensis) in this incompatible interaction. Gene expression was also strongly up-regulated by various abiotic stresses. CsHsp45.9 was mainly expressed in flowers with a flower-specific, stamen- and pistil-predominant expression pattern. This suggests that CsHsp45.9 harbors broad-spectrum responses to both biotic and abiotic stresses and may play a role in downy mildew resistance in cucumber.


Downregulation of DLGAP1-Antisense RNA 1 Alleviates Vascular Endothelial Cell Injury Via Activation of the Phosphoinositide 3-kinase/Akt Pathway Results from an Acute Limb Ischemia Rat Model.
This study aimed to investigate the effect of long non-coding RNA (lncRNA) DLGAP1 antisense RNA 1 (DLGAP1-AS1) on vascular endothelial cell (VEC) injury via the phosphoinositide 3-kinase (PI3K)/Akt pathway in rat models of acute lower limb ischaemia-reperfusion (I/R). Differentially expressed lncRNAs related to I/R were screened using the gene expression omnibus database. Acute lower limb I/R models were induced in male Wistar rats, in which the regulatory mechanisms of DLGAP1-AS1 silencing were analysed after the treatment of small interfering RNA (siRNA) against DLGAP1-AS1 or an inhibitor of the PI3K/Akt pathway. The relationship between DLGAP1-AS1 and the PI3K/Akt pathway was analysed. The levels of tumour necrosis factor (TNF)-α and vascular cell adhesion molecule-1 (VCAM-1), as well as malondialdehyde (MDA) concentration and creatine kinase (CK) activity, were measured. The number of circulating endothelial cells (CECs) and apoptosis of VECs were identified. Microarray based analysis indicated that DLGAP1-AS1 was highly expressed in I/R, which was further confirmed by detection of expression in rat models of acute lower limb I/R. Notably, the treatment of siRNA against DLGAP1-AS1 led to the activation of the PI3K/Akt pathway. In response to siRNA against DLGAP1-AS1, the levels of TNF-α and VCAM-1 were decreased, and MDA concentration and CK activity was downregulated. Reduced CEC numbers and suppressed VEC apoptosis were also observed. DLGAP1-AS1 silencing could further suppress the oxidative stress, exert an anti-apoptosis effect, and reduce inflammatory reaction, whereby VEC injury is alleviated by activation of the PI3K/Akt pathway in rats with acute lower limb I/R.


Early development of sensitivity to radial motion at different speeds.
We examined the sensitivity of 2- and 3-month-old infants to radial expansion/contraction at various speeds. The stimuli comprised one radial motion pattern (expansion or contraction) and one translational motion pattern (up, down, left or right; counterbalanced across infants) placed side by side. The two patterns in each stimulus had the same speed. Three-month-old infants could discriminate between radiation and translation, even under relatively low speeds (5.31 and 2.66 degrees /s), whereas discrimination between the two patterns by 2-month-old infants was very limited. Thus, the range of speeds at which infants can detect radial expansion/contraction changes extensively between 2 and 3 months of age. This change in radial motion sensitivity may reflect the development of cortical motion mechanisms in the dorsal pathway, which is specialised to detect radial motion.


Surface wettability and energy effects on the biological performance of poly-3-hydroxybutyrate films treated with RF plasma.
The surface properties of poly-3-hydroxybutyrate (P3HB) membranes were modified using oxygen and an ammonia radio-frequency (RF, 13.56 MHz) plasma. The plasma treatment procedures used in the study only affected the surface properties, including surface topography, without inducing any significant changes in the crystalline structure of the polymer, with the exception being a power level of 250 W. The wettability of the modified P3HB surfaces was significantly increased after the plasma treatment, irrespective of the treatment procedure used. It was revealed that both surface chemistry and surface roughness changes caused by the plasma treatment affected surface wettability. A treatment-induced surface aging effect was observed and resulted in an increase in the water contact angle and a decrease in the surface free energy. However, the difference in the water contact angle between the polymers that had been treated for 4 weeks and the untreated polymer surfaces was still significant. A dependence between cell adhesion and proliferation and the polar component of the surface energy was revealed. The increase in the polar component after the ammonia plasma modification significantly increased cell adhesion and proliferation on biodegradable polymer surfaces compared to the untreated P3HB and the P3HB modified using an oxygen plasma.


An anti-glioblastoma gold(i)-NHC complex distorts mitochondrial morphology and bioenergetics to induce tumor growth inhibition.
Glioblastoma multiforme (GBM) is the most lethal brain cancer subtype, often advanced by the time of initial diagnosis. Existing treatment modalities including surgery, chemotherapy and radiation have been stymied by recurrence, metastasis, drug resistance and brain targetability. Here, we report a geometrically distinct Au(i) complex ligated by N^N-bidentate ligands and supported by a N-heterocyclic ligand that modulates mitochondrial morphology to inhibit GBM in vitro and in vivo. This work benefits from the facile preparation of anti-GBM Au(i)-NHC complexes.


Interactive effects of nutrition, reproductive state and pollution on molecular stress responses of mussels, Mytilus galloprovincialis Lamarck, 1819.
Marine bivalves including mussels Mytilus galloprovincialis are commonly used as sentinels for pollution monitoring and ecosystem health assessment in the coastal zones. Use of biomarkers to assess the pollution effects assumes that the effects of pollutants on the biomarkers exceed the natural background variability; yet this assumption has rarely been tested. We exposed mussels at different reproductive stages and nutritive states to two concentrations of a polycyclic aromatic hydrocarbon (fluoranthene, 3 and 60 μg L-1) for three weeks. Expression levels of the molecular biomarkers related to the detoxification and general stress response [cytochrome P450 oxidase (CYP450), glutathione S-transferases (GST-α; GST-S1; GST-S2), the multixenobiotic resistance protein P-glycoprotein (PgP), metallothioneins (MT10 and MT20), heat shock proteins (HSP22, HSP70-2; HSP70-3; HSP70-4), as well as mRNA expression of two reproduction-related genes, vitellogenin (Vitel) and vitelline coat lysin M7 (VCLM7)] were measured. The mussels' nutrition and reproductive state affected the baseline mRNA levels of molecular biomarkers and modulated the transcriptional responses of biomarker genes to the pollutant exposure. Thus, mussel physiological state could act as a confounding factor in the evaluation of the response of pollution through molecular biomarkers. The biomarker baseline levels must be determined across a range of physiological states to enable the use of biomarkers in monitoring programs.


Biological evaluation and structure-activity relationships of bis-(3-aryl-3-oxo-propyl)-methylamine hydrochlorides and 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinol hydrochlorides as potential cytotoxic agents and their alkylating ability towards cellular glutathione in human leukemic T cells.
Various bis (3-aryl-3-oxo-propyl)methylamine hydrochlorides 1 and their corresponding structural and non-classical isomers 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinols 3 were evaluated against human leukemic T (Jurkat) cells and found to possess significant cytotoxicity. Among the series 1 (bis-Mannich bases) and 3 (corresponding piperidinols), compounds la, 1c and 1e showed cytotoxic potency which was approximately 1.6, 3.7 and 3.4 times that of the reference drug 5-fluorouracil, respectively. Except for compound 1d, conversion of bis-Mannich bases to their corresponding piperidinols 3a, 3b and 3e lowered the potency. Besides chloro derivative 1d, bis-Mannich bases displayed greater cytotoxicity compared with their mono-Mannich bases, series 5. Representative bis-Mannich bases (1a, 1e) and piperidinols (3a, 3e) decreased the glutathione level of Jurkat cells. Molecular modeling was utilized in order to evaluate whether the shape, size, critical volume, solvent accessible area and partition coefficient of the different compounds had contributed to the varying potencies observed. Bis-Mannich bases 1a, 1c and 1e may serve as candidate anticancer agents for future development.


Endostatin inhibits VEGF-A induced osteoclastic bone resorption in vitro.
Endostatin is a C-terminal fragment of collagen XVIII which is a component of basement membranes with the structural properties of both collagens and proteoglycans. Endostatin has a major role in angiogenesis which is intimately associated with bone development and remodeling. Signaling between the endothelial cells and the bone cells, for example, may have a role in recruitment of osteoclastic precursor cells. Our study aims at exploring a possibility that endostatin, either as a part of basement membrane or as a soluble molecule, may control osteoclastogenesis and osteoclastic bone resorption in vitro. Rat pit formation assay was employed in order to examine the effect of endostatin alone or in combination with vascular endothelial growth factor-A (VEGF-A) on bone resorption in vitro. Effect of these agents on osteoclast differentiation in vitro was also tested. Osteoclastogenesis and the number of osteoclasts were followed by tartrate resistant acid phosphatase (TRACP) staining and resorption was evaluated by measuring the area of excavated pits. Endostatin inhibited the VEGF-A stimulated osteoclastic bone resorption, whereas endostatin alone had no effect on the basal resorption level in the absence of VEGF-A. In addition, endostatin could inhibit osteoclast differentiation in vitro independent of VEGF-A. Our in vitro data indicate that collagen XVIII/endostatin can suppress VEGF-A induced osteoclastic bone resorption to the basal level. Osteoclastogenesis is also inhibited by endostatin. The regulatory effect of endostatin, however, is not critical since endostatin alone does not modify the basal bone resorption.


[Contribution of genetic and environmental factors in the phenotypic variability of major indices of child development at different stages of postnatal ontogenesis].
Main indices of physical development of monozygotic and dizygotic twins were investigated during 13 years period. Using the coefficients of the within-pair correlation of characters studied an attempt was made to estimate the correlative contribution of genetic and environmental determinants to formation of phenotypic variance of height, weight and chest circumference from birth up to 13 years old. The indices of composing components obtained suggest that underlying formation of phenotypic variance of each of the characters analysed are the mechanisms reflecting qualitative, quantitative and time peculiarities of functioning of polygenic systems involved in determination of characters studied and peculiarities of their interaction with environmental factors.


Primary Liver Cancer: An NCDB Analysis of Overall Survival and Margins After Hepatectomy.
Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) constitute the majority of primary liver cancers. This retrospective review aimed to determine whether site of care is a significant predictor of patient outcome after hepatectomy as measured by overall survival, hazard ratios (HRs), and resection margin status. Data regarding patients with a new diagnosis of ICC and HCC who underwent hepatectomy were analyzed from the national cancer database. The patients were divided into two cohorts: those receiving treatment at academic cancer centers (ACCs) and those receiving treatment at community cancer centers (CCCs). The study adjusted for confounding variables and selection bias using propensity score matching. Median overall survival (months), hazard ratios, and resection margin status (R0, R1/R2, unknown) were examined. The inclusion criteria were met by 10,463 patients. After propensity matching, 5600 patients remained, with half receiving treatment at ACCs and half at CCCs. Median overall survival from the date of diagnosis for patients undergoing hepatectomy was longer at ACCs than at CCCs (28.3 vs 24.8 months; p < 0.001). Additionally, multivariable Cox proportional hazards models showed that treatment at CCCs was associated with poorer survival than treatment at ACCs (HR, 1.226; 95% confidence interval [CI], 1.142-1.316; p < 0.0001). Treatment facility designation also was a predictive indicator of resection margin status, with patients at CCCs exhibiting higher odds of R1/R2 resections (odds ratio [OR], 1.41; 95% CI, 1.19-1.67; p < 0.0001). Hepatectomy for ICC and HCC performed at ACCs was associated with improved outcomes compared with CCCs. Centralization of care to ACCs may lead to improved patient outcomes.


The level of anxiety, depression and quality of life among patients with heart failure in Greece.
The assessment of the level of anxiety, depression and quality of life among patients with heart failure. It was an observational study. The populations were 231 patients with heart failure who were hospitalized in cardiology departments of 2 general hospitals in Athens, from September 1, 2010 through January 31, 2012. We used the "Minnesota Living with Heart Failure Questionnaire - MLHFQ" to evaluate patients' quality of life and the " State-Trait Anxiety Inventory - STAI" and the "Maastricht Questionnaire - MQ" to evaluate the level of stress and depression, respectively. The mean age of patients was 66.1±10.1years. The quality of life was poor, since the average score in MLHFQ was 65.4±20.6. Also, patients revealed high levels of both trait and state anxiety (mean score in STAI was 54.5±9.4 and 52.8±8.5 respectively) and depression (mean score in MQ was 34.3±8.4). Factors associated with poor quality of life and high levels of anxiety and depression were older age, low level of education, unemployment, poor economic situation, multiple hospitalizations (> 4 times) and heart failure stages III and IV in NYHA (p<0.001 in all cases). Patients with heart failure present severe symptoms of anxiety and depression and poor quality of life. Assessing those patients for these symptoms and providing holistic health care by a multidisciplinary team, will lead to the prevention and early treatment not only of physical but also of the psychosocial manifestations of the disease.


Reactive oxygen species explicit dosimetry to predict local tumor growth for Photofrin-mediated photodynamic therapy.
Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to calculate reactive oxygen species concentration ([ROS]rx) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Singlet oxygen is the primary cytotoxic species for ROS, which is responsible for cell death in type II PDT, although other type I ROS is included in the parameters used in our model. Using a combination of fluences (50-250 J∕cm2) and ϕ (75 or 150 mW∕cm2), tumor regrowth rate, k, was determined for each condition by fitting the tumor volume versus time to V0 *exp(k*t). Treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Explicit dosimetry of light fluence rate on tissue surface, tissue oxygen concentration, tissue optical properties, and Photofrin concentration were performed. Light fluence rate at 3 mm depth (ϕ 3mm) was determined for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Initial tissue oxygenation [3 O 2]0 was measured by an Oxylite oxygen probe before PDT and used to calculate [ROS]rx,calc. This value was compared to [ROS]rx,meas as calculated with the entire tissue oxygen spectrum [3 O 2](t), measured over the duration of light delivery for PDT. Cure index, CI = 1-k/kctr , for tumor growth up to 14 days after PDT was predicted by four dose metrics: light fluence, PDT dose, and [ROS]rx,calc, and [ROS]rx,meas. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ at a 3 mm tumor depth. These studies show that [ROS]rx,meas best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome.


Highly mobile pedunculated left atrial appendage thrombus falling into the mitral valve orifice.
We treated two patients with atrial fibrillation and stringlike left atrial appendage thrombus: a 66 year-old man who had apical hypertrophic cardiomyopathy and a 86 year-old woman with no underlying heart disease. In the patient with hypertrophic cardiomyopathy, transesophageal echocardiography showed a highly mobile stringlike echo protruding from the left atrial appendage and sometimes falling into the mitral orifice. Pathologic examination after excision proved the stringlike echo to be a pedunculated structure composed of red and white thrombi. Excision of thrombus was also planned for the woman, who had a history of recurrent cerebral embolism. Because her cerebral CT showed infarction with bleeding, however, surgery was postponed. The stringlike mobile thrombus was not detected by transesophageal echocardiography 1 month later, when a new embolic episode affected a foot. Clinical outcomes of these two patients differed remarkably. The critical findings by transesophageal echocardiography which facilitated differential diagnosis from cardiac tumors were: spontaneous contrast echo accompanying mural thrombuslike echo, and low flow velocity in the left atrial appendage. However, the differential diagnosis may be quite difficult in cases of tumors associated with atrial fibrillation.


Diterpene and biflavone derivatives from Thuja koraiensis and their cytotoxicities against A549 cells.
During the screening of the cytotoxicity of rare Korean endemic plants, the extract of Thuja koraiensis Nakai displayed potent cytotoxicity against the adenocarcinomic human alveolar basal epithelial A549 cell line. Through a series of separations via column chromatography, three undescribed abietanes, an undescribed labdane along with a labdane, and a biflavonoid were purified from methylene chloride (CH2Cl2) fraction possessing a potent cytotoxic effect. Extensive 1D and 2D NMR spectroscopic data analyses, in combination with quantum chemical calculations were conducted to establish the planar and absolute configurations of thujakoraienes A-C. The chemical structure of thujakoraiene D was elucidated by spectroscopic data analysis and competing enantioselective acylation. Thujakoraienes A and C along with 7,7″-di-O-methylamentoflavone, showed cytotoxic effects on A549 cells, with IC50 values of 64.86, 47.97, and 16.14 μM, respectively. Finally, thujakoraiene C and 7,7″-di-O-methylamentoflavone were identified as potent cytotoxic compounds in A549 cells, followed by an additional cytotoxicity test in the normal human lung fibroblast MRC-5 cell line. This is the first study on the non-volatile chemicals in the extract of T. koraiensis and comparison of chemical profiles of T. orientalis and T. koraiensis.


[Autism in adults with intellectual disabilities].
According to the World Health Organization (WHO) the estimated prevalence of intellectual disabilities (ID) is about 1-3% and 1 out of 4 individuals with ID suffer from an additional autistic spectrum disorder (ASD) (arithmetic mean 24.6%, 19 studies, n=9,675) whereby the prevalence increases with the severity of ID (IQ 50-70: 9.9%, IQ<50: 31.7%). Therefore, it is of particular importance for physicians treating individuals with ID who have psychiatric disorders or behavioral problems to take ASD into account as a differential diagnosis so that appropriate treatment can be initiated.Irrespective of the IQ the diagnosis is based on an impairment of social interaction and communication and restricted repetitive interests presenting before the age of 3 (infantile or Kanner autism). ASD can be diagnosed as a separate disorder in adults with ID, however, the social and communicative abilities in respect of the cognitive and developmental level have to be considered.Due to reduced verbal capacity, high prevalence of physical and mental disorders, difficulties in taking the past medical history and presentation of atypical symptoms, the diagnostic assessment for autism in adults with ID is challenging.This article describes the typical symptoms, diagnostic approach, frequent comorbidities, differential diagnoses treatment options and their limitations for adults with ID suspected of having ASD.


A bacteriophytochrome regulates the synthesis of LH4 complexes in Rhodopseudomonas palustris.
The non-sulphur purple bacterium Rhodopseudomonas palustris contains five pucAB genes for peripheral light-harvesting complexes. Bacteria grown under high-light conditions absorb at 800 and 850 nm but in low-light the 850 nm peak is almost absent and LH2 complexes are replaced by LH4. The genome contains six bacteriophytochromes (Bph). Bphs sense light in the red/far-red through a reversible Pr to Pfr transformation that controls gene expression. Bph3 (RPA1537) controls the expression of a cluster of photosynthetic genes, however most of the peripheral light harvesting complex genes are outside of this region. The pucAB-d genes encode LH4 peptides and are near two Bphs (RPA3015, RPA3016). We have characterised three Bphs and show that Bph4 RPA3015 and Bph3 RPA1537 have different dark stable states. It is known that Bph3 is active in its red absorbing Pr form and suggests a working hypothesis that Bph4 is active in the Pfr state. We show that LH4 expression can be induced with red light at the Pr absorption maximum (708 nm) of Bph4. The property of light transmission of water maybe an important factor in understanding this adaptation. Bph4 can sense the reduction in light intensity indirectly through an increase in ratio of transmitted red/far-red light. The red right activated Bph4 regulates the synthesis of LH4 which concentrates bacteriochlorophyll a pigment absorption at 800 nm to exploit a recovery in water light transmission in this region.


Improving the analysis of adverse event data in randomized controlled trials.
Analyzing treatment harm is vital but problematic with the relatively small sample sizes afforded in randomized controlled trials (RCTs). Good analysis practice for efficacy outcomes are well established but there has been minimal progress for the analysis of adverse events (AEs). In this commentary we examine four key issues for AE analysis. Namely, why harm data in RCTs is undervalued, why AE analysis is difficult, what aspects of current analysis practice are unsatisfactory, and the challenges for selection and interpretation of AEs results in publications. We discuss how the value of harm data from RCTs could be better realized by reframing the research question to one for detecting signals of adverse reactions. We align established good statistical practice to current unsatisfactory practice. We encourage use of Bayesian analyses to enable cumulative assessment of harm across trial research phases and discourage selecting AEs to report based on arbitrary rules. We propose comprehendible summaries to be based on core outcome sets, serious and pre-specified events, and events leading to discontinuation. Analysis of AEs in contemporary clinical trials needs attention to progress. In the following we have outlined immediate, mid and longer-term strategies for trialists to adopt to support a change in practice.


Peripheral pathways mediating salivary secretion after nucleus parvocellularis activation in the rat.
The present study demonstrates that activation of the nucleus parvocellularis in the pontine reticular formation of the rat evokes salivary hypersecretion. The secretory effect observed was found to be mediated by parasympathetic mechanisms, as transection of the preganglionic parasympathetic salivatory fibers at the level of the middle ear blocked the flow of saliva evoked by activation of the nucleus parvocellularis (Experiment 1). Furthermore, transection of these salivatory fibers was followed several days later by the development of a prandial model of drinking. These behavioral data suggest that the transection procedure employed in the present study indeed affected those parasympathetic fibers which control the secretory activity of all three pairs of major salivary glands (Experiment 2).


Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency.
The molecular mechanisms by which PROS1 mutations result in protein S deficiency are still unknown for many of the mutations, particularly for those that result in a premature termination codon. The aim of this study was to analyze the functional relevance on mRNA and protein expression of 12 natural PROS1 mutations associated with protein S deficiency. Five mutations were nonsense, three were small frameshift deletions, one was c.258,259AG>GT at the 3' end of exon 3, one was p.M640T and the last two were c.-7C>G and p.L15H, found in double heterozygosis as [c.-7C>G;44T>A]. The apparently neutral variant p.R233K was also analyzed. PROS1 cDNA was assessed by reverse transcriptase polymerase chain reaction of platelet mRNA. Expression of mutant proteins was determined by site-directed mutagenesis and analyses of transiently transfected PROS1 mutants in COS-7 cells. Only cDNA from the normal allele was observed from the five nonsense mutations, the frameshift deletion c.1731delT and from c.258,259AG>GT. Both the normal and the mutated alleles were observed from [c.-7C>G;44T>A], c.187,188delTG and p.M640T. Transient expression analyses of PROS1 mutants whose mRNA was normally expressed revealed greatly reduced secretion of p.L15H and c.1272delA, mild secretion values of p.M640T and normal secretion levels of c.-7C>G and, as expected, p.R233K. Whereas the main cause of quantitative protein S deficiency associated with missense mutations is defective synthesis, stability or secretion of the mutated protein, the main mechanism for the deficiency associated with mutations that generate a premature termination codon is not the synthesis of a truncated protein, but the exclusion of the mutated allele, probably by nonsense-mediated mRNA decay.