Neurophysiological aspects of auditory hallucinations. 99mTc-(HMPAO)-SPECT investigations in patients with auditory hallucinations and normal controls--a preliminary report.
In a symptom-oriented study 17 patients suffering from chronic auditory hallucinations were investigated by means of 99mTc-HMPAO-SPECT and compared with healthy controls. The results confirm the relative frontal hypoactivity in junction with a relative hyperactivity in the basal ganglia and mesial limbic structures in both hemispheres found in a previous pilot study in auditorily hallucinating patients. Our results should fortify the symptom-oriented approach in psychiatric research.


Activities of enzymes of the hexose monophosphate pathway in nervous system tumors induced by ethylnitrosourea.
The activities of three enzymes of the hexose monophosphate pathway (HMP) were measured in frozen samples of rat cerebral cortex and ethylnitrosourea-induced tumors of the rat nervous system. Results show that in most tumors, adequate amounts of glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), and transketolase (TK) were present so as not to be rate-limiting for utilization of the HMP. When enzyme activites were expressed on the basis of fresh weight, TK was increased in most tumors as compared with cerebral cortex; G6PDH and 6PGDH were more variable, showing either higher or lower activities in tumors as compared to control. Tumors in general had a lower protein content than cerebral cortex. When activities were expressed in terms of this protein content, mean values for the dehydrogenases in all groups of tumors were higher than the average value in cortex, indicating that G6PDH and 6PGDH were spared in tumors relative to other proteins. TK activities in tumors, expressed in terms of cytosol protein were lower than or in the same range as cortex. Increased activities of HMP enzymes in some tumors indicated that the potential activity of the HMP in some (but not all) tumors of the nervous system is greater than that of cerebral cortex.


X-ray structure analysis of the sodium salt of beijeran.
The three-dimensional structure of the sodium salt of beijeran has been determined by X-ray fiber diffraction analysis. The acidic polysaccharide forms an extended twofold helix. Two chains are nestled tightly in a monoclinic unit cell of dimensions a=12.72, b=11.41, c (fiber axis)=24.62 A and gamma=123.7 degree in an antiparallel fashion. In the crystalline lattice, helices are stacked tightly to form a thick sheet along the vertical plane passing through the short diagonal of the basal net. Adjacent sheets associate via a network of sodium ions and water molecules embedded between them. The morphology of sodium beijeran in the solid state is consistent with its observed rheological properties.


The sleep hormone oleamide modulates inhibitory ionotropic receptors in mammalian CNS in vitro.
1. We examine the sensitivity of GABA(A) and glycine receptors (same ionotropic superfamily) to oleamide. We address subunit-dependence/modulatory mechanisms and analogies with depressant drugs. 2. Oleamide modulated human GABA(A) currents (alpha(1)beta(2)gamma(2L)) in oocytes (EC(50), 28.94+/-s.e.mean of 1.4 microM; Maximum 216%+/-35 of control, n=4). Modulation of human alpha1 glycine homo-oligomers (significant), was less marked, with a lower EC(50) (P<0.05) than GABA receptors (EC(50), 22.12+/-1.4 microM; Maximum 171%+/-30, n=11). 3. Only the hypnogenic cis geometric isomer enhanced glycine currents (without altering slope or maximal current, it reduced the glycine EC(50) from 322 to 239 microM: P<0.001). Modulation was not voltage-dependent or associated with a shift in E(r). 4. beta 1 containing GABA(A) receptors (insensitive to many depressant drugs) were positively modulated by oleamide. Oleamide efficacy was circa 2x greater at alpha(1)beta(1)gamma(2L) than alpha(1)beta(2)gamma(2L) (P=0.007). Splice variation in gamma subunits did not alter oleamide sensitivity. 5. cis-9,10-Octadecenoamide had no effect on the equilibrium binding of [(3)H]-muscimol or [(3)H]-EBOB to mouse brain membranes. It does not directly mimic GABA, or operate as a neurosteroid-, benzodiazepine- or barbiturate-like modulator of GABA(A)-receptors. 6. The transport of [(3)H]-GABA into mouse brain synaptoneurosomes was unaffected by high micromolar concentrations of cis-9,10-octadecenoamide. Oleamide does not enhance GABA-ergic currents or prolong IPSCs by inhibiting GABA transport. 7. Oleamide is a non-selective modulator of inhibitory ionotropic receptors. The sleep lipid exerts its effects indirectly, or at a novel recognition site on the GABA(A) complex.


How accurate are manufacturers' recommendations in determining ineligibility for transfemoral transcatheter aortic valve implantation?
Up to one-third of patients indicated for transcatheter aortic valve implantation (TAVI) may be unsuitable for transfemoral TAVI (TF-TAVI) according to manufacturers' recommendations and numerous professional societies. This study aimed to investigate the predictive value of manufacturers' guidelines for major vascular access site complications using the Perclose ProGlide device. Among 208 patients undergoing TF-TAVI, 144 patients (69.2%) were deemed eligible for TF-TAVI according to the manufacturer's instructions. A minimal lumen diameter (MLD) of the femoral artery below the manufacturer's specified limits and/or the presence of circumferential calcification were the reasons for ineligibility. Calcium score (CS), sheath-to-femoral artery ratio (SFAR) and MLD were estimated from computed tomography imaging. Vascular complications (VCs) (defined according to VARC-2 criteria) were retrospectively compared. Patients in the ineligible group had higher SFAR (1.13±0.15 vs. 0.88±0.107, p<0.001) and CS (1.66±0.99 vs. 1.24±0.73; p=0.003), and significantly lower MLD (7.72±1.03 vs. 6.31±0.96 mm; p<0.001) compared to the eligible group. Major (6.3% vs. 12.3%, p=0.13) and minor VCs (10.4% vs. 15.6%, p=0.29) were similar in the eligible and ineligible groups. The ineligible group had higher rates of rupture (0.7% vs. 6.3%; p=0.03). SFAR was the only independent predictor of major VCs (OR 469.1, 95% CI 4.95-44466.57, p=0.008). The TAVI team should not decide whether the patient is suitable for a femoral approach based solely on the manufacturer's criteria, and should incorporate additional factors that could be predictive of major VCs.


Effect of MDR1 polymorphisms on the blood concentrations of tacrolimus in Turkish renal transplant patients.
Tacrolimus, a calcineurin inhibitör, is prescribed to prevent allograft rejection in renal transplantation. Tacrolimus not only has a narrow therapeutic index, but also shows significant interindividual differences. The absorption and metabolism of this drug are affected by multidrug resistance (MDR) 1 gene polymorphisms that correlated with single-nucleotide polymorphisms (SNPs) affecting in vivo P-glycoprotein activity. This study investigated associations of MDR1 gene C3435T polymorphism with tacrolimus blood concentrations and dose requirements as well as acute rejection episodes among Turkish renal transplant patients. One hundred living-donor transplant recipients and 150 healthy control subjects underwent C3435T genotyping using polymerase chain reaction-restriction fragment length polymorphism. Blood concentrations of tacrolimus were determined with the cloned enzyme donor immunoassay. The CC, CT, and TT genotype frequencies among patients were, respectively, 44.0%, 33.0%, and 23.0% versus 36.7%, 43.3%, and 20.0% among control subjects. There was no significant difference between (P = .061; P = .102; P = .211; respectively). The ratio of blood concentration to dose of tacrolimus for patients with mutant homozygous 3435 TT genotype was higher than that of wild-type 3435 CC genotype homozygous individuals. The doses for these patients were lower at 1, 3, and 12 months (P = .048; P = .03; P = .041, respectively). There were no significant differences between the groups regarding coprescription of drugs that affect tacrolimus concentrations, such as diltiazem. Acute rejection episodes were not associated with the CC vs CT or TT genotypes: odds ratio (OR), 0.517 (95% confidence interval [CI], 0.190-1.407; P = .192); OR 1.558 (95% CI, 0.587-4.136; P = .372); OR 1.346; (95% CI, 0.456-3.968; P = .590), respectively. Determination of MDR1 polymorphism may help to achieve target of tacrolimus blood concentrations.


Combined Irradiation by Gamma Rays and Carbon Nuclei Increases the C/EBP-β LIP Isoform Content in the Pituitary Gland of Rats.
C/EBP-β, a basic leucine zipper transcription factor, has important roles in the regulation of the body immune and inflammatory responses. Wistar rats subjected to combined irradiation were characterized by an increase in the content of the C/EBP-β LIP isoform in the pituitary gland. The obtained data indicate that moderate doses of ionizing radiation to initiate the endoplasmic reticulum stress response and are likely to initiate C/EBP-β-mediated cell death according to the apoptotic scenario. This study also confirms the earlier hypothesis about the alterations of the hypothalamic-pituitary-adrenocortical axis in response to moderate doses of ionizing radiation.


The use of a three-dimensional endoscope for different skull base tumors: results of a preliminary extended endonasal surgical series.
The evolution of skull base surgery over the past decade has been influenced by advancement in visualization technology. Recently, as a result of such improvements, three-dimensional (3-D) scopes have been widely used during endoscopic endonasal approaches. In the present study, we describe the use of 3-D stereoscopic endoscope for the treatment of a variety of skull base lesions. From January 2010 to June 2015, a 3-D endoscopic endonasal approach (4 and 4.9 mm, 0°, and 30° rigid endoscopes) was performed in 70 patients with the following lesions: 42 large extrasellar pituitary macroadenomas, seven tuberculum sellae meningiomas, seven clivus chordomas, five craniopharyngiomas, three fibrous dysplasia of the clivus, three sinonasal malignancies, one orbital lymphangioma, one trigeminal neurinoma, one primary suprasellar lymphoma. Total tumor removal was obtained in 50 patients (71.4 %) while in 14 (20 %), subtotal removal was possible in six (8.6 %) only partial removal was achieved. Overall complications included diabetes insipidus in eight patients (11.4 %), hypopituitarism in seven patients (10 %), CSF leak in five patients (7.1 %), cranial nerve injury in two patients (2.8 %), panhypopituitarism in two patients (2.8 %), meningitis in one (1.4 %) and one postoperative central retinal artery occlusion (1.4 %). There was no mortality in the series. The mean follow-up time was 39 months (range, 6-72 months). In our experience, the 3-D endoscope represents a critical development in visualization, thus enabling improved hand-eye coordination and depth perception, which are mandatory for the management of complex intradural neurovascular structures during tumor removal surgery.


Identification of semen in stain by determination of the specific activity of L-tartrate-inhibitable acid phosphatase.
For identification of semen in stain the specific activity of L-tartrate-inhibitable acid phosphatase (ACP) was determined. With each stain extract, both enzyme activity and protein concentration were determined, and the specific activity (enzyme activity/protein concentration) was calculated. Seminal stains showed a value of 23.8 +/- 15.2 (mean +/- SD) IU/mg protein, while vaginal fluid stains showed a value of 0.088 +/- 0.049 IU/mg protein. Stains of other body fluids did not show any L-tartrate-inhibitable ACP activity. Furthermore, only eight of 30 plant juice stains showed any levels of L-tartrate-inhibitable ACP, although all plants tested showed ACP activity. As the present method enables us to analyze forensic samples quantitatively, it seems to be useful for forensic practice.


Effect of metoprolol on blood glycerol, free fatty acids, triglycerides and glucose in relation to plasma catecholamines in hypertensive patients at rest and following submaximal work.
Studies were performed in nine male patients with moderate hypertension. Treatment with metoprolol, 50--150 mg three times daily for 4--17 weeks, had no effect on the plasma level of glycerol, free fatty acids, triglycerides or glucose under basal conditions, neither in the supine nor in the upright position. Submaximal work, performed postprandially, increased plasma glycerol before medication but not during metoprolol, in spite of a marked increase in plasma noradrenaline. The work load employed caused no change in free fatty acids, triglycerides or glucose, neither before medication nor during metoprolol.


Risk for relatives of patients with multiple sclerosis in central Sardinia, Italy.
Multiple sclerosis (MS) is a chronic, inflammatory, disabling disease of the central nervous system, known for its complex interplay between genetic and environmental factors. We used life table techniques to calculate age-adjusted recurrence risks for different categories of relatives of MS patients from Central Sardinia (Italy), a genetically homogeneous, stable population with a high degree of consanguinity. We included 313 probands and a total of 12,717 relatives in the analysis. The overall age-adjusted recurrence risk for relatives of MS probands is 1.90% [95% confidence interval (CI): 1.57-2.30]. The age-adjusted recurrence risk in parents was 1.26% (95% CI 0.60-2.63), in children 2.33% (95% CI 0.09-5.56), in sibs 4.76% (95% CI 3.57-6.32), in second-degree relatives 0.72% (95% CI 0.42-1.22), and in third-degree relatives 1.79% (95% CI 1.27-2.51). The sex of the probands (male) and of the relatives (female), and the number of affected relatives in the family significantly increase the risk of MS in relatives.


[Risk of postoperative hemorrhage in tonsillectomy. A comparison between general anesthesia and local anesthesia].
Postoperative bleeding after tonsillectomy is still a life-threatening problem. The incidence of postoperative bleeding, as well as many factors (kind of surgery, hemostasic problems) affecting this risk have been investigated. A possible factor that has not been well studied is the used anaesthetic procedure. A prospective study was completed comparing the risk of postoperative bleeding in patients operated in local vs. general anaesthesia. The study enrolled 1063 patients, who consecutively underwent tonsillectomy. In 16 (4.12%) of 388 patients operated under general and 51 (7.55%) of 675 patients operated under local anaesthesia postoperative bleeding occurred. After local anaesthesia postoperative bleeding was seen mainly at the day of operation (46 of 51), there was no late bleeding after the 6th postoperative day. After general anaesthesia in 6 of 16 cases postoperative bleeding occurred after the 6th postoperative day. Postoperative bleeding occurs more frequent in patients who underwent tonsillectomy in local anaesthesia. The risk of late postoperative bleeding however is higher with tonsillectomy in general anaesthesia.


Toward Development of Enhanced Preventive Interventions for HIV Sexual Risk among Alcohol-Using Populations: Confronting the 'Mere Pause from Thinking'.
The papers in this issue detail state-of-the science knowledge regarding the role of alcohol use in HIV/AIDS risk, as well as offer suggestions for ways forward for behavioral HIV prevention for at-risk alcohol-using populations. In light of recent evidence suggesting that the anticipated uptake of the newer biomedical HIV prevention approaches, prominently including pre-exposure prophylaxis, has been stalled owing to a host of barriers, it has become ever more clear that behavioral prevention avenues must continue to receive due consideration as a viable HIV/AIDS prevention approach. The papers collected here make a valuable contribution to "combination prevention" efforts to curb HIV spread.


5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production.
G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected.


[Disseminated intravascular coagulation in children. Therapeutic problems].
The AA, after discussion on physiopathological and clinical aspects of DIC in childhood, focused their attention mostly on the utilization of AT III concentrates.


Fetal growth rates and the very preterm delivery of twins.
Our objective was to determine whether slow fetal growth rates and twin growth patterns from 20 weeks' gestation to delivery are associated with very preterm delivery. Available charts were reviewed for twin pregnancies, delivered between 1979 and 2002, at 4 U.S. medical centers. The sample of 1612 pregnancies delivered at 28 week's gestation or greater and had at least 2 ultrasound evaluations of fetal size from 20 to 28 weeks or from 28 weeks to delivery for estimation of fetal growth rates (grams per week). Slow fetal growth (below the 10th percentile) was defined as less than 90 grams per week at 20-28 weeks and 168 g/week from 28 weeks to delivery. The main outcome measure was the timing of delivery. Of the women delivering twins, 5.3% delivered extremely preterm (28-30 weeks), 8.5% very preterm (31-32 weeks), and 40.1% preterm (33-36 weeks). Patterns of growth for the pair were highly associated with very preterm delivery. Compared with neither growing slowly (1.7%), 4.9% delivered very preterm if only 1 twin grew slowly. Very preterm was 14.6% (adjusted odds ratio 9.81; 95% confidence interval, 3.50-27.48) with both growing slowly from 28 weeks on and 20.0% (adjusted odds ratio 15.04; 95% confidence interval 5.13-44.11) with both growing slowly over both intervals. Survival analyses indicated that twins with normal growth in both intervals remained undelivered for a significantly longer number of days (P < .0001) than pairs in which one or both twins were growing slowly. Very preterm delivery of twins seems to be preceded by slowed or compromised fetal growth for the pair.


Bronchogenic cyst.
Two recent patients with bronchogenic cysts, presenting in an atypical manner, stimulated our review of this subject. Twenty patients with bronchogenic cysts have been treated at the Boston Floating Hospital over the past 20 yr. Of these patients, 19 out of 20 were symptomatic, the most common symptom being fever (6 out of 20). Half of our patients had no respiratory symptoms but only one was found to have an asymptomatic mass on chest x-ray. The majority of theses cysts were found within the pulmonary parenchyma, the right lung being affected three times more commonly than the left. These facts are at odds with the reports in the literature. Three were found in the neck. Bronchogenic cysts are generally thought to be small, solitary, and limited in area. However, a significant number in our series (8 out of 20) were large, multiple or multicystic, and involved segments, lobes, multiple lobes, and, on one occasion, an entire lung. The correct pre-operative diagnosis was made in only 30% of the cases. The fact that the diagnosis was often missed led to long delays in treatment resulting in recurrent infectious complications and repeated hospitalizations. The most common cause of error in diagnosis was failure to follow a pneumonia to complete resolution. Despite the frequent delays in diagnosis, surgical treatment was curative in all patients.


Fukushima study for Engaging people with type 2 Diabetes in Behaviour Associated Change (FEEDBACK): study protocol for a cluster randomised controlled trial.
The growing burden of type 2 diabetes mellitus (T2DM) and the rising cost of healthcare worldwide make it imperative to identify interventions that can promote sustained self-management behaviour in T2DM populations while minimising costs for healthcare systems. The present FEEDBACK study (Fukushima study for Engaging people with type 2 Diabetes in Behaviour Associated Change) aims to evaluate the effects of a novel behaviour change intervention designed to be easily implemented and scaled across a wide range of primary care settings. A cluster randomised controlled trial (RCT) with a 6-month follow-up will be conducted to evaluate the effects of the FEEDBACK intervention. FEEDBACK is a personalised, multi-component intervention intended to be delivered by general practitioners during a routine diabetes consultation. It consists of five steps aimed at enhancing doctor-patient partnership to motivate self-management behaviour: (1) communication of cardiovascular risks using a 'heart age' tool, (2) goal setting, (3) action planning, (4) behavioural contracting, and (5) feedback on behaviour. We aim to recruit 264 adults with T2DM and suboptimal glycaemic control from 20 primary care practices in Japan (cluster units) that will be randomly assigned to either the intervention or control group. The primary outcome measure will be the change in HbA1c levels at 6-month follow-up. Secondary outcome measures include the change in cardiovascular risk score, the probability to achieve the recommended glycaemic target (HbA1c <7.0% [53mmol/mol]) at 6-month follow-up, and a range of behavioural and psychosocial variables. The planned primary analyses will be carried out at the individual level, according to the intention-to-treat principle. Between-group comparisons for the primary outcome will be analysed using mixed-effects models. This study protocol received ethical approval from the research ethics committee of Kashima Hospital, Fukushima, Japan (reference number: 2022002). This article describes the design of a cluster RCT that will evaluate the effects of FEEDBACK, a personalised, multicomponent intervention aimed at enhancing doctor-patient partnership to engage adults with T2DM more effectively in self-management behaviour. The study protocol was prospectively registered in the UMIN Clinical Trials Registry (UMIN-CTR ID UMIN000049643 assigned on 29/11/2022). On submission of this manuscript, recruitment of participants is ongoing.


Characterization of lead induced metal-phytochelatin complexes in Chlamydomonas reinhardtii.
Accumulation of Pb and induction of phytochelatin synthesis were observed in Chlamydomonas reinhardtii upon Pb(II) exposure. Our aim was to examine whether Pb(II) is bound by phytochelatins (PCs) in C. reinhardtii and to examine formed complexes for their stoichiometry and composition. Metal-phytochelatin (Me-PC) complexes induced by Pb were isolated by size-exclusion chromatography in 13 collected fractions, which were analyzed for their PC and metal content by high-performance liquid chromatography and inductively coupled plasma mass spectrometry. A recovery of more than 90% of Pb from standard Pb-PC₂ complexes within the total volume of the size-exclusion column indicated the adequacy of the method for Pb-PC(n) complex separation and characterization. Phytochelatins were detected mainly in a molecular weight ranging from 1,000 to 5,300 daltons (Da), indicating the formation of complexes with various stoichiometries. Approximately 72% of total PC₂ eluted in the range from 1,000 to 1,600 Da, and 80% of total PC₃ eluted in the molecular weight range from 1,600 to 2,300 Da. The distribution of Cu, Zn, and Pb showed that more than 70% of these metals were associated with the high-molecular-weight fractions. Copper, zinc, and lead were also observed in PC-containing fractions, suggesting the formation of various Me-PC complexes. The results of the present study indicate that the role of PCs in Pb detoxification is minor, because only 13% of total Pb was associated with PCs.


Composite graft replacement of the ascending aorta and aortic valve. Late follow-up with intra-arterial digital subtraction angiography.
Between 1979 and 1986, 30 patients underwent replacement of the aortic valve and ascending aorta by a composite graft, with aortic wrapping of the graft. Thirteen patients had annuloaortic ectasia; six had DeBakey type I dissection (five acute, one chronic); three had DeBakey type II dissection (one acute, two chronic); three had left ventricular-aortic discontinuity caused by prosthetic valve endocarditis; three had sinus of Valsalva aneurysms after previous aortic valve procedures; and two had atherosclerotic aneurysms. Three patients died (10%). The mean duration of follow-up was 54 months. Fifteen patients consented to be restudied by intra-arterial digital subtraction angiography; studies were performed 6 to 58 months (mean 25 months) after composite graft replacement. Two patients had pseudoaneurysms at the right coronary anastomosis, which were repaired successfully. One patient showed persistent dissection beyond the distal aortic anastomosis; no reoperation has been done. One patient had pulmonary edema. Emergency study and reoperation showed disruption of the proximal aortic anastomosis and right coronary anastomosis. Anastomotic dehiscence after composite graft replacement is potentially lethal. Follow-up by means of intra-arterial digital subtraction angiography is simple and highly accurate. We suggest that dehiscences may occur early in the postoperative period and that restudy may be appropriate within a few months after operation.


Happiness and health behaviors in South Korean adolescents: a cross-sectional study.
We examined the associations between happiness and a wide range of health behaviors in South Korean adolescents. Study data were derived from the ninth Korea Youth Risk Behavior Web-based Survey administered from June to July 2013. In addition to happiness levels, the questionnaire included items on sociodemographics and health-related lifestyle factors (smoking, drinking, eating breakfast, fruit and vegetable consumption, physical activity, sedentary behavior, and hours of sleep). The multivariate analysis revealed that higher levels of happiness were associated with not smoking or drinking, eating breakfast, eating fruits daily, vegetable consumption, participating in at least 60 minutes of physical activity a day, avoiding sedentary behavior, and hours of sleep. Additionally, sex differences were found in relationships between happiness and eating fruit daily, participation in physical activity, and sedentary behavior. These results encourage public health professionals to consider the psychological aspects of adolescent life in working to improve their health behaviors and outcomes.


What is the role of lymphadenectomy in surgical management of patients with endometrial carcinoma?
The role of lymphadenectomy in the management of endometrial carcinoma remains controversial in gynecologic oncology. Comprehensive pelvic and paraaortic lymphadenectomy should be performed in patients with intermediate- and high-risk endometrial cancer.


Telephone support for persons with chronic mental illness.
These cases offer evidence of the potential utility of telephone support for one of the most challenging segments of the population. This group of clients often does not have strong support of any kind. Telephone support shows promise of offering cost-effective care for persons with psychiatric disabilities. Home healthcare nurses are encouraged to use this information as a basis for exploring the use of telephone support as a cost-effective system with their patients.


Acute pseudo-obstruction of the colon in a kidney-transplanted patient (Ogilvie's syndrome).
Ogilvie's syndrome is an acute massive dilation of the large bowel without organic obstruction. It can occur from a variety of causes and organ failures. We report on the first patient who has developed this syndrome twice, in both cases after kidney transplantation. The world literature concerning the subject is also reviewed.


Arterial ischemic stroke and hemorrhagic stroke in Chinese children: a retrospective analysis.
To study the characteristics of pediatric arterial ischemic stroke (AIS) and hemorrhagic stroke (HS) in southwest of China, and analyze the etiology and risk factor. This study retrospectively reviewed the records of all patients in both department of neurology and department of neurosurgery in Children's hospital of Chongqing medical university from January 2003 to March 2011, and patients were eligible for analysis if they had been diagnosed with AIS or HS. And SPSS 17.0 software was used for statistical analysis. The χ(2) test was used to exam relationships between stroke types and sex, age, and that between neuroradiological images and sex. 119 Boys (70.4%) and 50 girls (29.6%) were included. In these cases, HS accounted for the majority of the cases (n=109, 64.1%), and vitamin K deficiency was a major etiology in 65 out of 109 HS (59.6%), most of which occurred in breastfeeding infants (87.7%) and those who received no vitamin K after birth. AIS accounted for 35.3% of the cases, and minor head injury associated stroke (40.0%) was more common than vasculopathy associated stroke (16.6%) and other kinds of stroke. HS in children is more common than AIS. Vitamin K deficiency was a major etiology in these young infants who experienced HS, and many cases of AIS were associated with minor head injury.


Molecular genetics of anti-carbohydrate antibodies.
Antibodies directed against carbohydrate determinants provide useful model systems for understanding the structure and organisation of antibody genes and the generation of antibody diversity. We have used three such systems, PC, DEX and GAC, and have studied the heavy chains and VH gene segments of each. In two of these systems, PC and GAC, much of the diversity in heavy-chain protein sequences results from somatic mutation events superimposed on expression of a single VH gene. In the DEX system, it appears that germ-line sequence diversity may be an important contributor to the variability in heavy-chain sequence. Detailed structural analyses of this type will ultimately provide a complete picture of the mechanisms which underlie effective humoral immunity.


Influence of ABCC2, CYP2C8, and CYP2J2 Polymorphisms on Tacrolimus and Mycophenolate Sodium-Based Treatment in Brazilian Kidney Transplant Recipients.
To investigate the influence of single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP2C8, CYP2J2, and UGT2B7) and transporters (ABCC2 and ABCG2) on dose and dose-adjusted trough blood concentrations (C:D ratio), clinical outcomes, and occurrence of adverse events of tacrolimus and mycophenolate sodium in Brazilian kidney transplant recipients. Pharmacogenetic analysis of patients enrolled in a previously published study. One hundred forty-eight adult kidney transplant recipients treated with tacrolimus, enteric-coated mycophenolate sodium, and prednisone for 90 days posttransplantation. ABCC2 c.-24C>T and c.3972C>T, ABCG2 c.421C>A, CYP2C8*3, CYP2J2 c.-76G>T, and UGT2B7 c.372A>G SNPs were determined by real-time polymerase chain reaction. The CYP3A5*3C SNP data were used to eliminate the confounding effect of this variant on the results. ABCC2 c.3972T allele carriers showed higher tacrolimus C:D values than did carriers of the c.3972CC genotype. The CYP2C8*3 variant was also associated with slightly higher tacrolimus C:D values and higher estimated glomerular filtration rate but only in CYP3A5-nonexpressing patients (CYP3A5*3C/*3C carriers). None of the SNPs were associated with mycophenolate sodium dose or episodes of biopsy-confirmed acute rejection or delayed graft function. The CYP2J2 c.-76T allele was associated with increased risk for treatment-induced nausea and/or vomiting (OR: 5.30, 95% confidence interval 1.49-18.79, p<0.05). The ABCC2 c.3972C >T polymorphism affected tacrolimus C:D in Brazilian kidney transplant recipients. Further, CYP2C8*3 and CYP2J2 c.-76G>T SNPs influenced the renal function of these patients and the occurrence of adverse events during treatment with tacrolimus and mycophenolate sodium.


Coexisting endometrial and ovarian carcinomas: a retrospective clinicopathological study.
The purpose of this study was to characterize patients diagnosed with synchronous primary carcinomas of the endometrium and ovary. Between 1985 and 2002, 46 patients with synchronous primary carcinomas of the endometrium and ovary were identified. Clinical and pathological information was obtained from the database and pathological reports. Kaplan-Meier survival analysis, log rank tests of survival differences, and multivariate Cox regression analysis were performed. Median age at diagnosis was 55 years. Twenty-one patients (46%) had an endometrioid histology both of their endometrial and ovarian cancers. Patients with younger age, high uterine differentiation grade, and early-stage ovarian cancer had a more favorable prognosis than those with older age, low grade of differentiation, and advanced stage disease. The Cox proportional hazards model analysis indicates that young age and high grade of differentiation are independent prognostic factors. In this series of patients, women with synchronous primary cancer of the endometrium and ovary were young; the survival rate was greater in patients aged less than 50 years and in patients with an early stage. No significantly different survival between patients with endometrioid carcinoma and patients with non-endometrioid carcinomas was detected.


A reliable and inexpensive microprocessor system for collection and transfer of raw immunoassay data.
A very low cost microprocessor system has been designed to ease data handling problems in a large workload immunoassay laboratory. The microprocessor collects and stores data from many immunoassay detection devices simultaneously, and transfers the data to a minicomputer for analysis as each measurement batch is completed. Stored data are protected against a mains power failure during collection and against non-availability of the minicomputer at transfer time. The system provides fast and reliable transfer of very large amounts of raw data from measurement devices to computer, and therefore facilitates the use of a statistically sound data reduction software package.


Molecular mechanism of the uptake and toxicity of EGF-LipoAgNPs in EGFR-overexpressing cancer cells.
The surface of silver nanoparticles (AgNPs) is characterized by high reactivity resulting in prooxidative and cytotoxic properties. These effects are observed both in normal and in cancer cells, which overexpress the Epidermal Growth Factor Receptor (EGFR). In our previous paper, we have demonstrated that, with the use of liposomes labeled with the Epidermal Growth Factor (EGF), it is possible to direct the toxic effect of AgNPs in EGFR-overexpressing cells. Unfortunately, the mechanism of uptake and toxicity induction by such liposomes is still unknown. Therefore, the aim of this study was to determine the impact of EGF-LipoAgNPs on certain genes related to endocytosis and toxicity induction by such liposomes in human lung (A549) and tongue (SCC-15) cancer cells. The siRNA knock-out gene method was used in this study to determine the engagement of EGFR in this process. The confocal microscopy study revealed that the number of liposomes in the cytoplasm of the A549EGFR- and SCC-15EGFR- cells was lowered by 51.99 × 103 RFU and 138.50 × 103 RFU, respectively, proving the crucial role of EGFR in the liposome uptake. Moreover, the expression of the SHH and ATM genes was significantly increased, whereas the expression of the NRF2 gene was decreased after the treatment with EGF-LipoAgNPs and native AgNPs. Furthermore, the expression of the CLTC, AP2M1, CAV1, and SH3GLB1 genes indicated that the tested liposomes are uptaken via the clathrin-dependent pathway with engagement of the AP-2 complex and endophilin in this process. Summarizing, the created targeted delivery system of AgNPs causes an increase in the prooxidative and toxic effect of such NPs and has an impact on endocytosis regulatory genes, especially those related to the clathrin-mediated endocytosis.


Polysialic acid influences specific pathfinding by avian motoneurons.
The influence of polysialic acid (PSA) on the neural cell adhesion molecule on motoneuron outgrowth and pathway formation was investigated by determining its temporal and spatial pattern of expression and by the effect that its removal had on motoneuron projection patterns. Motoneurons first expressed PSA as their growth cones began to segregate into motoneuron pool-specific groups in the plexus region; furthermore, PSA levels differed between motoneurons projecting to different targets. When PSA was removed during the period of axonal segregation in the plexus region projection errors were common. However, later removal during the process of muscle nerve formation did not result in projection errors. These results suggest that PSA modulates interactions between motoneuron axons and guidance molecules in the plexus region during axonal pathfinding.


Liposome evaluation in inhibiting pump efflux of NorA of Staphylococcus aureus.
Liposomes, in addition to providing greater efficacy to antibiotics, decrease toxicity and increase selectivity. This work has as main objectives the sensitization of the need to solve bacterial resistance to antibiotics, addressing the potential of antibiotics carried by liposome. In the preparation of the liposomes, the lipids dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylserine (DPPS), and cholesterol (COL) with > 99% purity were used. The Staphylococcus aureus strains used were SA-1199B, which expresses the NorA gene encoding the NorA efflux protein, which expels hydrophilic fluoroquinolones and other drugs intercalating DNA dyes, and the wild strain SA-1199. The liposomes associated with antibiotics in the wild type of strain SA-1199 and the carrier strain of pump 1199B, had a better representation of growth inhibition than the wild type strain SA-1199. Given the potential for inhibition of efflux pump seen in the results, we highlight the creation of new drugs or alteration of existing drugs. They are not recognized by the efflux pumps and removed from the target cell.


Erratum to Body fluid biomarkers in Alzheimer's disease.
[This corrects the article on p. 70 in vol. 3, PMID: 25992369.].


Chemical carcinogenesis: from animal models to molecular models in one decade.
During the last decade, progress in chemical carcinogenesis research has been substantial, and understanding the cellular changes and molecular causes of initiation, promotion, and malignant conversion appears to be within reach. Cancer begins as a carcinogen-induced genetic change in a single cell. The interaction of a particular carcinogen with specific genetic sites results, in part, from selectivity of metabolically activated carcinogens for particular nucleosides or gene sequences. In turn, modification of the molecular structure at specific genetic loci will have tissue-specific and species-specific consequences dependent on the expression of a particular gene, its sequence, and the function of the gene product in the target cell. It is likely that inactivation of regulatory regions, genomic rearrangements, and point mutations in coding sequences all can result in an altered cell phenotype. The rasH gene (and perhaps other members of the ras gene family) appears to be a common target for coding sequence mutations in the initiation of carcinogenesis in several organ sites and species by specific carcinogens. Whatever genetic mechanisms are involved, an initiated cell phenotype common to many epithelial cell types is observed. Initiated cells have an altered program of terminal differentiation, are resistant to cytotoxic substances or show altered requirements for specific growth factors or nutrients. These cells would have a selective growth advantage in cytostatic or cytotoxic situations or under conditions favoring terminal differentiation. Tumor promoters, some acting through specific cellular receptors, produce a tissue environment conductive to the selective clonal outgrowth of the initiated cell population resulting in a clinically evident premalignant lesion. The tissue specificity for most promoters depends on the ability of a particular agent to produce the selective conditions required for the initiated phenotype of that organ. At the molecular level, phorbol ester tumor promoters bind to and activate protein kinase C and transduce signals through this second-messenger pathway. Heterogeneity in the species of protein kinase C molecule expressed by normal and initiated epidermal cells could account for the differential response pattern observed in these cell types during skin tumor promotion. Malignant conversion of benign tumors requires further genetic changes in the tumor cell. Such changes could result from inherent instability in the genome of initiated cells, from spontaneous mutations more likely to occur in the expanding population of proliferating benign tumor cells, or by additional exposure to exogenous genotoxic agents.(ABSTRACT TRUNCATED AT 400 WORDS)


Concentration-response relationships of disopyramide in patients with ventricular tachycardia.
The protein binding of disopyramide is altered when concentration is increased within the therapeutic range. A wide range of free concentrations may be produced at a given total concentration. The present study assessed whether intracardiac electrophysiologic responses to disopyramide related better to free or to total concentration. Intravenous infusions of disopyramide were evaluated in 17 patients with inducible sustained ventricular tachycardia. The first maintenance infusion produced total serum concentrations of 11.7 +/- 2 mumols/L, and no significant increase occurred at higher-dose infusions. However, free concentrations during the first and second maintenance infusions were significantly different at 5.3 +/- 1 mumols/L and 6.8 +/- 1 mumols/L, respectively. Free fraction also increased significantly, from 45% +/- 8% to 50% +/- 7%. Overall change in QTc interval and ventricular tachycardia cycle length correlated with free concentration but not with total concentration. This study showed that some intracardiac measurements correlate with free concentration but that none correlate with total concentration.


Brain development in infants born preterm: looking beyond injury.
Infants born very preterm are high risk for acquired brain injury and disturbances in brain maturation. Although survival rates for preterm infants have increased in the last decades owing to improved neonatal intensive care, motor disabilities including cerebral palsy persist, and impairments in cognitive, language, social, and executive functions have not decreased. Evidence from neuroimaging studies exploring brain structure, function, and metabolism has indicated abnormalities in the brain development trajectory of very preterm-born infants that persist through to adulthood. In this chapter, we review neuroimaging approaches for the identification of brain injury in the preterm neonate. Advances in medical imaging and availability of specialized equipment necessary to scan infants have facilitated the feasibility of conducting longitudinal studies to provide greater understanding of early brain injury and atypical brain development and their effects on neurodevelopmental outcome. Improved understanding of the risk factors for acquired brain injury and associated factors that affect brain development in this population is setting the stage for improving the brain health of children born preterm.


Parasite-induced risk of mortality elevates reproductive effort in male Drosophila.
A trade-off between sex and somatic maintenance is fundamental to life-history theory. Tests of this trade-off usually emphasize deleterious consequences of increased reproduction on life span. Here we show the reverse effect, that reductions in the expected life span elevate sexual activity. Experimentally parasitized male Drosophila nigrospiracula lived shorter lives, but before dying, they courted females significantly more than unparasitized controls. This greater courtship resulted in increased mating speed, and potentially greater reproductive success than parasitized males would have achieved otherwise. The results show that an environmental reduction in life span increases reproductive effort, and support the hypothesis of a trade-off between these key life-history traits.


Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial.
In the first interim analysis of the ORIENT-31 trial, compared with chemotherapy alone, sintilimab plus bevacizumab biosimilar IBI305 plus chemotherapy (pemetrexed and cisplatin) significantly improved progression-free survival in patients with EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC) who progressed on EGFR tyrosine-kinase inhibitor treatment. However, the benefit of anti-PD-1 or PD-L1 antibody added to chemotherapy in this patient population remains unclear, with no prospective evidence from phase 3 trials globally. We report the results from the prespecified second interim analysis of progression-free survival between sintilimab plus chemotherapy and chemotherapy alone, the updated results of sintilimab plus IBI305 plus chemotherapy, and preliminary overall survival results. This double-blind, randomised, placebo-controlled, phase 3 trial was done at 52 centres across China and included patients aged 18-75 years with locally advanced or metastatic (stage IIIB, IIIC, or IV according to the American Joint Committee on Cancer, eighth edition) EGFR-mutated non-squamous NSCLC, disease progression after EGFR tyrosine-kinase inhibitor treatment (according to the Response Evaluation Criteria in Solid Tumours version 1.1 [RECIST 1.1]), and at least one measurable lesion (according to RECIST 1.1). Patients were randomly assigned (1:1:1), using an interactive web response system, to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus chemotherapy, or chemotherapy alone on day 1 of each 3-week cycle for four cycles, followed by maintenance therapy of sintilimab, IBI305, and pemetrexed. All study drugs were administered intravenously. The primary endpoint was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee. Data cutoff was March 31, 2022, unless otherwise specified. The study is registered at ClinicalTrials.gov, NCT03802240 (ongoing). Between July 11, 2019, and March 31, 2022, 1011 patients were screened and 476 were randomly assigned (158 to the sintilimab plus IBI305 plus chemotherapy group, 158 to the sintilimab plus chemotherapy group, and 160 to the chemotherapy alone group). The median follow-up duration for progression-free survival was 12·9 months (IQR 8·2-17·8) in the sintilimab plus IBI305 plus chemotherapy group, 15·1 months (8·0-19·5) in the sintilimab plus chemotherapy group, and 14·4 months (9·8-23·8) in the chemotherapy alone group. Sintilimab plus chemotherapy significantly improved progression-free survival compared with chemotherapy alone (median 5·5 months [95% CI 4·5-6·1] vs 4·3 months [4·1-5·3]; hazard ratio [HR] 0·72 [95% CI 0·55-0·94]; two-sided p=0·016). Significant progression-free survival benefit was sustained with sintilimab plus IBI305 plus chemotherapy compared with chemotherapy alone (median 7·2 months [95% CI 6·6-9·3]; HR: 0·51 [0·39-0·67]; two-sided p<0·0001). As of data cutoff (July 4, 2022), the median overall survival was 21·1 months (95% CI 17·5-23·9) for sintilimab plus IBI305 plus chemotherapy (HR 0·98 [0·72-1·34]) and 20·5 months (15·8-25·3) for sintilimab plus chemotherapy group (HR 0·97 [0·71-1·32]) versus 19·2 months (15·8-22·4) for chemotherapy alone; after adjusting for crossover, the HR for sintilimab plus IBI305 plus chemotherapy to chemotherapy alone ranged from 0·79 (0·57-1·09) to 0·84 (0·61-1·15) and the HR for sintilimab plus chemotherapy to chemotherapy alone ranged from 0·78 (0·57-1·08) to 0·84 (0·61-1·16). The safety results were generally consistent with those in the first interim analysis; in particular, treatment-related adverse events of grade 3 or worse occurred in 88 (56%) of 158 patients in the sintilimab plus IBI305 plus chemotherapy group, 64 (41%) of 156 patients in the sintilimab plus chemotherapy group, and 79 (49%) of 160 patients in the chemotherapy alone group. This is the first prospective phase 3 trial to show the benefit of anti-PD-1 antibody plus chemotherapy in patients with EGFR-mutated NSCLC who progressed on treatment with tyrosine-kinase inhibitors. Compared with chemotherapy alone, sintilimab combined with pemetrexed and cisplatin showed significant and clinically meaningful improvement of progression-free survival with an optimal safety profile. Sintilimab plus IBI305 plus chemotherapy continued to show progression-free survival benefit compared with chemotherapy alone in this second interim analysis with an additional 8-month follow-up. National Natural Science Foundation of China, Shanghai Municipal Science & Technology Commission Research Project, and Innovent Biologics. For the Chinese translation of the abstract see Supplementary Materials section.


The neuroecology of bee flight behaviours.
By combining functional, ecological and evolutionary perspectives, neuroecology can provide key insights into understanding how behaviour and the underlying sensory and neural processes are shaped by ecology and evolutionary history. Bees are an ideal system for neuroecological studies because they represent a numerous and diverse insect group that inhabit a broad range of environments. Flight is central to the evolutionary success of bees and is the key to their survival and fitness but this review of recent work on fundamental flight behaviours in different species - landing, collision avoidance and speed control - reveals striking differences. We discuss the potential ecological and evolutionary drivers behind this variation but argue that to understand their adaptive value future work should include multidisciplinary approaches that integrate neuroscience, ecology, phylogeny and behaviour.


Effect of Methyl Jasmonate on the Gene Expression, Encoding Non-Protein Thiol Enzymes in Wheat under Cadmium.
The effect of the phytohormone methyl jasmonate (MJ) on the expression of the TaGS1 and TaPCS1 genes encoding glutathione synthetase and phytochelatin synthase, respectively, which are key enzymes in the synthesis of glutathione and phytochelatins in wheat (cv. Moskovskaya 39), was studied. It was shown for the first time that pretreatment of plants by exogenous MJ (1 μM) leads to an increase in the accumulation of transcripts of the TaGS1 and TaPCS1 genes in leaves without cadmium effect. When cadmium (CdSO4, 100 μM) was added into the nutrient solution, the transcript level of the TaGS1 gene in the plants pretreated by MJ increased (compared to the untreated plants), whereas the transcript level of TaPCS1 remained unaffected. The pretreatment of plants with MJ leads to a lower accumulation of cadmium in the roots and leaves of wheat. At the same time, MJ had no effect on the linear growth parameters of plants, but had a positive effect on the accumulation of biomass under cadmium. It was assumed that MJ is involved in plant tolerance to cadmium by increasing the expression of the TaGS1 and TaPCS1 genes and, as a result, enhancing the synthesis of chelating compounds, as well as by reducing the supply of metal ions to plants.


Comparison of vacuum-assisted excision (VAE) and breast lesion excision system (BLES) in the treatment of intraductal papillomas.
This study aims to compare the feasibility of VAE and BLES in the treatment of intraductal papillomas. Patients with a suspected intraductal papilloma who underwent a BLES or a VAE procedure were included in this retrospective study. The BLES procedures were performed between November 2011 and June 2016 and the VAE procedures between May 2018 and September 2020 at the Department of Radiology of Helsinki University Hospital (HUH). The procedures were performed with an intent of complete removal of the lesions. In total, 72 patients underwent 78 BLES procedures and 95 patients underwent 99 VAE procedures. Altogether 52 (60%) papillomas with or without atypia were completely removed with VAE, whereas 24 (46%) were completely removed with BLES, p = 0.115. The median radiological size of the high-risk lesions completely removed with BLES was 6 mm (4-12 mm), whereas with VAE it was 8 mm (3-22 mm), p = 0.016. Surgery was omitted in 90 (94.7%) non-malignant breast lesions treated with VAE and in 66 (90.4%) treated with BLES, p = 0.368. Both VAE and BLES were feasible in the treatment of intraductal papillomas. In most non-malignant lesions surgery was avoided, but VAE was feasible in larger lesions than BLES. However, follow-up ultrasound was needed more often after VAE. The histopathologic assessment is more reliable after BLES, as the lesion is removed as a single sample.


Studies on the attraction of Simulium damnosum s.l. (Diptera: Simuliidae) to its hosts. III. Experiments with animal-baited traps.
In the forest zone of the United Republic of Cameroon, a live chicken proved far more attractive to hunting S. damnosum s.l. than did a live sheep; but in the Sudan-savanna zone, a sheep was more attractive than a chicken. It is suggested that the populations of flies in the two areas represented different species of the S. damnosum s.l. complex with different host-finding mechanisms, that in the forest (? S. squamosum) hunting mainly by smell, and that in the Sudan savanna (? S. damnosum s.s.) hunting mainly by sight.


[Genetic structure of the Udmurt population].
Integrated study of the genetic structure of the Udmurt population with respect to different genetic systems has been performed. Data on the genes of genetic diseases, abiotic parameters analyzed by population statistic methods, and DNA polymorphism are summarized. The populations of six raions (districts) of Udmurt Republic (the Mozhga, Malaya Purga, Sharkan, Debesy, Igra, and Glazov raions) have been studied. The total population studied was 267,655 people (an urban population of 150,119 people and a rural population of 117,536 people), including 155,346 Udmurts. The population structure has been studied in six districts on the basis of the vital statistics, Crow's indices, Malecot's isolation by distance parameters, ethnically assortative marriage parameters, endogamy indices, inbreeding-endogamy (ie) indices, and frequencies of the genotype and allele frequencies of four DNA markers (17 alleles). The prevalences of hereditary diseases have been calculated for different population groups: urban and rural populations, Udmurts and other ethnic groups. These groups, especially the urban and rural populations, substantially differed from one another in the prevalences of autosomal dominant (AR) and autosomal recessive (AR) diseases. The correlation between the prevalence of AD and AR diseases and the ie index is positive and significant. The spectrum of hereditary diseases detected in six districts of Udmurtia comprises 149 diseases (80, 57, and 12 AD, AR, and X-linked diseases, respectively). Accumulation of individual diseases in districts of Udmurtia and accumulation of diseases in Udmurtia as compared to regions studied earlier has been found. Cluster analysis of the frequencies of genes of AD and AR diseases and DNA markers has determined the gene geographic position of Udmurts.


Preliminary estimates of the virtually safe dose for tumors obtained from the maximum tolerated dose.
The purpose of this paper was to examine the correlation between the maximum tolerated dose (MTD) and the low-dose estimate of the virtually safe dose (VSD) for animal carcinogens. Chronic bioassay results from the National Cancer Institute/National Toxicology Program carcinogenesis screening program were used. Estimates of the VSD were obtained by linear low-dose extrapolation for which an adequate dose-response relationship existed at the same tumor site in the same sex for both rats and mice. Estimates of the VSD were compared with the MTD for 69 tumor sites from 38 chemicals for rats and mice. The MTDs ranged from high to low toxicity (1 ppb to 4.4% in the diet). The overall geometric mean of the ratio of the MTD to the VSD corresponding to a maximum estimated risk of 10(-6) was 3.8 x 10(5). Of the 138 cases, only 3 cases were more than a factor of 10 from the mean ratio. This suggested that a quick estimate of the VSD could be obtained by dividing the MTD, obtained from a subchronic study, by 400,000. Further, if the human exposure is less than 10(-7) X MTD, the estimated risk is likely to be negligible even if the chemical is a carcinogen. It may not be worthwhile to conduct a chronic bioassay for the purpose of demonstrating a negligible risk, if the chemical is likely to be carcinogenic, unless the human exposure is extremely low.(ABSTRACT TRUNCATED AT 250 WORDS)


Long-term outcome of vaginal reconstruction: comparing techniques and timing.
In a retrospective review, to analyse the long-term outcomes of vaginal reconstruction, comparing techniques and timing. We identified 63 patients who underwent a total of 71 vaginoplasties in 1985-2000. The techniques used were posterior skin flap (42), intestinal replacement (21) and pull through (8). The majority of operations were performed before puberty (63%) and as primary procedures (79%). Presenting diagnoses were congenital adrenal hyperplasia (23), cloacal exstrophy (8), true persistent cloaca (12), androgen insensitivity (8), urogenital sinus anomaly (6), mixed gonadal dysgenesis (3), true hermaphroditism (2) and sacrococcygeal teratoma (1). The mean age at operation was 83.9 (2-235) and mean follow up was 116.8 (48-232) months. Strictures and discharge were the most common problems. Nine patients underwent revision surgery and a fistula repair was required in two patients. Mucosal prolapse was observed in one ileo- and one colovaginoplasty patient, and diversion colitis occurred after colovaginoplasty in one patient. More complications occurred in operations performed prior to than following puberty. If vaginoplasty is the only indicated operation, delaying until puberty may minimize complications. When other genital surgery is indicated or in the presence of symptoms pre-pubertal vaginoplasty should be performed, since the second procedure usually involves simple dilatations and is associated with good results.


Synthesis of Se polysaccharide catalyzed by sulfonic acid functionalized ionic liquids: Synergism effect of anion/cation.
The rational design and construction of controllable selenylation strategy are important for the study on the structure-activity relationship of Se polysaccharides. Herein, selenized Artemisia sphaerocephala polysaccharides (SePASs) were synthesized by using sulfonic acid functionalized ionic liquids (SFILs) as catalysts in order to study the regulation of the cation/anion constitute on the selenylation efficiency and Se polysaccharide structure. Impressively, SFILs could promote the efficient substitution of seleno-group on the polysaccharide backbone through the synergistic catalysis by cation/anions (Se content up to 5582.7 μg/g). Further, reaction mechanism and potential dissolution effect was supported by DFT calculation and polarized light microscopy. 13C NMR and FT-IR spectra analysis of SePASs exhibited that selenite existed in polysaccharides and the substitution position occured at C-6. SEC-MALLS, monosaccharide composition results revealed that strong acidity of SFILs lead to the driving forces toward low molecular mass polysaccharide fragments and synergistic effect of anion/cations in SFILs (-SO3H group of cations as proton donor, anions as nucleophile) showed regulation on average molecular mass. In addition, the strong attractions between the seleno-groups generated agglomeration of polysaccharide chain, which was proved by applying AFM analysis. Therefore, this work provided a new insight for manipulate Se content and MW of Se polysaccharides.


Recombinant protein production using the Semliki Forest Virus expression system.
We report here the successful scale up of transient recombinant protein expression to litre scale using Semliki Forest Virus System. The expression of bacterial β-galactosidase was initially compared in BHK and CHO cells and the conditions for optimal infection of BHK cells were identified. 10% FCS in a medium at pH 6.9 and infection in small volumes were found to be optimal. A high MOI results in an increased recombinant protein yield. Stirring does not affect the infection process. Finally we applied these optimal conditions to the production of a microsomal enzyme, human cyclooxygenase-2 in suspension spinners. Five independant productions at the 1 litre scale yielded reproducible substantial amounts of recombinant protein (16 mg microsomal protein 10(9) cells(-1)) with an average specific activity of 3942 ± 765 pg PGE(2) μg(-1) microsomal protein 5 min(-1).


Spheroplasts, poorly known but clinically relevant particles of urinary sediment.
In two patients under treatment with various antibiotics, spheroplasts were detected with an automated urine sediment analyzer. Urinalysis was performed by an AutionMAX AX 4030-sediMAX platform. Spheroplasts can be easily misclassified as yeasts or erythrocytes, but when automated urine sediment analyzers are used by well-trained, and experienced operators they can be correctly identified and classified. Appropriate training of urine laboratory professionals in spheroplast detection and association with UTI, together with timely communication with the microbiologist and caring clinician, will provide prompt targeted treatment.


STI571/doxorubicin concentration-dependent switch for diverse caspase actions in CML cell line K562.
We examined the response of the apoptosis-reluctant CML cell line K562 to doxorubicin alone or in combination with the tyrosine kinase inhibitor STI571. We found that at clinically relevant concentrations, doxorubicin induced differentiation and senescence, but did not induce apoptosis. Doxorubicin induced G(2)/M arrest and mitochondrial transmembrane potential dissipation. Interestingly, drug-induced differentiation could be diminished by caspase inhibitors. STI571 caused a graded response characterized by differentiation at low concentrations and apoptosis at higher. STI571 was not observed to induce senescence. Combination of STI571 and caspase inhibitors protected cells from apoptosis but did not influence differentiation. The diverse mode of action of both drugs contributed to the response observed during combination treatment. An additive effect on proliferation was obtained. The mechanisms contributing to inhibition of cellular proliferation were complex and strongly dependent on the applied drug concentrations. Differentiation or apoptosis were enhanced by combined treatment only in narrow ranges of concentrations. DOX and STI571 along diverse mechanisms contributed to elevated levels of activated caspases which might be then responsible for a switch from differentiation to apoptosis.


Risk of Noncontact Anterior Cruciate Ligament Injuries Is Not Associated With Slope and Concavity of the Tibial Plateau in Recreational Alpine Skiers: A Magnetic Resonance Imaging-Based Case-Control Study of 121 Patients.
Anatomic features of the tibial plateau (ie, posterior slope and medial concavity) have been associated with an increased risk of anterior cruciate ligament (ACL) injuries. However, it remains unclear whether these findings translate to ACL injuries sustained during recreational alpine skiing. To investigate the association in recreational alpine skiers between prominent morphological features of the tibial plateau (slope and concavity) and the risk of sustaining an ACL injury during a noncontact incident. Case-control study; Level of evidence, 3. Magnetic resonance imaging data of 121 recreational alpine skiers (74 female, 47 male) after a noncontact knee injury were used for this study. Of these patients, 80 (71% female [n = 57]) had a complete unilateral ACL tear (rupture group), and 41 (41% female [n = 17]) had no indications of an ACL injury (intact group). Two blinded independent examiners measured the slopes of the tibial plateau in the sagittal and coronal planes along with the maximum depth of the medial tibial plateau. Measurements were compared between sexes and between groups using t tests. Logistic regression was used to assess the associations between quantified anatomic indices and the risk of ACL injuries. Within 121 study patients, female skiers had greater odds of an ACL tear compared with male skiers (odds ratio, 3.5; 95% CI, 1.6-7.8; P < .001). Female skiers were more likely to have a greater lateral tibial slope (LTS) (P = .02) and medial tibial slope (MTS) (P = .02) with a shallower medial tibial depth (MTD) (P = .02) compared with male skiers. No differences between sexes were observed in the coronal tibial slope (CTS) (P = .97). Male and female skiers as a combined group showed no associations between quantified anatomic indices and the risk of sustaining an ACL tear (P > .10). Likewise, no significant differences were observed between the intact versus rupture group in any of the quantified anatomic indices (P > .10). Similar findings were observed when the analyses were repeated on male and female skiers separately. Despite differences between sexes in knee anatomy and the injury risk, the sagittal and coronal slopes (LTS, MTS, CTS), as well as the concavity of the medial tibial plateau (MTD), were not associated with the risk of an ACL tear during a noncontact injury among recreational alpine skiers.


Current perspectives in the use of molecular imaging to target surgical treatments for genitourinary cancers.
Molecular imaging (MI) entails the visualisation, characterisation, and measurement of biologic processes at the molecular and cellular levels in humans and other living systems. Translating this technology to interventions in real-time enables interventional MI/image-guided surgery, for example, by providing better detection of tumours and their dimensions. To summarise and critically analyse the available evidence on image-guided surgery for genitourinary (GU) oncologic diseases. A comprehensive literature review was performed using PubMed and the Thomson Reuters Web of Science. In the free-text protocol, the following terms were applied: molecular imaging, genitourinary oncologic surgery, surgical navigation, image-guided surgery, and augmented reality. Review articles, editorials, commentaries, and letters to the editor were included if deemed to contain relevant information. We selected 79 articles according to the search strategy based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria and the IDEAL method. MI techniques included optical imaging and fluorescent techniques, the augmented reality (AR) navigation system, magnetic resonance imaging spectroscopy, positron emission tomography, and single-photon emission computed tomography. Experimental studies on the AR navigation system were restricted to the detection and therapy of adrenal and renal malignancies and in the relatively infrequent cases of prostate cancer, whereas fluorescence techniques and optical imaging presented a wide application of intraoperative GU oncologic surgery. In most cases, image-guided surgery was shown to improve the surgical resectability of tumours. Based on the evidence to date, image-guided surgery has promise in the near future for multiple GU malignancies. Further optimisation of targeted imaging agents, along with the integration of imaging modalities, is necessary to further enhance intraoperative GU oncologic surgery.


Adult With Congenital Heart Disease in Developing Country: Scope, Challenges and Possible Solutions.
Adults with congenital heart disease (CHD) are rapidly increasing in numbers in developed countries where facilities for interventions for CHD are available to infants and children. Over 90 % of children survive to adulthood in these countries. However, less than 50 % of children born in developing countries undergo any form of intervention due to nonavailability of paediatric cardiac centres. Prevalence of CHD in adults is estimated at 3000 per million population in developed countries. Such data is not available from developing countries, but prevalence is likely to be much lower due to early attrition. In these countries, adult population with CHD mostly consists of relatively milder forms of CHD with a very small proportion of post-operated patients. Specialized centres for care of adults with CHD are sparse or nonexistent in most developing countries, although the situation is changing for the better in some of these countries. Major challenges to care of adults with CHD include lack of trained persons, low levels of awareness about the disease and lack of government interest. Sustainable strategies which are practical in the local environment are required to deal with these challenges. An urgent need is to initiate training of cardiologists and other team members, required for optimal care of these patients. Special clinics for adults with CHD, run by the trained staff, can be incorporated into already operational cardiac centres. Formation of expert groups and patient support groups will help to formulate local guidelines and to pursue advocacy with the government. Maintenance of registries for adults with CHD is necessary to generate data on disease burden and to set research priorities. It is likely that care for adult CHD will be delivered in less than ideal settings considering the limited resources available.


Fruit and vegetables: intake and sociodemographic determinants among Portuguese mothers.
Fruit and vegetable intake is crucial in health promotion and disease prevention. Inadequate intake is found among adult populations worldwide. To assess fruit and vegetable intake among Portuguese mothers and to examine its association with sociodemographic determinants. A national cross-sectional survey was performed in Portugal as part of the Pro Children study. Data from self-administrated precoded 24-hour recall and food frequency questionnaires answered by 1,853 mothers of 11- to 13-year-old children were analyzed. Descriptive analysis of the data was followed by logistic regression to assess associations between daily fruit and vegetable intake and sociodemographic determinants. The mean fruit and vegetable intake was 221.2 and 170.0 g/day, respectively. Only 46% of the mothers met the WHO recommendations (≥400 g fruit and vegetables/day). Daily fruit intake was significantly higher among mothers who live with a spouse/partner, and who belong to a higher social class. For vegetables, daily intake was significantly higher among mothers with a higher education and social class. This study shows that the mean intake of fruit and vegetables among Portuguese mothers is far below international recommendations. Effective strategies to promote fruit and vegetable intake are needed, especially for mothers belonging to lower social classes and educational levels.


Mocravimod, a S1P receptor modulator, increases T cell counts in bone marrow biopsies from patients undergoing allogeneic hematopoietic stem cell transplantation.
Graft-versus-leukemia (GvL) effects are critical to prevent relapses after allogeneic hematopoietic cell transplantation (allo-HCT). However, the success of allo-HCT is limited by graft-versus-host disease (GvHD). Both, CD4+ and CD8+ T cells contribute to GvHD and GvL. The sphingosine-1-phosphate receptor (S1PR) signaling plays a crucial role in lymphocyte trafficking. Mocravimod is an S1PR modulator and its administration leads to blocking lymphocyte egress from lymphoid organs. We hypothesized that this applies to the bone marrow (BM) too, and analyzed BM biopsies from the clinical study with mocravimod (phase I trial in allo-HCT patients; NCT01830010) by immunohistochemical staining for CD3, CD4, CD8, TIA1, FoxP3, PD1, T-Bet, GATA3, and ROR-γt to identify and quantify T cell subsets in situ. Allo-HCT patients without receiving mocravimod were used as controls. BM from 9 patients in the mocravimod group and 10 patients in the control group were examined. CD3+ T cells were found to accumulate in the BM of mocravimod-treated patients compared to controls, both on day 30 and 90 post-transplant. The effect was stronger for CD4+ T cells, than CD8+ T cells, which is in line with data from murine studies showing that CD4+ T cells are more sensitive to mocravimod treatment than CD8+ T cells. Clinically-relevant acute GvHD events (grade II-IV) were slightly lower, but comparable to controls when mocravimod was administered. Taken together, data are supportive of mocravimod's mode of action and bring additional evidence of fewer relapses for allo-HCT patients treated with S1PR modulators.


Developmental changes of nerve growth factor levels in sympathetic ganglia and their target organs.
The predominant source of nerve growth factor (NGF) used by mature sympathetic neurons originates in their target organs (Heumann, R., Korsching, S., Scott, J., and Thoenen, H. (1984), EMBO J. 3, 3183-3189; Korsching, S., and Thoenen, H. (1985), J. Neurosci. 5, 1058-1061). We have determined the NGF content of two sympathetically innervated mouse organs, submandibular gland and heart ventricle, and of sympathetic ganglia from mouse and rat between embryonic Day 12 (E12) and adulthood. NGF levels were measured by a two-site enzyme immunassay (Korsching, S., and Thoenen, H. (1983), Proc. Natl. Acad. Sci. USA 80, 3513-3516). In heart ventricle and submandibular gland, NGF first became detectable around the time of initial innervation by sympathetic neurons (E12 and E13, respectively) and increased respectively 14- and 7-fold in the following 2 days, to reach adult levels already at E14 for heart ventricle (1.4 +/- 0.2 ng NGF/g wet wt). NGF in the superior cervical ganglion (SCG) was first detected at the same time as in its target organ, the submandibular gland. NGF content in the SCG then increased 6-fold during the next 2 days and continued to increase until the end of the third postnatal week, when adult levels were reached. Although the levels of NGF in the adult mouse submandibular gland are sexually dimorphic and six orders of magnitude higher than those in other sympathetic target organs, no sex difference in the NGF content was found in either developing submandibular gland or SCG until the end of the third postnatal week. Moreover, the steep NGF increase observed in the male submandibular gland after postnatal Day 18 (250-fold within the following 3 days and up to the 55,000-fold in the next 7 days) was not reflected in a corresponding increase in the NGF content of the male SCG. These data indicate that, in accordance with earlier findings (see Levi-Montalcini, R., and Angeletti, P. U. (1968), Physiol. Rev. 48, 534-569), SCG neurons do not have access to the large amounts of NGF synthesized during and after adolescence in the mouse submandibular gland. Our results support the concept that initial fiber outgrowth of sympathetic neurons is neither dependent on NGF nor mediated by it. The time course of NGF levels in the SCG is consistent with the concept that sympathetic neurons are provided with NGF by means of retrograde axonal transport from the innervated organs already early in development.


Blastocystis hominis: neutral red supravital staining and its application to in vitro drug sensitivity testing.
A simple in vitro drug sensitivity testing system for Blastocystis hominis clinical isolates was developed. Application of supravital staining by neutral red allowed quantitative viability assessment. Four xenic cultures, isolated from human sources, were grown in modified monophasic Robinson's medium and tested for sensitivities to nine available drugs. Assessment was done using the cell-count method from air-dried preparations after supravital staining with neutral red. Also, the light absorbence method was evaluated. Trimethoprim, metronidazole, quinacrine, tetracycline, paromomycin, and two new antiprotozoal drugs, nitazoxanide and deacetyl-nitazoxanide, showed cytostatic or cytocidal effects on all or some Blastocystis isolates. Chloroquine and sulphamethoxazole did not demonstrate any effect at the concentrations studied.


Medulloblastoma in children--the Ottawa experience.
A retrospective review of 36 children diagnosed with medulloblastoma in the Ottawa area between 1974 and 1997 was completed (mean age 7.8+/-4.2 years, range 1.2-15.3 years). Via a suboccipital approach, complete tumor resection was achieved in 75% and subtotal resection (>90%) in 25%, without any operative mortality. The tumor was located in the vermis in 39% and in the cerebellar hemisphere in 11%; it occupied both locations in 50%. In 47% of the children a ventriculoperitoneal shunt was required. Postoperatively, craniospinal radiation at 3600 cGy with a boost to the posterior fossa was administered. Chemotherapy was used in 56%. The 1-year survival rate was 92%, and survival plateaued at 54% at 5 years. Children less than 3 years of age fared worse than those over 3 years old. While the male-to-female ratio was 1.6:1, there was no gender difference in survival. Chang's classification was used to grade the tumors. T stage did not have an impact on survival, but M stage did. No statistically significant difference in survival was found between the patients who had a total resection and those who had a subtotal resection. There was no difference in survival in terms of tumor location, hydrocephalus or ventriculoperitoneal shunt. Chemotherapy showed no survival benefit. The recurrence rate was 26%, and its timing followed Collin's law. Recurrence led to death within 1-9 months. GH deficiency was diagnosed in 5 patients and hypothyroidism in 4 patients. The mean follow-up time was 4.4+/-3.7 years, with a range of 2.5 months to 16.5 years. Fourteen patients died, 5 were lost to follow-up, and 7 were transferred to adult care without persistent disease. Ten children are presently being followed up by the Neuro-oncology Clinic. Four children continue to be followed through psychology services. Our results are comparable to those in larger series, and are similar to those of the Montreal Children's Hospital.


Nanoscale assembly processes revealed in the nacroprismatic transition zone of Pinna nobilis mollusc shells.
Intricate biomineralization processes in molluscs engineer hierarchical structures with meso-, nano- and atomic architectures that give the final composite material exceptional mechanical strength and optical iridescence on the macroscale. This multiscale biological assembly inspires new synthetic routes to complex materials. Our investigation of the prism-nacre interface reveals nanoscale details governing the onset of nacre formation using high-resolution scanning transmission electron microscopy. A wedge-polishing technique provides unprecedented, large-area specimens required to span the entire interface. Within this region, we find a transition from nanofibrillar aggregation to irregular early-nacre layers, to well-ordered mature nacre suggesting the assembly process is driven by aggregation of nanoparticles (∼50-80 nm) within an organic matrix that arrange in fibre-like polycrystalline configurations. The particle number increases successively and, when critical packing is reached, they merge into early-nacre platelets. These results give new insights into nacre formation and particle-accretion mechanisms that may be common to many calcareous biominerals.


Dupilumab-induced eosinophilia in patients with diffuse type 2 chronic rhinosinusitis.
Dupilumab, a monoclonal anti-IL-4Rα antibody, is approved for several type 2 mediated inflammatory diseases like asthma, atopic dermatitis, and diffuse type 2 chronic rhinosinusitis (CRS). Clinical studies had reported a transient increase in blood eosinophils during dupilumab therapy. This study aimed to assess the impact of elevated blood eosinophils on clinical outcome and to investigate the cause of high blood eosinophil levels under dupilumab therapy. Patients suffering from diffuse type 2 CRS treated with dupilumab were examined on days 0, 28, 90, and 180 after therapy start. Sino-Nasal-Outcome-Test Score (SNOT-22), Total Nasal Polyp Score (TNPS), and blood samples were collected. Cytokine measurements and proteomics analysis were conducted. Flow cytometry analysis measured receptor expression on eosinophils. Sixty-eighty patients were included. Baseline eosinophilia ≥0.3G/L was observed in 63.2% of patients, and in 30.9% of patients, eosinophils increased by ≥0.5G/L under dupilumab. Subjects with eosinophilia ≥0.3G/L at baseline had the best SNOT-22 mean change compared to no eosinophilia. Eosinophil elevation during dupilumab therapy had no impact on clinical scores. The eosinophil adhesion molecule VCAM-1 decreased significantly during therapy in all patients. The chemokine receptor CXCR4 was significantly down- and IL-4 upregulated in subjects with eosinophil increase. Our findings suggest that increased eosinophils in type 2 CRS are associated with a good clinical response to dupilumab. Patients with elevated IL-4 at baseline developed dupilumab-induced transient eosinophilia. We identified the downregulation of VCAM-1 and surface markers CD49d and CXCR4 on eosinophils as possible explanations of dupilumab-induced eosinophilia.


Candidates and major determinants for endovascular repair of abdominal aortic aneurysms in Korean patients.
The purpose of this study was to determine what proportion of patients with an abdominal aortic aneurysm (AAA) would be eligible for endovascular aneurysm repair (EVAR) and to examine the major determinants for suitability of EVAR with the currently available indications. We retrospectively reviewed 3-D reconstructed computed tomography angiography of 88 patients with an atherosclerotic AAA who underwent open repair or EVAR between October 2003 and October 2010 at the Cardiovascular Center, Seoul National University Bundang Hospital. Of the 88 patients, 71 (80.7%) were treated with open repair and 17 (19.3%) were treated with EVAR. The rate of minor complications, postprocedural intensive care unit stay, and total hospital stay were significantly lower in the EVAR group. When the suitability of EVAR was reevaluated using morphologic criteria, a total of 33 (37.5%) patients were considered eligible for EVAR. Multivariate analysis revealed that proximal neck length, proximal neck angle, and aneurismal sac size were independent determinants for suitability of EVAR. Taking into account the increased clinical experience and the availability of new devices, EVAR would be applicable in about 40% of atherosclerotic AAA cases in this series of Korean patients. Accurate identification of candidates for EVAR by detailed preoperative evaluation, especially for morphologic characteristics, is essential.


Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets.
Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome-wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA-seq have the potential to produce nonbiased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA, and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x environmental interactions affecting brain functioning in health and disease.


[Consumption coagulopathy found in mitral stenosis associated with atrial thrombus].
Two cases of consumption coagulopathy found in the patients having mitral stenosis with atrial thrombus were reported. In case 1, although anticoagulant (Warfarin) administration did not correct the hemostatic abnormality, combination of tranexamic acid with anticoagulant was effective. In case 2, atrial thrombus found in the echocardiography prior to the onset of thromboembolism in the lower limbs has been disappeared after embolism. Anticoagulant was effective for the improvement of hemostatic abnormality. We considered mitral stenosis with atrial thrombus as one of causes of the consumption coagulopathy.


Left bundle branch block, atrioventricular block, torsade de pointes and long QT syndrome: is this too much for a rare cardiomyopathy?
Left ventricular noncompaction (LVNC) is now recognized as a distinct form of cardiomyopathy with a clinical presentation and natural history of its own. Common manifestations of LVNC include heart failure, ventricular arrhythmias and embolic events, but serious atrioventricular conduction disturbances are rarely reported in the literature. The authors describe the case of a 40-year-old woman who went to the emergency department due to syncope. The ECG revealed left bundle branch block (LBBB) and 2:1 atrioventricular block (AVB) and the patient was admitted for pacemaker implantation. During hospitalization she developed torsade de pointes and complete AVB with increased QTc. The echocardiogram showed images compatible with LVNC. This case provides additional evidence that LVNC may be complicated by 2:1 (or complete) AVB, intraventricular conduction disturbances (LBBB) and repolarization abnormalities (long QT). This combination of electrocardiographic changes has rarely been reported in the literature. We describe a series of affected patients, focusing on electrocardiographic characteristics.


Expression and characterization of human interferon-beta1 in the methylotrophic yeast Pichia pastoris.
We describe the heterologous expression of a human interferon-beta1 in the methylotrophic yeast Pichia pastoris. Biologically active recombinant human interferon-beta1 (rHuIFN-beta1) was secreted from shake-flask-grown P. pastoris cells into the medium using the Saccharomyces cerevisiae alpha-mating factor prepro-leader sequence at the level of (1-3) x 10(5) i.u. (international units)/ml (6-12 mg/litre). An rHuIFN-beta1 with an N-terminal sequence identical with that of native HuIFN-beta1 was purified and the specific activity was determined (2-3 x 10(7) i.u./mg). It was found that the secreted recombinant protein was partially N-glycosylated.


Investigation of the glycosyltransferase enzymes involved in the initial stages of the N-linked protein glycosylation pathway in Aspergillus niger.
A protocol has been developed to produce functional microsomes from mycelium of Aspergillus niger. Using these preparations, radioactive biochemical assays have been designed and optimised to measure the in vitro activities of three of the enzymes of the N-linked dolichol phosphate (Dol-P) glycosylation pathway: UDP-N-GlcNAc:dolichol-P GlcNAc-1-P transferase (GPT), Dol-P mannose synthase (DPMS) and Dol-P glucose synthase (DPGS). Exogenous Dol-P and Triton X-100 are essential for in vitro activity. All three Dol-P:glycosyl transferases had alkaline pH optima and activity rapidly decreased below neutrality. Characterisation of the glycolipid products by anion-exchange chromatography and TLC showed that they were Dol-P-P-GlcNAc, Dol-P-Glc and Dol-P-Man for GPT, DPGS and DPMS, respectively. The antibiotic tunicamycin completely inhibited GPT activity at a concentration of 100-200 ng ml(-1) and an IC50 of 40 ng ml(-1), but had little effect on the other two enzymes. The ratio of the activity of the three enzymes to each other suggested that DPMS may be involved in other cellular activities and is probably under different control mechanisms than the other two.


Consumption of deep-fried foods and risk of prostate cancer.
Evidence suggests that high-heat cooking methods may increase the risk of prostate cancer (PCa). The addition of oil/fat, as in deep-frying, may be of particular concern, and has not specifically been investigated in relation to PCa. Potential mechanisms include the formation of potentially carcinogenic agents such as aldehydes, acrolein, heterocyclic amines, polycyclic aromatic hydrocarbons, and acrylamide. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between tertiles of intake of deep-fried foods from a food frequency questionnaire (French fries, fried chicken, fried fish, doughnuts and snack chips) and PCa risk, adjusted for potential confounders, among 1,549 cases and 1,492 controls. We additionally examined associations with more aggressive PCa (defined as regional/distant stage, elevated Gleason score or prostate-specific antigen level). Compared with <1/week, there was a positive association with PCa risk for intake ≥1/week of French fries (OR = 1.37; 95% CI, 1.11-1.69), fried chicken (OR = 1.30; 95% CI, 1.04-1.62), fried fish (OR = 1.32; 95% CI, 1.05-1.66), and doughnuts (OR = 1.35; 95% CI, 1.11-1.66). There was no association for snack chips (OR = 1.08; 95% CI, 0.89-1.32). Most of the estimates were slightly stronger for more aggressive disease (OR = 1.41; 95% CI, 1.04-1.92 for fried fish). Regular consumption of select deep-fried foods is associated with increased PCa risk. Whether this risk is specific to deep-fried foods, or whether it represents risk associated with regular intake of foods exposed to high heat and/or other aspects of the Western lifestyle, such as fast food consumption, remains to be determined.


Proof of the Structure of the Stemodia chilensis Tetracyclic Diterpenoid (+)-19-Acetoxystemodan-12-ol by Synthesis from (+)-Podocarpic Acid: X-ray Structure Determination of a Key Intermediate.
The first synthesis of (+)-19-acetoxystemodan-12-ol (1), a stemodane diterpenoid isolated from Stemodia chilensis, is described. The structure was supported by an X-ray crystallographic analysis of intermediate (+)-9a, which confirmed the proposed structure and excluded the structure of (-)-19-hydroxystemod-12-ene as a possible candidate for the Chilean Calceolaria diterpenoid to which the (-)-19-hydroxystemar-13-ene structure (9b) had been erroneously assigned.


Untangling Influences in the Longitudinal Relationship Between Depressive Symptoms and Drinking Frequency in High School.
In young people, alcohol consumption and depressive symptoms are related, but the temporal ordering of the relationship is an open question. Previous studies have not disaggregated influences of interindividual and intraindividual components affecting the relationship. We investigated whether a reciprocal relationship between frequency of alcohol use and depressive symptoms exists in the general population of adolescents after removing interindividual influences. A total of 1,293 Canadian adolescents provided data on depressive symptoms and frequency of alcohol use every 3 months from grade 7 to 11 (1999-2005) for a total of 20 cycles. We used latent curve models with structured residuals, which disaggregate interindividual and intraindividual components to assess the directionality of the relationship. Both drinking frequency and depressive symptoms increased linearly and quadratically over time, with significant interindividual variation around the origin and rate of change. Intercepts and slopes for drinking frequency and depressive symptoms differed by sex and age. After controlling for sex, age, maternal education, sensation seeking, impulsivity and clustering by school, a significant positive association was observed between depressive symptoms and drinking frequency 3 months later (.032 [.004, .060]; p = .024), but no association was observed between drinking frequency and subsequent depressive symptoms (.011 [-.006 to .029]; p = .193). Our data provide longitudinal evidence that changes in depressive symptoms exceeding one's "normal" level predict increases in drinking frequency. This suggests that teaching youth to recognize and cope with mood changes would be worthwhile.


Concentrates containing factor IX could improve haemostasis under conditions of thrombocytopenia: studies in an in vitro model.
We explored the effect on haemostasis of different factor IX (FIX) concentrates under thrombocytopenic conditions using an in vitro perfusion technique. A moderate experimental thrombocytopenia (25 000-30 000 platelets/microl) was induced by means of a filtration procedure in blood anticoagulated with low-molecular-weight heparin. The effects of three different FIX concentrates - a prothrombin complex concentrate (PCC), an intermediate-purity concentrate (FIX/X), and a high-purity concentrate (HPFIX) - on platelet deposition and fibrin formation on subendothelium were assessed at two different shear rates (600/second and 1200/second). Activation of the coagulation system was monitored through assessment of prothrombin activation fragment 1 + 2 (F1 + 2). Fibrin deposition increased after addition of FIX concentrates, but only showed a significant increase in experiments performed after incubation of PCC at the lower shear rate (600/second) (64.25 +/- 9.61% vs. control 31.22 +/- 8.02%; P < 0.05). Addition of FIX concentrates caused a small increase in the percentage of platelet deposition and area of those aggregates. These differences reached levels of statistical significance in the presence of FIX/X and HPFIX in experiments performed at a shear rate of 600/second. F1 + 2 baseline values in anticoagulated thrombocytopenic blood were 1.15 +/- 0.13 nm and reached levels of 2.49 +/- 0.24 and 3.60 +/- 0.33 nm at shear rates of 600 and 1200/second, respectively. Increments in F1 + 2 observed after addition of different FIX concentrates always remained in the previous ranges. Data from the present study provide experimental support favouring the concept that FIX concentrates containing other activated factors could improve haemostasis under conditions of moderate thrombocytopenia.


Evaluation of Quality of Lower Limb Arthroplasty Observational Studies Using the Assessment of Quality in Lower Limb Arthroplasty (AQUILA) Checklist.
This study used the assessment of quality in lower limb arthroplasty (AQUILA) checklist to assess the quality of lower limb arthroplasty observational studies. Among 132 studies the mean reporting quality score was 5.4 (SD=1.2) out of 8 possible points. Most studies adequately reported reasons for revisions (98%) and prosthesis brand and fixation (95%) in sufficient detail. Only 3% of studies adequately reported the number of patients unwilling to participate, 15% stated a clear primary research question or hypothesis, 11% reported a worst-case analysis or competing risk analysis for endpoints, and 42% reported more than 5% of patients were lost to follow-up. There is significant room for improvement in the reporting and methodology of lower limb arthroplasty observational studies. Level III.