Uniportal video-assisted thoracic surgery Roman experience-a report of the first 16-month Roman experience.
The acceptance of uniportal video-assisted thoracic surgery (U-VATS) for thoracic procedures has been growing worldwide. This study reports one of the widest Italian U-VATS experiences. The prospectively collected data of 237 patients underwent a U-VATS procedure, between May 2016 and September 2017, were retrospectively reviewed. A wide range of procedures, like major and minor lung resections, esophageal surgery, pleural and mediastinal one, was performed. The main aim of the study was evaluating general outcomes in terms of safety and effectiveness, and analyzing short-term results of U-VATS approach. The mean age of population was 59.93±16.03 years. In 208 cases (85.3%) a U-VATS lung resection was performed, in 10 cases (4.1%) an esophagectomy or an esophageal diverticulectomy, in 15 (6.1%) a mediastinal procedure and in 11 (4.5%) a toilette for pleural empyema or removal of pleural lesions. The chest tube duration was 4.24±3.73 days and the postoperative hospital stay was 4.62±4.59 days. The intraoperative and thirty-day mortality were null. Mean level of pain in I postoperative day was 2.30±1.26 on VAS scale and the mean duration was of 1.54±1.21 days. In 93% of cases there was a resolution of pain after chest tube removal. Furthermore, the average level of cosmetic satisfaction was 2.73±0.49 (measured on a 0-3 scale). According to our experience, U-VATS seems to be a safe and practicable mini-invasive technique, above all for surgeons who already have thoracoscopy experience or made proper training attending multilevel courses, hands-on conferences and wet-labs.


Hyperkalaemic complete heart block. A report of 2 unique cases and a review of the literature.
Two White male patients with temporary complete heart block (CHB) secondary to hyperkalaemia are presented. One, a 40-year-old man, developed CHB with ensuing shock within the first 24 hours of repeat aortic valve replacement for a paraprosthetic leak caused by previous endocarditis. This patient experienced iatrogenic hyperkalaemia. The second was an 81-year-old man who had chronic renal failure and presented with Stokes-Adams attacks. This patient was initially thought to have degenerative CHB and nearly underwent inadvertent permanent pacemaker insertion. Both patients were initially treated with emergency temporary cardiac pacing with subsequent successful management. Temporary CHB secondary to hyperkalaemia, from whatever cause, has very rarely been documented in the literature. A review of this potentially lethal complication is undertaken and the significance of unifascicular and bifascicular conduction block as a consequence of hyperkalaemia is discussed.


[Mitral valve repair with concomitant coronary bypass for partial rupture of an anterior papillary muscle].
We report a case of severe mitral regurgitation due to partial rupture of an anterior papillary muscle. A 63-year-old man was admitted to a hospital with heart failure. He was treated with diuretic agents effectively. Echocardiography demonstrated severe mitral regurgitation with prolapse of posterior leaflet and small mass-like structure on the prolapsed segment that was diagnosed the thickened leaflet. Coronary angiography revealed total occlusion of left anterior descending artery (LAD) filled with good collateral from right posterior descending artery and severe diffuse stenosis of circumflex artery (Cx). The patient underwent surgery on the 33rd day after admission with heart failure. At surgery, we recognized rupture of one of the heads of anterior papillary muscle that was entangled in chordae of the prolapsed segment. Mitral valve repair and coronary revascularization to LAD and Cx was successfully performed. His postoperative course was uneventful, and he was discharged on the 28th postoperative day.


Circulating cell-free methylated DNA and lactate dehydrogenase release in colorectal cancer.
Hypermethylation of DNA is an epigenetic alteration commonly found in colorectal cancer (CRC) and can also be detected in blood samples of cancer patients. Methylation of the genes helicase-like transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1) have been proposed as prognostic, and neurogenin 1 (NEUROG1) as diagnostic biomarker. However the underlying mechanisms leading to the release of these genes are unclear. This study aimed at examining the possible correlation of the presence of methylated genes NEUROG1, HLTF and HPP1 in serum with tissue breakdown as a possible mechanism using serum lactate dehydrogenase (LDH) as a surrogate marker. Additionally the prognostic impact of these markers was examined. Pretherapeutic serum samples from 259 patients from all cancer stages were analyzed. Presence of hypermethylation of the genes HLTF, HPP1, and NEUROG1 was examined using methylation-specific quantitative PCR (MethyLight). LDH was determined using an UV kinetic test. Hypermethylation of HLTF and HPP1 was detected significantly more often in patients with elevated LDH levels (32% vs. 12% [p = 0.0005], and 68% vs. 11% [p < 0.0001], respectively). Also, higher LDH values correlated with a higher percentage of a fully methylated reference in a linear fashion (Spearman correlation coefficient 0.18 for HLTF [p = 0.004]; 0.49 [p < .0001] for HPP1). No correlation between methylation of NEUROG1 and LDH was found in this study. Concerning the clinical characteristics, high levels of LDH as well as methylation of HLTF and HPP1 were significantly associated with larger and more advanced stages of CRC. Accordingly, these three markers were correlated with significantly shorter survival in the overall population. Moreover, all three identified patients with a worse prognosis in the subgroup of stage IV patients. We were able to provide evidence that methylation of HLTF and especially HPP1 detected in serum is strongly correlated with cell death in CRC using LDH as surrogate marker. Additionally, we found that prognostic information is given by both HLTF and HPP1 as well as LDH. In sum, determining the methylation of HLTF and HPP1 in serum might be useful in order to identify patients with more aggressive tumors.


Genetic Kinship Analyses Reveal That Gray's Beaked Whales Strand in Unrelated Groups.
Some marine mammals are so rarely seen that their life history and social structure remain a mystery. Around New Zealand, Gray's beaked whales (Mesoplodon grayi) are almost never seen alive, yet they are a commonly stranded species. Gray's are unique among the beaked whales in that they frequently strand in groups, providing an opportunity to investigate their social organization. We examined group composition and genetic kinship in 113 Gray's beaked whales with samples collected over a 20-year period. Fifty-six individuals stranded in 19 groups (2 or more individuals), and 57 whales stranded individually. Mitochondrial control region haplotypes and microsatellite genotypes (16 loci) were obtained for 103 whales. We estimated pairwise relatedness between all pairs of individuals and average relatedness within, and between, groups. We identified 6 mother-calf pairs and 2 half-siblings, including 2 whales in different strandings 17 years and 1500 km apart. Surprisingly, none of the adults stranding together were related suggesting that groups are not formed through the retention of kin. These data suggest that both sexes may disperse from their mothers, and groups consisting of unrelated subadults are common. We also found no instances of paternity within the groups. Our results provide the first insights into dispersal, social organization, and the mating system in this rarely sighted species. Why whales strand is still unknown but, in Gray's beaked whales, the dead can tell us much about the living.


Echocardiographic Algorithm for Post-Myocardial Infarction LV Thrombus: A Gatekeeper for Thrombus Evaluation by Delayed Enhancement CMR.
The goal of this study was to determine the prevalence of post-myocardial infarction (MI) left ventricular (LV) thrombus in the current era and to develop an effective algorithm (predicated on echocardiography [echo]) to discern patients warranting further testing for thrombus via delayed enhancement (DE) cardiac magnetic resonance (CMR). LV thrombus affects post-MI management. DE-CMR provides thrombus tissue characterization and is a well-validated but an impractical screening modality for all patients after an MI. A same-day echo and CMR were performed according to a tailored protocol, which entailed uniform echo contrast (irrespective of image quality) and dedicated DE-CMR for thrombus tissue characterization. A total of 201 patients were studied; 8% had thrombus according to DE-CMR. All thrombi were apically located; 94% of thrombi occurred in the context of a left anterior descending (LAD) infarct-related artery. Although patients with thrombus had more prolonged chest pain and larger MI (p ≤ 0.01), only 18% had aneurysm on echo (cine-CMR 24%). Noncontrast (35%) and contrast (64%) echo yielded limited sensitivity for thrombus on DE-CMR. Thrombus was associated with stepwise increments in basal → apical contractile dysfunction on echo and quantitative cine-CMR; the echo-measured apical wall motion score was higher among patients with thrombus (p < 0.001) and paralleled cine-CMR decrements in apical ejection fraction and peak ejection rates (both p < 0.005). Thrombus-associated decrements in apical contractile dysfunction were significant even among patients with LAD infarction (p < 0.05). The echo-based apical wall motion score improved overall performance (area under the curve 0.89 ± 0.44) for thrombus compared with ejection fraction (area under the curve 0.80 ± 0.61; p = 0.01). Apical wall motion partitions would have enabled all patients with LV thrombus to be appropriately referred for DE-CMR testing (100% sensitivity and negative predictive value), while avoiding further testing in more than one-half (56% to 63%) of patients. LV thrombus remains common, especially after LAD MI, and can occur even in the absence of aneurysm. Although DE-CMR yielded improved overall thrombus detection, apical wall motion on a noncontrast echocardiogram can be an effective stratification tool to identify patients in whom DE-CMR thrombus assessment is most warranted. (Diagnostic Utility of Contrast Echocardiography for Detection of LV Thrombi Post ST Elevation Myocardial Infarction; NCT00539045).


First Report of Alternaria Blight of Potato Caused by Alternaria tenuissima in China.
Potato (Solanum tuberosum L.) is grown worldwide as a major food crop. Potato early blight is an important disease caused by Alternaria solani (4). In 2011, diseased potato leaves with blight symptoms were collected from 21 sites (incidence averaged 60% for about 2,000 ha of potato fields examined) in Gansu Province, northwest China. Small pieces of tissue taken from the margin between healthy and diseased tissues were surface-disinfected in 0.3% NaOCl for 2 min, rinsed with sterilized, distilled water, then placed on potato dextrose agar (PDA) at 25°C in the dark. Two of 24 Alternaria isolates from single-spore cultures were identified preliminarily as A. tenuissima, and the remaining isolates as A. solani or A. alternata, based on morphological traits. Colony appearance on potato carrot agar (PCA) was loosely cottony under a day/night cycle of 8 h fluorescent light/16 h dark at 22°C for 7 days (3). The isolates were characterized by formation of unbranched conidial chains up to 12 conidia in length, with one or two lateral branches forming occasionally. Conidia were typically ovoid to obclavate, and ranged from 20.4 to 42.4 × 7.7 to 13.2 μm. Transverse septa and longitudinal septa of conidia varied from 1 to 6 and 0 to 2, respectively. Short conidiophores arose singly and were 15.1 to 76.8 μm long by 2.4 to 6.2 μm wide. The internal transcribed spacer (ITS) region of rDNA and partial coding sequence of a histone gene were amplified from genomic DNA of the two A. tenuissima isolates using the ITS1/ITS4 and H3-1a/H3-1b primers (2), respectively. The ITS sequences of the two isolates (GenBank Accession Nos. JX495165 and JX495166) were 100% identical to those of A. tenuissima strains sdau 07-100 and BL08-3 (GQ871507 and AB470887), as well as to other Alternaria species, but the partial histone gene sequences (JX495167 and JX495168) were 99% identical to those of A. tenuissima isolates CR27, MA1, MA6, and CN-L-01 (AF404622, AF404633, AF404634, and EF371552, respectively) with less similarity to those of other Alternaria spp. Therefore, the isolates were identified as A. tenuissima based on morphological and molecular characteristics. Pathogenicity tests were conducted by inoculating detached leaves (30 per isolate) from 45-day-old plants of potato cv. Favorita with 20 μl drops (one drop per leaf) of a conidial suspension containing 106 conidia/ml in sterilized, distilled water. Thirty control leaves were inoculated similarly with sterilized, distilled water. Inoculated leaves were incubated in chambers at 25°C and 90% RH with a 12-h photoperiod/day. After 7 days, symptoms on the inoculated leaves were similar to those naturally occurring on the original plants, and the two cultures were reisolated consistently from those leaves, and the species identity was confirmed by morphological and molecular characteristics, fulfilling Koch's postulates. The control leaves remained asymptomatic and Alternaria was not isolated from those leaves. Alternaria blight of potato caused by A. tenuissima was previously detected in Iran (1). To our knowledge, this is the first report of A. tenuissima causing blight on potatoes in China. References: (1) S. T. Ardestani et al. Iran. J. Plant Pathol. 45:83, 2010. (2) N. L. Glass and G. C. Donaldson. Appl. Environ. Microbiol. 61:1323, 1995. (3) E. G. Simmons. Alternaria. An Identification Manual. CBS Fungal Biodiversity Centre, Utrecht, the Netherlands, 2007. (4) J. E. van der Waals et al. Plant Dis. 88:959, 2004.


MicroRNAs as Important Players and Biomarkers in Oral Carcinogenesis.
Oral cancer, represented mainly by oral squamous cell carcinoma (OSCC), is the eighth most common type of human cancer worldwide. The number of new OSCC cases is increasing worldwide, especially in the low-income countries, and the prognosis remains poor in spite of recent advances in the diagnostic and therapeutic modalities. MicroRNAs (miRNAs), 18-25 nucleotides long noncoding RNA molecules, have recently gained significant attention as potential regulators and biomarkers for carcinogenesis. Recent data show that several miRNAs are deregulated in OSCC, and they have either a tumor suppressive or an oncogenic role in oral carcinogenesis. This review summarizes current knowledge on the role of miRNAs as tumor promotors or tumor suppressors in OSCC development and discusses their potential value as diagnostic and prognostic markers in OSCC.


Electrical responses of eggs to acrosomal protein similar to those induced by sperm.
The earliest known response of eggs to sperm in many species is a change in egg membrane potential. However, for no species is it known what components of the sperm cause the opening of the egg plasma membrane channels. Protein isolated from sperm acrosomal granules of the marine worm Urechis caused electrical responses in oocytes with the same form, amplitude, and ion dependence as the fertilization potentials induced by living sperm. Sperm initiated fertilization potentials in oocytes when sperm-oocyte fusion, but not binding, was inhibited by clamping oocyte membrane potentials to positive values. Acrosomal protein also initiated electrical responses in clamped oocytes. These results support the hypothesis that it is the sperm acrosomal protein that opens ion channels in the oocyte membrane.


Ovarian microcystic stromal tumor: A novel extracolonic tumor in familial adenomatous polyposis.
Ovarian microcystic stromal tumor (MCST) is a very rare neoplasm; hence, its nomenclature was recently designated as "Distinctive morphologic and immunohistochemical features" in 2009. Its exact origin, etiological genetic alterations, and background are not yet clearly known. Familial adenomatous polyposis (FAP) is an autosomal dominant disease that leads to development of colorectal polyps via germ-line mutations of the APC gene on chromosome 5q21∼22. In this study, we report a 40-year-old female patient who had ovarian MCST and FAP. On sequencing the APC gene in ovarian MSCT, we detected a novel somatic mutation of the APC gene in exon 11, with a heterozygous deletion at nucleotide position c.1540delG (p.Ala514 Profs*9). Mutations of β-catenin (CTNNB1) and FOXL2 were not detected. Although one case demonstrating involvement of Wnt/β-catenin in ovarian MCST associated with FAP has been presented previously, no detailed information was provided. Thus, this is the ovarian MCST with a somatic mutation of APC in a patient with FAP.


Effect of controlled oxygen therapy on arterial blood gases in acute respiratory failure.
Seven patients in acute exacerbation of chronic respiratory failure were given 24.5% and later 28% oxygen through Ventimasks. The mean increases in arterial PO(2) were 11 and 21 mm. Hg while breathing 24.5% and 28% oxygen respectively compared with control values while breathing air. Associated increases in arterial PCO(2) were 4 and 8 mm. Hg, respectively. In five of the patients these increases in inspired oxygen concentration resulted in useful increases in tissue oxygen supply without significant deterioration in ventilation, but in two patients arterial PCO(2) rose excessively and artificial ventilation was required.


Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention.
Long COVID is a common occurrence following COVID-19 infection. The most common symptom reported is fatigue. Limited interventional treatment options exist. We report the first evaluation of hyperbaric oxygen therapy (HBOT) for long COVID treatment. A total of 10 consecutive patients received 10 sessions of HBOT to 2.4 atmospheres over 12 days. Each treatment session lasted 105 minutes, consisting of three 30-minute exposures to 100% oxygen, interspersed with 5-minute air breaks. Validated fatigue and cognitive scoring assessments were performed at day 1 and 10. Statistical analysis was with Wilcoxon signed-rank testing reported alongside effect sizes. HBOT yielded a statistically significant improvement in the Chalder fatigue scale (p=0.0059; d=1.75 (very large)), global cognition (p=0.0137; d=-1.07 (large)), executive function (p=0.0039; d=-1.06 (large)), attention (p=0.0020; d=-1.2 (very large)), information processing (p=0.0059; d=-1.25 (very large)) and verbal function (p=0.0098; d=-0.92 (large)). Long COVID-related fatigue can be debilitating, and may affect young people who were previously in economic employment. The results presented here suggest potential benefits of HBOT, with statistically significant results following 10 sessions.


Initial experience with the new ethylene vinyl alcohol copolymer based liquid embolic agent Menox in the endovascular treatment of cerebral arteriovenous malformations.
Liquid embolic agents (LEAs) are the determinant tool for successful embolization of cranial arteriovenous shunts. There are few currently available LEAs. The aim of the study was to summarize our initial experience with a recently introduced non-adhesive ethylene vinyl alcohol (EVOH) copolymer based LEA (Menox 18) in the endovascular treatment of cerebral arteriovenous malformations. From April 2018 to November 2018, 24 patients harboring cerebral arteriovenous malformations underwent endovascular embolization with Menox 18. Clinical features, angiographic results, procedural details, complications, and follow-up details were prospectively collected and retrospectively analyzed. Curative embolization in one endovascular session was achieved in 14/24 (58.3%) of the treated patients. Partial embolization was achieved in 10 patients (42.6%) in whom staged treatment with radiosurgery or microsurgical resection was planned. No mortality was recorded in our series. Clinical complications after embolization occurred in 1/24 (4.66%) patients. No technical complications were noted CONCLUSIONS: Our pilot study suggests that the Menox embolization system offers similar technical and clinical results in comparison with the other currently available LEAs. Further studies with larger cohorts and long term follow-up data are needed to fully evaluate its efficacy.


Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry.
Most cancer cells predominantly produce energy by glycolysis rather than oxidative phosphorylation via the tricarboxylic acid (TCA) cycle, even in the presence of an adequate oxygen supply (Warburg effect). However, little has been reported regarding the direct measurements of global metabolites in clinical tumor tissues. Here, we applied capillary electrophoresis time-of-flight mass spectrometry, which enables comprehensive and quantitative analysis of charged metabolites, to simultaneously measure their levels in tumor and grossly normal tissues obtained from 16 colon and 12 stomach cancer patients. Quantification of 94 metabolites in colon and 95 metabolites in stomach involved in glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acid and nucleotide metabolisms resulted in the identification of several cancer-specific metabolic traits. Extremely low glucose and high lactate and glycolytic intermediate concentrations were found in both colon and stomach tumor tissues, which indicated enhanced glycolysis and thus confirmed the Warburg effect. Significant accumulation of all amino acids except glutamine in the tumors implied autophagic degradation of proteins and active glutamine breakdown for energy production, i.e., glutaminolysis. In addition, significant organ-specific differences were found in the levels of TCA cycle intermediates, which reflected the dependency of each tissue on aerobic respiration according to oxygen availability. The results uncovered unexpectedly poor nutritional conditions in the actual tumor microenvironment and showed that capillary electrophoresis coupled to mass spectrometry-based metabolomics, which is capable of quantifying the levels of energy metabolites in tissues, could be a powerful tool for the development of novel anticancer agents that target cancer-specific metabolism.


Interventions used to improve control of blood pressure in patients with hypertension.
It is well recognized that patients with high blood pressure (hypertension) in the community frequently fail to meet treatment goals- a condition labeled as "uncontrolled" hypertension. The optimal way in which to organize and deliver care to patients who have hypertension so that they reach treatment goals has not been clearly identified. To determine the effectiveness of interventions to improve control of blood pressure in patients with elevated blood pressure. To evaluate the ability of reminders to improve the follow-up of patients with elevated blood pressure. All-language search of all articles (any year) in the Cochrane Controlled Trials Register (CCTR), Medline and Embase from June 2000. Randomised controlled trials (RCTs) of patients with hypertension that evaluated the following interventions: (1) self-monitoring (2) educational interventions directed to the patient (3) educational interventions directed to the health professional (4) health professional (nurse or pharmacist) led care (5) organisational interventions that aimed to improve the delivery of care (6) appointment reminder systems. OUTCOMES ASSESSED WERE: (1) mean systolic and diastolic blood pressure (2) control of blood pressure (3) proportion of patients followed up at clinic. Two authors extracted data independently and in duplicate and assessed each study according to the criteria outlined by the Cochrane Collaboration Handbook. 59 RCTs met our inclusion criteria. The methodological quality of included studies was variable. An organized system of regular review linked to vigorous antihypertensive drug therapy was shown to reduce blood pressure (weighted mean difference -8.2/-4.2 mmHg, -11.7/-6.5 mmHg, -10.6/-7.6 mmHg for 3 strata of entry blood pressure) and all-cause mortality at five years follow-up (6.38% versus 7.78%, difference 1.4%) in a single large RCT- the Hypertension Detection and Follow-Up study. Other interventions had variable effects. Self-monitoring was associated with moderate net reduction in diastolic blood pressure (weighted mean difference (WMD): -2.03 mmHg, 95%CI: -2.69 to -1.38 mmHg, respectively. Appointment reminders increased the proportion of individuals who attended for follow-up. RCTs of educational interventions directed at patients or health professionals were heterogeneous but appeared unlikely to be associated with large net reductions in blood pressure by themselves. Health professional (nurse or pharmacist) led care may be a promising way of delivering care, with the majority of RCTs being associated with improved blood pressure control, but requires further evaluation. Family practices and community-based clinics need to have an organized system of regular follow-up and review of their hypertensive patients. Antihypertensive drug therapy should be implemented by means of a systematic stepped care approach when patients do not reach target blood pressure levels.


Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus.
Autoantibodies against cytokines, chemokines, and growth factors inhibit normal immunity and are implicated in inflammatory autoimmune disease and diseases of immune deficiency. In an effort to evaluate serum from autoimmune and immunodeficient patients for Abs against cytokines, chemokines, and growth factors in a high-throughput and unbiased manner, we constructed a multiplex protein microarray for detection of serum factor-binding Abs and used the microarray to detect autoantibody targets in SLE. We designed a nitrocellulose-surface microarray containing human cytokines, chemokines, and other circulating proteins and demonstrated that the array permitted specific detection of serum factor-binding probes. We used the arrays to detect previously described autoantibodies against cytokines in samples from individuals with autoimmune polyendocrine syndrome type 1 and chronic mycobacterial infection. Serum profiling from individuals with SLE revealed that among several targets, elevated IgG autoantibody reactivity to B cell-activating factor (BAFF) was associated with SLE compared with control samples. BAFF reactivity correlated with the severity of disease-associated features, including IFN-α-driven SLE pathology. Our results showed that serum factor protein microarrays facilitate detection of autoantibody reactivity to serum factors in human samples and that BAFF-reactive autoantibodies may be associated with an elevated inflammatory disease state within the spectrum of SLE.


[Hepatitis B: who should be treated?].
Currently, therapy for hepatitis B has a limited effect and can rarely eradicate infection (ALT normalization, undetectable HBV DNA, HBsAg/anti-HBs seroconversion). Minimal progress in terms of treatment success has been achieved in the past four years. Changes from the previous Croatian Consensus Conferences in 2005 and 2009 are based on standings of the Consensus Conference of the American Association for the Study of Liver Disease (AASLD) 2009, Consensus Conference of the European Association for the Study of Liver (EASL) 2012, and Asia-Pacific Association Guidelines for the Study of Liver (APASL) 2012. In this paper, we will mention only differences in relation to the before mentioned Croatian guidelines from 2005 and 2009. New developments relating to the application of noninvasive methods for assessing fibrosis, quantification of HBsAg to predict treatment outcome, registration of new drugs, and some new recommendations for more efficient and rational treatment will be reviewed. New findings as well as recommendations for the treatment of patients in special circumstances including treatment of pregnant women, patients with drug resistance, patients with co-infection, hepatic decompensation, patients on immune and chemotherapy, patients after liver transplantation, and patients with HCC will also be included.


Cognitive reserve in ageing and Alzheimer's disease.
The concept of cognitive reserve provides an explanation for differences between individuals in susceptibility to age-related brain changes or pathology related to Alzheimer's disease, whereby some people can tolerate more of these changes than others and maintain function. Epidemiological studies suggest that lifelong experiences, including educational and occupational attainment, and leisure activities in later life, can increase this reserve. For example, the risk of developing Alzheimer's disease is reduced in individuals with higher educational or occupational attainment. Reserve can conveniently be divided into two types: brain reserve, which refers to differences in the brain structure that may increase tolerance to pathology, and cognitive reserve, which refers to differences between individuals in how tasks are performed that might enable some people to be more resilient to brain changes than others. Greater understanding of the concept of cognitive reserve could lead to interventions to slow cognitive ageing or reduce the risk of dementia.


Guanosine 3',5'-cyclic monophosphate as a mediator of inhibition of renin release.
The role of guanosine 3',5'-cyclic monophosphate (cGMP) as an inhibitory mediator of tissue renin release was examined in two different in vitro preparations. In rat superficial cortical slices, renin release stimulated by isoproterenol (10(-5) M) was ablated by atriopeptin III (ANP, 2.1 x 10(-8) M), nitroprusside (NP, 10(-3) M), and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 10(-3) and 10(-6) M). Arachidonic acid (10(-3) M)-stimulated renin release was also inhibited by ANP and 8-BrcGMP (10(-3) and 10(-6) M). Both ANP and NP increased tissue cGMP concentrations significantly (P less than 0.05), but neither had an effect on adenosine 3',5'-cyclic monophosphate (cAMP) concentrations. When methylene blue (10(-5) M), an inhibitor of guanylate cyclase, was added to slices incubated with isoproterenol and ANP, the inhibition of renin release by ANP was abolished. These results were confirmed in a preparation of isolated cultured rat juxtaglomerular cells. In these cells, isoproterenol induced a significant increase (58%, P less than 0.01) in renin release, which was inhibited by the addition of 8-BrcGMP (10(-6) M). These data demonstrate a direct inhibitory effect of ANP on isoproterenol- and arachidonic acid-induced renin release. The results with NP, 8-BrcGMP, and methylene blue suggest that cGMP is an intracellular mediator of this inhibition.


API5 induces cisplatin resistance through FGFR signaling in human cancer cells.
Most tumors frequently undergo initial treatment with a chemotherapeutic agent but ultimately develop resistance, which limits the success of chemotherapies. As cisplatin exerts a high therapeutic effect in a variety of cancer types, it is often used in diverse strategies, such as neoadjuvant, adjuvant and combination chemotherapies. However, cisplatin resistance has often manifested regardless of cancer type, and it represents an unmet clinical need. Since we found that API5 expression was positively correlated with chemotherapy resistance in several specimens from patients with cervical cancer, we decided to investigate whether API5 is involved in the development of resistance after chemotherapy and to explore whether targeting API5 or its downstream effectors can reverse chemo-resistance. For this purpose, cisplatin-resistant cells (CaSki P3 CR) were established using three rounds of in vivo selection with cisplatin in a xenografted mouse. In the CaSki P3 CR cells, we observed that API5 acted as a chemo-resistant factor by rendering cancer cells resistant to cisplatin-induced apoptosis. Mechanistic investigations revealed that API5 mediated chemo-resistance by activating FGFR1 signaling, which led to Bim degradation. Importantly, FGFR1 inhibition using either an siRNA or a specific inhibitor disrupted cisplatin resistance in various types of API5high cancer cells in an in vitro cell culture system as well as in an in vivo xenograft model. Thus, our results demonstrated that API5 promotes chemo-resistance and that targeting either API5 or its downstream FGFR1 effectors can sensitize chemo-refractory cancers.


Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth.
FAK (focal adhesion kinase) and IGF-1R (insulin-like growth factor receptor-1) directly interact with each other and thereby activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function has been shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. As a novel approach in human melanoma, we evaluated the effect of a small-molecule compound that disrupts the protein interaction of FAK and IGF-1R. Previously, using virtual screening and functional testing, we identified a lead compound (INT2-31) that targets the known FAK-IGF-1R protein interaction site. We studied the ability of this compound to disrupt FAK-IGF-1R protein interactions, inhibit downstream signaling, decrease human melanoma cell proliferation, alter cell cycle progression, induce apoptosis and decrease tumor growth in vivo. INT2-31 blocked the interaction of FAK and IGF-1R in vitro and in vivo in melanoma cells and tumor xenografts through precluding the activation of IRS-1, leading to reduced phosphorylation of AKT upon IGF-1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05-10 μM). More importantly, 15 mg/kg of INT2-31 given for 21 d via intraperitoneal injection disrupted the interaction of FAK and IGF-1R and effectively decreased phosphorylation of tumor AKT, resulting in significant melanoma tumor regression in vivo. Our data suggest that the FAK-IGF-1R protein interaction is an important target, and disruption of this interaction with a novel small molecule (INT2-31) has potential anti-neoplastic therapeutic effects in human melanoma.


Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness.
Bronchial mucosal inflammation and epithelial damage are characteristic features of asthma. Activation of T helper lymphocytes may contribute to this process by mechanisms including the release of cytokines promoting eosinophil infiltration and activation. Bronchial washings and bronchoalveolar lavage fluid were obtained from 29 atopic asthmatic patients (19 with current symptoms and 10 symptom free) and 13 normal volunteers. Flow cytometry was used to assess T cell phenotype and activation status in bronchoalveolar lavage fluid and peripheral blood, and differential cell counts were made on bronchial washings and bronchoalveolar lavage fluid. Findings were related to severity of disease as reflected by symptom scores, baseline lung function, and airway responsiveness. CD4 T lymphocytes in bronchoalveolar lavage fluid and blood from asthmatic patients were activated by comparison with controls (CD4 CD25, median 16.8% v 8.7% for bronchoalveolar lavage fluid, and 15.3% v 8.7% in blood). Bronchoalveolar lavage fluid CD4 T cells from both asthmatic patients and controls were of memory phenotype (95.8% and 96.8% CD45RO and 1.7% and 0.4% CD45RA respectively), whereas both CD45RO and CD45RA T cells were present in blood. Patients with asthma and current symptoms showed increased bronchoalveolar T cell activation compared with patients without symptoms (CD4 CD25 18.7% v 12.3%). Within the asthmatic group there was a significant association between CD4 CD25 lymphocytes and asthma symptom scores (rs = 0.75), airway methacholine responsiveness (log PC20, rs = -0.43) and baseline FEV1 (rs = -0.39). A correlation was also found between CD4 CD25 lymphocytes and eosinophils in bronchoalveolar lavage fluid (rs = 0.48). Eosinophils in bronchoalveolar lavage fluid were increased in asthmatic patients compared with controls and the percentage of eosinophils in bronchoalveolar lavage fluid correlated with asthma symptom score. A relation was found between percentage of epithelial cells in bronchoalveolar lavage fluid and FEV1 and methacholine PC20. These results support the hypothesis that selective activation of memory CD4 T cells contributes to eosinophil accumulation, bronchial hyperresponsiveness, and symptoms in asthma.


Heidelberg Retina Tomograph 3 machine learning classifiers for glaucoma detection.
To assess performance of classifiers trained on Heidelberg Retina Tomograph 3 (HRT3) parameters for discriminating between healthy and glaucomatous eyes. Classifiers were trained using HRT3 parameters from 60 healthy subjects and 140 glaucomatous subjects. The classifiers were trained on all 95 variables and smaller sets created with backward elimination. Seven types of classifiers, including Support Vector Machines with radial basis (SVM-radial), and Recursive Partitioning and Regression Trees (RPART), were trained on the parameters. The area under the ROC curve (AUC) was calculated for classifiers, individual parameters and HRT3 glaucoma probability scores (GPS). Classifier AUCs and leave-one-out accuracy were compared with the highest individual parameter and GPS AUCs and accuracies. The highest AUC and accuracy for an individual parameter were 0.848 and 0.79, for vertical cup/disc ratio (vC/D). For GPS, global GPS performed best with AUC 0.829 and accuracy 0.78. SVM-radial with all parameters showed significant improvement over global GPS and vC/D with AUC 0.916 and accuracy 0.85. RPART with all parameters provided significant improvement over global GPS with AUC 0.899 and significant improvement over global GPS and vC/D with accuracy 0.875. Machine learning classifiers of HRT3 data provide significant enhancement over current methods for detection of glaucoma.


Smoking, body mass index, disease activity, and the risk of rapid radiographic progression in patients with early rheumatoid arthritis.
Identification of risk factors for rapid joint destruction in early rheumatoid arthritis (RA) can be helpful for optimizing treatment, and improving our understanding of destructive arthritis and its mechanisms. The objective of this study was to investigate the relationship between early RA patient characteristics and subsequent rapid radiographic progression (RRP). An inception cohort of patients with early RA (symptom duration < 12 months), recruited during 1995-2005 from a defined area (Malmö, Sweden), was investigated. Radiographs of the hands and feet were scored in chronological order according to the modified Sharp-van der Heijde score (SHS), by a trained reader. RRP was defined as an increase of ≥ 5 points in SHS per year. Two hundred and thirty-three patients were included. Radiographs were available from 216 patients at baseline, 206 patients at 1 year, and 171 patients at 5 years. Thirty-six patients (22%) had RRP up to 5 years. In logistic regression models, rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP), and increased erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) at baseline, predicted RRP over 5 years. Patients identified as overweight or obese had a significantly reduced risk of RRP up to 5 years (odds ratio (OR) 0.26; 95% confidence interval (CI) 0.11-0.63; adjusted for RF, baseline erosions, and ESR). Similar point estimates were obtained when stratifying for antibody status, and in models adjusted for smoking. A history of ever smoking was associated with a significantly increased risk of RRP up to 5 years, independent of body mass index (BMI) (OR 3.17; 95% CI 1.22-8.28; adjusted for BMI). At the 1-year follow-up, erosive changes, Disease Activity Score of 28 joints, Health Assessment Questionnaire, swollen joint count, and patient's global assessment of disease activity and pain were also significantly associated with RRP up to 5 years. A history of smoking, presence of RF and/or anti-CCP and early erosions, high initial disease activity and active disease at 1 year, all increase the risk of RRP. Patients with a high BMI may have a reduced risk of severe joint damage. This pattern was not explained by differences in disease activity or antibody status. The results of this study suggest independent effects of smoking and BMI on the risk of RRP.


The 4p1000 initiative: Opportunities, limitations and challenges for implementing soil organic carbon sequestration as a sustainable development strategy.
Climate change adaptation, mitigation and food security may be addressed at the same time by enhancing soil organic carbon (SOC) sequestration through environmentally sound land management practices. This is promoted by the "4 per 1000" Initiative, a multi-stakeholder platform aiming at increasing SOC storage through sustainable practices. The scientific and technical committee of the Initiative is working to identify indicators, research priorities and region-specific practices needed for their implementation. The Initiative received its name due to the global importance of soils for climate change, which can be illustrated by a thought experiment showing that an annual growth rate of only 0.4% of the standing global SOC stocks would have the potential to counterbalance the current increase in atmospheric CO2. However, there are numerous barriers to the rise in SOC stocks and while SOC sequestration can contribute to partly offsetting greenhouse gas emissions, its main benefits are related to increased soil quality and climate change adaptation. The Initiative provides a collaborative platform for policy makers, practitioners, scientists and stakeholders to engage in finding solutions. Criticism of the Initiative has been related to the poor definition of its numerical target, which was not understood as an aspirational goal. The objective of this paper is to present the aims of the initiative, to discuss critical issues and to present challenges for its implementation. We identify barriers, risks and trade-offs and advocate for collaboration between multiple parties in order to stimulate innovation and to initiate the transition of agricultural systems toward sustainability.


A randomized comparison of pupil-centered versus vertex-centered ablation in LASIK correction of hyperopia.
To compare visual and optical outcomes of pupil-centered vs vertex-centered ablation in patients undergoing laser-assisted in situ keratomileusis (LASIK) for hyperopia. Randomized, double-masked, prospective, single-center trial. Institutional practice. Sixty eyes of 30 patients with low and moderate hyperopia. Intervention procedure: Eyes underwent LASIK (Allegretto excimer laser). In 30 eyes, the ablation was centered on the pupil, while in the 30 other eyes the ablation was centered on the corneal reflex. Primary outcome measure was the safety index. Main secondary outcome measures were efficacy index, manifest refraction, uncorrected visual acuity, best spectacle-corrected visual acuity (BCVA), and ocular high-order aberrations for a 6-mm pupil size. At 3 months postoperatively, the safety index was 0.99 ± 0.04 in the pupil-centered group and 0.99 ± 0.08 in the vertex-centered group (P = .97). The efficacy index was also similar for both groups: 0.96 ± 0.05 in pupil-centered eyes and 0.93 ± 0.09 in vertex-centered eyes (P = .31). Optical aberrations were similar for pupil-centered and vertex-centered eyes. Considering only eyes showing large pupil decentration, we found a tendency for better visual results in favor of pupil-centered eyes in terms of safety index and a slight but significant increase of coma in vertex-centered eyes. LASIK is an effective procedure for treatment of hyperopia. Pupil-centered and vertex-centered treatments provide similar visual and optical outcomes. However, in eyes showing large temporal pupil decentration, pupil-centered ablation seemed to produce a lower amount of coma and, as a consequence, a reduced loss of BCVA compared with vertex-centered patients.


Sources of human psychological differences: the Minnesota Study of Twins Reared Apart.
Since 1979, a continuing study of monozygotic and dizygotic twins, separated in infancy and reared apart, has subjected more than 100 sets of reared-apart twins or triplets to a week of intensive psychological and physiological assessment. Like the prior, smaller studies of monozygotic twins reared apart, about 70% of the variance in IQ was found to be associated with genetic variation. On multiple measures of personality and temperament, occupational and leisure-time interests, and social attitudes, monozygotic twins reared apart are about as similar as are monozygotic twins reared together. These findings extend and support those from numerous other twin, family, and adoption studies. It is a plausible hypothesis that genetic differences affect psychological differences largely indirectly, by influencing the effective environment of the developing child. This evidence for the strong heritability of most psychological traits, sensibly construed, does not detract from the value or importance of parenting, education, and other propaedeutic interventions.


Interleukin-5 facilitates lung metastasis by modulating the immune microenvironment.
Although the lung is the most common metastatic site for cancer cells, biologic mechanisms regulating lung metastasis are not fully understood. Using heterotopic and intravenous injection models of lung metastasis in mice, we found that IL5, a cytokine involved in allergic and infectious diseases, facilitates metastatic colonization through recruitment of sentinel eosinophils and regulation of other inflammatory/immune cells in the microenvironment of the distal lung. Genetic IL5 deficiency offered marked protection of the lungs from metastasis of different types of tumor cells, including lung cancer, melanoma, and colon cancer. IL5 neutralization protected subjects from metastasis, whereas IL5 reconstitution or adoptive transfer of eosinophils into IL5-deficient mice exerted prometastatic effects. However, IL5 deficiency did not affect the growth of the primary tumor or the size of metastatic lesions. Mechanistic investigations revealed that eosinophils produce CCL22, which recruits regulatory T cells to the lungs. During early stages of metastasis, Treg created a protumorigenic microenvironment, potentially by suppressing IFNγ-producing natural killer cells and M1-polarized macrophages. Together, our results establish a network of allergic inflammatory circuitry that can be co-opted by metastatic cancer cells to facilitate lung colonization, suggesting interventions to target this pathway may offer therapeutic benefits to prevent or treat lung metastasis.


Some properties of new nesting areas of sea turtles in north-eastern Mediterranean situated on the extension of the Samandag Beach, Turkey.
One of the most endangered species in tropical seas, Chelonia mydas (green turtles) prefer undisturbed sand beaches to lay their eggs. While Caretta caretta lays their eggs all over the Mediterranean beaches of Turkey, C. mydas nesting locations are limited with north-eastern site (Alata, Kazanli, Akyatan and Samandag) of the country and some beaches in Cyprus. Until 2003, no nesting place of both species between Akyatan and Samandag was recorded. From north to south, the beaches examined in 2003 summer are Arsuz, Konacik, Kale, Tr-H-3, Tr-H-2, and Tr-H-1 in addition to well-known and studied nesting beaches of sea turtle species in Hatay Province: Cevlik, Seyhhizir and Meydan. Since the Hatay Provincial Coast between Cevlik and Arsuz is hilly and no stabilized road is available, these small beaches were not known to have both C. mydas and C. caretta nests. Some physical and chemical sand properties, the number of nests belong to both species and selected nest specifications were investigated in this study. Kale Beach was found to be the most important nesting place in this less populated area. Based on results, Kale, Tr-H-3 and Tr-H-1 beaches were recorded to have high hatchling success.


Cost-effectiveness of extended release naltrexone to prevent relapse among criminal justice-involved individuals with a history of opioid use disorder.
Criminal justice-involved individuals are highly susceptible to opioid relapse and overdose-related deaths. In a recent randomized trial, we demonstrated the effectiveness of extended-release naltrexone (XR-NTX; Vivitrol® ) in preventing opioid relapse among criminal justice-involved US adults with a history of opioid use disorder. The cost of XR-NTX may be a significant barrier to adoption. Thus, it is important to account for improved quality of life and downstream cost-offsets. Our aims were to (1) estimate the incremental cost per quality-adjusted life-year (QALY) gained for XR-NTX versus treatment as usual (TAU) and evaluate it relative to generally accepted value thresholds; and (2) estimate the incremental cost per additional year of opioid abstinence. Economic evaluation of the aforementioned trial from the taxpayer perspective. Participants were randomized to 25 weeks of XR-NTX injections or TAU; follow-up occurred at 52 and 78 weeks. Five study sites in the US Northeast corridor. A total of 308 participants were randomized to XR-NTX (n = 153) or TAU (n = 155). Incremental costs relative to incremental economic and clinical effectiveness measures, QALYs and abstinent years, respectively. The 25-week cost per QALY and abstinent-year figures were $162 150 and $46 329, respectively. The 78-week figures were $76 400/QALY and $16 371/abstinent year. At 25 weeks, we can be 10% certain that XR-NTX is cost-effective at a value threshold of $100 000/QALY and 62% certain at $200 000/QALY. At 78 weeks, the cost-effectiveness probabilities are 59% at $100 000/QALY and 76% at $200 000/QALY. We can be 95% confident that the intervention would be considered 'good value' at $90 000/abstinent year at 25 weeks and $500/abstinent year at 78 weeks. While extended-release naltrexone appears to be effective in increasing both quality-adjusted life-years (QALYs) and abstinence, it does not appear to be cost-effective using generally accepted value thresholds for QALYs, due to the high price of the injection.


Systems toxicology approach to understand the kinetics of benzo(a)pyrene uptake, biotransformation, and DNA adduct formation in a liver cell model.
Cell-based models are important for deriving mechanistic information about stress response pathways that have evolved to protect cells from toxic insult, such as exposure to environmental pollutants. One determinant of the stress response is the amount of chemical entering the cell and the cell's ability to detoxify and remove the chemical. If the stress response is overwhelmed, an adverse outcome will ensue. It was the goal of our study to quantify uptake and elimination rates of benzo(a)pyrene (BaP), a ubiquitous environmental pollutant, in a murine liver cell line. We evaluated the kinetic behavior in the context of BaP uptake, biotransformation, DNA adduct formation and repair along with the transcriptional and cell proliferation response. A low (50 nM) and a high (5 μM) BaP concentration were chosen in order to differentiate the role of exposure concentration in the time-resolved interaction of BaP with cells. While rates of uptake and the initial transcriptional response were similar for both BaP concentrations, cells exposed to 50 nM BaP completely recovered from exposure within 24 h, whereas cells exposed to 5 μM BaP did not. Biotransformation proceeded faster on 50 nM BaP, and the few DNA adducts formed were completely repaired after transient cell cycle arrest. In contrast, DNA adducts greatly accumulated in cells exposed to 5 μM BaP, despite significant biotransformation; complete cell cycle arrest and toxicity evolved. On the basis of the kinetic rate constants and cellular response, we conclude that at least short-term, pulsed exposures to 50 nM BaP, which we consider environmentally relevant, can be handled by cells without adverse outcome. Further studies are needed to determine the ability of cells to recover from repeated exposure. Our study emphasizes the importance of quantifying chemical uptake and fate in cell models to differentiate a stress response from an adverse outcome for better risk assessment.


Photonic crystal-based bending waveguides for optical interconnections.
Various bending waveguides with different bending angles in photonic crystal are proposed and studied. Analyses show that the bending waveguides can provide a high transmission for the whole frequencies within the photonic band gap. Numerical simulations confirm that high transmissions over 98.5% can be achieved for the proposed waveguides.


Nonalcoholic fatty liver disease in children: recent practice guidelines, where do they take us?
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States. It is strongly associated with childhood obesity, insulin resistance and metabolic syndrome. Although some children with NAFLD may remain asymptomatic, progression to nonalcoholic steatohepatitis (NASH), and to advanced stages of fibrosis and cirrhosis is well recognized. Unfortunately, despite the increase in awareness of this disease, there are still no reliable non-invasive diagnostic tests and liver biopsy remains the gold standard for the diagnosis of NASH and staging of fibrosis. In addition, there are no approved pharmacological treatments currently. Lifestyle modification remains the cornerstone of treatment. Team based multidisciplinary approach involving hepatologists, endocrinologists, exercise physiologist, dieticians, and cardiologists may lead to better outcomes. Recently, the American Association for the Study of Liver Diseases (AASLD) and European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) committees have made recommendations for the diagnosis and management of NAFLD in pediatric patients. This review focuses on current literature on epidemiology, natural history, pathogenesis along with summarizing the recent guidelines on diagnosis and treatment of pediatric NAFLD.


Postnatal refinement of peripheral olfactory projections.
Axonal projections from the olfactory epithelium to the olfactory bulb are organized into glomeruli according to the expressed odorant receptor. Using gene-targeted mice, we show that glomerular maturation proceeds along different time courses for two similar receptors and requires sensory input during distinct sensitive periods. During early development, some glomeruli are innervated by axons of neurons that do not express the same receptor. These heterogeneous glomeruli normally disappear with age, but they persist in adults deprived of sensory input by unilateral and permanent naris closure. Persistence may be due, in part, to prolonged survival of olfactory sensory neurons.


Results of the prospective, randomized, multicenter clinical trial evaluating a biosynthesized cellulose graft for repair of dural defects.
After intradural cranial surgery, a dural substitute is often required for dural closure. Although preferred, limitations of autograft include local availability and additional surgical site morbidity. Thus, allografts, xenografts, and synthetics are frequently used. To report 6-month results of a randomized, controlled trial of a biosynthesized cellulose (BSC) composed duraplasty device compared with commercially available dural replacements. A total of 99 patients (62 BSC; 37 control) were treated on protocol, using a 2:1 (BSC:control) blocked randomization schedule. Physical examinations were performed pre- and postoperatively within 10 days and at 1, 3, and 6 months. Magnetic resonance imaging was performed preoperatively and at 6 months. The primary study endpoint was the absence of pseudomeningocele and extracerebral fluid collection confirmed radiographically and the absence of cerebrospinal fluid fistula at 6 months. At 6 months, the primary hypothesis, noninferiority of the BSC implant compared with the control group, was confirmed (P = .0206). Overall success was achieved by 96.6% of BSC and 97.1% of control patients. No significant difference was revealed between treatment groups for surgical site infection (P = 1.0000) or wound healing assessment (P ≥ .3685) outcomes, or radiologic endpoints (P ≥ .4061). Device strength and seal quality favored BSC. This randomized, controlled trial establishes BSC as noninferior to commercially available dural replacement devices. BSC offers a hypothetical advantage concerning prion and other infectious agent exposure; superior handling qualities are evident. Longer term data are necessary to identify limitations of BSC and its potential equivalence to the gold standard of pericranium.


Association between amygdala reactivity and a dopamine transporter gene polymorphism.
Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [(15)O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.


NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation.
Tachykinins are expressed within bladder-innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium or sensory afferents directly. Here, we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signaling from the bladder during distension, urothelial transmitter release ex vivo, and direct responses to neurokinin A (NKA) on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder-afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100 nM). Intravesical NKA significantly decreased bladder compliance but had no direct effect on mechanosensitivity to bladder distension (30 µl/min). GR159897 alone enhanced bladder compliance but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, whereas acetylcholine levels were reduced. NKA-mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.


Intrapulmonary and intracardiac shunting with exercise at altitude.
Recent studies in normal participants have shown that right to left shunt blood vessels in the lung open up during exercise. We describe the first field study to investigate this phenomenon at altitude. This study aimed to assess the effect of altitude and partial acclimatization on inducible right to left shunting at rest and with exercise. A contrast-enhanced transcranial Doppler imaging technique to detect microbubbles after injection of blood and saline agitated with air was used to measure right to left shunting in 10 normal participants at rest and immediately after exercising to maximum oxygen consumption (VO(2max)) at 80 m, on acute exposure to 3450 m, and finally after a week above 3450 m. At 80 m, exercising resulted in right to left shunting via patent foramen ovale in 2 participants, but there was no evidence of shunting in the remaining 8 participants. Cerebral microbubbles were detected at rest in the 2 participants with patent foramen ovale on acute exposure to 3450 m, and the shunting increased on exercise (P = .04). In 5 of the remaining 8 participants without patent foramen ovale, cerebral microbubbles were detected on exercise (P = .04) but not at rest. Partial acclimatization had minimal effect on the prevalence or magnitude of the intrapulmonary or intracardiac shunts. Oxygenation was similar in those with shunts compared with those without shunts. Intrapulmonary shunting occurs on exercise at altitude, but the clinical and physiologic significances have yet to be determined. Despite the occurrence of shunting in most participants, our results suggest that this phenomenon is not a significant factor in altitude and exercise-induced hypoxia.


Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors?
PARP inhibition is synthetic lethal with defective DNA repair via homologous recombination. Phase I and II clinical trials show that PARP inhibitors are effective at well-tolerated doses and have antitumor activity for BRCA1- and BRCA2-associated cancers. However, not all patients respond equally well and tumors may eventually become resistant. Thus far, the only resistance mechanism that has been found in human tumors is genetic reversion that corrects or bypasses the original BRCA1- or BRCA2-inactivating mutation. However, data from fundamental and preclinical research suggest that resistance to PARP inhibitors may be induced by additional mechanisms involving hypomorphic activity of mutant BRCA1 alleles, upregulation of drug efflux pumps, and rewiring of the DNA damage response. Preclinical models will be instrumental to develop methods for adequate patient stratification, as well as treatment strategies that prevent or counteract resistance to PARP inhibitors.


Motion sickness: an evolutionary hypothesis.
Since the occurrence of vomiting as a response to motion is both widespread and apparently disadvantageous, it presents a problem for evolutionary theory. An hypothesis is proposed suggesting that motion sickness is triggered by difficulties which arise in the programming of movements of the eyes or head when the relations between the spatial frameworks defined by the visual, vestibular, or proprioceptive inputs are repeatedly and unpredictably perturbed. Such perturbations may be produced by certain types of motion, or by disturbances in sensory input or motor control produced by ingested toxins. The last would be the important cause in nature, the main function of the emesis being to rid the individual of ingested neurotoxins. Its occurrence in response to motion would be an accidental by product of this system.


Exercise Improves Physical Function and Mental Health of Brain Cancer Survivors: Two Exploratory Case Studies.
Background Malignant brain tumors are unpredictable and incurable, with 5-year survival rates less than 30%. The poor prognosis combined with intensive treatment necessitates the inclusion of complementary and supportive therapies that optimize quality of life and reduce treatment-related declines in health. Exercise therapy has been shown to be beneficial in other cancer populations, but no evidence is available for brain cancer survivors. Therefore, we report results from 2 preliminary cases. Methods Two female patients diagnosed with glioblastoma multiforme and oligodendroglioma participated in a structured and supervised 12-week exercise program. The program consisted of two 1-hour resistance and aerobic exercise sessions per week and additional self-managed aerobic sessions. Outcome measures of strength, cardiovascular fitness, and several psychological indicators (depression, anxiety, and quality of life) were recorded at baseline, after 6 weeks and at the conclusion of the intervention. Results Exercise was well tolerated; both participants completed all 24 sessions and the home-based component with no adverse effects. Objective outcome measures displayed positive responses relating to reduced morbidity. Similar positive responses were found for psychological outcomes. Scores on the Hospital Anxiety and Depression Scale showed clinically meaningful improvements in depression and total distress. Conclusion These findings provide initial evidence that, despite the difficulties associated with brain cancer treatment and survivorship, exercise may be safe and beneficial and should be considered in the overall management of patients with brain cancer.


A photoactivatable nanopatterned substrate for analyzing collective cell migration with precisely tuned cell-extracellular matrix ligand interactions.
Collective cell migration is involved in many biological and pathological processes. Various factors have been shown to regulate the decision to migrate collectively or individually, but the impact of cell-extracellular matrix (ECM) interactions is still debated. Here, we developed a method for analyzing collective cell migration by precisely tuning the interactions between cells and ECM ligands. Gold nanoparticles are arrayed on a glass substrate with a defined nanometer spacing by block copolymer micellar nanolithography (BCML), and photocleavable poly(ethylene glycol) (Mw = 12 kDa, PEG12K) and a cyclic RGD peptide, as an ECM ligand, are immobilized on this substrate. The remaining glass regions are passivated with PEG2K-silane to make cells interact with the surface via the nanoperiodically presented cyclic RGD ligands upon the photocleavage of PEG12K. On this nanostructured substrate, HeLa cells are first patterned in photo-illuminated regions, and cell migration is induced by a second photocleavage of the surrounding PEG12K. The HeLa cells gradually lose their cell-cell contacts and become disconnected on the nanopatterned substrate with 10-nm particles and 57-nm spacing, in contrast to their behavior on the homogenous substrate. Interestingly, the relationship between the observed migration collectivity and the cell-ECM ligand interactions is the opposite of that expected based on conventional soft matter models. It is likely that the reduced phosphorylation at tyrosine-861 of focal adhesion kinase (FAK) on the nanopatterned surface is responsible for this unique migration behavior. These results demonstrate the usefulness of the presented method in understanding the process of determining collective and non-collective migration features in defined micro- and nano-environments and resolving the crosstalk between cell-cell and cell-ECM adhesions.


Analyzing the field of bioinformatics with the multi-faceted topic modeling technique.
Bioinformatics is an interdisciplinary field at the intersection of molecular biology and computing technology. To characterize the field as convergent domain, researchers have used bibliometrics, augmented with text-mining techniques for content analysis. In previous studies, Latent Dirichlet Allocation (LDA) was the most representative topic modeling technique for identifying topic structure of subject areas. However, as opposed to revealing the topic structure in relation to metadata such as authors, publication date, and journals, LDA only displays the simple topic structure. In this paper, we adopt the Tang et al.'s Author-Conference-Topic (ACT) model to study the field of bioinformatics from the perspective of keyphrases, authors, and journals. The ACT model is capable of incorporating the paper, author, and conference into the topic distribution simultaneously. To obtain more meaningful results, we use journals and keyphrases instead of conferences and bag-of-words.. For analysis, we use PubMed to collected forty-six bioinformatics journals from the MEDLINE database. We conducted time series topic analysis over four periods from 1996 to 2015 to further examine the interdisciplinary nature of bioinformatics. We analyze the ACT Model results in each period. Additionally, for further integrated analysis, we conduct a time series analysis among the top-ranked keyphrases, journals, and authors according to their frequency. We also examine the patterns in the top journals by simultaneously identifying the topical probability in each period, as well as the top authors and keyphrases. The results indicate that in recent years diversified topics have become more prevalent and convergent topics have become more clearly represented. The results of our analysis implies that overtime the field of bioinformatics becomes more interdisciplinary where there is a steady increase in peripheral fields such as conceptual, mathematical, and system biology. These results are confirmed by integrated analysis of topic distribution as well as top ranked keyphrases, authors, and journals.


Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.
The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.


A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies.
Widespread multifactor interactions present a significant challenge in determining risk factors of complex diseases. Several combinatorial approaches, such as the multifactor dimensionality reduction (MDR) method, have emerged as a promising tool for better detecting gene-gene (G x G) and gene-environment (G x E) interactions. We recently developed a general combinatorial approach, namely the generalized multifactor dimensionality reduction (GMDR) method, which can entertain both qualitative and quantitative phenotypes and allows for both discrete and continuous covariates to detect G x G and G x E interactions in a sample of unrelated individuals. In this article, we report the development of an algorithm that can be used to study G x G and G x E interactions for family-based designs, called pedigree-based GMDR (PGMDR). Compared to the available method, our proposed method has several major improvements, including allowing for covariate adjustments and being applicable to arbitrary phenotypes, arbitrary pedigree structures, and arbitrary patterns of missing marker genotypes. Our Monte Carlo simulations provide evidence that the PGMDR method is superior in performance to identify epistatic loci compared to the MDR-pedigree disequilibrium test (PDT). Finally, we applied our proposed approach to a genetic data set on tobacco dependence and found a significant interaction between two taste receptor genes (i.e., TAS2R16 and TAS2R38) in affecting nicotine dependence.


The effects of health shocks on employment and health insurance: the role of employer-provided health insurance.
Employment-contingent health insurance (ECHI) has been criticized for tying insurance to continued employment. Our research sheds light on two central issues regarding employment-contingent health insurance: whether such insurance "locks" people who experience a health shock into remaining at work; and whether it puts people at risk for insurance loss upon the onset of illness, because health shocks pose challenges to continued employment. We study how men's dependence on their own employer for health insurance affects labor supply responses and health insurance coverage following a health shock. We use the Health and Retirement Study (HRS) surveys from 1996 through 2008 to observe employment and health insurance status at interviews 2 years apart, and whether a health shock occurred in the intervening period between the interviews. All employed married men with health insurance either through their own employer or their spouse's employer, interviewed in at least two consecutive HRS waves with non-missing data on employment, insurance, health, demographic, and other variables, and under age 64 at the second interview are included in the study sample. We then limited the sample to men who were initially healthy. Our analytical sample consisted of 1,582 men of whom 1,379 had ECHI at the first interview, while 203 were covered by their spouse's employer. Hospitalization affected 209 men with ECHI and 36 men with spouse insurance. A new disease diagnosis was reported by 103 men with ECHI and 22 men with other insurance. There were 171 men with ECHI and 25 men with spouse employer insurance who had a self-reported health decline. Labor supply response differences associated with ECHI-with men with health shocks and ECHI more likely to continue working-appear to be driven by specific types of health shocks associated with future higher health care costs but not with immediate increases in morbidity that limit continued employment. Men with ECHI who have a self-reported health decline are significantly more likely to lose health insurance than men with insurance through a spouse. With the passage of health care reform, the tendency of men with ECHI as opposed to other sources of insurance to remain employed following a health shock may be diminished, along with the likelihood of losing health insurance.


PathwayMatrix: visualizing binary relationships between proteins in biological pathways.
Molecular activation pathways are inherently complex, and understanding relations across many biochemical reactions and reaction types is difficult. Visualizing and analyzing a pathway is a challenge due to the network size and the diversity of relations between proteins and molecules. In this paper, we introduce PathwayMatrix, a visualization tool that presents the binary relations between proteins in the pathway via the use of an interactive adjacency matrix. We provide filtering, lensing, clustering, and brushing and linking capabilities in order to present relevant details about proteins within a pathway. We evaluated PathwayMatrix by conducting a series of in-depth interviews with domain experts who provided positive feedback, leading us to believe that our visualization technique could be helpful for the larger community of researchers utilizing pathway visualizations. PathwayMatrix is freely available at https://github.com/CreativeCodingLab/PathwayMatrix.


Endotypes of difficult-to-control asthma in inner-city African American children.
African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.


TET2 as an epigenetic master regulator for normal and malignant hematopoiesis.
DNA methylation is one of the critical epigenetic modifications regulating various cellular processes such as differentiation or proliferation, and its dysregulation leads to disordered stem cell function or cellular transformation. The ten-eleven translocation (TET) gene family, initially found as a chromosomal translocation partner in leukemia, turned out to be a key enzyme for DNA demethylation. TET genes hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, which is then converted to unmodified cytosine through multiple mechanisms. Somatic mutations of the TET2 gene were reported in a variety of human hematological malignancies such as leukemia, myelodysplastic syndrome, and malignant lymphoma, suggesting a critical role for TET2 in hematopoiesis. The importance of the TET-mediated cytosine demethylation pathway is also underscored by a recurrent mutation of isocitrate dehydrogenase 1 (IDH1) and IDH2 in hematological malignancies, whose mutation inhibits TET function through a novel oncometabolite, 2-hydroxyglutarate. Studies using mouse models revealed that TET2 is critical for the function of hematopoietic stem cells, and disruption of TET2 results in the expansion of multipotent as well as myeloid progenitors, leading to the accumulation of premalignant clones. In addition to cytosine demethylation, TET proteins are involved in chromatin modifications and other cellular processes through the interaction with O-linked β-N-acetylglucosamine transferase. In summary, TET2 is a critical regulator for hematopoietic stem cell homeostasis whose functional impairment leads to hematological malignancies. Future studies will uncover the whole picture of epigenetic and signaling networks wired with TET2, which will help to develop ways to intervene in cellular pathways dysregulated by TET2 mutations.


Characterization of three de novo derivative chromosomes 16 by "reverse chromosome painting" and molecular analysis.
We have analyzed three de novo chromosome 16 rearrangements--two with a 16p+ chromosome and one a 16q+--none of which could be fully characterized by conventional cytogenetics. In each case, flow karyotypes have been produced, and the aberrant chromosome has been isolated by flow sorting. The origin of the additional material has been ascertained by amplifying and labeling the DNA of the abnormal chromosome by degenerate-oligonucleotide-primer-PCR and hybridizing it in situ to normal metaphase spreads (reverse chromosome painting). Both 16p+ chromosomes contain more than 30 Mb of DNA from the short arm of chromosome 9(9p21.2-pter), while the 16q+ contains approximately 9 Mb of DNA from 2q37. The breakpoints on chromosome 16 have been localized in each case; the two breakpoints on the short arm are at different points within the terminal band, 16p13.3. The breakpoint on the long arm of chromosome 16 is very close to (within 230 kb of) the 16q telomere. Determination of the regions of monosomy and trisomy allowed the observed phenotypes to be compared with other reported cases involving aneuploidy for these regions.


Residual thoracolumbar/lumbar curve is related to self-image after posterior spinal fusion for Lenke 1 and 2 curves in adolescent idiopathic scoliosis patients.
Although it is well known that major curve severity in adolescent idiopathic scoliosis (AIS) is inversely related to self-image, surgeons often encounter patients who complain of low self-image with preoperatively mild curves or postoperatively well-corrected main curves, suggesting the presence of other factors. This study examined factors contributing to self-image in AIS. A total of 86 consecutive patients who underwent posterior spinal fusion for AIS Lenke 1 or 2 curves and were followed for a minimum of 2 years were included in this study of patient self-image based on data that included scores reported on the Scoliosis Research Society survey (SRS-22r). The authors evaluated sex, BMI, Risser grade, age, angle of trunk rotation, Cobb angle of the main thoracic (MT) curve, Cobb angle of the thoracolumbar/lumbar (TL/L) curve, apical vertebral translation (AVT), T5-12 kyphotic angle, and clavicular angle. Univariate and multivariate general linear models were employed to identify preoperative and 2-year postoperative factors that impact self-image. Univariate analysis revealed no significant correlation between preoperative MT curve Cobb angle and SRS-22r self-image score (p = 0.51), although patients with a higher MT curve AVT had a significantly worse preoperative self-image (p < 0.01). Two years postoperatively, larger Cobb angle of the TL/L curve (p = 0.01) and higher Risser grade (p = 0.03) resulted in significantly lower self-image scores. In multivariate testing, preoperative MT curve AVT remained significantly related to diminished self-image (p < 0.01). Two years later, higher TL/L curve (p < 0.01), Risser grade (p = 0.03), and MT curve AVT (p = 0.03) had significant associations with lower self-image scores. Preoperative MT curve AVT appears more strongly related to self-image than does Cobb angle. Two years postoperatively, persistent TL/L region curvature and high Risser grade may also be associated with diminished patient self-image.


Keyboard data entry use among osteopathic medical students and residents.
Candidates taking the Comprehensive Osteopathic Medical Licensing Examination-USA Level 2-Performance Evaluation (COMLEX-USA Level 2-PE) are currently evaluated on their ability to document clinical findings using a handwritten postencounter note. However, keyboard data entry is increasingly used for medical documentation. To determine the use and perception of keyboard data entry among osteopathic medical students and residents in educational and clinical settings. A Web-based survey regarding frequency of and preference for keyboard data entry was distributed to 9801 osteopathic medical students, 17,268 osteopathic residents, and 34 clinical deans of colleges of osteopathic medicine (COMs). In addition, 31 COMs' clinical skills center directors were contacted to participate in a telephone survey about the use of keyboard data entry in their centers. A total of 1711 students, 1198 residents, 14 clinical deans, and 17 clinical skills center directors responded to the surveys. The majority of students (872 [51%]) reported using electronic keyboard data entry at their COM's clinical skills center for postencounter notes. Among respondents, 379 students (23%), 77 residents (9%), and 1 clinical dean reported that electronic keyboard data entry is never or rarely used during clinical rotations. Most trainees (1592 students [93%], 864 residents [94%]) reported that they were either comfortable or very comfortable with typing. Given the option of recording methods for SOAP (subjective, objective, assessment, plan) note findings on the COMLEX-USA Level 2-PE, 7 clinical deans were unsure of their students' preferences, while the remaining favored keyboard data entry (5) over handwriting (2). The majority of student and resident respondents would choose keyboard data entry (1009 [60%] and 511 [55%], respectively). Osteopathic medical students and residents are comfortable with typing; they are exposed to and would prefer using an electronic form of entry for medical documentation. These results support a conversion from written postencounter notes to keyboard data entry of notes on the COMLEX-USA Level 2-PE.


Factors associated with the level of movement-related everyday activity and quality of life in people with chronic heart failure.
Cardiac rehabilitation has been shown to be effective in people with chronic heart failure (CHF), particularly in terms of exercise capacity. However, no effects have been found on the level of movement-related everyday activity. Therefore, rehabilitation programs also should focus on enhancing the level of movement-related everyday activity. The aim of this study was to explore factors associated with the level of movement-related everyday activity and with quality of life in people with CHF. Measurements of movement-related everyday activity (using an accelerometry-based Activity Monitor), quality of life, and associated factors were performed in 36 people with stable CHF (New York Heart Association classes II and III). Knee flexion and extension torque, and particularly extension torque, were significantly associated with movement-related everyday activity (r = .43-.49, P < .05), whereas nonphysiological factors such as feelings of being disabled were associated with quality of life (r = .37-.77, P < or = .01, P < .05). No relationship was found between movement-related everyday activity and quality of life (r = .20-.22, P > .05). The results indicate that knee torque is associated with the level of movement-related everyday activity in people with CHF and that quality of life is mediated by nonphysiological factors.


A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with many characteristic features, including hyperandrogenaemia, insulin resistance and obesity which may have significant implications for pregnancy outcomes and long-term health of the woman. This meta-analysis was conducted to evaluate the risk of pregnancy and neonatal complications in women with PCOS. Electronic databases were searched for the following MeSH headings: PCOS, hyperandrogenism, pregnancy outcome, pregnancy complications, diabetes mellitus, type II. A handsearch of human reproduction and fertility and sterility was also conducted. Studies in which pregnancy outcomes in women with PCOS were compared with controls were considered for inclusion in this meta-analysis. Fifteen of 525 identified studies were included, involving 720 women presenting with PCOS and 4505 controls. Women with PCOS demonstrated a significantly higher risk of developing gestational diabetes [odds ratio (OR) 2.94; 95% confidence interval (CI): 1.70-5.08], pregnancy-induced hypertension (OR 3.67; 95% CI: 1.98-6.81), pre-eclampsia (OR 3.47; 95% CI: 1.95-6.17) and preterm birth (OR 1.75; 95% CI: 1.16-2.62). Their babies had a significantly higher risk of admission to a neonatal intensive care unit (OR 2.31; 95% CI: 1.25-4.26) and a higher perinatal mortality (OR 3.07; 95% CI: 1.03-9.21), unrelated to multiple births. In conclusion, women with PCOS are at increased risk of pregnancy and neonatal complications. Pre-pregnancy, antenatal and intrapartum care should be aimed at reducing these risks.


NF-κB induces abnormal centrosome amplification by upregulation of CDK2 in laryngeal squamous cell cancer.
Centrosome amplification can drive chromosomal instability (CIN) which is a major source of tumor initiation. The present study aimed to investigate the impact of nuclear factor kappa B (NF-κB) on centrosome amplification of Hep-2 cells. Immunofluorescence was performed to display centrosomes. BAY11-7082 was used as an inhibitor of NF-κB to assess the inhibition of centrosome amplification, and cyclin-dependent kinase 2 (CDK2), ensuring cell cycle cycle coordination with centrosome cycle was detected by Western blotting. Furthermore, a 1556-bp fragment of the CDK2 promoter was analyzed using the TRANSFAC-TESS software. Luciferase assay, including a series of truncated CDK2 promoters and site mutations, was carried out to determine NF-κB binding sites in the CDK2 promoter. Electrophoresis mobility shift and chromatin immunoprecipitation assays were applied to confirm whether NF-κB indeed binds to the 5'-promoter region of the CDK2 gene. To reveal the clinical significance of CDK2 expression in laryngeal squamous cell cancer, mRNA and protein levels were assessed by RT-PCR and Western blotting, respectively. We found that the transcription factor NF-κB plays a role in centrosome amplification in Hep-2 cells. Centrosome amplification is reduced by inhibition of the NF-κB pathway. Moreover, expression of the p65 subunit of NF-κB is sufficient to promote centrosome amplification and increase in CDK2 protein levels. We further identified a functional NF-κB binding site located in the CDK2 promoter. Single mutation of the NF-κB site III (construct mutIII) however resulted in 76±5% (p<0.01) luciferase activity reduction. Electromobility shift assays and chromatin immunoprecipitaton results suggest that NF-κB indeed binds to this responsive element associating with CDK2 expression and centrosome amplification. RT-PCR and Western blotting results revealed that both mRNA and protein levels of CDK2 were significantly higher in tumor tissues than those in paired adjacent normal laryngeal tissues.


Obesity modifies the implantation window and disrupts intrauterine embryo positioning in rats.
Obesity is a chronic disease that impairs female reproduction. When gestation is achieved, maternal obesity can cause offspring's health complications. We intended to evaluate the effects of maternal pre-conceptional obesity on uterine contractile activity, embryo implantation and offspring development. Using cafeteria diet-induced obesity as an animal model, we found that maternal obesity delays embryo transport from the oviduct to the uterus and alters the intrauterine embryo positioning. Adrenergic receptor (AR) signaling is involved in embryo positioning, so all AR isoforms were screened in the pre-implantation uteri. We found that the β2AR is the dominant isoform in the rat uteri and that obesity causes its upregulation. Although β2AR activation is known to induce uterine relaxation, higher spontaneous contractile activity was detected in obese dams. Uteri from obese dams showed a higher sensitivity to salbutamol (a selective agonist of β2AR) than controls, consistent with the higher β2AR levels detected in those animals. Despite this, in obese dams, some embryos were still in the oviduct at the predicted time of initial embryo attachment, embryo implantation is successfully carried out since the total number of fetuses on gd 18.5 were similar between control and obese dams. These findings show that obesity is modifying the implantation window. Moreover, we found that maternal obesity resulted in macrosomia in the offspring, which is an important predictor of fetal programming of postnatal health. Hence, our results show that maternal obesity prior to pregnancy not only disturbs the implantation process, but also affects offspring development.


Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes.
Interleukin-10 (IL-10)-related T cell-derived inducible factor (IL-TIF; provisionally designated IL-22) is a cytokine with limited homology to IL-10. We report here the identification of a functional IL-TIF receptor complex that consists of two receptor chains, the orphan CRF2-9 and IL-10R2, the second chain of the IL-10 receptor complex. Expression of the CRF2-9 chain in monkey COS cells renders them sensitive to IL-TIF. However, in hamster cells both chains, CRF2-9 and IL-10R2, must be expressed to assemble the functional IL-TIF receptor complex. The CRF2-9 chain (or the IL-TIF-R1 chain) is responsible for Stat recruitment. Substitution of the CRF2-9 intracellular domain with the IFN-gammaR1 intracellular domain changes the pattern of IL-TIF-induced Stat activation. The CRF2-9 gene is expressed in normal liver and kidney, suggesting a possible role for IL-TIF in regulating gene expression in these tissues. Each chain, CRF2-9 and IL-10R2, is capable of binding IL-TIF independently and can be cross-linked to the radiolabeled IL-TIF. However, binding of IL-TIF to the receptor complex is greater than binding to either receptor chain alone. Sharing of the common IL-10R2 chain between the IL-10 and IL-TIF receptor complexes is the first such case for receptor complexes with chains belonging to the class II cytokine receptor family, establishing a novel paradigm for IL-10-related ligands similar to the shared use of the gamma common chain (gamma(c)) by several cytokines, including IL-2, IL-4, IL-7, IL-9, and IL-15.


The effects of stereotactic radiosurgery on secondary facial pain.
Twenty-seven patients with tumor-related secondary facial pain were treated by stereotactic radiosurgical procedures between November 1991 and October 1998. They had 14 meningiomas, 11 schwannomas (one trigeminal, 10 vestibular), one nasopharyngeal cancer and one chordoma. The mean maximum dose administered was 26.4 Gy (range 16 to 35 Gy) and the margin of the tumor was encompassed within the 45 to 90% isodose. The patients were analyzed based on their pain relief with a mean follow-up duration of 32.1 months. In 24 patients (85.7%), there was initial pain improvement after radiosurgery, but half had recurrent pain. A pain response was obtained in 12 cases (pain response rate = 42.9%), five were pain free and seven had pain reduction. On the follow-up MRI, a decrease in tumor volume of more than 20% of the preoperative volume occurred in 14 of 25 cases. The mean time interval to initial pain improvement (10.3 months) and pain response (5.7 months) were shorter than for a decrease in tumor volume (18.6 months). Tumor-related secondary facial pain was less responsive to stereotactic radiosurgery than idiopathic trigeminal neuralgia. It would seem that the mechanism of pain relief in radiosurgery is not only trigeminal root decompression secondary to tumor volume reduction, but also other mechanisms involving inactivation of abnormal electrical transmission may be involved.


Big cats in our backyards: persistence of large carnivores in a human dominated landscape in India.
Protected areas are extremely important for the long term viability of biodiversity in a densely populated country like India where land is a scarce resource. However, protected areas cover only 5% of the land area in India and in the case of large carnivores that range widely, human use landscapes will function as important habitats required for gene flow to occur between protected areas. In this study, we used photographic capture recapture analysis to assess the density of large carnivores in a human-dominated agricultural landscape with density >300 people/km(2) in western Maharashtra, India. We found evidence of a wide suite of wild carnivores inhabiting a cropland landscape devoid of wilderness and wild herbivore prey. Furthermore, the large carnivores; leopard (Panthera pardus) and striped hyaena (Hyaena hyaena) occurred at relatively high density of 4.8±1.2 (sd) adults/100 km(2) and 5.03±1.3 (sd) adults/100 km(2) respectively. This situation has never been reported before where 10 large carnivores/100 km(2) are sharing space with dense human populations in a completely modified landscape. Human attacks by leopards were rare despite a potentially volatile situation considering that the leopard has been involved in serious conflict, including human deaths in adjoining areas. The results of our work push the frontiers of our understanding of the adaptability of both, humans and wildlife to each other's presence. The results also highlight the urgent need to shift from a PA centric to a landscape level conservation approach, where issues are more complex, and the potential for conflict is also very high. It also highlights the need for a serious rethink of conservation policy, law and practice where the current management focus is restricted to wildlife inside Protected Areas.