Treatment with cucurbitacin B alone and in combination with gefitinib induces cell cycle inhibition and apoptosis via EGFR and JAK/STAT pathway in human colorectal cancer cell lines.
The epidermal growth factor receptor (EGFR) associated with signaling pathways, such as Janus kinase (JAK)/signal transducer and activator of transcription (STAT), plays an important role in colorectal cancers (CRCs). Gefitinib (Gef) is an orally active inhibitor targeting the adenosine tri phosphate-binding domain of EGFR, and cucurbitacin B (CuB) is a selective inhibitor of JAK/STAT signaling with potent antitumor activity via suppression of STAT3 phosphorylation, but the underlying mechanism is not clear. We aimed to investigate the apoptotic and antiproliferative effects of CuB as a single agent and in combination with Gef on both HT-29 and HCT-116 cell lines. Cell proliferation, cell cycle distribution, and apoptosis were evaluated using viability assay, fluorescent microscopy, cytotoxicity assay, proliferation, DNA fragmentation, and cleaved caspase 3 levels. Real-time polymerase chain reaction and Western blot analyses were performed to determine the expression of relevant genes and proteins including antiapoptotic, proapoptotic, and cell cycle regulation. EGFR, phosphorylated EGFR (pEGFR), STAT3, and pSTAT3 proteins were evalutaed with Western blot analysis. Our results showed that, compared to CuB alone, CuB plus Gef treatment caused a significant growth and cell cycle inhibition and induced apoptosis in both cell lines. Also CuB plus Gef treatment decreased DNA synthesis rate more effectively than CuB alone. Treatment with CuB alone and in combination with Gef decreased the expression levels of B-Cell CLL/Lymphoma 2 (Bcl-2), BCL2-like 1 (BCL2L1), cyclin D1, pSTAT3, and pEGFR and increased the expression levels of Bcl-2-like protein 4, Bcl-2 homologous antagonist/killer, Bcl-2-associated death promoter, Bcl-2-like protein 11, and p27kip1 levels. Our results suggest that treatment with CuB alone and more likely in combination with Gef may be a considerable alternative therapeutic approach for CRC, at least in vitro.


Repair of aneurysms of the thoracic aorta: 12-year experience in a high-risk population.
We present our 12-year experience with surgical treatment of aneurysms of the thoracic aorta in a high-risk patient population. Of 52 patients with aneurysms, 36 patients, aged 19 to 80 years, had operation. In 24 of the 36, there were three or more associated major disease processes, such as chronic bronchitis, hypertensive cardiovascular disease, aortic valve disease, cerebrovascular disease, abdominal aortic aneurysm, and coronary artery disease. Eight patients with acute type A (ascending aorta) and seven with acute type B (descending aorta) aneurysms had emergency repair, with survival in four and seven, respectively. All patients with chronic type A or B aneurysms had elective repair, and all patients with acute or chronic type A aneurysms had surgical treatment. Four patients with acute type A and two with acute type B aneurysms had elective operation, with survival in three and one, respectively. Nine patients with chronic type A and six with chronic type B aneurysms had elective operation, and all survived. Twelve patients with chronic type B aneurysms did not have operation, and all were alive at early follow-up. Mortality for patients having acute type A aneurysms requiring emergency operation was greater than that after elective repair of acute or chronic type A aneurysms. Short-term survival for chronic type B aneurysms was similar whether the patient was treated medically or surgically.


Healthcare utilization and associated barriers experienced by wheelchair users: A pilot study.
More than twenty-five years after passage of the ADA, little remains known about the experiences of wheelchair users when attempting to access health care and how accessibility may influence health care utilization. To describe health care utilization among wheelchair users and characterize barriers encountered when attempting to obtain access to health care. An internet-based survey of wheelchair users was conducted. Measures included demographics, condition, socioeconomic status, health care utilization and receipt of preventive services within the past year, physical barriers encountered at outpatient facilities, and satisfaction with care. Four hundred thirty-two wheelchair users responded to the survey. Nearly all respondents (97.2%) had a primary care appointment within the past year and most reported 3-5 visits to both primary and specialty care providers. Most encountered physical barriers when accessing care (73.8% primary, 68.5% specialty). Participants received most preventive interventions at rates similar to national averages with the exception of Pap tests. Most participants remained clothed for their primary care evaluation (76.1%), and were examined seated in their wheelchair (69.7%). More than half of participants (54.1%) felt they received incomplete care, and 57% believed their physician had no more than a moderate understanding of their disability-specific medical concerns. Wheelchair users face persistent barriers to care, may receive less than thorough physical evaluations, receive fewer screenings for cervical cancer, and largely believe they receive incomplete care.


Commensal microbiota stimulate systemic neutrophil migration through induction of serum amyloid A.
Neutrophils serve critical roles in inflammatory responses to infection and injury, and mechanisms governing their activity represent attractive targets for controlling inflammation. The commensal microbiota is known to regulate the activity of neutrophils and other leucocytes in the intestine, but the systemic impact of the microbiota on neutrophils remains unknown. Here we utilized in vivo imaging in gnotobiotic zebrafish to reveal diverse effects of microbiota colonization on systemic neutrophil development and function. The presence of a microbiota resulted in increased neutrophil number and myeloperoxidase expression, and altered neutrophil localization and migratory behaviours. These effects of the microbiota on neutrophil homeostasis were accompanied by an increased recruitment of neutrophils to injury. Genetic analysis identified the microbiota-induced acute phase protein serum amyloid A (Saa) as a host factor mediating microbial stimulation of tissue-specific neutrophil migratory behaviours. In vitro studies revealed that zebrafish cells respond to Saa exposure by activating NF-κB, and that Saa-dependent neutrophil migration requires NF-κB-dependent gene expression. These results implicate the commensal microbiota as an important environmental factor regulating diverse aspects of systemic neutrophil development and function, and reveal a critical role for a Saa-NF-κB signalling axis in mediating neutrophil migratory responses.


Adeno-associated virus serotype 2 induces cell-mediated immune responses directed against multiple epitopes of the capsid protein VP1.
Adeno-associated virus serotype 2 (AAV-2) has been developed as a gene therapy vector. Antibody and cell-mediated immune responses to AAV-2 or AAV-2-transfected cells may confound the therapeutic use of such vectors in clinical practice. In one of the most detailed examinations of AAV-2 immunity in humans to date, cell-mediated and humoral immune responses to AAV-2 were characterized from a panel of healthy blood donors. The extent of AAV-2-specific antibody in humans was determined by examination of circulating AAV-2-specific total IgG levels in plasma from 45 normal donors. Forty-one donors were seropositive and responses were dominated by IgG1 and IgG2 subclasses. Conversely, AAV-2-specific IgG3 levels were consistently low in all donors. Cell-mediated immune recall responses were detectable in nearly half the population studied. In vitro restimulation with AAV-2 of peripheral blood mononuclear cell cultures from 16 donors elicited gamma interferon (IFN-gamma) (ten donors), interleukin-10 (IL-10) (eight donors) and interleukin-13 (IL-13) (four donors) responses. Using a series of overlapping peptides derived from the sequence of the VP1 viral capsid protein, a total of 59 candidate T-cell epitopes were identified. Human leukocyte antigen characterization of donors revealed that the population studied included diverse haplotypes, but that at least 17 epitopes were recognized by multiple donors and could be regarded as immunodominant. These data indicate that robust immunological memory to AAV-2 is established. The diversity of sequences recognized suggests that attempts to modify the AAV-2 capsid, as a strategy to avoid confounding immunity, will not be feasible.


Collagenous Gastritis in a Young Female With IgA Deficiency.
Collagenous gastritis, without colonic involvement, is exceptionally rare. It is not known to be associated with IgA deficiency and scleroderma. This is the first report of this type of association. We present a 26-year-old white female with a past medical history of gastroesophageal reflux disease and scleroderma. She was evaluated for complaints of abdominal pain and diarrhea. Esophagogastroduodenoscopy showed gastritis and duodenitis. Colonoscopy was normal. The histopathological report showed collagenous gastritis and focal lymphocytic duodenitis. A definitive treatment has not been established for this condition. Reporting such cases furthers understanding of the disease and will help to establish diagnostic criteria and to develop therapeutic strategies.


Too many trees to see the forest: performance, event-related potential, and functional magnetic resonance imaging manifestations of integrative congenital prosopagnosia.
Neuropsychological, event-related potential (ERP), and functional magnetic resonance imaging (fMRI) methods were combined to provide a comprehensive description of performance and neurobiological profiles for K.W., a case of congenital prosopagnosia. We demonstrate that K.W.'s visual perception is characterized by almost unprecedented inability to identify faces, a large bias toward local features, and an extreme deficit in global/configural processing that is not confined to faces. This pattern could be appropriately labeled congenital integrative prosopagnosia, and accounts for some, albeit not all, cases of face recognition impairments without identifiable brain lesions. Absence of face selectivity is evident in both biological markers of face processing, fMRI (the fusiform face area [FFA]), and ERPs (N170). Nevertheless, these two neural signatures probably manifest different perceptual mechanisms. Whereas the N170 is triggered by the occurrence of physiognomic stimuli in the visual field, the deficient face-selective fMRI activation in the caudal brain correlates with the severity of global processing deficits. This correlation suggests that the FFA might be associated with global/configural computation, a crucial part of face identification.


A content analysis of the consumer-facing online information about My Health Record: Implications for increasing knowledge and awareness to facilitate uptake and use.
Low health literacy, low levels of positive belief and privacy and security concerns have been identified as a significant barrier to personal electronic health record uptake and use. An important tool for overcoming these barriers is the consumer-facing information which accompanies the system. My Health Record (MyHR) is the Australian national e-health record system, for which a large suite of online resources exists to facilitate consumer registration and use. This study uses a number of different measures of health resource quality to assess the MyHR online consumer-facing information and identify any gaps or areas for improvement. To analyse the quality and content of the online consumer-facing resources which support the uptake and use of MyHR. Australian information resources aimed at healthcare consumers about the MyHR were included in this study. A comprehensive search using Internet search engines was conducted to locate all online consumer-facing resources about MyHR from both government and non-government sources. Readability (measured by Flesch-Kincaid grade level), year of publication/review, publishing organisation type, presentation style, linked websites, target audience, and themes were identified as important measures of health information quality, and these were recorded and reported on for each resource. Eighty resources met the inclusion criteria. The mean Flesch-Kincaid grade level was 11.8. Most resources were created by Australian government sources ( n = 55), and the most common target audience was the general public ( n = 65). Registration ( n = 51), privacy/security ( n = 49), and benefits of use ( n = 46) were the most common resource themes. The authors identified a number of gaps and areas for improvement in the provision of consumer-facing information about MyHR. Readability is too high for the general Australian population, and there are few translated resources, which means that the information provided does not cater to people with low literacy levels, communication disability, and/or difficulties in understanding written English. The target audiences for resources do not reflect priority groups that were identified during the MyHR development processes. There are also gaps in information provision about how consumers can use MyHR as a tool to meaningfully engage with health professionals and services to support their own person-centred care.


Leadership-organizational culture relationship in nursing units of acute care hospitals.
The phenomena of leadership and organizational culture (OC) has been defined as the driving forces in the success or failure of an organization. Today, nurse managers must demonstrate leadership behaviors or styles that are appropriate for the constantly changing, complex, and turbulent health care delivery system. In this study, researchers explored the relationship between nurse managers' leadership styles and OC of nursing units within an acute care hospital that had achieved excellent organizational performance as demonstrated by a consistent increase in patient satisfaction ratings. The data from this study support that transformational and transactional contingent reward leaderships as nurse manager leadership styles that are associated with nursing unit OC that have the ability to balance the dynamics of flexibility and stability within their nursing units and are essential for maintaining organizational effectiveness. It is essential for first-line nursing leaders to acquire knowledge and skills on organizational cultural competence.


The decay of motor adaptation to novel movement dynamics reveals an asymmetry in the stability of motion state-dependent learning.
Motor adaptation paradigms provide a quantitative method to study short-term modification of motor commands. Despite the growing understanding of the role motion states (e.g., velocity) play in this form of motor learning, there is little information on the relative stability of memories based on these movement characteristics, especially in comparison to the initial adaptation. Here, we trained subjects to make reaching movements perturbed by force patterns dependent upon either limb position or velocity. Following training, subjects were exposed to a series of error-clamp trials to measure the temporal characteristics of the feedforward motor output during the decay of learning. The compensatory force patterns were largely based on the perturbation kinematic (e.g., velocity), but also showed a small contribution from the other motion kinematic (e.g., position). However, the velocity contribution in response to the position-based perturbation decayed at a slower rate than the position contribution to velocity-based training, suggesting a difference in stability. Next, we modified a previous model of motor adaptation to reflect this difference and simulated the behavior for different learning goals. We were interested in the stability of learning when the perturbations were based on different combinations of limb position or velocity that subsequently resulted in biased amounts of motion-based learning. We trained additional subjects on these combined motion-state perturbations and confirmed the predictions of the model. Specifically, we show that (1) there is a significant separation between the observed gain-space trajectories for the learning and decay of adaptation and (2) for combined motion-state perturbations, the gain associated to changes in limb position decayed at a faster rate than the velocity-dependent gain, even when the position-dependent gain at the end of training was significantly greater. Collectively, these results suggest that the state-dependent adaptation associated with movement velocity is relatively more stable than that based on position.


Multiple beam generation using a stratified volume holographic grating.
The parameters of several stratified volume holographic gratings are optimized in order to obtain high diffraction efficiency beam spliters. Two-, three-, five-, seven-, and nine-beam fan-outs are theoretically studied and compared with what has been achieved by other means. With a simple optical setup, a fan-out element that generates seven beams of equal intensity is experimentally realized and a comparison with theory is made.


Combined linkage and association analysis identifies rare and low frequency variants for blood pressure at 1q31.
High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.


Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data.
Longitudinal and multi-site clinical studies create the imperative to characterize and correct technological sources of variance that limit image reproducibility in high-resolution structural MRI studies, thus facilitating precise, quantitative, platform-independent, multi-site evaluation. In this work, we investigated the effects that imaging gradient non-linearity have on reproducibility of multi-site human MRI. We applied an image distortion correction method based on spherical harmonics description of the gradients and verified the accuracy of the method using phantom data. The correction method was then applied to the brain image data from a group of subjects scanned twice at multiple sites having different 1.5 T platforms. Within-site and across-site variability of the image data was assessed by evaluating voxel-based image intensity reproducibility. The image intensity reproducibility of the human brain data was significantly improved with distortion correction, suggesting that this method may offer improved reproducibility in morphometry studies. We provide the source code for the gradient distortion algorithm together with the phantom data.


Pulse oximetry in the newborn: is the left hand pre- or post-ductal?
Over the past few years, great efforts have been made to screen duct-dependent congenital heart diseases in the newborn. Arterial pulse oximetry screening (foot and/or right hand) has been put forth as the most useful strategy to prevent circulatory collapse. The left hand, however, has always been ignored, as it was unclear if the ductus arteriosus influences left-hand arterial perfusion. The objective of our study was to evaluate the impact of the arterial duct on neonatal pulse oximetry saturation (POS) on the left hand. In this observational study, arterial oxygen saturation on both hands and on one foot was measured within the first 4 hours of life. Two hundred fifty-one newborns were studied: 53% males and 47% were delivered by caesarean section. The median gestational age was 38 4/7 weeks (90% CI, 32 6/7 - 41 2/7 weeks), the median birth weight was 3140 g (90% CI, 1655 - 4110 g) and the median age at recording was 60 minutes (90% CI, 15 - 210 minutes). The mean POS for the overall study population was 95.7% (90% CI, 90 - 100%) on the right hand, 95.7% (90% CI, 90 - 100%) on the left hand, and 94.9% (90% CI, 86 - 100%) on the foot. Four subgroups (preterm infants, babies with respiratory disorders, neonates delivered by caesarean section, and newborns < or =15 minutes of age) were formed and analysed separately. None of the subgroups showed a statistically significant difference between the right and left hands. Additionally, multivariate logistic regression did not identify any associated factors influencing the POS on the left hand. With the exception of some children with complex or duct dependent congenital heart defects and some children with persistent pulmonary hypertension, POS on both hands can be considered equally pre-ductal.


The selectable marker human dihydrofolate reductase enables sequential genetic manipulation of the Plasmodium berghei genome.
Genetic transformation of malaria parasites has been limited by the number of selectable markers available. For the rodent malaria parasite, Plasmodium berghei, only a single selection marker has been at hand, utilising the dihydrofolate reductase-thymidylate synthase gene from either P. berghei or Toxoplasma gondii to confer resistance to the anti-malarial drug pyrimethamine. Here we report the use of the human dihydrofolate reductase (hDHFR) gene as a new selectable marker, which confers resistance to the antifolate inhibitor WR99210 upon both pyrimethamine sensitive and resistant isolates of P. berghei. Transfection with circular constructs containing the hDHFR gene resulted in the generation of highly resistant parasites containing multiple copies of episomally-maintained plasmids. These parasites showed around a 1000-fold increase in resistance to WR99210 compared to the parental parasites. We were also able to generate and select transgenic parasites harbouring only a single copy of hDHFR targeted into their genome, despite the fact that these parasites showed only a fivefold increase in resistance to WR99210 compared to the parental parasites. Importantly, and for the first time with malaria parasites, the hDHFR gene could be used in conjunction with the existing pyrimethamine selectable markers. This was demonstrated by reintroducing the circumsporozoite (CS) gene into transgenic CS-knockout mutant parasites that contained the P. berghei DHFR-TS selectable marker. The development of hDHFR as a second selectable marker will greatly expand the use of transformation technology in Plasmodium, enabling more extensive genetic manipulation and thus facilitating more comprehensive studies on the biology of the malaria parasite.


International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.
Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.


Force to debond brackets from high-fusing and low-fusing porcelain systems.
The purpose of this study was to test the hypothesis that porcelain surface finishing, ie, low- and high-fusing porcelain, has an effect on the amount of force required to debond orthodontic brackets. A total of 20 high-fusing and 20 low-fusing porcelain specimens were prepared, polished, and bonded with standard edgewise brackets using a suggested porcelain bonding protocol. The brackets were debonded with a universal testing machine at shear mode. Resin removal was performed using two methods: a multifluted carbide bur with and without the use of Sof-Lex polishing discs. Representative specimens were studied under a scanning electron microscope before and after debonding to assess the surface morphology and potential surface damage. Statistical analysis with a t-test revealed that there was no difference between the two porcelain treatments on the force to debond values and no qualitative differences were observed on the porcelain surface between the two resin clean-up methods. From a clinical perspective, the practitioner can bond ceramic restorations without previous knowledge of the porcelain type used.


Soleus H-reflex gain in humans walking and running under simulated reduced gravity.
The Hoffmann (H-) reflex is an electrical analogue of the monosynaptic stretch reflex, elicited by bypassing the muscle spindle and directly stimulating the afferent nerve. Studying H-reflex modulation provides insight into how the nervous system centrally modulates stretch reflex responses.A common measure of H-reflex gain is the slope of the relationship between H-reflex amplitude and EMG amplitude. To examine soleus H-reflex gain across a range of EMG levels during human locomotion, we used simulated reduced gravity to reduce muscle activity. We hypothesised that H-reflex gain would be independent of gravity level.We recorded EMG from eight subjects walking (1.25 m s-1) and running (3.0 m s-1) at four gravity levels (1.0, 0.75, 0.5 and 0.25 G (Earth gravity)). We normalised the stimulus M-wave and resulting H-reflex to the maximal M-wave amplitude (Mmax) elicited throughout the stride to correct for movement of stimulus and recording electrodes relative to nerve and muscle fibres. Peak soleus EMG amplitude decreased by ~30% for walking and for running over the fourfold change in gravity. As hypothesised, slopes of linear regressions fitted to H-reflex versus EMG data were independent of gravity for walking and running (ANOVA, P > 0.8). The slopes were also independent of gait (P > 0.6), contrary to previous studies. Walking had a greater y-intercept (19.9% Mmax) than running (-2.5% Mmax; P < 0.001). At all levels of EMG, walking H-reflex amplitudes were higher than running H-reflex amplitudes by a constant amount. We conclude that the nervous system adjusts H-reflex threshold but not H-reflex gain between walking and running. These findings provide insight into potential neural mechanisms responsible for spinal modulation of the stretch reflex during human locomotion.


Cia5d regulates a new fibroblast-like synoviocyte invasion-associated gene expression signature.
The in vitro invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) have been shown to correlate with disease severity and radiographic damage. We recently determined that FLSs obtained from pristane-induced arthritis (PIA)-susceptible DA rats are also highly invasive in the same in vitro assay through Matrigel. The transfer of alleles derived from the arthritis-resistant F344 strain at the arthritis severity locus Cia5d (RNO10), as in DA.F344(Cia5d) congenics, was enough to significantly and specifically reduce the invasive properties of FLSs. This genetically controlled difference in FLS invasion involves increased production of soluble membrane-type 1 matrix metalloproteinase (MMP) by DA, and is dependent on increased activation of MMP-2. In the present study we aimed to characterize the pattern of gene expression that correlates with differences in invasion in order to identify pathways regulated by the Cia5d locus. Synovial tissues were collected from DA and DA.F344(Cia5d) rats 21 days after the induction of PIA. Tissues were digested and FLSs isolated. After a minimum of four passages, FLSs were plated on Matrigel-covered dishes at similar densities, followed by RNA extraction. Illumina RatRef-12 expression BeadChip arrays were used. Expression data were normalized, followed by t-test, logistic regression, and cluster analysis. Real-time PCR was used to validate the microarray data. Out of the 22,523 RefSeq gene probes present in the array, 7,665 genes were expressed by the FLSs. The expression of 66 genes was significantly different between the DA and DA.F344(Cia5d) FLSs (P < 0.01). Nineteen of the 66 differentially expressed genes (28.7%) are involved in the regulation of cell cycle progression or cancer-associated phenotypes, such as invasion and contact inhibition. These included Cxcl10, Vil2 and Nras, three genes that are upregulated in DA and known to regulate MMP-2 expression and activation. Nine of the 66 genes (13.6%) are involved in the regulation of estrogen receptor signaling or transcription. Five candidate genes located within the Cia5d interval were also differentially expressed. We have identified a novel FLS invasion associated gene expression signature that is regulated by Cia5d. Many of the genes found to be differentially expressed were previously implicated in cancer cell phenotypes, including invasion. This suggests a parallel in the behavior of arthritis FLSs and cancer cells, and identifies novel pathways and genes for therapeutic intervention and prognostication.


Twin growth discrepancy in early pregnancy.
To assess whether early fetal growth restriction in a twin, expressed as the intertwin discrepancy in crown-rump length (CRL) between two viable twins at 7 + 0 to 9 + 6 weeks' gestation, is predictive of subsequent single fetal loss. This was a retrospective analysis of data collected prospectively over 3 years. Women attending an early pregnancy unit underwent a transvaginal ultrasound examination. In women with a viable twin pregnancy between 7 + 0 and 9 + 6 weeks of gestation, the CRL ratio between the two embryos was calculated. Women were followed up and the intertwin discrepancy in CRL at the 7 + 0 to 9 + 6-week scan was compared between cases in which there was spontaneous reduction to a singleton and those in which both twins remained viable at the 11-14-week scan. There were 77 women included in the study and nine (12%) of these had a single fetal loss. Pregnancies with subsequent single fetal loss were more likely to have a larger median CRL discrepancy (42.0%; interquartile range (IQR), 23.8-64.3%) than were those which retained two viable fetuses (6.1%; IQR, 2.2-12.5%) (P < 0.0001). The median CRL discrepancy in subsequently viable monochorionic diamniotic twins (10.9%; IQR, 1.9-17.5%) was no different from that in dichorionic diamniotic twin pregnancies (5.9%; IQR, 2.1-12.3%) (P = 0.305). Regardless of chorionicity, there was a relationship between increasing CRL discrepancy and single fetal loss; the likelihood of a subsequently viable twin pregnancy was 97% if the discrepancy was < 20%, while if the discrepancy was > 60% there were no cases of both twins remaining viable (P < 0.0001). Receiver-operating characteristics curve analysis of CRL discrepancy in predicting single fetal loss gave an area under the curve of 0.93, with an optimum cut-off point of 16.9% discrepancy (sensitivity, 88.9%; 95% CI, 51.8-99.7; and specificity, 86.7%; 95% CI, 76.3-93.8). There is a significant relationship between CRL discrepancy at 7 + 0 to 9 + 6 weeks and the likelihood of subsequent single intrauterine fetal loss. This suggests that spontaneous fetal demise of one twin may be preceded by growth restriction in the first trimester.


Pearl Oyster Bacterial Community Structure Is Governed by Location and Tissue-Type, but Vibrio Species Are Shared Among Oyster Tissues.
Diseases of bivalves of aquacultural importance, including the valuable Australian silver-lipped pearl oyster (Pinctada maxima), have been increasing in frequency and severity. The bivalve microbiome is linked to health and disease dynamics, particularly in oysters, with putative pathogens within the Vibrio genus commonly implicated in oyster diseases. Previous studies have been biased toward the Pacific oyster because of its global dominance in oyster aquaculture, while much less is known about the microbiome of P. maxima. We sought to address this knowledge gap by characterizing the P. maxima bacterial community, and we hypothesized that bacterial community composition, and specifically the occurrence of Vibrio, will vary according to the sampled microenvironment. We also predicted that the inside shell swab bacterial composition could represent a source of microbial spillover biofilm into the solid pearl oyster tissues, thus providing a useful predictive sampling environment. We found that there was significant heterogeneity in bacterial composition between different pearl oyster tissues, which is consistent with patterns reported in other bivalve species and supports the hypothesis that each tissue type represents a unique microenvironment for bacterial colonization. We suggest that, based on the strong effect of tissue-type on the pearl oyster bacterial community, future studies should apply caution when attempting to compare microbial patterns from different locations, and when searching for disease agents. The lack of association with water at each farm also supported the unique nature of the microbial communities in oyster tissues. In contrast to the whole bacterial community, there was no significant difference in the Vibrio community among tissue types nor location. These results suggest that Vibrio species are shared among different pearl oyster tissues. In particular, the similarity between the haemolymph, inside shell and solid tissues, suggests that the haemolymph and inside shell environment is a source of microbial spillover into the oyster tissues, and a potentially useful tool for non-destructive routine disease testing and early warning surveillance. These data provide important foundational information for future studies identifying the factors that drive microbial assembly in a valuable aquaculture species.


Statistically validated networks in bipartite complex systems.
Many complex systems present an intrinsic bipartite structure where elements of one set link to elements of the second set. In these complex systems, such as the system of actors and movies, elements of one set are qualitatively different than elements of the other set. The properties of these complex systems are typically investigated by constructing and analyzing a projected network on one of the two sets (for example the actor network or the movie network). Complex systems are often very heterogeneous in the number of relationships that the elements of one set establish with the elements of the other set, and this heterogeneity makes it very difficult to discriminate links of the projected network that are just reflecting system's heterogeneity from links relevant to unveil the properties of the system. Here we introduce an unsupervised method to statistically validate each link of a projected network against a null hypothesis that takes into account system heterogeneity. We apply the method to a biological, an economic and a social complex system. The method we propose is able to detect network structures which are very informative about the organization and specialization of the investigated systems, and identifies those relationships between elements of the projected network that cannot be explained simply by system heterogeneity. We also show that our method applies to bipartite systems in which different relationships might have different qualitative nature, generating statistically validated networks in which such difference is preserved.


Erythrocyte Mr 28,000 transmembrane protein exists as a multisubunit oligomer similar to channel proteins.
A novel Mr 28,000 erythrocyte transmembrane protein was recently purified and found to exist in two forms, "28kDa" and "gly28kDa," the latter containing N-linked carbohydrate (Denker, B. M., Smith, B. L., Kuhajda, F. P., and Agre, P. (1988) J. Biol. Chem. 263, 15634-15642). Although 28kDa protein resembles the Rh polypeptides biochemically, structural homologies were not identified by immunoblot or two-dimensional iodopeptide maps. The NH2-terminal amino acid sequence for the first 35 residues of purified 28kDa protein is 37% identical to the 26-kDa major intrinsic protein of lens (Gorin, M. B., Yancey, S. B., Cline, J., Revel, J.-P., and Horwitz, J. Cell 39, 49-59). Antisera to a synthetic peptide corresponding to the NH2-terminus of 28kDa protein gave a single reaction of molecular mass 28kDa on immunoblots of erythrocyte membranes. Selective digestions of intact erythrocytes and inside-out membrane vesicles with carboxypeptidase Y indicated the existence of a 5-kDa COOH-terminal cytoplasmic domain. Multiple studies indicated that 28kDa and gly28kDa proteins exist together as a multisubunit oligomer: 1) similar partial solubilizations in Triton X-100; 2) co-purification during ion exchange and lectin affinity chromatography; 3) cross-linking in low concentrations of glutaraldehyde; and 4) physical analyses of purified proteins and solubilized membranes in 1% (v/v) Triton X-100 showed 28kDa and gly28kDa proteins behave as a large single unit with Stokes radius of 61 A and sedimentation coefficient of 5.7 S. These studies indicate that the 28kDa and gly28kDa proteins are distinct from the Rh polypeptides and exist as a multisubunit oligomer. The 28kDa protein has NH2-terminal amino acid sequence homology and membrane organization similar to major intrinsic protein and other members of a newly recognized family of transmembrane channel proteins.


Is surveillance of the small bowel indicated for Lynch syndrome families?
Small bowel cancer (SBC) is one of the tumours associated with Lynch syndrome (LS). To advise on screening for this tumour it is paramount to be informed about the lifetime risk. The aim of this study was to calculate the lifetime risk of SBC in LS and to identify possible risk factors. Clinical and pathological data were collected on 1496 proven or putative carriers of a mismatch repair gene mutation from 189 families. Kaplan-Meier survival analysis was used to calculate the lifetime risk and to assess potential risk factors. 28 (1.9%) of the 1496 (putative) mutation carriers were identified with SBC. The median age at diagnosis was 52 years (range 23-69 years). The lifetime risk of developing SBC was 4.2%. There was no difference in risk between males and females (log rank: p = 0.2470), or between MLH1 and MSH2 mutation carriers (log rank: p = 0.2754). SBC was not observed in MSH6 mutation carriers (n = 203). The previous occurrence of colorectal cancer and a family history of SBC did not increase the risk significantly. Approximately, one out of 25 mutation carriers will develop SBC during life. No specific risk factors were identified. The risk appeared to be too low to advise screening by means of an invasive burdensome procedure like double balloon enteroscopy. However, screening by a non-invasive procedure (videocapsule endoscopy) might be considered if future studies will show its cost effectiveness. In patients with unexplained abdominal complaints and/or unexplained iron deficiency anaemia SBC should be considered.


[Peripheral thromboembolic complications in heart transplantation: prevalence and review of the literature].
Peripheral thrombotic complications were retrospectively analyzed in a series of 164 consecutive patients undergoing orthotopic cardiac transplantation (CT) at the University Clinic of Navarra from 1984 to 1999. The overall survival during the first year after CT was 82%. All patients, besides the immunosuppressive regimen, received antiplatelet treatment postoperatively. The prevalence of thrombotic complications was 18% (29 events in 25 patients): 21 (13%) corresponded to arterial thrombosis, mainly cerebrovascular, whereas 8 (5%) were venous thrombosis. The time between the CT and the onset of thrombosis was 2 +/- 1.8 years. Mortality in patients with thrombosis did not differ significantly from the global mortality. The analysis in relation to the presence of cardiovascular risk factors only showed statistical significant differences for the age (older in the group with thrombosis, p = 0.02). In conclusion, there is a high prevalence of peripheral thrombotic complications in patients undergoing CT despite the antithrombotic regimen administered. The lack of correlation with the traditional cardiovascular risk factors suggest additional mechanisms for thrombosis in these patients.


Designed azolopyridinium salts block protective antigen pores in vitro and protect cells from anthrax toxin.
Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way. Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the µM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro. These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax.


Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.
The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.


A dye-sensitized visible light photocatalyst-Bi24O31Cl10.
The p-block semiconductors are regarded as a new family of visible-light photocatalysts because of their dispersive and anisotropic band structures as well as high chemical stability. The bismuth oxide halides belong to this family and have band structures and dispersion relations that can be engineered by modulating the stoichiometry of the halogen elements. Herein, we have developed a new visible-light photocatalyst Bi24O31Cl10 by band engineering, which shows high dye-sensitized photocatalytic activity. Density functional theory calculations reveal that the p-block elements determine the nature of the dispersive electronic structures and narrow band gap in Bi24O31Cl10. Bi24O31Cl10 exhibits excellent visible-light photocatalytic activity towards the degradation of Rhodamine B, which is promoted by dye sensitization due to compatible energy levels and high electronic mobility. In addition, Bi24O31Cl10 is also a suitable photoanode material for dye-sensitized solar cells and shows power conversion efficiency of 1.5%.


Coronary Artery Disease Presentation and Its Association with Shortened Activated Partial Thromboplastin Time.
Background: Standard coagulation screening tests are important constituents of basic examinations in clinical laboratories. There is no clear evidence of a relation between the type of clinical presentation and coagulation parameters in patients with suspected coronary artery disease. Methods: This cross-sectional study included 539 patients who underwent coronary angiography in Tehran Heart Center between November 2012 and January 2013. Patients presented with ST-segment-elevation myocardial infarction (STEMI), non-STEMI, unstable angina, or stable angina. Prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) were measured before angiography and compared between the clinical presentation groups. Results: The mean age of the patients was 59.156 ± 11.05 years, and 47.7% were male. STEMI was reported in 41(7.6%) patients, non-STEMI in 42 (7.8%), unstable angina in 304 (56.4%), and stable angina in 152 (28.2%). No difference in the mean PT and INR was found between the groups. The mean APTT was significantly lower among the patients presenting with STEMI and non-STEMI (26.58 ± 2.32 s in the STEMI, 26.85 ± 2.41 s in the non-STEMI, 27.64 ± 2.54 s in the unstable, and 27.93 ± 2.53 s in the stable angina groups, respectively, p value = 0.005). After adjustment, the association between the patients' presentations and APTT was significant (OR for 5 s increase in APTT = 1.661, 95% CI = 1.184 to 2.332; p value = 0.003). Conclusion: We observed that the patients who presented with STEMI had the lowest value of APTT, whereas those who presented with stable angina had the highest. The value of APTT in patients undergoing coronary angiography may have a potential to predict the extent and severity of coronary stenosis.


Sensitivity of birth certificate reports of birth defects in Atlanta, 1995-2005: effects of maternal, infant, and hospital characteristics.
We assessed variations in the sensitivity of birth defect diagnoses derived from birth certificate data by maternal, infant, and hospital characteristics. We compared birth certificate data for 1995-2005 births in Atlanta with data from the Metropolitan Atlanta Congenital Defects Program (MACDP). We calculated the sensitivity of birth certificates for reporting defects often discernable at birth (e.g., anencephaly, spina bifida, cleft lip, clubfoot, Down syndrome, and rectal atresia or stenosis). We used multivariable logistic regression models to examine associations with sociodemographic and hospital factors. The overall sensitivity of birth certificates was 23% and ranged from 7% for rectal atresia/stenosis to 69% for anencephaly. Non-Hispanic black maternal race/ethnicity, less than a high school education, and preterm birth were independently associated with a lower probability of a birth defect diagnosis being reported on a birth certificate. Sensitivity also was lower for hospitals with > 1,000 births per year. The underreporting of birth defects on birth certificates is influenced by sociodemographic and hospital characteristics. Interpretation of birth defects prevalence estimates derived from birth certificate reports should take these issues into account.


The Harvest suite for rapid core-genome alignment and visualization of thousands of intraspecific microbial genomes.
Whole-genome sequences are now available for many microbial species and clades, however existing whole-genome alignment methods are limited in their ability to perform sequence comparisons of multiple sequences simultaneously. Here we present the Harvest suite of core-genome alignment and visualization tools for the rapid and simultaneous analysis of thousands of intraspecific microbial strains. Harvest includes Parsnp, a fast core-genome multi-aligner, and Gingr, a dynamic visual platform. Together they provide interactive core-genome alignments, variant calls, recombination detection, and phylogenetic trees. Using simulated and real data we demonstrate that our approach exhibits unrivaled speed while maintaining the accuracy of existing methods. The Harvest suite is open-source and freely available from: http://github.com/marbl/harvest.


Tetanus, diphtheria, and acellular pertussis vaccination among women of childbearing age-United States, 2013.
The incidence of pertussis in the United States has increased since the 1990s. Tetanus, diphtheria, and acellular pertussis (Tdap) vaccination of pregnant women provides passive protection to infants. Tdap vaccination is currently recommended for pregnant women during each pregnancy, but coverage among pregnant women and women of childbearing age has been suboptimal. Data from the 2013 Behavioral Risk Factor Surveillance System (BRFSS) and 2013 National Health Interview Survey (NHIS) were used to determine national and state-specific Tdap vaccination coverage among women of childbearing age by self-reported pregnancy status at the time of the survey. Although this study could not assess coverage of Tdap vaccination received during pregnancy because questions on whether Tdap vaccination was received during pregnancy were not asked in BRFSS and NHIS, demographic and access-to-care factors associated with Tdap vaccination coverage in this population were assessed. Tdap vaccination coverage among all women 18-44 years old was 38.4% based on the BRFSS and 23.3% based on the NHIS. Overall, coverage did not differ by pregnancy status at the time of the survey. Coverage among all women 18-44 years old varied widely by state. Age, race and ethnicity, education, number of children in the household, and access-to-care characteristics were independently associated with Tdap vaccination in both surveys. We identified associations of demographic and access-to-care characteristics with Tdap vaccination that can guide strategies to improve vaccination rates in women during pregnancy.


The New England 4G framework for the treatment of a common health concerns: a gambling case analysis.
Approaches using self-help have proved successful at treating a range of mental and physical conditions. Guidance by a trained worker enhances the effects of self-help materials, in particular those based on Cognitive-Behavior Therapy. In the United Kingdom, the Improving Access to Psychological Therapies (IAPT) program was introduced to provide better outcomes for people experiencing mild or moderate anxiety and depression. This stepped care approach included low intensity, guided self-help offered by a newly trained workforce of Psychological Wellbeing Workers. The IAPT program has been extensively evaluated and shown to be cost effective and leads to positive treatment outcomes. This paper describes how the IAPT model has been adapted for use in Australia with gamblers. Two case studies illustrate the application of this guided approach to systematically accessing existing self-help treatments for problem gamblers. Assessment information is gathered, before a plan of action, including a problem statement and achievable goals, is agreed upon by the worker and the person with the gambling problem. The worker then gives the person options based on self-help CBT interventions and, once an option has been chosen, the worker guides the person as they work through various activities. The benefits of this approach are discussed.


Aminoglycoside resistance by ArmA-mediated ribosomal 16S methylation in human bacterial pathogens.
Aminoglycosides are a medically important class of antibiotics used to treat serious infections. Methylation of the ribosomal target is an emerging mechanism that produces a high level of resistance to all clinically available aminoglycosides for systemic therapy except streptomycin. ArmA was the first methyltransferase using this mechanism to be discovered in a clinical isolate. We demonstrate that ArmA methylates the N7 position of nucleotide G1405 in 16S rRNA. Methylation at this position is presumed to mediate cellular resistance by blocking aminoglycoside binding by ribosomes. To test this hypothesis, we measured the binding of gentamicin by 30S subunits. Under our conditions, we did not observe binding by ribosomes methylated by ArmA. Furthermore, the ArmA methylation reaction is specific for the 30S ribosomal subunit; neither 16S rRNA alone nor the 70S ribosome is a substrate for this reaction under our experimental conditions, implicating ribosomal proteins in substrate recognition. The biochemical characteristics of ArmA place it in the Agr family of methyltransferases, whose members are predominantly anti-suicide genes from Actinomycetes aminoglycoside producers. The discrepancy between the 30% GC content of armA and the >60% GC content of Actinomycetes, however, calls into question the origin of armA. We demonstrate that surprisingly, the natural promoter of armA from gram-negative Klebsiella pneumoniae was active in gram-positive Bacillus subtilis, suggesting that armA originated from a low-GC, gram-positive aminoglycoside-producing organism.


Associations between neighbourhood characteristics and depression: a twin study.
Depression is an important contributor to the global burden of disease. Besides several known individual-level factors that contribute to depression, there is a growing recognition that neighbourhood environment can also profoundly affect mental health. This study assessed associations between three neighbourhood constructs-socioeconomic deprivation, residential instability and income inequality-and depression among adult twin pairs. The twin design is used to examine the association between neighbourhood constructs and depression, controlling for selection factors (ie, genetic and shared environmental factors) that have confounded purported associations. We used multilevel random-intercept Poisson regression among 3738 same-sex twin pairs from a community-based twin registry to examine the association between neighbourhood constructs and depression. The within-pair association controls for confounding by genetic and environmental factors shared between twins within a pair, and is the main parameter of interest. Models were adjusted for individual-level income, education and marital status, and further by neighbourhood-level population density. When twins were analysed as individuals (phenotypic model), all neighbourhood constructs were significantly associated with depression. However, only neighbourhood socioeconomic deprivation showed a significant within-pair association with depression. A 10-unit within-pair difference in neighbourhood socioeconomic deprivation was associated with 6% greater depressive symptoms (1.06, 95% CI 1.01 to 1.11); the association did not substantially change in adjusted models. This study provides new evidence linking neighbourhood socioeconomic deprivation with greater depression. Future studies should employ longitudinal designs to better test social causation versus social selection.


The impact of the World Trade Center attack on FDNY firefighter retirement, disabilities, and pension benefits.
Our goal was to examine the effect of the World Trade Center (WTC) attack and subsequent New York City Fire Department (FDNY) rescue/recovery activities on firefighter retirements. We also analyzed the financial impact associated with the increased number and proportion of service-connected "accidental" disability retirements on the FDNY pension system. A total of 7,763 firefighters retired between 9/11/1994 and 9/10/2008. We compared the total number of retirements and the number and proportion of accidental disability retirements 7 years before and 7 years after the WTC attack. We categorized WTC-related accidental disability retirements by medical cause and worked with the New York City Office of the Actuary to approximate the financial impact by cause. In the 7 years before 9/11 there were 3,261 retirements, 48% (1,571) of which were accidental disability retirements. In the 7 years after 9/11, there were 4,502 retirements, 66% (2,970) were accidental disability retirements, of which 47% (1,402) were associated with WTC-related injuries or illnesses. After 9/11, the increase in accidental disability retirements was, for the most part, due to respiratory-related illnesses. Additional increases were attributed to psychological-related illnesses and musculoskeletal injuries incurred at the WTC site. Pension benefits associated with WTC-related accidental disability retirements have produced an increased financial burden of over $826 million on the FDNY pension system. The WTC attacks affected the health of the FDNY workforce resulting in more post-9/11 retirements than expected, and a larger proportion of these retirees with accidental disability pensions.


"Profiling pathological narcissism according to DSM-5 domains and traits: A study on consecutively admitted Italian psychotherapy Patients": Correction to Fossati et al. (2016).
Reports an error in "Profiling pathological narcissism according to DSM-5 domains and traits: A study on consecutively admitted Italian psychotherapy patients" by Andrea Fossati, Antonella Somma, Serena Borroni, Aaron L. Pincus, Kristian E. Markon and Robert F. Krueger (Psychological Assessment, Advanced Online Publication, Jun 23, 2016, np). In the article, several values were reversed and the mean was misreported in Table 2. The corrected table is present in the erratum. (The following abstract of the original article appeared in record 2016-31181-001.) Pathological narcissism represents a clinically relevant, albeit controversial personality construct, with multiple conceptualizations that are operationalized by different measures. Even in the recently published Diagnostic and Statistical Manual for Mental Disorders-Fifth Edition (DSM-5), 2 different views of narcissistic personality disorder (NPD) are formulated (i.e., Section II and Section III). The DSM-5 Section III alternative PD model diagnosis of NPD is based on self and interpersonal dysfunction (Criterion A) and a profile of maladaptive personality traits (Criterion B), specifically elevated scores on Attention Seeking and Grandiosity. Given the diversity of conceptualizations of pathological narcissism, we evaluated the convergences and divergences in DSM-5 trait profiles characterizing multiple measures of narcissism in a clinical sample of 278 consecutively admitted Italian psychotherapy patients. Patients were administered the Italian versions of the Personality Inventory for DSM-5 (PID-5) and 4 measures of NPD, (a) the Narcissistic Personality Inventory (NPI); (b) the NPD scale of the Personality Diagnostic Questionnaire-4+; (c) the Structured Clinical Interview for Axis II Personality Disorders, Version 2.0 (SCID-II) as an observer-rated measure of NPD; and (d) the Pathological Narcissism Inventory (PNI). Multiple regression analyses showed that PID-5 traits explained from 13% to more than 60% of the variance in the different NPD measures. Attention Seeking was consistently associated with all measures of NPD, whereas Grandiosity was associated with some of the NPD measures. All measures of NPD were also significantly related to additional DSM-5 maladaptive traits. (PsycINFO Database Record


Diagnosis and clinical management of duplications and deletions.
Chromosome deletions and duplications-copy number variations (CNVs)-are a major contribution to the genome variability and can be either pathogenic or not. A particular class, the microdeletions and microduplications, which alter <5 Mb, have been extensively associated with developmental delay and intellectual disability. Although their prevalence in pregnancies and newborn is relatively low, their estimates in preimplantation embryos are poorly defined. The introduction of novel technologies for preimplantation genetic diagnosis of aneuploidies (PGD-A) caused new possibilities and challenges associated with diagnosis of subchromosomal CNVs. Both technical aspects of performing genomewide microarray or next generation sequencing analysis on single cells and interpretation issues are subject of debate. The latter include the reliability of detection of CNVs from embryonic biopsies, their clinical classification based on reproductive outcomes, as well as how before and after test counseling should be organized. It is also important to consider that the current resolution of these technologies from single cells is usually >10 Mb, thus ruling out the possibility to diagnose the most important recurrent microdeletion and microduplication syndromes. Furthermore, at present we face with a lack of well-designed studies addressing the actual resolution and accuracy of CNVs detection in PGD-A and no reference databases is available to evaluate their pathogenicity. Accordingly, it seems reasonable at the moment to avoid the reporting of subchromosomal CNVs in PGD-A. However, although these issues require proper handling, they should not lead us away from providing an improved preimplantation genetic diagnosis.


Andreas Vesalius, the Predecessor of Neurosurgery: How his Progressive Scientific Achievements Affected his Professional Life and Destiny.
Andreas Vesalius, the father of modern anatomy and a predecessor of neuroscience, was a distinguished medical scholar and Renaissance figure of the 16th Century Scientific Revolution. He challenged traditional anatomy by applying empirical methods of cadaveric dissection to the study of the human body. His revolutionary book, De Humani Corporis Fabrica, established anatomy as a scientific discipline that challenged conventional medical knowledge, but often caused controversy. Charles V, the Holy Roman Emperor and King of Spain to whom De Humani was dedicated, appointed Vesalius to his court. While in Spain, Vesalius' work antagonized the academic establishment, current medical knowledge, and ecclesial authority. Consequently, his methods were unacceptable to the academic and religious status quo, therefore, we believe that his professional life-as well as his tragic death-was affected by the political state of affairs that dominated 16th Century Europe. Ultimately, he went on a pilgrimage to the Holy Land that jeopardized his life. While returning home, his ship was driven ashore on the Greek island of Zakynthos (Zante) where he became ill and suddenly died in 1564 at the age of 49. Vesalius' ideas helped free medicine from the limitations of the 16th Century and advanced scientific knowledge. His influence is still felt more than 500 years later. In this article, we acknowledge Vesalius' neuroanatomic contributions and we discuss the historical facts and political circumstances that influenced his scientific career and personal life, emphasizing the conditions of his pilgrimage to the Holy Land that led to his untimely death.


Potentiation of gastric toxicity of ibuprofen by paracetamol in the rat.
A fixed dose combination of ibuprofen (400 mg) and paracetamol (325 mg) is by far the most extensively prescribed medicament for a variety of musculoskeletal disorders in India. Following clinical observations that this drug combination induces significant adverse effects, its gastric toxicity was investigated in rats. Ibuprofen (25 mg kg-1 p.o., twice daily x 5 days), paracetamol (20 mg kg-1 p.o, twice daily x 5 days), and a combination of the two, had no significant effect on free and total gastric acidity in pylorus-ligated rats. Ibuprofen induced visible gastric ulceration whereas paracetamol did not. However, the combination of these two drugs had an additive effect inducing severe gastric erosions, ulcerations and bleeding. The augmented toxicity of this drug combination appeared to be a consequence of attenuated gastric mucin activity and reduction in the gastric muco-protective barrier. This investigation indicates the likely hazard of an irrational fixed dose drug combination.


Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface.
Thyroid hormone (TH) action is mediated by TH receptors (TRs), which are members of the nuclear hormone receptor superfamily. In vitro studies have demonstrated that TR activity is regulated by interactions with corepressor and coactivator proteins (CoRs and CoAs, respectively). TH stimulation is thought to involve dissociation of CoRs and recruitment of CoAs to the liganded TR. In contrast, negative regulation by TH is thought to occur via recruitment of CoRs to the liganded TR. The physiological role of CoAs bound to TRs, however, has yet to be defined. In this study, we used gene-targeting techniques to mutate the TR-beta locus within its activation function-2 (AF-2) domain (E457A). This mutation was chosen because it completely abolished CoA recruitment in vitro, while preserving normal triiodothyronine (T3) binding and CoR interactions. As expected, TH-stimulated gene expression was reduced in homozygous E457A mice. However, these animals also displayed abnormal regulation of the hypothalamic-pituitary-thyroid axis. Serum thyroxine, T3, and thyroid-stimulating hormone (TSH) levels and pituitary Tshb mRNA levels were inappropriately elevated compared with those of WT animals, and L-T3 treatment failed to suppress serum TSH and pituitary Tshb mRNA levels. Therefore, the AF-2 domain of TR-beta is required for positive and, paradoxically, for negative regulation by TH in vivo.


Ornithine decarboxylase activity in relation to DNA synthesis in mouse interfollicular epidermis and hair follicles.
The relationship between ornithine decarboxylase (L-ornithine carboxylyase, EC 188.8.131.52) activity and DNA synthetic activity was studied in mouse epidermis. Interfollicular epidermis and hair follicles were investigated separately. It was found that, in hair follicles, the variations of DNA replicative activity, which are reflected in the cyclic growth of hair, are paralleled by corresponding changes in ornithine decarboxylase activity. In both interfollicular epidermis and hair follicles, stimulation of DNA synthetic activity by plucking of hair induced a rapid and marked increase in ornithine decarboxylase activity. The relationship of steady-state and induced ornithine decarboxylase activity to DNA synthetic activity was compared in hair follicles and interfollicular epidermis. A correlation between the activity of this enzyme and DNA replication was found thereby in each of these tissues.


Effect of Phacoemulsification on Visual Acuity and Macular Morphology in Patients with Wet Age-Related Macular Degeneration.
BACKGROUND This article discusses the effectiveness of phacoemulsification cataract surgery with intraocular lens implantation in patients with wet age-related macular degeneration in the inactive phase of the disease. MATERIAL AND METHODS Forty-nine patients (50 eyes) aged 78.94±5.54 years, previously treated with intravitreal injections of anti-vascular endothelial growth factor agents, were qualified for a prospective, randomized 12-month study. The participants were divided into 2 groups. Group I consisted of 25 patients (25 eyes) who were subjected to phacoemulsification cataract surgery. Group II consisted of 24 patients (25 eyes) who were not subjected to phacoemulsification cataract surgery despite having a lens opacity of grade II or higher according to the Lens Opacities Classification System. RESULTS After 12 months of follow-up, patients in group I gained on average 8.04 letters (p<0.001). Furthermore, 20% of the eyes had a significant improvement in best corrected visual acuity of ≥15 Early Treatment of Diabetic Retinopathy Study Chart letters. Patients in group II lost on average 1.96 letters (p>0.05). No significant differences between central retinal thickness values in either group (p>0.05) were noted. The mean number of intravitreal injections of anti-vascular endothelial growth factor agents during the study was 2.64±1.98 in group I and 2.92±2.40 in group II (p>0.05). CONCLUSIONS Phacoemulsification performed in eyes with wet age-related macular degeneration during the inactive phase of the disease significantly improves visual acuity. In addition, it does not significantly influence the frequency of intravitreal injections of anti-vascular endothelial growth factor agents or disease activity.


Influence of the refractive index core profile on modal scattering of terminated two-dimensional waveguides.
We examine the influence of the refractive index core profile on the modal scattering of abruptly terminated slab waveguides. The analysis is based on the integral equation method with accelerating parameters, while for the field description in the waveguide core, an appropriate Lanczos-Fourier expansion is employed. The electric-field distribution on the terminal plane, the reflection and transformation coefficient of the TE guided modes, and the far-field radiation pattern are computed. Numerical results are presented for slab waveguides with step, linear, and parabolic refractive index profiles of the core. Finally, several approximate analytical solutions are derived to study the problem in question and to explain the results obtained.


Paleo-Balkan and Slavic contributions to the genetic pool of Moldavians: insights from the Y chromosome.
Moldova has a rich historical and cultural heritage, which may be reflected in the current genetic makeup of its population. To date, no comprehensive studies exist about the population genetic structure of modern Moldavians. To bridge this gap with respect to paternal lineages, we analyzed 37 binary and 17 multiallelic (STRs) polymorphisms on the non-recombining portion of the Y chromosome in 125 Moldavian males. In addition, 53 Ukrainians from eastern Moldova and 54 Romanians from the neighboring eastern Romania were typed using the same set of markers. In Moldavians, 19 Y chromosome haplogroups were identified, the most common being I-M423 (20.8%), R-M17* (17.6%), R-M458 (12.8%), E-v13 (8.8%), R-M269* and R-M412* (both 7.2%). In Romanians, 14 haplogroups were found including I-M423 (40.7%), R-M17* (16.7%), R-M405 (7.4%), E-v13 and R-M412* (both 5.6%). In Ukrainians, 13 haplogroups were identified including R-M17 (34.0%), I-M423 (20.8%), R-M269* (9.4%), N-M178, R-M458 and R-M73 (each 5.7%). Our results show that a significant majority of the Moldavian paternal gene pool belongs to eastern/central European and Balkan/eastern Mediterranean Y lineages. Phylogenetic and AMOVA analyses based on Y-STR loci also revealed that Moldavians are close to both eastern/central European and Balkan-Carpathian populations. The data correlate well with historical accounts and geographical location of the region and thus allow to hypothesize that extant Moldavian paternal genetic lineages arose from extensive recent admixture between genetically autochthonous populations of the Balkan-Carpathian zone and neighboring Slavic groups.


A reduction in Pten tumor suppressor activity promotes ErbB-2-induced mouse prostate adenocarcinoma formation through the activation of signaling cascades downstream of PDK1.
Loss of function at the Pten tumor-suppressor locus is a common genetic modification found in human prostate cancer. While recent in vivo and in vitro data support an important role of aberrant ErbB-2 signaling to clinically relevant prostate target genes, such as cyclin D1, the role of Pten in ErbB-2-induced prostate epithelial proliferation is not well understood. In the Pten-deficient prostate cancer cell line, LNCaP, restoration of Pten was able to inhibit ErbB-2- and heregulin-induced cell cycle progression, as well as cyclin D1 protein levels and promoter activity. Previously, we established that probasin-driven ErbB-2 transgenic mice presented with high-grade prostate intraepithelial neoplasia and increased nuclear cyclin D1 levels. We show that mono-allelic loss of pten in the probasin-driven-ErbB-2 model resulted in increased nuclear cyclin D1 and proliferating cell nuclear antigen levels and decreased disease latency compared to either individual genetic model and, unlike the probasin-driven-ErbB-2 mice, progression to adenocarcinoma. Activated 3-phosphoinositide-dependent protein kinase-1 was observed during cancer initiation combined with the activation of p70S6K (phospho-T389) and inactivation of the 4E-binding protein-1 (phosphorylated on T37/46) and was primarily restricted to those cases of prostate cancer that had progressed to adenocarcinoma. Activation of mTOR was not seen. Our data demonstrates that Pten functions downstream of ErbB-2 to restrict prostate epithelial transformation by blocking full activation of the PDK1 signaling cascade.


Is there synchronicity in nitrogen input and output fluxes at the Noland Divide Watershed, a small N-saturated forested catchment in the Great Smoky Mountains National Park?
High-elevation red spruce [Picea rubens Sarg.]-Fraser fir [Abies fraseri (Pursh.) Poir] forests in the Southern Appalachians currently receive large nitrogen (N) inputs via atmospheric deposition (30 kg N ha(-1) year(-1)) but have limited N retention capacity due to a combination of stand age, heavy fir mortality caused by exotic insect infestations, and numerous gaps caused by windfalls and ice storms. This study examined the magnitude and timing of the N fluxes into, through, and out of a small, first-order catchment in the Great Smoky Mountains National Park. It also examined the role of climatic conditions in causing interannual variations in the N output signal. About half of the atmospheric N input was exported annually in the streamwater, primarily as nitrate (NO3-N). While most incoming ammonium (NH4-N) was retained in the canopy and the forest floor, the NO3-N fluxes were very dynamic in space as well as in time. There was a clear decoupling between NO3-N input and output fluxes. Atmospheric N input was greatest in the growing season while largest NO3-N losses typically occurred in the dormant season. Also, as water passed through the various catchment compartments, the NO3-N flux declined below the canopy, increased in the upper soil due to internal N mineralization and nitrification, and declined again deeper in the mineral soil due to plant uptake and microbial processing. Temperature control on N production and hydrologic control on NO3-N leaching during the growing season likely caused the observed inter-annual variation in fall peak NO3-N concentrations and N discharge rates in the stream.


1 H-NMR metabolomics profiling of recombinant tobacco plants holding a promoter of a sesquiterpene cyclase.
Nicotiana tabacum is a plant model intensively used in the bio-engineering pharmaceutical industry as a platform to produce drugs and therapeutic agents. Currently, no information regarding the non-targeted metabolome of transgenic tobacco containing recombinant regulatory sequences is available. To compare the proton nuclear magnetic resonance (1 H-NMR) metabolomics profiling of a recombinant Nicotiana tabacum strain containing a promoter of a sesquiterpene cyclase from Capsicum annuum driving GUS expression, versus wild-type samples. Methodology The non-targeted 1 H-NMR metabolome was obtained and processed by principal component analysis (PCA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). The differential metabolites were quantified by quantitative NMR. PCA and OPLS-DA revealed 37 metabolites including 16 discriminant compounds for transgenic samples. Ethanol (0.4 mg g-1 ), the main differential compound, was exclusively detected in transgenic tobacco; however, high levels of formate (0.28 mg g-1 ) and acetate (0.3 mg g-1 ) were simultaneously observed in the same group of samples. Cembratriene-4,6-diol, an antitumour and neuroprotective compound, and capsidiol, a known phytoalexin, increased by about 30% in transgenic samples. In addition, the endogenous levels of the antioxidant caffeoylquinic acid isomers increased by 50% in comparison to those of wild-type tobaccos. Our results support the occurrence of metabolic differences between wild type and transgenic tobacco containing a promoter of a Capsicum sesquiterpene cyclase gene. Interestingly, the recombinant transgenic strain studied accumulated high amounts of added value compounds with biological activity.


Fermentable-sugar-level-dependent regulation of leukotoxin synthesis in a variably toxic strain of Actinobacillus actinomycetemcomitans.
Actinobacillus actinomycetemcomitans, a Gram-negative periodontopathic bacterium, produces a leukotoxin belonging to the RTX family. The production of leukotoxin varies greatly among different strains of this species and under different culture conditions. A toxin-production-variable strain, 301-b, stably produces significant amounts of leukotoxin in anaerobic fructose-limited chemostat cultures, but does not do so in the presence of excess fructose. This communication describes the cloning and sequencing of the leukotoxin promoter region from 301-b, showing that this strain has a promoter region similar to that from strain 652, a moderately toxic strain. Northern blot analysis using a leukotoxin gene probe demonstrated that change in toxin production in response to the level of external fructose was due to alteration in the transcriptional level of the leukotoxin gene. Pulsing of fructose into the fructose-limited chemostat culture remarkably reduced the intracellular cAMP level from 40 pmol (mg dry wt cells)(-1) to 3.1 pmol (mg dry wt cells)(-1), which was restored when the culture was returned to fructose-limited conditions. Further, it was found that addition of external cAMP to the culture with excess fructose resulted in an apparent recovery of leukotoxin production. Taken together, these findings indicate that a cAMP-dependent mechanism, possibly a catabolite-repression-like system, may be involved in the regulation of leukotoxin production in this bacterium.


Coagulase-negative staphylococcal bloodstream and prosthetic-device-associated infections: the role of biofilm formation and distribution of adhesin and toxin genes.
Coagulase-negative staphylococci (CNS), especially Staphylococcus epidermidis and Staphylococcus haemolyticus, have emerged as opportunistic pathogens in immunocompromised patients and those with indwelling medical devices. In this study, CNS recovered from patients with bloodstream infections (BSIs) or prosthetic-device-associated infections (PDAIs) were compared in terms of biofilm formation, antimicrobial resistance, clonal distribution, and carriage of adhesin and toxin genes. A total of 226 CNS isolates (168 S. epidermidis and 58 S. haemolyticus) recovered from hospital inpatients with BSIs (100 isolates) or PDAIs (126 isolates) were tested for biofilm formation, antimicrobial susceptibility, and mecA, ica operon, adhesin (aap, bap, fnbA, atlE, fbe) and toxin (tst, sea, sec) genes. The selected CNS were classified into pulsotypes by PFGE and assigned to sequence types by multilocus sequence typing. In total, 106/226 isolates (46.9%) produced biofilm, whereas 150 (66.4%) carried the ica operon. Most isolates carried mecA and were multidrug resistant (90.7%). CNS recovered from BSIs were significantly more likely to produce biofilm (P=0.003), be resistant to antimicrobials and carry mecA (P<0.001), as compared with isolates derived from PDAIs. CNS from PDAIs were more likely to carry the aap and bap genes (P=0.006 and P=0.045, respectively). No significant differences in the carriage of toxin genes were identified (P>0.05). Although PFGE revealed genetic diversity, especially among S. epidermidis, analysis of representative strains from the main PFGE types by multilocus sequence typing revealed three major clones (ST2, ST5 and ST16). A clonal relationship was found with respect to antimicrobial susceptibility and ica and aap gene carriage, reinforcing the premise of clonal expansion in hospital settings. The results of this study suggest that the pathogenesis of BSIs is associated with biofilm formation and high-level antimicrobial resistance, whereas PDAIs are related to the adhesion capabilities of S. epidermidis and S. haemolyticus strains.


Insight into the evolution and origin of leprosy bacilli from the genome sequence of Mycobacterium lepromatosis.
Mycobacterium lepromatosis is an uncultured human pathogen associated with diffuse lepromatous leprosy and a reactional state known as Lucio's phenomenon. By using deep sequencing with and without DNA enrichment, we obtained the near-complete genome sequence of M. lepromatosis present in a skin biopsy from a Mexican patient, and compared it with that of Mycobacterium leprae, which has undergone extensive reductive evolution. The genomes display extensive synteny and are similar in size (∼3.27 Mb). Protein-coding genes share 93% nucleotide sequence identity, whereas pseudogenes are only 82% identical. The events that led to pseudogenization of 50% of the genome likely occurred before divergence from their most recent common ancestor (MRCA), and both M. lepromatosis and M. leprae have since accumulated new pseudogenes or acquired specific deletions. Functional comparisons suggest that M. lepromatosis has lost several enzymes required for amino acid synthesis whereas M. leprae has a defective heme pathway. M. lepromatosis has retained all functions required to infect the Schwann cells of the peripheral nervous system and therefore may also be neuropathogenic. A phylogeographic survey of 227 leprosy biopsies by differential PCR revealed that 221 contained M. leprae whereas only six, all from Mexico, harbored M. lepromatosis. Phylogenetic comparisons indicate that M. lepromatosis is closer than M. leprae to the MRCA, and a Bayesian dating analysis suggests that they diverged from their MRCA approximately 13.9 Mya. Thus, despite their ancient separation, the two leprosy bacilli are remarkably conserved and still cause similar pathologic conditions.


Combining covalent bonding and electrostatic attraction to achieve highly viable species with ultrashort beryllium-beryllium distances: a computational design.
Though ultrashort metal-metal distances (USMMD, dM-M < 1.900 Å) were primarily realized between transition metals, USMMDs between main group metal atoms such as beryllium atoms have also been designed previously using two strategies: (1) formation of multiple bonding orbitals or (2) having favourable electrostatic attraction. We recently turned our attention to the reported species IH → Be2H2 ← IH (where IH denotes imidazol-2-ylidene) because the orbital energy level of its π-type HOMO is noted to be very high, which may result in intrinsic instability. In the present study, we combined the abovementioned strategies to solve the high orbital energy level problem without losing the ultrashort Be-Be distances. It was found that breaking of such π-type HOMO by addition of a -CH2- group onto the bridging position of two beryllium atoms led to the formation of IH → Be2H2CH2 ← IH species, which not only possesses an ultrashort Be-Be distance in the -Be2H2CH2- moiety, but also has a relatively low HOMO energy level. Replacing the IH ligands with NH3 and PH3 resulted in the formation of NH3 → Be2H2CH2 ← NH3 and PH3 → Be2H2CH2 ← PH3 species with similar features. The electronic structure analyses suggest that the ultrashort Be-Be distances in these species are achieved by the combined effects of the formation of two Be-H-Be 3c-2e bonds and having favourable Coulombic attractions between the carbon atom of the -CH2- group and two beryllium atoms. Remarkably, when the IH, NH3, and PH3 ligands were replaced by large ligands with bulky groups, such as 1,3-bis(2,6-diisopropyl phenyl)imidazol-2-ylidene (IDip), triphenylamine (NPh3), and triphenylphoshpine (PPh3), respectively, the resultant species IDip → Be2H2CH2 ← IDip, NPh3 → Be2H2CH2 ← NPh3, and PPh3 → Be2H2CH2 ← PPh3 exhibit good steric protection around the -Be2H2CH2- core. These species are thus examples for the experimental realization of species with ultrashort metal-metal distances between main group metals.


Assessing the value of laser in situ keratomileusis by patient-reported outcomes using quality of life assessment.
To assess the value of laser in situ keratomileusis (LASIK) by patient-reported outcomes using quality of life assessment. This study included 288 consecutive patients treated by LASIK between July and December 2001 at two eye clinics. A Myopia-specific Quality of Life Questionnaire was developed in this study. The baseline quality of life corresponding to the situation where refractive error was corrected by glasses or contact lenses before LASIK treatment was evaluated by self-administered questionnaire. The evaluation was repeated at 4 days, and 1, 3, and 6 months after LASIK treatment. All question items were rated on a scale ranging from 1 (maximal dysfunction) to 5 (minimal dysfunction). Factor analysis identified 34 questions in 4 subscales-visual function, visual symptoms, social role function, and psychological well-being. The Myopia-specific Quality of Life Questionnaire subscales proved to be internally consistent (Cronbach alpha = 0.70-0.95). Criterion validity was assessed by evaluating Spearman correlation between the overall or domain-specific quality of life and traditional measures of patient status. Overall Myopia-specific Quality of Life Questionnaire score changed from 3.21 preoperatively to 3.76, 4.00, 4.07, and 4.11 at 4 days, and 1, 3, and 6 months after surgery, respectively. Social role function showed the biggest improvement (score change: 1.51, P < .05), followed by psychological well-being (0.90, P < .05), visual function (0.72, P < .05), and visual symptoms (0.49, P < .05). Regression analysis results showed that the degree of uncorrected visual acuity, discomfort associated with myopia preoperatively, and location of eye center were significant factors affecting the magnitude of changes in quality of life after LASIK. This study confirms that the value of LASIK went beyond the clinical achievement of refractive correction and extended to the improvement of quality of life.


Neuroendocrine differentiation in prostate carcinoma: focusing on its pathophysiologic mechanisms and pathological features.
Neuroendocrine differentiation in prostate carcinoma: focusing on its pathophysiologic mechanisms and pathological features. C. Alberti Prostate carcinoma, even at advanced stages, responds in most patients to androgen deprivation therapies, that are able to exploit the androgen-sensitivity of prostate cancer cells. However, more than half of such tumors, within one to three years, escape these treatments, thus progressing to the hormone-refractory condition. Intriguing links between the development of hormone-insensitivity and neuroendocrine (NE) differentiation in prostate carcinoma have been hypothesized. While, some time ago, NE cells have been considered as derived from progenitor neural crest cells, currently are thought to arise, as well as both basal and secretory cells of prostate gland, from common pluripotent stem cells. NE cell are nonproliferative, terminally differentiated, PSA/acid phosphatase and androgen receptor (AR)-negative cells, moreover exhibiting an antiapoptotic phenotype due to survivin expression. They secrete a wide range of peptide hormones and biogenic amine serotonin and express neuronal markers such as chromogranins A, B, C (CgA, B, C) and neuron specific enolase (NSE) together with synaptophysin. The propensity of prostate cancer cells to undergo a transdifferentiation pathway towards NE phenotype is due to several microenvironmental conditions such as androgen depletion (induced by LH-RH analogs or antagonists, antiandrogens, 5-α-reductase inhibitors), ionizing-radiation therapy, adrenergic factors, increase in interleukin-6 signaling cascade. NE differentiation in prostate malignancy arises in three different forms: carcinoid, oat cell carcinoma, focally NE-differentiated conventional tumor. Selective expression of stem cell-associated markers, such as CD44/Oct4A gene, in NE cancerous cells explain their therapy escape together with tumor recurrence and metastasis. Malignant NE cells, although unable to proliferate, increase the proliferation of the neighboring nonneuroendocrine cancer cells, by providing them with hormone peptide-mediated growth paracrine stimuli. Aberrantly activated glutamic acid decarboxylase-independent pathway for production of GABA (γ-amino-butyric acid) appears to be a constant feature of invasive NE tumors. Serum levels of CgA reflect NE differentiation in prostate carcinoma more suitably than those of NSE. Intriguingly, intermittent androgen deprivation therapy, by preventing NE differentiation, significantly reduces the risk of a rise in serum CgA levels meanwhile delaying the time of cancer progression due to hormone-independence. Although valuable insights into the nature of NE differentiation in prostate carcinoma have been achieved in the last decades, additional understanding is needed about its pathogenetic mechanisms in order to devise novel therapy strategies to target them.


Pathological Gambling and Associated Drug and Alcohol Abuse, Emotion Regulation, and Anxious-Depressive Symptomatology.
Background and aims Pathological gambling is associated with comorbid disorders, such as anxiety, depression, and drug and alcohol abuse. Difficulties of emotion regulation may be one of the factors related to the presence of addictive disorders, along with comorbid symptomatology in pathological gamblers. Therefore, the aim of this study was to evaluate the difficulties of emotion regulation, drug and alcohol abuse, and anxious and depressive symptomatology in pathological gamblers, and the mediating role of difficulties of emotion regulation between anxiety and pathological gambling. Methods The study sample included 167 male pathological gamblers (mean age = 39.29 years) and 107 non-gamblers (mean age = 33.43 years). Pathological gambling (SOGS), difficulties of emotion regulation (DERS), drug and alcohol abuse (MUTICAGE CAD-4), and anxious and depressive symptomatology (SA-45) were measured. Student's t, Pearson's r, stepwise multiple linear regression and multiple mediation analyses were conducted. The study was approved by an Investigational Review Board. Results Relative to non-gamblers, pathological gamblers exhibited greater difficulties of emotion regulation, as well as more anxiety, depression, and drug abuse. Moreover, pathological gambling correlated with emotion regulation difficulties, anxiety, depression, and drug abuse. Besides, emotion regulation difficulties correlated with and predicted pathological gambling, drug and alcohol abuse, and anxious and depressive symptomatology. Finally, emotion regulation difficulties mediated the relationship between anxiety and pathological gambling controlling the effect of age, both when controlling and not controlling for the effect of other abuses. Discussion and conclusions These results suggest that difficulties of emotion regulation may provide new keys to understanding and treating pathological gambling and comorbid disorders.


Verbal-performance discrepancies: relationship to birth risk and specific reading retardation.
169 unselected children were given the WPPSI at 4 1/2 years and the WISC-R at 8 1/2 years. Retrospective data on perinatal risk factors and neurological disease in childhood were collected. Verbal-performance discrepancies at 4 1/2 years were not related to perinatal risk, childhood neurological disease, left-handedness or subsequent reading ability. A weak relationship was found between WISC-R verbal-performance discrepancies and perinatal history. At 8 1/2 years, VIQ correlated much more strongly with reading ability than did PIQ. Consequently, the relationship between verbal-performance discrepancy and specific reading retardation depends critically on how reading retardation is defined. Logical problems concerning the definition of specific reading retardation are discussed.