Nonoperative management of patients with a diagnosis of high-grade small bowel obstruction by computed tomography.
To determine the natural history and treatment of high-grade small bowel obstruction (HGSBO). Small bowel obstruction is a frequent complication of abdominal surgery. Complete and strangulating obstructions are managed operatively while partial obstructions receive a trial of nonoperative therapy. The management and outcome of patients with HGSBO diagnosed by computed tomography (CT) has not been examined. Retrospective medical record review. Outcomes for nonoperative vs operative management were analyzed using Fisher exact and log-rank tests. Tertiary care referral center. One thousand five hundred sixty-eight consecutive patients admitted from the emergency department with a diagnosis of small bowel obstruction between 2000 and 2005 by CT criteria. Recurrence of symptoms and complications. One hundred forty-five patients (9%) with HGSBO were identified, with 88% follow-up (median, 332 days; range, 4-2067 days). Sixty-six (46%) were successfully managed nonoperatively while 79 (54%) required an operation. Length of stay and complications were significantly increased in the operative group (4.7 days vs 10.8 days and 3% vs 23%; P < .001). Nonoperative management was associated with a higher recurrence rate (24% vs 9%; P < .005) and shorter time to recurrence (39 days vs 105 days; P < .005) compared with operative intervention. Computed tomography signs of ischemia, admission laboratory results, and presence of cancer or inflammatory bowel disease were not predictive of an operation. Patients with HGSBO by CT can be managed safely with nonoperative therapy; however, they have a significantly higher rate of recurrence requiring readmission or operation within 5 years.


RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans.
The homeostatic maintenance of the genomic DNA is crucial for regulating aging processes. However, the role of RNA homeostasis in aging processes remains unknown. RNA helicases are a large family of enzymes that regulate the biogenesis and homeostasis of RNA. However, the functional significance of RNA helicases in aging has not been explored. Here, we report that a large fraction of RNA helicases regulate the lifespan of Caenorhabditis elegans. In particular, we show that a DEAD-box RNA helicase, helicase 1 (HEL-1), promotes longevity by specifically activating the DAF-16/forkhead box O (FOXO) transcription factor signaling pathway. We find that HEL-1 is required for the longevity conferred by reduced insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) and is sufficient for extending lifespan. We further show that the expression of HEL-1 in the intestine and neurons contributes to longevity. HEL-1 enhances the induction of a large fraction of DAF-16 target genes. Thus, the RNA helicase HEL-1 appears to promote longevity in response to decreased IIS as a transcription coregulator of DAF-16. Because HEL-1 and IIS are evolutionarily well conserved, a similar mechanism for longevity regulation via an RNA helicase-dependent regulation of FOXO signaling may operate in mammals, including humans.


End-range mobilization techniques in adhesive capsulitis of the shoulder joint: A multiple-subject case report.
The purpose of this case report is to describe the use of end-range mobilization techniques in the management of patients with adhesive capsulitis. Four men and 3 women (mean age=50.2 years, SD=6.0, range=41-65) with adhesive capsulitis of the glenohumeral joint (mean disease duration=8.4 months, SD=3.3, range=3-12) were treated with end-range mobilization techniques, twice a week for 3 months. Indexes of pain, joint mobility, and function were measured by the same observer before treatment, after 3 months of treatment, and at the time of a 9-month follow-up. In addition, arthrographic assessment of joint capacity (ie, the amount of fluid the joint can contain) and measurement of range of motion of glenohumeral abduction on a plain radiograph were conducted initially and after 3 months of treatment. After 3 months of treatment, there were increases in active range of motion. Mean abduction increased from 91 degrees (SD=16, range=70-120) to 151 degrees (SD=22, range=110-170), mean flexion in the sagittal plane increased from 113 degrees (SD=17, range=90-145) to 147 degrees (SD=18, range=115-175), and mean lateral rotation increased from 13 degrees (SD=13, range=0-40) to 31 degrees (SD=11, range=15-50). There were also increases in passive range of motion: Mean abduction increased from 96 degrees (SD=18, range=70-125) to 159 degrees (SD=24, range 110-180), mean flexion in the sagittal plane increased from 120 degrees (SD=16, range=95-145) to 154 degrees (SD=19, range=120-180), and mean lateral rotation increased from 21 degrees (SD=11, range=10-45) to 41 degrees (SD=8, range=35-55). The mean capacity of the glenohumeral joint capsule (its ability to contain fluid) increased from 10 cc (SD=3, range=6-15) to 15 cc (SD=3, range=10-20). Four patients rated their improvement in shoulder function as excellent, 2 patients rated it as good, and 1 patient rated it as moderate. All patients maintained their gain in joint mobility at the 9-month follow-up. There seems to be a role for intensive mobilization techniques in the treatment of adhesive capsulitis. Controlled studies regarding the effectiveness of end-range mobilization techniques in the treatment of adhesive capsulitis are warranted.


Epidemiological characteristics and laboratory diagnosis of fungal keratitis. A three-year study.
To study the epidemiological characteristics and laboratory diagnosis of fungal keratitis seen at a tertiary eye care referral centre in South India. A retrospective review of all culture-proven fungal keratitis seen over a 3-year period, September 1999 through August 2002. Fungal aetiology were confirmed in 1095 (34.4%) of 3183 corneal ulcers. The predominant fungal species isolated was Fusarium spp (471; 42.82%) followed by Aspergillus spp (286; 26%). Males (712; 65.08%) were more often affected (P<0.0001). A large proportion of the patients (732; 66.85%) were in the younger age group (21 to 50 years). A majority (879; 80.27%) came from rural areas (P<0.0001), and most patients (709; 64.75%) were farmers (P<0.0001). Ocular trauma (1009; 92.15%) was a highly significant risk factor (P<0.0001) and vegetative injuries (671; 61.28%) were identified as a significant cause for fungal keratitis (P<0.0001). 172 (15.71%) patients had concurrent diabetes mellitus. The sensitivity of 10% potassium hydroxide (KOH) wet mount preparation was higher (99.23%) than Gram-stained smear (88.73%) (P<0.0001). Incidence of fungal keratitis was higher between June and September. Agricultural activity and related ocular trauma were principal causes of mycotic keratitis. A potassium hydroxide (KOH) wet mount preparation is a simple, and sensitive, method for diagnosis


Receptive fields selection for binary feature description.
Feature description for local image patch is widely used in computer vision. While the conventional way to design local descriptor is based on expert experience and knowledge, learning-based methods for designing local descriptor become more and more popular because of their good performance and data-driven property. This paper proposes a novel data-driven method for designing binary feature descriptor, which we call receptive fields descriptor (RFD). Technically, RFD is constructed by thresholding responses of a set of receptive fields, which are selected from a large number of candidates according to their distinctiveness and correlations in a greedy way. Using two different kinds of receptive fields (namely rectangular pooling area and Gaussian pooling area) for selection, we obtain two binary descriptors RFDR and RFDG .accordingly. Image matching experiments on the well-known patch data set and Oxford data set demonstrate that RFD significantly outperforms the state-of-the-art binary descriptors, and is comparable with the best float-valued descriptors at a fraction of processing time. Finally, experiments on object recognition tasks confirm that both RFDR and RFDG successfully bridge the performance gap between binary descriptors and their floating-point competitors.


Saliency-assisted navigation of very large landscape images.
The field of visualization has addressed navigation of very large datasets, usually meshes and volumes. Significantly less attention has been devoted to the issues surrounding navigation of very large images. In the last few years the explosive growth in the resolution of camera sensors and robotic image acquisition techniques has widened the gap between the display and image resolutions to three orders of magnitude or more. This paper presents the first steps towards navigation of very large images, particularly landscape images, from an interactive visualization perspective. The grand challenge in navigation of very large images is identifying regions of potential interest. In this paper we outline a three-step approach. In the first step we use multi-scale saliency to narrow down the potential areas of interest. In the second step we outline a method based on statistical signatures to further cull out regions of high conformity. In the final step we allow a user to interactively identify the exceptional regions of high interest that merit further attention. We show that our approach of progressive elicitation is fast and allows rapid identification of regions of interest. Unlike previous work in this area, our approach is scalable and computationally reasonable on very large images. We validate the results of our approach by comparing them to user-tagged regions of interest on several very large landscape images from the Internet.


The immunological aspects of latency in tuberculosis.
A unique feature of Mycobacterium tuberculosis is its ability to exist in the granuloma of an asymptomatic host in a latent state that can subsequently reactivate to cause active disease. The latent state of infection poses a major obstacle to eradicating tuberculosis. In latent tuberculosis, the host immune response is capable of controlling the infection and yet falls short of eradicating the pathogen. That the host immune response contributes to the maintenance of latent tuberculous infection is supported by the observation that certain immunodeficient states, including those associated with the human immunodeficiency virus and tumor necrosis factor neutralization therapy, are associated with increased risks for developing reactivation disease. Latent tuberculosis is the product of a complex set of interactions between M. tuberculosis and the host immune response. The molecular basis for the persistence phenotype of M. Tuberculosis and the pertinent host immune mechanisms that contribute to the maintenance of tuberculous latency are just beginning to be understood. This review discusses the interactions between M. tuberculosis and the macrophage, the primary host cell that the tubercle bacillus parasitizes.


Does the installation of blue lights on train platforms prevent suicide? A before-and-after observational study from Japan.
Railway and metro suicides constitute a major problem in many parts of the world. Japan has experienced an increase in the number of suicides by persons diving in front of an oncoming train in the last several years. Some major railway operators in Japan have begun installing blue light-emitting-diode (LED) lamps on railway platforms and at railway crossings as a method of deterring suicides, which is less costly than installing platform screen doors. However, the effectiveness of the blue lights in this regard has not yet been proven. This study evaluates the effect of blue lights on the number of suicides at 71 train stations by using panel data between 2000 and 2010 from a railway company in a metropolitan area of Japan. We use a regression model and compare the number of suicides before and after and with and without the intervention by the blue light. We used the number of suicides at 11 stations with the intervention as the treatment group and at the other 60 stations without the intervention as the control group. Our regression analysis shows that the introduction of blue lights resulted in a 84% decrease in the number of suicides (CI: 14-97%). The analysis relies on data from a single railroad company and it does not examine the underlying suicide-mitigation mechanism of blue lights. As blue lights are easier and less expensive to install than platform screen doors, they can be a cost-effective method for suicide prevention.


[Access to health care in Colombia].
Contributing towards improving knowledge about access to health services in Colombia following health-sector reform, highlighting the main results and gaps in research. Original papers were systematically reviewed through a comprehensive search and analysis of original papers published between 1994 and 2009. After selection criteria had been applied, 27 papers were included in the review. Analysis was based on Aday Aday & Andersen and Gold's theoretical frameworks, distinguishing between potential and actual healthcare access and considering the characteristics of the population, health services and insurers influencing service use. There was little explanatory analysis of service use applying determinant models; this was also partial (limited to geographical areas, diseases or specific groups). Likewise, only a few studies analysed contextual factors influencing service use (health policies and health providers and insures) or social actors' perspectives. The available studies did not seem to indicate increased actual access (except for subsidised system users) but, on the contrary the existence of barriers relating to population (insurance coverage, income and education) and health service factors (geographic and organizational accessibility and quality of care). This review led to identifying important limitations in the analysis of healthcare access in Colombia and highlighted the need for further research on actual access and the better incorporation of context variables and actors perspectives in understanding the impact of reform on health service use.


Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice.
Diabetic individuals are at considerable risk for invasive infection by Staphylococcus aureus, however, the mechanisms underlying this enhanced susceptibility to infection are unclear. We observed increased mortality following i.v. S. aureus infection in diabetic mice compared with nondiabetic controls, correlating with increased numbers of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDNs have been implicated in the inflammatory pathology of diseases such as lupus, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β-activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin-neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.


An occupational therapy program for chronic back pain.
This paper describes a multidisciplinary approach to the evaluation and treatment of the patient with chronic spinal pain with particular emphasis on the cooperative roles of the physical disabilities occupational therapist and the psychosocial occupational therapist. The goal of the total program is to help patients progress from a sick role of dependent, painful behavior to a less pain-centered, more productive role--one in which they have begun to assume control over the way they feel and function. The success of the program is measured by the patient's increased activity level and improved ability to cope with the demands of home and job. A review of patient records after one year of operation showed that only 4 of 54 patients who completed both phases of the program were returning to the orthopedic back clinic as outpatients.


Systematic Quality Monitoring For Specialized Palliative Care Services: Development of a Minimal Set of Quality Indicators for Palliative Care Study (QPAC).
A feasibility evaluation of a comprehensive quality indicator set for palliative care identified the need for a minimal selection of these indicators to monitor quality of palliative care services with short questionnaires for the patients, caregivers, and family carers. To develop a minimal indicator set for efficient quality assessment in palliative care. A 2 round modified Research ANd Development corporation in collaboration with the University of California at Los Angeles (RAND/UCLA) expert consultation. Thirteen experts in palliative care (professionals and patient representatives). In a home assignment, experts were asked to score 80 developed indicators for "priority" to be included in the minimal set on a scale from 0 (lowest priority) to 9 (highest priority). The second round consisted of a plenary meeting in which the minimal set was finalized. Thirty-nine of the 80 indicators were discarded, while 19 were definitely selected after the home assignment, and 22 were proposed for discussion during the meeting; 12 of these survived the selection round. The final minimal indicator set for palliative care consists of 5 indicators about the physical aspects of care; 6 about the psychosocial aspects of care; 13 about information, communication, and care planning; 5 about type of care; and 2 about continuity of care. A minimal set of 31 indicators reflecting all the important issues in palliative care was created for palliative care services to assess the quality of their care in a quick and efficient manner. Additional topic-specific optional modules are available for more thorough assessment of specific aspects of care.


Effect of prenatal exposure to diethylstilbestrol on gubernacular development in fetal male mice.
To study the effect of prenatal exposure to diethylstilbestrol (DES) and the role of actin and proliferating cell nuclear antigen (PCNA) on testicular gubernaculum development in fetal male Kunming mice. Pregnant mice were randomly assigned to 6 groups and injected with DES subcutaneously from gestational day 9 (E9) to day 17 (E17) at doses of 0, 25, 50, 100, 200 microg.kg-1.d-1 in 0.2 mL dimethyl sulfoxide (DMSO). On E17 they were sacrificed and fetuses quickly removed for fixation. Male fetuses were sliced on serial coronal plane. Histological changes were observed under the light microscope (LM) and ultrastructural changes with the scanning and transmission electron microscopes (SEM and TEM). The expression intensity of actin and PCNA in the gubernacula was quantitated by immunohistochemistry. The mortality of the fetuses was higher in the DES-treated groups than that in the DMSO and saline controls (P<0.05). Under LM the gubernacula were seen to be poorly developed with smaller bulbs. On SEM the bulbs lose the clear demarcation between the mesenchymal inner core and the muscular outer layer and looked like a small cone instead of the normal cylindrical appearance. On TEM there were some smaller disordered myofibrils and sparse cytoplasmic organelles in the gubernacular muscular cells of the treated groups. The expression intensity of actin and PCNA in the gubernacula was significantly weaker in the treated groups than that in the DMSO and saline controls (P<0.05). DES induces underdevelopment of the gubernacula in a dose-dependent manner in fetal male mice and down regulates the actin and PCNA expression.


No elevated genomic damage in children and adolescents with attention deficit/hyperactivity disorder after methylphenidate therapy.
Attention-deficit/hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children and adolescents and is often treated with methylphenidate (MPH), resulting in MPH exposure in more than 1% of all children in many countries. A 2005 report on cytogenetic effects in peripheral lymphocytes from 12 ADHD children treated for 3 months with MPH raised questions about its genetic toxicity and potential carcinogenicity. In 2007, we described no elevated micronucleus frequency in 21 children after 3 months of MPH-treatment; since the difference between the two studies could not be explained we now enlarged the overall sample size, and added a healthy control group, a new chronically treated group and positive control slides. Furthermore, micronuclei were analyzed in a second tissue, buccal mucosa. A healthy control group (23 individuals), a chronically MPH-treated (>12 months) group (21 patients), and a drug naïve group of ADHD-affected children (26 patients), which was analyzed again after 3 months (17 patients) and 6 months (11 patients), provided samples for analysis of micronucleated lymphocytes. With inclusion of 14 previously obtained blood samples, an overall group size of 31 patients was reached for the comparison of the 3 months observation time with before for micronucleated lymphocytes. For buccal mucosa cells, an additional inclusion of 10 more chronically treated patients (no lymphocytes donated) yielded sample numbers of 22 (healthy), 17 (chronically treated), 23 (ADHD drug naïve), 14 (3 months) and 11 (6 months). No significant alteration in genomic damage as seen as micronucleus frequency in peripheral lypmphocytes or buccal mucosa cells was detected after MPH treatment. No indication for genomic damage induced by MPH was obtained in this study, as in our previous study. Together with our previous study, our overall number of MPH-treated patients is now 68 (30 chronically treated, 38 prospectively followed), plus 23 healthy controls. Ongoing studies in the USA, as well as continuation of recently published epidemiological cancer incidence analysis should provide additional reassurance for MPH-treated ADHD patients.


Predominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia.
In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in striking contrast to its reported virtual absence in the black population in general. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three screening methods resulted in the identification of seven different mutations in the coding region of the low density lipoprotein (LDLR) gene in 10 of the patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W, R385Q, E387K, P678L, and R793Q) detected in single families. The Sotho patient with missense mutation R232W was also heterozygous for a de novo splicing defect 313+1G-->A. Several silent mutations/polymorphisms were detected in the LDLR and apolipoprotein B genes, including a base change (g-->t) at nucleotide position -175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compared to controls and occurred in cis with mutation E387K in one family. Analysis of four intragenic LDLR gene polymorphisms showed that the same chromosomal background was identified at this locus in the four FH patients with the 6 bp deletion. Detection of the 6 bp deletion in Xhosa, Pedi, and Tswana FH patients suggests that it is an ancient mutation predating tribal separation approximately 3000 years ago.


Lysosomal activity associated with developmental axon pruning.
Clearance of cellular debris is a critical feature of the developing nervous system, as evidenced by the severe neurological consequences of lysosomal storage diseases in children. An important developmental process, which generates considerable cellular debris, is synapse elimination, in which many axonal branches are pruned. The fate of these pruned branches is not known. Here, we investigate the role of lysosomal activity in neurons and glia in the removal of axon branches during early postnatal life. Using a probe for lysosomal activity, we observed robust staining associated with retreating motor axons. Lysosomal function was involved in axon removal because retreating axons were cleared more slowly in a mouse model of a lysosomal storage disease. In addition, we found lysosomal activity in the cerebellum at the time of, and at sites where, climbing fibers are eliminated. We propose that lysosomal activity is a central feature of synapse elimination. Moreover, staining for lysosomal activity may serve as a marker for regions of the developing nervous system undergoing axon pruning.


Diagnosis and treatment of multiple endocrine neoplasia type 1 (MEN1).
Multiple endocrine neoplasia type 1 (MEN1; formerly known as Wermer syndrome) is a rare disorder characterized by the combined occurrence of two or more tumors involving parathyroid, pancreatic islets and anterior pituitary glands; some other tumors have also been described. In most cases it is inherited in an autosomic dominant manner but it may occur sporadically. The MEN1 gene (MEN1) is located on chromosome 11q13, it is composed of ten exons that encode a 610 amino acid protein called menin. Menin, with no homology to any other known protein, interacts with several different proteins and plays an important role in regulation of cell growth, cell cycle, genome stability and synapse plasticity. Familiar MEN1 has a high degree of penetrance with clinical or biochemical manifestations of the disease in 80% and 98%, respectively, by the fifth decade. Clinical manifestations are related to tumor localizations and their secretory products. Hyperparathyroidism is the most common feature of MEN1 (95% of patients), pancreatic islet tumors or pancreatic NET (neuroendocrine tumor) occur in 40-70% and pituitary tumors in 30-40% of MEN 1 patients. In addition, other tumors, such as adrenal cortical tumors, carcinoid tumors, lipomas, angiofibromas, colagenomas and meningiomas may be present. Occurrence of de novo mutations appear in 10% of all patients with MEN1. A correlation between genotype and phenotype has not been found and, even more, combinations of these tumors may be different in members of the same family. Untreated patients have a decreased life expectancy, with a 50% probability of death by the age of 50 years and the cause of death is mostly directly related to MEN1, being the most important causes malignant pancreatic neuroendocrine tumors (NET) and thymic carcinoids. Treatment for each type of endocrine tumor is generally similar as in non-MEN1 associated tumors, but results are less successful according to multiplicity of tumors, higher metastatic disease, larger and more aggressive tumors and more resistant to treatment. The prognosis might improve by preclinical tumor diagnosis and appropriated treatment.


Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer.
Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk.


Complications associated with total hip arthroplasty in four large nondomestic felids.
A 9-year-old 37-kg sexually intact male snow leopard (Panthera uncia) with no history of lameness but radiographic evidence of right femoral subluxation and flattening of both femoral heads, 2 juvenile (< 1 year old) 25-kg sexually intact male cheetahs (Acinoynx jubatus) with unilateral hind limb lameness resulting from trauma, and an 11-year-old 110-kg sexually intact female Amur tiger (Panthera tigris altaica) with a 2-year history of left hip joint osteoarthritis were examined. No clinically relevant clinical findings other than hip joint problems were identified. All 4 felids underwent staged bilateral (snow leopard) or unilateral (cheetahs and tiger [Panthera tigris]) total hip arthroplasty (THA). In the snow leopard, both femoral THA components were found to be luxated 1 year after surgery. Treatment consisted of autogenous corticocancellous rib graft augmentation of the dorsal acetabular rims and synthetic suture capsulorrhaphies. The snow leopard lived for an additional 4 years with no additional THA-related complications. In the other 3 animals, catastrophic complications (luxation in the cheetahs and femoral fracture in the tiger) occurred shortly after THA. The THA implants were removed, and excision arthroplasty was performed. Long-term outcomes were good in all 3. Findings underscore the challenges associated with THA in large nondomestic felids. Given the high risk for early catastrophic failure as a result of luxation or fracture, plans must be made and resources must be available in case revision surgery or implant removal with excision arthroplasty becomes necessary.


Evaluation of an Australian Alcohol Media Literacy Program.
A 10-lesson alcohol media literacy program was developed, underpinned by the message interpretation processing model, inoculation theory, and constructivist learning theory, and was tailored to be culturally relevant to the Australian context. This program aimed to increase students' media deconstruction skills and reduce intent to drink alcohol. The purpose of this study was to evaluate the effectiveness of the program in achieving these goals through a short-term quasi-experimental trial. Elementary schools were assigned to either the intervention group (83 students) or a wait-list control group (82 students). Student questionnaires were administered at three time points (baseline, after the intervention group completed the program, and after the wait-list control group completed the program) to evaluate the effectiveness of the intervention. The intervention and wait-list control groups reported significantly higher media deconstruction skills as a result of the intervention. Both groups reported significantly lower social norms, whereas the wait-list control group reported significantly lower positive alcohol expectancies. There were no significant changes to self-efficacy to refuse alcohol, preference for alcohol-branded merchandise, and understanding of persuasive intent as a result of the intervention. To date, the majority of alcohol media literacy studies have been conducted in the United States and have focused on deconstructing television and print-based ads. This evaluation provides evidence that an alcohol media literacy program that was developed for a specific cultural context, and that incorporates a broad range of multimodal advertisements, can have a positive impact on beliefs and attitudes that are known predictors/precursors of drinking behaviors.


A study on prevalence of bacteria in the hands of children and their perception on hand washing in two schools of Bangalore and Kolkata.
Contaminated hands play a major role in fecal-oral transmission of diseases. In 1847, Dr Semmelweis Ignac pointed to the link between infection and unclean hands, and demonstrated that washing hands could reduce transmission of puerperal fever (child birth fever), a dreaded disease with high mortality in those days. A cross-sectional study was conducted to find out the extent of germs present in hand, and also the students' perception on hand washing. This was assessed by questionnaire as well as by collection of swab from hand and performing bacteriological culture in the laboratory. In regard to students' perception about the dirty areas of the hands, it was observed that majority (78%) felt palm was likely to be more dirty while less than 70% felt that web spaces could harbor dirt. Almost 86% reported that they washed hands before eating lunch, but only 21.3% said they always used soap while 47.3% never used it. Availability of soap all the time in the school was reported by only 18.4% students. The swabs of 61% children showed potential pathogens. The commonest of these was Staphylococcus aureus which was seen in 44% samples. The students' hands were contaminated before taking food. Although they washed hands before meals, they hardly used soap due to non-availability of soap. The school authority should be asked to keep soaps in the toilets for hand washing.


Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence.
It is difficult to estimate the diagnostic accuracy of biopsy for prostate cancer because men with negative biopsy do not undergo radical prostatectomy and thus have no confirmation of biopsy findings. We performed 18-core needle biopsies on autopsy prostates from 164 men who had no history of prostate cancer. Six-core biopsies were taken from each of the mid peripheral zone (MPZ), the lateral peripheral zone (LPZ), and the central zone (CZ). We tested associations between age and tumor characteristics and analyzed the sensitivity of biopsies at each site. All statistical tests were two-sided. Prostate cancer was present in 47 (29%) prostates. Of the 47 cancers detected, 20 were clinically significant according to histologic criteria. Tumor volume was associated with tumor grade (P = .012) and with age (P<.001). The biopsies from the CZ did not detect any cancer that was not present in biopsies of either the MPZ or LPZ. The sensitivity of the biopsies taken from the MPZ and LPZ together (53%, 95% confidence interval [CI] = 38% to 68%) was therefore the same as that of 18-core biopsies and was superior to that of biopsies of the MPZ alone (30%, 95% CI = 17% to 45%) (P = .003). The sensitivities of biopsies from the MPZ for clinically significant and insignificant cancer were 55% (95% CI = 32% to 77%) and 11% (95% CI = 2% to 29%), respectively, compared with 80% (95% CI = 56% to 94%) and 33% (95% CI = 17% to 54%) for those from the MPZ and LPZ combined. The ability to detect prostate cancer was more related to the biopsy site than to the number of biopsy cores taken. The 12-core biopsies, six cores each from the MPZ and LPZ, were most likely to detect the majority of clinically significant cancers but also detected many insignificant cancers. When the six-core biopsies from the CZ were added, no increase in sensitivity was observed.


CD40 expression in malignant plasma cells. Role in stimulation of autocrine IL-6 secretion by a human myeloma cell line.
Myeloma is a neoplasia characterized by the accumulation of malignant plasma cells in the bone marrow. In these studies, we have demonstrated that CD40 is expressed in human myeloma cells and have used a recently established IL-6-dependent myeloma cell line, ANBL-6, to examine the potential function of CD40 expression in myeloma cells. In addition to its expression on the ANBL-6 cells, we show that CD40 is expressed on freshly isolated myeloma cells from seven of seven patients tested. To address the role of CD40 expression in myeloma cells, we have examined the responsiveness of the ANBL-6 cell line to a CD40-specific mAb, G28-5. This cell line has previously been shown to proliferate only in response to IL-6. Of interest in this study, G28-5 also induced proliferation of the ANBL-6 cells. This proliferation was substantially inhibited by an IL-6-neutralizing mAb. Analysis of ANBL-6 cell culture supernatants by ELISA demonstrated that G28-5-stimulated cells secreted significant levels of IL-6, whereas unstimulated cell culture supernatants contained undetectable levels of IL-6. Furthermore, CV-1/EBNA cells expressing the human CD40 ligand also induced the proliferation of the ANBL-6 cell line, an effect that was inhibited by the anti-IL-6 mAb. Lastly, RNA blot analysis demonstrated an increase in IL-6 message in G28-5-stimulated ANBL-6 cells over unstimulated cells. These results indicate that the primary mechanism of anti-CD40-stimulated proliferation of the ANBL-6 cells is the induction of autocrine IL-6 production. Moreover, these data suggest that the expression of CD40 in malignant plasma cells may play a role in tumor cell expansion, possibly by stimulating the induction of autocrine IL-6 secretion.


Drug-eluting stent, but not bare metal stent, accentuates the systematic inflammatory response in patients.
The systematic pro-inflammatory responses after percutaneous coronary intervention with drug-eluting stents (DES) remain poorly defined. Therefore, we compared the systematic pro-inflammatory state of circulating mononuclear cells (MNCs) between DES and bare metal stent (BMS) implantation. Patients with indications for treatment with stents were randomized in a 1:1 ratio to placement of DES or BMS. The primary endpoint was a change of pro-inflammatory state at 12 weeks post-procedure. Thirty-six consecutive patients received DES or BMS. At 12 weeks after stent implantation, the lipid profile and high-sensitivity C-reactive protein (hs-CRP) improved significantly in both groups. The mRNA levels and plasma concentrations of interleukin-6, tumor necrosis factor-α and matrix metalloproteinase-9 were significantly elevated in the DES group, which was not observed in the BMS group. An increase in NF-κB binding activity and a decrease in PPAR-γ expression in MNCs were observed in the DES group, along with increases in IκB phosphorylation and p50 expression. However, similar changes were not observed in the BMS group. Systematic inflammatory responses were accentuated after the patients were treated percutaneously with DES, despite their improved lipid profile and hs-CRP. These data may provide fundamental information for optimizing therapeutic strategy in the era of DES.


Nutrient intakes and compliance with nutrient recommendations in children aged 1-4 years in Ireland.
The early childhood years represent a period of rapid growth and development characterised by unique requirements for energy and individual nutrients. The present study uses data from the National Pre-School Nutrition Survey, a nationally representative sample of Irish children (1-4 years) (n = 500), aiming to estimate energy and nutrient intakes across age and compliance with recommendations (UK and European). A 4-day weighed food-record was used to collect dietary data and statistical modelling (National Cancer Institute method) was applied to estimate usual nutrient intakes. Intakes of carbohydrate [48-50% energy (E)], protein (15-16%E), total fat (32-34%E), dietary fibre (2.5 g MJ-1 ), α-linolenic acid (0.45%E) and most micronutrients were in good compliance with recommendations. However, intakes of long chain polyunsaturated fatty acids (LCPUFA) (65-80 mg) were low and significant proportions of children had inadequate intakes (< estimated average requirement) of vitamin D and iron. Small proportions of children with intakes exceeding the upper level for retinol, folic acid, zinc, copper and iodine, are unlikely to give rise to adverse health effects. Mean intakes of free sugars (12%E) and salt (3.1 g day-1 ) exceeded recommendations and increased with age, whereas mean intake of saturated fat (15%E) decreased with age. By the age of 4 years, patterns established for intakes of salt, saturated fat and free sugars were unfavourable and similar to those observed in the diets of older children. Further research is needed to identify dietary strategies that improve the quality of the diet in young children, particularly in relation to excess of saturated fat, free sugars and salt, as well as inadequacy of iron, vitamin D and LCPUFA.


Dose prescription in carbon ion radiotherapy: a planning study to compare NIRS and LEM approaches with a clinically-oriented strategy.
In carbon ion radiotherapy there is an urgent clinical need to develop objective tools for the conversion of relative biological effectiveness (RBE)-weighted doses based on different models. In this work we introduce a clinically oriented method to compare NIRS-based and LEM-based GyE systems, minimizing differences in physical dose distributions between treatment plans. Carbon ion plans were optimized on target volumes of cubic and spherical shapes, for RBE-weighted dose prescription levels ranging from 3.6 to 4.4 GyE. Plans were calculated for target sizes from 4 to 12 cm defining three beam geometries: single beam, opposed beam and orthogonal beam configurations. The two treatment planning systems currently employed in clinical practice were used, providing the NIRS-based and LEM-based GyE calculations. Physical dose distributions of NIRS-based and LEM-based treatment plans were compared. LEM-based prescription doses that minimize differences in physical dose distributions between the two systems were found. These doses were compared with the mean RBE-weighted dose obtained with a Monte Carlo code (FLUKA) interfaced with LEM I. In the investigated dose range, LEM-based RBE-weighted prescription doses, that minimize differences with NIRS plans, should be higher than NIRS reported prescription doses. The optimal dose depends on target size, shape and position, number of beams and dose level. The opposed beam configuration resulted in the smallest average prescription dose difference (0.45 ± 0.09 GyE). The second approach of recalculating NIRS RBE-weighted dose with a Monte Carlo code interfaced with LEM resulted in no significant difference with the results obtained from the planning study. The delivery of a voxel by voxel iso-effective plan, if different RBE models are employed, is not feasible; it is however possible to minimize differences in a treatment plan with the simple approach presented here. Dose prescription ultimately represents a clinical task under the responsibility of the radiation oncologist, the presented analysis intends to be a quantitative and objective way to assist the clinical decision.


Robotic thymectomy.
Thymectomy is the most frequent surgical operation involving the mediastinum, both for the treatment of thymic tumors and for the multidisciplinary management of myasthenia gravis (MG). Different surgical approaches have been described, either traditional open approaches or minimally invasive ones. Robotic thymectomy represents a further step in the evolution of minimally invasive surgery. Available data show that robotic thymectomy may be considered a safe and feasible operation, with encouraging long-term results in myasthenic patients and promising results in patients with early stage thymoma, both in terms of surgical and oncological outcomes. We present the surgical technique of robotic thymectomy that we apply for patients affected by myasthenia gravis and early stage thymoma.


p8 is a new target of gemcitabine in pancreatic cancer cells.
Gemcitabine is the only available chemotherapeutic treatment of pancreatic cancers. It is, however, moderately effective, showing a tumor response rate of only 12%. The aim of this work was to identify new pathways involved in the resistance of pancreatic cancer cells to gemcitabine, in the hope of developing new adjuvant strategies to enhance its therapeutic efficacy. Comparison of gene expression patterns of five human pancreatic cancer cell lines showing different degrees of resistance to gemcitabine revealed specific overexpression of several genes in the most resistant. One of them encoded the antiapoptotic p8 protein. We found that (a) knocking down p8 expression in gemcitabine-resistant cells promoted cell death and increased caspase-3 activity; (b) forced overexpression of p8 in gemcitabine-sensitive cells increased their resistance to gemcitabine-induced apoptosis; and (c) gemcitabine down-regulated p8 mRNA expression. These results suggest that, in pancreatic cancer cells, a large part of gemcitabine-induced apoptosis results from the inhibition of the constitutive antiapoptotic activity of p8. Hence, targeting the p8-associated pathway could be a new adjuvant therapy improving the response of patients with pancreatic cancer to gemcitabine treatment.


No evidence for an association between the -871 T/C promoter polymorphism in the B-cell-activating factor gene and primary Sjögren's syndrome.
Polyclonal B cell activation might be related to pathogenic over-expression of B-cell-activating factor (BAFF) in primary Sjögren's syndrome (pSS) and other autoimmune diseases. We therefore investigated whether BAFF over-expression in pSS could be a primary, genetically determined event that leads to the disease. The complete BAFF gene was sequenced in Caucasian pSS patients and control individuals. The only single nucleotide polymorphism frequently observed, namely -871 T/C in the promoter region, was then genotyped in 162 French patients with pSS and 90 French control individuals. No significant differences in allele (T allele frequency: 49.7% in patients with pSS versus 50% in controls; P = 0.94) and genotype frequencies of BAFF polymorphism were detected between pSS patients and control individuals. BAFF gene polymorphism was not associated with a specific pattern of antibody secretion either. T allele carriers had significantly increased BAFF protein serum levels (mean values of 8.6 and 5.7 ng/ml in patients with TT and TC genotypes, respectively, versus 3.3 ng/ml in patients with CC genotype; P = 0.01), although no correlation was observed between BAFF polymorphism and mRNA level. In conclusion, BAFF gene polymorphism is neither involved in genetic predisposition to pSS nor associated with a specific pattern of antibody production.


Factors affecting onset of puberty in Denizli province in Turkey.
The relationship between the possible factors affecting pubertal onset and pubertal timing was investigated in the Denizli province in Turkey. A total number of 3311 subjects (1562 girls, 1749 boys) aged 6-16.5 years participated in this study. Body mass index (BMI) was calculated. Pubertal stages were assessed according to methods of Marshall and Tanner. Testicular volume was determined using Prader orchidometer. Menarcheal age was recorded. All parents and students completed different questionnaires on demographic variables affecting pubertal timing such as socioeconomic conditions, psychosocial factors, exercise, nutritional status, chronic diseases, migration and birth weight. Using distribution percentiles of pubertal stages according to age, the relation between pubertal timing and factors affecting puberty was investigated. There was no significant association between exercise, birth weight, migration, chronic disease, and socioeconomic status and age of puberty onset. Menarcheal age of overweight and obese girls was significantly lower than that of girls with normal weight. In-family stress was the cause of early puberty in girls and of delayed puberty in boys.


A TEM protocol for quality assurance of in vitro cellular barrier models and its application to the assessment of nanoparticle transport mechanisms across barriers.
We report here a protocol to characterise and monitor the quality of in vitro human cellular barrier models using Transmission Electron Microscopy (TEM), which can be applied for transport assays, mechanistic studies and screening of drug/compound (including nanoparticle) penetration across such biological barriers. Data from two examples of biological barriers are given, namely the hCMEC/D3 endothelial blood-brain barrier model, and the Caco-2 intestinal epithelial barrier model, to show the general applicability of the method. Several aspects of this method are applicable to the quality assurance of in vitro barrier models, e.g., assessment of the multi or mono-layer structure of the endothelial cells; identification of any potential "holes" in the barrier that could confound transport assay results; validation of tight junction expression; and determination of the types and amounts of key cellular organelles present in the barrier to account for any significant changes in phenotype that may occur compared to the in vivo situation. The method described here provides a key advantage in that it prevents loss of the filter membrane during monolayer sectioning, thereby preserving critical details associated with the basal cell membrane. Applicability of the protocol for other in vitro biological barriers, such as the blood-foetus, blood-testes, blood-cerebrospinal fluid (CSF) and lung alveolar-capillary barriers is also discussed. Additionally, we demonstrate the use of the method for assessment of nanoparticle transport across cellular barriers and elucidation of transcytosis mechanisms. Sequential events of cellular endocytosis, localisation and transcytosis can be described in detail by TEM imaging, revealing useful sub-cellular details that provide evidence for the mechanism of nanoparticle transport in the hCMEC/D3 blood-brain barrier model and the Caco-2 intestinal epithelial cell model. Potential artefacts resulting from the nanoparticles interacting with the Transwell membranes can also be assessed.


Fast super-resolution with affine motion using an adaptive Wiener filter and its application to airborne imaging.
Fast nonuniform interpolation based super-resolution (SR) has traditionally been limited to applications with translational interframe motion. This is in part because such methods are based on an underlying assumption that the warping and blurring components in the observation model commute. For translational motion this is the case, but it is not true in general. This presents a problem for applications such as airborne imaging where translation may be insufficient. Here we present a new Fourier domain analysis to show that, for many image systems, an affine warping model with limited zoom and shear approximately commutes with the point spread function when diffraction effects are modeled. Based on this important result, we present a new fast adaptive Wiener filter (AWF) SR algorithm for non-translational motion and study its performance with affine motion. The fast AWF SR method employs a new smart observation window that allows us to precompute all the needed filter weights for any type of motion without sacrificing much of the full performance of the AWF. We evaluate the proposed algorithm using simulated data and real infrared airborne imagery that contains a thermal resolution target allowing for objective resolution analysis.


Lipid- and polymer-based nanostructures for cancer theranostics.
The relatively new field of nanotheranostics combines the advantages of in vivo diagnosis with the ability to administer treatment through a single nano-sized carrier, offering new opportunities for cancer diagnosis and therapy. Nanotheranostics has facilitated the development of nanomedicine through direct visualization of drug blood circulation and biodistribution. From a clinical perspective, nanotheranostics allows therapies to be administered and monitored in real time, thus decreasing the potential of under- or over-dosing and allowing for more personalized treatment regimens. Herein, we review recent development of nanotheranostics using lipid- and polymer-based formulations, with a particular focus on their applications in cancer research. Recent advances in nanotechnology aimed to combine therapeutic molecules with imaging agents for magnetic resonance imaging, radionuclide imaging, or fluorescence imaging are discussed.


Stochastic variation of transcript abundance in C57BL/6J mice.
Transcripts can exhibit significant variation in tissue samples from inbred laboratory mice. We have designed and carried out a microarray experiment to examine transcript variation across samples from adipose, heart, kidney, and liver tissues of C57BL/6J mice and to partition variation into within-mouse and between-mouse components. Within-mouse variance captures variation due to heterogeneity of gene expression within tissues, RNA-extraction, and array processing. Between-mouse variance reflects differences in transcript abundance between genetically identical mice. The nature and extent of transcript variation differs across tissues. Adipose has the largest total variance and the largest within-mouse variance. Liver has the smallest total variance, but it has the most between-mouse variance. Genes with high variability can be classified into groups with correlated patterns of expression that are enriched for specific biological functions. Variation between mice is associated with circadian rhythm, growth hormone signaling, immune response, androgen regulation, lipid metabolism, and the extracellular matrix. Genes showing correlated patterns of within-mouse variation are also associated with biological functions that largely reflect heterogeneity of cell types within tissues. Genetically identical mice can experience different individual outcomes for medically important traits. Variation in gene expression observed between genetically identical mice can identify functional classes of genes that are likely to vary in the absence of experimental perturbations, can inform experimental design decisions, and provides a baseline for the interpretation of gene expression data in interventional studies. The extent of transcript variation among genetically identical mice underscores the importance of stochastic and micro-environmental factors and their phenotypic consequences.


Chimera: enabling hierarchy based multi-objective optimization for self-driving laboratories.
Finding the ideal conditions satisfying multiple pre-defined targets simultaneously is a challenging decision-making process, which impacts science, engineering, and economics. Additional complexity arises for tasks involving experimentation or expensive computations, as the number of evaluated conditions must be kept low. We propose Chimera as a general purpose achievement scalarizing function for multi-target optimization where evaluations are the limiting factor. Chimera combines concepts of a priori scalarizing with lexicographic approaches and is applicable to any set of n unknown objectives. Importantly, it does not require detailed prior knowledge about individual objectives. The performance of Chimera is demonstrated on several well-established analytic multi-objective benchmark sets using different single-objective optimization algorithms. We further illustrate the applicability and performance of Chimera with two practical examples: (i) the auto-calibration of a virtual robotic sampling sequence for direct-injection, and (ii) the inverse-design of a four-pigment excitonic system for an efficient energy transport. The results indicate that Chimera enables a wide class of optimization algorithms to rapidly find ideal conditions. Additionally, the presented applications highlight the interpretability of Chimera to corroborate design choices for tailoring system parameters.


Azithromycin for treating uncomplicated malaria.
To prevent the development of drug resistance, the World Health Organization (WHO) recommends treating malaria with combination therapy. Azithromycin, an antibiotic with antimalarial properties, may be a useful additional option for antimalarial therapy. To compare the use of azithromycin alone or in combination with other antimalarial drugs with the use of alternative antimalarial drugs for treating uncomplicated malaria caused by Plasmodium falciparum or Plasmodium vivax. We searched the Cochrane Infectious Diseases Group Specialized Register (August 2010); CENTRAL (The Cochrane Library Issue 3, 2010); MEDLINE (1966 to August 2010); EMBASE (1974 to August 2010); LILACS (August 2010); the metaRegister of Controlled Trials (mRCT, August 2010); conference proceedings; and reference lists. We also contacted researchers and a pharmaceutical company. Randomized controlled trials comparing azithromycin, either alone or combined with another antimalarial drug, with another antimalarial drug used alone or combined with another antimalarial drug, or with azithromycin combined with another antimalarial drug if different combinations or doses of azithromycin were used. The primary outcome was treatment failure by day 28, defined as parasitological or clinical evidence of treatment failure between the start of treatment and day 28. Secondary outcomes included treatment failure by day 28 corrected for new infections confirmed by polymerase chain reaction (PCR), fever and parasite clearance time, and adverse events. Two people independently applied the inclusion criteria, extracted data and assessed methodological quality. We used risk ratio (RR) and 95% confidence intervals (CI). Fifteen trials met the inclusion criteria (2284 participants, 69% males, 16% children). They were conducted in disparate malaria endemic areas, with the earlier studies conducted in Thailand (five) and India (two), and the more recent studies (eight) spread across three continents (South America, Africa, Asia). The 15 studies involved 41 treatment arms, 12 different drugs, and 28 different treatment regimens. Two studies examined P. vivax.Three-day azithromycin (AZ) monotherapy did not perform well for P. vivax or P. falciparum (Thailand: P. vivax failure rate 0.5 g daily, 56%, 95% CI 31 to 78. India: P. vivax failure rate 1 g daily,12%, 95% CI 7 to 21; P. falciparum failure rate 1 g daily, 64%, 95% CI 36 to 86.) A 1 g azithromycin and 0.6 g chloroquine combination daily for three days for uncomplicated P. falciparum infections was associated with increased treatment failure in India and Indonesia compared with the combination of sulphadoxine-pyrimethamine and chloroquine (pooled RR 2.66, 95% CI 1.25 to 5.67), and compared with the combination atovaquone-proguanil in a multicentre trial in Columbia and Surinam (RR 24.72, 95% CI 6.16 to 99.20). No increased risk of treatment failure was seen in two studies in Africa with mefloquine as the comparator drug (pooled RR 2.02, 95% CI 0.51 to 7.96, P = 0.3); the pooled RR for PCR-corrected data for the combination versus mefloquine was 1.01, 95% CI 0.18 to 5.84 (P = 1.0). An increased treatment failure risk was seen when comparing azithromycin in a dose of 1.2 to 1.5 mg in combination with artesunate (200 mg per day for three days) with artemether-lumefantrine (pooled RR 3.08, 95% CI 2.09 to 4.55; PCR-corrected pooled RR 3.63, 95% CI 2.02 to 6.52).Serious adverse events and treatment discontinuation were similar across treatment arms. More adverse events were reported when comparing the 1 g azithromycin/ 0.6 g chloroquine combination with mefloquine (pooled RR 1.20, 95% CI 1.06 to 1.36) or atovaquone-proguanil (RR 1.41, 95% CI 1.09 to1.83). Currently, there is no evidence for the superiority or equivalence of azithromycin monotherapy or combination therapy for the treatment of P. falciparum or P. vivax compared with other antimalarials or with the current first-line antimalarial combinations. The available evidence suggests that azithromycin is a weak antimalarial with some appealing safety characteristics. Unless the ongoing dose, formulation and product optimisation process results in a universally efficacious product, or a specific niche application is identified that is complementary to the current scala of more efficacious antimalarial combinations, azithromycin's future for the treatment of malaria does not look promising.


Stem cell and extracellular matrix-related molecules increase following melatonin treatment in the skin of postmenopausal rats.
The menopause has a negative effect in the skin. Melatonin affects skin functions and structures through actions mediated by cell-surface and putative-nuclear receptors expressed in skin cell. We have therefore determined the effects of melatonin treatment on stem cell in the epidermis and extracellular matrix related molecules in the dermis the skin of postmenopausal rats. A total of 45 female rats were divided into 5 groups: control group, group A [ovariectomy (OVX)], group B (OVX +10 mg/kg/day melatonin), group C (OVX +30 mg/kg/day melatonin), group S (sham operated + 10 mg/kg/day melatonin). Ventral skin samples were excised at 12th week after ovariectomy. Hematoxylin-eosin, periodic acid- methylamine silver, elastic van Gieson staining techniques were used to measure histomorphometrically the thickness of elastic fibers and basement membrane, depths of the epidermis, dermis, and subcutaneous fat layer. Immunohistochemical staining methods were used for fibroblast growth factor β (FGF β), collagen type I, fibronectin, β-catenin, c-kit, c-Myc evaluation. Epidermal thickness, subcutaneous fat layer, and elastic fibers were significantly decreased in group C, and there was a significant increase after melatonin treatment. Although there was no difference in dermal thickness of group C, melatonin also significantly increased the dermal thickness. High FGF β, type I collagen, fibronectin, β-catenin, c-Myc immunoreactivity developed following melatonin in all groups. Thus melatonin treatment of postmenopausal rats was mostly due to the decrease of stem cell and extracellular matrix-related molecules in the skin.


Kidney graft outcome and quality (after transplantation) from uncontrolled deceased donors after cardiac arrest.
The use of uncontrolled deceased donors after cardiac arrest (uDDCA) has been developed in France to compensate for organ shortage. The quality of these kidneys remains unclear. We analyzed kidney graft function and histology from 27 uDDCA and compared them with kidneys from 30 extended criteria donors (ECD) and from 24 simultaneous pancreas kidney (SPK) donors as a control group of optimal deceased donors. Kidneys from ECD and SPK donors were preserved by static cold storage while kidneys from uDDCA were preserved by pulsatile perfusion. The uDDCA graft function at 3 years posttransplantation (estimated with MDRD and measured with inulin clearance) did not differ from that of the ECD group (eGFR 44.1 vs. 37.4 mL/min/1.73 m(2) , p = 0.13; mGFR 44.6 vs. 36.1 mL/min/1.73 m(2) , p = 0.07 in the uDDCA and ECD groups, respectively). The histological assessment of 3-month and 1-year protocol biopsies did not show differences for interstitial lesions between the uDDCA and ECD grafts (IF score at M3 was 30 vs. 28% and at M12 36 vs. 33%, p = NS). In conclusion, the results at 3 years with carefully selected and machine-perfused uDDCA kidneys have been comparable to ECD kidneys and encourage continuation of this program and development of similar programs.


The structure of dimethylallyl tryptophan synthase reveals a common architecture of aromatic prenyltransferases in fungi and bacteria.
Ergot alkaloids are toxins and important pharmaceuticals that are produced biotechnologically on an industrial scale. The first committed step of ergot alkaloid biosynthesis is catalyzed by dimethylallyl tryptophan synthase (DMATS; EC 184.108.40.206). Orthologs of DMATS are found in many fungal genomes. We report here the x-ray structure of DMATS, determined at a resolution of 1.76 A. A complex of DMATS from Aspergillus fumigatus with its aromatic substrate L-tryptophan and with an analogue of its isoprenoid substrate dimethylallyl diphosphate reveals the structural basis of this enzyme-catalyzed Friedel-Crafts reaction, which shows strict regiospecificity for position 4 of the indole nucleus of tryptophan as well as unusual independence of the presence of Mg(2+) ions. The 3D structure of DMATS belongs to a rare beta/alpha barrel fold, called prenyltransferase barrel, that was recently discovered in a small group of bacterial enzymes with no sequence similarity to DMATS. These bacterial enzymes catalyze the prenylation of aromatic substrates in the biosynthesis of secondary metabolites (i.e., a reaction similar to that of DMATS).


Titanium oxide shell coatings decrease the cytotoxicity of ZnO nanoparticles.
Although nanozinc oxide (nano-ZnO) is applied widely in photocatalysts and gas sensors and in biological fields, it can cause serious oxidative stress and DNA damage to mammalian cells. Our aim in this study was to reduce the cytotoxicity of nano-ZnO by coating it with a TiO(2) layer. We used a sol-gel method to synthesize core (nano-ZnO)/shell (TiO(2)) nanoparticles (NPs) with various degrees of coating. Transmission electron microscopy and Raman spectroscopy confirmed that TiO(2) was coated on the nano-ZnO. Moreover, a decrease in the intensity of the pre-edge signal in Ti K-edge X-ray absorption near edge structure spectra revealed that the core/shell NPs had more Ti-O coordination than pure TiO(2) particles; in addition, the Zn K-edge extended X-ray absorption fine structure spectra revealed that after the ZnO NPs had been coated with TiO(2), the coordination number of the ZnO shell increased to 3.3 but that of the ZnZn shell decreased to 6.2, providing further evidence for the ZnO/TiO(2) core/shell structure. To ensure that the core/shell structures did indeed decrease the toxicity of nano-ZnO, we tested the effects of equal amounts of physical mixtures of ZnO and TiO(2) NPs for comparison, employing methyl tetrazolium (MTT), interleukin-8 (IL-8), lactate dehydrogenase (LDH), and 2',7'-dichlorofluorescin diacetate (DCFH-DA) to assess the particle-induced cytotoxicity, inflammatory response, membrane damage, and intercellular reactive oxygen species (ROS). From X-ray diffraction patterns, we identified the TiO(2) shell as having an amorphous phase, which, unfortunately, exhibited slight cytotoxicity toward the human lung epithelial cell line (A549). Nevertheless, our core/shell nanostructures exhibited less oxidative stress toward A549 cells than did their corresponding ZnO/TiO(2) physical mixtures. In addition, a greater coating of TiO(2) decreased the toxicity of the ZnO NPs. It appears that the ZnO/TiO(2) core/shell structure moderated the toxicity of nano-ZnO by curtailing the release of zinc ions and decreasing the contact area of the ZnO cores.


Rationally-designed vaccine adjuvants: separating efficacy from toxicity.
Adjuvants, substances included in many vaccines in order to improve immune responses, are challenging to develop and license because adjuvant compounds that stimulate strong protective immunity also frequently induce significant toxicity. Adjuvant design and development has until recently been largely empirical; but with the current knowledge that most adjuvants act via receptors of the innate immune system, molecular-based approaches are rapidly advancing the field. Data support the concept that proinflammatory pathways induced by innate immune receptor triggering underlie many of the observed toxic effects. Importantly, the cellular signaling pathways that lead to inflammation are known, for a number of innate immune receptors, to be distinct from those that are involved in the costimulation of protective adaptive immune responses, leading to approaches for attenuating inflammatory signaling that should lead to safer and more effective vaccine adjuvants. This article addresses whether there is a clear rationale for the separation of toxicity from efficacy in the function of adjuvants based upon innate immune receptor ligands.


Effects of a Physical Activity Program Potentiated with ICTs on the Formation and Dissolution of Friendship Networks of Children in a Middle-Income Country.
This paper assesses the potential cohesion effect of a physical activity (PA) school-based intervention potentiated using text messages (SMS) through analyzing longitudinally the friendship network structure and the mechanisms of the formation and dissolution of friendships. Three schools (n = 125 participants) in Bogotá, Colombia, were randomly assigned into three groups: Modulo Activo Recreo Activo (MARA) + SMS (networks 1 and 2), MARA (networks 3 and 4), and control (no intervention: networks 5-7). We collected socio-economic, health-related, network structure, and intervention satisfaction variables in the baseline and after 10 weeks on July-November 2013. For each classroom network, we conducted four models using a temporal and static network approach to assess (1) temporal social network changes, (2) friendship homophily, (3) friendship formation and dissolution mechanisms, and (4) effect of SMS on the networks' cohesion. We found that (1) social cohesion emerged in the four intervened networks that were measured over time with transitivity and homophily driven by clustering, (2) the intervention affected the mechanisms of friendship formation and dissolution, and (3) MARA + SMS on average created more social cohesion and 3.8 more friendships than the program alone. Potentially, school-based interventions with information and communication technologies (ICT) such as MARA + SMS could encourage social cohesion among children. The particular characteristics of each school network need to be considered when developing school-based interventions.


Exploring MIA-QSARs' for antimalarial quinolon-4(1H)-imines.
A series of quinolon-4(1H)-imines have been recently discovered as antimalarials, targeting both the exoerythrocytic and erythrocytic stages of the parasite's development stages, which correspond to the phase of clinical symptoms. Endowed with chemical and metabolic stability, the quinolon-4(1H)- imines are thus presented as promissory dual-stage antimalarials. Three versions of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) methods, namely traditional MIA-QSAR, augmented MIA-QSAR (aug-MIA-QSAR) and color-encoded aug-MIA-QSAR (aug- MIA-QSARcolor), were applied to model the antimalarial activities in this series of compounds. The multiple linear regression models indicated that the aug-MIA-QSAR method is more predictive and reliable than the others (R(2) = 0.8079, R(2)cv = 0.6647 and R(2)pred = 0.9691) for this series of compounds. The selected aug- MIA-QSAR descriptors were used for pattern recognition using discriminant analysis by partial least squares (PLS-DA), in order to separate compounds with low, moderate and high bioactivities.


Mapping the chromatin landscape and Blimp1 transcriptional targets that regulate trophoblast differentiation.
Trophoblast stem cells (TSCs) give rise to specialized cell types within the placenta. However, the regulatory mechanisms that guide trophoblast cell fate decisions during placenta development remain ill defined. Here we exploited ATAC-seq and transcriptional profiling strategies to describe dynamic changes in gene expression and chromatin accessibility during TSC differentiation. We detect significantly increased chromatin accessibility at key genes upregulated as TSCs exit from the stem cell state. However, downregulated gene expression is not simply due to the loss of chromatin accessibility in proximal regions. Additionally, transcriptional targets recognized by the zinc finger transcriptional repressor Prdm1/Blimp1, an essential regulator of placenta development, were identified in ChIP-seq experiments. Comparisons with previously reported ChIP-seq datasets for primordial germ cell-like cells and E18.5 small intestine, combined with functional annotation analysis revealed that Blimp1 has broadly shared as well as cell type-specific functional activities unique to the trophoblast lineage. Importantly, Blimp1 not only silences TSC gene expression but also prevents aberrant activation of divergent developmental programmes. Overall the present study provides new insights into the chromatin landscape and Blimp1-dependent regulatory networks governing trophoblast gene expression.


Leaching mechanisms of Cr(VI) from chromite ore processing residue.
Batch leaching tests, qualitative and quantitative x-ray powder diffraction (XRPD) analyses, and geochemical modeling were used to investigate the leaching mechanisms of Cr(VI) from chromite ore processing residue (COPR) samples obtained from an urban area in Hudson County, New Jersey. The pH of the leaching solutions was adjusted to cover a wide range between 1 and 12.5. The concentration levels for total chromium (Cr) and Cr(VI) in the leaching solutions were virtually identical for pH values >5. For pH values <5, the concentration of total Cr exceeded that of Cr(VI) with the difference between the two attributed to Cr(III). Geochemical modeling results indicated that the solubility of Cr(VI) is controlled by Cr(VI)-hydrocalumite and Cr(VI)-ettringite at pH >10.5 and by adsorption at pH <8. However, experimental results suggested that Cr(VI) solubility is controlled partially by Cr(VI)-hydrocalumite at pH >10.5 and by hydrotalcites at pH >8 in addition to adsorption of anionic chromate species onto inherently present metal oxides and hydroxides at pH <8. As pH decreased to <10, most of the Cr(VI) bearing minerals become unstable and their dissolution contributes to the increase in Cr(VI) concentration in the leachate solution. At low pH ( <1.5), Cr(III) solid phases and the oxides responsible for Cr(VI) adsorption dissolve and release Cr(III) and Cr(VI) into solution.


Activation and role of MAP kinase-dependent pathways in retinal pigment epithelial cells: ERK and RPE cell proliferation.
Retinal pigment epithelial (RPE) cell proliferation plays a key role in the pathogenesis of ocular diseases involving the posterior segment. Mitogen-activated protein kinases (MAPKs) are involved in the control of cell proliferation. This study was conducted to investigate the involvement of the extracellular signal-regulated kinase (ERK) pathway, the major MAPK pathway implicated in cell growth during the induction of RPE cell proliferation. RPE cell proliferation was stimulated with 10% fetal calf serum (FCS). Activation of the Ras/Raf/MAP kinase-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway was detected by Western blot analysis and immunochemistry with specific anti-phosphosignaling protein antibodies. Pharmacologic and antisense (AS) oligonucleotide (ODN) strategies were used to analyze the ERK signaling involved in serum-induced cell proliferation. FCS (10%) induced more vigorous RPE cell proliferation than did FGF2, VEGF, platelet-derived growth factor (PDGF), or epidermal growth factor (EGF), alone or in combination. Pharmacologic inhibition of Ras and Raf-1 reduced cell proliferation by 67% to 100% and by 62% to 79%, respectively, demonstrating that activation of the Ras/Raf-1 pathway was essential for FCS-induced RPE cell proliferation. MEK1/2, ERK2, and P90 ribosomal S6 kinase (P90(RSK)), the kinases downstream from ERK2, were strongly activated during cell proliferation. Pharmacologic inhibition of MEK1/2 abolished activation of ERK2, but reduced cell proliferation by only 32%, showing that MEK/ERK participates in the signaling involved in RPE cell growth. Both inhibition of ERK2 activation, which reduced cyclin D1 production, and inhibition of cyclin D1 by AS ODN decreased cell proliferation, suggesting that RPE cell proliferation is mediated by cyclin D1 through ERK2. The requirement for Ras and the regulatory role of ERK2 in cyclin D1 production and in cell proliferation suggest that the Ras/Raf/MEK/ERK pathway plays a key role in the control of RPE cell proliferation. These data may have important implications for the development of more selective methods for the inhibition of retinal proliferation.


Genetic rearrangements in the rfb regions of Vibrio cholerae O1 and O139.
The recent emergence of a pathogenic new non-O1 serotype (O139) of Vibrio cholerae has led to numerous studies in an attempt to identify the origins of this new strain. Our studies indicate that O139 strains have clear differences in the surface polysaccharides when compared with O1 strains: the lipopolysaccharide can be described as semi-rough. Southern hybridization with the O1 rfb region demonstrates that O139 strains no longer contain any of the rfb genes required for the synthesis of the O1 O-antigen or its modification and also lack at least 6 kb of additional contiguous DNA. However, O139 strains have retained rfaD and have a single open reading frame closely related to three small open reading frames of the O1 rfb region. This region is closely related to the H-repeat of Escherichia coli and to the transposases of a number of insertion sequence elements and has all the features of an insertion sequence element that has been designated VcIS1. Transposon insertion mutants defective in O139 O-antigen (and capsule) biosynthesis map to the same fragment as VcIS1. Preliminary sequence data of complementing clones indicate that this DNA encodes a galactosyl-transferase and other enzymes for the utilization of galactose in polysaccharide biosynthesis. We propose a mechanism by which both the Ogawa serotype of O1 strains and the O139 serotype strains may have evolved.


ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels.
The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and nonselective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based high-throughput screen of a novel Kir7.1 channel inhibitor, VU714. Site-directed mutagenesis of pore-lining amino acid residues identified glutamate 149 and alanine 150 as essential determinants of VU714 activity. Lead optimization with medicinal chemistry generated ML418, which exhibits sub-micromolar activity (IC50 = 310 nM) and superior selectivity over other Kir channels (at least 17-fold selective over Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and Kir4.1) except for Kir6.2/SUR1 (equally potent). Evaluation in the EuroFins Lead Profiling panel of 64 GPCRs, ion-channels, and transporters for off-target activity of ML418 revealed a relatively clean ancillary pharmacology. While ML418 exhibited low CLHEP in human microsomes which could be modulated with lipophilicity adjustments, it showed high CLHEP in rat microsomes regardless of lipophilicity. A subsequent in vivo PK study of ML418 by intraperitoneal (IP) administration (30 mg/kg dosage) revealed a suitable PK profile (Cmax = 0.20 μM and Tmax = 3 h) and favorable CNS distribution (mouse brain/plasma Kp of 10.9 to support in vivo studies. ML418, which represents the current state-of-the-art in Kir7.1 inhibitors, should be useful for exploring the physiology of Kir7.1 in vitro and in vivo.


Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations.
To measure the rates of visual acuity, visual field, and ERG loss in patients with X-linked retinitis pigmentosa due to RPGR mutations and to determine whether these rates differ from those of patients with dominant retinitis pigmentosa due to RHO mutations. Snellen visual acuities, Goldmann visual field areas (V4e white test light), and 30 Hz (cone) full-field ERG amplitudes were recorded for an average of 9.8 years in 113 patients with RPGR mutations. After censoring data to eliminate ceiling and floor effects, we used longitudinal regression to estimate mean rates of change and to compare these rates with those of a previously studied cohort of 134 patients with dominant retinitis pigmentosa due to RHO mutations, who were followed for an average of 8.9 years. Survival analysis was used to compare the age distribution of legal blindness in these two groups. To explain group differences in visual acuity, optical coherence tomograms were recorded in some patients to visualize central retinal structure. Mean annual exponential rates of decline for the patients with RPGR mutations were 4.0% for visual acuity, 4.7% for visual field area, and 7.1% for ERG amplitude. Each of these rates was significantly different from zero (P < 0.001). The rates of visual acuity and visual field loss were significantly faster than the corresponding rates in the RHO patients (1.6%, P < 0.001 and 2.9%, P = 0.002, respectively), whereas the rate of ERG amplitude loss was comparable to that in the RHO patients (7.7%, P = 0.39). The median age of legal blindness was 32 years younger in the RPGR patients than in the RHO patients, due primarily to loss of visual acuity rather than to loss of visual field. Loss of acuity in RPGR patients appeared to be associated with foveal thinning. Patients with X-linked retinitis pigmentosa due to RPGR mutations lose visual acuity and visual field more rapidly than do patients with dominant retinitis pigmentosa due to RHO mutations.


Distributed neural systems for the generation of visual images.
Visual perception of houses, faces, and chairs evoke differential responses in ventral temporal cortex. Using fMRI, we compared activations evoked by perception and imagery of these object categories. We found content-related activation during imagery in extrastriate cortex, but this activity was restricted to small subsets of the regions that showed category-related activation during perception. Within ventral temporal cortex, activation during imagery evoked stronger responses on the left whereas perception evoked stronger responses on the right. Additionally, visual imagery evoked activity in parietal and frontal cortex, but this activity was not content related. These results suggest that content-related activation during imagery in visual extrastriate cortex may be implemented by "top-down" mechanisms in parietal and frontal cortex that mediate the retrieval of face and object representations from long-term memory and their maintenance through visual imagery.


Photonic-assisted microwave frequency measurement with higher resolution and tunable range.
A photonic-assisted approach to microwave frequency measurement is proposed based on frequency-to-power mapping with the help of the so-called amplitude comparison function. The key component is a dual-output Mach-Zehnder modulator (MZM) working at chirped modulation. The proposed scheme is characterized as having simplicity, higher resolution, and tunable measurement range. Owing to experimental constraint, an equivalent experiment has been carried out using a common single-output MZM at different bias points to prove the concept.


A comparative analysis of prenatal care and fetal growth in eight South American countries.
There has been little work that comprehensively compared the relationship between prenatal care and infant health across multiple countries using similar data sources and analytical models. Such comparative analyses are useful for understanding the background of differences in infant health between populations. We evaluated the association between prenatal care visits and fetal growth measured by birth weight (BW) in grams or low birth weight (<2500 grams; LBW) adjusted for gestational age in eight South American countries using similarly collected data across countries and the same analytical models. OLS and logistic regressions were estimated adjusting for a large set of relevant infant, maternal, and household characteristics and birth year and hospital fixed effects. Birth data were acquired from 140 hospitals that are part of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) network. The analytical sample included 56,014 live-born infants (∼69% of total sample) with complete data born without congenital anomalies in the years 1996-2011 in Brazil, Argentina, Chile, Venezuela, Ecuador, Colombia, Bolivia, and Uruguay. Prenatal care visits were significantly (at p<.05) and positively associated with BW and negatively associated with LBW for all countries. The OLS coefficients ranged from 9 grams per visit in Bolivia to 36 grams in Uruguay. The association with LBW was strongest for Chile (OR = 0.87 per visit) and lowest for Argentina and Venezuela (OR = 0.95). The association decreased in the recent decade compared to earlier years. Our findings suggest that estimates of association between prenatal care and fetal growth are population-specific and may not be generalizable to other populations. Furthermore, as one of the indicators for a country's healthcare system for maternal and child health, prenatal care is a highly variable indicator between countries in South America.


Hypertension and its risk factors among male adolescents in intermediate and secondary schools in Sakaka City, Aljouf Region of Saudi Arabia.
Hypertension among adolescents is an emerging public health problem. The current study aims to estimate the burden of hypertension and identify its risk factors among male adolescents of intermediate and secondary schools. This is a school-based cross-sectional study that targeted 400 male adolescents in the age group of 15-17 years. Blood pressure was defined as per the "Fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents". An electronic device approved for use by the European Society of Hypertension International Protocol revision 2010, (Omron M3W; HEM-7202-E) was used for measuring blood pressure. CDC's body mass index tool was adopted for defining overweight and obesity. Descriptive analysis for hypertension and the risk factors were carried out. Chi-square test and odds ratios were calculated to assess any association between categorical variables. Overall 36 (9.0%) adolescents had prehypertension and 69 (17.2%) had hypertension. Systolic prehypertension, systolic hypertension, diastolic prehypertension, and diastolic hypertension were present in 6.5%, 17.2%, 5.8%, and 9.0% of the adolescents, respectively. Bivariate analysis revealed that overweight and obesity, no physical activity, or once-a-week physical activity, positive family history of hypertension, and smoking were predictors of systolic prehypertension and showed a significant relationship with systolic hypertension. There is a considerable prevalence of prehypertension and hypertension, among school-going male adolescents. We recommend school-based health education programs and routine screening directed toward the risk factors of noncommunicable diseases like hypertension with special attention to obesity, physical inactivity, and smoking.


Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12.
Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules - receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST) - have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP.


Lifespan development of attentiveness in domestic dogs: drawing parallels with humans.
Attention is pivotal to consciousness, perception, cognition, and working memory in all mammals, and therefore changes in attention over the lifespan are likely to influence development and aging of all of these functions. Due to their evolutionary and developmental history, the dog is being recognized as an important species for modeling human healthspan, aging and associated diseases. In this study, we investigated the normal lifespan development of attentiveness of pet dogs in naturalistic situations, and compared the resulting cross-sectional developmental trajectories with data from previous studies in humans. We tested a sample of 145 Border collies (6 months to 14 years) with humans and objects or food as attention attractors, in order to assess their attentional capture, sustained and selective attention, and sensorimotor abilities. Our results reveal differences in task relevance in sustained attentional performance when watching a human or a moving object, which may be explained by life-long learning processes involving such stimuli. During task switching we found that dogs' selective attention and sensorimotor abilities showed differences between age groups, with performance peaking at middle age. Dogs' sensorimotor abilities showed a quadratic distribution with age and were correlated with selective attention performance. Our results support the hypothesis that the development and senescence of sensorimotor and attentional control may be fundamentally interrelated. Additionally, attentional capture, sustained attention, and sensorimotor control developmental trajectories paralleled those found in humans. Given that the development of attention is similar across humans and dogs, we propose that the same regulatory mechanisms are likely to be present in both species. Finally, this cross-sectional study provides the first description of age group changes in attention over the lifespan of pet dogs.


Matrix-degrading protease ADAMTS-5 cleaves inter-α-inhibitor and releases active heavy chain 2 in synovial fluids from arthritic patients.
Destruction of the cartilage matrix in joints is an important feature of arthritis. Proteolytic degradation of cartilage glycoproteins can contribute to the loss of matrix integrity. Human inter-α-inhibitor (IαI), which stabilizes the extracellular matrix, is composed of the light-chain serine proteinase inhibitor bikunin and two homologous heavy chains (HC1 and HC2) covalently linked through chondroitin 4-sulfate. Inflammation promotes the transfer of HCs from chondroitin 4-sulfate to hyaluronan by tumor necrosis factor-stimulated gene-6 protein (TSG-6). This reaction generates a covalent complex between the heavy chains and hyaluronan that can promote leukocyte invasion. This study demonstrates that both IαI and the HC-hyaluronan complex are substrates for the extracellular matrix proteases ADAMTS-5 and matrix metalloprotease (MMP) -3, -7, and -13. The major cleavage sites for all four proteases are found in the C terminus of HC2. ADAMTS-5 and MMP-7 displayed the highest activity toward HC2. ADAMTS-5 degradation products were identified in mass spectrometric analysis of 29 of 33 arthropathic patients, indicating that ADAMTS-5 cleavage occurs in synovial fluid in arthritis. After cleavage, free HC2, together with TSG-6, is able to catalyze the transfer of heavy chains to hyaluronan. The release of extracellular matrix bound HC2 is likely to increase the mobility of the HC2/TSG-6 catalytic unit and consequently increase the rate of the HC transfer reaction. Ultimately, ADAMTS-5 cleavage of HC2 could alter the physiological and mechanical properties of the extracellular matrix and contribute to the progression of arthritis.


Cardiac remodeling during and after renin-angiotensin system stimulation in Cyp1a1-Ren2 transgenic rats.
This study investigated renin-angiotensin system (RAS)-induced cardiac remodeling and its reversibility in the presence and absence of high blood pressure (BP) in Cyp1a1-Ren2 transgenic inducible hypertensive rats (IHR). In IHR (pro)renin levels and BP can be dose-dependently titrated by oral administration of indole-3-carbinol (I3C). Young (four-weeks old) and adult (30-weeks old) IHR were fed I3C for four weeks (leading to systolic BP >200 mmHg). RAS-stimulation was stopped and animals were followed-up for a consecutive period. Cardiac function and geometry was determined echocardiographically and the hearts were excised for molecular and immunohistochemical analyses. Echocardiographic studies revealed that four weeks of RAS-stimulation incited a cardiac remodeling process characterized by increased left ventricular (LV) wall thickness, decreased LV volumes, and shortening of the left ventricle. Hypertrophic genes were highly upregulated, whereas in substantial activation a fibrotic response was absent. Four weeks after withdrawal of I3C, (pro)renin levels were normalized in all IHR. While in adult IHR BP returned to normal, hypertension was sustained in young IHR. Despite the latter, myocardial hypertrophy was fully regressed in both young and adult IHR. We conclude that (pro)renin-induced severe hypertension in IHR causes an age-independent fully reversible myocardial concentric hypertrophic remodeling, despite a continued elevated BP in young IHR.


Physician responsibility for removal of implants: the case for a computerized program for tracking overdue double-J stents.
Ureteral stents are used in various modern urologic procedures. Although forgotten double-J (JJ) stents are an infrequent problem, they are associated with significant medical problems. Encrustation from excessive indwelling time increases morbidity and may require extracorporeal shock wave lithotripsy to free the coils of the cementing calcerous material. An effective system should be in place to ensure timely removal. The previously used "card" system not only is difficult to manage but has proved unreliable. We describe a computerized program that tracks JJ stents and alerts physicians about stents that need removal. Two hundred eighteen patients who were stented between January 1997 and December 1998 were tracked through an integrated computerized program. This program keeps a log of all patients who received a JJ stent and determines the last date by which it should be removed. Patients are reminded if they have not returned for removal of the implant 2 weeks before it is overdue. Two hundred twenty-five JJ stents were placed in 218 patients. Comparison of data between the periods before and after computer program inception showed that the incidence of stents retained longer than their expiration time decreased from 12.5% to 1.2% in the first year of the program and 1.5% in the second year of the program. Forgotten implants pose a significant management dilemma for physicians. Our tracking program significantly lowered the incidence of overdue JJ stents from 12.5% to 1.2% and 1.5% in the first and second years, of the program respectively (p = .00039). We propose that this technically simple program should be in place for all implants placed in patients. The problems we encountered in the smooth running of this system could be averted by incorporating several recommendations.


The SCARB1 gene is associated with lipid response to dietary and pharmacological interventions.
The scavenger receptor class B type 1 (SCARB1) gene is a key component in the reverse cholesterol transport pathway and thus plays an important role in lipid metabolism. Studies suggest that the SCARB1 gene may contribute to variation in plasma lipid levels at fasting; however, the results have been inconsistent, and it is unclear whether SCARB1 may also influence lipid response to dietary and pharmacologic interventions. In this study, we examined genetic variation in the SCARB1 gene in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study for associations with basal lipid levels, changes in lipid measures after dietary fat intake, and fenofibrate treatment. We found that the exon 1 variant SCARB1_G2S was significantly associated with postfenofibrate change for triglycerides (TG) (P = 0.004). Subjects bearing SCARB1_G2S minor allele A tend to have higher responsiveness to fenofibrate in lowering TG. In summary, our study suggested that the SCARB1 gene may serve as a useful marker that predicts variation in baseline lipid levels, postprandial lipid response, and response to fenofibrate intervention.