Prevalence of asthma among Middle Eastern children: A systematic review.
Background: The prevalence of asthma and allergy has increased during the last decades, especially in children. However, little is known about it in the Middle East region. This systematic review is aimed to estimate the prevalence of asthma among the Middle Eastern children. Methods: Local and international scientific databases including SID, Iranmedex, Medline and Science Direct were systematically searched for relevant keywords including; asthma, prevalence, children, International Study of Asthma and Allergies in Childhood (ISACC) and the names of Middle Eastern countries for the period of 1996-2011. Papers in Persian and English which met the defined criteria were included into the study. Bibliographies of the extracted articles were also searched. After extraction of data, heterogeneity between studies and publication bias were measured using Egger's-test. Effect size was pooled by the random-effect model. Since significant heterogeneity was found between studies, univariate meta-regression analyses were done to assess the association of variables with the overall results. Results: Fifty studies in the Middle East examined the prevalence of asthma and allergy in children under the age of 18 years according to the ISAAC criteria and were included. A total number of 289,717 children were examined in the included studies and the prevalence varied from 0.7 % in Isfahan to 22.3 % in Bagdad. The total prevalence of diagnosed asthma was calculated 7.53 % (95% Cl: 6.38-8.75). Prevalence of asthma in the 13-14 years age group was 7.57% (95% Cl: 5.78-9.29) and in 6-7 years age group was 7.43% (95% Cl: 5.75-9.10). The prevalence of asthma among girls, based on random effect model, was 6.30% (95% Cl: 4.97-7.61) and among boys, it was 8.91% (95% Cl: 6.80-11.04). Conclusion: The prevalence of asthma in the Middle East is lower than most developed countries. However, there is not enough longitudinal data to estimate the trend over time. In order to have more accurate estimates and to provide evidence for proper planning, standard epidemiologic studies should be conducted in countries of the region.


[Association between socioeconomic factors and infant deaths due to diarrhea, pneumonia, and malnutrition in a metropolitan area of Southeast Brazil: a case-control study].
A population-based case-control study was carried out to identify determinant factors for post-neonatal infant deaths due to diarrhea, pneumonia, and malnutrition in Greater Metropolitan Belo Horizonte, Southeast Brazil. From May 1, 1991, to April 30, 1992, 511 post-neonatal deaths due to diarrhea, pneumonia, and malnutrition were selected after investigation of medical records to validate cause of death. Of this total, 396 deaths were compared to a neighborhood control group, matched for age. The study was carried out in a low-income area with a high proportion of families living in shantytowns. The article discusses the methodology and selected socioeconomic factors. Logistic regression analysis indicated that number of household appliances, mother's and father's education, and mother's marital and work status were significantly associated with risk of infant death, i.e., they were determinants of infant deaths due to avoidable causes.


Dysplastic haemopoiesis following orthotopic liver transplantation: comparison with similar changes in HIV infection and primary myelodysplasia.
To validate scientifically our prior empiric observations that patients develop significant haemopoietic dysplasia following solid organ transplantation, we developed a quantitative lineage-specific scoring system to evaluate dysplastic features of bone marrow aspirates and core biopsies. We used this scoring system to compare retrospectively randomly selected bone marrow aspirates and core biopsies from 19 patients undergoing orthotopic liver transplantation (OLT), 21 with a known history of human immunodeficiency virus (HIV) infection, and 18 with primary or chemotherapy-related myelodysplastic syndromes (MDS). Our results show that the OLT patient group developed significant but milder haemopoietic dysplastic changes than the HIV or MDS groups, and that the MDS group developed more severe dysplasia of the myeloid lineage than the other groups. The possible roles for drugs and infectious agents in the pathophysiology of dysplastic changes are discussed.


Global atmospheric chemistry of CFC-123.
THE compound 1,1-dichloro-2,2,2-trifluoroethane (CFC-123), which is potentially usable as a foam-blowing agent in the plastics industry, an aerosol propellant and a refrigerant, has been proposed as an industrial substitute for trichlorofluoromethane (CFC-11), the use of which is increasingly restricted because of its effects on the ozone layer and on climate(1-3). It is expected that CFC-123, although like CFC-11 an absorber of infrared radiation, will be less stable in the atmosphere because of its expected reaction with OH radicals in the troposphere. Using a three-dimensional global model of the atmosphere, we have calculated the chemical destruction rates of CFC-123 by various processes, confirming that the chief sink is destruction by OH radicals below 12 km, which accounts for 88% of its loss. The calculated destruction rate is greatest in the equatorial region below 2 km. The calculated steady-state lifetime of CFC-123 is 1.5 years, based on the best available estimate of the rate constant of the reaction with OH. This lifetime is very much shorter than that of CFC-11, the destruction of which is largely confined to the stratosphere. For equal rates (by mass) of CFC-123 and CFC-11 emission to the atmosphere, the molar content in the atmosphere and the injection rate of chlorine into the stratosphere are, respectively, 48 and 14 times greater for CFC-11 than for CFC-123 in steady-state.


The relationship between the error catastrophe, survival of the flattest, and natural selection.
The quasispecies model is a general model of evolution that is generally applicable to replication up to high mutation rates. It predicts that at a sufficiently high mutation rate, quasispecies with higher mutational robustness can displace quasispecies with higher replicative capacity, a phenomenon called "survival of the flattest". In some fitness landscapes it also predicts the existence of a maximum mutation rate, called the error threshold, beyond which the quasispecies enters into error catastrophe, losing its genetic information. The aim of this paper is to study the relationship between survival of the flattest and the transition to error catastrophe, as well as the connection between these concepts and natural selection. By means of a very simplified model, we show that the transition to an error catastrophe corresponds to a value of zero for the selective coefficient of the mutant phenotype with respect to the master phenotype, indicating that transition to the error catastrophe is in this case similar to the selection of a more robust species. This correspondence has been confirmed by considering a single-peak landscape in which sequences are grouped with respect to their Hamming distant from the master sequence. When the robustness of a class is changed by modification of its quality factor, the distribution of the population changes in accordance with the new value of the robustness, although an error catastrophe can be detected at the same values as in the general case. When two quasispecies of different robustness competes with one another, the entry of one of them into error catastrophe causes displacement of the other, because of the greater robustness of the former. Previous works are explicitly reinterpreted in the light of the results obtained in this paper. The main conclusion of this paper is that the entry into error catastrophe is a specific case of survival of the flattest acting on phenotypes that differ in the trade-off between replicative ability and mutational robustness. In fact, entry into error catastrophe occurs when the mutant phenotype acquires a selective advantage over the master phenotype. As both entry into error catastrophe and survival of the flattest are caused by natural selection when mutation rate is increased, we propose differentiating between them by the level of selection at which natural selection acts. So we propose to consider the transition to error catastrophe as a phenomenon of intra-quasispecies selection, and survival of the flattest as a phenomenon of inter-quasispecies selection.


Regeneration of cardiomyocytes from bone marrow: Use of mesenchymal stem cell for cardiovascular tissue engineering.
We have isolated a cardiomyogenic cell line (CMG cell) from murine bone marrow mesenchymal stem cells. The cells showed a fibroblast-like morphology, but the morphology changed after 5-azacytidine exposure. They began spontaneous beating after 2 weeks, and expressed ANP and BNP. Electron microscopy revealed a cardiomyocyte-like ultrastructure. These cells had several types of action potentials; sinus node-like and ventricular cell-like action potentials. The isoform of contractile protein genes indicated that their muscle phenotype was similar to fetal ventricular cardiomyocytes. They expressed alpha(1A), alpha(1B), alpha(1D), beta(1), and beta(2) adrenergic and M(1) and M(2) muscarinic receptors. Stimulation with phenylephrine, isoproterenol and carbachol increased ERK phosphorylation and second messengers. Isoproterenol increased the beating rate, which was blocked with CGP20712A (beta(1)-selective blocker). These findings indicated that cell transplantation therapy for the patients with heart failure might possibly be achieved using the regenerated cardiomyocytes from autologous bone marrow cells in the near future.


CpG methylation controls reactivation of HIV from latency.
DNA methylation of retroviral promoters and enhancers localized in the provirus 5' long terminal repeat (LTR) is considered to be a mechanism of transcriptional suppression that allows retroviruses to evade host immune responses and antiretroviral drugs. However, the role of DNA methylation in the control of HIV-1 latency has never been unambiguously demonstrated, in contrast to the apparent importance of transcriptional interference and chromatin structure, and has never been studied in HIV-1-infected patients. Here, we show in an in vitro model of reactivable latency and in a latent reservoir of HIV-1-infected patients that CpG methylation of the HIV-1 5' LTR is an additional epigenetic restriction mechanism, which controls resistance of latent HIV-1 to reactivation signals and thus determines the stability of the HIV-1 latency. CpG methylation acts as a late event during establishment of HIV-1 latency and is not required for the initial provirus silencing. Indeed, the latent reservoir of some aviremic patients contained high proportions of the non-methylated 5' LTR. The latency controlled solely by transcriptional interference and by chromatin-dependent mechanisms in the absence of significant promoter DNA methylation tends to be leaky and easily reactivable. In the latent reservoir of HIV-1-infected individuals without detectable plasma viremia, we found HIV-1 promoters and enhancers to be hypermethylated and resistant to reactivation, as opposed to the hypomethylated 5' LTR in viremic patients. However, even dense methylation of the HIV-1 5'LTR did not confer complete resistance to reactivation of latent HIV-1 with some histone deacetylase inhibitors, protein kinase C agonists, TNF-alpha, and their combinations with 5-aza-2deoxycytidine: the densely methylated HIV-1 promoter was most efficiently reactivated in virtual absence of T cell activation by suberoylanilide hydroxamic acid. Tight but incomplete control of HIV-1 latency by CpG methylation might have important implications for strategies aimed at eradicating HIV-1 infection.


Oral tetracyclines may not be effective in treating acne: dominance of the placebo effect.
Oral tetracyclines (tetracycline, doxycycline, minocycline and lymecycline) have been commonly regarded as effective for treating both inflammatory and non-inflammatory acne. An excellent review of efficacy of 57 clinical trials by Simonart et al. in 2007 concluded that compared to the baseline before treatment, efficacies of all tetracyclines were similar (mean reduction in inflammatory lesions and non-inflammatory lesion being 54.3 ± 1.4% and 45 ± 2.6%, respectively) and were not affected by dosage amount (40 - 1,000 mg per day) and treatment period (4 - 24 weeks). These interesting findings may be pharmacodynamically rationalized by weak intrinsic anti-acne activity of tetracyclines and strong placebo effects. This hypothesis was supported by published data indicating that during weeks or months of daily administration, the placebo effect approached the effect of minocycline or doxycline in reducing acne lesions in three separate studies. The present work suggests the importance of considering placebo effects in the evaluation of anti-acne products. The treatability of acne was discussed in view of the slow and weak intrinsic anti-acne property of oral tetracyclines, and the reported fast (within days) elimination (curing) of severe acne by intralesional corticosteroids and antibiotics. The subantimicrobial or non-antimicrobial doses (e.g., only a small fraction) of various oral tetracyclines may be much lower than those commonly recognized.


Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration.
Drusen are hallmarks of age-related macular degeneration (AMD). Amyloid-beta 1-40 (Aβ 1-40), a constituent of drusen, is known to stimulate inflammatory pathways in RPE; however, its effect in vivo is not known. The purpose of this study was to examine the effect of Aβ 1-40 on cytokine expression and inflammasome activation relevant to AMD in an animal model. Wild-type rats received intravitreal injections of Aβ 1-40, and eyes were taken at days 1, 4, 14, and 49 postinjection. The RPE, neuroretina, and vitreous were analyzed for cytokine expression, inflammasome activation, and microglial response via RT-PCR, immunohistochemistry, and suspension array assay. Retinal cell loss was assessed via apoptotic markers and retinal thickness. Aβ 1-40 stimulated upregulation of IL-6, TNF-α, IL-1β, IL-18, caspase-1, NLRP3, and XAF1 genes in the RPE/choroid and the neuroretina. Increased IL-1β and IL-6 immunoreactivity was found in retinal sections, and elevated levels of IL-1β and IL-18 were found in the vitreous of Aβ-injected eyes. Aβ 1-40 induced a moderate increase in CD11b/c-reactive cells on day 1 postinjection only. No evidence of the proapoptotic XAF1 protein, p53, TUNEL immunoreactivity, or retinal thinning was observed. These results confirm earlier in vitro work and support the proinflammatory role of drusen component Aβ 1-40 in the RPE and retina. Inflammasome activation may be responsible for this effect in vivo. This model is useful for understanding cellular triggers of inflammasome activation and proposed early inflammatory events in the outer retina associated with the etiology of AMD.


Acute, lethal, natural killer cell-resistant myeloproliferative disease induced by polyomavirus in severe combined immunodeficient mice.
Infection of severe combined immunodeficient mice, which lack T and B lymphocytes, with polyomavirus (PyV) induced an acute hematological disorder leading to the death of the mice by 2 weeks postinfection. The disease was characterized by a dramatic decrease in megakaryocytes, multiple hemorrhages, anemia, thrombocytopenia, splenomegaly, a massive myeloproliferation and splenic erythroproliferation with a defect in maturation of the myeloid elements similar to that in acute leukemia. This pathology in severe combined immunodeficient mice is very different from that of the well-characterized tumor profiles induced by PyV in normal newborn or nude mice. Viral T and capsid (VP1) antigens and viral genome were detected in some cells in the spleen, but not in the majority of the proliferating myeloid cells. This suggests that the myeloproliferation is induced by some indirect mechanism, such as secretion of growth factors or cytokines by virus-infected cells, rather than by direct transformation by PyV. Neither the spread of PyV, its replication in different organs, nor the pathogenesis or the time of death were altered by depleting natural killer cells in vivo by anti-natural killer cell antibodies. Analysis of the spleen leukocyte population indicated that the cells expressed high levels of class I major histocompatibility complex antigens and were resistant to lysis by activated natural killer cells.


Polarization-induced distortion in stimulated Brillouin scattering slow-light systems.
The vector analysis of stimulated Brillouin scattering amplification in birefringent fibers is extended to include signal pulses. The analysis finds that the different slow-light delays experienced by the states of polarization corresponding to maximum and minimum gain may result in severe pulse distortion. Thus, a generally polarized pulse, experiencing only a moderate gain, can become broader than a pulse aligned for maximum gain and delay. The effect is demonstrated in both numerical simulations and experiments.


Mycotoxin problem in Africa: current status, implications to food safety and health and possible management strategies.
Mycotoxins are toxic secondary metabolites of fungal origin and contaminate agricultural commodities before or under post-harvest conditions. They are mainly produced by fungi in the Aspergillus, Penicillium and Fusarium genera. When ingested, inhaled or absorbed through the skin, mycotoxins will cause lowered performance, sickness or death on humans and animals. Factors that contribute to mycotoxin contamination of food and feed in Africa include environmental, socio-economic and food production. Environmental conditions especially high humidity and temperatures favour fungal proliferation resulting in contamination of food and feed. The socio-economic status of majority of inhabitants of sub-Saharan Africa predisposes them to consumption of mycotoxin contaminated products either directly or at various points in the food chain. The resulting implications include immuno-suppression, impaired growth, various cancers and death depending on the type, period and amount of exposure. A synergistic effect between mycotoxin exposure and some important diseases in the continent such as malaria, kwashiorkor and HIV/AIDS have been suggested. Mycotoxin concerns have grown during the last few decades because of their implications to human and animal health, productivity, economics of their management and trade. This has led to development of maximum tolerated limits for mycotoxins in various countries. Even with the standards in place, the greatest recorded fatal mycotoxin-poisoning outbreak caused by contamination of maize with aflatoxins occurred in Africa in 2004. Pre-harvest practices; time of harvesting; handling of produce during harvesting; moisture levels at harvesting, transportation, marketing and processing; insect damage all contribute to mycotoxin contamination. Possible intervention strategies include good agricultural practices such as early harvesting, proper drying, sanitation, proper storage and insect management among others. Other possible interventions include biological control, chemical control, decontamination, breeding for resistance as well as surveillance and awareness creation. There is need for efficient, cost-effective sampling and analytical methods that can be used for detection analysis of mycotoxins in developing countries.


Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience.
To investigate whether the rate of neurologic recovery or the incidence of long-term sequelae differed for children with neuroblastoma (NB) initially treated with chemotherapy versus surgical decompression with laminectomy, we reviewed the Pediatric Oncology Group (POG) experience. A retrospective review of children diagnosed with intraspinal NB registered on POG NB Biology Protocol 9047 was performed. Survival, neurologic outcome, and orthopedic sequelae were evaluated according to age of the patient at diagnosis, stage of disease, duration and severity of neurologic symptoms, and therapeutic intervention. Between May 1990 and January 1998, 83 children with intraspinal NB were entered onto the study. Five-year survival for this cohort of patients was 71% +/- 9%. Forty-three (52%) of the patients had neurologic symptoms at diagnosis. After treatment, six of 15 severely affected patients, who presented with paralysis, completely recovered neurologic function. Two of five patients with moderate deficits, consisting of paresis and bowel/bladder dysfunction, completely recovered neurologic function. Seventeen of 22 assessable children, who had mild symptoms comprised of paresis alone, fully recovered. Seven of 24 assessable patients who had undergone laminectomy developed scoliosis, whereas spinal deformities were only detected in one of 49 assessable patients managed without laminectomy (P =.001). The frequency of complete neurologic recovery in children with intraspinal NB inversely correlated with the severity of the presenting neurologic deficits. The rate of neurologic recovery was similar for patients treated with chemotherapy compared to those managed with laminectomy. Fewer orthopedic sequelae were observed in the children managed with chemotherapy than were seen in children managed with laminectomy.


The implementation of the Plan Esperanza and response to the imPACT Review.
Following the implementation of the National Cancer Prevention and Control Results-based Budget Programme (PpR Cancer-024) in 2011, the Peruvian Government approved the Plan Esperanza-a population-based national cancer control plan-in 2012. Legislation that ensured full government-supported funding for people who were otherwise unable to access or afford care and treatment accompanied the Plan. In 2013, the Ministry of Health requested an integrated mission of the Programme of Action for Cancer Therapy (imPACT) report to strengthen cancer control in Peru. The imPACT Review, which was executed in 2014, assessed Peru's achievements in cancer control, and areas for improvement, including cancer control planning, further development of population-based cancer registration, increased prevention, early diagnosis, treatment and palliative care, and the engagement and participation of civil society in the health-care system. This Series paper gives a brief history of the development of the Plan Esperanza, describes the innovative funding model that supports it, and summarises how funds are disseminated on the basis of disease, geography, and demographics. An overview of the imPACT Review, and the government's response in the context of the Plan Esperanza, is provided. The development and execution of the Plan Esperanza and the execution of and response to the imPACT Review demonstrates the Peruvian Government's commitment to fighting cancer across the country, including in remote and urban areas.


Sleep disorders, health, and safety in police officers.
Sleep disorders often remain undiagnosed. Untreated sleep disorders among police officers may adversely affect their health and safety and pose a risk to the public. To quantify associations between sleep disorder risk and self-reported health, safety, and performance outcomes in police officers. Cross-sectional and prospective cohort study of North American police officers participating in either an online or an on-site screening (n=4957) and monthly follow-up surveys (n=3545 officers representing 15,735 person-months) between July 2005 and December 2007. A total of 3693 officers in the United States and Canada participated in the online screening survey, and 1264 officers from a municipal police department and a state police department participated in the on-site survey. Comorbid health conditions (cross-sectional); performance and safety outcomes (prospective). Of the 4957 participants, 40.4% screened positive for at least 1 sleep disorder, most of whom had not been diagnosed previously. Of the total cohort, 1666 (33.6%) screened positive for obstructive sleep apnea, 281 (6.5%) for moderate to severe insomnia, 269 (5.4%) for shift work disorder (14.5% of those who worked the night shift). Of the 4608 participants who completed the sleepiness scale, 1312 (28.5%) reported excessive sleepiness. Of the total cohort, 1294 (26.1%) reported falling asleep while driving at least 1 time a month. Respondents who screened positive for obstructive sleep apnea or any sleep disorder had an increased prevalence of reported physical and mental health conditions, including diabetes, depression, and cardiovascular disease. An analysis of up to 2 years of monthly follow-up surveys showed that those respondents who screened positive for a sleep disorder vs those who did not had a higher rate of reporting that they had made a serious administrative error (17.9% vs 12.7%; adjusted odds ratio [OR], 1.43 [95% CI, 1.23-1.67]); of falling asleep while driving (14.4% vs 9.2%; adjusted OR, 1.51 [95% CI, 1.20-1.90]); of making an error or safety violation attributed to fatigue (23.7% vs 15.5%; adjusted OR, 1.63 [95% CI, 1.43-1.85]); and of exhibiting other adverse work-related outcomes including uncontrolled anger toward suspects (34.1% vs 28.5%; adjusted OR, 1.25 [95% CI, 1.09-1.43]), absenteeism (26.0% vs 20.9%; adjusted OR, 1.23 [95% CI, 1.08-1.40]), and falling asleep during meetings (14.1% vs 7.0%; adjusted OR, 1.95 [95% CI, 1.52-2.52]). Among a group of North American police officers, sleep disorders were common and were significantly associated with increased risk of self-reported adverse health, performance, and safety outcomes.


Novel objects alter immediate early gene expression globally for ZENK and regionally for c-Fos in neophobic and non-neophobic house sparrows.
Neophobia - an animal's reluctance to approach novel objects, try new foods, or explore unfamiliar environments - affects whether animals can adapt to new environments and exploit novel resources. However, despite its importance, the neurobiological mechanisms underlying this personality trait are poorly understood. In this study, we examined regional brain activity using the expression of two immediate early genes (IEGs), ZENK and c-Fos, in response to novel objects or control conditions in captive house sparrows (Passer domesticus, n = 22). When exposed to novel objects, we predicted that we would see differential IEG activity in brain regions involved in regulating stress and emotion (hippocampus, medial ventral arcopallium, lateral septum), reward and learning (striatum), and executive function (NCL) between neophobic and non-neophobic individuals. To classify birds by phenotype, we used behavior trials that tested willingness to approach a food dish in the presence of several different novel objects, habituation to one novel object, and willingness to try several different novel foods. We then exposed birds to a new novel object or a control condition and assessed protein expression of two IEGs in neophobic vs non-neophobic individuals after this final exposure. An analysis of average sparrow feeding times in the presence of novel objects showed a bimodal distribution of neophobia behavior. There was also high repeatability of individual novel object responses, and average responses to all three trial types (novel object, novel food, and habituation to a novel object) were significantly correlated. Although we saw no differences between neophobic and non-neophobic birds in IEG expression in response to novel objects in any of the 6 brain regions examined, there was a significant global decrease in ZENK expression and a significant increase in c-Fos expression in the medial ventral arcopallium and the caudal hippocampus in response to novel objects compared to controls, suggesting that these two regions may be important in novelty detection and threat perception. Additionally, there was no object effect in the rostral hippocampus, which supports the hypothesis that the avian hippocampus may have a rostrocaudal functional gradient similar to the septotemporal gradient in mammals.


[Development of Higher Brain Function Tests in Rodents and Its Application to Neurotoxicity Assessment of Environmental Chemicals].
The brain during developmental period is thought to be highly sensitive to environmental insults including exposure to chemicals. However, it has been extremely difficult to detect and assess the features and degree of adversity particularly at low exposure levels. I describe here the effects of maternal exposure to dioxin on higher brain functions later in life, which we detected using our originally developed behavioral tests for quantifying higher brain functions in rodents. We first found changes in the mRNA expression levels of glutamate NMDA receptor subunits that have critical roles in learning and memory function in the neocortex and hippocampus. To assess the neocortical and hippocampal functions in rats, we established novel behavioral tests for assessing paired-associate learning, which is the hippocampal and medial prefrontal NMDA-dependent function. Maternal exposure to dioxin, at a low level of which does not affect simple memory formation, resulted in the disturbance of the paired-associate learning. On the basis of the above learning paradigm, we next developed a behavioral flexibility task and a social competitive task for mice using the automated behavioral assessment system 'IntelliCage': this system can accommodate 16 mice at the same time to monitor and record their behavior. Using this system, we found that male mice born to dams exposed to very low doses of dioxin showed inflexibility in a serial reversal learning task and socially low-dominance behavior under a competitive situation. Immunohistochemical analysis of putative neuronal activity markers revealed hypoactivity in the medial prefrontal cortex (mPFC) of dioxin-exposed mice. We speculate that mPFC hypoactivity reflects the dioxin-induced higher brain dysfunction and may be associated with some psychiatric illnesses and related problems. These behavioral tests were found to be useful for studying the higher brain functions of rats and mice.


Altered ceramide acyl chain length and ceramide synthase gene expression in Parkinson's disease.
Genetic studies have provided increasing evidence that ceramide homeostasis plays a role in neurodegenerative diseases including Parkinson's disease (PD). It is known that the relative amounts of different ceramide molecular species, as defined by their fatty acyl chain length, regulate ceramide function in lipid membranes and in signaling pathways. In the present study we used a comprehensive sphingolipidomic case-control approach to determine the effects of PD on ceramide composition in postmortem brain tissue from the anterior cingulate cortex (a region with significant PD pathology) and the occipital cortex (spared in PD), also assessing mRNA expression of the major ceramide synthase genes that regulate ceramide acyl chain composition in the same tissue using quantitative PCR. In PD anterior cingulate cortex but not occipital cortex, total ceramide and sphingomyelin levels were reduced from control levels by 53% (P < 0.001) and 42% (P < 0.001), respectively. Of the 13 ceramide and 15 sphingomyelin molecular lipid species identified and quantified, there was a significant shift in the ceramide acyl chain composition toward shorter acyl chain length in the PD anterior cingulate cortex. This PD-associated change in ceramide acyl chain composition was accompanied by an upregulation of ceramide synthase-1 gene expression, which we consider may represent a response to reduced ceramide levels. These data suggest a significant shift in ceramide function in lipid membranes and signaling pathways occurs in regions with PD pathology. Identifying the regulatory mechanisms precipitating this change may provide novel targets for future therapeutics.


Ptr ToxA requires multiple motifs for complete activity.
Ptr ToxA was the first proteinaceous necrosis-inducing toxin identified and cloned from the wheat pathogen, Pyrenophora tritici-repentis. How this protein causes necrosis in sensitive wheat cultivars is not known. In an effort to understand the structural features of Ptr ToxA required for induction of necrosis, we employed a combination of site-directed mutagenesis and peptide inhibition studies. Mutagenesis was carried out on conserved motifs within the active domain of Ptr ToxA. Proteins with mutations of potential casein kinase 2 phosphorylation sites but not protein kinase C phosphorylation sites have significantly reduced activity. Additionally, mutations in a region with high homology to amino acids surrounding and including the RGD cell attachment motif of vitronectin result in proteins with significantly less activity than Ptr ToxA. The importance of the vitronectin-like motif was confirmed by a decrease of Ptr ToxA-induced activity when coinfiltrated with peptides corresponding to amino acids within this motif. Reduction in Ptr ToxA activity by competition with mutant proteins demonstrates the necessity of multiple motifs for Ptr ToxA activity.


Phase I/II study of oxaliplatin with weekly bolus fluorouracil and high-dose leucovorin (ROX) as first-line therapy for patients with colorectal cancer.
Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD. The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m2) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m2) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied. Oxaliplatin (85 mg/m2) with weekly bolus 5-FU (400 mg/m2) and high-dose l-LV (250 mg/m2) is recommended for further phase III studies in patients with metastatic colorectal cancer.


Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial.
Escitalopram, the therapeutically active isomer of the racemic selective serotonin reuptake inhibitor antidepressant citalopram, has shown significant anxiolytic effects in placebo-controlled clinical trials of social anxiety disorder, generalized anxiety disorder, and anxiety symptoms associated with major depression. This study evaluated the safety and efficacy of escitalopram in outpatients diagnosed with panic disorder. Male and female outpatients between 18 and 80 years of age meeting DSM-IV criteria for panic disorder, with or without agoraphobia, were randomly assigned to 10 weeks of double-blind treatment with escitalopram, citalopram, or placebo in a study conducted from September 1999 to July 2001. The primary measure of efficacy was panic attack frequency at week 10 relative to baseline, as assessed by the Modified Sheehan Panic and Anticipatory Anxiety Scale. A total of 366 subjects (128 escitalopram patients, 119 citalopram patients, and 119 placebo patients) received at least 1 dose of double-blind treatment. The frequency of panic attacks was statistically significantly improved (p =.04), and the increase in percentage of patients with zero panic attacks reached borderline significance (p =.051), in the escitalopram-treated group relative to the placebo-treated group. Both escitalopram and citalopram statistically significantly reduced panic disorder symptoms and severity versus placebo at endpoint (p </=.05), as measured by the Panic and Agoraphobia Scale total score, the Clinical Global Impressions scale, the Patient Global Evaluation, and the Quality of Life Enjoyment and Satisfaction Questionnaire. Treatment with escitalopram was safe and well tolerated, with a similar incidence of the most common adverse events for the escitalopram and placebo groups. The rate of discontinuation for adverse events was 6.3% for escitalopram, 8.4% for citalopram, and 7.6% for placebo. Escitalopram is efficacious, safe, and well tolerated in the treatment of panic disorder.


Identifying potential differences in cause-of-death coding practices across Russian regions.
Reliable and comparable data on causes of death are crucial for public health analysis, but the usefulness of these data can be markedly diminished when the approach to coding is not standardized across territories and/or over time. Because the Russian system of producing information on causes of death is highly decentralized, there may be discrepancies in the coding practices employed across the country. In this study, we evaluate the uniformity of cause-of-death coding practices across Russian regions using an indirect method. Based on 2002-2012 mortality data, we estimate the prevalence of the major causes of death (70 causes) in the mortality structures of 52 Russian regions. For each region-cause combination we measured the degree to which the share of a certain cause in the mortality structure of a certain region deviates from the respective inter-regional average share. We use heat map visualization and a regression model to determine whether there is regularity in the causes and the regions that is more likely to deviate from the average level across all regions. In addition to analyzing the comparability of cause-specific mortality structures in a spatial dimension, we examine the regional cause-of-death time series to identify the causes with temporal trends that vary greatly across regions. A high level of consistency was found both across regions and over time for transport accidents, most of the neoplasms, congenital malformations, and perinatal conditions. However, a high degree of inconsistency was found for mental and behavioral disorders, diseases of the nervous system, endocrine disorders, ill-defined causes of death, and certain cardiovascular diseases. This finding suggests that the coding practices for these causes of death are not uniform across regions. The level of consistency improves when causes of death can be grouped into broader diagnostic categories. This systematic analysis allows us to present a broader picture of the quality of cause-of-death coding at the regional level. For some causes of death, there is a high degree of variance across regions in the likelihood that these causes will be chosen as the underlying causes. In addition, for some causes of death the mortality statistics reflect the coding practices, rather than the real epidemiological situation.


Interrater reliability: the kappa statistic.
The kappa statistic is frequently used to test interrater reliability. The importance of rater reliability lies in the fact that it represents the extent to which the data collected in the study are correct representations of the variables measured. Measurement of the extent to which data collectors (raters) assign the same score to the same variable is called interrater reliability. While there have been a variety of methods to measure interrater reliability, traditionally it was measured as percent agreement, calculated as the number of agreement scores divided by the total number of scores. In 1960, Jacob Cohen critiqued use of percent agreement due to its inability to account for chance agreement. He introduced the Cohen's kappa, developed to account for the possibility that raters actually guess on at least some variables due to uncertainty. Like most correlation statistics, the kappa can range from -1 to +1. While the kappa is one of the most commonly used statistics to test interrater reliability, it has limitations. Judgments about what level of kappa should be acceptable for health research are questioned. Cohen's suggested interpretation may be too lenient for health related studies because it implies that a score as low as 0.41 might be acceptable. Kappa and percent agreement are compared, and levels for both kappa and percent agreement that should be demanded in healthcare studies are suggested.


Words, grammar, and number concepts: Evidence from development and aphasia.
Bloom's book underscores the importance of specifying the role of words and grammar in cognition. We propose that the cognitive power of language lies in the lexicon rather than grammar. We suggest ways in which studies involving children and patients with aphasia can provide insights into the basis of abstract cognition in the domain of number and mathematics.


Inhaled insulin: extending the horizons of inhalation therapy.
Targeted glycemic control in patients with type 1 and type 2 diabetes is grossly inadequate, despite data demonstrating reduced microvascular and macrovascular diabetic complications with intensive treatment. A significant proportion of individuals with poorly-controlled type 2 diabetes are resistant to initiating treatment with insulin. Several decades-long search for alternative forms of insulin delivery has finally resulted in the U.S. Food and Drug Administration's approval of the first inhaled insulin delivery system, Exubera. Inhaled insulin provides hope that minimizing barriers to initiating insulin therapy will improve the overall glycemic control in both type 1 and type 2 diabetic patients. Inhaled insulin is a powder formulation that has been approved for pre-meal administration in both type 1 and type 2 diabetic patients. The delivery system for Exubera employs compressed air for producing an aerosol, which is then inhaled by the patient. Insulin is transported across the alveolar-epithelial barrier into the blood and has onset of glucose-lowering activity within 10-20 min of inhalation. The duration of action of inhaled insulin is similar to that of subcutaneous regular insulin. Although there are some limitations to the use of inhaled insulin, the potential to improve adherence and thereby achieve target glycohemoglobin levels (< or = 6.5-7.0%) in poorly controlled diabetic patients outweigh its disadvantages.


Early development of broadly neutralizing antibodies in HIV-1-infected infants.
Eliciting protective neutralizing antibodies (NAbs) against HIV-1 is daunting because of the extensive genetic and antigenic diversity of HIV-1. Moreover, broad and potent responses are uncommon even during persistent infection, with only a subset of adults developing broadly neutralizing antibodies (bNAbs) that recognize viral variants from different HIV-1 clades. It is not known whether bNAbs can also arise in HIV-1-infected infants, who typically progress to disease faster than adults, presumably in part due to an immature immune system. Here, we show that bNAbs develop at least as commonly in infants as in adults. Cross-clade NAb responses were detected in 20/28 infected infants, in some cases within 1 year of infection. Among infants with breadth of responses within the top quartile, neutralization of tier 2 or 3 variants from multiple clades was detected at 20 months after infection. These findings suggest that, even in early life, there is sufficient B cell functionality to mount bNAbs against HIV-1. Additionally, the relatively early appearance of bNAbs in infants may provide a unique setting for understanding the pathways of B cell maturation leading to bNAbs.


Negotiations of Blame and Care among HIV-positive Mothers and Daughters in South Africa's Eastern Cape.
Research delineates two epidemiological categories among HIV-positive adolescents: those who contract the virus sexually and those who inherit it as infants. In this article, we are interested in how tacit inferences about adolescents' mode of infection contribute to their experiences of HIV-related blame, and their ability to achieve care, in their intimate, everyday settings. The analysis arises from ethnographic research with 23 HIV-positive adolescents living in South Africa's Eastern Cape. From these, we draw particularly on the narratives of four HIV-positive teenage girls and their HIV-positive mothers. The article explores the social stakes entailed in ascriptions of adolescents' mode of infection, particularly in terms of how blame was allocated between mothers and daughters. It further considers how these families have sought to negotiate repudiation and thereby sustain intergenerational care. The article furthers limited research on the life projects and dilemmas of this HIV-positive adolescent cohort.


Characterization and phospholipase D mediation of the angiotensin II priming response in adrenal glomerulosa cells.
Bovine adrenal glomerulosa cells are primed by an initial treatment with angiotensin II (AngII) to respond with enhanced secretion to a second exposure to AngII or agents that increase calcium influx. We hypothesized that the mechanism of priming involves a persistent increase in diacylglycerol (DAG) generated via sustained activity of phospholipase D (PLD). In this report, we sought to define the time frame of this priming response as well as determine its mechanism using assays of aldosterone secretion, PLD activation, and radiolabeled diacylglycerol levels. We found that in primary cultures priming was observed for up to 50 min after AngII washout, suggesting that the priming window is protracted in these cultures relative to freshly isolated cells. The phorbol ester, phorbol 12,13-dibutyrate (PDBu), was used to investigate the role of sustained PLD activation in the persistent DAG and priming responses. PDBu was able to both prime glomerulosa cells to respond with enhanced secretion to AngII and elicit a persistent increase in DAG after PDBu washout. This persistent increase in DAG levels with an initial exposure to PDBu or AngII was not the result of maintained PLD activity after agent removal because PLD activation returned to basal levels by 30 min after washout. Finally, inhibition of PLD signaling during the initial AngII treatment inhibited the subsequent response to AngII or another agent that increases calcium influx. Thus, our results suggest that persistent DAG resulting from PLD signaling mediates the priming response to AngII or PDBu.


Idiopathic retinal vasculitis, arteriolar macroaneurysms and neuroretinitis: clinical course and treatment.
The purpose of the study is to describe the clinical course and treatment of idiopathic retinitis, vasculitis, aneurysms and neuroretinitis. The study utilized non-randomized, retrospective and interventional case series. The eight eyes of six patients were analysed. Testing included wide fluorescein angiography, indocyanine green angiography and systemic evaluation. Treatment involved observation, panretinal laser photocoagulation (PRP) for peripheral retinal ischemia, grid laser for macular oedema and focal laser on the macroaneurysms. The main outcome measures were initial visual acuity (VA), initial stage at diagnosis, clinical course, surgical intervention, final VA, final stage and complications of disease. Five out of eight eyes with retinal ischemia in more than two quadrants that were treated with PRP and grid laser for macular oedema maintained excellent VA and demonstrated no progression of retinal ischemia during follow-up. The two eyes which exhibited retinal ischemia in less than two quadrants and macular oedema were treated with grid laser and focal laser on the macroaneurysms, but did not undergo PRP. VA improved by two lines of the Snellen chart, and there was no progression of retinal ischemia during the 3 and 4 years of follow-up. One eye with neither retinal ischemia nor macular oedema was not treated, and the clinical picture remained stable during the follow-up. Early PRP may be considered in the presence of angiographic evidence of peripheral retinal non-perfusion. However, treatment could be withheld until the patient develops retinal ischemia in more than two quadrants.


The role of frictional contact of constituent blocks on the stability of masonry domes.
The observation of old construction works confirms that masonry domes can withstand tensile hoop stresses, at least up to a certain level. Here, such tensile resistance, rather than a priori assumed as a property of the bulk material, is attributed to the contact forces that are developed at the interfaces between interlocked blocks under normal pressure, specified by Coulomb's friction law. According to this rationale, the aspect ratio of the blocks, as well as the bond pattern, becomes of fundamental importance. To investigate the complex assembly of blocks, supposed rigid, we present a non-smooth contact dynamic analysis, implemented in a custom software based on the Project Chrono C++ framework and complemented with parametric-design interfaces for pre- and post-processing complex geometries. Through this advanced tool, we investigate the role of frictional forces resisting hoop stresses in the stability of domes, either circular or oval, under static and dynamic loading, focusing, in particular, on the structural role played by the underlying drum and the surmounting tiburium.


Adlay Seed (Coix lacryma-jobi L. var. Ma-yuen Stapf.) Ethanolic Extract Fractions and Subfractions Induce Cell Cycle Arrest and Apoptosis in Human Breast and Cervical Cancer Cell Lines.
The antitumor effects of Coix lacryma-jobi L. var. ma-yuen Stapf. (adlay seed) ethanolic extract have been increasingly shown. This study aimed to investigate the beneficial effects of both the fractions and subfractions of adlay seed ethanolic extract on the human breast (MCF-7) and cervical (HeLa) cancer cell lines, as well as exploring their possible mechanisms of action. The ethanolic extracts were obtained from different parts of adlay seed, including AHE (adlay hull extract), ATE (adlay testa extract), ABE (adlay bran extract) and PAE (polished adlay extract). The results of a 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl- tetrazolium bromide (MTT) assay showed that AHE-Ea and ATE-Ea showed significant growth inhibitory effects in a dose-dependent manner. The results also showed that the AHE-Ea-K, AHE-Ea-L, ATE-Ea-E and ATE-Ea-F subfractions inhibited cell proliferation, induced cell cycle arrest in the G0/G1 phase and decreased CDK4/Cyclin D1 protein expression. Finally, the extract activated caspase-3 activity and PARP protein expression, which induced MCF-7 and HeLa cell apoptosis. We then used liquid chromatography-mass spectrometry (LC/MS) to identify the potential active components., Quercetin showed an anticancer capacity. In conclusion, the AHE-Ea-K, AHE-Ea-L, ATE-Ea-E and ATE-Ea-F subfractions showed antitumor effects through the inhibition of MCF-7 and HeLa cell line viability, as well as inducing apoptosis and cell cycle arrest.


Comparing methods suitable for monitoring marine mammals in low visibility conditions during seismic surveys.
Loud sound emitted during offshore industrial activities can impact marine mammals. Regulations typically prescribe marine mammal monitoring before and/or during these activities to implement mitigation measures that minimise potential acoustic impacts. Using seismic surveys under low visibility conditions as a case study, we review which monitoring methods are suitable and compare their relative strengths and weaknesses. Passive acoustic monitoring has been implemented as either a complementary or alternative method to visual monitoring in low visibility conditions. Other methods such as RADAR, active sonar and thermal infrared have also been tested, but are rarely recommended by regulatory bodies. The efficiency of the monitoring method(s) will depend on the animal behaviour and environmental conditions, however, using a combination of complementary systems generally improves the overall detection performance. We recommend that the performance of monitoring systems, over a range of conditions, is explored in a modelling framework for a variety of species.


cTBS delivered to the left somatosensory cortex changes its functional connectivity during rest.
The primary somatosensory cortex (SI) plays a critical role in somatosensation as well as in action performance and social cognition. Although the SI has been a major target of experimental and clinical research using non-invasive transcranial magnetic stimulation (TMS), to date information on the effect of TMS over the SI on its resting-state functional connectivity is very scant. Here, we explored whether continuous theta burst stimulation (cTBS), a repetitive TMS protocol, administered over the SI can change the functional connectivity of the brain at rest, as measured using resting-state functional magnetic resonance imaging (rs-fMRI). In a randomized order on two different days we administered active TMS or sham TMS over the left SI. TMS was delivered off-line before scanning by means of cTBS. The target area was selected previously and individually for each subject as the part of the SI activated both when the participant executes and observes actions. Three analytical approaches, both theory driven (partial correlations and seed based whole brain regression) and more data driven (Independent Component Analysis), indicated a reduction in functional connectivity between the stimulated part of the SI and several brain regions functionally associated with the SI including the dorsal premotor cortex, the cerebellum, basal ganglia, and anterior cingulate cortex. These findings highlight the impact of cTBS delivered over the SI on its functional connectivity at rest. Our data may have implications for experimental and therapeutic applications of cTBS over the SI.


The Fc receptor on thymus-derived lymphocytes. IV. Inhibition of binding of antigen-antibody complexes to Fc receptor-positive T cells by anti-Ia sera.
Treatment of splenic T lymphocytes with anti-Ia antiserum inhibits the binding of antigen-antibody (AgAb) complexes to the majority (less than 50%) of Fc receptor-positive (FcR+) T cells. A similar inhibition was observed with anti-H-2D and anti-H-2K sera but not with anti-Thy 1.2. Despite the presence of Ia determinants on peripheral T cells, as established by the inhibition of AgAb binding, Ia could not be detected on peripheral T cells by immunofluorescence assays. Data obtained with the AgAb-binding inhibition assay indicate that determinants controlled by loci mapping in the I-A and I-C, S, or G regions are present on the FcR+ T cells. Evidence is presented that subpopulations of T cells within the FcR+ T-cell population may be distinguishable on the basis of which I-region-controlled determinant is expressed. The data are discussed in terms of phenotypic and functional heterogeneity of T lymphocytes.


Anoctamins are a family of Ca2+-activated Cl- channels.
Anoctamin 1 (Ano1; TMEM16A) and anoctamin 2 (Ano2; TMEM16B) are novel Cl(-) channels transiently activated by an increase in intracellular Ca(2+). These channels are essential for epithelial Cl(-) secretion, smooth muscle peristalsis and olfactory signal transduction. They are central to inherited diseases and cancer and can act as heat sensors. Surprisingly, another member of this protein family, Ano6, operates as a Ca(2+)-activated phospholipid scramblase, and others were reported as intracellular proteins. It is therefore unclear whether anoctamins constitute a family of Ca(2+)-activated Cl(-) channels, or are proteins with heterogeneous functions. Using whole-cell patch clamping we demonstrate that Ano4-10 are all able to produce transient Ca(2+)-activated Cl(-) currents when expressed in HEK293 cells. Although some anoctamins (Ano1, 2, 4, 6, 7) were found to be well expressed in the plasma membrane, others (Ano8, 9, 10) show rather poor membrane expression and were mostly retained in the cytosol. The transient nature of the Cl(-) currents was demonstrated to be independent of intracellular Ca(2+) levels. We show that inactivation of Ano1 currents occurs in the continuous presence of elevated Ca(2+) concentrations, possibly by calmodulin-dependent kinase. The present results demonstrate that anoctamins are a family of Ca(2+)-activated Cl(-) channels, which also induce permeability for cations. They may operate as Cl(-) channels located in the plasma membrane or in intracellular compartments. These results increase our understanding of the physiological significance of anoctamins and their role in disease.


Dose-Dependent Associations of Dietary Glycemic Index, Glycemic Load, and Fiber With 3-Year Weight Loss Maintenance and Glycemic Status in a High-Risk Population: A Secondary Analysis of the Diabetes Prevention Study PREVIEW.
To examine longitudinal and dose-dependent associations of dietary glycemic index (GI), glycemic load (GL), and fiber with body weight and glycemic status during 3-year weight loss maintenance (WLM) in adults at high risk of type 2 diabetes. In this secondary analysis we used pooled data from the PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World (PREVIEW) randomized controlled trial, which was designed to test the effects of four diet and physical activity interventions. A total of 1,279 participants with overweight or obesity (age 25-70 years and BMI ≥25 kg ⋅ m-2) and prediabetes at baseline were included. We used multiadjusted linear mixed models with repeated measurements to assess longitudinal and dose-dependent associations by merging the participants into one group and dividing them into GI, GL, and fiber tertiles, respectively. In the available-case analysis, each 10-unit increment in GI was associated with a greater regain of weight (0.46 kg ⋅ year-1; 95% CI 0.23, 0.68; P < 0.001) and increase in HbA1c. Each 20-unit increment in GL was associated with a greater regain of weight (0.49 kg ⋅ year-1; 0.24, 0.75; P < 0.001) and increase in HbA1c. The associations of GI and GL with HbA1c were independent of weight change. Compared with those in the lowest tertiles, participants in the highest GI and GL tertiles had significantly greater weight regain and increases in HbA1c. Fiber was inversely associated with increases in waist circumference, but the associations with weight regain and glycemic status did not remain robust in different analyses. Dietary GI and GL were positively associated with weight regain and deteriorating glycemic status. Stronger evidence on the role of fiber is needed.


Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs.
Bisphosphonate doses used in cancer treatment are substantially higher than those used for osteoporosis. Little is known about the effects of these high doses on tissue-level remodeling suppression. The aim of this study was to assess the effects of cancer dosing regimens of zoledronic acid on tissue-level bone remodeling at different skeletal sites. Skeletally mature female beagle dogs were treated with monthly intravenous infusions of vehicle (VEH, saline) or zoledronic acid (ZOL, 0.067 mg/kg); an additional group of animals was treated daily with oral alendronate (ALN, 0.2 mg/kg/day). Doses of ZOL and ALN were, on a milligram per kilogram basis, consistent with those used for cancer and osteoporosis, respectively. Following either 3 or 6 months of treatment, animals were euthanized, and mandible, rib, and tibia were processed for dynamic bone histology. There was no evidence of oral lesions or bone matrix necrosis in the mandibles of any animals. After 3 months, the rate of intracortical bone remodeling in the mandible was significantly suppressed with ZOL (-95%) compared with VEH; by 6 months, ZOL had produced nearly complete suppression (-99%) compared with VEH. ZOL also significantly suppressed remodeling in the rib cortex at both 3 (-83%) and 6 (-85%) months compared with VEH; tibia cortex bone formation rate was nonsignificantly lower with ZOL treatment (-68% to -75%). Remodeling suppression in ZOL-treated animals was significantly greater than in ALN-treated animals at both the mandible and the rib; ALN and VEH were not different for any of the assessed parameters at any of the sites. Compared across skeletal sites, the absolute level of remodeling suppression with ZOL treatment was significantly greater at sites with higher remodeling, whereas the percent reduction was similar among the sites. These results document nearly complete intracortical remodeling suppression resulting from monthly intravenous zoledronic acid dosing, with changes being most dramatic at the mandible.


A side-by-side comparison of three allergen sampling methods in settled house dust.
Understanding allergen exposure and potential relationships with asthma requires allergen sampling methods, but methods have yet to be standardized. We compared allergen measurements from dust collected from 200 households with asthmatics and conducted a side-by-side vacuum sampling of settled dust in each home's kitchen, living room and subject's bedroom by three methods (EMM, HVS4 and AIHA). Each sample was analyzed for dust mite, cockroach, mouse, rat, cat and dog allergens. The number of samples with sufficient dust mass for allergen analysis was significantly higher for Eureka Mighty Mite (EMM) and high volume small surface sampler (HVS4) compared with American Industrial Hygiene Association (AIHA) in all rooms and surfaces tested (all P<0.05). The allergen concentration (weight of allergen divided by total weight of dust sampled) measured by the EMM and HVS4 methods was higher than that measured by the AIHA. Allergen loadings (weight of allergen divided by surface area sampled) were significantly higher for HVS4 than for AIHA and EMM. Cockroach and rat allergens were rarely detected via any method. The EMM method is most likely to collect sufficient dust from surfaces in the home and is relatively practical and easy. The AIHA and HVS4 methods suffer from insufficient dust collection and/or difficulty in use.


Neurofilament light chain as a biomarker in neurological disorders.
In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.


When Hearing Does Not Mean Understanding: On the Neural Processing of Syntactically Complex Sentences by Listeners With Hearing Loss.
Purpose Adults with mild-to-moderate age-related hearing loss typically exhibit issues with speech understanding, but their processing of syntactically complex sentences is not well understood. We test the hypothesis that listeners with hearing loss' difficulties with comprehension and processing of syntactically complex sentences are due to the processing of degraded input interfering with the successful processing of complex sentences. Method We performed a neuroimaging study with a sentence comprehension task, varying sentence complexity (through subject-object order and verb-arguments order) and cognitive demands (presence or absence of a secondary task) within subjects. Groups of older subjects with hearing loss (n = 20) and age-matched normal-hearing controls (n = 20) were tested. Results The comprehension data show effects of syntactic complexity and hearing ability, with normal-hearing controls outperforming listeners with hearing loss, seemingly more so on syntactically complex sentences. The secondary task did not influence off-line comprehension. The imaging data show effects of group, sentence complexity, and task, with listeners with hearing loss showing decreased activation in typical speech processing areas, such as the inferior frontal gyrus and superior temporal gyrus. No interactions between group, sentence complexity, and task were found in the neuroimaging data. Conclusions The results suggest that listeners with hearing loss process speech differently from their normal-hearing peers, possibly due to the increased demands of processing degraded auditory input. Increased cognitive demands by means of a secondary visual shape processing task influence neural sentence processing, but no evidence was found that it does so in a different way for listeners with hearing loss and normal-hearing listeners.


Antioxidant SkQ1 Alleviates Signs of Alzheimer's Disease-like Pathology in Old OXYS Rats by Reversing Mitochondrial Deterioration.
Mitochondrial dysfunction is called the missing link between brain aging and Alzheimer's disease (AD), the most common type of age-related dementia worldwide. Among the most advanced and promising of approaches to prevention or slowing of AD are therapeutic strategies targeting mitochondria. Mitochondria-targeted antioxidant SkQ1 can suppress the development of AD signs, but its therapeutic potential in AD at clinical stages is currently unknown. Using OXYS rats that simulate key characteristics of sporadic AD, we evaluated effects of SkQ1 treatment from the age of 19 to 24 months on the locomotor and exploratory activities, signs of neurodegeneration detectable by magnetic resonance imaging (MRI), amyloid-β (Aβ) protein levels in the hippocampus and serum, and structure of the mitochondrial apparatus in hippocampal neurons. Treatment with SkQ1 increased behavioral activity in OXYS and Wistar (control) rats. According to MRI, SkQ1 decreased the percentage of animals with demyelination only among Wistar rats. At the same time, the antioxidant reduced hippocampal Аβ1-40 and Аβ1-42 protein levels in both rat strains and did not affect serum Аβ levels. The number of mitochondria was significantly lower in OXYS rats; SkQ1 had no effect on this parameter but significantly reduced the destructive changes in mitochondria of both rat strains. As a result, in OXYS rats, the proportion of severely damaged mitochondria decreased, whereas in Wistar rats, the proportion of intact mitochondria increased. According to our past and present results, the repair of the mitochondrial apparatus by SkQ1 is a promising strategy against AD.


The epidemiology of drowning worldwide.
The purpose of this analysis was to quantify the magnitude of death and disability from drowning and near-drowning worldwide and to provide epidemiological data on which to base prevention efforts. All data are from the Global Burden of Disease 2000 (Version 1) estimates in which deaths and disabilities are based on the WHO International Classification of Diseases. Extrapolations were made by age, sex, and WHO region. The six WHO regions of the world were further divided into high-income, and low- and middle-income based on the 1998 World Development indicators. According to the GBD 2000 data, an estimated 449,000 people drowned worldwide (7.4 per 100,000 population) and a further 1.3 million Disability Adjusted Life Years (DALYs) were lost as a result of premature death or disability from drowning. 97% of drownings occurred in low- and middle-income countries. Although 38% of drownings occurred in the Western Pacific Region, Africa had the highest drowning mortality rate (13.1 per 100,000 population). Males had higher drowning mortality rates than females for all ages and in all regions. Children under the age of 5 years had the highest drowning mortality rate for both sexes in all of the WHO regions except for Africa, where children aged 5 to 14 years had the highest mortality rate. Worldwide, for children under the age of 15 years, drowning accounted for a higher mortality rate than any other cause of injury. Drowning is a significant problem worldwide particularly for children under the age of 15 years. Low- and middle-income countries have the highest rates of drowning and account for more than 90% of such fatalities. Primary prevention efforts should thus be focused on these countries where many children who cannot swim drown in large bodies of water.


LARD: a new lymphoid-specific death domain containing receptor regulated by alternative pre-mRNA splicing.
Fas and TNF-R1 are cysteine-rich cell surface receptors related to the low-affinity nerve growth factor receptor family. Engagement of these receptors by their respective ligands, FasL and tumor necrosis factor, leads to apoptosis that is signaled through a conserved intracellular portion of the receptor termed the "death domain." We have cloned a new member of this family, lymphocyte-associated receptor of death (LARD), which leads to spontaneous apoptosis when expressed in 293T cells. The expression of LARD is more tightly regulated than that of either Fas or TNF-R1 as it is found predominantly on lymphocytes (T and B cells) but not on macrophages or a number of transformed lymphocyte cell lines. Alternative pre-mRNA splicing generates at least 11 distinct isoforms of LARD. The full-length isoform, LARD-1, extends to include the transmembrane and death domains, whereas the other isoforms encode potentially secreted molecules. Naive B and T cells express very little LARD-1 but express combinations of the other isoforms. Upon T cell activation, a programmed change in alternative splicing occurs so that the full-length, membrane-bound LARD-1 predominates. This may have implications for the control of lymphocyte proliferation following activation.


Identifying influential and susceptible members of social networks.
Identifying social influence in networks is critical to understanding how behaviors spread. We present a method that uses in vivo randomized experimentation to identify influence and susceptibility in networks while avoiding the biases inherent in traditional estimates of social contagion. Estimation in a representative sample of 1.3 million Facebook users showed that younger users are more susceptible to influence than older users, men are more influential than women, women influence men more than they influence other women, and married individuals are the least susceptible to influence in the decision to adopt the product offered. Analysis of influence and susceptibility together with network structure revealed that influential individuals are less susceptible to influence than noninfluential individuals and that they cluster in the network while susceptible individuals do not, which suggests that influential people with influential friends may be instrumental in the spread of this product in the network.


Management of a rifampicin-resistant meningococcal infection in a teenager.
We report a secondary case of rifampicin-resistant meningococcal disease and our experience in managing contact cases. Rifampicin resistance resulting from rpoB gene mutations is still uncommon enough that changing the current recommendations for chemoprophylaxis is unwarranted. However, ensuring limited but appropriate chemoprophylaxis may prevent the development of antimicrobial resistance. Thus, the definition of contact cases should be strictly respected. In the case of culture-positive Neisseria meningitidis, in vitro susceptibility testing to rifampicin must be systematically performed in order to detect rifampicin-resistant strains and, thus, institute appropriate prophylaxis in order to prevent secondary transmission.


The effect of transforming growth factor beta on the plasminogen activator activity of normal human osteoblast-like cells and a human osteosarcoma cell line MG-63.
Transforming growth beta (TGF-beta) has been proposed to have a role in bone remodeling by affecting the differentiation and activity of osteoblasts and osteoclasts and by inhibiting the production of proteinases, such as plasminogen activators (PAs). Studies on PAs have largely been based on data from nonhuman and fetal cell lines, however. The purpose of this study was to investigate the effect of TGF-beta on the PA activity of normal human osteoblast-like cells and to compare this with its action on the human osteosarcoma cell line MG-63. The action of interleukin-1 beta (IL-1 beta) was also assessed because it has been shown to increase PA activity in other connective tissue cell types. Normal osteoblast-like cells had low to undetectable basal urokinase (uPA) and tissue plasminogen activator (tPA) activity, which was significantly stimulated by TGF-beta 1. This action was shown to be dependent on transcription and new protein synthesis. TGF-beta 2 had a similar action. IL-1 beta did not stimulate PA activity. In contrast, the MG-63 cell line had high basal tPA and uPA activities. TGF-beta 1 decreased basal PA activity, the effect being most marked for uPA activity. IL-1 beta stimulated uPA and tPA activity. TGF-beta 1 inhibited IL-1 beta-stimulated uPA activity, but the effect on tPA was more variable. This study has shown that TGF-beta has opposite effects on the PA activity of the two osteoblast-like cell types studied. Care must therefore be used before extrapolating data from one cell type to another.(ABSTRACT TRUNCATED AT 250 WORDS)


J-shaped relationship between habitual coffee consumption and 10-year (2002-2012) cardiovascular disease incidence: the ATTICA study.
The purpose of this work was to evaluate the association between coffee consumption and 10-year cardiovascular disease (CVD) incidence in the ATTICA study, and whether this is modified by the presence or absence of metabolic syndrome (MetS) at baseline. During 2001-2002, 3042 healthy adults (1514 men and 1528 women) living in the greater area of Athens were voluntarily recruited to the ATTICA study. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Coffee consumption was assessed by a validated food-frequency questionnaire at baseline (abstention, low, moderate, heavy). Incidence of fatal or non-fatal CVD event was recorded using WHO-ICD-10 criteria and MetS was defined by the National Cholesterol Education Program Adult Treatment panel III (revised) criteria. Overall, after controlling for potential CVD risk factors, the multivariate analysis revealed a J-shaped association between daily coffee drinking and the risk for a first CVD event in a 10-year period. Particularly, the odds ratio for low (<150 ml/day), moderate (150-250 ml/day) and heavy coffee consumption (>250 ml/day), compared to abstention, were 0.44 (95% CI 0.29-0.68), 0.49 (95% CI 0.27-0.92) and 2.48 (95% CI 1.56-1.93), respectively. This inverse association was also verified among participants without MetS at baseline, but not among participants with the MetS. These data support the protective effect of drinking moderate quantities of coffee (equivalent to approximately 1-2 cups daily) against CVD incidents. This protective effect was only significant for participants without MetS at baseline.


Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of neuroblastoma cells.
Nuclear lamins support the nuclear envelope and provide anchorage sites for chromatin. They are involved in DNA synthesis, transcription, and replication. It has previously been reported that the lack of Lamin A/C expression in lymphoma and leukaemia is due to CpG island promoter hypermethylation. Here, we provide evidence that Lamin A/C is silenced via this mechanism in a subset of neuroblastoma cells. Moreover, Lamin A/C expression can be restored with a demethylating agent. Importantly, Lamin A/C reintroduction reduced cell growth kinetics and impaired migration, invasion, and anchorage-independent cell growth. Cytoskeletal restructuring was also induced. In addition, the introduction of lamin Δ50, known as Progerin, caused senescence in these neuroblastoma cells. These cells were stiffer and developed a cytoskeletal structure that differed from that observed upon Lamin A/C introduction. Of relevance, short hairpin RNA Lamin A/C depletion in unmethylated neuroblastoma cells enhanced the aforementioned tumour properties. A cytoskeletal structure similar to that observed in methylated cells was induced. Furthermore, atomic force microscopy revealed that Lamin A/C knockdown decreased cellular stiffness in the lamellar region. Finally, the bioinformatic analysis of a set of methylation arrays of neuroblastoma primary tumours showed that a group of patients (around 3%) gives a methylation signal in some of the CpG sites located within the Lamin A/C promoter region analysed by bisulphite sequencing PCR. These findings highlight the importance of Lamin A/C epigenetic inactivation for a subset of neuroblastomas, leading to enhanced tumour properties and cytoskeletal changes. Additionally, these findings may have treatment implications because tumour cells lacking Lamin A/C exhibit more aggressive behaviour.


Designing and implementing interventions to change clinicians' practice in the management of uncomplicated malaria: lessons from Cameroon.
Effective case management of uncomplicated malaria is a fundamental pillar of malaria control. Little is known about the various steps in designing interventions to accompany the roll out of rapid diagnostic tests (RDTs) and artemisinin-based combination therapy (ACT). This study documents the process of designing and implementing interventions to change clinicians' practice in the management of uncomplicated malaria. A literature review combined with formative quantitative and qualitative research were carried out to determine patterns of malaria diagnosis and treatment and to understand how malaria and its treatment are enacted by clinicians. These findings were used, alongside a comprehensive review of previous interventions, to identify possible strategies for changing the behaviour of clinicians when diagnosing and treating uncomplicated malaria. These strategies were discussed with ministry of health representatives and other stakeholders. Two intervention packages - a basic and an enhanced training were outlined, together with logic model to show how each was hypothesized to increase testing for malaria, improve adherence to test results and increase appropriate use of ACT. The basic training targeted clinicians' knowledge of malaria diagnosis, rapid diagnostic testing and malaria treatment. The enhanced training included additional modules on adapting to change, professionalism and communicating effectively. Modules were delivered using small-group work, card games, drama and role play. Interventions were piloted, adapted and trainers were trained before final implementation. Ninety-six clinicians from 37 health facilities in Bamenda and Yaounde sites attended either 1-day basic or 3-day enhanced training. The trained clinicians then trained 632 of their peers at their health facilities. Evaluation of the training revealed that 68% of participants receiving the basic and 92% of those receiving the enhanced training strongly agreed that it is not appropriate to prescribe anti-malarials to a patient if they have a negative RDT result. Formative research was an important first step, and it was valuable to engage stakeholders early in the process. A logic model and literature reviews were useful to identify key elements and mechanisms for behaviour change intervention. An iterative process with feedback loops allowed appropriate development and implementation of the intervention. ClinicalTrials.gov: NCT01350752.


Formation mechanisms of trichloromethyl-containing compounds in the terrestrial environment: a critical review.
Natural trichloromethyl compounds present in the terrestrial environment are important contributors to chlorine in the lower atmosphere and may be also a cause for concern when high concentrations are detected in soils and groundwater. During the last decade our knowledge of the mechanisms involved in the formation of these compounds has grown. This critical review summarizes our current understanding and uncertainties on the mechanisms leading to the formation of natural trichloromethyl compounds. The objective of the review is to gather information regarding the natural processes that lead to the formation of trichloromethyl compounds and then to compare these mechanisms with the much more comprehensive literature on the reactions occurring during chemical chlorination of organic material. It turns out that the reaction mechanisms during chemical chlorination are likely to be similar to those occurring naturally and that significant knowledge may therefore be transferred between the scientific disciplines of chemical chlorination and natural organohalogens. There is however still a need for additional research before we understand fully the mechanisms occurring during the formation of natural trichloromethyl compounds and open questions and future research needs are identified in the last part of the review.


The relevance of structural features of cellulose and its interactions to dissolution, regeneration, gelation and plasticization phenomena.
Cellulose is the most abundant polymer and a very important renewable resource. Since cellulose cannot be shaped by melting, a major route for its use for novel materials, new chemical compounds and renewable energy must go via the solution state. Investigations during several decades have led to the identification of several solvents of notably different character. The mechanisms of dissolution in terms of intermolecular interactions have been discussed from early work but, even on fundamental aspects, conflicting and opposite views appear. In view of this, strategies for developing new solvent systems for various applications have remained obscure. There is for example a strong need for using forest products for higher value materials and for environmental and cost reasons to use water-based solvents. Several new water-based solvents have been developed recently but there is no consensus regarding the underlying mechanisms. Here we wish to address the most important mechanisms described in the literature and confront them with experimental observations. A broadened view is helpful for improving the current picture and thus cellulose derivatives and phenomena such as fiber dissolution, swelling, regeneration, plasticization and dispersion are considered. In addition to the matter of hydrogen bonding versus hydrophobic interactions, the role of ionization as well as some applications of new knowledge gained are highlighted.


Reduced social preferences in autism: evidence from charitable donations.
People with autism have abnormal preferences, ranging from an apparent lack of preference for social stimuli to unusually strong preferences for restricted sets of highly idiosyncratic stimuli. Yet the profile of preferences across social and nonsocial domains has not been mapped out in detail, and the processes responsible remain poorly understood. To assess preferences across a range of stimuli, we measured real monetary donations to 50 charities spanning categories pertaining to people, mental health, animals, or the environment. We compared the donations made by 16 high-functioning adults with autism to those made by neurotypical controls matched on age, gender and education. We additionally collected ratings of how people evaluated the different charities. Compared with controls, high-functioning adults with autism donated less overall and also showed a significantly disproportionate reduction in donations to people charities compared with donations to the other charities. Furthermore, whereas controls discriminated strongly between different people charities, choosing to donate a lot of money to some and very little to others, much less discrimination was seen in the autism group. Ratings that probed how participants constructed their preferences did not differ between groups, except for a difference in the perceived impact of pictures and text information about people charities. Strikingly, there were some charities related to mental health, and autism in particular, to which the autism group donated considerably more than did the controls. People with autism were found to have reduced preference and sensitivity towards charities benefiting other people. The findings provide evidence for a domain-specific impairment in social cognition in autism spectrum disorder, and in particular in linking otherwise intact social knowledge to the construction of value signals on which preferences regarding other people are based.


Quantitative proteome analysis of human plasma following in vivo lipopolysaccharide administration using 16O/18O labeling and the accurate mass and time tag approach.
Identification of novel diagnostic or therapeutic biomarkers from human blood plasma would benefit significantly from quantitative measurements of the proteome constituents over a range of physiological conditions. Herein we describe an initial demonstration of proteome-wide quantitative analysis of human plasma. The approach utilizes postdigestion trypsin-catalyzed 16O/18O peptide labeling, two-dimensional LC-FTICR mass spectrometry, and the accurate mass and time (AMT) tag strategy to identify and quantify peptides/proteins from complex samples. A peptide accurate mass and LC elution time AMT tag data base was initially generated using MS/MS following extensive multidimensional LC separations to provide the basis for subsequent peptide identifications. The AMT tag data base contains >8,000 putative identified peptides, providing 938 confident plasma protein identifications. The quantitative approach was applied without depletion of high abundance proteins for comparative analyses of plasma samples from an individual prior to and 9 h after lipopolysaccharide (LPS) administration. Accurate quantification of changes in protein abundance was demonstrated by both 1:1 labeling of control plasma and the comparison between the plasma samples following LPS administration. A total of 429 distinct plasma proteins were quantified from the comparative analyses, and the protein abundances for 25 proteins, including several known inflammatory response mediators, were observed to change significantly following LPS administration.


Effects of Transcutaneous Auricular Vagus Nerve Stimulation on Peripheral and Central Tumor Necrosis Factor Alpha in Rats with Depression-Chronic Somatic Pain Comorbidity.
Depression and pain disorders share a high degree of comorbidity. Inflammatory mechanisms play an important role in the pathogenesis of depression-chronic somatic pain comorbidity. In this study, we investigated the effects of acupuncture on blood and brain regional tumor necrosis factor alpha (TNF-α) in rats with depression and chronic somatic pain comorbidity. Forty Sprague-Dawley rats were randomly divided into the following 4 groups with 10 each: control, model, model treated with transcutaneous auricular vagus nerve stimulation (taVNS), and model treated with electroacupuncture (EA). Chronic unpredictable mild stress (CUMS) with chronic constriction injury of the sciatic nerve (CCI) was used to produce depression and chronic somatic pain comorbidity in the latter 3 groups. The rats of the taVNS and EA groups received, respectively, taVNS and EA at ST 36 for 28 days. Pain intensity was measured using a mechanical withdrawal threshold and thermal stimulation latency once biweekly. Depressive behavior was examined using a sucrose preference test at baseline and the end of modeling and intervention. The level of plasma TNF-α and the expression of TNF-α in the prefrontal cortex (PFC), hippocampus, amygdala, and hypothalamus were measured. While CUMS plus CCI produced remarkable depression-like behavior and pain disorders, EA and taVNS significantly improved depression and reduced pain intensity. CUMS plus CCI also resulted in a significant increase in plasma TNF-α level and the expression in all brain regions examined compared to the intact controls. Both EA and taVNS interventions, however, suppressed the elevated level of TNF-α. These results suggest that EA and taVNS have antidepressant and analgesic effects. Such effects may be associated with the suppression of TNF-α-related neuroinflammation.


Assessing the Relative Climate Impact of Carbon Utilization for Concrete, Chemical, and Mineral Production.
Estimates show that 6.2 gigatons of carbon dioxide (CO2) can be captured and utilized across three pathways, concrete, chemical, and minerals, by 2050. However, it is difficult to compare the climate benefit across these three carbon capture and utilization (CCU) pathways to determine the most effective use of captured CO2. The life cycle assessment methods to evaluate the climate benefit of CCU chemicals should additionally account for the change in material properties of concrete due to CO2 utilization. Furthermore, with most CO2 utilization technologies being in the early stages of research and development, the uncertainty and variability in process and inventory data present a significant challenge in evaluating the climate benefit. We present a stochastically determined climate return on investment (ROI) metric to rank and prioritize CO2 utilization across 20 concrete, chemical and mineral pathways based on the realized climate benefit. We show that two concrete pathways, which use CO2 during concrete mixing, and two chemical pathways, which produce formic acid through hydrogenation of CO2 and carbon monoxide through dry reforming of methane, generate the greatest climate ROI and are the only CCU pathways with a higher likelihood of generating a climate benefit than a climate burden.


Two-Stage Revision Anterior Cruciate Ligament Reconstruction.
The number of primary anterior cruciate ligament (ACL) tears is rapidly increasing. In patients who wish to return to their preoperative level of function, specifically as it pertains to participation in sports, the gold standard of treatment following an ACL tear remains an anterior cruciate ligament (ACL) reconstruction. Despite a majority of good/excellent results following primary ACL reconstruction, there is a growing subset of patients with persistent or recurrent functional instability who require revision ACL reconstruction. Preoperative planning for revision ACL reconstruction requires a careful understanding of the root cause of ACL failure, including possible technical causes of primary ACL failure and the presence of combined knee pathology that was not addressed at the index ACL reconstruction. The decision to perform 2-stage revision ACL reconstruction is multifactorial and is reached by technical considerations that may make a 1-stage revision less optimal, including tunnel widening, arthrofibrosis, active infection, and others. Concomitant knee pathology such as meniscal deficiency, malalignment (including an increase in posterior tibial slope), chondral lesions, and other ligamentous laxity may also require a staged approach to treatment. This evidence-based review covers the indications for 2-stage revision ACL reconstruction, surgical techniques, evidence for and technique of bone grafting prior ACL tunnels, and outcomes of 2-stage revision stratified by initial cause of ACL reconstruction failure. With proper preoperative planning and an understanding of the cause of failure following the primary ACL reconstruction, revision ACL reconstruction can offer excellent outcomes in the motivated patient. [Orthopedics. 2016; 39(3):e456-e464.].


DNA: an extensible molecule.
The force-displacement response of a single duplex DNA molecule was measured. The force saturates at a plateau around 70 piconewtons, which ends when the DNA has been stretched about 1.7 times its contour length. This behavior reveals a highly cooperative transition to a state here termed S-DNA. Addition of an intercalator suppresses this transition. Molecular modeling of the process also yields a force plateau and suggests a structure for the extended form. These results may shed light on biological processes involving DNA extension and open the route for mechanical studies on individual molecules in a previously unexplored range.


Cloning and characterization of the cDNAs encoding Na+ channel-specific toxins 1 and 2 of the scorpion Centruroides noxius Hoffmann.
Using a cDNA library prepared from venomous glands of the Mexican scorpion Centruroides noxius Hoffmann the genes that encode toxins 1 and 2 were identified, cloned and sequenced. In view of the proposed mechanism for processing the mature peptides coded by these two genes, the corresponding peptide-toxins were sequenced de novo. Mass spectrometric and 1H-NMR analyses of the C-terminal peptide produced by enzymatic digestion of both toxins indicated that the last residue is serine-amide. Sequence comparison revealed that these two genes have a similarity of 56% and 80% at the amino acid and nucleotide levels, respectively. Small corrections to the published primary structures were introduced: Cn toxin 1 has an extra serine residue at position 65 and the residue in position 60 is a proline, while the amino acids at positions 34 and 35 of Cn 2 are, respectively, tyrosine and glycine. Sequence comparison of toxins from the genus Centruroides suggests the presence of at least three classes of distinct peptides in these venoms.


A comparison of risk factors for mortality from heart failure in Asian and non-Asian populations: an overview of individual participant data from 32 prospective cohorts from the Asia-Pacific Region.
Most of what is known regarding the epidemiology of mortality from heart failure (HF) comes from studies within Western populations with few data available from the Asia-Pacific region where the burden of heart failure is increasing. Individual level data from 543694 (85% Asian; 36% female) participants from 32 cohorts in the Asia Pacific Cohort Studies Collaboration were included in the analysis. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) for mortality from HF were estimated separately for Asians and non-Asians for a quintet of cardiovascular risk factors: systolic blood pressure, diabetes, body mass index, cigarette smoking and total cholesterol. All analyses were stratified by sex and study. During 3,793,229 person years of follow-up there were 614 HF deaths (80% Asian). The positive associations between elevated blood pressure, obesity, and cigarette smoking were consistent for Asians and non-Asians. There was evidence to indicate that diabetes was a weaker risk factor for death from HF for Asians compared with non-Asians: HR 1.26 (95% CI: 0.74-2.13) versus 3.04 (95% CI 1.76-5.25) respectively; p for interaction = 0.022. Additional adjustment for covariates did not materially change the overall associations. There was no good evidence to indicate that total cholesterol was a risk factor for HF mortality in either population. Most traditional cardiovascular risk factors including elevated blood pressure, obesity and cigarette smoking appear to operate similarly to increase the risk of death from HF in Asians and non-Asians populations alike.


Multicenter phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma.
Imatinib myselate is a molecularly targeted drug that inhibits Abl tyrosine kinase, as well as type III tyrosine kinase receptors such as platelet-derived growth factor receptor (PDGFR), KIT, colony-stimulating factor 1 receptor (CSF-1R), and discoidin domain receptor (DDR). Ph1 chromosome-positive chronic myeloid leukemias (CMLs), KIT-positive gastrointestinal stromal tumors (GISTs), and PDGFR-positive dermatofibrosarcoma protuberans (DFSP) have been reported to be responsive to imatinib treatment. We conducted a multicenter Phase II trial of imatinib in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Patient ages ranged from 12 and 75 years. Eligibility criteria included (1) metastatic sarcomas with a definitive diagnosis based on histopathology or that were completely unresectable and locally advanced; (2) relapsed or refractory cases that had completed standard treatment; and (3) a tumor confirmed by immunohistochemical staining to be KIT- or PDGFR-positive. A 600-mg dose of imatinib was administered to patients once a day, with each patient receiving six courses of the drug and each course lasting 4 weeks. In cases categorized as stable or progressive, the imatinib dose was increased to 800 mg/day administered twice daily. A total of 25 patients who met the eligibility criteria were enrolled in the trial; 22 were evaluated for response. The response rate with a 600 mg/day dose of imatinib was 4.5% (0 complete response, 1 partial response). There were no other objective responses after increasing imatinib to 800 mg/day (0/10). We estimated 50% progression-free survival to be 61.0 days for an imatinib dose of 600 mg/day based on the Kaplan-Meier method. Side effects of imatinib were generally similar to those observed in previous clinical trials. Our results did not indicate effectiveness of imatinib monotherapy at a dose of 600 or 800 mg/day in patients with relapsed or refractory KIT-positive (excluding GISTs) or PDGFR-positive sarcomas. Our findings suggest the need to evaluate the synergistic effect of combination therapy with other anticancer drugs.