Effect of Oophorectomy on Survival After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers.
Women who carry a germline mutation in either the BRCA1 or BRCA2 gene face a lifetime risk of breast cancer of up to 70%, and once they receive a diagnosis of breast cancer, they face high risks of both second primary breast and ovarian cancers. Preventive bilateral salpingo-oophorectomy is recommended to women with a BRCA mutation at age 35 years or thereafter to prevent breast and ovarian cancer, but it is unclear whether oophorectomy has an impact on survival in women with BRCA-associated breast cancer. To estimate the impact of oophorectomy on survival in women with breast cancer with a BRCA1 or BRCA2 mutation. Retrospective analysis of patients selected by pedigree review of families who received counseling at 1 of 12 participating clinical genetics centers. Patients were 676 women with stage I or II breast cancer and a BRCA1 or BRCA2 mutation who were observed for up to 20 years after receiving a diagnosis between 1975 and 2008. Survival experience was compared for women who did and who did not undergo oophorectomy. In all analyses, the primary end point was death due to breast cancer. Of the 676 women, 345 underwent oophorectomy after the diagnosis of breast cancer and 331 retained both ovaries. The 20-year survival for the entire patient cohort was 77.4%. The adjusted hazard ratio for death attributed to breast cancer in women who underwent oophorectomy was 0.38 (95% CI, 0.19-0.77; P = .007) for BRCA1 carriers and 0.57 (95% CI, 0.23-1.43; P = .23) for BRCA2 carriers. The hazard ratio for breast cancer-specific mortality was 0.76 (95% CI, 0.32-1.78; P = .53) for women with estrogen receptor-positive breast cancer and 0.07 (95% CI, 0.01-0.51; P = .009) for women with estrogen receptor-negative breast cancer. Oophorectomy is associated with a decrease in mortality in women with breast cancer and a BRCA1 mutation. Women with estrogen receptor-negative breast cancer and a BRCA1 mutation should undergo oophorectomy shortly after diagnosis.


Hemorrhage into a lumbar synovial cyst causing an acute cauda equina syndrome. Case report.
Juxtafacet cysts of the lumbar spine have been reported with increasing frequency but their pathogenesis remains obscure. These cysts most frequently present with back pain, followed by chronic progressive radiculopathy or gradual onset of symptoms of spinal canal compromise. The authors report an unusual case of hemorrhage into a right L3-4 synovial cyst causing an acute cauda equina syndrome and describe its successful surgical treatment. The clinical, radiographic, and pathological features are discussed.


Prevalence of overweight and obesity in elderly people from Vitória-ES, Brazil.
The scope of this study was to estimate the prevalence of overweight and obesity and its association with socio-economic status in a sample of non-institutionalized elderly people from Vitória-ES, Brazil. This was a cross-sectional survey with a sample of 882 elderly people aged 60 and over. Obesity and overweight were assessed using the body mass index (BMI) and waist circumference (WC). All subjects answered a personal and socio-demographic questionnaire in relation to age, gender, marital status, physical activity, number of children, chronic diseases and smoking. Associations between categorical variables were tested using chi-square analysis with a 5% significance level. The prevalence of overweight and obesity was high (41.8% and 23.4%, respectively) and 50.7% of the elderly had a substantially increased waist circumference. About 4.3% of the individuals had diabetes, 50.4% had hypertension and 14.9% were found to have both diseases. It was observed that both the BMI and WC were significant associated (p<0.05) with sex, marital status, the presence of diseases and with cigarette smoking.


Defining Frailty in Research Abstracts: A Systematic Review and Recommendations for Standardization.
Multiple definitions of frailty are used. We sought to quantify the frequency that frailty is insufficiently defined in published abstracts. We conducted a systematic review of MEDLINE/PubMed for English abstracts of original research investigating frailty as an exposure or outcome in humans from 2015-2017. A complete definition of frailty included: 1) a named measure of frailty, including "frailty" alone, 2) details on variables included (e.g. grip strength), 3) number of variables included (e.g. 33-item frailty index), and 4) details on cutoffs or levels of frailty unless a definition was used continuously. Our search yielded 1,110 titles; 490 abstracts met review criteria, 348 abstracts had any definition of frailty and were included. Majority reported a single measure of frailty (n=313, 90%). The most commonly used measures were variations of Fried's phenotype (n=167, 48%) and Rockwood's cumulative deficit model (n=101, 29%). Only 56 abstracts had complete definitions (16%). In 123 abstracts (35%), a means of measuring frailty was named, but no additional details were given. When details of the frailty measure were described, they generally referred to cutoffs or levels rather than variables used in the measure. A minority of abstracts of original manuscripts related to frailty research had adequate definitions of frailty. We encourage scientists to adopt a standardized approach to defining the term for all abstracts related to frailty research to facilitate systematic reviews, meta-analysis, and accurate reporting of frailty science.


Low Reporting of Cointerventions in Recent Cardiovascular Clinical Trials: A Systematic Review.
Background A cointervention in a randomized clinical trial (RCT) is medical care given in addition to the tested intervention. If cointerventions are unbalanced between trial arms, the results may be biased. We hypothesized that cointerventions would be more adequately reported in RCTs without full blinding or at risk of bias. Methods and Results To describe the reporting of cointerventions and to evaluate the factors associated with their reporting, we did a systematic search of all RCTs evaluating pharmacological interventions on cardiovascular outcomes published in 5 high-impact journals. The reporting of cointerventions, blinding, and risk of bias were extracted and evaluated independently by 2 reviewers (E.M., L.A.). Cointerventions were inadequately reported in 87 of 123 RCTs (70.7%), with 56 (45.5%) providing no information on cointerventions and 31 (25.2%) providing only partial information. Of the RCTs, 52 (42.3%) had inadequate blinding of participants and/or personnel and 63 (51.2%) of the RCTs were judged at risk of bias. In univariable analysis, the reporting of cointerventions was not associated with blinding of participants and/or personnel (odds ratio [OR], 1.04; 95% CI, 0.47-2.27 for adequately versus inadequately blinded trials) or with risk of bias (OR, 1.47; 95% CI, 0.67-3.21 for at low risk of bias versus trials at risk of bias). In multivariable analysis, only a follow-up of <1 month was associated with the adequate reporting of cointerventions (OR, 3.63; 95% CI, 1.21-10.91). Conclusions More than two-thirds of recent major cardiovascular trials did not adequately report cointerventions. The quality of reporting was not better among trials that were not fully blinded or at risk for bias. Registration URL: https://www.crd.york.ac.uk/PROSPERO/. Unique identifier: CRD42018106771.


International primate neuroscience research regulation, public engagement and transparency opportunities.
Scientific excellence is a necessity for progress in biomedical research. As research becomes ever more international, establishing international collaborations will be key to advancing our scientific knowledge. Understanding the similarities in standards applied by different nations to animal research, and where the differences might lie, is crucial. Cultural differences and societal values will also contribute to these similarities and differences between countries and continents. Our overview is not comprehensive for all species, but rather focuses on non-human primate (NHP) research, involving New World marmosets and Old World macaques, conducted in countries where NHPs are involved in neuroimaging research. Here, an overview of the ethics and regulations is provided to help assess welfare standards amongst primate research institutions. A comparative examination of these standards was conducted to provide a basis for establishing a common set of standards for animal welfare. These criteria may serve to develop international guidelines, which can be managed by an International Animal Welfare and Use Committee (IAWUC). Internationally, scientists have a moral responsibility to ensure excellent care and welfare of their animals, which in turn, influences the quality of their research. When working with animal models, maintaining a high quality of care ("culture of care") and welfare is essential. The transparent promotion of this level of care and welfare, along with the results of the research and its impact, may reduce public concerns associated with animal experiments in neuroscience research.


Welfare-Adjusted Life Years (WALY): A novel metric of animal welfare that combines the impacts of impaired welfare and abbreviated lifespan.
Currently, separate measures are used to estimate the impact of animal diseases on mortality and animal welfare. This article introduces a novel metric, the Welfare-Adjusted Life Year (WALY), to estimate disease impact by combining welfare compromise and premature death components. Adapting the Disability-Adjusted Life Year approach used in human health audits, we propose WALY as the sum of a) the years lived with impaired welfare due to a particular cause and b) the years of life lost due to the premature death from the same cause. The years lived with impaired welfare are the product of the average duration of each welfare impediment, reflecting the actual condition that compromises animal welfare, the probability of an incident case developing and impaired welfare weights, representing the degree of impaired welfare. The years of life lost are calculated using the standard expected lifespan at the time of premature death. To demonstrate the concept, we estimated WALYs for 10 common canine diseases, namely mitral valve disease, dilated cardiomyopathy, chronic kidney disease, diabetes mellitus, atopic dermatitis, splenic haemangiosarcoma, appendicular osteosarcoma, cranial cruciate ligament disease, thoracolumbar intervertebral disc disease and cervical spondylomyelopathy. A survey of veterinarians (n = 61) was conducted to elicit impaired welfare weights for 35 welfare impediments. Paired comparison was the primary method to elicit weights, whereas visual analogue scale and time trade-off approaches rescaled these weights onto the desired scale, from 0 (the optimal welfare imaginable) to 1 (the worst welfare imaginable). WALYs for the 10 diseases were then estimated using the impaired welfare weights and published epidemiological data on disease impacts. Welfare impediment "amputation: one limb" and "respiratory distress" had the lowest and highest impaired welfare weights at 0.134 and 0.796, rescaled with a visual analogue scale, and 0.117 and 0.857, rescaled with time trade-off. Among the 10 diseases, thoracolumbar intervertebral disc disease and atopic dermatitis had the smallest and greatest adverse impact on dogs with WALYs at 2.83 (95% UI: 1.54-3.94) and 9.73 (95% uncertainty interval [UI]: 7.17-11.8), respectively. This study developed the WALY metric and demonstrated that it summarises welfare compromise as perceived by humans and total impact of diseases in individual animals. The WALY can potentially be used for prioritisation of disease eradication and control programs, quantification of population welfare and longitudinal surveillance of animal welfare in companion animals and may possibly be extended to production animals.


Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer.
Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost-effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC.


Aqueous humor dynamics during the day and night in juvenile and adult rabbits.
To determine the day and night differences in intraocular pressure (IOP), aqueous flow, outflow facility, uveoscleral outflow, and central corneal thickness (CCT) in juvenile and adult rabbits. Studies were performed on twelve 3-month-old and ten 12-month-old male New Zealand White rabbits. Daytime measurements were made between 9 AM (3 hours after lights on) and 3 PM, and nighttime measurements were made between 11 PM and 5 AM. IOP was measured by pneumotonometry and aqueous flow by fluorophotometry. Outflow facility was determined by both fluorophotometry and tonography. Uveoscleral outflow was calculated by the Goldmann equation. CCT was measured by ultrasound pachymetry. Repeated-measures ANOVAs and Student's two-tailed t-tests were used for statistical comparisons. When nighttime versus daytime readings were compared, IOP, aqueous flow and uveoscleral outflow were higher, fluorophotometric outflow facility was lower, and CCT was thinner in both age groups. When the juvenile rabbits were compared to adult rabbits, IOP was lower, aqueous flow and uveoscleral outflow were higher, and fluorophotometric outflow facility and CCT were not different during the day or night. Tonographic outflow facility did not change in a 24-hour period in the juvenile rabbits. The increased IOP at night in rabbits can be explained mainly by a decrease in outflow facility. An increase in aqueous flow at night is counterbalanced by an increase in uveoscleral outflow. Although the rates of aqueous flow and uveoscleral outflow slow with maturity, their relative day/night differences remain the same.


Management of chronic hepatitis B patients in immunetolerant phase: what latest guidelines recommend.
The natural history of chronic hepatitis B (CHB) is complex and may run through different immune phases that may overlap. In particulars, the immune-tolerant phase is the most interesting and not as well understood as we thought. The concept of true immune tolerance have been under challenged from immunology points of view. The major international guidelines have not yet reached a consensus on the definition of the immune-tolerant phase. While positive hepatitis B e antigen (HBeAg), high serum hepatitis B virus (HBV) DNA and normal serum alanine aminotransferase (ALT) levels are the three key features of this phase, some guidelines also put age into consideration. A new nomenclature, Phase 1 or HBeAg-positive chronic HBV infection, is given by the latest European Association for the Study of the Liver (EASL) published in April 2017. While current guidelines advise against starting antiviral treatment for immune-tolerant CHB patients, some new data suggest treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.


Effects of repetitive norgestomet treatments on pregnancy rates in cyclic and anestrous beef heifers.
Sixty-eight 12- to 14-month-old crossbred beef heifers averaging 285 kg were assigned at random to treated (n = 35) and control (n = 33) groups to evaluate the use of repetitive norgestomet treatments. Treated heifers received an ear implant containing 6 mg norgestomet on two occasions 16 days apart. Injections of 3 mg norgestomet and 5 mg estradiol valerate (EV) were given intramuscularly the same day as first implantation (Syncro-Mate-B). Implants were removed after eight days. Four bulls were then placed in each of two pastures containing half of the treated and half of the control heifers for 24 days after the time of the first implant removal. Progesterone concentrations from blood samples collected prior to the first treatment were used to determine reproductive status. The overall pregnancy rate 64 days after first implant removal for treated anestrous heifers (61%; 14 23 ) was similar (p > 0.25) to untreated (73%; 11 15 ) and treated (75%; 9 12 ) cyclic heifers, but higher (p < 0.1) than for untreated anestrous heifers (33%; 6 18 ). This treatment advantage resulted from an increased (p < 0.01) pregnancy rate after the second implant removal. In summary, repetitive norgestomet treatments enhanced pregnancy rate in anestrous heifers within a 24-day breeding season.


Factors associated with general self-efficacy and resilience among youth heads of households in Kenya.
This study assesses resilience and general self-efficacy among Kenyan orphans and vulnerable children (n = 1060) active in a community-based program combining economic household strengthening with psychosocial support. Quantile regression analyses modeled associations between the 25th, 50th, and 75th percentiles of resilience and general self-efficacy and multiple covariates. Program participation positively predicted increased general self-efficacy at all levels. Program participation predicted increased resilience at the 25th percentile but decreased resilience at the 75th percentile. Other significant predictors included economic, educational, sexual behavior and other demographic factors. This study suggests support for an integrated approach to economic and psychosocial empowerment.


Functional analysis of upstream common polymorphisms of the dopamine transporter gene.
The human dopamine transporter (DAT, SLC6A3) has been extensively investigated because of its potential involvement in neuropsychiatric disorders. The core elements responsible for its transcription have been identified. A regulatory role for certain genomic variants upstream to the core promoter is known. Recently, other single-nucleotide polymorphisms (SNPs) have been identified in this region and are thought to be associated with schizophrenia and bipolar I disorder. Hence, we have investigated the impact of common SNPs in a 2.8-kilobase region flanking the core promoter region (-2.7 to +63 base pair) in the neuroblastoma cell line SH-SY5Y. Haplotypes generated by site-directed mutagenesis revealed varying impact of individual SNPs on promoter activity using dual luciferase assays. In silico analyses also predicted allele-specific binding of transcription factors for some of these SNPs. Though electrophoretic mobility shift assays indicated several factors that appeared to bind to specific sites within this region, allele-specific binding was not detected for any SNP apart from rs3756450. We have thus identified novel putative regulatory domains flanking the core promoter of DAT that merit further investigation.


Mistiming of thought and perception predicts delusionality.
The timing of thoughts and perceptions plays an essential role in belief formation. Just as people can experience in-the-moment perceptual illusions, however, they can also be deceived about how events unfold in time. Here, we consider how a particular type of temporal distortion, in which the apparent future influences "earlier" events in conscious awareness, might affect people's most fundamental beliefs about themselves and the world. Making use of a task that has been shown to elicit such reversals in the temporal experience of prediction and observation, we find that people who are more prone to think that they predicted an event that they actually already observed are also more likely to report holding delusion-like beliefs. Moreover, this relationship appears to be specific to how people experience prediction and is not explained by domain-general deficits in temporal discrimination. These findings may help uncover low-level perceptual mechanisms underlying delusional belief or schizotypy more broadly and may ultimately prove useful as a tool for identifying those at risk for psychotic illness.


Relapse prevention with gepirone ER in outpatients with major depression.
To evaluate long-term efficacy and tolerability of the serotonin 5-HT1A receptor agonist, gepirone extended release (ER), a multicenter, randomized, placebo-controlled relapse prevention study was performed in patients with recurrent major depression (DSM-IV criteria). Patients 18 to 70 years, with a primary diagnosis of recurrent major depression (DSM-IV; 296.3) and a screening and baseline HAMD-17 total score >/=20 were eligible. After a 3- to 14-day (dependent on pretrial medication) single-blind placebo washout period, eligible patients entered an 8- or 12-week (depending on time to remission) open-label gepirone ER treatment period. They initially received a dose of 20 mg/d gepirone ER and were titrated to a dose of 40 to 80 mg/d. Patients who achieved remission (HAMD-17 total score </=8) were randomized to double-blind continuation of their gepirone ER treatment or placebo for 40 to 44 weeks. The primary end point was a comparison of the relapse rates between gepirone ER and placebo. Relapse was defined as a HAMD-17 total score >/=16 or discontinuation for lack of efficacy. A total of 420 patients were treated in the open-label phase. Of these, 303 (72.1%) completed the open-label phase and 250 (59.5%) fulfilled the criteria for remission and were randomized into the double-blind continuation phase (gepirone ER: n = 126; placebo: n = 124). The mean (+/-SD) final titrated dose of gepirone ER was 61.9 (+/-17.0) mg/d in the double-blind continuation phase. The relapse rate in the gepirone ER group was statistically significantly lower than that in the placebo group, 23.0% versus 34.7%, respectively (P = 0.024). During the open-label phase, adverse events that occurred in more than 5% of patients were nausea (15.7%), dizziness (13.1%), headache (12.9%), insomnia (6.2%), and vertigo (6.0%). During the continuation phase, the incidence of newly or re-emerging adverse events was similar with gepirone ER (43.7%) and placebo (42.7%). Adverse events different from those occurring during the open-label phase were not apparent. All adverse events occurred in less than 5% of patients with the exception of flu syndrome and headache. In conclusion, gepirone ER at a dose range of 40 to 80 mg/d is effective for relapse prevention in patients with recurrent major depression. It is well tolerated during long-term treatment for up to approximately one year.


ICRP Publication 115. Lung cancer risk from radon and progeny and statement on radon.
Recent epidemiological studies of the association between lung cancer and exposure to radon and its decay products are reviewed. Particular emphasis is given to pooled case-control studies of residential exposures, and to cohorts of underground miners exposed to relatively low levels of radon. The residential and miner epidemiological studies provide consistent estimates of the risk of lung cancer, with significant associations observed at average annual concentrations of approximately 200 Bq/m³ and cumulative occupational levels of approximately 50 working level months (WLM), respectively. Based on recent results from combined analyses of epidemiological studies of miners, a lifetime excess absolute risk of 5 × 10⁻⁴ per WLM [14 × 10⁻⁵ per (mJh/m³)] should now be used as the nominal probability coefficient for radon- and radon-progeny-induced lung cancer, replacing the previous Publication 65 (ICRP, 1993) value of 2.8 × 10⁻⁴ per WLM [8 × 10⁻⁵ per (mJh/m³)]. Current knowledge of radon-associated risks for organs other than the lungs does not justify the selection of a detriment coefficient different from the fatality coefficient for radon-induced lung cancer. Publication 65 (ICRP, 2003) recommended that doses from radon and its progeny should be calculated using a dose conversion convention based on epidemiological data. It is now concluded that radon and its progeny should be treated in the same way as other radionuclides within the ICRP system of protection; that is, doses from radon and its progeny should be calculated using ICRP biokinetic and dosimetric models. ICRP will provide dose coefficients per unit exposure to radon and its progeny for different reference conditions of domestic and occupational exposure, with specified equilibrium factors and aerosol characteristics.


Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude mice.
The lack of tumor models that can reliably predict for response to anticancer agents remains a major deficiency in the field of experimental cancer therapy. Although heterotransplants of certain human solid tumors can be successfully grown in nude mice, they have never been appropriately explored for prediction of in vivo chemosensitivity to anticancer agents. We determined the tumor response rate and studied the influence of several biological and molecular tumor parameters on the in vivo sensitivity to paclitaxel in a series of heterotransplanted human non-small cell lung cancer (NSCLC) tumors. One hundred consecutive resected NSCLC tumors were heterotransplanted s.c. in nude mice. The in vivo sensitivity to i.v. paclitaxel (60 mg/kg every 3 weeks) was studied in 34 successfully grown heterotransplants. Treatment started when the tumors reached a size of 5 mm in diameter, and strict standard clinical criteria (>50% shrinkage in tumor weight or cross-sectional surface) were used to define tumor response. Baseline multidrug resistance protein (MRP), Her-2/neu, and epidermal growth factor receptor (EGFR) expression, and pre- and posttherapy bax and bcl-2 expression were determined by Western blot analysis. p53 status was determined by sequencing. The overall take rate was 46% (95% confidence interval, 36-56%) and was significantly higher (P < 0.05) for squamous carcinoma tumors (75%) than for adenocarcinoma tumors (30%) and bronchoalveolar tumors (23%). The heterotransplants were morphologically very similar to the original tumors. The response rate to paclitaxel was 21% (95% confidence interval, 9-38%). Baseline tumor parameters associated with response were no Her-2/neu expression (none of the responding tumors expressed Her-2/neu versus 48% of the nonresponding tumors, P = 0.05) and baseline bcl-2 expression (all responding tumors expressed bcl-2 versus only 43% of the nonresponding tumors, P = 0.02). There was a trend toward a higher response rate in bax-positive tumors, and MRP- and EGFR-negative tumors, but it was not statistically significant. The response was independent of baseline p53 status and baseline mitotic index. Responding tumors had a higher bax/bcl-2 ratio 24 h after therapy, but the difference was only marginally significant (2.8 for responding tumors versus 1.1 for nonresponding tumors, P = 0.07). The extent of mitotic arrest at 24 h after therapy was not associated with response. Human NSCLC heterotransplants are morphologically identical to the original tumors and have a response rate to paclitaxel that is equivalent to that reported in Phase II studies in patients with advanced NSCLC treated with single-agent paclitaxel. NSCLC heterotransplants deserve to be explored to evaluate new agents for lung cancer and to predict clinical response on an individual basis in selected groups of patients.


The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis.
The 19q13 amplicon in pancreatic cancer cells contains a novel pancreatic differentiation 2 (PD2) gene (accession number AJ401156), which was identified by differential screening analysis. PD2 is the human homologue of the RNA polymerase II-associated factor 1 (hPaf1). In yeast, Paf1 is part of the transcription machinery, acting as a docking protein in between the complexes Rad6-Bre1, COMPASS-Dot1p, and the phosphorylated carboxyl terminal domain of the RNA polymerase II. As such, Paf1 is directly involved in transcription elongation via histone H2B ubiquitination and histone H3 methylation. The PD2 sequence is highly conserved from Drosophila to humans with up to 98% identity between rodent and human, suggesting the functional importance of PD2/hPaf1 to maintain cellular homeostasis. PD2 is a modular protein composed of RNA recognition motif, DEAD-boxes, an aspartic/serine (DS)-domain, a regulator of the chromosome condensation domain and myc-type helix-loop-helix domains. Our results further showed that PD2 is a nuclear 80 kDa protein, which interacts with RNA polymerase II. In addition, we have demonstrated that the overexpression of PD2 in the NIH 3T3 cells result in enhanced growth rates in vitro and tumor formation in vivo. Altogether, this paper presents strong evidence that the overexpression of PD2/hPaf1 is involved in cancer development.


Recognition of time-distorted sentences by normal-hearing and cochlear-implant listeners.
This study evaluated the effects of time compression and expansion on sentence recognition by normal-hearing (NH) listeners and cochlear-implant (CI) recipients of the Nucleus-22 device. Sentence recognition was measured in five CI users using custom 4-channel continuous interleaved sampler (CIS) processors and five NH listeners using either 4-channel or 32-channel noise-band processors. For NH listeners, recognition was largely unaffected by time expansion, regardless of spectral resolution. However, recognition of time-compressed speech varied significantly with spectral resolution. When fine spectral resolution (32 channels) was available, speech recognition was unaffected even when the duration of sentences was shortened to 40% of their original length (equivalent to a mean duration of 40 ms/phoneme). However, a mean duration of 60 ms/phoneme was required to achieve the same level of recognition when only coarse spectral resolution (4 channels) was available. Recognition patterns were highly variable across CI listeners. The best CI listener performed as well as NH subjects listening to corresponding spectral conditions; however, three out of five CI listeners performed significantly poorer in recognizing time-compressed speech. Further investigation revealed that these three poorer-performing CI users also had more difficulty with simple temporal gap-detection tasks. The results indicate that limited spectral resolution reduces the ability to recognize time-compressed speech. Some CI listeners have more difficulty with time-compressed speech, as produced by rapid speakers, because of reduced spectral resolution and deficits in auditory temporal processing.


Current Progress in Developing Subunit Vaccines against Enterotoxigenic Escherichia coli-Associated Diarrhea.
Diarrhea continues to be a leading cause of death in children <5 years of age, and enterotoxigenic Escherichia coli (ETEC) is the most common bacterial cause of children's diarrhea. Currently, there are no available vaccines against ETEC-associated diarrhea. Whole-cell vaccine candidates have been under development but require further improvements because they provide inadequate protection and produce unwanted adverse effects. Meanwhile, a newer approach using polypeptide or subunit vaccine candidates focusing on ETEC colonization factor antigens (CFAs) and enterotoxins, the major virulence determinants of ETEC diarrhea, shows substantial promise. A conservative CFA/I adhesin tip antigen and a CFA MEFA (multiepitope fusion antigen) were shown to induce cross-reactive antiadhesin antibodies that protected against adherence by multiple important CFAs. Genetic fusion of toxoids derived from ETEC heat-labile toxin (LT) and heat-stable toxin (STa) induced antibodies neutralizing both enterotoxins. Moreover, CFA-toxoid MEFA polypeptides, generated by fusing CFA MEFA to an STa-LT toxoid fusion, induced antiadhesin antibodies that broadly inhibited adherence of the seven most important ETEC CFAs associated with about 80% of the diarrhea cases caused by ETEC strains with known CFAs. This same antigen preparation also induced antitoxin antibodies that neutralized both toxins that are associated with all cases of ETEC diarrhea. Results from these studies suggest that polypeptide or subunit vaccines have the potential to effectively protect against ETEC diarrhea. In addition, novel adhesins and mucin proteases have been investigated as potential alternatives or, more likely, additional antigens for ETEC subunit vaccine development.


Depression and social stress in Pakistan.
The high prevalence of depression in developing countries is not well understood. This study aimed to replicate the previous finding of a high prevalence of depression in Pakistan and assess in detail the associated social difficulties. A two-phase survey of a general population sample in a Pakistani village was performed. The first-phase screen used the Personal Health Questionnaire (PHQ) and the self-rating questionnaire (SRQ). A one in two sample of high scorers and a one in three sample of the low scorers were interviewed using the Psychiatric Assessment Schedule (PAS) and Life Events and Difficulties Schedule (LEDS). A total of 259 people were screened (96% response rate). The second stage yielded 55 cases, of whom 54 had depressive disorder, and 48 non-cases. The adjusted prevalence of depressive disorders was 44-4% (95% CI 35.3 to 53.6): 25.5% in males and 57.5% in females. Nearly all cases had lasted longer than 1 year. Comparison of the cases and non-cases indicated that cases were less well educated, had more children and experienced more marked, independent chronic difficulties. Multivariate analysis indicated that severe financial and housing difficulties, large number of children and low educational level were particularly closely associated with depression. This study confirms the high prevalence of depressive disorders in Pakistan and suggests that this may be higher than other developing countries because of the high proportion of the population who experience social adversity.


Defective intestinal amino acid absorption in Ace2 null mice.
Mutations in the main intestinal and kidney luminal neutral amino acid transporter B(0)AT1 (Slc6a19) lead to Hartnup disorder, a condition that is characterized by neutral aminoaciduria and in some cases pellagra-like symptoms. These latter symptoms caused by low-niacin are thought to result from defective intestinal absorption of its precursor L-tryptophan. Since Ace2 is necessary for intestinal B(0)AT1 expression, we tested the impact of intestinal B(0)AT1 absence in ace2 null mice. Their weight gain following weaning was decreased, and Na(+)-dependent uptake of B(0)AT1 substrates measured in everted intestinal rings was defective. Additionally, high-affinity Na(+)-dependent transport of L-proline, presumably via SIT1 (Slc6a20), was absent, whereas glucose uptake via SGLT1 (Slc5a1) was not affected. Measurements of small intestine luminal amino acid content following gavage showed that more L-tryptophan than other B(0)AT1 substrates reach the ileum in wild-type mice, which is in line with its known lower apparent affinity. In ace2 null mice, the absorption defect was confirmed by a severalfold increase of L-tryptophan and of other neutral amino acids reaching the ileum lumen. Furthermore, plasma and muscle levels of glycine and L-tryptophan were significantly decreased in ace2 null mice, with other neutral amino acids displaying a similar trend. A low-protein/low-niacin diet challenge led to differential changes in plasma amino acid levels in both wild-type and ace2 null mice, but only in ace2 null mice to a stop in weight gain. Despite the combination of low-niacin with a low-protein diet, plasma niacin concentrations remained normal in ace2 null mice and no pellagra symptoms, such as photosensitive skin rash or ataxia, were observed. In summary, mice lacking Ace2-dependent intestinal amino acid transport display no total niacin deficiency nor clear pellagra symptoms, even under a low-protein and low-niacin diet, despite gross amino acid homeostasis alterations.


Predicting pain and function outcomes in people consulting with shoulder pain: the PANDA-S clinical cohort and qualitative study protocol.
People presenting with shoulder pain considered to be of musculoskeletal origin is common in primary care but diagnosing the cause of the pain is contentious, leading to uncertainty in management. To inform optimal primary care for patients with shoulder pain, the study aims to (1) to investigate the short-term and long-term outcomes (overall prognosis) of shoulder pain, (2) estimate costs of care, (3) develop a prognostic model for predicting individuals' level and risk of pain and disability at 6 months and (4) investigate experiences and opinions of patients and healthcare professionals regarding diagnosis, prognosis and management of shoulder pain. The Prognostic And Diagnostic Assessment of the Shoulder (PANDA-S) study is a longitudinal clinical cohort with linked qualitative study. At least 400 people presenting to general practice and physiotherapy services in the UK will be recruited. Participants will complete questionnaires at baseline, 3, 6, 12, 24 and 36 months. Short-term data will be collected weekly between baseline and 12 weeks via Short Message Serevice (SMS) text or software application. Participants will be offered clinical (physiotherapist) and ultrasound (sonographer) assessments at baseline. Qualitative interviews with ≈15 dyads of patients and their healthcare professional (general practitioner or physiotherapist).Short-term and long-term trajectories of Shoulder Pain and Disability Index (using SPADI) will be described, using latent class growth analysis. Health economic analysis will estimate direct costs of care and indirect costs related to work absence and productivity losses. Multivariable regression analysis will be used to develop a prognostic model predicting future levels of pain and disability at 6 months using penalisation methods to adjust for overfitting. The added predictive value of prespecified physical examination tests and ultrasound findings will be examined. For the qualitative interviews an inductive, exploratory framework will be adopted using thematic analysis to investigate decision making, perspectives of patients and clinicians on the importance of diagnostic and prognostic information when negotiating treatment and referral options. The PANDA-S study has ethical approval from Yorkshire and The Humber-Sheffield Research Ethics Committee, UK (18/YH/0346, IRAS Number: 242750). Results will be disseminated through peer-reviewed publications, social and mainstream media, professional conferences, and the patient and public involvement and engagement group supporting this study, and through newsletters, leaflets and posters in participating sites. ISRCTN46948079.


Transient spatiotopic integration across saccadic eye movements mediates visual stability.
Eye movements pose major problems to the visual system, because each new saccade changes the mapping of external objects on the retina. It is known that stimuli briefly presented around the time of saccades are systematically mislocalized, whereas continuously visible objects are perceived as spatially stable even when they undergo large transsaccadic displacements. In this study we investigated the relationship between these two phenomena and measured how human subjects perceive the position of pairs of bars briefly displayed around the time of large horizontal saccades. We show that they interact strongly, with the perisaccadic bar being drawn toward the other, dramatically altering the pattern of perisaccadic mislocalization. The interaction field extends over a wide range (200 ms and 20°) and is oriented along the retinotopic trajectory of the saccade-induced motion, suggesting a mechanism that integrates pre- and postsaccadic stimuli at different retinal locations but similar external positions. We show how transient changes in spatial integration mechanisms, which are consistent with the present psychophysical results and with the properties of "remapping cells" reported in the literature, can create transient craniotopy by merging the distinct retinal images of the pre- and postsaccadic fixations to signal a single stable object.


Pharmacokinetics and antibody responses to the CD3 antibody otelixizumab used in the treatment of type 1 diabetes.
Otelixizumab is a chimeric CD3 antibody that has been genetically engineered to remove the glycosylation site in the Fc domain. This limits its ability to bind to complement or Fc receptors and reduces the risk of adverse clinical reactions due to cytokine release. In a trial for treatment of type 1 diabetes, a short treatment with otelixizumab resulted in a reduced requirement for insulin lasting at least 18 months. In the course of this trial, the blood concentrations of the antibody were measured by flow cytometry to determine its pharmacokinetic profile. Dose-dependent accumulation of otelixizumab was demonstrated and modeling of the data indicated that the terminal half-life was approximately 1.5 days. Antibody responses to otelixizumab were measured by 2 methods: a bridging enzyme-linked immunosorbent assay and surface plasmon resonance. The surface plasmon resonance method had a greater sensitivity and was able to detect responses in all patients, starting at 8 days after the commencement of therapy. Neutralizing antibodies were detected in a significant proportion of patients by days 22 to 29. Although no adverse clinical effects were associated with these antibody responses and they did not appear to affect the clearance of the drug, they might have important implications for possible retreatment of the patients.


Concurrent life-course trajectories of employment and marijuana-use: exploring interdependence of longitudinal outcomes.
This study analyzes data on 7661 individuals who participated in the 1979 National Longitudinal Survey of Youth (NLSY79) to estimate trajectories of employment and marijuana-use over a 17-year period. Bivariate random intercept and slope modeling is applied to examine concurrently the cross-correlation between the two concurrent longitudinal trajectories from age 23 to 39. Parameter estimates indicate baseline level (at age 23) of employment to be negatively correlated with marijuana, suggesting marijuana-use is associated with lower workforce productivity at age 23. The longitudinal employment slope is positively correlated with employment intercept for both males and females, indicating that survey participants with higher levels of employment at age 23 are more likely to have a positive impact on employment trajectory over time. For males, however, the employment slope is also significantly correlated with marijuana intercept (r=-0.07), indicating marijuana-use in early adulthood may uniquely lower workforce productivity over age.


Improving the driving practices of pizza deliverers: Response generalization and moderating effects of driving history.
A practical intervention program, targeting the safety belt use of pizza deliverers at two stores, increased significantly the use of both safety belts (143% above baseline) and turn signals (25% above baseline). Control subjects (i.e., pizza deliverers at a third no-intervention store and patrons driving to the pizza stores) showed no changes in belt or turn signal use over the course of 7-month study. The intervention program was staggered across two pizza stores and consisted of a group meeting wherein employees discussed the value of safety belts, received feedback regarding their low safety belt use, offered suggestions for increasing their belt use, and made a personal commitment to buckle up by signing buckle-up promise cards. Subsequently, employee-designed buckle-up reminder signs were placed in the pizza stores. By linking license plate numbers to individual driving records, we examined certain aspects of driving history as moderators of pre- and postintervention belt use. Although baseline belt use was significantly lower for drivers with one or more driving demerits or accidents in the previous 5 years, after the intervention these risk groups increased their belt use significantly and at the same rate as drivers with no demerits or accidents. Whereas baseline belt use was similar for younger (under 25) and older (25 or older) drivers, younger drivers were markedly more influenced by the intervention than were older drivers. Individual variation in belt use during baseline, intervention, and follow-up phases indicated that some drivers require more effective and costly intervention programs to motivate their safe driving practices.


Recent Progress in Xenotransplantation, with Emphasis on Virological Safety.
Xenotransplantation is a new technology that may help to overcome the shortage of human tissues and organs available for the treatment of tissue and organ failure. Remarkable progress has recently been made in this field. First, understanding of the mechanisms of immunological rejection, mainly of the hyperacute rejection, allowed generating numerous genetically modified pigs to overcome rejection. Second, based on these genetically modified animals and new immunosuppression regimens, long-term survival of non-human primate recipients of heart, kidney, and islet cell cells has been reported. And third, potential zoonotic microorganisms have been identified in pigs and sensitive methods to detect them have been generated. In 2 clinical trials treating diabetic patients with porcine islet cells, no porcine microorganisms were transmitted to human recipients. Furthermore, strategies to eliminate potentially zoonotic microorganisms from donor pigs in order to prevent transmission to the recipients have been developed, including designated pathogen-free (DPF) breeding. In addition, strategies to prevent transmission of porcine endogenous retroviruses (PERVs) have been developed, including a knockout of all proviruses in the pig genome by gene editing. PERVs are integrated in the genome of all pigs and therefore they cannot be eliminated by DPF breeding. Since they are able to infect human cells, they represent a special risk in xenotransplantation. Despite the achievements, some problems remain: numerous genetically multi-modified pigs have been generated without fully evaluating their advantage, and microbiological screening of pigs to be used for transplantations and elimination of pathogenic microorganisms from the donor pigs are still not satisfactory.


Effect of high-intensity training versus moderate training on peak oxygen uptake and chronotropic response in heart transplant recipients: a randomized crossover trial.
In heart transplant (HTx) recipients, there has been reluctance to recommend high-intensity interval training (HIIT) due to denervation and chronotropic impairment of the heart. We compared the effects of 12 weeks' HIIT versus continued moderate exercise (CON) on exercise capacity and chronotropic response in stable HTx recipients >12 months after transplantation in a randomized crossover trial. The study was completed by 16 HTx recipients (mean age 52 years, 75% males). Baseline peak oxygen uptake (VO2peak ) was 22.9 mL/kg/min. HIIT increased VO2peak by 4.9 ± 2.7 mL/min/kg (17%) and CON by 2.6 ± 2.2 mL/kg/min (10%) (significantly higher in HIIT; p < 0.001). During HIIT, systolic blood pressure decreased significantly (p = 0.037) with no significant change in CON (p = 0.241; between group difference p = 0.027). Peak heart rate (HRpeak ) increased significantly by 4.3 beats per minute (p = 0.014) after HIIT with no significant change in CON (p = 0.34; between group difference p = 0.027). Heart rate recovery (HRrecovery ) improved in both groups with a trend toward greater improvement after HIIT. The 5-month washout showed a significant loss of improvement. HIIT was well tolerated, had a superior effect on oxygen uptake, and led to an unexpected increase in HRpeak accompanied by a faster HRrecovery . This indicates that the benefits of HIIT are partly a result of improved chronotropic response.


Characterisation of the first enzymes committed to lysine biosynthesis in Arabidopsis thaliana.
In plants, the lysine biosynthetic pathway is an attractive target for both the development of herbicides and increasing the nutritional value of crops given that lysine is a limiting amino acid in cereals. Dihydrodipicolinate synthase (DHDPS) and dihydrodipicolinate reductase (DHDPR) catalyse the first two committed steps of lysine biosynthesis. Here, we carry out for the first time a comprehensive characterisation of the structure and activity of both DHDPS and DHDPR from Arabidopsis thaliana. The A. thaliana DHDPS enzyme (At-DHDPS2) has similar activity to the bacterial form of the enzyme, but is more strongly allosterically inhibited by (S)-lysine. Structural studies of At-DHDPS2 show (S)-lysine bound at a cleft between two monomers, highlighting the allosteric site; however, unlike previous studies, binding is not accompanied by conformational changes, suggesting that binding may cause changes in protein dynamics rather than large conformation changes. DHDPR from A. thaliana (At-DHDPR2) has similar specificity for both NADH and NADPH during catalysis, and has tighter binding of substrate than has previously been reported. While all known bacterial DHDPR enzymes have a tetrameric structure, analytical ultracentrifugation, and scattering data unequivocally show that At-DHDPR2 exists as a dimer in solution. The exact arrangement of the dimeric protein is as yet unknown, but ab initio modelling of x-ray scattering data is consistent with an elongated structure in solution, which does not correspond to any of the possible dimeric pairings observed in the X-ray crystal structure of DHDPR from other organisms. This increased knowledge of the structure and function of plant lysine biosynthetic enzymes will aid future work aimed at improving primary production.


Advanced Patient-Centered Communication for Health Behavior Change: Motivational Interviewing Workshops for Medical Learners.
Medical settings are critical access points for behavior change counseling, and lifestyle behavior change is considered a key component of chronic disease management. The Association of American Medical Colleges recommends that future physicians be competent in shared decision making and patient-centered behavioral guidance to prevent illness and improve patient self-management of chronic disease. Motivational interviewing (MI) is a patient-centered, directive method of communication to enhance behavior change. Specific teachable strategies underlie the collaborative MI communication style that aims to reduce discord and build motivation for change. We present our three-session 12-hour MI curriculum as an advanced form of patient-centered communication. Each session includes presession assignment, large-group interactive lecture, and small-group activities for practice. An interdisciplinary team consisting of medical educators and health behavior change research-educators who are also members of the Motivational Interviewing Network of Trainers created the submission. The purpose of this resource is to provide medical educators with a short curriculum that incorporates materials and learning activities to promote skill in MI. In addition to positive feedback from student evaluations including the areas of relevance to training and self-rated skills improvement, preliminary pre- and posttraining scores from the medical students show significant improvement in expression of empathy and the ratio of reflections to questions. Implementation of the curriculum allows learners the opportunity to practice evidence-based communication that promotes intrinsic motivation for health behavior change in patients, a key treatment focus in chronic disease management.


Evaluation of helper-dependent canine adenovirus vectors in a 3D human CNS model.
Gene therapy is a promising approach with enormous potential for treatment of neurodegenerative disorders. Viral vectors derived from canine adenovirus type 2 (CAV-2) present attractive features for gene delivery strategies in the human brain, by preferentially transducing neurons, are capable of efficient axonal transport to afferent brain structures, have a 30-kb cloning capacity and have low innate and induced immunogenicity in preclinical tests. For clinical translation, in-depth preclinical evaluation of efficacy and safety in a human setting is primordial. Stem cell-derived human neural cells have a great potential as complementary tools by bridging the gap between animal models, which often diverge considerably from human phenotype, and clinical trials. Herein, we explore helper-dependent CAV-2 (hd-CAV-2) efficacy and safety for gene delivery in a human stem cell-derived 3D neural in vitro model. Assessment of hd-CAV-2 vector efficacy was performed at different multiplicities of infection, by evaluating transgene expression and impact on cell viability, ultrastructural cellular organization and neuronal gene expression. Under optimized conditions, hd-CAV-2 transduction led to stable long-term transgene expression with minimal toxicity. hd-CAV-2 preferentially transduced neurons, whereas human adenovirus type 5 (HAdV5) showed increased tropism toward glial cells. This work demonstrates, in a physiologically relevant 3D model, that hd-CAV-2 vectors are efficient tools for gene delivery to human neurons, with stable long-term transgene expression and minimal cytotoxicity.


Risk and protective factors for internalizing and externalizing outcomes among HIV-affected youth in Haiti.
The present study aims to: (1) estimate the levels of internalizing symptoms and externalizing behaviors among youth affected by HIV in central Haiti; and (2) examine the risk and protective factors associated with these outcomes to identify potential areas of intervention for HIV-affected youth. Baseline data for 492 youth affected by HIV (ages 10-17) and their 330 caregivers were collected for a pilot study of a psychosocial support intervention. Participants were recruited from a list of HIV-positive patients receiving care at Partners In Health/Zanmi Lasante clinic sites. Internalizing and externalizing behaviors were assessed using the Strengths and Difficulties Questionnaire. Demographic, economic, and social indicators were collected using a structured questionnaire administered by trained social workers. Youth affected by HIV in central Haiti displayed high levels of internalizing and, to a lesser degree, externalizing symptoms. Multivariate regression analysis demonstrated risk factors most strongly associated with internalizing symptoms (socioeconomic status, parental depressive symptoms) and externalizing behaviors (household living arrangements, such as living with a stepparent). Social support had a protective effect on externalizing behaviors for both caregiver (β=-0.03, p=0.01) and self-report (β=-0.05, p<0.0001). High levels of psychological distress were observed in this population, especially with respect to internalizing outcomes. Interventions should address the economic security, mental health, and access to antiretroviral therapy for families affected by HIV, as well as emphasize the importance of building supportive caregiver-child relationships to decrease the psychological symptoms and impact of other life stressors experienced by youth affected by HIV in Haiti and similar resource-limited settings.


Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.
Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE). In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan-Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR. This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30-60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0-65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child-Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively. SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.


An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells.
Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylamino-parthenolide (DMAPT), which induces rapid death of primary human LSCs from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-kappaB, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo.


New reconstructive technologies after decompressive craniectomy in traumatic brain injury: the role of three-dimensional titanium mesh.
Functional and aesthetic reconstruction after wide decompressive craniectomy directly correlates with subsequent quality of life. Advancements in the development of biomaterials have now made three-dimensional (3-D) titanium mesh a new option for the repair of skull defects after craniectomy. The purpose of this study was to review aesthetic and surgical outcomes and complications of patients who had skull defects repaired with 3-D titanium mesh. The records of 40 adult patients (31 unilateral craniectomies and 9 bilateral craniectomies) who underwent a computer-assisted designed titanium mesh implant at a university hospital from January 2008 to January 2010 were retrospectively reviewed. Aesthetic outcomes, cranial nerve V and VII function, and complications (hardware extrusions, meningitis, osteomyelitis, brain abscess, and pneumocephalus) were evaluated. The craniofacial symmetry, implant stability, and functional outcomes were excellent for all patients. No patients had trigeminal or facial dysfunction. All had excellent cosmetic results as measured by post-reduction radiographs and personal and family perceptions of the forehead contour. Two patients had delayed wound healing and subsequent subclinical wound infections, which resolved after treatment with antibiotics for 2 weeks. Craniofacial skeletal reconstruction with 3-D titanium mesh results in excellent forehead contour and cosmesis, and subsequently a better quality of life with few complications. Titanium mesh reconstruction offers a favorable alternative to other graft materials in the repair of large skull defects.


Disfiguring disease, degeneration and climate in Colombia, 1880-1920.
This text aims to unite two neglected areas of study in Colombian medical historiography: disfiguring disease and the concept of climate. It seeks to show how physicians in the late nineteenth and early twentieth centuries in Colombia associate a clinical semiology of disfiguring disease with the influence of certain climatic and hereditary conditions. Characterizing disfiguring disease associated with climate implies revising the way in which, at the close of the nineteenth century, medical discourse constructed etiological explanations using the applied rationalism of the period. Thus, the ideal pathological terrain was both the body of the patient and the territory he or she inhabited.


A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.
Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. To examine whether CoQ10 could slow disease progression in early PD. A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. clinicaltrials.gov Identifier: NCT00740714.


Artesunate plus sulfadoxine-pyrimethamine for uncomplicated malaria in Kenyan children: a randomized, double-blind, placebo-controlled trial.
Plasmodium falciparum has developed resistance to almost all routinely used antimalarial drugs. Sulfadoxine-pyrimethamine (SP) has replaced chloroquine as first-line treatment of uncomplicated malaria infection in Kenya but resistance to SP is already reported. The addition of artemisinin derivatives to SP may delay the development of drug resistance, improve cure rates, and reduce transmission. The efficacy and safety of artesunate plus SP in the treatment of uncomplicated P. falciparum malaria was evaluated in a randomized trial of 600 children at Siaya District Hospital, western Kenya between October 1999 and March 2000. Children aged < 5 years were randomly assigned to receive SP alone (1.25 mg/kg based on pyrimethamine), or in combination with artesunate (4 mg/kg/d) for either 1 or 3 d. Parasitological failure by days 14 and 28 (polymerase chain reaction [PCR]-corrected for new infections) were the primary endpoints. Treatment failure rates by day 14 were 25.5% in the SP alone group, 16.2% (risk difference [delta]-9.3%, 95% CI -17.3 to -1.2%, P= 0.027) in the 1-dose artesunate group, and 9.4% (delta-16.2%, 95% CI -23.6 to -8.7%, P< 0.001) in the 3-dose artesunate group. Corresponding rates by day 28 were 46.0% in the SP alone group, 38.2% (delta-7.8%, 95% CI -17.7 to 2.1%, P= 0.16) in the 1-dose artesunate group, and 26.0% (delta-20.0%, 95% CI -29.4 to -10.6%, P < 0.001) in the 3-dose artesunate group. The artesunate and SP combination was well tolerated. There were no serious drug-related adverse events. Parasite clearance and gametocyte carriage were reduced significantly in both combination groups compared with SP alone. Three days of artesunate were required to reduce significantly the risk of treatment failure by day 28. However, the high background rate of parasitological failure with SP may make this combination unsuitable for widespread use in Kenya.


The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases.
Mitogen-induced activation of p70(s6k) is associated with the phosphorylation of specific sites which are negatively affected by the immunosuppressant rapamycin, the fungal metabolite wortmannin, and the methylxanthine SQ20006. Recent reports have focused on the role of the amino terminus of the p85(s6k) isoform in mediating kinase activity, with the observation that amino-terminal truncation mutants are activated in the presence of rapamycin while retaining their sensitivity to wortmannin. Here we show that the effects of previously described amino- and carboxy-terminal truncations on kinase activity are ultimately reflected in the phosphorylation state of the enzyme. Mutation of the principal rapamycin-targeted phosphorylation site, T-389, to an acidic residue generates a form of the kinase which is as resistant to wortmannin or SQ20006 as it is to rapamycin, consistent with the previous observation that T-389 was a common target of all three inhibitors. Truncation of the first 54 residues of the amino terminus blocks the serum-induced phosphorylation of three rapamycin-sensitive sites, T-229 in the activation loop and T-389 and S-404 in the linker region. This correlates with a severe reduction in the ability of the kinase to be activated by serum. However, loss of mitogen activation conferred by the removal of the amino terminus is reversed by additional truncation of the carboxy-terminal domain, with the resulting mutant demonstrating phosphorylation of the remaining two rapamycin-sensitive sites, T-229 and T-389. In this double-truncation mutant, phosphorylation of T-229 occurs in the basal state, whereas mitogen stimulation is required to induce acute upregulation of T-389 phosphorylation. The phosphorylation of both sites proceeds unimpaired in the presence of rapamycin, indicating that the kinases responsible for the phosphorylation of these sites are not inhibited by the macrolide. In contrast, activation of the double-truncation mutant is blocked in the presence of wortmannin or SQ20006, and these agents completely block the phosphorylation of T-389 while having only a marginal effect on T-229 phosphorylation. When the T-389 site is mutated to an acidic residue in the double-truncation background, the activation of the resulting mutant is insensitive to the wortmannin and SQ20006 block, but interestingly, the mutant is activated to a significantly greater level than a control in the presence of rapamycin. These data are consistent with the hypothesis that T-389 is the principal regulatory phosphorylation site, which, in combination with hyperphosphorylation of the autoinhibitory domain S/TP sites, is acutely regulated by external effectors, whereas T-229 phosphorylation is regulated primarily by internal mechanisms.


The relationship between the daily profile of chosen biochemical markers of bone metabolism and melatonin and other hormone secretion in rats under physiological conditions.
The mechanism of generating and synchronizing daily rhythms of bone and mineral metabolism markers has not been entirely explained. Most studies indicate that LD cycle and/or feeding schedules provide important synchronizers of these rhythms. It seems that endogenous factors, including systemic and local hormones can be important in the mechanism of dependence of bone and mineral metabolism parameters rhythms on LD cycle and feeding schedule. To assess the relationship between the daily profile of chosen biochemical parameters of bone and mineral metabolism (serum ALP, PICP, ICTP and iP and urinary excretion of HYP and total calcium) and daily secretion of MEL, GH/IGF-I axis activity and parathyroid, thyroid, adrenal cortex and gonads function in 48 adult male rats. Material for studies was collected every 3 hours within a day. Hormones, PICP and ICTP concentrations were determined with the use of RIA method and ALP, HYP, total calcium and iP values--spectrophotometrically. Existence of a negative correlation between daily oscillations of studied markers of osteogenesis (ALP and PICP) and daily profile of MEL and PTH secretion and positive with daily fluctuations of GH and IGF-I was shown. Moreover, ALP values correlated negatively with daily oscillations of CT. Concentrations of bone resorption markers (ICTP, HYP and total calcium) correlated negatively with daily fluctuations of MEL and positively with GH, IGF-I and thyroid hormones. The present results suggest that physiological daily rhythmicity of PTH, MEL, GH, IGF-I and thyroid hormones most probably play an important role in regulating the daily rhythm of biochemical markers of bone metabolism.


The new landscape of therapy for myelofibrosis.
The landscape of therapy for myelofibrosis (MF) is evolving at a pace not previously seen for this clonal myeloproliferative neoplasm. The discovery of the JAK2 V617F mutation in 2005 has led to the rapid development of therapy specifically developed for afflicted MF patients. Indeed, the successful phase III studies of ruxolitinib demonstrating improved symptomatic burden, splenomegaly and survival led to the first approved myelofibrosis drug in the United States and Europe. Multiple additional JAK2 inhibitors are currently in or nearing phase III testing, including SAR302503 (fedratinib), SB1518 (pacritinib) and CYT387 (momelotinib), seeking to offer incremental benefits to ruxolitinib in regards to cytopenias or other disease features. In parallel, phase III testing of pomalidomide is ongoing, with the goal of solidifying the role of immunomodulatory therapy in MF-associated anemia. Multiple single agents strategies are ongoing with histone deacetylase inhibitors, hedgehog inhibitors and hypomethylation agents. Incremental advances are further sought, either in additive or synergistic fashion, from combination strategies of ruxolitinib with multiple different approaches ranging from allogeneic stem cell transplant to current therapies mitigating anemia and further impacting the bone marrow microenvironment or histology. Transitioning from a pre-2011 era devoid of approved MF therapies to one of multiple agents that target not only disease course but symptomatic burden has indeed changed the platform from which MF providers are able to launch individualized treatment plans. In this article, we discuss the diagnostic and therapeutic milestones achieved through MF research and review the emerging pharmacologic agents on the treatment horizon.


Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant?
A raised intraepithelial lymphocyte (IEL) count with normal villous architecture is a recognised finding in latent coeliac disease. Little information is available in cases without gluten sensitive enteropathy in adults. To assess the frequency of such a finding in routine practice and to determine whether it is clinically relevant. Patients with subjectively increased IELs as the only abnormality were identified prospectively from a routine duodenal biopsy series over a 12 month period. The biopsy specimens in these index cases were re-examined together with two controls with normal histology for each case, and three counts of IEL/100 epithelial cells were made in all samples. The index cases were then contacted and interviewed to obtain clinical information, approximately 12 months from the initial biopsy. Further data were obtained from their clinical records. Fourteen of 626 (2.2%) patients who had duodenal biopsies over the 12 month period had a subjective increase in IELs with normal villous architecture. Fifteen patients with newly diagnosed gluten sensitive enteropathy were also identified during the study period. Formal counting of the index cases and controls revealed a significant difference in IELs/100 epithelial cell counts between the two (mean, 38 (SD, 6.2) v 12.4 (4.6); p < 0.0001). Three of the 14 index cases tested had a positive coeliac antibody test compared with 12 of 15 newly diagnosed patients with coeliac disease and 10 of 93 patients with normal histology. The major clinical diagnostic categories in raised IEL cases were those with positive coeliac serology (n = 3), unexplained anaemia (n = 3), and chronic liver disease (n = 3). Six of 10 patients who were interviewed had ongoing gastrointestinal symptoms one year later. Three patients had had follow up duodenal biopsies, at the discretion of their responsible clinicians, with no change in IEL counts despite the commencement of a gluten free diet in two patients. A raised IEL count with normal villous architecture is not uncommon. Six of the 14 patients may have had latent coeliac disease. The cause in at least half of cases is not obvious at present. The finding of a raised IEL count with normal villous architecture is of sufficient clinical importance to be highlighted in routine duodenal biopsy reports.


Treatment of tobacco dependence in mental health and addictive disorders.
People with mental health and addictive (MHA) disorders smoke at high rates and require tobacco treatment as a part of their comprehensive psychiatric care. Psychiatric care providers often do not address tobacco use among people with mental illness, possibly owing to the belief that their patients will not be able to quit successfully or that even short-term abstinence will adversely influence psychiatric status. Progress in the development of treatments has been slow in part because smokers with current MHA disorders have been excluded from most smoking cessation trials. There are several smoking cessation treatment options, including psychological and pharmacological interventions, that should be offered to people with an MHA disorder who smoke. Building motivation and readiness to quit smoking is a major challenge, and therefore motivational interventions are essential. We review the treatment options for people with tobacco dependence and MHA disorders, offer recommendations on tobacco assessment and tailored treatment strategies, and provide suggestions for future research. Treatment efficacy could be enhanced through promoting smoking reduction as an initial treatment goal, extending duration of treatment, and delivering it within an integrated care model that also aims to reduce the availability of tobacco in MHA treatment settings and in the community.


Mental, behavioral and neurodevelopmental disorders in the ICD-11: an international perspective on key changes and controversies.
An update of the chapter on Mental, Behavioral and Neurodevelopmental Disorders in the International Classification of Diseases and Related Health Problems (ICD) is of great interest around the world. The recent approval of the 11th Revision of the ICD (ICD-11) by the World Health Organization (WHO) raises broad questions about the status of nosology of mental disorders as a whole as well as more focused questions regarding changes to the diagnostic guidelines for specific conditions and the implications of these changes for practice and research. This Forum brings together a broad range of experts to reflect on key changes and controversies in the ICD-11 classification of mental disorders. Taken together, there is consensus that the WHO's focus on global applicability and clinical utility in developing the diagnostic guidelines for this chapter will maximize the likelihood that it will be adopted by mental health professionals and administrators. This focus is also expected to enhance the application of the guidelines in non-specialist settings and their usefulness for scaling up evidence-based interventions. The new mental disorders classification in ICD-11 and its accompanying diagnostic guidelines therefore represent an important, albeit iterative, advance for the field.


Nanotechnology Meets Biology: Peptide-based Methods for the Fabrication of Functional Materials.
Nature exploits sustainable methods for the creation of inorganic materials on the nanoscale for a variety of applications. To achieve such capabilities, biomolecules such as peptides and proteins have been developed that recognize and bind the different compositions of materials. While a diverse set of materials binding sequences are present in the biosphere, biocombinatorial techniques have been used to rapidly identify peptides that facilitate the formation of new materials of technological importance. Interestingly, the binding motif of the peptides at the inorganic surface is likely to control the size, structure, composition, shape, and functionality of the final materials. In order to advance these intriguing new biomimetic approaches, a complete understanding of this biotic/abiotic interface is required. In this Perspective, we highlight recent advances in the biofunctionalization of nanoparticles with potential applications ranging from catalysis and energy storage to plasmonics and biosensing. We specifically focus on the physical characterization of the peptide-based surface from which specificity and activity are likely embedded.


Project THANKS: Examining HIV/AIDS-Related Barriers and Facilitators to Care in African American Women: A Community Perspective.
Project THANKS, (Turning HIV/AIDS into Knowledge for Sisters), is an evidence-based intervention that utilizes a community-based participatory and empowerment building approach for African American female substance abusers living with HIV and other chronic diseases. This qualitative study sought to gain insight from women living with HIV on how to improve Project THANKS. African American women living with substance abuse disorders, HIV, and other comorbidities were recruited from three community based health centers in New Jersey (N = 31). Ninety minute focus group sessions were implemented in each health center. The focus group sessions were designed to understand the perceived factors influencing the participants' ability to self-manage their health conditions and challenges they are currently facing regarding their diagnoses. The barriers and suggestions presented by participants included addressing stigmatization, managing mental health symptoms, improving physician-patient trust, accessing health education, educating community members, and proper nutrition. In addition, an engaged and trusting relationship with their healthcare provider and having positive sources of support were cited as motivators to adhering to their HIV treatment regimen. Participants living with HIV/AIDS also expressed more concern with difficulty treating their comorbidities than participants with only HIV/AIDS. Receiving input from African American women living with HIV related comorbidities was essential in improving the intervention to include a behavioral and primary health approach. Future programmatic interventions of Project THANKS will include a targeted focus on addressing mental health needs in women by offering meditation services and mental health referrals. In addition, Project THANKS will incorporate activities to improve communication with physicians, families, and media outlets to empower women to take an active role in their primary and social support needs.


Different Ipsi- and Contralateral Glial Responses to Anti-VEGF and Triamcinolone Intravitreal Injections in Rats.
To investigate the glial response of the rat retina to single or repeated intravitreal injections (IVI). Albino Sprague-Dawley rats received one or three (one every 7 days) IVI of anti-rat VEGF (5 μL; 0.015 μg/μL), triamcinolone (2.5 or 5 μL; 40 μg/μL; Trigón Depot), bevacizumab (5 μL; 25 μg/μL; Avastin), or their vehicles (PBS and balanced salt solution) and were processed 7 days after the last injection. Retinas were dissected as whole mounts and incubated with antibodies against: Iba1 (Ionized Calcium-Binding Adapter Molecule 1) to label retinal microglia, GFAP (Glial Fibrillary Acidic Protein) to label macroglial cells, and vimentin to label Müller cells. The retinas were examined with fluorescence and confocal microscopy, and the numbers of microglial cells in the inner retinal layers were quantified using a semiautomatic method. All the injected substances caused an important micro- and macroglial response locally at the injection site and all throughout the injected retina that was exacerbated by repeated injections. The microglial response was also observed but was milder in the contralateral noninjected eyes. The IVI of the humanized antibody bevacizumab caused a very strong microglial reaction in the ipsilateral retina. Two types of macroglial response were observed: astrocyte hypertrophy and Müller end-foot hypertrophy. While astrocyte hypertrophy was widespread throughout the injected retina, Müller end-foot hypertrophy was localized and more extensive with triamcinolone use or after repeated injections. Intravitreal injections cause micro- and macroglial responses that vary depending on the injected agent but increase with repeated injections. This inflammatory glial response may influence the effects of the injected substances on the retina.


Color generalization across hue and saturation in chicks described by a simple (Bayesian) model.
Color conveys important information for birds in tasks such as foraging and mate choice, but in the natural world color signals can vary substantially, so birds may benefit from generalizing responses to perceptually discriminable colors. Studying color generalization is therefore a way to understand how birds take account of suprathreshold stimulus variations in decision making. Former studies on color generalization have focused on hue variation, but natural colors often vary in saturation, which could be an additional, independent source of information. We combine behavioral experiments and statistical modeling to investigate whether color generalization by poultry chicks depends on the chromatic dimension in which colors vary. Chicks were trained to discriminate colors separated by equal distances on a hue or a saturation dimension, in a receptor-based color space. Generalization tests then compared the birds' responses to familiar and novel colors lying on the same chromatic dimension. To characterize generalization we introduce a Bayesian model that extracts a threshold color distance beyond which chicks treat novel colors as significantly different from the rewarded training color. These thresholds were the same for generalization along the hue and saturation dimensions, demonstrating that responses to novel colors depend on similarity and expected variation of color signals but are independent of the chromatic dimension.


Low-risk cigarettes: a prescription.
Antismoking education campaigns in out society have met with only partial success: today 55 to 60 million Americans smoke, and the habit is increasing among teenagers and women. It is important to protect individuals who continue to smoke despite all warnings. There is evidence that this can be accomplished in at least two ways. First, it may be possible to remove toxic smoke components and thus reduce specific hazards. Second, the doseresponse evidence suggests that, if the total intake of smoke can be reduced, after an appropriate time a reduction in disease incidence should occur. The technology to achieve these results has been developed and can be applied to the manufacture of commercial cigarettes. These cigarettes will not conform to traditional flavour patterns, but consumer perception can be made to change and compensating flavours and fragrances can be added. The feasibility of less hazardous cigarettes raises the question of whether there are limits of cigarette and smoke composition that may approach relative safety. These limits can be defined as the smoke intake doses at which the risk of disease in smokers approaches that in nonsmokers. Such values can be extimated by dose-response analysis of several epidemiological studies and by extrapolation of blood concentrations at different rates of intake for certain smoke components, such as carbon monoxide. Critical values determined by these methods should not be interpreted as indicators of safe smoking levels; they do imply, however, that a rapid shift in cigarette consumption habits toward the proposed range of values will make possible a substantial reduction in the current epidemic proportions of smoking-related diseases.


Are fibre supplements really necessary in diverticular disease of the colon? A controlled clinical trial.
Fifty-eight patients with uncomplicated diverticular disease of the colon took bran crispbread, ispaghula drink, and placebo for four months each in a randomised, cross-over, double-blind controlled trial. Assessments were made subjectively, using a monthly self-administered questionnaire, and objectively, by examining a seven-day stool collection at the end of each treatment period. In terms of a pain score, lower bowel symptom score (the pain score and sensation of incomplete emptying, straining, stool consistency, flatus, and aperients taken), and total symptom score (belching, nausea, vomiting, dyspepsia, and abdominal distension) fibre supplementation conferred no benefit. Symptoms of constipation, however, when assessed alone, were significantly relieved. Both fibre regimens produced the expected changes in stool weight, consistency, and frequency. It is concluded that dietary fibre supplements in the commonly used doses do no more than relieve constipation. Perhaps the impression that fibre helps diverticular disease is simply a manifestation of Western civilisation's obsession with the need for regular frequent defecation.


Multiple copies of hemolysin genes and associated sequences in the chromosomes of uropathogenic Escherichia coli strains.
The O6 serogroup Escherichia coli strain 536 carries two hemolysin (hly) determinants integrated into the chromosome. The two hly determinants are not completely identical, either functionally or structurally, as demonstrated by spontaneous deletion mutants carrying only one of them and by cloning each of the two determinants separately into cosmid vectors. Each hly determinant is independently deleted at a frequency of 10(-4), leading to variants which exhibit similar levels of internal hemolysin but different amounts of secreted hemolysin. The two hly determinants were also identified in the O4 E. coli strain 519. The three E. coli strains 251, 764, and 768, which belong to the serogroup O18, and the O4 strain 367 harbor a single chromosomal hly determinant, as demonstrated by hybridization with hly-gene-specific probes. However, a hybridization probe derived from a sequence adjacent to the hlyC-proximal end of the plasmid pHly 152-encoded hly determinant hybridizes with several additional chromosomal bands in hemolytic O18 and O6 E. coli strains and even in E. coli K-12. The size of the probe causing the multiple hybridization suggests a 1,500- to 1,800-base pair sequence directly flanking hlyC. Spontaneous hemolysin-negative mutants were isolated from strains 764 and 768, which had lost the entire hly determinant but retained all copies of the hlyC-associated sequence.2+.


A retrospective study comparing the loss of anchorage following the extraction of maxillary first or second premolars during orthodontic treatment with fixed appliances in adolescent patients.
This retrospective study assessed the difference in anchorage loss using 3D superimposition of study models between cases treated with extraction of maxillary first premolars and maxillary second premolars carried out in orthodontic specialist practice. Sixty subjects who have undergone extractions of either maxillary first or second premolars as part of their orthodontic treatment were selected. Eligibility criteria included patients with a Class I, mild Class II or III malocclusions, mild-to-moderate crowding with no anchorage reinforcement. Pre- and post-treatment maxillary dental study cases were scanned using a surface laser scanner to produced 3D digital images which were superimposed using areas of stability on the anterior hard palate. Anchorage loss was measured by the mesial movement of the maxillary first permanent molar. The mean mesial movement for the maxillary first molars, when adjusted for confounding factors was 4.7 mm (SD 1.6) in the maxillary first premolar extraction group and 4.6 mm (SD 1.6) in the maxillary second premolar extraction group. There is no difference in anchorage loss when comparing the extraction of the maxillary first premolars to the extraction maxillary second premolars.


Environmental factors contributing to the spread of H5N1 avian influenza in mainland China.
Since late 2003, highly pathogenic avian influenza (HPAI) outbreaks caused by infection with H5N1 virus has led to the deaths of millions of poultry and more than 10 thousands of wild birds, and as of 18-March 2008, at least 373 laboratory-confirmed human infections with 236 fatalities, have occurred. The unrestrained worldwide spread of this disease has caused great anxiety about the potential of another global pandemic. However, the effect of environmental factors influencing the spread of HPAI H5N1 virus is unclear. A database including incident dates and locations was developed for 128 confirmed HPAI H5N1 outbreaks in poultry and wild birds, as well as 21 human cases in mainland China during 2004-2006. These data, together with information on wild bird migration, poultry densities, and environmental variables (water bodies, wetlands, transportation routes, main cities, precipitation and elevation), were integrated into a Geographical Information System (GIS). A case-control design was used to identify the environmental factors associated with the incidence of the disease. Multivariate logistic regression analysis indicated that minimal distance to the nearest national highway, annual precipitation and the interaction between minimal distance to the nearest lake and wetland, were important predictive environmental variables for the risk of HPAI. A risk map was constructed based on these factors. Our study indicates that environmental factors contribute to the spread of the disease. The risk map can be used to target countermeasures to stop further spread of the HPAI H5N1 at its source.


Some clinical, haematological and biochemical effects of four tranquilizers in camels (Camelus dromedarius).
Six healthy camels were treated with the tranquilizers propionyl promazine (Combelen), xylazine (Rompun), acepromazine (Calmivet) or chlorpromazine (Largactil) at single intramuscular doses of 0.5, 0.25, 0.1, or 3 mg/kg, respectively; and the onset, duration and degree of sedation produced by each drug was assessed for six hours. The effect of the treatments on some haematological and biochemical parameters was also studied. The onset and duration of action of the tranquilizers were 10 min and 2.1 +/- 0.5 h for propionyl promazine, 4 min and 3.1 +/- 0.4 h for xylazine, 5 min and 2.3 +/- 0.5 h for acepromazine, 7 min and 2.5 +/- 0.4 h for chlorpromazine, respectively. It was observed that 5-10 min after the administration of the four drugs, camels showed slight irritability, dropping of the lower lips and scratching of the nostrils against objects. During the first hour after medication camels showed frequent urination, defaecation and lacrimation. Xylazine seemed to be superior to the other three drugs in producing sedation. No significant effect on the rectal temperature or the respiratory rates of treated camels was seen after the administration of the four drugs. There were consistent, but statistically insignificant decreases (about 10 p. 100) in the haemoglobin concentration and erythrocyte counts of camels one hour after treatment with the tranquilizers. The four drugs, particularly xylazine and propionyl promazine produced significant hyperglycaemia, but did not alter significantly the plasma concentration of urea or activity of aspartate aminotransferase.


Hematopoietic growth factors: overview and clinical applications, Part III.
The growth and differentiation of blood cells is regulated by a group of at least 12 glycoproteins, collectively known as hematopoietic growth factors. Advances in protein biochemistry and molecular genetics have provided the tools for the bulk production of these hormones for clinical application. Clinical trials of macrophage colony-stimulating factor, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-3 have all demonstrated significant effects on the peripheral blood counts of the recipients. The clinical usefulness of at least two of these agents in ameliorating post-chemotherapy myelosuppression, in the treatment of other cytopenias, and in enhancing engraftment after bone marrow transplantation has already been demonstrated. Potential applications to the therapy and diagnosis of other clinical disorders is under study. The history of the elucidation of these growth factors, our current understanding of their properties, interactions, and clinical effects, and the potential prospects for their future use in the manipulation of human blood cell production are the subject of this review.