Use of practice guidelines in the primary care of children with attention-deficit/hyperactivity disorder.
Several guidelines have been published for the care of children with attention-deficit/hyperactivity disorder (ADHD); however, few data describe adoption of practice guidelines. Our study sought 1) to describe primary care diagnosis and management of ADHD, 2) to determine whether the care is in accordance with American Academy of Pediatrics (AAP) practice guidelines, and 3) to describe factors associated with guideline adherence. We conducted a mail survey of 1374 primary care physicians in Michigan. Main outcome measures were reported adherence to practices specified in the AAP guidelines; ADHD practice patterns; and other measures, including attitudes about parent, teacher, and community influences on ADHD diagnosis and treatment. Bivariate and multivariate analyses were performed to assess patient and physician factors associated with adherence to guideline components. The overall response rate was 60%. The majority (77.4%) of primary care physicians were familiar with AAP guidelines on ADHD, and many (61.1%) reported incorporating the guidelines into their practice. Differences were apparent by specialty: 91.5% of pediatricians were familiar with the guidelines in contrast to 59.8% of family physicians. The majority of clinicians reported practices consistent with individual components of the diagnostic and treatment guidelines. However, when adherence to multiple components was analyzed together, only 25.8% of clinicians reported routine use of all 4 diagnostic components in the survey. In addition, some physicians continue to use diagnostic modalities that are currently not recommended for routine evaluation of school-aged children with ADHD--continuous performance testing, neuroimaging, and laboratory tests (eg, thyroid, lead, or iron testing). With regard to ADHD treatment, the majority (66.6%) of respondents reported routine recommendation of pharmacotherapy and titration of medications in the first month when prescribed (81.3%). However, just over half (53.1%) reported routine follow-up visits (3-4 times per year) for children who have ADHD and are taking medications. Most (53.4%) clinicians also recommended behavioral therapy for children who had a diagnosis of ADHD. Patterns of specialty differences were less consistent for treatment components: pediatricians were more likely to recommend medications, but family physicians reported more frequent follow-up evaluations for children who receive medications. There were no specialty differences in recommendations for behavioral therapy. In addition to physician specialty variations, differences in management were apparent by practice type and other demographic characteristics. There were few significant associations between adherence to guideline components and physician attitudes about parent, teacher, or community influences. However, these factors were noted by many respondents. Only 32.5% agreed that their community had adequate, accessible mental health resources. Half (50.1%) of the physicians reported that insurers limit coverage for assessment and treatment of ADHD. Primary care physicians generally report awareness of pediatric ADHD guidelines and follow these clinical practice recommendations. However, some physician variations are apparent, and areas for improvement are noted. Many primary care physicians report poor access to mental health services, limited insurance coverage, and other potential system barriers to the delivery of ADHD care. Additional study is needed to confirm provider-reported data; to determine what constitutes high-quality, long-term management of this chronic condition; and to confirm how reported practices associate with long-term outcomes for children with ADHD.


Occupation and risk of sudden death in a United States community: a case-control analysis.
Work environment is said to influence cardiovascular risk. We assessed whether nature of occupation affects risk of sudden cardiac death (SCD) in the general population. In the ongoing, prospective Oregon Sudden Unexpected Death Study (catchment population 1 million), working-age SCD cases (18-65 years) were compared with controls who died from any cause. Usual occupation obtained from death certificates was classified using the US Census Bureau standard occupational classification descriptions and categorised as white collar, blue collar or homemaker. Odds ratio (OR) for SCD by occupation category was obtained and clinical profile of SCD cases was compared by occupation type. Among SCD cases (n=646; 74% male) compared to controls (n=622; 73.6% male), the proportion of white collar workers was higher among male SCD cases (52.7% vs 43.7%; p=0.01); the difference in females was smaller (59.5% vs 55%; p=0.62). Adjusting for race and smoking status, male white collar workers had a higher risk of SCD compared to blue collar workers (OR=1.67, (1.26 to 2.23), p<0.001). A similar, non-significant trend was observed among females (OR 1.49 (0.81 to 2.75); p=0.20). White collar SCD cases were less likely to be current smokers (34.7% vs 45.3%, p=0.008), drug misusers (13.1% vs 18.5%) or have diabetes (21.4% vs 28.2%, both p=0.07) compared to blue collar workers. Other cardiac risk factors were similar. A white collar occupation was associated with increased risk of SCD, when compared to blue collar occupations. Since differences in conventional risk factors did not explain this elevated risk, work-related behavioural and psychosocial stressors warrant a closer evaluation.


Real-time measurement of blood vessel occlusion during microsurgery.
Measurement and feedback of vascular properties during microsurgery is generally not available. We carried out real-time in vivo measurement and analysis of microsurgical occlusion of 1-2-mm diameter arteries and veins in rodents. A pair of forceps mounted with strain gauges was designed for applying and directly measuring the force on tissue. Forces between 0 and 450 mN were applied, with the device having a resolution of 0.5 mN. We performed in vivo experiments on the rat femoral (n = 5) and abdominal (n = 8) blood vessels to measure the elastic restoration force of the tissue in response to radial compression at different levels of force. On average, the minimum occlusion force was 57 mN for the rat artery. During steady application of force, the perturbations in the blood vessel due to heartbeat are visible in the force data. These force oscillations ranged between 1 and 3 mN around the mean steady-state force applied. It was determined that the magnitude of the Fourier spectral peak corresponding to heartbeat frequency can be used as a measure of the patency of the blood vessel, and can provide feedback to microsurgeons to avoid damage to the vessel by application of excess force.


Theory of aberration fields for general optical systems with freeform surfaces.
This paper utilizes the framework of nodal aberration theory to describe the aberration field behavior that emerges in optical systems with freeform optical surfaces, particularly φ-polynomial surfaces, including Zernike polynomial surfaces, that lie anywhere in the optical system. If the freeform surface is located at the stop or pupil, the net aberration contribution of the freeform surface is field constant. As the freeform optical surface is displaced longitudinally away from the stop or pupil of the optical system, the net aberration contribution becomes field dependent. It is demonstrated that there are no new aberration types when describing the aberration fields that arise with the introduction of freeform optical surfaces. Significantly it is shown that the aberration fields that emerge with the inclusion of freeform surfaces in an optical system are exactly those that have been described by nodal aberration theory for tilted and decentered optical systems. The key contribution here lies in establishing the field dependence and nodal behavior of each freeform term that is essential knowledge for effective application to optical system design. With this development, the nodes that are distributed throughout the field of view for each aberration type can be anticipated and targeted during optimization for the correction or control of the aberrations in an optical system with freeform surfaces. This work does not place any symmetry constraints on the optical system, which could be packaged in a fully three dimensional geometry, without fold mirrors.


Mitochondrial DNA variation and changes in adiponectin and endothelial function in HIV-infected adults after antiretroviral therapy initiation.
Studies in persons of European descent have suggested that mitochondrial DNA (mtDNA) haplogroups influence antiretroviral therapy (ART) toxicity. We explored associations between mtDNA variants and changes in endothelial function and biomarkers among non-Hispanic white, ART-naive subjects starting ART. A5152s was a substudy of A5142, a randomized trial of initial class-sparing ART regimens that included efavirenz or lopinavir/ritonavir with nucleoside reverse transcriptase inhibitors (NRTIs), or both without NRTIs. Brachial artery flow-mediated dilation (FMD) and cardiovascular biomarker assessments were performed at baseline and at weeks 4 and 24. Ten haplogroup-defining mtDNA polymorphisms were determined. FMD and biomarker changes from baseline to week 24 by mtDNA variant were assessed using Wilcoxon rank-sum tests. Thirty-nine non-Hispanic white participants had DNA and 24-week data. The nonsynonymous m.10398A>G mtDNA polymorphism (N=8) was associated with higher median baseline adiponectin (5.0 vs. 4.2 μg/ml; p=0.003), greater absolute (-1.9 vs. -0.2 μg/ml) and relative (-33% vs. -3%) adiponectin decreases (p<0.001 for both), and lower week 24 brachial artery FMD (3.6% vs. 5.4%; p=0.04). Individual mtDNA haplogroups, including haplogroups H (N=13) and U (N=6), were not associated with adiponectin or FMD changes. In this small pilot study, adiponectin and brachial artery FMD on ART differed in non-Hispanic whites with a nonsynonymous mtDNA variant associated with several human diseases. These preliminary findings support the hypothesis that mtDNA variation influences metabolic ART effects. Validation studies in larger populations and in different racial/ethnic groups that include m.10398G carriers are needed.


Identification of two H3-histamine receptor subtypes.
The H3-histamine receptor provides feedback inhibition of histamine synthesis and release as well as inhibition of other neurotransmitter release. We have characterized this receptor by radioligand binding studies with the H3 agonist N alpha-[3H]methylhistamine ([3H]NAMHA). The results of [3H]NAMHA saturation binding and NAMHA inhibition of [3H]NAMHA binding were consistent with an apparently single class of receptors (KD = 0.37 nM, Bmax = 73 fmol/mg of protein) and competition assays with other agonists and the antagonists impromidine and dimaprit disclosed only a single class of sites. In contrast, inhibition of [3H]NAMHA binding by the specific high affinity H3 antagonist thioperamide revealed two classes of sites (KiA = 5 nM, BmaxA = 30 fmol/mg of protein; KiB = 68 nM, BmaxB = 48 fmol/mg of protein). Burimamide, another antagonist that, like thioperamide, contains a thiourea group, likewise discriminated between two classes of sites. In addition to differences between some antagonist potencies for the two receptors, there is a differential guanine nucleotide sensitivity of the two. The affinity of the H3A receptor for [3H] NAMHA was reduced less than 2-fold, whereas [3H]NAMHA binding to the H3B receptor was undetectable in the presence of guanosine 5'-O-(3-thiotriphosphate). The distinction between H3A and H3B receptor subtypes, the former a high affinity and the latter a low affinity thioperamide site, draws support from published in vitro data.


Cancer in Africa: the way forward.
While progress in oncology has been remarkable in recent decades, not every cancer patient is benefitting from the advances made in treating their disease. The contrast in diagnosis, treatment and its outcome between high-resource and low-resource countries is dramatic. Africa presents an enormous challenge with population growth and life expectancy increasing in many countries as the toll of AIDS and other communicable diseases declines. However, there has been little investment in capacity of any sort to deal with the current cancer problem, never mind the rapid increase in incidence which is underway. This is a critical area for investment and not only of a purely financial nature. It is bad to have cancer and worse to have cancer if you are poor. The gap between rich and poor, highly educated and less educated and the North-South divide is substantial and continuing to grow. Radical solutions are urgently needed: the status quo is not an appropriate response to the current situation. Recognising that no single government or source of philanthropy has the means to solve this problem, new models are needed to cope with and improve this situation.


Diet and Respiratory Infections: Specific or Generalized Associations?
Background: Based on our recently reported associations between specific dietary behaviors and the risk of COVID-19 infection in the UK Biobank (UKB) cohort, we further investigate whether these associations are specific to COVID-19 or extend to other respiratory infections. Methods: Pneumonia and influenza diagnoses were retrieved from hospital and death record data linked to the UKB. Baseline, self-reported (2006−2010) dietary behaviors included being breastfed as a baby and intakes of coffee, tea, oily fish, processed meat, red meat (unprocessed), fruit, and vegetables. Logistic regression estimated the odds of pneumonia/influenza from baseline to 31 December 2019 with each dietary component, adjusting for baseline socio-demographic factors, medical history, and other lifestyle behaviors. We considered effect modification by sex and genetic factors related to pneumonia, COVID-19, and caffeine metabolism. Results: Of 470,853 UKB participants, 4.0% had pneumonia and 0.2% had influenza during follow up. Increased consumption of coffee, tea, oily fish, and fruit at baseline were significantly and independently associated with a lower risk of future pneumonia events. Increased consumption of red meat was associated with a significantly higher risk. After multivariable adjustment, the odds of pneumonia (p ≤ 0.001 for all) were lower by 6−9% when consuming 1−3 cups of coffee/day (vs. <1 cup/day), 8−11% when consuming 1+ cups of tea/day (vs. <1 cup/day), 10−12% when consuming oily fish in higher quartiles (vs. the lowest quartile—Q1), and 9−14% when consuming fruit in higher quartiles (vs. Q1); it was 9% higher when consuming red meat in the fourth quartile (vs. Q1). Similar patterns of associations were observed for influenza but only associations with tea and oily fish met statistical significance. The association between fruit and pneumonia risk was stronger in women than in men (p = 0.001 for interaction). Conclusions: In the UKB, consumption of coffee, tea, oily fish, and fruit were favorably associated with incident pneumonia/influenza and red meat was adversely associated. Findings for coffee parallel those we reported previously for COVID-19 infection, while other findings are specific to these more common respiratory infections.


Coming home: A prospective study of family reintegration following deployment to a war zone.
The consequences of deployment extend beyond the service member to impact the entire family. The current investigation evaluated the unique challenges of family reintegration for partnered service members using a prospective design. In total, 76 partnered service members who deployed on a year-long, high-risk mission to Iraq were assessed across the entirety of the deployment cycle, i.e., pre-, during, and postdeployment. At follow-up, nearly 1 in 5 partnered service members reported moderate to severe difficulties in multiple aspects of family reintegration. Prospective interpersonal indicators such as preparations for deployment as a couple, shared commitment to the military, and predeployment relationship distress predicted postdeployment family reintegration difficulties. Significant interpersonal risk factors were medium to large in their effect sizes. Airmen's willingness to disclose deployment- and combat-related experiences, and postdeployment relationship distress served as concurrent interpersonal correlates of difficulties with family reintegration. Intrapersonal factors, including posttraumatic stress symptoms and alcohol misuse were concurrently related to challenges with family reintegration; predeployment alcohol misuse also predicted subsequent family reintegration difficulties. Additional analyses indicated that pre- and postdeployment relationship distress, combat disclosure, and postdeployment alcohol misuse each contributed to family reintegration when controlling for other intra- and interpersonal risk factors. Implications for prevention and early intervention strategies as well as future research are discussed.


The Use of Point-of-Care Bacterial Autofluorescence Imaging in the Management of Diabetic Foot Ulcers: A Pilot Randomized Controlled Trial.
To estimate comparative healing rates and decision-making associated with the use of bacterial autofluorescence imaging in the management of diabetic foot ulcers (DFUs). This is a single-center (multidisciplinary outpatient clinic), prospective pilot, randomized controlled trial (RCT) in patients with an active DFU and no suspected clinical infection. Consenting patients were randomly assigned 1:1 to either treatment as usual informed by autofluorescence imaging (intervention), or treatment as usual alone (control). The primary outcome was the proportion of ulcers healed at 12 weeks by blinded assessment. Secondary outcomes included wound area reduction at 4 and 12 weeks, patient quality of life, and change in management decisions after autofluorescence imaging. Between November 2017 and November 2019, 56 patients were randomly assigned to the control or intervention group. The proportion of ulcers healed at 12 weeks in the autofluorescence arm was 45% (n = 13 of 29) vs. 22% (n = 6 of 27) in the control arm. Wound area reduction was 40.4% (autofluorescence) vs. 38.6% (control) at 4 weeks and 91.3% (autofluorescence) vs. 72.8% (control) at 12 weeks. Wound debridement was the most common intervention in wounds with positive autofluorescence imaging. There was a stepwise trend in healing favoring those with negative autofluorescence imaging, followed by those with positive autofluorescence who had intervention, and finally those with positive autofluorescence with no intervention. In the first RCT, to our knowledge, assessing the use of autofluorescence imaging in DFU management, our results suggest that a powered RCT is feasible and justified. Autofluorescence may be valuable in addition to standard care in the management of DFU.


Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection.
Lyme Disease caused by infection with Borrelia burgdorferi is an emerging infectious disease and already by far the most common vector-borne disease in the U.S. Similar to many other infections, infection with B. burgdorferi results in strong antibody response induction, which can be used clinically as a diagnostic measure of prior exposure. However, clinical studies have shown a sometimes-precipitous decline of such antibodies shortly following antibiotic treatment, revealing a potential deficit in the host's ability to induce and/or maintain long-term protective antibodies. This is further supported by reports of frequent repeat infections with B. burgdorferi in endemic areas. The mechanisms underlying such a lack of long-term humoral immunity, however, remain unknown. We show here that B. burgdorferi infected mice show a similar rapid disappearance of Borrelia-specific antibodies after infection and subsequent antibiotic treatment. This failure was associated with development of only short-lived germinal centers, micro-anatomical locations from which long-lived immunity originates. These showed structural abnormalities and failed to induce memory B cells and long-lived plasma cells for months after the infection, rendering the mice susceptible to reinfection with the same strain of B. burgdorferi. The inability to induce long-lived immune responses was not due to the particular nature of the immunogenic antigens of B. burgdorferi, as antibodies to both T-dependent and T-independent Borrelia antigens lacked longevity and B cell memory induction. Furthermore, influenza immunization administered at the time of Borrelia infection also failed to induce robust antibody responses, dramatically reducing the protective antiviral capacity of the humoral response. Collectively, these studies show that B. burgdorferi-infection results in targeted and temporary immunosuppression of the host and bring new insight into the mechanisms underlying the failure to develop long-term immunity to this emerging disease threat.


Resting-state connectivity reveals a role for sensorimotor systems in vocal emotional processing in children.
Voices are a primary source of emotional information in everyday interactions. Being able to process non-verbal vocal emotional cues, namely those embedded in speech prosody, impacts on our behaviour and communication. Extant research has delineated the role of temporal and inferior frontal brain regions for vocal emotional processing. A growing number of studies also suggest the involvement of the motor system, but little is known about such potential involvement. Using resting-state fMRI, we ask if the patterns of motor system intrinsic connectivity play a role in emotional prosody recognition in children. Fifty-five 8-year-old children completed an emotional prosody recognition task and a resting-state scan. Better performance in emotion recognition was predicted by a stronger connectivity between the inferior frontal gyrus (IFG) and motor regions including primary motor, lateral premotor and supplementary motor sites. This is mostly driven by the IFG pars triangularis and cannot be explained by differences in domain-general cognitive abilities. These findings indicate that individual differences in the engagement of sensorimotor systems, and in its coupling with inferior frontal regions, underpin variation in children's emotional speech perception skills. They suggest that sensorimotor and higher-order evaluative processes interact to aid emotion recognition, and have implications for models of vocal emotional communication.


Clinical-Grade Oncolytic Adenovirus Purification Using Polysorbate 20 as an Alternative for Cell Lysis.
Oncolytic virus therapy is currently considered as a promising therapeutic approach for cancer treatment. Adenovirus is well-known and extensively characterized as an oncolytic agent. The increasing number of clinical trials using this virus generates the demand for the development of a well-established purification approach. Triton X-100 is commonly used in cell lysis buffer preparations. The addition of this surfactant in the list of substances with the very high concern of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation promoted the research for effective alternatives. In this work, a purification strategy for oncolytic adenovirus compatible with phase I clinical trials, using an approved surfactant - Polysorbate 20 was developed. The proposed downstream train, composed by clarification, concentration using tangential flow filtration, intermediate purification with anion exchange chromatography, followed by a second concentration and a final polishing step was evaluated for both Triton X-100 and Polysorbate 20 processes. The impact of cell lysis with Polysorbate20 and Triton X-100 for each downstream step was evaluated in terms of product recovery and impurities removal. Overall, 61 ± 4% of infectious viral particles were recovered. Depletion of host cell proteins and ds-DNA was 99.9% and 97.1%, respectively. The results indicated that Polysorbate 20 can be used as a replacement for Triton X-100 during cell lysis with no impact on product recovery, potency, and purity. Moreover, the developed process is scalable and able to provide a highly purified product to be used in phase I and II clinical trials.


Cost-effectiveness of monitoring glaucoma patients in shared care: an economic evaluation alongside a randomized controlled trial.
Population aging increases the number of glaucoma patients which leads to higher workloads of glaucoma specialists. If stable glaucoma patients were monitored by optometrists and ophthalmic technicians in a glaucoma follow-up unit (GFU) rather than by glaucoma specialists, the specialists' workload and waiting lists might be reduced.We compared costs and quality of care at the GFU with those of usual care by glaucoma specialists in the Rotterdam Eye Hospital (REH) in a 30-month randomized clinical trial. Because quality of care turned out to be similar, we focus here on the costs. Stable glaucoma patients were randomized between the GFU and the glaucoma specialist group. Costs per patient year were calculated from four perspectives: those of patients, the Rotterdam Eye Hospital (REH), Dutch healthcare system, and society. The outcome measures were: compliance to the protocol; patient satisfaction; stability according to the practitioner; mean difference in IOP; results of the examinations; and number of treatment changes. Baseline characteristics (such as age, intraocular pressure and target pressure) were comparable between the GFU group (n = 410) and the glaucoma specialist group (n = 405).Despite a higher number of visits per year, mean hospital costs per patient year were lower in the GFU group (€139 vs. €161). Patients' time and travel costs were similar. Healthcare costs were significantly lower for the GFU group (€230 vs. €251), as were societal costs (€310 vs. €339) (p < 0.01). Bootstrap-, sensitivity- and scenario-analyses showed that the costs were robust when varying hospital policy and the duration of visits and tests. We conclude that this GFU is cost-effective and deserves to be considered for implementation in other hospitals.


Comparison of nonspeaking and speaking mentally retarded adults' clarification strategies.
Interactions between speaking and nonspeaking persons using communication boards have frequently been found to be plagued by conversational breakdowns. Previous investigators, drawing upon anecdotal evidence, have painted a scenario in which the nonspeaker confuses the listener by transmitting an ambiguous message, the listener then requests clarification, the nonspeaker fails to clarify, and the discourse is abruptly terminated. The present study examined 5 speaking and 5 nonspeaking moderately-severely mentally retarded subjects' responses to their listeners' requests for clarification. An informal conversational format was used to evoke 40 possible repairs from each subject. Few differences were noted with respect to the ways in which speaking and nonspeaking subjects revised or failed to revise their messages. Both groups were highly responsive to their listeners' requests for clarification; subjects rarely ignored or changed the topic of discourse following these listener requests. However, unlike previous reports of nonretarded normally developing language-disordered children operating at comparable mental and linguistic levels, these speaking and nonspeaking subjects generally repeated their ambiguous messages rather than revising them. The results indicated the need to develop techniques for teaching speaking and nonspeaking retarded adults alternate methods of repairing conversational breakdowns.


Findings at follow-up endoscopies in subjects with suspected colorectal abnormalities: effects of baseline findings and time to follow-up.
Guidelines for colonoscopic surveillance after the removal of colorectal polyps already exist in the United Kingdom and United States. However, there is a continuing need to build up an evidence base on the likely effect of different follow-up policies for specific current findings. This article reports on the colonoscopic surveillance of a cohort of patients in Taiwan. The risk of various outcomes at the second examination is assessed according to findings at the first examination and the interval between examinations. Data from baseline and follow-up examinations for 2,287 individuals attending the National Taiwan University Hospital were collected retrospectively. Multivariate logistic regression was used to identify risk factors for the following 4 outcomes: any positive findings; multiple (> or =3) polyps; large (> or =10 mm) polyp(s); or villous adenoma(s) or cancer. The effect of the interval between examinations was assessed in all models. Older age was an independent risk factor for all outcomes. The number of baseline polyps was a significant risk factor for both positive results and multiple polyps, more severe baseline histology was a risk factor for large polyps and villous adenomas/cancer, and larger baseline polyps were a risk factor for large polyps at follow-up. Interval time was only an independent risk factor for villous adenomas/cancer, which tended to be found at shorter follow-up times. The total number of abnormalities found at follow-up was significantly related to the number of follow-up examinations but not to the total follow-up time. Results suggest that, with the possible exception of subjects with villous adenomas at baseline, most reexaminations can safely be delayed for > or =5 years. In the majority of cases staff at the hospital were correctly identifying those subjects at particularly high risk and assigning shorter follow-up intervals accordingly. Models indicate that many of the findings seen at follow-up were due to missed baseline findings.


Lack of functional specialization of neurons in the mouse primary visual cortex that have expressed calretinin.
Calretinin is a calcium-binding protein often used as a marker for a subset of inhibitory interneurons in the mammalian neocortex. We studied the labeled cells in offspring from a cross of a Cre-dependent reporter line with the CR-ires-Cre mice, which express Cre-recombinase in the same pattern as calretinin. We found that in the mature visual cortex, only a minority of the cells that have expressed calretinin and Cre-recombinase during their lifetime is GABAergic and only about 20% are immunoreactive for calretinin. The reason behind this is that calretinin is transiently expressed in many cortical pyramidal neurons during development. To determine whether neurons that express or have expressed calretinin share any distinct functional characteristics, we recorded their visual response properties using GCaMP6s calcium imaging. The average orientation selectivity, size tuning, and temporal and spatial frequency tuning of this group of cells, however, match the response profile of the general neuronal population, revealing the lack of functional specialization for the features studied.


Sensitive quantitation of Ochratoxin A in cocoa beans using differential pulse voltammetry based aptasensor.
In this work, we propose for the first time a sensitive Ochratoxin A (OTA) detection in cocoa beans using competitive aptasensor by differential pulse voltammetry (DPV). In the proposed method, biotin labeled and free OTA competed to bind with immobilized aptamer onto the surface of a screen printed carbon electrode (SPCE), and percentage binding was calculated. The detection was performed after adding avidin-ALP to perform avidin-biotin reaction; the signal was generated through a suitable substrate 1-naphthyl phosphate (1-NP), for alkaline phosphatase (ALP). The cocoa samples were extracted and purified using molecular imprinted polymer (MIP) columns specifically designed for OTA. The developed aptasensor showed a good linearity in the range 0.15-5 ng/mL with the limit of detection (LOD) 0.07 ng/mL and 3.7% relative standard deviation (RSD). The aptasensor displayed good recovery values in the range 82.1-85% with 3.87% RSD, thus, demonstrated the efficiency of proposed aptasensor for such matrices.


Panel 6: Vaccines.
Objective To review the literature on progress regarding (1) effectiveness of vaccines for prevention of otitis media (OM) and (2) development of vaccine antigens for OM bacterial and viral pathogens. Data Sources PubMed database of the National Library of Science. Review Methods We performed literature searches in PubMed for OM pathogens and candidate vaccine antigens, and we restricted the searches to articles in English that were published between July 2011 and June 2015. Panel members reviewed literature in their area of expertise. Conclusions Pneumococcal conjugate vaccines (PCVs) are somewhat effective for the prevention of pneumococcal OM, recurrent OM, OM visits, and tympanostomy tube insertions. Widespread use of PCVs has been associated with shifts in pneumococcal serotypes and bacterial pathogens associated with OM, diminishing PCV effectiveness against AOM. The 10-valent pneumococcal vaccine containing Haemophilus influenzae protein D (PHiD-CV) is effective for pneumococcal OM, but results from studies describing the potential impact on OM due to H influenzae have been inconsistent. Progress in vaccine development for H influenzae, Moraxella catarrhalis, and OM-associated respiratory viruses has been limited. Additional research is needed to extend vaccine protection to additional pneumococcal serotypes and other otopathogens. There are likely to be licensure challenges for protein-based vaccines, and data on correlates of protection for OM vaccine antigens are urgently needed. Implications for Practice OM continues to be a significant health care burden globally. Prevention is preferable to treatment, and vaccine development remains an important goal. As a polymicrobial disease, OM poses significant but not insurmountable challenges for vaccine development.


Treatment of adjuvant arthritis with granulocyte-colony stimulating factor and peptide derived from heat shock protein 65.
Adjuvant arthritis in Lewis rats is induced by the subcutaneous injection of Mycobacterium tuberculosis in mineral oil, and the predominant T cell immune reactivity is against the heat shock protein 65 derived peptide 176-190. We treated Lewis rats with human recombinant G-CSF followed by (i.v) administration of peptide 176-190 after induction of adjuvant arthritis (AA), and observed decreased disease severity, joint destruction, new bone formation and joint ankylosis. Treatment with G-CSF alone was also effective, but to a lesser extent. In addition, we found that splenocytes from rats treated with G-CSF had reduced antigen presenting capacity compared with splenocytes from vehicle treated rats. Primed lymph node cells from G-CSF plus peptide treated rats showed a marked reduction in proliferation and secretion of IFN-gamma after stimulation with the heat shock protein peptide in vitro as compared to controls.


Antibiotics for persistent nasal discharge (rhinosinusitis) in children.
Nasal discharge (rhinosinusitis) is extremely common in children. It is the result of inflammation of the mucosa of the upper respiratory tract, and is usually due to either infection or allergy. To determine the effectiveness of antibiotics versus placebo or standard therapy in treating children with persistent nasal discharge (rhinosinusitis) for at least 10 days. The Cochrane Controlled Trials Register, MEDLINE, EMBASE, and the references of relevant articles were searched. Authors and pharmaceutical companies were contacted. Date of most recent searches: February 2002. All randomised controlled trials that compared antibiotics versus placebo or standard therapy. Trials which included the use of other medications were included if all participants were allowed equal access to such medications or if the additional or alternative therapies were regarded as ineffective. Trials that only combined or compared antibiotics with surgery, or sinus puncture and lavage, were not included in the review. Data were extracted by a single reviewer for the following eight outcomes: overall clinical failure (primary outcome), failure to cure, failure to improve, clinical improvement, time to resolution, complications, side-effects and bacteriologic failure. For the dichotomous outcome variables of each individual study, proportional and absolute risk reductions were calculated using a modified intention-to-treat analysis. The summary weighted risk ratio and 95% confidence interval (fixed effects model) were calculated using the inverse of the variance of each study result for weighting (Cochrane statistical package, REVMAN version 4.1). A total of six studies involving 562 children compared antibiotics with placebo or standard therapy. Only the primary outcome (overall clinical failure) was reported in all studies. Around 40% of all randomised children did not have a clinical success documented when reviewed two to six weeks after randomisation. The control event rate varied from to 22 to 71% (mean 46%). The risk ratio estimated using a fixed effects model was 0.75 (95% CI 0.61 to 0.92). There was no evidence of statistical heterogeneity. Side effects occurred in 4 of 189 control group children (four studies). More children treated with antibiotics had side effects (17 of 330), but this difference was not statistically significant (RR 1.75, 95% CI 0.63 to 4.82). For children with persistent nasal discharge or older children with radiographically confirmed sinusitis, the available evidence suggests that antibiotics given for 10 days will reduce the probability of persistence in the short to medium-term. The benefits appear to be modest and around eight children must be treated in order to achieve one additional cure (NNT 8, 95% CI 5 to 29). No long term benefits have been documented. These conclusions are based on a small number of small randomised controlled trials and may require revision as additional data become available.


Strengthening literature search strategies for systematic reviews reporting population health in the Middle East and North Africa: A meta-research study.
In the Middle East and North Africa (MENA), data are produced in languages other than English and available through gray literature sources. We assessed the comprehensiveness of literature search strategies of systematic reviews (SRs) reporting population health primary data on MENA. Utilizing the registered protocol (PROSPERO CRD42017076736), we conducted a meta-research analysis on a cohort of SRs (systematic PubMed search: from 2008 to 2016) and evaluated their search strategies following AMSTAR recommendations. A total of 379 SRs were included. Few SRs (10.3%, n = 39) conducted a comprehensive literature search including at least two databases, reference lists of included primary studies, gray literature sources, and no language restriction. Nevertheless, 90.5% (n = 343) searched at least two databases and 67.0% (n = 254) searched gray literature sources. Authors from MENA searched statistically more for gray literature than authors from Western countries (P = 0.022). Reference lists of the included studies were searched in 40.4% (n = 153) of the SRs. Searching the reference lists was positively associated with searching for gray literature (P < 0.001). Only 38.8% (n = 147) of the SRs had no language restriction or searched in English and in at least one language relevant to MENA, whereas 27.2% (n = 103) did not report this information. Literature searches for SRs reporting population health data on MENA were limited in reporting quality, language restrictions, and lack of reference list searches. This was probably due to lack of adherence to the reporting guidelines. To ensure compilation of optimum evidence, expanding literature searches to reference list search and for additional languages relevant to MENA are required.


DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network.
Molecular subtyping of cancer offers tremendous promise for the optimization of a precision oncology approach to anticancer therapy. Recent advances in pancreatic cancer research uncovered various molecular subtypes with tumors expressing a squamous/basal-like gene expression signature displaying a worse prognosis. Through unbiased epigenome mapping, we identified deltaNp63 as a major driver of a gene signature in pancreatic cancer cell lines, which we report to faithfully represent the highly aggressive pancreatic squamous subtype observed in vivo, and display the specific epigenetic marking of genes associated with decreased survival. Importantly, depletion of deltaNp63 in these systems significantly decreased cell proliferation and gene expression patterns associated with a squamous subtype and transcriptionally mimicked a subtype switch. Using genomic localization data of deltaNp63 in pancreatic cancer cell lines coupled with epigenome mapping data from patient-derived xenografts, we uncovered that deltaNp63 mainly exerts its effects by activating subtype-specific super enhancers. Furthermore, we identified a group of 45 subtype-specific super enhancers that are associated with poorer prognosis and are highly dependent on deltaNp63. Genes associated with these enhancers included a network of transcription factors, including HIF1A, BHLHE40, and RXRA, which form a highly intertwined transcriptional regulatory network with deltaNp63 to further activate downstream genes associated with poor survival.


Monte Carlo simulation of pathogen behavior during the sprout production process.
Food-borne disease outbreaks linked to the consumption of raw sprouts have become a concern over the past decade. A Monte Carlo simulation model of the sprout production process was created to determine the most-effective points for pathogen control. Published literature was reviewed, and relevant data were compiled. Appropriate statistical distributions were determined and used to create the Monte Carlo model with Analytica software. Factors modeled included initial pathogen concentration and prevalence, seed disinfection effectiveness, and sampling of seeds prior to sprouting, sampling of irrigation water, or sampling of the finished product. Pathogen concentration and uniformity of seed contamination had a large effect on the fraction of contaminated batches predicted by the simulation. The model predicted that sprout sampling and irrigation water sampling at the end of the sprouting process would be more effective in pathogen detection than seed sampling prior to production. Day of sampling and type of sample (sprout or water) taken had a minimal effect on rate of detection. Seed disinfection reduced the proportion of contaminated batches, but in some cases it also reduced the ability to detect the pathogen when it was present, because cell numbers were reduced below the detection limit. Both the amount sampled and the pathogen detection limit were shown to be important variables in determining sampling effectiveness. This simulation can also be used to guide further research and compare the levels of effectiveness of different risk reduction strategies.


Molecular imaging of Alzheimer disease pathology.
Development of molecular imaging agents for fibrillar β-amyloid positron-emission tomography during the past decade has brought molecular imaging of Alzheimer disease pathology into the spotlight. Large cohort studies with longitudinal follow-up in cognitively normal individuals and patients with mild cognitive impairment and Alzheimer disease indicate that β-amyloid deposition can be detected many years before the onset of symptoms with molecular imaging, and its progression can be followed longitudinally. The utility of β-amyloid PET in the differential diagnosis of Alzheimer disease is greatest when there is no pathologic overlap between 2 dementia syndromes, such as in frontotemporal lobar degeneration and Alzheimer disease. However β-amyloid PET alone may be insufficient in distinguishing dementia syndromes that commonly have overlapping β-amyloid pathology, such as dementia with Lewy bodies and vascular dementia, which represent the 2 most common dementia pathologies after Alzheimer disease. The role of molecular imaging in Alzheimer disease clinical trials is growing rapidly, especially in an era when preventive interventions are designed to eradicate the pathology targeted by molecular imaging agents.


The measurement of thrombin in clotting blood by radioimmunoassay.
We have developed a radioimmunoassay for human thrombin using rabbit anti-human thrombin IgG. The assay can measure 2 ng thrombin/ml plasma, 500-fold more sensitive than clotting assays. Human prothrombin is less reactive in the assay than thrombin by at least four orders of magnitude, and there is no demonstrable cross-reactivity with human factor Xa, the clotting factor structurally most similar to thrombin. The assay does not detect thrombin bound to anthithrombin III. Using the assay, we have demonstrated that plasma from 20 normal subjects does not contain detectable thrombin. We measured thrombin generation in clotting blood in polypropylene tubes and observed that thrombin appears (approximately equal to 3 ng/ml) within 45 S-5 min after venipuncture. This material is thrombin, not intermediates of prothrombin activation, since it disappears after addition of heparin, which promotes thrombin antithrombin III complex formation. After a plateau of 2-10 min, there is further thrombin generation, which results in clotting after 15-27 min at a level of 40-50 ng thrombin/ml. The thrombin generated 9-25 min before clotting may activate factors V and VIII and stimulate platelet aggregation and release. In contrast, the cascade hypothesis assigns a role for thrombin only late in blood clotting. Radioimmunoassay of thrombin and other clotting factors will be useful for clinical and physiological studies of blood clotting especially since the assay seems specific for thrombin and is independent of other activities that affect bioassays.


The in vitro direct mycobacterial growth inhibition assay (MGIA) for the early evaluation of TB vaccine candidates and assessment of protective immunity: a protocol for non-human primate cells.
The only currently available approach to early efficacy testing of tuberculosis (TB) vaccine candidates is in vivo preclinical challenge models. These typically include mice, guinea pigs and non-human primates (NHPs), which must be exposed to virulent M.tb in a 'challenge' experiment following vaccination in order to evaluate protective efficacy. This procedure results in disease development and is classified as 'Moderate' in severity under EU legislation and UK ASPA licensure. Furthermore, experiments are relatively long and animals must be maintained in high containment level facilities, making them relatively costly. We describe an in vitro protocol for the direct mycobacterial growth inhibition assay (MGIA) for use in the macaque model of TB vaccine development with the aim of overcoming some of these limitations. Importantly, using an in vitro assay in place of in vivo M.tb challenge represents a significant refinement to the existing procedure for early vaccine efficacy testing. Peripheral blood mononuclear cell and autologous serum samples collected from vaccinated and unvaccinated control animals are co-cultured with mycobacteria in a 48-well plate format for 96 hours. Adherent monocytes are then lysed to release intracellular mycobacteria which is quantified using the BACTEC MGIT system and colony-forming units determined relative to an inoculum control and stock standard curve. We discuss related optimisation and characterisation experiments, and review evidence that the direct NHP MGIA provides a biologically relevant model of vaccine-induced protection. The potential end-users of the NHP MGIA are academic and industry organisations that conduct the assessment of TB vaccine candidates and associated protective immunity using the NHP model. This approach aims to provide a method for high-throughput down-selection of vaccine candidates going forward to in vivo efficacy testing, thus expediting the development of a more efficacious TB vaccine and offering potential refinement and reduction to the use of NHPs for this purpose.


Size exclusion chromatography of plasmid DNA isoforms.
There is considerable interest in using size exclusion chromatography (SEC) to analyze and purify specific plasmid isoforms, but there is currently no fundamental understanding of the effects of plasmid size and morphology on plasmid behavior in SEC. Experiments were performed for plasmids from 3.0 to 17.0kbp in size. The linear and open-circular isoforms were generated from the supercoiled plasmid by appropriate enzymatic digestion. SEC retention data were obtained using a Sephacryl S-1000 SF resin packed column and an Agilent HPLC system over a range of flow rates using buffers of different ionic strength and composition. The plasmid partition coefficients, K(P), were evaluated from the first statistical moment of the chromatographic peak. The partition coefficient decreased with increasing plasmid size as expected; K(P) varied from 0.299 to 0.045 for supercoiled plasmids of 3.0 to 17.0kbp. The partition coefficient also increased with increasing ionic strength due to the compaction of the DNA associated with the shielding of the intramolecular electrostatic interactions. For any plasmid size, the supercoiled isoform had the highest K(P) followed by the open-circular and then the linear isoform, consistent with independent estimates of the plasmid radius of gyration as determined by static light scattering. The experimental data were analyzed using available theoretical models for the partitioning of linear and cyclic polymer chains in well-defined pore geometries. These results provide important insights into the behavior of different plasmid isoforms in size exclusion chromatography.


Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection.
Endoplasmic reticulum (ER)-resident proteins are continually retrieved from the Golgi and returned to the ER by Lys-Asp-Glu-Leu (KDEL) receptors, which bind to an eponymous tetrapeptide motif at their substrate's C terminus. Mice and humans possess three paralogous KDEL receptors, but little is known about their functional redundancy, or if their mutation can be physiologically tolerated. Here, we present a recessive mouse missense allele of the prototypical mammalian KDEL receptor, KDEL ER protein retention receptor 1 (KDELR1). Kdelr1 homozygous mutants were mildly lymphopenic, as were mice with a CRISPR/Cas9-engineered frameshift allele. Lymphopenia was cell intrinsic and, in the case of T cells, was associated with reduced expression of the T-cell receptor (TCR) and increased expression of CD44, and could be partially corrected by an MHC class I-restricted TCR transgene. Antiviral immunity was also compromised, with Kdelr1 mutant mice unable to clear an otherwise self-limiting viral infection. These data reveal a nonredundant cellular function for KDELR1, upon which lymphocytes distinctly depend.


Expectation prior to human papilloma virus vaccination: 11 to 12-Year-old girls' written narratives.
Expectations prior to needle-related procedures can influence individuals' decision making and compliance with immunization programmes. To protect from human papilloma virus (HPV) and cervical cancer, the immunization needs to be given before sexual debut raising interest for this study's aim to investigate how 11 to 12-year-old girls narrate about their expectations prior to HPV vaccination. A total of 27 girls aged 11 to 12 years participated in this qualitative narrative study by writing short narratives describing their expectations. The requirement for inclusion was to have accepted HPV vaccination. Data were subjected to qualitative content analysis. Findings showed the following expectations: going to hurt, going to be scared and going to turn out fine. The expectations were based on the girls' previous experiences, knowledge and self-image. The latent content revealed that the girls tried to transform uneasiness to confidence. The conclusion drawn from this study is that most girls of this age seem confident about their ability to cope with possible unpleasantness related to vaccinations. However, nurses need to find strategies to help those children who feel uneasy about needle-related procedures.


[Effect of acupuncture--general anesthesia on hemodynamics in perioperative period of patients undergoing cholecystectomy].
To observe the effect of acupuncture-general anesthesia on hemodynamics in the perioperative period of patients undergoing laparoscopic cholecystectomy. Sixty patients of ASA class I-II scheduled to receive laparoscopic cholecystectomy were randomly assigned to two groups equally, Group A, the control group, and Group B, the compound anesthesia group. The general anesthesia applied on them during operation was induced by combined midazolam, fentanyl, propofol and vecuronium bromide, but for those in Group B, 15 min of electric stimulation at bilateral Neiguan (PC6), Hegu (LI4) and Quchi (LI11) was given with an acupuncture anesthesia apparatus before the drug induction as acupuncture anesthesia induction, then the general anesthesia started and maintained the same as that in Group A. Changes of cardiac function and hemodynamics were monitored using thoracic electrical bio-impedance method at different time points of operation, i.e. the baseline before induction (T0), after induction when loss of consciousness (T1), during intubation (T2), beginning of operation (T3), ending of operation (T4), during extubation (T5) and 10 min after extubation (T6). No significant difference between the two groups was found in operation lasting time and anesthesia maintaining time (P > 0.05). The amount of vecuronium bromide consumed in an unit of time in Group B was significantly lower than that in Group A (P < 0.05). The mean arterial pressure (MAP), heart rate (HR), rate pressure product (RPP), cardiac output (CO), systemic vascular resistance (SVR), and blood flow acceleration index (ACI) in Group A at T1 were all significantly lower (P < 0.05 or P < 0.01), but became significantly higher at T2 and T5 as compared with those of baseline (P < 0.05 or P < 0.01), while no significant change of them was found in Group B. Moreover, MAP, RPP, SVR and ACI were significantly higher in Group A than those in Group B at T2 and T5 (P < 0.05 or P < 0.01). The acupuncture-general anesthesia shows a bi-directional effect for diminishing the fluctuation of hemodynamics and stabilizing the blood circulation, and also can reduce the consumption of narcotics during operation, so it has an extensive value in clinical practice.


Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma.
Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction. The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines. Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.


Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: Initial application to the GENFI cohort.
Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.


A methodological perspective on genetic risk prediction studies in type 2 diabetes: recommendations for future research.
Fueled by the successes of genome-wide association studies, numerous studies have investigated the predictive ability of genetic risk models in type 2 diabetes. In this paper, we review these studies from a methodological perspective, focusing on the variables included in the risk models as well as the study designs and populations investigated. We argue and show that differences in study design and characteristics of the study population have an impact on the observed predictive ability of risk models. This observation emphasizes that genetic risk prediction studies should be conducted in those populations in which the prediction models will ultimately be applied, if proven useful. Of all genetic risk prediction studies to date, only a few were conducted in populations that might be relevant for targeting preventive interventions.


The social interaction of return to work explored from co-workers experiences.
The objective was to explore the role and contribution of co-workers in the return-to-work process. The social interaction of co-workers in the return-to-work process are analysed within the framework of the Swedish national and local employer organisational return-to-work policies. An exploratory qualitative method was used, consisting of open-ended interviews with 33 workplace actors across seven work units. Organisational return-to-work policies were collected from the three public sector employers. The key findings that emerged during analysis showed that some co-workers have a more work-task oriented approach towards the return-to-work process, whilst others had a more social relational approach. In both situations, the social relations worked hand in hand with job tasks (how task were allocated, and how returning workers were supported by others) and could make or break the return-to-work process. A suggestion for improvement of return-to-work models and policies is the need to take into account the social relations amongst workplace actors, especially involving co-workers when planning for return-to-work interventions. Otherwise the proper attention to work arrangements, social communication and the role of co-workers in the return-to-work process might not be seen.


Expression of microRNAs and target proteins in skeletal muscle of rats selectively bred for high and low running capacity.
Impairments in mitochondrial function and substrate metabolism are implicated in the etiology of obesity and Type 2 diabetes. MicroRNAs (miRNAs) can degrade mRNA or repress protein translation and have been implicated in the development of such disorders. We used a contrasting rat model system of selectively bred high- (HCR) or low- (LCR) intrinsic running capacity with established differences in metabolic health to investigate the molecular mechanisms through which miRNAs regulate target proteins mediating mitochondrial function and substrate oxidation processes. Quantification of select miRNAs using the rat miFinder miRNA PCR array revealed differential expression of 15 skeletal muscles (musculus tibialis anterior) miRNAs between HCR and LCR rats (14 with higher expression in LCR; P < 0.05). Ingenuity Pathway Analysis predicted these altered miRNAs to collectively target multiple proteins implicated in mitochondrial dysfunction and energy substrate metabolism. Total protein abundance of citrate synthase (CS; miR-19 target) and voltage-dependent anion channel 1 (miR-7a target) were higher in HCR compared with LCR cohorts (~57 and ~26%, respectively; P < 0.05). A negative correlation was observed for miR-19a-3p and CS (r = 0.32, P = 0.015) protein expression. To determine whether miR-19a-3p can regulate CS in vitro, we performed luciferase reporter and transfection assays in C2C12 myotubes. MiR-19a-3p binding to the CS untranslated region did not change luciferase reporter activity; however, miR-19a-3p transfection decreased CS protein expression (∼70%; P < 0.05). The differential miRNA expression targeting proteins implicated in mitochondrial dysfunction and energy substrate metabolism may contribute to the molecular basis, mediating the divergent metabolic health profiles of LCR and HCR rats.


Sleepless in America: inadequate sleep and relationships to health and well-being of our nation's children.
Our goal was to identify characteristics associated with inadequate sleep for a national random sample of elementary school-aged children (6-11 years) and adolescents (12-17 years). Data from 68418 participants in the 2003 National Survey of Children's Health were analyzed by using weighted bivariate and multivariate regression models. The dependent variable was report of not getting enough sleep for a child of his or her age >or=1 night of the past week. Independent variables included demographic characteristics, child health, school and other activities, and family life. Parents of elementary school-aged children with inadequate sleep were more likely to report that their child was having problems at school or had a father with fair or poor health. Parents of adolescents with inadequate sleep were more likely to report that their child had an atopic condition, frequent or severe headaches, a parent with less-than-excellent emotional health, or experienced frequent parental anger. Inadequate sleep in both age groups was associated with parental report that their child usually or always displayed depressive symptomatology, family disagreements involved heated arguing, or parental concern that the child was not always safe at home, at school, or in their neighborhood. Approximately 15 million American children are affected by inadequate sleep. Primary care providers should routinely identify and address inadequate sleep and its associated health, school, and family factors.


Assessing fall risk using wearable sensors: a practical discussion. A review of the practicalities and challenges associated with the use of wearable sensors for quantification of fall risk in older people.
Identification of older people most at risk of falling may facilitate early preventative intervention to reduce the likelihood of falls occurring. While many clinical fall risk assessment techniques exist, they often require subjective assessor interpretation, or are not appropriate for unsupervised screening of larger populations owing to a number of issues including safety, ability to reliably perform the assessment, and requirements for unwieldy apparatus. Researchers have more recently attempted to address some of these deficits by instrumenting new or existing physical fall risk assessments with wearable motion sensors to make such assessments more objective, quicker to administer, and potentially more appropriate for deployment for unsupervised use in the community. The objective of this paper is to discuss various practical questions involving sensor-based fall risk assessment (SFRA). Many of the issues discussed contribute to answering the important question of whether SFRA should or can be used in either a supervised or an unsupervised manner, and what possible deployment scenarios exist for it.


Serological and Molecular Methods to Study Epidemiological Aspects of Human T-Cell Lymphotropic Virus Type 1 Infection.
We estimated that at least 5-10 million individuals are infected with HTLV-1. Importantly, this number is based on the study of nearly 1.5 billion people living in known human T-cell lymphotropic virus type 1 (HTLV-1) endemic areas, for which reliable epidemiological data are available. However, for some highly populated regions including India, the Maghreb, East Africa, and some regions of China, no consistent data are yet available which prevents a more accurate estimation. Thus, the number of HTLV-1 infected people in the world is probably much higher. The prevalence of HTLV-1 prevalence varies depending on age, sex, and economic level in most HTLV-1 endemic areas. HTLV-1 seroprevalence gradually increases with age, especially in women. HTLV-1 has a simian origin and was originally acquired by humans through interspecies transmission from STLV-1 infected monkeys in the Old World. Three main modes of HTLV-1 transmission have been described; (1) from mother-to-child after prolonged breast-feeding lasting more than six months, (2) through sexual intercourse, which mainly, but not exclusively, occurs from male to female and lastly, (3) from contaminated blood products, which contain HTLV-1 infected lymphocytes. In specific areas, such as Central Africa, zoonotic transmission from STLV-1 infected monkeys to humans is still ongoing.The diagnostic methods used to study the epidemiological aspects of HTLV-1 infection mainly consist of serological assays for the detection of antibodies specifically directed against different HTLV-1 antigens. Screening tests are usually based on enzyme-linked immunoabsorbent assay (ELISA), chemiluminescence enzyme-linked immunoassay (CLEIA) or particle agglutination (PA). Confirmatory tests include mostly Western blots (WB)s or innogenetics line immunoassay (INNO-LIA™) and to a lesser extent immunofluorescence assay (IFA). The search for integrated provirus in the DNA from peripheral blood cells can be performed by qualitative and/or quantitative polymerase chain reaction (qPCR). qPCR is widely used in most diagnostic laboratories and quantification of proviral DNA is useful for the diagnosis and follow-up of HTLV-1 associated diseases such as adult T-cell leukemia (ATL) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). PCR also provides amplicons for further sequence analysis to determine the HTLV-1 genotype present in the infected person. The use of new generation sequencing methodologies to molecularly characterize full and/or partial HTLV-1 genomic regions is increasing. HTLV-1 genotyping generates valuable molecular epidemiological data to better understand the evolutionary history of this virus.


Firefly luciferase gene: structure and expression in mammalian cells.
The nucleotide sequence of the luciferase gene from the firefly Photinus pyralis was determined from the analysis of cDNA and genomic clones. The gene contains six introns, all less than 60 bases in length. The 5' end of the luciferase mRNA was determined by both S1 nuclease analysis and primer extension. Although the luciferase cDNA clone lacked the six N-terminal codons of the open reading frame, we were able to reconstruct the equivalent of a full-length cDNA using the genomic clone as a source of the missing 5' sequence. The full-length, intronless luciferase gene was inserted into mammalian expression vectors and introduced into monkey (CV-1) cells in which enzymatically active firefly luciferase was transiently expressed. In addition, cell lines stably expressing firefly luciferase were isolated. Deleting a portion of the 5'-untranslated region of the luciferase gene removed an upstream initiation (AUG) codon and resulted in a twofold increase in the level of luciferase expression. The ability of the full-length luciferase gene to activate cryptic or enhancerless promoters was also greatly reduced or eliminated by this 5' deletion. Assaying the expression of luciferase provides a rapid and inexpensive method for monitoring promoter activity. Depending on the instrumentation employed to detect luciferase activity, we estimate this assay to be from 30- to 1,000-fold more sensitive than assaying chloramphenicol acetyltransferase expression.


Mechanism for the selective interaction of C-terminal Eps15 homology domain proteins with specific Asn-Pro-Phe-containing partners.
Epidermal growth factor receptor tyrosine kinase substrate 15 (Eps15) homology (EH)-domain proteins can be divided into two classes: those with an N-terminal EH-domain(s), and the C-terminal Eps15 homology domain-containing proteins (EHDs). Whereas many N-terminal EH-domain proteins regulate internalization events, the best characterized C-terminal EHD, EHD1, regulates endocytic recycling. Because EH-domains interact with the tripeptide Asn-Pro-Phe (NPF), it is of critical importance to elucidate the molecular mechanisms that allow EHD1 and its paralogs to interact selectively with a subset of the hundreds of NPF-containing proteins expressed in mammalian cells. Here, we capitalize on our findings that C-terminal EH-domains possess highly positively charged interaction surfaces and that many NPF-containing proteins that interact with C-terminal (but not N-terminal) EH-domains are followed by acidic residues. Using the recently identified EHD1 interaction partner molecule interacting with CasL (MICAL)-Like 1 (MICAL-L1) as a model, we have demonstrated that only the first of its two NPF motifs is required for EHD1 binding. Because only this first NPF is followed by acidic residues, we have utilized glutathione S-transferase pulldowns, two-hybrid analysis, and NMR to demonstrate that the flanking acidic residues "fine tune" the binding affinity to EHD1. Indeed, our NMR solution structure of the EHD1 EH-domain in complex with the MICAL-L1 NPFEEEEED peptide indicates that the first two flanking Glu residues lie in a position favorable to form salt bridges with Lys residues within the EH-domain. Our data provide a novel explanation for the selective interaction of C-terminal EH-domains with specific NPF-containing proteins and allow for the prediction of new interaction partners with C-terminal EHDs.


Sensibility following innervated free TRAM flap for breast reconstruction: Part II. Innervation improves patient-rated quality of life.
Restoring sensory innervation may be a useful adjunct in free flap head and neck reconstruction but, as yet, has not been shown to improve outcomes of breast reconstruction. The authors' previous study demonstrated objectively improved sensation in a group of innervated transverse rectus abdominis musculocutaneous (TRAM) flap breast reconstruction patients relative to noninnervated flaps. This study compared patient-rated outcomes of free TRAM breast reconstruction in innervated versus noninnervated flaps. Twenty-seven women were randomized prospectively to undergo either innervated or noninnervated free TRAM flap breast reconstruction. For innervated flaps, the T10 intercostal nerve was harvested with the TRAM flap and neurotized to the T4 sensory nerve at the recipient site. Three validated outcome tools were administered after surgery: the Medical Outcomes Study 36-Item Short Form Health Survey, the Body Image after Breast Cancer Questionnaire, and the Functional Assessment of Cancer Therapy-Breast. Results were correlated with previously reported objective sensibility outcomes. Eighteen of 27 women returned their questionnaires a mean 48 months after free TRAM flap reconstruction. Demographic analysis revealed no significant differences in patient age, height, smoking, radiation therapy, and nipple-areola complex reconstruction between randomized patient groups. There was a statistically significant improvement in all three measures in patients who were randomized to receive innervated free TRAM flaps compared with those receiving noninnervated flaps. This study demonstrates that innervation of free TRAM flaps used for breast reconstruction not only improves sensibility but also has a positive effect on patient-rated quality of life.


[Orgasm and its impact on quality of life after radical prostatectomy].
Orgasm is a neurophysiological event, which produces bulbous cavernous muscle contraction that usually coincided with ejaculation. The aim of this study was to assess the orgasm's presence and quality in patients treated with radical prostatectomy, as well as its impact on quality of life of these patients. The medical records of 152 patients with radical prostatectomy were reviewed retrospectively. Patients were operated between january 1999 and december 01, with an average age of 64.4 (44-75) years and the follow-up period was 33 (21-45) months. 42 (31.6%) patients showed erectile dysfunction (ED) previous to surgery. The research was performed by a personal interview through a questionnaire. 134 patients (96.4%) treated showed post operative ED, 91.6% of patients had stable relationship and 44.4% have sexual intercourse, 23.3% masturbation only and 32.3% no sexual activity. 84 patients (55.2%) were not interested in receiving treatment and 25 (16.4%) referred a reduced libido. Concerning to orgasm sensation, 140 patients (92.1%) preserved a subjectively normal orgasm, 4 (2.6%) referred lack of it and 8 (5.2%) a weakened or anomalous sensation. Furthermore 24 patients (15.7) had urine loss during orgasm. After radical prostatectomy, both the orgasmic function and libido were kept by the majority of patients despite the neuro vascular bundle damaged caused. Only a minority of patients having urine loss, as a consequence of surgical procedure.


Tracking neuropsychological recovery following concussion in sport.
The purpose of this study was to illustrate the serial use of computerized neuropsychological screening with ImPACT to monitor recovery in a clinical case series of injured athletes. Amateur athletes with concussions (n= 30, average age= 16.1, SD= 2.1 years) underwent pre-season testing and three post-concussion evaluations within the following intervals: 1-2 days, 3-7 days (M= 5.2 days) and 1-3 weeks (M= 10.3 days). The study selection criteria increased the probability of including athletes with slow recovery. Repeated measures ANOVAs revealed significant main effects for all five composite scores (verbal memory, visual memory, reaction time, processing speed and total symptoms). In group analyses, performance decrements and symptoms relating to concussion appeared to largely resolve by 5 days post-injury and fully resolve by 10 days. Athletes' scores were examined individually using the reliable change methodology. At 1 day post-injury, 90% had two or more reliable declines in performance or increases in symptom reporting. At 10 days, 37% were still showing two or more reliable changes from pre-season levels. This study illustrates the importance of analysing individual athletes' test data because group analyses can obscure slow recovery in a substantial minority of athletes.


Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation.
Egr2 and 3 are important for maintaining immune homeostasis. Here we define a fundamental function of Egr2 and 3 operating as a checkpoint that controls the transition between clonal expansion and differentiation of effector T cells. Egr2 and 3 deficiency resulted in defective clonal expansion but hyperactivation and excessive differentiation of T cells in response to viral infection. Conversely, sustained Egr2 expression enhanced expansion but severely impaired effector differentiation. Egr2 bound to and controlled the expression of genes regulating proliferation (Myc and Myb) and differentiation repressors (Bcl6, Id3), while repressing transcription factors required for effector function (Zeb2, RORa, RORc, and Bhlhe40). Egr2 and 3 expression in T cells was regulated reciprocally by antigen and IFNγ, providing a mechanism for adjusting proliferation and differentiation of individual T cells. Thus, Egr2 and 3 are upstream regulators of effector CD4 and CD8 T cells that are essential for optimal responses with limited immunopathology.


Malignancy and survival in dermatitis herpetiformis: a comparison with coeliac disease.
Dermatitis herpetiformis is a lifelong, gluten sensitive skin disease. Patients with dermatitis herpetiformis, similar to patients with coeliac disease not adhering to a gluten free diet, seem to have increased risk for lymphoma. This study looked at the occurrence of malignancy and survival of patients with dermatitis herpetiformis and compared the results with those seen in patients with coeliac disease or in the general population. A total of 305 adult patients with dermatitis herpetiformis diagnosed at the University Hospital of Tampere in 1970-1992 were studied. Most patients started a gluten free diet and at the end of the study 93% of the patients were adhering to the diet. A control group comprised 383 adult patients with coeliac disease, 81% of them adhered to a gluten free diet, 6% had a normal diet, and in 13% the diet history remained unknown. The occurrence of malignant diseases and survival of the patients were assessed up to the end of 1993. Standardised incidence ratios (SIR) with 95% confidence intervals were used for the malignant diseases. The survival of the patients was compared with that of the general population. Thirteen (4.3%) patients with dermatitis herpetiformis developed 14 malignant disorders during the follow up (SIR 1.25; 95% confidence intervals 0.68 to 2.09). A non-Hodgkin's lymphoma occurred in four patients with dermatitis herpetiformis, significantly more than expected (SIR 10.3; 2.8-26.3). Thirteen (4.3%) patients with dermatitis herpetiformis died during the follow up but there was no increased general mortality. In coeliac disease, 13 (3.4%) patients developed malignancy (SIR 1.16; 0.62 to 1.97), 31 (8.1%) patients died but the survival rate did not differ from that in the general population. The incidence of non-Hodgkin's lymphoma was significantly increased in patients with dermatitis herpetiformis. The results also confirm that the patients with dermatitis herpetiformis treated mainly with a gluten free diet have no increased general mortality.


Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice.
Active delivery of recombinant autoantigens or allergens at the intestinal mucosa by genetically modified Lactococcus lactis (LL) provides a novel therapeutic approach for the induction of tolerance. Celiac disease is associated with either HLA-DQ2- or HLA-DQ8-restricted responses to specific antigenic epitopes of gliadin, and may be treated by induction of Ag-specific tolerance. We investigated whether oral administration of LL-delivered DQ8-specific gliadin epitope induces Ag-specific tolerance. LL was engineered to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and the induction of Ag-specific tolerance was studied in NOD AB degrees DQ8 transgenic mice. Tolerance was assessed by delayed-type hypersensitivity reaction, cytokine measurements, eDQ8d-specific proliferation, and regulatory T cell analysis. Oral administration of LL-eDQ8d induced suppression of local and systemic DQ8-restricted T cell responses in NOD AB degrees DQ8 transgenic mice. Treatment resulted in an Ag-specific decrease of the proliferative capacity of inguinal lymph node (ILN) cells and lamina propria cells. Production of IL-10 and TGF-beta and a significant induction of Foxp3(+) regulatory T cells were associated with the eDQ8d-specific suppression induced by LL-eDQ8d. These data provide support for the development of effective therapeutic approaches for gluten-sensitive disorders using orally administered Ag-secreting LL. Such treatments may be effective even in the setting of established hypersensitivity.


Depression and Anxiety in Adults With Hidradenitis Suppurativa: A Systematic Review and Meta-analysis.
Previous studies suggest that depression and anxiety are common in patients with hidradenitis suppurativa (HS), more so than other dermatological conditions. Yet, to the authors' knowledge, no previous systematic review or meta-analysis has estimated the prevalence or odds ratio (OR) for those psychiatric comorbidities in this population. To assess the prevalence and odds for depression and anxiety in patients with HS. From July 25 to September 30, 2018, observational studies investigating the prevalence and odds for depression and anxiety in adults with HS were systematically searched without language restriction from the inception of each database to July 25, 2018, in PubMed/MEDLINE, Embase, and PsycINFO databases. Searches used various configurations of the terms hidradenitis suppurativa; acne inversa; depressive disorder; depression; anxiety; anxiety disorders; phobia, social; suicide; and suicide, attempted. In addition, the reference lists of included references were screened manually. Two investigators independently screened references that measured prevalence rates and odds for depressive and anxiety symptoms in patients with HS. Of 136 unique references, 10 ultimately met inclusion criteria. Relevant data were extracted from eligible references. Authors were contacted to provide further information when necessary. Methodological quality of included studies was assessed through a modified version of the Newcastle-Ottawa Scale. Random-effects models were used to synthesize available evidence. Prevalence rates and ORs for depression and anxiety in adults with HS were the primary outcome measures. Heterogeneity across studies was assessed with the I2 statistic. Sources of heterogeneity were explored through subgroup and meta-regression analyses. Ten studies comprising 40 307 participants with HS met inclusion criteria. The overall prevalence of depression was 16.9% (95% CI, 9.9%-27.2%). Heterogeneity was large. In the subgroup of studies that considered a clinical criteria-based diagnosis of depression, the prevalence of depression was 11.9% (95% CI, 4.9%-26.2%), compared with 26.8% (95% CI, 20.4%-34.5%) in studies that used a screening instrument. The methodological quality of included studies moderated those findings. The OR for depression in individuals with HS compared with individuals without HS was 1.84 (95% CI, 1.57-2.15). The prevalence of anxiety was 4.9% (95% CI, 1.7%-13.2%); there were insufficient data to determine an odds ratio for anxiety in persons with HS because 2 studies included a comparison group. This systematic review and meta-analysis indicates that depression and anxiety are common comorbid conditions in patients with HS. Results suggest that the development of strategies to recognize and treat those psychiatric comorbidities in patients with HS is warranted.


Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells.
Heat shock protein 27 (Hsp27) is a cytoprotective chaperone that is phosphoactivated during cell stress that prevents aggregation and/or regulate activity and degradation of certain client proteins. Recent evidence suggests that Hsp27 may be involved in tumor progression and the development of treatment resistance in various tumors, including bladder cancer. The purpose of this study was to examine, both in vitro and in vivo, the effects of overexpression of Hsp27 and, correspondingly, the down-regulation of Hsp27 using small interfering (si) RNA and OGX-427, a second-generation antisense oligonucleotide targeting Hsp27. Hsp27 overexpression increased UMUC-3 cell growth and resistance to paclitaxel. Both OGX-427 and Hsp27 siRNA decreased Hsp27 protein and mRNA levels by >90% in a dose- and sequence-specific manner in human bladder cancer UMUC-3 cells. OGX-427 or Hsp27 siRNA treatment induced apoptosis and enhanced sensitivity to paclitaxel in UMUC-3 cells. In vivo, OGX-427 significantly inhibited tumor growth in mice, enhanced sensitivity to paclitaxel, and induced significantly higher levels of apoptosis compared with xenografts treated with control oligonucleotides. Collectively, these findings suggest that Hsp27 knockdown with OGX-427 and combined therapy with paclitaxel could be a novel strategy to inhibit the progression of bladder cancer.


Assignment of haem ligands and detection of electronic absorption bands of molybdenum in the di-haem periplasmic nitrate reductase of Paracoccus pantotrophus.
The periplasmic nitrate reductase (NAP) from Paracoccus pantotrophus is a soluble two-subunit enzyme (NapAB) that binds two c-type haems, a [4Fe-4S] cluster and a bis-molybdopterin guanine dinucleotide cofactor that catalyses the reduction of nitrate to nitrite. In the present work the NapAB complex has been studied by magneto-optical spectroscopy to probe co-ordination of both the NapB haems and the NapA active site Mo. The absorption spectrum of the NapAB complex is dominated by features from the NapB c-type cytochromes. Using a combination of electron paramagnetic resonance spectroscopy and magnetic circular dichroism it was demonstrated that both haems are low-spin with bis-histidine axial ligation. In addition, a window between 600 and 800 nm was identified in which weak absorption features that may arise from Mo could be detected. The low-temperature MCD spectrum shows oppositely signed bands in this region (peak 648 nm, trough 714 nm) which have been assigned to S-to-Mo(V) charge transfer transitions.


Convergence of soil nitrogen isotopes across global climate gradients.
Quantifying global patterns of terrestrial nitrogen (N) cycling is central to predicting future patterns of primary productivity, carbon sequestration, nutrient fluxes to aquatic systems, and climate forcing. With limited direct measures of soil N cycling at the global scale, syntheses of the (15)N:(14)N ratio of soil organic matter across climate gradients provide key insights into understanding global patterns of N cycling. In synthesizing data from over 6000 soil samples, we show strong global relationships among soil N isotopes, mean annual temperature (MAT), mean annual precipitation (MAP), and the concentrations of organic carbon and clay in soil. In both hot ecosystems and dry ecosystems, soil organic matter was more enriched in (15)N than in corresponding cold ecosystems or wet ecosystems. Below a MAT of 9.8°C, soil δ(15)N was invariant with MAT. At the global scale, soil organic C concentrations also declined with increasing MAT and decreasing MAP. After standardizing for variation among mineral soils in soil C and clay concentrations, soil δ(15)N showed no consistent trends across global climate and latitudinal gradients. Our analyses could place new constraints on interpretations of patterns of ecosystem N cycling and global budgets of gaseous N loss.


The detox strategy in smoking comprising nutraceutical formulas of non-hydrolyzed carnosine or carcinine used to protect human health.
The increased oxidative stress in patients with smoking-associated disease, such as chronic obstructive pulmonary disease, is the result of an increased burden of inhaled oxidants as well as increased amounts of reactive oxygen species generated by various inflammatory, immune and epithelial cells of the airways. Nicotine sustains tobacco addiction, a major cause of disability and premature death. In addition to the neurochemical effects of nicotine, behavioural factors also affect the severity of nicotine withdrawal symptoms. For some people, the feel, smell and sight of a cigarette and the ritual of obtaining, handling, lighting and smoking a cigarette are all associated with the pleasurable effects of smoking. For individuals who are motivated to quit smoking, a combination of pharmacotherapy and behavioural therapy has been shown to be most effective in controlling the symptoms of nicotine withdrawal. In the previous studies, we proposed the viability and versatility of the imidazole-containing dipeptide-based compounds in the nutritional compositions as the telomere protection targeted therapeutic system for smokers in combination with in vitro cellular culture techniques being an investigative tool to study telomere attrition in cells induced by cigarette smoke (CS) and smoke constituents. Our working therapeutic concept is that imidazole-containing dipeptide-based compounds (non-hydrolyzed carnosine and carcinine) can modulate the telomerase activity in the normal cells and can provide the redox regulation of the cellular function under the terms of environmental and oxidative stress and in this way protect the length and the structure of telomeres from attrition. The detoxifying system of non-hydrolyzed carnosine or carcinine can be applied in the therapeutic nutrition formulations or installed in the cigarette filter. Patented specific oral formulations of non-hydrolyzed carnosine and carcinine provide a powerful manipulation tool for targeted therapeutic inhibition of cumulative oxidative stress and inflammation and protection from telomere attrition associated with smoking. It is demonstrated in this work that both non-hydrolyzed carnosine and carcinine are characterized by greater bioavailability than pure l-carnosine subjected to enzymatic hydrolysis with carnosinase, and perform the detoxification of the α,β-unsaturated carbonyl compounds present in tobacco smoke. We argue that while an array of factors has shaped the history of the 'safer' cigarette, it is the current understanding of the industry's past deceptions and continuing avoidance of the moral implications of the sale of products that cause the enormous suffering and death of millions that makes reconsideration of 'safer' cigarettes challenging. In contrast to this, the data presented in the article show that recommended oral forms of non-hydrolyzed carnosine and carcinine protect against CS-induced disease and inflammation, and synergistic agents with the actions of imidazole-containing dipeptide compounds in developed formulations may have therapeutic utility in inflammatory lung diseases where CS plays a role.


The distribution and correlates of self-rated health in elderly Chinese: the China Kadoorie Biobank study.
Self-rated health (SRH) have been widely used as a valid indicator of health status at the population and individual level. We aimed to investigate the distribution and correlates of global SRH and age-comparative SRH in elderly Chinese. Survey of 57,693 men and 67,089 women aged 60 years and above was conducted in five rural (Gansu, Sichuan, Hunan, Henan, Zhejiang) and five urban areas (Heilongjiang, Shandong, Jiangsu, Guangxi, Hainan) in China between 2004 and 2008. Logistic regression models were used to calculate the relations of different factors with global SRH and age-comparative SRH. Among the participants, 38.33% reported their global SRH as good or excellent while 61.67% as fair or poor, and 17.70% reported better age-comparative SRH while 17.99% as worse. In the multivariate model, compared to women, men tended to report a good global SRH and better age-comparative SRH, urban residents tend to report good global SRH and better age-comparative SRH. The socioeconomic and health behavior factors that were associated with good global SRH and better age-comparative SRH (with varying strengths of association) included: high educational level, high household income, house ownership, quitting smoking by own choices, occasional and current alcohol drinking, overweight, and high physical activity level. The factors that were associated with poor global SRH and worse age-comparative SRH included: quitting smoking by illness, former drinking, underweight, and weight lost ≥2.5 kg in the previous year. We found a moderate level of good global SRH and a low level of better age-comparative SRH among elderly Chinese. We identified a number of demographic, socioeconomic and health behavior factors that were related to SRH measures. Our study emphasizes the importance of incorporating both global and age-comparative SRH measures in future studies, and considering gender inequalities and urban/rural disparity, as well as socioeconomic status and health behaviors as important modifiers of health.


Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation.
Current chemotherapeutic and butyrate therapeutics that induce fetal hemoglobin expression generally also suppress erythropoiesis, limiting the production of cells containing fetal hemoglobin (F cells). Recently, selected short-chain fatty acid derivatives (SCFADs) were identified that induce endogenous gamma-globin expression in K562 cells and human burst-forming units-erythroid and that increase proliferation of human erythroid progenitors and a multilineage interleukin-3-dependent hematopoietic cell line. In this report, gamma-globin inducibility by these SCFADs was further demonstrated in mice transgenic for the locus control region and the entire beta-globin gene locus in a yeast artificial chromosome and in 2 globin promoter-reporter assays. Conditioned media experiments strongly suggest that their proliferative activity is a direct effect of the test compounds. Investigation of potential mechanisms of action of these SCFADs demonstrates that these compounds induce prolonged expression of the growth-promoting genes c-myb and c-myc. Both butyrate and specific growth-stimulatory SCFADs induced prolonged signal transducer and activator of transcription (STAT)-5 phosphorylation and activation, and c-cis expression, persisting for more than 120 minutes, whereas with IL-3 alone phosphorylation disappeared within minutes. In contrast to butyrate treatment, the growth-stimulating SCFADs did not result in bulk histone H4 hyperacetylation or induction of p21(Waf/Cip), which mediates the suppression of cellular growth by butyrate. These findings suggest that the absence of bulk histone hyperacetylation and p21 induction, but prolonged induction of cis, myb, myc, and STAT-5 activation, contribute to the cellular proliferation induced by selected SCFADs.


Supramolecular chirality of amphiphilic block copolymer films made through two steps: self-assembling first, and then solution coating.
Supramolecular chirality is achieved in amphiphilic block copolymer films made through two-step fabrication: self-assembling first and then solution coating. The amphiphilic block copolymer is composed of poly(N-isopropyl acrylamide) (pNIPAM) as hydrophilic segments and poly(methyl methacrylate) with chiral side groups as hydrophobic segments. The films fabricated by two steps show sensible circular dichroism (CD) signals around a wavelength of 200 nm. However, CD signals cannot be detected from films made by directly coating the solution of copolymers on the quartz surface. The CD signal at about 200 nm is from supramolecular arrangement of benzene units connected to the chiral group in the hydrophobic segment. This result is thought to be originated from the aggregation of the copolymer during the first step of the film forming process, and the corresponding investigation into factors affecting this process has been performed in this work. It is also found that the films fabricated by two steps can adsorb chiral small molecules enantioselectively, while the films obtained by coating the solution of copolymers directly have no such enatioselective adsorption ability.