Analgesic therapy in postherpetic neuralgia: a quantitative systematic review.
Postherpetic neuralgia (PHN) is a complication of acute herpes zoster, which is emerging as a preferred clinical trial model for chronic neuropathic pain. Although there are published meta-analyses of analgesic therapy in PHN, and neuropathic pain in general, the evidence base has been substantially enhanced by the recent publication of several major trials. Therefore, we have conducted a systematic review and meta-analysis for both efficacy and adverse events of analgesic therapy for PHN. We systematically searched databases (MEDLINE 1966-2004, EMBASE 1988-2004, CINAHL 1982-2002, and PubMed [29 October 2004]) for trials of PHN. We also searched references of retrieved studies and review articles for further trials. We included trials that examined adult patients with PHN of greater duration than 3 mo, that were blinded, randomised, and had at least one measure of pain outcome. Dichotomous pain outcome data were extracted for 50% decrease in baseline pain using a hierarchy of pain/pain-relief measurement tools. Where available, dichotomous data were also collected for adverse events. Calculated estimates of efficacy included relative benefit and number needed to treat. Of 62 studies identified, 35 were randomised controlled trials. Of these, 31 were placebo controlled and suitable for meta-analysis, from which it was possible to extract dichotomous efficacy outcome data from 25. This meta-analysis revealed that there is evidence to support the use of the following orally administered therapies: tricyclic antidepressants, "strong" opioids, gabapentin, tramadol, and pregabalin. Topical therapies associated with efficacy were lidocaine 5% patch and capsaicin. Finally, a single study of spinal intrathecal administration of lidocaine and methyl prednisolone demonstrated efficacy, although this has yet to be replicated. Data suggest that the following therapies are not associated with efficacy in PHN: certain NMDA receptor antagonists (e.g., oral memantine, oral dextromethorphan, intravenous ketamine), codeine, ibuprofen, lorazepam, certain 5HT1 receptor agonists, and acyclovir. Topical administration of benzydamine, diclofenac/diethyl ether, and vincristine (iontophoresis) are similarly not associated with efficacy, nor are intrathecal administration of lidocaine alone or epidural administration of lidocaine and methylprednisolone, intravenous therapy with lidocaine, subcutaneous injection of Cronassial, or acupuncture. However, many of the trials that demonstrated a lack of efficacy represented comparatively low numbers of patient episodes or were single-dose studies, so it may be appropriate to regard such interventions as "not yet adequately tested" rather than demonstrating "no evidence of efficacy." Topical aspirin/diethyl ether has not been adequately tested. The evidence base supports the oral use of tricyclic antidepressants, certain opioids, and gabapentinoids in PHN. Topical therapy with lidocaine patches and capsaicin is similarly supported. Intrathecal administration of methylprednisolone appears to be associated with high efficacy, but its safety requires further evaluation.


Development of a novel headspace sorptive extraction method to study the aging of volatile compounds in spent handgun cartridges.
Estimating the time since the last discharge of firearms and/or spent cartridges may be a useful piece of information in forensic firearm-related cases. The current approach consists of studying the diffusion of selected volatile organic compounds (such as naphthalene) released during the shooting using solid-phase microextraction (SPME). However, this technique works poorly on handgun cartridges because the extracted quantities quickly fall below the limit of detection. In order to find more effective solutions and further investigate the aging of organic gunshot residue after the discharge of handgun cartridges, an extensive study was carried out in this work using a novel approach based on high-capacity headspace sorptive extraction (HSSE). By adopting this technique, for the first time 51 gunshot residue (GSR) volatile organic compounds could be simultaneously detected from fired handgun cartridge cases. Application to aged specimens showed that many of those compounds presented significant and complementary aging profiles. Compound-to-compound ratios were also tested and proved to be beneficial both in reducing the variability of the aging curves and in enlarging the time window useful in a forensic casework perspective. The obtained results were thus particularly promising for the development of a new complete forensic dating methodology.


Graduate medical education training in clinical epidemiology, critical appraisal, and evidence-based medicine: a critical review of curricula.
To systematically review the published literature on graduate medical education (GME) curricula in clinical epidemiology, critical appraisal, and evidence-based medicine (EBM). The author searched the Medline and Educational Resources Information Center (ERIC) databases from 1973 through 1998, and also searched the references of the captured papers. The author reviewed all peer-reviewed reports of GME curricula (with or without effectiveness studies) in critical appraisal, clinical epidemiology, or evidence-based medicine, extracting objectives, formats, and evaluations (including effectiveness, process, and satisfaction). For effectiveness evaluations, he also identified the outcomes, outcome measures, methodologic characteristics, and results. The search produced 18 reports. The most common objective of the curricula described in the reports was improving critical skills; the most common format was resident-directed small-group seminar. The most common outcome-evaluation measure was a multiple-choice examination. Only seven of the reports evaluated the curricula's effectiveness, and only four met a minimum methodologic standard of a pretest-posttest controlled trial. The impacts on critical appraisal skills of the curricula in those four reports ranged from no effect to a 23% net absolute increase in test scores. These reports provide useful guides for medical educators, but many suffered from incomplete descriptions and inadequate evaluations of their curricula. The curricula themselves often focused on critical appraisal to the exclusion of other EBM skills and had limited effectiveness. In addition to increased methodologic rigor, future studies should focus on more meaningful outcome evaluations. Curricula should use residents' actual clinical experiences and teach EBM skills in real time in existing clinical and educational venues.


Effect of Inhaled Lavender and Sleep Hygiene on Self-Reported Sleep Issues: A Randomized Controlled Trial.
To compare the effectiveness of lavender (Lavandula angustifolia) and sleep hygiene versus sleep hygiene alone on sleep quantity and sleep quality and to determine sustained effect at two-week follow-up. A randomized controlled trial with investigator blinding and steps taken to blind the participants. Participants' usual sleep setting. Seventy-nine college students with self-reported sleep issues. The intervention took place over five nights with baseline, postintervention, and two-week follow-up assessments. Both groups practiced good sleep hygiene and wore an inhalation patch on their chest at night. One group wore a patch with 55 μl of lavender essential oil and the other group wore a blank patch. Sleep quantity was measured using a Fitbit(®) tracker and a sleep diary, and sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI) and the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) sleep disturbance short form. The lavender and sleep hygiene group demonstrated better sleep quality at postintervention and two-week follow-up (PSQI p=0 .01, <0.001 and PROMIS p=0.04, 0.007, respectively). The sleep-hygiene-only group also demonstrated better sleep quality but to a lesser extent (PSQI p=0.02, 0.06 and PROMIS p=0.03, 0.03, respectively). Additionally, a clinical effect was found for the lavender group at postintervention, along with a significant finding for waking feeling refreshed (p=0.01). Sleep quantity did not differ between groups. Lavender and sleep hygiene together, and sleep hygiene alone to a lesser degree, improved sleep quality for college students with self-reported sleep issues, with an effect remaining at follow-up.


Functional Photoacoustic Imaging for Placental Monitoring: A Mini Review.
The placenta, a highly vascularized interface between the mother and fetus, undergoes dramatic anatomical and functional changes during pregnancy. These changes occur both during healthy development and adverse pathologies of pregnancy, such as preeclampsia (PE). Abnormal placental development can lead to life-long health impacts on both the mother and child. Photoacoustic (PA) imaging, extensively developed for preclinical imaging applications in oncology and cardiovascular disease, uses optical energy to generate acoustic waves through thermoelastic expansion of light-absorbing chromophores within tissue. Recently, PA imaging has been used to study preclinical placental anatomy and function. If clinical translation of PA imaging of the placenta is achieved, the impact on maternal-fetal health could be expansive. This perspective highlights the recent progress in PA imaging for placental monitoring and discusses the progress needed for human clinical translation.


A Randomized, Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable, Locally Advanced Head and Neck Cancer.
We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced head and neck squamous cell carcinoma. Patients were randomized to receive three cycles of docetaxel and cisplatin (TP regimen) with or without cetuximab (TP plus cetuximab [CTP] vs. TP) as induction chemotherapy. Patients in the CTP arm received CCRT with cetuximab and cisplatin, whereas patients in the TP arm received cisplatin alone. The primary endpoint was the objective response rate (ORR) after induction chemotherapy. Overall, 92 patients were enrolled. The ORRs for induction chemotherapy in the CTP and TP arms were not different (81% vs. 82%). Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and resulted in more frequent dose reductions of the induction chemotherapy, although this did not reach statistical significance. In the CTP and TP arms, respectively, the 3-year progression-free survival (PFS) rates were 70% and 56% (p = .359), and the overall survival (OS) rates were 88% and 74% (p = .313). When limited to patients who completed induction chemotherapy, 3-year PFS rates of 78% and 59% (p = .085) and OS rates of 94% and 73% (p = .045) were observed in the CTP and TP arms, respectively. Adding cetuximab to sequential treatment did not increase the treatment efficacy and resulted in greater toxicity. In the intent-to-treat population, neither PFS nor OS was improved by the addition of cetuximab to sequential treatment; however, a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy.


The consumer-driven development and acceptability testing of a website designed to connect rural cancer patients and their families, carers and health professionals with appropriate information and psychosocial support.
Websites offer new opportunities to provide health-related information to rural communities. However, how acceptable they are to this population is unknown. This paper describes the consumer-led development of a website that provides rural-specific information on psychosocial care for rural South Australians affected by cancer, and examines its acceptability to users. The Country Cancer Support website was developed with people affected by cancer living in rural South Australia (N = 11), using a Participatory Action Research Framework and evidence-based behaviour change strategies. There were 32,389 visits in the first 3 years. An online survey (N = 111) revealed that users found the website easy to use, helpful and relevant. Most rural cancer patients and supporters (98.11%) believed it had been written by people who understood what they were going through. Patients and supporters for whom it was relevant, reported feeling more motivated and confident in accessing psychosocial support services in their rural area (66.67%) and/or capital city (67.65%) and/or in travelling for medical treatment (75.86%). Many also felt less isolated (73.33%) and/or distressed (53.57%). All health professionals reported gaining new knowledge. This study shows that carefully designed websites can successfully address rural populations' health information needs and increase intentions to access psychosocial support.


The Russian School Twin Registry (RSTR): project PROGRESS.
The Russian School Twin Registry (RSTR) was established in 2012, supported by a grant from the Government of the Russian Federation. The main aim of the registry is to contribute to Progress in Education through Gene-Environment Studies (PROGRESS). The formation of the registry is ongoing and it is expected that most schools in the Russian Federation (approximately 50,000 schools) will contribute data to the registry. With a total of 13.7 million students in Grades 1-11 (ages 7-18), the potential number of twin pairs exceeds 100,000. Apart from the large sample size and its representative nature, the RSTR has one unique feature: in collaboration with the International Advisory Committee to the Registry, genetically sensitive cross-cultural investigations are planned, aided by the use of the common assessment instruments. Other strengths of the registry include the assessment of a large sample of non-twin school children, including those studying in the same classes as the twins in the registry. It is hoped that the RSTR will provide an important research platform for national and international educationally relevant research.


Hormonal contraception in women with IDDM. Influence on glycometabolic control and lipoprotein metabolism.
Safe and effective contraceptive methods are essential for women with insulin-dependent diabetes mellitus (IDDM), but opinions on the use of hormonal oral contraceptives by these women are conflicting. We evaluated the effects on glycometabolic control and lipoprotein metabolism in women with IDDM treated with an oral contraceptive not previously studied in a diabetic population. A total of 22 women with IDDM received a monophasic combination of ethinyl estradiol and gestodene for 1 year; 20 women of comparable diabetic status using nonhormonal contraception were selected as control subjects. Evaluation was performed before and after 1, 3, 6, and 12 months of hormonal intake using nonparametric statistical methods. Except for a higher median age of the control group, the baseline values for all clinical and metabolic variables were similar in the two groups, and in neither of the groups were changes in blood pressure, body mass index, or glycemic control observed. In the oral contraceptive group, decreased serum levels of low-density lipoprotein (LDL) cholesterol and increased levels of triglycerides and lipoprotein A were noted, whereas total cholesterol and high-density lipoprotein cholesterol levels were unchanged. In the control group, a decrease of LDL cholesterol was observed. No effect of tobacco smoking on glycometabolic control or lipoprotein metabolism could be demonstrated during hormonal intake. No evidence of impaired glycometabolic control or adverse changes in serum levels of lipoproteins known to be associated with atherosclerosis was observed in women with well-controlled IDDM during 1 year of oral contraception with ethinyl estradiol and gestodene.


Clindamycin versus trimethoprim-sulfamethoxazole for uncomplicated skin infections.
Skin and skin-structure infections are common in ambulatory settings. However, the efficacy of various antibiotic regimens in the era of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is unclear. We enrolled outpatients with uncomplicated skin infections who had cellulitis, abscesses larger than 5 cm in diameter (smaller for younger children), or both. Patients were enrolled at four study sites. All abscesses underwent incision and drainage. Patients were randomly assigned in a 1:1 ratio to receive either clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) for 10 days. Patients and investigators were unaware of the treatment assignments and microbiologic test results. The primary outcome was clinical cure 7 to 10 days after the end of treatment. A total of 524 patients were enrolled (264 in the clindamycin group and 260 in the TMP-SMX group), including 155 children (29.6%). One hundred sixty patients (30.5%) had an abscess, 280 (53.4%) had cellulitis, and 82 (15.6%) had mixed infection, defined as at least one abscess lesion and one cellulitis lesion. S. aureus was isolated from the lesions of 217 patients (41.4%); the isolates in 167 (77.0%) of these patients were MRSA. The proportion of patients cured was similar in the two treatment groups in the intention-to-treat population (80.3% in the clindamycin group and 77.7% in the TMP-SMX group; difference, -2.6 percentage points; 95% confidence interval [CI], -10.2 to 4.9; P=0.52) and in the populations of patients who could be evaluated (466 patients; 89.5% in the clindamycin group and 88.2% in the TMP-SMX group; difference, -1.2 percentage points; 95% CI, -7.6 to 5.1; P=0.77). Cure rates did not differ significantly between the two treatments in the subgroups of children, adults, and patients with abscess versus cellulitis. The proportion of patients with adverse events was similar in the two groups. We found no significant difference between clindamycin and TMP-SMX, with respect to either efficacy or side-effect profile, for the treatment of uncomplicated skin infections, including both cellulitis and abscesses. (Funded by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health; ClinicalTrials.gov number, NCT00730028.).


Identification of multiple transcription initiation, polyadenylation, and splice sites in the Drosophila melanogaster TART family of telomeric retrotransposons.
The Drosophila non-long terminal repeat (non-LTR) retrotransposons TART and HeT-A specifically retrotranspose to chromosome ends to maintain Drosophila telomeric DNA. Relatively little is known, though, about the regulation of their expression and their retrotransposition to telomeres. We have used rapid amplification of cDNA ends (RACE) to identify multiple transcription initiation and polyadenylation sites for sense and antisense transcripts of three subfamilies of TART elements in Drosophila melanogaster. These results are consistent with the production of an array of TART transcripts. In contrast to other Drosophila non-LTR elements, a major initiation site for sense transcripts was mapped near the 3' end of the TART 5'-untranslated region (5'-UTR), rather than at the start of the 5'-UTR. A sequence overlapping this sense start site contains a good match to an initiator consensus for the transcription start sites of Drosophila LTR retrotransposons. Interestingly, analysis of 5' RACE products for antisense transcripts and the GenBank EST database revealed that TART antisense transcripts contain multiple introns. Our results highlight differences between transcription of TART and of other Drosophila non-LTR elements and they provide a foundation for testing the relationship between exceptional aspects of TART transcription and TART's specialized role at telomeres.


Pterygium among Latino migrant farmworkers in North Carolina.
The authors describe the prevalence and severity of pterygium among Latino migrant farmworkers in North Carolina and delineate its risk factors. They selected a sample of 304 farmworkers working in eastern North Carolina in 2005. Digital photographs were taken of each farmworker, including a facial view showing the eyes. Two physicians independently rated each farmworker for the presence and severity of pterygia, with an initial intercoder agreement of 91%. Sixty-eight (23.3%) participants had a pterygium in at least 1 eye; 28 (9.5%) had bilateral pterygia. Age was significantly associated with pterygia (odds ratio = 1.07; 95% confidence interval = 1.03-1.11). Research on the causes of pterygium among farmworkers is needed. In the interim, improvements in farmworkers' preventive behaviors, such as wearing ultraviolet protective lenses and brimmed hats, are reasonable and inexpensive measures.


Death of Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes in shelf-stable, dairy-based, pourable salad dressings.
The objectives of this study were to determine the death rates of Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes in three commercially manufactured full-fat ranch salad dressings, three reduced-fat ranch salad dressings, two full-fat blue cheese salad dressings, and two reduced-fat blue cheese salad dressings and to affirm the expectation that these dressings do not support the growth of these pathogens. The respective initial pH values of the four types of shelf-stable, dairy-based, pourable dressings were 2.87 to 3.72, 2.82 to 3.19, 3.08 to 3.87, and 2.83 to 3.49, respectively. Dressings were inoculated with low (2.4 to 2.5 log CFU/g) and high (5.3 to 5.9 log CFU/g) populations of separate five-strain mixtures of each pathogen and stored at 25 degrees C for up to 15 days. Regardless of the initial inoculum population, all test pathogens rapidly died in all salad dressings. Salmonella was undetectable by enrichment (<1 CFU/25-ml sample in three replicate trials) in all salad dressings within 1 day, and E. coli O157:H7 and L. monocytogenes were reduced to undetectable levels by enrichment between 1 and 8 days and 2 and 8 days, respectively. E. coli O157:H7 was not detected in 4 of the 10 salad dressings stored for 2 or more days and 9 of the 10 dressings stored for 6 or more days after inoculation. L. monocytogenes was detected in 9 of the 10 salad dressings stored for 3 days but in only one dressing, by enrichment, at 6 days, indicating that it had the highest tolerance among the three pathogens to the acidic environment imposed by the dressings. Overall, the type of dressing (i.e., ranch versus blue cheese) and level of fat in the dressings did not have a marked effect on the rate of inactivation of pathogens. Total counts and populations of lactic acid bacteria and yeasts and molds remained low or undetectable (<1.0 log CFU/ml) throughout the 15-day storage period. Based on these observations, shelf-stable, dairy-based, pourable ranch and blue cheese salad dressings manufactured by three companies and stored at 25 degrees C do not support the growth of Salmonella, E. coli O157:H7, and L. monocytogenes and should not be considered as potentially hazardous foods (time-temperature control for safety foods) as defined by the U.S. Food and Drug Administration Food Code.


The behaviour of purchasing smuggled cigarettes in Taiwan.
Since market liberalization in 1987, the Taiwan Tobacco and Wine Monopoly Bureau (TTWMB) annual statistics indicate that both the demand for imported cigarettes as well as the number of seized smuggled packs have increased with an average revenue loss of NT dollars 4942 million over the past 15 years. The NT dollars 10 average increase in cigarette prices after Taiwan entered the World Trade Organization (WTO) and the implementation of the Tobacco and Alcohol Tax Law in 2002 are forcing policy makers to examine smuggling even more closely. This study evaluates factors that affect an individual smoker's decision to purchase smuggled cigarettes, particularly when faced with higher prices. 437 male smokers of imported cigarettes were drawn from a national interview survey on cigarette consumption, which the Division of Health Policy Research at the National Health Research Institutes conducted during the year 2000. Multiple logistic regression models were used to analyse the behaviour of purchasing smuggled cigarettes with respect to demographic factors, economic factors, smoking behaviour, and other variables. Cigarette price was the driving factor most closely linked to the purchase of smuggled cigarettes--a 1% increase in cigarette price raised the likelihood of purchasing smuggled cigarettes at least 2.60 times (95% confidence interval (CI) 1.08 to 6.26). Smokers who spent more than NT 1000/month dollars on cigarettes were twice as likely to purchase smuggled cigarettes as those who spent less than NT 1000 dollars (odds ratio (OR) 2.34, 95% CI 1.48 to 3.70). Betel nut chewers were more likely to purchase smuggled cigarettes (OR 1.80, 95% CI 1.09 to 2.90). Smokers who opposed cigarette taxation policy were 1.69 times more likely to buy smuggled cigarettes. Personal income was not significantly associated with smuggled cigarettes purchases. This study evaluates what causes smokers to purchase smuggled cigarettes. We have determined that cigarette price is the most important factor and that betel nut vendors are the main suppliers. Our study provides policy makers with information that can help them develop effective strategies to curb cigarette smuggling after Taiwan's recent cigarette tax reform, which has increased cigarette prices.


The impact of gape on the performance of the skull in chisel-tooth digging and scratch digging mole-rats (Rodentia: Bathyergidae).
The African mole-rats (Bathyergidae) are a family of rodents highly adapted for life underground. Previous research has shown that chisel-tooth digging mole-rats (which use their incisors to dig burrows) are clearly distinguishable from scratch diggers (which only use the forelimbs to tunnel) on the basis of morphology of the skull, and that the differences are linked to the production of high bite forces and wide gapes. We hypothesized that the skull of a chisel-tooth digging mole-rat would perform better at wider gapes than that of a scratch digging mole-rat during incisor biting. To test this hypothesis, we created finite-element models of the cranium of the scratch digging Bathyergus suillus and the chisel-tooth digging Fukomys mechowii, and loaded them to simulate incisor bites at different gapes. Muscle loads were scaled such that the ratio of force to surface area was the same in both models. We measured three performance variables: overall stress across the cranium, mechanical efficiency of biting and degree of deformation across the skull. The Fukomys model had a more efficient incisor bite at all gapes, despite having greater average stress across the skull. In addition, the Fukomys model deformed less at wider gapes, whereas the Bathyergus model deformed less at narrower gapes. These properties of the cranial morphology of Fukomys and Bathyergus are congruent with their respective chisel-tooth and scratch digging behaviours and, all other factors being equal, would enable the more efficient production of bite force at wider gapes in Fukomys. However, in vivo measurements of muscle forces and activation patterns are needed to fully understand the complex biomechanics of tooth digging.


Dinuclear ZnII and mixed CuII-ZnII complexes of artificial patellamides as phosphatase models.
The patellamides (cyclic pseudo-octapeptides) are produced by Prochloron, a symbiont of the ascidians, marine invertebrate filter feeders. These pseudo-octapeptides are present in the cytoplasm and a possible natural function of putative metal complexes of these compounds is hydrolase activity, however the true biological role is still unknown. The dinuclear CuII complexes of synthetic patellamide derivatives have been shown in in vitro experiments to be efficient hydrolase model catalysts. Many hydrolase enzymes, specifically phosphatases and carboanhydrases, are ZnII-based enzymes and therefore, we have studied the ZnII and mixed ZnII/CuII solution chemistry of a series of synthetic patellamide derivatives, including solution structural and computational work, with the special focus on model phosphatase chemistry with bis-(2,4-dinitrophenyl)phosphate (BDNPP) as the substrate. The ZnII complexes of a series of ligands are shown to form complexes of similar structure and stability compared to the well-studied CuII analogues and the phosphatase reactivities are also similar. Since the complex stabilities and phosphatase activities are generally a little lower compared to those of CuII and since the concentration of ZnII in Prochloron cells is slightly smaller, we conclude that the CuII complexes of the patellamides are more likely to be of biological importance.


Connecting Histopathology Imaging and Proteomics in Kidney Cancer through Machine Learning.
Proteomics data encode molecular features of diagnostic value and accurately reflect key underlying biological mechanisms in cancers. Histopathology imaging is a well-established clinical approach to cancer diagnosis. The predictive relationship between large-scale proteomics and H&E-stained histopathology images remains largely uncharacterized. Here we investigate such associations through the application of machine learning, including deep neural networks, to proteomics and histology imaging datasets generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) from clear cell renal cell carcinoma patients. We report robust correlations between a set of diagnostic proteins and predictions generated by an imaging-based classification model. Proteins significantly correlated with the histology-based predictions are significantly implicated in immune responses, extracellular matrix reorganization, and metabolism. Moreover, we showed that the genes encoding these proteins also reliably recapitulate the biological associations with imaging-derived predictions based on strong gene-protein expression correlations. Our findings offer novel insights into the integrative modeling of histology and omics data through machine learning, as well as the methodological basis for new research opportunities in this and other cancer types.


An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice.
Progressive hearing loss is common in the human population, but little is known about the molecular basis. We report a new N-ethyl-N-nitrosurea (ENU)-induced mouse mutant, diminuendo, with a single base change in the seed region of Mirn96. Heterozygotes show progressive loss of hearing and hair cell anomalies, whereas homozygotes have no cochlear responses. Most microRNAs are believed to downregulate target genes by binding to specific sites on their mRNAs, so mutation of the seed should lead to target gene upregulation. Microarray analysis revealed 96 transcripts with significantly altered expression in homozygotes; notably, Slc26a5, Ocm, Gfi1, Ptprq and Pitpnm1 were downregulated. Hypergeometric P-value analysis showed that hundreds of genes were upregulated in mutants. Different genes, with target sites complementary to the mutant seed, were downregulated. This is the first microRNA found associated with deafness, and diminuendo represents a model for understanding and potentially moderating progressive hair cell degeneration in hearing loss more generally.


Hyperbolic and plasmonic properties of silicon/Ag aligned nanowire arrays.
The hyperbolic and plasmonic properties of silicon nanowire/Ag arrays have been investigated. The aligned nanowire arrays were formed and coated by atomic layer deposition of Ag, which itself is a metamaterial due to its unique mosaic film structure. The theoretical and numerical studies suggest that the fabricated arrays have hyperbolic dispersion in the visible and IR ranges of the spectrum. The theoretical predictions have been indirectly confirmed by polarized reflection spectra, showing reduction of the reflection in p polarization in comparison to that in s polarization. Studies of dye emission on top of Si/Ag nanowire arrays show strong emission quenching and shortening of dye emission kinetics. This behavior is also consistent with the predictions for hyperbolic media. The measured SERS signals were enhanced by almost an order of magnitude for closely packed and aligned nanowires, compared to random nanowire composites. These results agree with electric field simulations of these array structures.


DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes.
Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-of-function DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed high-resolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-left-right dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.


Outcome of pregnancy in Asian women with systemic lupus erythematosus: experience of a single perinatal centre in Singapore.
To study maternal and fetal outcomes in women with systemic lupus erythematosus (SLE). Retrospective study of 27 pregnancies in 18 women with SLE in a single centre. The mean age was 30 years and most patients were nulliparous. Twenty-six of 27 pregnancies were in disease remission at the time of booking. Renal impairment was present in 7 pregnancies (6 women), of whom 2 were in end-stage renal disease on dialysis. Gestational diabetes developed in 4 pregnancies. There were 6 cases of pre-existing hypertension and 5 with superimposed pre-eclampsia. One woman developed intrapartum eclampsia. Two women had secondary antiphospholipid syndrome (APS) and suffered late fetal losses; in addition, they also developed SLE flares in the form of autoimmune haemolytic anaemia in the postpartum period. There was no maternal mortality. There was one termination of pregnancy for severe renal disease. The median gestational age at delivery was 38 weeks (range, 24 to 40 weeks) and the mean birth weight was 3047 g; the median Apgar scores were 8 and 9 at 1 and 5 minutes of life, respectively. There were 5 cases of intrauterine growth restriction (IUGR), 4 of which occurred in women with renal impairment. There were no cases of congenital heart block or neonatal lupus. There was a late fetal loss at 24 weeks in a woman with secondary APS. There were 2 preterm deliveries (7.4%) due to intervention for IUGR. Good pregnancy outcomes can be expected in women with SLE in remission. Pre-pregnancy counselling is crucial to achieve this. All pregnancies should still be considered high risk and be managed jointly between the obstetricians, the perinatologists and the physicians. In particular, those with renal impairment are at increased risk of IUGR, superimposed pre-eclampsia and preterm births. Co-existing APS augurs a poorer prognosis for pregnancy outcome, and may present atypically as autoimmune haemolytic anaemia in the postpartum period.


Modal loss mechanism of micro-structured VCSELs studied using full vector FDTD method.
Modal properties of vertical cavity surface-emitting lasers (VCSELs) with holey structures are studied using a finite difference time domain (FDTD) method. We investigate loss behavior with respect to the variation of structural parameters, and explain the loss mechanism of VCSELs. We also propose an effective method to estimate the modal loss based on mode profiles obtained using FDTD simulation. Our results could provide an important guideline for optimization of the microstructures of high-power single-mode VCSELs.


Lung cancer screening: from imaging to biomarker.
Despite several decades of intensive effort to improve the imaging techniques for lung cancer diagnosis and treatment, primary lung cancer is still the number one cause of cancer death in the United States and worldwide. The major causes of this high mortality rate are distant metastasis evident at diagnosis and ineffective treatment for locally advanced disease. Indeed, approximately forty percent of newly diagnosed lung cancer patients have distant metastasis. Currently, the only potential curative therapy is surgical resection of early stage lung cancer. Therefore, early detection of lung cancer could potentially increase the chance of cure by surgery and underlines the importance of screening and detection of lung cancer. In the past fifty years, screening of lung cancer by chest X-Ray (CXR), sputum cytology, computed tomography (CT), fluorescence endoscopy and low-dose spiral CT (LDCT) has not improved survival except for the recent report in 2010 by the National Lung Screening Trial (NLST), which showed a 20 percent mortality reduction in high risk participants screened with LDCT compared to those screened with CXRs. Furthermore, serum biomarkers for detection of lung cancer using free circulating DNA and RNA, exosomal microRNA, circulating tumor cells and various lung cancer specific antigens have been studied extensively and novel screening methods are being developed with encouraging results. The history of lung cancer screening trials using CXR, sputum cytology and LDCT, as well as results of trials involving various serum biomarkers, are reviewed herein.


Pregnancy insulin, glucose, and BMI contribute to birth outcomes in nondiabetic mothers.
We investigated the effects of normal variations in maternal glycemia on birth size and other birth outcomes. Women in two unselected birth cohorts, one retrospective (n = 3,158) and one prospective (n = 668), underwent an oral glucose challenge at 28 weeks of gestation. In the retrospective study, glycemia was linked to routine birth records. In the prospective study, offspring adiposity was assessed by skinfold thickness from birth to age 24 months. In the retrospective study, within the nondiabetic range (2.1-7.8 mmol/l), each 1 mmol/l rise in the mother's 60-min glucose level was associated with a (mean +/- SEM) 2.1 +/- 0.8% (P = 0.006) rise in absolute risk of assisted vaginal delivery, a 3.4 +/- 0.8% (P < 0.0001) rise in emergency cesarean delivery, a 3.1 +/- 0.7% (P < 0.0001) rise in elective cesarean delivery, and a 46 +/- 8 g (P < 0.0001) increase in offspring birth weight. In the prospective study, fetal macrosomia (birth weight >90th centile) was independently related to the mother's fasting glucose (odds ratio 2.61 per +1 mmol/l [95% CI 1.15-5.93]) and prepregnancy BMI (1.10 per +1 kg/m(2) [1.04-1.18]). The mother's higher fasting glycemia (P = 0.004), lower insulin sensitivity (P = 0.01), and lower insulin secretion (P = 0.02) were independently related to greater offspring adiposity at birth. During postnatal follow-up, the correlation between the mother's glycemia and offspring adiposity disappeared by 3 months, whereas prepregnancy BMI was associated with offspring adiposity that was only apparent at 12 and 24 months (both P < 0.05). Prepregnancy BMI, pregnancy glycemia, insulin sensitivity, and insulin secretion all contribute to offspring adiposity and macrosomia and may be separate targets for intervention to optimize birth outcomes and later offspring health.


Review: magnetic resonance imaging of male/female differences in human adolescent brain anatomy.
Improvements in neuroimaging technologies, and greater access to their use, have generated a plethora of data regarding male/female differences in the developing brain. Examination of these differences may shed light on the pathophysiology of the many illnesses that differ between the sexes and ultimately lead to more effective interventions. In this review, we attempt to synthesize the anatomic magnetic resonance imaging (MRI) literature of male/female brain differences with emphasis on studies encompassing adolescence - a time of divergence in physical and behavioral characteristics. Across all ages total brain size is consistently reported to be about 10% larger in males. Structures commonly reported to be different between sexes include the caudate nucleus, amygdala, hippocampus, and cerebellum - all noted to have a relatively high density of sex steroid receptors. The direction and magnitude of reported brain differences depends on the methodology of data acquisition and analysis, whether and how the subcomponents are adjusted for the total brain volume difference, and the age of the participants in the studies. Longitudinal studies indicate regional cortical gray matter volumes follow inverted U shaped developmental trajectories with peak size occurring one to three years earlier in females. Cortical gray matter differences are modulated by androgen receptor genotyope and by circulating levels of hormones. White matter volumes increase throughout childhood and adolescence in both sexes but more rapidly in adolescent males resulting in an expanding magnitude of sex differences from childhood to adulthood.


Musician children detect pitch violations in both music and language better than nonmusician children: behavioral and electrophysiological approaches.
The idea that extensive musical training can influence processing in cognitive domains other than music has received considerable attention from the educational system and the media. Here we analyzed behavioral data and recorded event-related brain potentials (ERPs) from 8-year-old children to test the hypothesis that musical training facilitates pitch processing not only in music but also in language. We used a parametric manipulation of pitch so that the final notes or words of musical phrases or sentences were congruous, weakly incongruous, or strongly incongruous. Musician children outperformed nonmusician children in the detection of the weak incongruity in both music and language. Moreover, the greatest differences in the ERPs of musician and nonmusician children were also found for the weak incongruity: whereas for musician children, early negative components developed in music and late positive components in language, no such components were found for nonmusician children. Finally, comparison of these results with previous ones from adults suggests that some aspects of pitch processing are in effect earlier in music than in language. Thus, the present results reveal positive transfer effects between cognitive domains and shed light on the time course and neural basis of the development of prosodic and melodic processing.


Multi-parametric classification of Alzheimer's disease and mild cognitive impairment: the impact of quantitative magnetization transfer MR imaging.
Multi-parametric and quantitative magnetic resonance imaging (MRI) techniques have come into the focus of interest, both as a research and diagnostic modality for the evaluation of patients suffering from mild cognitive decline and overt dementia. In this study we address the question, if disease related quantitative magnetization transfer effects (qMT) within the intra- and extracellular matrices of the hippocampus may aid in the differentiation between clinically diagnosed patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI) and healthy controls. We evaluated 22 patients with AD (n=12) and MCI (n=10) and 22 healthy elderly (n=12) and younger (n=10) controls with multi-parametric MRI. Neuropsychological testing was performed in patients and elderly controls (n=34). In order to quantify the qMT effects, the absorption spectrum was sampled at relevant off-resonance frequencies. The qMT-parameters were calculated according to a two-pool spin-bath model including the T1- and T2 relaxation parameters of the free pool, determined in separate experiments. Histograms (fixed bin-size) of the normalized qMT-parameter values (z-scores) within the anterior and posterior hippocampus (hippocampal head and body) were subjected to a fuzzy-c-means classification algorithm with downstreamed PCA projection. The within-cluster sums of point-to-centroid distances were used to examine the effects of qMT- and diffusion anisotropy parameters on the discrimination of healthy volunteers, patients with Alzheimer and MCIs. The qMT-parameters T2(r) (T2 of the restricted pool) and F (fractional pool size) differentiated between the three groups (control, MCI and AD) in the anterior hippocampus. In our cohort, the MT ratio, as proposed in previous reports, did not differentiate between MCI and AD or healthy controls and MCI, but between healthy controls and AD.


Cubes on a string: a series of linear coordination polymers with cubane-like nodes and dicarboxylate linkers.
A series of semicrystalline and amorphous one-dimensional (1D) polymeric chains consisting of cubane-like CoII4L4 units (L = S-1,2-bis(benzimidazol-2-yl)ethanol) and dicarboxylates were synthesized and characterized by single crystal diffraction and X-ray total scattering. The polycationic chains are composed of [Co4L4(dicarboxylate)]2+ monomeric units, while one molecular dicarboxylate counterion is balancing the charge of each monomer. The linear compound series has five members, and the crystal structures were solved for [Co4L4(tph)](tph) and [Co4L4(ndc)](ndc), where tph = terephthalate and ndc = 2,6-naphthalenedicarboxylate. Partly crystalline compounds were produced by slow assembly at elevated temperature (over days), while the amorphous compounds were formed by fast precipitation (within minutes). Pair distribution function (PDF) analysis based on X-ray total scattering data reveals the presence of the cubane-like entity in both the amorphous and semicrystalline samples. While the powders are non-porous, precipitation is a fast and versatile method to produce compounds with cubane-like centres with moderate surface areas of 17-49 m2 g-1 allowing for surface chemical reactions. The powders have a high concentration of Lewis base sites as verified by their selective adsorption of CO2 over N2. The use of an amorphous cubane-like polymer for the electrocatalytic oxygen evolution reaction was demonstrated.


Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: a prospective randomized double-blind clinical trial.
We sought to determine the impact of the addition of Dor fundoplication on the incidence of postoperative gastroesophageal reflux (GER) after Heller myotomy. Based only on case series, many surgeons believe that an antireflux procedure should be added to the Heller myotomy. However, no prospective randomized data support this approach. In this prospective, randomized, double-blind, institutional review board-approved clinical trial, patients with achalasia were assigned to undergo Heller myotomy or Heller myotomy plus Dor fundoplication. Patients were studied via 24-hour pH study and manometry at 6 months postoperatively. Pathologic GER was defined as distal esophageal time acid exposure time greater than 4.2% per 24-hour period. The outcome variables were analyzed on an intention-to-treat basis. Forty-three patients were enrolled. There were no differences in the baseline characteristics between study groups. Pathologic GER occurred in 10 of 21 patients (47.6%) after Heller and in 2 of 22 patients (9.1%) after Heller plus Dor (P = 0.005). Heller plus Dor was associated with a significant reduction in the risk of GER (relative risk 0.11; 95% confidence interval 0.02-0.59; P = 0.01). Median distal esophageal acid exposure time was lower in the Heller plus Dor (0.4%; range, 0-16.7) compared with the Heller group (4.9%; range, 0.1-43.6; P = 0.001). No significant difference in surgical outcome between the 2 techniques with respect to postoperative lower-esophageal sphincter pressure or postoperative dysphagia score was observed. Heller Myotomy plus Dor Fundoplication was superior to Heller myotomy alone in regard to the incidence of postoperative GER.


Mechanism of impaired regeneration of fatty liver in mouse partial hepatectomy model.
The mechanism of injury in steatotic liver under pathological conditions been extensively examined. However, the mechanism of an impaired regeneration is still not well understood. The aim of this study was to analyze the mechanism of impaired regeneration of steatotic liver after partial hepatectomy (PH). db/db fatty mice and lean littermates were used for the experiments. Following 70% PH, the survival rate and recovery of liver mass were examined. Liver tissue was histologically examined and analyzed by western blotting and RT-PCR. Of 35 db/db mice, 25 died within 48 h of PH, while all of the control mice survived. Liver regeneration of surviving db/db mice was largely impaired. In db/db mice, mitosis of hepatocytes after PH was disturbed, even though proliferating cell nuclear antigen (PCNA) expression (G1 to S phase marker) in hepatocytes was equally observed in both mice groups. Interestingly, phosphorylation of Cdc2 in db/db mice was suppressed by reduced expression of Wee1 and Myt1, which phosphorylate Cdc2 in S to G2 phase. In steatotic liver, cell-cycle-related proliferative disorders occurred at mid-S phase after PCNA expression. Reduced expression of Wee1 and Myt1 kinases may therefore maintain Cdc2 in an unphosphorylated state and block cell cycle progression in mid-S phase. These kinases may be critical factors involved in the impaired liver regeneration in fatty liver.


Glycated low-density lipoprotein attenuates shear stress-induced nitric oxide synthesis by inhibition of shear stress-activated L-arginine uptake in endothelial cells.
Little is known about the mechanism(s) of endothelial dysfunction in diabetes. In this study, the effect of nonenzymatic glycated LDL, a phenomenon induced by elevated D-glucose levels associated with diabetes, on porcine aortic endothelial cells was investigated. Two fractions of LDL from diabetic patients were separated by affinity column chromatography and are referred to herein as fraction alpha (nonglycated LDL) and fraction beta (glycated LDL). Incubation of endothelial cells for 24 h with total LDL isolated from diabetic subjects (dLDL) increased the release of superoxide anions (*O2-) by fivefold, while no effect of LDL isolated from healthy individuals (nLDL) was found. Fraction beta, but not fraction alpha, evoked the *O2- release. In vitro-glycated LDL mimicked the effect of dLDL/fraction beta on *O2- release that correlated with its degree of glycation (R2 = 0.96). Moreover, nitric oxide (NO) stability (measured with a porphyrinic-based electrode) and NO bioactivity (measured by its ability to elevate cellular cGMP levels) were reduced in cells treated with dLDL by 46 and 41%, respectively. dLDL (but not nLDL or fraction alpha) abolished shear stress-induced L-arginine uptake. The inhibitory effect of dLDL on shear stress-induced L-arginine uptake was mimicked by in vitro-glycated LDL. The efficiency of in vitro-glycated LDL to diminish shear stress-evoked L-arginine uptake correlated with the extent of glycation (R2 = 0.88). Moreover, dLDL, but not nLDL or fraction alpha, reduced shear stress-mediated cGMP formation and NOx production by 47 and 88%, respectively. This effect was also mimicked by in vitro-glycated LDL, correlating with its degree of glycation (R2 = 0.86). Under these experimental conditions, glycated LDL reduced shear stress-induced increase in NO synthesis by inhibition of shear stress-stimulated L-arginine uptake and NO bioactivity due to increased endothelial cell *O2- release. These properties may contribute to the reduced vasodilatory response and the vascular complications in diabetes.


Electrochemistry on a localized surface plasmon resonance sensor.
The optical signal of a localized surface plasmon resonance (LSPR)-based sensor combined with electrochemistry was investigated. Gold nanoparticles were immobilized on an indium tin oxide (ITO) substrate, which functioned as working electrode. Using cyclic voltammetry synchronized with LSPR sensing, surface reactions on gold were detected both electrically and optically. In the capacitive charging regime, optical signals linear to the applied potential were detected. Gold was found to be dissolved above the oxidation potential and partially redeposited during the reduction, which changed size and conformation of the gold nanoparticles. In kinetic measurements, slower potential establishment was observed at lower salt concentrations. Simulations by multiple multipole program (MMP) suggested the formation of a lossy layer by combination of charge depletion of gold and negative ion adsorption even below the reaction potential. We consider the results presented here of importance for any future sensors based on combined plasmonics and electrochemistry.


Simultaneous measurements of three-dimensional reflectivity distributions in scattering media based on optical frequency-domain reflectometry.
A new type of tomography system based on optical frequency-domain reflectometry is presented. Using an area sensor, the system can simultaneously measure three-dimensional reflectivity distributions in scattering media without the need for mechanical scanning. In preliminary experiments we demonstrate that a target (resolution chart) placed behind biological tissue can be imaged with high depth resolution (47 microm) for a short measurement time.


Detection of non-targeted transgenes by whole-genome resequencing for gene-doping control.
Gene doping has raised concerns in human and equestrian sports and the horseracing industry. There are two possible types of gene doping in the sports and racing industry: (1) administration of a gene-doping substance to postnatal animals and (2) generation of genetically engineered animals by modifying eggs. In this study, we aimed to identify genetically engineered animals by whole-genome resequencing (WGR) for gene-doping control. Transgenic cell lines, in which the erythropoietin gene (EPO) cDNA form was inserted into the genome of horse fibroblasts, were constructed as a model of genetically modified horse. Genome-wide screening of non-targeted transgenes was performed to find structural variation using DELLY based on split-read and paired-end algorithms and Control-FREEC based on read-depth algorithm. We detected the EPO transgene as an intron deletion in the WGR data by the split-read algorithm of DELLY. In addition, single-nucleotide polymorphisms and insertions/deletions artificially introduced in the EPO transgene were identified by WGR. Therefore, genome-wide screening using WGR can contribute to gene-doping control even if the targets are unknown. This is the first study to detect transgenes as intron deletions for gene-doping detection.


Metabolic syndrome as a risk factor for total hip or knee replacement due to primary osteoarthritis: a prospective cohort study (the HUNT study and the Norwegian Arthroplasty Register).
Biochemical changes associated with obesity may accelerate osteoarthritis beyond the effect of mechanical factors. This study investigated whether metabolic syndrome and its components (visceral obesity, hypertension, dyslipidemia and insulin resistance) were risk factors for subsequent total hip replacement (THR) or total knee replacement (TKR) due to primary osteoarthritis. In this prospective cohort study, data from the second survey of the Nord-Trøndelag Health Study 2 (HUNT2) were linked to the Norwegian Arthroplasty Register for identification of the outcome of THR or TKR. The analyses were stratified by age (<50, 50-69.9 and ≥70 years) and adjusted for gender, body mass index, smoking, physical activity and education. Of the 62,661 participants, 12,593 (20.1%) were identified as having metabolic syndrome, and we recorded 1,840 (2.9%) THRs and 1,111 (1.8%) TKRs during a mean follow-up time of 15.4 years. Cox regression analyses did not show any association between full metabolic syndrome and THR or TKR, except in persons <50 years with metabolic syndrome who had a decreased risk of THR (hazard ratio [HR] 0.58, 95% CI 0.40-0.83). However, when including only participants whose exposure status did not change during follow-up, this protective association was no longer significant. Increased waist circumference was associated with increased risk of TKR in participants <50 years (HR 1.62, 95% CI 1.10-2.39) and 50-69.9 years (HR 1.43, 95% CI 1.14-1.80). Hypertension significantly increased the risk of TKR in participants <50 years (HR 1.38, 95% CI 1.05-1.81), and this risk was greater for men. This study found an increased risk of TKR in men <50 years with hypertension and persons <70 years with increased waist circumference. Apart from this, neither metabolic syndrome nor its components were associated with increased risk of THR or TKR due to primary osteoarthritis.


Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome.
Neurologic Post Treatment Lyme disease (nPTLS) and Chronic Fatigue (CFS) are syndromes of unknown etiology. They share features of fatigue and cognitive dysfunction, making it difficult to differentiate them. Unresolved is whether nPTLS is a subset of CFS. Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins. Preliminary pathway analysis demonstrated that the data could be useful for hypothesis generation on the pathogenetic mechanisms underlying these two related syndromes. nPTLS and CFS have distinguishing CSF protein complements. Each condition has a number of CSF proteins that can be useful in providing candidates for future validation studies and insights on the respective mechanisms of pathogenesis. Distinguishing nPTLS and CFS permits more focused study of each condition, and can lead to novel diagnostics and therapeutic interventions.


Occupational therapy for service members with mild traumatic brain injury.
More occupational therapists are needed to provide client-centered, evidence-based rehabilitation to the large numbers of service members who sustained mild traumatic brain injury (mTBI) while deployed in Afghanistan and Iraq. The Proponency for Rehabilitation and Reintegration tasked a team of occupational and physical therapists to assemble evidence-based best practices specific to mTBI. Despite the fact that evidence-based reviews, guidelines, and research regarding occupational therapy for mTBI are sparse, the team developed the Clinical Practice Guidance: Occupational Therapy and Physical Therapy for Mild Traumatic Brain Injury. Occupational therapy practice recommendations specific to client education, vision, cognition, resumption of roles, and emotional well-being are summarized for civilians and characterized as practice standards or practice options. By using evidence-informed and holistic services, occupational therapists have the potential to lead rehabilitation and reintegration efforts for service members with mTBI and advance changes in the profession itself.


Effect of melittin on pituitary-adrenal responsiveness to stress.
We previously have shown that melittin evokes a sustained increase in plasma corticosterone levels of the female rat. Significant increases occurred only during the morning and the duration of the response was increased from 48 h to 8 days by a second milittin injection 3 days after initial exposure to melittin. To further evaluate the effect of melittin on adrenocortical function, rats were given melittin at 09.00 h on days 1 and 4 and on day 8 rats were subjected to a variety of different stresses. Saline-injected rats served as controls. Blood for determining non-stress and stress levels of corticosterone concentration (RIA) was collected by decapitation. In all cases morning but not afternoon non-stress plasma corticosterone levels of melittin-injected rats were higher than those of saline-injected controls; afternoon non-stress corticosterone levels did not differ between groups. Melittin- and saline-treated rats showed comparable corticosterone responses to a morning 2-min restraint stress. In contrast, melittin treatment facilitated the pituitary-adrenal response to rotational and surgical stress as well as the stress of removing one rat from a cage of two. Fifteen min after removal of the first rat of a cage of two, plasma corticosterone levels of the melittin-injected rat were significantly higher than those of saline-injected rats. Likewise, plasma corticosterone levels of melittin-treated rats were higher (P less than 0.05) than those of saline-injected rats 15 min after rotational (10 rpm) and surgical (jugular cutdown and blood withdrawal) stress.(ABSTRACT TRUNCATED AT 250 WORDS)


Carotenogenesis during tuber development and storage in potato.
Germplasm of Solanum tuberosum and Solanum phureja exhibit a wide (over 20-fold) variation in tuber carotenoid content. The levels of carotenoids during tuber development and storage were compared in a high carotenoid-accumulating S. phureja accession (DB375\1) with two S. tuberosum cultivars (Pentland Javelin and Desiree) that accumulate lower levels of tuber carotenoid. On a dry weight basis, total carotenoid levels were at a maximum early in tuber development. However, in the S. phureja accession, carotenoid levels remained at a high level throughout tuber development, whereas in the S. tuberosum accessions, carotenoid content decreased as dry weight increased. The carotenoid profiles of tissues during tuber development were analysed in greater detail by reverse phase HPLC. In S. phureja tubers at maturity the major carotenoids were zeaxanthin, antheraxanthin, and violaxanthin. Following 9 months storage at 4 degrees C the levels of zeaxanthin and antheraxanthin decreased, whereas the level of lutein increased; overall, however, there was only a small decrease in total carotenoid content. In order to explore the reasons for the wide variation in tuber carotenoid content, the expression patterns of the major genes encoding the enzymes of the carotenoid biosynthetic pathway were compared. Significant differences in the profiles were detected, suggesting that transcriptional control or mRNA stability gives rise to the large differences in tuber carotenoid content. In particular, there was an inverse trend between the level of zeaxanthin epoxidase transcript level and tuber carotenoid content in a range of potato germplasm, giving rise to an hypothesis for the regulation of carotenogenesis in potato tubers.


Belatacept for kidney transplant recipients.
Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage. 1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased). We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion. Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI). Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity. We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).The belatacept dose used (high versus low), type of donor kidney the recipient received (extended versus standard criteria) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival, incidence of acute rejection or estimated GFR. Selective outcome reporting meant that data for some key subgroup comparisons were sparse and that estimates of the effect of treatment in these groups of recipients remain imprecise. There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.


A Posterior Oblique Approach to the Lumbar Disk Spaces, Vertebral Bodies, and Lumbar Plexus: A Cadaveric Feasibility Study.
A laboratory cadaveric study. We aimed to demonstrate the feasibility of a posterior oblique approach, sharing the same advantages as the transpsoas technique while minimizing the risk of lumbar plexus or psoas muscle injuries. The transpsoas approach for interbody fusion and corpectomy offers advantages over posterior and anterior approaches. However, possible risks include traumatization of the psoas muscle or lumbar plexus. All lumbar disk spaces and vertebral bodies were exposed by a posterior oblique approach from left and right on a human cadaveric specimen. The exposure obtained and a step-by-step documentation of the procedure is outlined in detail. We were able to achieve wide exposure of all lumbar disk spaces and vertebral bodies above the L5/S1 disk space. Only the psoas muscle was retracted, and the lumbar plexus nerves were easily visualized and gently retracted. Sharp dissection was only required around the tip of the transverse processes. A posterior oblique approach seems to be less invasive than the transpsoas approach. Exposure of the anterior column structures above the iliac crest is comparable. The oblique approach offers direct access to the lumbar plexus and the extraforaminal segments of the nerve roots.


Risk assessment of a cohort exposed to aromatic amines. Initial results.
A cohort of 1,385 workers potentially exposed to carcinogenic amines was evaluated to determine the extent of its risk for bladder cancer. The cumulative incidence of bladder cancer was determined from death certificates, from interviews with community urologists, and from a screening program. A total of 13 confirmed cases of bladder cancer were identified at the conclusion of the first year of study. The entire cohort has approximately a fourfold excess risk of bladder cancer; however, black workers with more than 10 years of employment had a risk ratio of 111 (based on three cases). The onset of disease occurred, on the average, 15 years earlier in these black workers than in the general U.S. population. The cumulative incidence of bladder cancer increased with the duration of employment, ranging from 0.4% for workers with five or fewer years of employment to 36% for those with greater than 20 years. No significant differences were found between cases and noncases for cigarette smoking, coffee drinking, use of artificial sweeteners, or prior employment in high-risk occupations. More cases of bladder cancer are expected in this cohort because many members have not yet achieved the average latency found for the confirmed cases.


Sexual offending in women and psychiatric disorder: a national case-control study.
Women commit 4-5% of all sexual crimes, but there is considerable uncertainty about associations with psychosis and substance abuse. We examined the prevalence of psychiatric hospitalization, psychotic disorders, and substance abuse in a nationwide sample of female sexual offenders. We obtained data from Swedish national registers for criminal convictions, hospital discharge diagnoses, and demographic and socioeconomic factors between 1988 and 2000, and merged them using unique identifiers. Convicted female sexual offenders (n = 93) were compared with all females convicted of non-sexual violent offences (n = 13,452) and a random sample of general population women (n = 20,597). Over 13 years, 36.6% of female sexual offenders had been admitted to psychiatric hospital and 7.5% been discharged with a diagnosis of a psychotic disorder. Compared to non-sexual violent offenders, there were no significant differences in the proportion diagnosed with psychosis or substance abuse. Compared to women in the general population, however, there was a significantly increased risk in sex offenders of psychiatric hospitalization (age-adjusted odds ratio [AOR] = 15.4; 95% CI: 10.0-23.7), being diagnosed with a psychotic disorder (AOR = 16.2; 95% CI: 7.2-36.4), and with substance use disorders (AOR = 22.6; 95% CI: 13.0-39.1). We conclude that the prevalence of psychotic and substance use disorders was not different between sexual offenders and other violent offenders, suggesting non-specificity of sexual offending in women. Nevertheless, substantially increased prevalences of psychiatric disorder, underline the importance of screening and assessment of female sexual and other violent offenders.


Invasive pneumococcal disease in healthy adults: increase of empyema associated with the clonal-type Sweden(1)-ST306.
Adult invasive pneumococcal disease (IPD) occurs mainly in the elderly and patients with co-morbidities. Little is known about the clinical characteristics, serotypes and genotypes causing IPD in healthy adults. We studied 745 culture-proven cases of IPD in adult patients aged 18-64 years (1996-2010). Patients were included in two groups: 1.) adults with co-morbidities, and 2.) healthy adults, who had no prior or coincident diagnosis of a chronic or immunosuppressive underlying disease. Microbiological studies included pneumococcal serotyping and genotyping. Of 745 IPD episodes, 525 (70%) occurred in patients with co-morbidities and 220 (30%) in healthy adults. The healthy adults with IPD were often smokers (56%) or alcohol abusers (18%). As compared to patients with co-morbidities, the healthy adults had (P<0.05): younger age (43.5+/-13.1 vs. 48.7+/-11.3 years); higher proportions of women (45% vs. 24%), pneumonia with empyema (15% vs. 7%) and infection with non-PCV7 serotypes including serotypes 1 (25% vs. 5%), 7F (13% vs. 4%), and 5 (7% vs. 2%); and lower mortality (5% vs. 20%). Empyema was more frequently caused by serotype 1. No death occurred among 79 patients with serotype 1 IPD. There was an emergence of virulent clonal-types Sweden(1)-ST306 and Netherlands(7F)-ST191. The vaccine serotype coverage with the PCV13 was higher in healthy adults than in patients with co-morbidities: 82% and 56%, respectively, P<0.001. In this clinical study, one-third of adults with IPD had no underlying chronic or immunosuppressive diseases (healthy adults). They were often smokers and alcohol abusers, and frequently presents with pneumonia and empyema caused by virulent clones of non-PCV7 serotypes such as the Sweden(1)-ST306. Thus, implementing tobacco and alcohol abuse-cessation measures and a proper pneumococcal vaccination, such as PCV13 policy, in active smokers and alcohol abusers may diminish the burden of IPD in adults.


In vivo evaluation of retinal neurodegeneration in patients with multiple sclerosis.
To evaluate macular morphology in the eyes of patients with multiple sclerosis (MS) with or without optic neuritis (ON) in previous history. Optical coherence tomography (OCT) examination was performed in thirty-nine patients with MS and in thirty-three healthy subjects. The raw macular OCT data were processed using OCTRIMA software. The circumpapillary retinal nerve fiber layer (RNFL) thickness and the weighted mean thickness of the total retina and 6 intraretinal layers were obtained for each eye. The eyes of MS patients were divided into a group of 39 ON-affected eyes, and into a group of 34 eyes with no history of ON for the statistical analyses. Receiver operating characteristic (ROC) curves were constructed to determine which parameter can discriminate best between the non-affected group and controls. The circumpapillary RNFL thickness was significantly decreased in the non-affected eyes compared to controls group only in the temporal quadrant (p = 0.001) while it was decreased in the affected eyes of the MS patients in all quadrants compared to the non-affected eyes (p<0.05 in each comparison). The thickness of the total retina, RNFL, ganglion cell layer and inner plexiform layer complex (GCL+IPL) and ganglion cell complex (GCC, comprising the RNFL and GCL+IPL) in the macula was significantly decreased in the non-affected eyes compared to controls (p<0.05 for each comparison) and in the ON-affected eyes compared to the non-affected eyes (p<0.001 for each comparison). The largest area under the ROC curve (0.892) was obtained for the weighted mean thickness of the GCC. The EDSS score showed the strongest correlation with the GCL+IPL and GCC thickness (p = 0.007, r = 0.43 for both variables). Thinning of the inner retinal layers is present in eyes of MS patients regardless of previous ON. Macular OCT image segmentation might provide a better insight into the pathology of neuronal loss and could therefore play an important role in the diagnosis and follow-up of patients with MS.


Evaluation of the Glypican 3 promoter for transcriptional targeting of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a major health problem as evidenced by its increasing incidence and high morbidity and mortality rates. Most patients with HCC have underlying liver disease and dysfunction which limits the current therapeutic options. Treatments that spare the liver and destroy the HCC are needed. Targeting transcriptional differences between HCC and liver cells may provide this therapeutic window. In this study, we examine the potential of the Glypican 3 (GPC3) promoter as a targeting strategy. GPC3 is an oncofetal protein belonging to the proteoglycan family which is normally only expressed during fetal development. However, in HCC, the expression of this protein is reactivated. Here, we show that GPC3 is expressed primarily in HCC and not in normal liver lines. We show that the GPC3 promoter can be used to drive expression of significantly more luciferase and eYFP in HCC cell lines compared to normal liver cells. Further, we show that vectors containing cytosine deaminase (CD) under GPC3 promotor control induced significantly more killing of HCC cell lines after treatment with 5-FC compared to normal liver cell lines. These data suggest that transcriptionally targeted delivery of transgene in HCC cells can be achieved using the GPC3 promoter and this targeting strategy produces limited toxicity to normal liver cells.


Family caregivers' views on coordination of care in Huntington's disease: a qualitative study.
Collaboration between family caregivers and health professionals in specialised hospitals or community-based primary healthcare systems can be challenging. During the course of severe chronic disease, several health professionals might be involved at a given time, and the patient's illness may be unpredictable or not well understood by some of those involved in the treatment and care. The aim of this study was to explore the experiences and expectations of family caregivers for persons with Huntington's disease concerning collaboration with healthcare professionals. To shed light on collaboration from the perspectives of family caregivers, we conducted an explorative, qualitative interview study with 15 adult participants experienced from caring for family members in all stages of Huntington's disease. Data were analysed with systematic text condensation, a cross-case method for thematic analysis of qualitative data. We found that family caregivers approached health services hoping to understand the illness course and to share their concerns and stories with skilled and trustworthy professionals. Family caregivers felt their involvement in consultations and access to ongoing exchanges of knowledge were important factors in improved health services. They also felt that the clarity of roles and responsibilities was crucial to collaboration. Family caregivers should be acknowledged for their competences and should be involved as contributors in partnerships with healthcare professionals. Our study suggests that building respectful partnerships with family caregivers and facilitating the mutual sharing of knowledge may improve the coordination of care. It is important to establish clarity of roles adjusted to caregivers' individual resources for managing responsibilities in the care process.


Copper-mediated synthesis of drug-like bicyclopentanes.
Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements2. These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.


A biomechanical investigation of the sacroiliac joint in the setting of lumbosacral fusion: impact of pelvic fixation versus sacroiliac joint fixation.
The sacroiliac joint (SIJ) is a known source of low-back pain. Randomized clinical trials support sacroiliac fusion over conservative management for SIJ dysfunction. Clinical studies suggest that SIJ degeneration occurs in the setting of lumbosacral fusions. However, there are few biomechanical studies to provide a good understanding of the effect of lumbosacral fusion on the SIJ. In the present study, researchers performed a biomechanical investigation to discern the effect of pelvic versus SIJ fixation on the SIJ in lumbosacral fusion. Seven fresh-frozen human cadaveric specimens were used. There was one intact specimen and six operative constructs: 1) posterior pedicle screws and rods from T10 to S1 (PS); 2) PS + bilateral iliac screw fixation (BIS); 3) PS + unilateral iliac screw fixation (UIS); 4) PS + UIS + 3 contralateral unilateral SIJ screws (UIS + 3SIJ); 5) PS + 3 unilateral SIJ screws (3SIJ); and 6) PS + 6 bilateral SIJ screws (6SIJ). A custom-built 6 degrees-of-freedom apparatus was used to simulate three bending modes: flexion-extension (FE), lateral bending (LB), and axial rotation (AR). Range of motion (ROM) was recorded at L5-S1 and the SIJ. All six operative constructs had significantly reduced ROM at L5-S1 in all three bending modes compared to that of the intact specimen (p < 0.05). In the FE mode, the BIS construct had a significant reduction in L5-S1 ROM as compared to the other five constructs (p < 0.05). SIJ ROM was greatest in the FE mode compared to LB and AR. Although the FE mode did not show any statistically significant differences in SIJ ROM across the constructs, there were appreciable differences. The PS construct had the highest SIJ ROM. The BIS construct reduced bilateral SIJ ROM by 44% in comparison to the PS construct. The BIS and 6SIJ constructs showed reductions in SIJ ROM nearly equal to those of the PS construct. UIS and 3SIJ showed an appreciable reduction in unfused SIJ ROM compared to PS. This investigation demonstrated the effects of various fusion constructs using pelvic and sacroiliac fixation in lumbosacral fusion. This study adds biomechanical evidence of adjacent segment stress in the SIJ in fusion constructs extending to S1. Unilateral pelvic fixation, or SIJ fusion, led to an appreciable but nonsignificant reduction in the ROM of the unfused contralateral SIJ. Bilateral pelvic fixation showed the greatest significant reduction of movement at L5-S1 and was equivalent to bilateral sacroiliac fusion in reducing SIJ motion.


Hypovirulence of chestnut blight fungus conferred by an infectious viral cDNA.
Strains of the chestnut blight fungus Cryphonectria parasitica that contain viral double-stranded RNAs often exhibit reduced virulence. Such hypovirulent strains act as biocontrol agents by virtue of their ability to convert virulent strains to hypovirulence after anastomosis. Transformation of virulent C. parasitica strains with a full-length complementary DNA copy of a hypovirulence-associated viral RNA conferred the complete hypovirulence phenotype. Cytoplasmic double-stranded RNA was resurrected from the chromosomally integrated complementary DNA copy and was able to convert compatible virulent strains to hypovirulence. These results establish viral double-stranded RNA as the casual agent of hypovirulence and demonstrate the feasibility of engineering hypovirulent fungal strains.


Emissions and climate-relevant optical properties of pollutants emitted from a three-stone fire and the Berkeley-Darfur stove tested under laboratory conditions.
Cooking in the developing world generates pollutants that endanger the health of billions of people and contribute to climate change. This study quantified pollutants emitted when cooking with a three-stone fire (TSF) and the Berkeley-Darfur Stove (BDS), the latter of which encloses the fire to increase fuel efficiency. The stoves were operated at the Lawrence Berkeley National Laboratory testing facility with a narrow range of fuel feed rates to minimize performance variability. Fast (1 Hz) measurements of pollutants enabled discrimination between the stoves' emission profiles and development of woodsmoke-specific calibrations for the aethalometer (black carbon, BC) and DustTrak (fine particles, PM2.5). The BDS used 65±5% (average±95% confidence interval) of the wood consumed by the TSF and emitted 50±5% of the carbon monoxide emitted by the TSF for an equivalent cooking task, indicating its higher thermal efficiency and a modest improvement in combustion efficiency. The BDS reduced total PM2.5 by 50% but achieved only a 30% reduction in BC emissions. The BDS-emitted particles were, therefore, more sunlight-absorbing: the average single scattering albedo at 532 nm was 0.36 for the BDS and 0.47 for the TSF. Mass emissions of PM2.5 and BC varied more than emissions of CO and wood consumption over all tests, and emissions and wood consumption varied more among TSF than BDS tests. The international community and the Global Alliance for Clean Cookstoves have proposed performance targets for the highest tier of cookstoves that correspond to greater reductions in fuel consumption and PM2.5 emissions of approximately 65% and 95%, respectively, compared to baseline cooking with the TSF. Given the accompanying decrease in BC emissions for stoves that achieve this stretch goal and BC's extremely high global warming potential, the short-term climate change mitigation from avoided BC emissions could exceed that from avoided CO2 emissions.


The synthetic parasite-derived peptide GK1 increases survival in a preclinical mouse melanoma model.
The therapeutic efficacy of a synthetic parasite-derived peptide GK1, an immune response booster, was evaluated in a mouse melanoma model. This melanoma model correlates with human stage IIb melanoma, which is treated with wide surgical excision; a parallel study employing a surgical treatment was carried out as an instructive goal. C57BL/6 mice were injected subcutaneously in the flank with 2×10(5) B16-F10 murine melanoma cells. When the tumors reached 20 mm3, mice were separated into two different groups; the GK1 group, treated weekly with peritumoral injections of GK1 (10 μg/100 μL of sterile saline solution) and the control group, treated weekly with an antiseptic peritumoral injection of 100 μL of sterile saline solution without further intervention. All mice were monitored daily for clinical appearance, tumor size, and survival. Surgical treatment was performed in parallel when the tumor size was 20 mm3 (group A), 500 mm3 (group B), and >500 mm3 (group C). The GK1 peptide effectively increased the mean survival time by 9.05 days, corresponding to an increase of 42.58%, and significantly delayed tumor growth from day 3 to 12 of treatment. In addition, tumor necrosis was significantly increased (p<0.05) in the treated mice. The overall survival rates obtained with surgical treatment at 6 months were 83.33% for group A, 40% for group B, and 0% for group C, with significant differences (p<0.05) among the groups. The GK1 peptide demonstrated therapeutic properties in a mouse melanoma model, as treatment resulted in a significant increase in the mean survival time of the treated animals (42.58%). The potential for GK1 to be used as a primary or adjuvant component of chemotherapeutic cocktails for the treatment of experimental and human cancers remains to be determined, and surgical removal remains a challenge for any new experimental treatment of melanoma in mouse models.


Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases.
To study the use of chemotherapy for Merkel cell carcinoma (MCC) of the skin. Twenty-five cases of MCC were treated at the London Regional Cancer Center between 1987 and 1997. Thirteen cases treated with chemotherapy were reviewed with 191 cases from the literature. At presentation, 24 patients had localized skin lesions (stage I) and one had locoregional involvement (stage II). Among the nine cases with recurrent nodal disease, six had chemotherapy as a component of salvage treatment. They were all free of disease at a median of 19 months (range, 12 to 37 months). In contrast, two patients who had salvage radiotherapy alone died of disease. Overall survival (OS) and disease-free survival (DFS) were 59% and 43%, respectively, at two years. Median OS and DFS were 29 months (range, 1 to 133 months) and 9 months (range, 1 to 133 months), respectively. Nodal disease developed in 12 (50%) of 24 patients with stage I disease, and distant metastases developed in six (25%) of 24. Including those from the literature, there were 204 cases treated with chemotherapy. Cyclophosphamide/doxorubicin (or epirubicin)/vincristine combination +/- prednisone was the most commonly used chemotherapy regimen (47 cases), with an overall response rate of 75.7% (35.1% complete, 35. 1% partial, and 5.4% minor responses). Etoposide/cisplatin (or carboplatin) was the next most commonly used regimen (27 cases), with an overall response rate of 60% (36% complete and 24% partial responses). The difference in response rate was not statistically significant (P =.19). Among the 204 cases, there were seven (3.4%) toxic deaths. Chemoradiation for locally recurrent or advanced disease may be an option for patients with a good performance status.


Phantom studies and preliminary clinical experience with the BSD 2000.
The BSD 2000 system is an array of microwave antennas operating in the 60-120 MHz range. It is a four-quadrant regional hyperthermia device with phase control permitting the operator to choose the point of constructive interference. A computer preplanning system is provided. We have compared the computer predictions with measured relative specific absorption rate (SAR) distributions in muscle equivalent phantoms and pig cadaver. The predicted SAR distribution is in qualitative agreement with observation, although differences of approximately 3-5 cm in the location of iso- SAR contours were noted. The longitudinal dependence of relative of distance cephalad to the central plane of the power distribution was measured, and it was found that a length of 15-20 cm was covered by the 50% iso-SAR. SAR measurements in the spinal canal of a pig cadaver showed that, even at resonance frequency, the measured SAR in the cervical spine was small (0.07 of central axis SAR). However, the spinal canal SAR as measured in the central plane of an evenly balanced configuration was 0.6 of the peak SAR. Marked reduction of the spinal canal SAR could be obtained with steering techniques and was in good agreement with the computer preplan. This paper reviews preliminary clinical experience with 17 patients. All but 2 patients were treated with steering techniques to permit partial sparing of normal tissues. The goal of maintaining central tumour temperature at or above 42 degrees C for at least 30 min was maintained in 41 of 67 sessions (61%) and in at least one session for all but 2 patients. Seventy-seven per cent of monitored tumor points attained at least 42 degrees C in patients for whom thermal mapping was performed. Significant cardiovascular stress developed during hyperthermia in two patients. There have been five complete responses and seven partial responses in the 17 patients.


Forest ecosystem development in post-mining landscapes: a case study of the Lusatian lignite district.
The restoration of surface mining landscapes requries the (re)creation of ecosystems. In Lusatia (eastern Germany), large-scale open-cast lignite mining operations generated spoil dumps widely consisting of acidified, phytotoxic substrates. Amelioration and rehabilitation measures have been developed and applied to these substrates since the 1950s. However, it is still not clear whether these approaches are sustainable. This paper reports on collaborative research work into the ecological potential of forest ecosystem development on typical minesites in the Lusatian lignite district. At first sight, pine stands on minesites along a chronosequence comprising about 35 years did not show differences when compared with stands on non-mined sites of the general region. Furthermore, with some modification, conceptual models for flora and fauna succession in forest stands on non-mined sites seem to be applicable, at least for the early stages of forest ecosystem development. For example, soil organism abundance and activity at minesites had already reached levels typical of non-mined sites after about 20-30 years. In contrast, mine soils are very different from non-mined soils of the test region. Chemically, mine soil development is dominated by processes originating from pyrite oxidation. Geogenic, i.e. lignitic, soil organic carbon was shown to substitute for some functions of pedogenic soil organic matter. Rooting was hampered but not completely impeded in strongly acidified soil compartments. Roots and mycorrhizae are apparently able to make use of the characteristic heterogeneity of young mine soils. Considering these recent results and the knowledge accumulated during more than 30 years of research on minesite rehabilitation internationally, it can be stated that minesite restoration might be used as an ideal case study for forest ecosystem development starting at "point zero" on "terra nova".


Proteins containing peptide sequences related to Lys-Phe-Glu-Arg-Gln are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats.
In response to serum withdrawal, when overall rates of proteolysis increase in cultured fibroblasts, proteins containing peptide regions similar to Lys-Phe-Gln-Arg-Gln (KFERQ) are targeted to lysosomes for degradation, and the intracellular concentrations of these proteins decline [Chiang & Dice (1988) J. Biol. Chem. 263, 6797-6805]. To test whether such proteins are also selectively depleted in mammalian tissues in vivo, we have used affinity-purified polyclonal antibodies to KFERQ to detect proteins containing such sequences in tissues of fed and fasted rats. Immunoreactive cytosolic proteins were partially depleted from liver and heart of fasted rats, but the time course differed for these two tissues. Immunoreactive proteins in liver were lost during days 2 and 3 of fasting, whereas such proteins in heart were depleted within day 1 of fasting. In the same fasted rats, levels of immunoreactive cytosolic proteins did not change in two skeletal muscles, the dark soleus and the pale extensor digitorum longus. Immunoreactive proteins in a myofibrillar fraction were also partially depleted in heart, but not in skeletal muscles, of fasted rats. The most likely explanation for these results is that the protein loss in different tissues upon fasting results from selective activation of different proteolytic pathways. The increased proteolysis in liver and heart of fasted animals includes activation of the KFERQ-selective lysosomal pathway, whereas increased proteolysis in skeletal muscle does not.