Seventy-two Cycles of FOLFIRINOX: Long Term Treatment in a Patient with Metastatic Adenocarcinoma of the Pancreatic Tail.
Pancreatic adenocarcinoma is one of the most lethal malignancies worldwide. In patients with unresectable tumor there are several strategies of palliative chemotherapy, either gemcitabine based regimens or FOLFIRINOX, which is supposed to be most efficient but also most toxic. Hence, management of toxicity is crucial to perform a therapy consisting of FOLFIRINOX. We report on a 69-year-old female patient suffering from adenocarcinoma of the pancreatic tail with multiple liver metastases. Palliative chemotherapy comprising leucovorin, fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) was initiated in February 2011 and was tolerated very well. Subsequent computed tomography-scans showed significant reduction of the tumor load in the liver as well as in the primary pancreatic tumor. The serum levels of the tumor marker CA 19-9 were elevated initially and decreased concomitantly. Thus, chemotherapy was continued for more than 3 years, and up to 72 cycles were administered until April 2014. Due to intermittent neutropenia and mucositis the initial dose was reduced to 60% of the calculated standard dose. In April 2014, an intermediate staging by computed tomography and FDG-PET revealed significant reduction of the size of the primary pancreatic tumor compared with February 2011. Liver metastases could hardly be detected anymore. After pausing chemotherapy for 12 weeks, one liver metastasis reappeared and was treated by RFA in August 2014. Meanwhile, in October 2014 there is no radiological evidence on any existing tumor or metastasis. Our report demonstrates that a sufficient tolerance of chemotherapy with FOLFIRINOX is achievable, what makes a long term treatment with FOLFIRINOX feasible and can lead to impressive results.


Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants.
Given the proposed dopaminergic mechanism of low-dose naltrexone (LDN), we examined its efficacy as augmentation for depressive breakthrough on pro-dopaminergic antidepressant regimens. 12 adults (67% female, mean age = 45±12) with recurrent DSM-IV major depressive disorder (MDD) on dopaminergic antidepressant regimens (stimulants, dopamine agonists, bupropion [≥300mg/day], aripiprazole [≤2.5mg/day], or sertraline [≥150mg/day]) were randomized to naltrexone 1mg b.i.d. (n=6) or placebo (n=6) augmentation for 3 weeks. All subjects completed the trial. Hamilton Depression Rating Scale (HAM-D-17) scores (primary outcome measure) decreased from 21.2±2.0 to 11.7±7.7 for LDN, from 23.7±2.3 to 17.8±5.9 for placebo (Cohen's d=0.62; p=0.3 between treatment groups). HAM-D-28 scores decreased from 26.2±4.0 to 12.0±9.8 for LDN, from 26.3±2.6 to 19.8±6.6 for placebo (d=1.15; p=0.097). Montgomery-Asberg Depression Rating Scale (MADRS-10 item) scores decreased from 30.4±4.9 to 12.2±8.4 for LDN, from 30.7±4.3 to 22.8±8.5) for placebo (d=1.45; p=0.035). MADRS-15 item scores decreased from 36.6±6.2 to 13.2±8.8 for LDN, from 36.7±4.2 to 26.0±10.0 for placebo (d=1.49; p=0.035). Clinical Global Improvement Scale-Severity (CGI-S) scores decreased from 4.3±0.5 to 3.0±1.1 for LDN, from 4.3±0.5 to 4.0±0.6 for placebo (d=1.22; p=0.064). Small study; restrictions on allowed antidepressants. LDN augmentation showed some benefit for MDD relapse on dopaminergic agents. Confirmation in larger studies is needed.


Role of surgery for locally advanced and metastatic renal cell carcinoma.
Both locally advanced and metastatic renal cell carcinoma (RCC) present a challenge in terms of their optimal management. This article reviews the literature and evaluates the role of surgery in the treatment of advanced RCC. Surgery is the optimal treatment for locally advanced RCC and minimal, resectable, metastatic disease. Patients with metastatic disease, and some forms of locally advanced disease, may also benefit from multimodal management with local surgical therapy and systemic treatment using either immunotherapy or targeted therapy. Regardless of the disease stage, patients with locally advanced or metastatic RCC represent heterogenous patient populations with different disease characteristics and risk factors. Individualization of care in the setting of a sound oncologic framework may optimize the risk/benefit ratio within individual patient cohorts.


No modifying effect of education level on the association between lifestyle behaviors and cardiovascular mortality: the Japan Collaborative Cohort Study.
We examined the effect of education level on the association between healthy lifestyle behaviors and cardiovascular mortality in the Japanese population. A total of 42,647 community-based men and women aged 40-79 years were enrolled at baseline (1988-1990), followed through 2009. The components of the healthy lifestyle score included the intake of fruits, fish, and milk; body mass index; exercise; avoidance of smoking; moderate alcohol intake; and moderate sleep duration. During the 19.3 years of follow-up, 8,314 all-cause and 2,377 total cardiovascular mortality cases were noted. Inverse associations were observed between healthy lifestyle scores and total cardiovascular disease (CVD) for both the lower and higher education level groups. Multivariable hazard ratios (95% confidence interval) for CVD mortality from the highest to the lowest healthy lifestyle scores, and the population attributable fraction (95% CIs) without healthy lifestyle scores of 7-8 were 0.51 (0.33-0.52) and 42% (24-58%), and 0.38 (0.27-0.47) and 55% (36-69%) for the higher and lower education levels, respectively. Our findings suggest that the association between higher CVD mortality and lower education level can be explained by the individuals' lower adherence to a healthy lifestyle; hence, lifestyle modification would be beneficial for the prevention of cardiovascular mortality, irrespective of the education level.


Limbic system surgery for treatment-refractory obsessive-compulsive disorder: a prospective long-term follow-up of 64 patients.
Obsessive-compulsive disorder (OCD) is a common and disabling psychiatric illness, and in a significant proportion of patients with OCD the disease is refractory to conventional pharmacotherapy and psychotherapy. For more than half a century, patients with severe, treatment-resistant OCD have been treated with stereotactic limbic system lesions, including dorsal anterior cingulotomy. The authors present their results describing the efficacy and durability of limbic system surgery for OCD, characterizing a large cohort of patients treated at a single institution with a mean follow-up of more than 5 years. The authors identified 64 consecutive patients undergoing cingulotomy for refractory OCD at the Massachusetts General Hospital between 1989 and 2009. Changes in OCD and major depressive disorder symptom severity were assessed at both the initial and most recent postoperative follow-up by using the Yale-Brown Obsessive Compulsive Scale and the Beck Depression Inventory, respectively. Full and partial OCD symptom responses were defined as Yale-Brown Obsessive Compulsive Scale score reductions of ≥ 35% and 25%-34%, respectively. Regarding OCD symptom improvement, at the first postoperative follow-up (mean 10.7 months), 35% of patients demonstrated a full response and 7% were partial responders. Thirty patients had a subsequent procedure (repeat cingulotomy or subcaudate tractotomy). By the most recent follow-up (mean 63.8 months), rates climbed to 47% and 22% for full and partial responses, respectively. Of the 24 patients with at least a partial response at initial follow-up, 20 (83%) retained at least a partial response at final follow-up. Comorbid major depressive disorder severity decreased by 17% at the most recent follow-up. Limbic system surgery based on initial cingulotomy offers a durable and effective treatment option for appropriately selected patients with severe OCD who have not responded to conventional pharmacotherapy or psychotherapy.


Mycoplasma genitalium is associated with symptomatic and asymptomatic non-gonococcal urethritis in men.
To examine the prevalence of Mycoplasma genitalium in a large number of male patients attending a sexually transmitted infections (STI) clinic and to determine if there is an association with objective non-gonococcal urethritis (NGU) in patients with and without clinical symptoms. Patients were tested for both M genitalium and Chlamydia trachomatis if they had symptoms or microscopic signs of NGU or if they were perceived to be at high-risk of exposure to a STI (n = 8468). Urethral smears were examined for polymorphic mononuclear leucocytes. We found that M genitalium infection was associated with symptoms of non-chlamydial NGU (discharge and dysuria; OR 4.3; 95% CI 3.4 to 5.5). We also found that M genitalium infection was associated with signs of non-chlamydial NGU independently with or without symptoms of NGU (with symptoms: OR 4.7; 95% CI 3.2 to 6.7; without symptoms: OR 3.1; 95% CI 2.0 to 4.6). Prevalence of M genitalium was also associated with severity of urethritis as quantified by microscopic examination of urethral smears. These data add further evidence to the association of M genitalium infection with NGU and should allow better risk analysis of recent recommendations of not performing urethral smears in asymptomatic men attending STI clinics.


Meditative movement for depression and anxiety.
This review focuses on Meditative Movement (MM) and its effects on anxiety, depression, and other affective states. MM is a term identifying forms of exercise that use movement in conjunction with meditative attention to body sensations, including proprioception, interoception, and kinesthesis. MM includes the traditional Chinese methods of Qigong (Chi Kung) and Taijiquan (Tai Chi), some forms of Yoga, and other Asian practices, as well as Western Somatic practices; however this review focuses primarily on Qigong and Taijiquan. We clarify the differences between MM and conventional exercise, present descriptions of several of the key methodologies of MM, and suggest how research into these practices may be approached in a systematic way. We also present evidence for possible mechanisms of the effects of MM on affective states, including the roles of posture, rhythm, coherent breathing, and the involvement of specific cortical and subcortical structures. We survey research outcomes summarized in reviews published since 2007. Results suggest that MM may be at least as effective as conventional exercise or other interventions in ameliorating anxiety and depression; however, study quality is generally poor and there are many confounding factors. This makes it difficult to draw definitive conclusions at this time. We suggest, however, that more research is warranted, and we offer specific suggestions for ensuring high-quality and productive future studies.


Accelerating light beams with arbitrarily transverse shapes.
Accelerating beams are wave packets that preserve their shape while propagating along curved trajectories. Their unique characteristics have opened the door to applications that range from optical micromanipulation and plasma-channel generation to laser micromachining. Here, we demonstrate, theoretically and experimentally, that accelerating beams can be generated with a variety of arbitrarily chosen transverse shapes. We present a general method to construct such beams in the paraxial and nonparaxial regime and demonstrate experimentally their propagation in the paraxial case. The key ingredient of our method is the use of the spectral representation of the accelerating beams, which offers a unique and compact description of these beams. The on-demand accelerating light patterns described here are likely to give rise to new applications and add versatility to the current ones.


Effects of combined phytochemicals on skin tumorigenesis in SENCAR mice.
The purpose of our study was to determine the effect of the combined action of phytochemicals on the early stages of skin tumorigenesis, i.e. initiation and promotion. We tested calcium D-glucarate (CG) given in the diet, while resveratrol (RES) and ursolic acid (UA) were applied topically. The 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted multistage skin carcinogenesis model in SENCAR mice was used. Mice received one topical dose of DMBA, then after one month, two weekly doses of TPA for 14 weeks until sacrifice. RES or UA were applied 20 min prior to DMBA or TPA treatment and 2% dietary CG was given from 2 weeks prior to 2 weeks after the DMBA dose or continually beginning 2 weeks prior to the first dose of TPA. UA applied alone and in combination with CG during the promotion stage was the only inhibitor of tumor multiplicity and tumor incidence. A number of combinations reduced epidermal proliferation, but only UA and the combination UA+CG applied during promotion significantly reduced epidermal hyperplasia. DMBA/TPA application resulted in significant increases in c-jun and p50, which were reversed by a number of different treatments. DMBA/TPA treatment also strongly increased mRNA levels of inflammation markers COX-2 and IL-6. All anti-promotion treatments caused a marked decrease in COX-2 and IL-6 expression compared to the DMBA/TPA control. These results show that UA is a potent inhibitor of skin tumor promotion and inflammatory signaling and it may be useful in the prevention of skin cancer and other epithelial cancers in humans.


Quantifying Polymer Chain Orientation in Strong and Tough Nanofibers with Low Crystallinity: Toward Next Generation Nanostructured Superfibers.
Advanced fibers revolutionized structural materials in the second half of the 20th century. However, all high-strength fibers developed to date are brittle. Recently, pioneering simultaneous ultrahigh strength and toughness were discovered in fine (<250 nm) individual electrospun polymer nanofibers (NFs). This highly desirable combination of properties was attributed to high macromolecular chain alignment coupled with low crystallinity. Quantitative analysis of the degree of preferred chain orientation will be crucial for control of NF mechanical properties. However, quantification of supramolecular nanoarchitecture in NFs with low crystallinity in the ultrafine diameter range is highly challenging. Here, we discuss the applicability of traditional as well as emerging methods for quantification of polymer chain orientation in nanoscale one-dimensional samples. Advantages and limitations of different techniques are critically evaluated on experimental examples. It is shown that straightforward application of some of the techniques to sub-wavelength-diameter NFs can lead to severe quantitative and even qualitative artifacts. Sources of such size-related artifacts, stemming from instrumental, materials, and geometric phenomena at the nanoscale, are analyzed on the example of polarized Raman method but are relevant to other spectroscopic techniques. A proposed modified, artifact-free method is demonstrated. Outstanding issues and their proposed solutions are discussed. The results provide guidance for accurate nanofiber characterization to improve fundamental understanding and accelerate development of nanofibers and related nanostructured materials produced by electrospinning or other methods. We expect that the discussion in this review will also be useful to studies of many biological systems that exhibit nanofilamentary architectures and combinations of high strength and toughness.


Improving knowledge of public health accreditation through a group vetting session of a practice-based research network.
This article describes efforts to improve knowledge of and acceptance of the proposed voluntary health department accreditation program, put forth by Public Health Accreditation Board (PHAB), by conducting a group vetting session. The vetting session closely followed the PHAB guidelines, and participants received pre- and postvetting surveys to gauge their knowledge of the accreditation standards and related items and their perception of the utility of the standards and the ability of their agencies to meet the standards. Respondents reported that the vetting session did improve their knowledge and understanding of the standards (increase in mean score from 3.6 to 4.4). In addition, respondents had overwhelmingly favorable responses to the draft standards (28 of 31 received positive responses from more than 85% of participants). This suggests that conducting group vetting sessions may be an effective way to increase awareness of the PHAB standards and may help prepare local health agencies for the accreditation process.


Early obliteration of pediatric brain arteriovenous malformations after stereotactic radiosurgery: an international multicenter study.
Stereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs. The authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared. The overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation. Approximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.


Autistic traits influence gaze-oriented attention to happy but not fearful faces.
The relationship between autistic traits and gaze-oriented attention to fearful and happy faces was investigated at the behavioral and neuronal levels. Upright and inverted dynamic face stimuli were used in a gaze-cueing paradigm while event related potentials (ERPs) were recorded. Participants responded faster to gazed-at than to non-gazed-at targets, and this gaze orienting effect (GOE) diminished with inversion, suggesting it relies on facial configuration. It was also larger for fearful than happy faces but only in participants with high autism-spectrum quotient (AQ) scores. While the GOE to fearful faces was of similar magnitude regardless of AQ scores, a diminished GOE to happy faces was found in participants with high AQ scores. At the ERP level, a congruency effect on target-elicited P1 component reflected enhanced visual processing of gazed-at targets. In addition, cue-triggered early directing attention negativity and anterior directing attention negativity reflected, respectively, attention orienting and attention holding at gazed-at locations. These neural markers of spatial attention orienting were not modulated by emotion and were not found in participants with high AQ scores. Together, these findings suggest that autistic traits influence attention orienting to gaze and its modulation by social emotions such as happiness.


Fig wasps: mechanism of pollen transfer.
The fig (Ficus) is absolutely dependent upon pollination by minute agaonid wasps for development of fertile seeds. In some species of the wasp genera Agaon, Allotriozoon, Blastophaga, Ceratosolen, Elisabethiella, Liporrhopalum, and Pleistodontes, the females possess concavities ("corbiculae") to carry pollen. The New World Tetrapus and some Old World Blastophaga lack pollen-carrying structures and may carry pollen dusted over the body or in the digestive tract.


Anxiety is common and independently associated with clinical features of epilepsy.
The objective of this study was to assess for independent association of anxiety symptoms with epilepsy localization and other epilepsy-related and demographic factors in a large tertiary care adult epilepsy population. Among 540 adults, anxiety was measured by the Symptom Checklist 90-R (SCL-90R) anxiety subscale, and detailed demographics, epilepsy localization, and depression scores (SCL-90R) were collected. High anxiety was defined by SCL-90R anxiety T-score ≥ 60. Stepwise multiple logistic regression was carried out to assess for independent association of high anxiety scores with demographic and clinical factors. High anxiety symptoms were present in 46.1% of participants (N = 250). Focal or unknown epilepsy type and depression scores were independently associated with high anxiety (adjusted odds ratios (OR): 2.89 (95% confidence interval [CI] = 1.33-6.29, p = 0.007) and 2.12 (95% CI = 1.83-2.45, p < 0.001), respectively; depression odds per 5-point increase in scale). Among the focal epilepsy subpopulation, mesial temporal sclerosis was also independently associated with high anxiety, with adjusted OR: 2.12 (95% CI = 1.11-4.04, p = 0.023). Lower education, non-white race/ethnicity, Spanish native language, prior head trauma, antiseizure drug polytherapy, and left focus or bilateral foci (in focal epilepsy) were associated with high anxiety in simple logistic regression, but these associations were not independent. A total of 46 individuals (18.4% of those with high anxiety) scored high for anxiety but not depression. Only 26% of those with high anxiety symptoms were taking a potentially anxiolytic medication. Anxiety symptoms, often without concomitant depression, were highly prevalent in this epilepsy sample and independently associated with focal/unknown epilepsy and mesial temporal sclerosis. These results strongly support the value of screening specifically for anxiety in the epilepsy clinic, to direct patients to appropriate treatment.


Teenage welfare receipt and subsequent dependence among black adolescent mothers.
Black teenage mothers who receive benefits through Aid to Families with Dependent Children (AFDC) around the time they give birth are more likely to be receiving AFDC at age 26 than are other black teenage mothers or women who do not have a teenage birth, even after adjustments are made for differences in parental background and the economic accomplishments of siblings. Moreover, they are also more likely to have a lower earned family income and a lower total family income (when transfer income such as AFDC is taken into account). The results of this analysis suggest that AFDC receipt around the time of a nonmarital teenage birth itself may be an independent cause of future economic problems for these young mothers, although they do not elucidate the causal mechanism by which such an association might operate.


TLR5 as an anti-inflammatory target and modifier gene in cystic fibrosis.
New treatments are needed to improve the health of people with cystic fibrosis (CF). Reducing lung-damaging inflammation is likely to be beneficial, but specific anti-inflammatory targets have not been identified. By combining cellular immunology with a population-based genetic modifier study, we examined TLR5 as an anti-inflammatory target and modifier gene in CF. Using two pairs of human CF and control airway epithelial cells, we demonstrated that the TLR5-flagellin interaction is a major mediator of inflammation following exposure to Pseudomonas aeruginosa. To validate TLR5 as an anti-inflammatory target, we analyzed the disease modifying effects of the TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) in a large cohort of CF patients (n = 2219). rs5744168 encodes a premature stop codon and the T allele is associated with a 45.5-76.3% reduction in flagellin responsiveness (p < 0.0001). To test the hypothesis that reduced TLR5 responsiveness would be associated with improved health in CF patients, we examined the relationship between rs5744168 and two clinical phenotypes: lung function and body weight. Adults with CF carrying the TLR5 premature stop codon (CT or TT genotype) had a higher body mass index than did CF patients homozygous for the fully functional allele (CC genotype) (p = 0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Although follow-up studies are needed to confirm the impact of TLR5 on nutritional status, this translational research provides evidence that genetic variation in TLR5 resulting in reduced flagellin responsiveness is associated with improved health indicators in adults with CF.


Changing clinical practice. Prospective study of the impact of continuing medical education and quality assurance programs on use of prophylaxis for venous thromboembolism.
To determine the effect of continuing medical education (CME) with and without a quality assurance component (CME+QA) on physician practices in the prevention of venous thromboembolism. A communitywide study was performed in 15 short-stay hospitals in central Massachusetts. The study population included 3158 patients in acute-care hospitals with multiple risk factors for venous thromboembolism. Study hospitals were randomly assigned to one of two educational strategies or to a control group that received no intervention. The proportion of patients at high risk for venous thromboembolism who received effective methods of prophylaxis increased significantly from 29% in 1986 to 52% in 1989 (P < .001). This increase was seen in all study groups: control hospitals, 40% to 51% (P < .001); CME hospitals, 21% to 49% (P < .0001); and CME+QA hospitals, 27% to 55% (P < .0001). The increase in prophylaxis use from 1986 to 1989 was significantly greater among patients cared for in hospitals whose physicians participated in a formal CME program (an increase of 28%) than in control hospitals (an increase of 11%) (P < .001). There was no significant difference in the use of prophylaxis in hospitals whose physicians received CME+QA interventions compared with hospitals whose physicians received CME interventions alone (identical increases of 28%). A formal CME program significantly increased the frequency with which physicians prescribed prophylaxis for venous thromboembolism. We believe the key factor in our CME interventions that motivated clinicians to change their practices was the provision of hospital-specific data demonstrating a compelling need for improvement. Despite the substantial investment by hospitals in QA, traditional QA intervention appeared to provide no additional benefit. Even after extensive CME/QA interventions, prophylaxis for venous thromboembolism remained underutilized, suggesting the need to develop new approaches to changing clinical practice.


Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile.
Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.


Standing long-jump performance is enhanced when using an external focus of attention.
Several experiments have demonstrated that focusing a performer's attention externally (i.e., on the effects of a movement) rather than internally (i.e., on specific parts of the body) enhances performance when the task requires object manipulation (i.e., throwing a ball to a target). The purpose of this experiment was to investigate if whole-body movements (e.g., standing long jump), without object manipulation, are influenced by an internal or external focus of attention. After participants (n = 120) completed a short warm-up, they were assigned to either an internal (INT) or external (EXT) focus of attention group. All participants completed 5 standing long jumps separated by a 2-minute seated rest. Before each jump, participants in the INT condition were read the following instructions: "When you are attempting to jump as far as possible, I want you to focus your attention on extending your knees as rapidly as possible." Participants in the EXT condition were read the following instructions: "When you are attempting to jump as far as possible, I want you to focus your attention on jumping as far past the start line as possible." An independent samples t-test revealed a significant difference (p = 0.003) in the average distance jumped between the EXT (187.37 +/- 42.66 cm) group and the INT group (177.33 +/- 40.97 cm). The results suggest that providing instructions that focus attention externally enhances standing long-jump performance compared with instructions that focus attention internally. This finding is valuable for strength and conditioning professionals that use jumping tests to evaluate performance.


Nutrition-education program improves preschoolers' at-home diet: a group randomized trial.
This study evaluated whether a nutrition-education program in child-care centers improved children's at-home daily consumption of fruits and vegetables, at-home use of low-fat/fat-free milk, and other at-home dietary behaviors. Twenty-four child-care centers serving low-income families were matched by region, type, and size, and then randomly assigned to either an intervention or control condition. In the 12 intervention centers, registered dietitian nutritionists provided nutrition education to children and parents separately during a 6- to 10-week period. They also held two training sessions for center staff, to educate them on healthy eating and physical activity policies at the centers, and distributed weekly parent newsletters that included activities and recipes. Parents (n=1,143) completed a mail or telephone survey at baseline and follow-up to report information on their child's fruit, vegetable, and milk consumption and other dietary behaviors at home. This study used general and generalized linear mixed models to evaluate program impacts, while accounting for the clustering of children within centers. This study included child age, child sex, household size, respondent race/ethnicity, respondent age, and respondent sex as covariates. The program had a substantial impact on children's at-home daily consumption of vegetables and use of low-fat/fat-free milk. This study also found a significant increase in the frequency of child-initiated vegetable snacking, which might have contributed to the significant increase in vegetable consumption. The program did not have a significant impact on fruit consumption or parental offerings of fruits and vegetables, child-initiated fruit snacking, or child fruit consumption. This intervention in child-care settings that emphasized children, parents, and teachers significantly increased at-home vegetable and low-fat/fat-free milk consumption among low-income preschoolers.


Crystal structures of ribonuclease A complexes with 5'-diphosphoadenosine 3'-phosphate and 5'-diphosphoadenosine 2'-phosphate at 1.7 A resolution.
High-resolution (1.7 A) crystal structures have been determined for bovine pancreatic ribonuclease A (RNase A) complexed with 5'-diphosphoadenosine 3'-phosphate (ppA-3'-p) and 5'-diphosphoadenosine 2'-phosphate (ppA-2'-p), as well as for a native structure refined to 2.0 A. These nucleotide phosphates are the two most potent inhibitors of RNase A reported so far, with Ki values of 240 and 520 nM, respectively. The binding modes and conformations of ppA-3'-p and ppA-2'-p were found to differ markedly from those anticipated on the basis of earlier structures of RNase A complexes. The key difference is that the 5'-beta-phosphate rather than the 5'-alpha-phosphate of each inhibitor occupies the P1 phosphate binding site. As a consequence, the ribose moieties of the two nucleotides are shifted by approximately 2 A compared to the positions of their counterparts in earlier complexes, and the adenine rings are rotated into unusual syn conformations. Thus, the six-membered and five-membered rings of both adenines are reversed with respect to the others but nonetheless engage in extensive interactions with the residues that form the B2 purine binding site of RNase A. Despite the close structural similarity of the two inhibitors, the puckers of their furanose rings are different: C2'-endo and C3'-endo, respectively. Moreover, their 5'-alpha-phosphates and 3'(2')-monophosphates interact with largely different sets of RNase residues. The results of this crystallographic study emphasize the difficulties inherent in qualitative modeling of protein-inhibitor interactions and the compelling reasons for high-resolution structural studies in which quantitative design of improved inhibitors was enabled. The structures presented here provide a promising starting point for the rational design of tight-binding RNase inhibitors, which may be used as therapeutic agents in restraining the ribonucleolytic activities of RNase homologues such as angiogenin, eosinophil-derived neurotoxin, and eosinophil cationic protein.


The E3 ligase HACE1 is a critical chromosome 6q21 tumor suppressor involved in multiple cancers.
Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers.


Association of Urinary Sodium Excretion With Blood Pressure and Cardiovascular Clinical Events in 17,033 Latin Americans.
Information on actual sodium intake and its relationships with blood pressure (BP) and clinical events in South America is limited. The aim of this cohort study was to assess the relationship of sodium intake with BP, cardiovascular (CV) events, and mortality in South America. We studied 17,033 individuals, aged 35-70 years, from 4 South American countries (Argentina, Brazil, Chile, and Colombia). Measures of sodium excretion, estimated from morning fasting urine, were used as a surrogate for daily sodium intake. We measured BP and monitored the composite outcome of death and major CV events. Overall mean sodium excretion was 4.70±1.43g/day. A positive, nonuniform association between sodium and BP was detected, with a significant steeper slope for the relationship at higher sodium excretion levels (P < 0.001 for interaction). With a median follow-up of 4.7 years, the primary composite outcome (all-cause death, myocardial infarction, stroke, or heart failure) occurred in 568 participants (3.4%). Compared with sodium excretion of 5-6g/day (reference group), participants who excreted >7g/day had increased risks of the primary outcome (odds ratio (OR) 1.73; 95% confidence interval (CI) 1.24 to 2.40; P < 0.001), as well as death from any cause (OR 1.87; 95% CI 1.23 to 2.83; P = 0.003) and major CV disease (OR 1.77; 95% CI 1.12 to 2.81; P = 0.014). Sodium excretion of <3g/day was associated with a statistically nonsignificant increased risk of the primary outcome (OR 1.20; 95% CI 0.86 to 1.65; P = 0.26) and death from any cause (OR 1.25; 95% CI 0.81 to 1.93; P = 0.29), and a significant increased risk of major CV disease (OR 1.50; 95% CI 1.01 to 2.24; P = 0.048), as compared to the reference group. Our results support a positive, nonuniform association between estimated urinary sodium excretion and BP, and a possible J-shaped pattern of association between sodium excretion over the entire range and clinical outcomes.


Breaking bad news. A review of the literature.
To review the literature on breaking bad news while highlighting its limitations and describing a theoretical model from which the bad news process can be understood and studied. Sources were obtained through the MEDLINE database, using "bad news" as the primary descriptor and limiting the sources to English-language articles published since 1985. All articles dealing specifically with bad news were examined. These works included letters, opinions, reviews, and empirical studies. Recommendations from these articles were examined, sorted into discrete categories, and summarized. The 13 most consistently mentioned recommendations (eg, delivering the news at the patient's pace, conveying some hope, and giving the news with empathy) were examined. Although much has been written on the topic of breaking bad news, the literature is in need of empirical work. Research should begin with the simple question of whether how the news is conveyed accounts for variance in adjustment before moving to more specific questions about which aspects of conveying bad news are most beneficial. It is suggested that the bad news process can be understood from the transactional approach to stress and coping.


Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis.
Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene-gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint=0.45, p=0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6×10(-9) to 7.5×10(-7)). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.


Caries experience, the caries burden and associated factors in children in England, Wales and Northern Ireland 2013.
Background The 2013 Children's Dental Health Survey is the fifth in a series of national surveys.Aims To describe caries prevalence and severity and factors affecting these, in children in England, Wales and Northern Ireland in 2013.Methodology A representative sample of children (aged 5, 8, 12 and 15 years) in England, Wales and Northern Ireland were invited to participate in dental examinations. Caries was measured at both the dentine ('obvious caries') and dentine plus enamel ('clinical caries') levels and analysis included identifying those with indicators of significant burden of caries and identifying predictive factors.Results In 5-year-olds, 40% had obvious caries experience increasing to 56% when enamel lesions were included. In 15-year-olds, the respective figures were 46% and 63%. Fourteen percent of 5-year-olds and 15% of 15-year-olds had a least one indicator of significant levels of caries and those from deprived backgrounds were more likely to fall into this group.Conclusions Overall, the prevalence of caries in children is continuing to decrease, but the rate is slowing. The level of disease for those with disease is much higher than the average values might suggest and there remain a sizeable minority with a significant burden of caries, associated with deprivation. This complex picture poses significant clinical and public health challenges.


Unsupervised image categorization by hypergraph partition.
We present a framework for unsupervised image categorization in which images containing specific objects are taken as vertices in a hypergraph and the task of image clustering is formulated as the problem of hypergraph partition. First, a novel method is proposed to select the region of interest (ROI) of each image, and then hyperedges are constructed based on shape and appearance features extracted from the ROIs. Each vertex (image) and its k-nearest neighbors (based on shape or appearance descriptors) form two kinds of hyperedges. The weight of a hyperedge is computed as the sum of the pairwise affinities within the hyperedge. Through all of the hyperedges, not only the local grouping relationships among the images are described, but also the merits of the shape and appearance characteristics are integrated together to enhance the clustering performance. Finally, a generalized spectral clustering technique is used to solve the hypergraph partition problem. We compare the proposed method to several methods and its effectiveness is demonstrated by extensive experiments on three image databases.


Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways.
Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through _3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts.


Annual Research Review: Digital health interventions for children and young people with mental health problems - a systematic and meta-review.
Digital health interventions (DHIs), including computer-assisted therapy, smartphone apps and wearable technologies, are heralded as having enormous potential to improve uptake and accessibility, efficiency, clinical effectiveness and personalisation of mental health interventions. It is generally assumed that DHIs will be preferred by children and young people (CYP) given their ubiquitous digital activity. However, it remains uncertain whether: DHIs for CYP are clinically and cost-effective, CYP prefer DHIs to traditional services, DHIs widen access and how they should be evaluated and adopted by mental health services. This review evaluates the evidence-base for DHIs and considers the key research questions and approaches to evaluation and implementation. We conducted a meta-review of scoping, narrative, systematic or meta-analytical reviews investigating the effectiveness of DHIs for mental health problems in CYP. We also updated a systematic review of randomised controlled trials (RCTs) of DHIs for CYP published in the last 3 years. Twenty-one reviews were included in the meta-review. The findings provide some support for the clinical benefit of DHIs, particularly computerised cognitive behavioural therapy (cCBT), for depression and anxiety in adolescents and young adults. The systematic review identified 30 new RCTs evaluating DHIs for attention deficit/hyperactivity disorder (ADHD), autism, anxiety, depression, psychosis, eating disorders and PTSD. The benefits of DHIs in managing ADHD, autism, psychosis and eating disorders are uncertain, and evidence is lacking regarding the cost-effectiveness of DHIs. Key methodological limitations make it difficult to draw definitive conclusions from existing clinical trials of DHIs. Issues include variable uptake and engagement with DHIs, lack of an agreed typology/taxonomy for DHIs, small sample sizes, lack of blinded outcome assessment, combining different comparators, short-term follow-up and poor specification of the level of human support. Research and practice recommendations are presented that address the key research questions and methodological issues for the evaluation and clinical implementation of DHIs for CYP.


Fructus Ligustri Lucidi aqueous extract promotes calcium balance and short-chain fatty acids production in ovariectomized rats.
Fructus Ligustri Lucidi (FLL) is an edible herb with anti-osteoporotic activity, yet whether and how the aqueous extract of this herb affect calcium metabolism in preservation of bone quality remain unclear. To investigate the effects of FLL aqueous extract on calcium balance and short-chain fatty acids (SCFAs) production in ovariectomized (OVX) rats. OVX rats were daily and orally administrated with FLL aqueous extract (3.5 g/kg) for 14 weeks. The levels of N-terminal propeptide of type I collagen (PINP) and C-terminal telopeptide of type I collagen (CTx-I) in rat serum were evaluated by ELISA assays. The concentration of calcium in serum, urine, and feces were determined by biochemical assays. Bone quality was determined by Micro-CT, a three-point bending assay, and Fourier Transform Infrared (FTIR) Spectrometry. The expressions of Calbindin D28K and Calcium-sensing receptor (CaSR) in kidney as well as the Vitamin D receptor (VDR), the transient receptor potential vanilloid receptor 6 (TRPV6), Calbindin D9k in the duodenum were measured by immunohistochemistry, western blotting, or real-time PCR. The short-chain fatty acids (SCFAs) levels in the feces of the cecum were tested by gas chromatograghy. The administration of FLL to OVX rats resulted in a significant improvement in bone mineral density and biomechanical strength as well as in maintaining bone microstructures and material quality. Meanwhile, the decreased levels of PINP and increased levels of CTx-I in OVX rats were restored by FLL treatment. Additionally, FLL treatment increased calcium absorption, upregulated VDR, TRPV6, Calbindin D9k expressions in the duodenum, Calbindin D28K in kidney, and down-regulated CaSR expression in the kidney, as well as enhanced SCFAs levels in the feces of OVX rats. FLL aqueous extract may preserve bone quality through regulation of the calcium balance and intestinal SCFAs production in OVX rats. This offers translational value of FLL into osteoporosis clinical trial.


Recent advances in uniportal video-assisted thoracoscopic surgery.
Thanks to the recent improvements in video-assisted thoracoscopic techniques (VATS) and anesthetic procedures, a great deal of complex lung resections can be performed avoiding open surgery. The experience gained through VATS techniques, enhancement of the surgical instruments, improvement of high definition cameras and avoidance of intubated general anesthesia have been the greatest advances to minimize the trauma to the patient. Uniportal VATS for major resections has become a revolution in the treatment of lung pathologies since initially described 4 years ago. The huge number of surgical videos posted on specialized websites, live surgery events and experimental courses has contributed to the rapid learning of uniportal major thoracoscopic surgery during the last years. The future of the thoracic surgery is based on evolution of surgical procedures and anesthetic techniques to try to reduce the trauma to the patient. Further development of new technologies probably will focus on sealing devices for all vessels and fissure, refined staplers and instruments, improvements in 3D systems or wireless cameras, and robotic surgery. As thoracoscopic techniques continue to evolve exponentially, we can see the emergence of new approaches in the anesthetical and the perioperative management of these patients. Advances in anesthesia include lobectomies performed without the employment of general anesthesia, through maintaining spontaneous ventilation, and with minimally sedated patients. Uniportal VATS resections under spontaneous ventilation probably represent the least invasive approach to operate lung cancer.


Exploring resonance levels and nanostructuring in the PbTe-CdTe system and enhancement of the thermoelectric figure of merit.
We explored the effect of Cd substitution on the thermoelectric properties of PbTe in an effort to test a theoretical hypothesis that Cd atoms on Pb sites of the rock salt lattice can increase the Seebeck coefficient via the formation of a resonance level in the density of states near the Fermi energy. We find that the solubility of Cd is less than previously reported, and CdTe precipitation occurs to create nanostructuring, which strongly suppresses the lattice thermal conductivity. We present detailed characterization including structural and spectroscopic data, transmission electron microscopy, and thermoelectric transport properties of samples of PbTe-x% CdTe-0.055% PbI(2) (x = 1, 3, 5, 7, 10), PbTe-1% CdTe-y% PbI(2) (y = 0.03, 0.045, 0.055, 0.08, 0.1, 0.2), PbTe-5% CdTe-y% PbI(2) (y = 0.01, 0.03, 0.055, 0.08), and PbTe-1% CdTe-z% Sb (z = 0.3, 0.5, 1, 1.5, 2, 3, 4, 5, 6). All samples follow the Pisarenko relationship, and no enhancement of the Seebeck coefficient was observed that could be attributed to a resonance level or a distortion in the density of states. A maximum ZT of approximately 1.2 at approximately 720 K was achieved for the PbTe-1% CdTe-0.055% PbI(2) sample arising from a high power factor of approximately 17 microW/(cm K(2)) and a very low lattice thermal conductivity of approximately 0.5 W/(m K) at approximately 720 K.


[Limitation of life-sustaining treatment. A prospective study in a clinical ward].
The purpose of this study is to describe the limiting life-sustaining treatment process of patients admitted to a general ward. A prospective descriptive study was designed. The setting was the general ward of universitary hospital. Study participants were patients assisted by the internal medicine department during a 60-consecutive days period who had limitations of life sustaining treatments. During the study period, 402 patients were hospitalized, 62 (15%) of them had limitations of life support care. The median patient age of the last group was 86 years (78-90), 66% were women and the length of stay was 12 days (8-18). A low quality of life was the most frequent cause of limitation (69%). Information about the limitations was provided to 43 families (69%) and 8 patients (13%). The primary care physician participated in the decision in 50% of the cases, while the attending physician, the resident in charge, patient's family and patients themselves participated in 50%, 40%, 42% and 11% of the cases respectively. The decision of limiting life-sustaining treatments was recorded in seven patient's charts (11%). Seventeen (27%) patients with limitations died during the hospital stay while 44 (71%) were discharged. In conclusion, we found a frequent life sustaining treatment limitation in our patients. These decisions did not follow a uniform or systemized process. The need of guidelines to sort the medical and ethical challenges imposed to the medical team is undeniable.


Orexin a phosphorylates the γ-Aminobutyric acid type A receptor β2 subunit on a serine residue and changes the surface expression of the receptor in SH-SY5Y cells exposed to propofol.
Propofol activates the γ-aminobutyric acid type A receptor (GABAA R) and causes a reversible neurite retraction, leaving a thin, thread-like structure behind; it also reverses the transport of vesicles in rat cortical neurons. The awakening peptide orexin A (OA) inhibits this retraction via phospholipase D (PLD) and protein kinase Cɛ (PKCɛ). The human SH-SY5Y cells express both GABAA Rs and orexin 1 and 2 receptors. These cells are used to examine the interaction between OA and the GABAA R. The effects of OA are studied with flow cytometry and immunoblotting. This study shows that OA stimulates phosphorylation on the serine residues of the GABAA R β2 subunit and that the phosphorylation is caused by the activation of PLD and PKCɛ. OA administration followed by propofol reduces the cell surface expression of the GABAA R, whereas propofol stimulation before OA increases the surface expression. The GABAA R β2 subunit is important for receptor recirculation, and the effect of OA on propofol-stimulated cells may be due to a disturbed recirculation of the GABAA R.


Myxoid dermatofibroma on a great toe: a case report.
Dermatofibroma is a common benign fibrohistiocytic tumor with many clinicopathological variants. Myxoid dermatofibroma is one of these variants, which is characterized by marked stromal mucin deposition. This report presents a case of myxoid dermatofibroma on a great toe that had been slowly growing for two years. Histopathologically, the relatively well-circumscribed dermal tumor was separated from the epidermis by a small grenz zone. The tumor tissue consisted of oval to spindle-shaped cells with well-defined cell borders and spindly condensed nuclei. No cytologic atypia or mitotic figures were found. Although most of the tumor cells were embedded in a prominently myxoid stroma, typical features of classic dermatofibroma including a storiform growth pattern and more densely packed collagen were observed at the periphery. Immunohistochemically, the tumor cells showed positive staining for CD68 and CD99, and negative staining for CD34 and S-100. Histopathological differential diagnoses of myxoid dermatofibroma include soft tissue neoplasms with myxoid tumor stroma, such as superficial acral fibromyxoma, cellular digital fibroma, superficial angiomyxoma, myxoid dermatofibrosarcoma protuberans and low-grade fibromyxoid sarcoma. Immunohistochemical staining can be useful in the differential diagnosis of these tumors. This case highlights the challenges encountered in the histopathological interpretation of myxoid dermatofibroma. Pathologists should keep in mind the diagnosis of myxoid dermatofibroma when dealing with myxoid neoplastic lesions arising on acral sites.


Beta-carotene and lung cancer: a case study.
The conflicting evidence of the relation between beta-carotene and lung cancer in humans serves as a poignant case study with respect to what types of evidence are sufficient to support or change a nutrition recommendation. This article is a review of the available evidence of the relation between beta-carotene and lung cancer, including data regarding beta-carotene intake (from diet and supplements), beta-carotene biochemical status, and vegetable and fruit consumption, and a discussion of the role of this evidence in making nutrition recommendations. More than 30 case-control and cohort studies were conducted over many years in various populations and indicated that people who eat more vegetables and fruit, foods rich in carotenoids, and carotenoids (beta-carotene in particular), as well as those with higher blood beta-carotene concentrations, have a lower risk of lung cancer than those who eat fewer such foods or have lower beta-carotene concentrations. In contrast, the intervention results from large, controlled trials of beta-carotene supplementation do not support the observed beneficial associations or a role for supplemental beta-carotene in lung cancer prevention; instead, they provide striking evidence for adverse effects (ie, excess lung cancer incidence and overall mortality) in smokers. The findings require that caution be exercised in recommending supplemental beta-carotene, particularly for smokers, and argue against changing the vegetable-fruit recommendations in the direction of greater nutrient specificity. This case study of beta-carotene and lung cancer stresses the importance of having results from at least one, and preferably more, large, randomized intervention trial before public health recommendations concerning micronutrient supplementation are considered.


The pathogenesis of discogenic low back pain.
Discogenic low back pain is a common cause of disability, but its pathogenesis is poorly understood. We collected 19 specimens of lumbar intervertebral discs from 17 patients with discogenic low back pain during posterior lumbar interbody fusion, 12 from physiologically ageing discs and ten from normal control discs. We investigated the histological features and assessed the immunoreactive activity of neurofilament (NF200) and neuropeptides such as substance P (SP) and vasoactive-intestinal peptide (VIP) in the nerve fibres. The distinct histological characteristic of the painful disc was the formation of a zone of vascularised granulation tissue from the nucleus pulposus to the outer part of the annulus fibrosus along the edges of the fissures. SP-, NF- and VIP-immunoreactive nerve fibres in the painful discs were more extensive than in the control discs. Growth of nerves deep into the annulus fibrosus and nucleus pulposus was observed mainly along the zone of granulation tissue in the painful discs. This suggests that the zone of granulation tissue with extensive innervation along the tears in the posterior part of the painful disc may be responsible for causing the pain of discography and of discogenic low back pain.


[Investigation of voiding dysfunction in a population-based sample of children aged 3 to 9 years].
To describe voiding patterns and related dysfunctions in a population-based sample of children aged 3 to 9 years. A cross-sectional population-based survey including 580 children. A probabilistic sample of households in the urban area of Pelotas in southern Brazil was selected following a multiple-stage protocol. Voiding and fecal patterns were investigated using the dysfunction score created by Farhat et al. and modified by the addition of high urinary frequency (more than eight times a day). Boys with scores above eight and girls above five were clinically investigated, as well as a sub-sample of the remaining children. Nocturia (60.4%), urinary urgency (49.7%) and holding maneuvers (42.1%) were the most frequently reported symptoms. The prevalence of enuresis was 20.1% in boys and 15.1% in girls. The prevalence of urinary dysfunction was 22.8%. Most symptoms were more frequently reported by girls and younger children. Among girls, low socioeconomic level was related to an increased prevalence of enuresis and straining to urinate, while among boys urgency was more common among the poor. Only 10.5% of the parents of the children with voiding dysfunction consulted a doctor because of their problems. The voiding symptoms studied presented high prevalence rates, and therefore should be investigated in clinical practice, with direct questions about each symptom, aiming to diagnose voiding dysfunction.


An early phase of instructive plasticity before the typical onset of sensory experience.
While early experience with moving stimuli is necessary for the development of direction selectivity in visual cortex of carnivores, it is unclear whether experience exerts a permissive or instructive influence. To test if the specific parameters of the experienced stimuli could instructively sculpt the emergent responses, visually naive ferrets were exposed to several hours of experience with unusual spatiotemporal patterns. In the most immature ferrets, cortical neurons developed selectivity to these patterns, indicating an instructive influence. In animals that were 1-10 days more mature, exposure to the same patterns led to a developmentally-typical increase in direction selectivity. We conclude that visual development progresses via an early phase of instructive plasticity, when the specific patterns of neural activity shape the specific parameters of the emerging response properties, followed by a late phase of permissive maturation, when sensory-driven activity merely serves to enhance the response properties already seeded in cortical circuits.


A Game-Theoretic Approach to Design Secure and Resilient Distributed Support Vector Machines.
Distributed support vector machines (DSVMs) have been developed to solve large-scale classification problems in networked systems with a large number of sensors and control units. However, the systems become more vulnerable, as detection and defense are increasingly difficult and expensive. This paper aims to develop secure and resilient DSVM algorithms under adversarial environments in which an attacker can manipulate the training data to achieve his objective. We establish a game-theoretic framework to capture the conflicting interests between an adversary and a set of distributed data processing units. The Nash equilibrium of the game allows predicting the outcome of learning algorithms in adversarial environments and enhancing the resilience of the machine learning through dynamic distributed learning algorithms. We prove that the convergence of the distributed algorithm is guaranteed without assumptions on the training data or network topologies. Numerical experiments are conducted to corroborate the results. We show that the network topology plays an important role in the security of DSVM. Networks with fewer nodes and higher average degrees are more secure. Moreover, a balanced network is found to be less vulnerable to attacks.


Practical Diagnostic Accuracy of Nasopharyngeal Swab Testing for Novel Coronavirus Disease 2019 (COVID-19).
The novel coronavirus (SARS-CoV-2) is the cause of COVID-19, which has had a devastating international impact. Prior reports of testing have reported low sensitivities of nasopharyngeal polymerase chain reaction (PCR), and reports of viral co-infections have varied from 0-20%. Therefore, we sought to determine the accuracy of nasopharyngeal PCR for COVID-19 and rates of viral co-infection. We conducted a retrospective chart review of all patients who received viral testing between March 1, 2020-April 28, 2020. Test results of a complete viral pathogen panel and COVID-19 testing were abstracted. We compared patients with more than one COVID-19 test for diagnostic accuracy against the gold standard of chart review. We identified 1950 patients, of whom 1024 were tested for COVID-19. There were 221 repeat tests for COVID-19. Among patients with a repeat test, COVID-19 swabs had a sensitivity of 84.6% (95% confidence interval (CI), 69.5-94.4%) and a specificity of 99.5% (95%CI, 97-100%) compared to a clinical and radiographic criterion reference by chart review. We found viral co-infection rates of 2.3% in patients without COVID-19 and 6.1% in patients with COVID-19. Rates of co-infection appeared to be related to base rates of infection in the community and not a specific property of COVID-19. COVID-19 nasopharyngeal PCR specimens are accurate but have imperfect sensitivity. Repeat testing for high-risk patients should be considered, and presence of an alternative virus should not be used to limit testing for COVID-19 for patients where it would affect treatment or isolation.


Trends in mortality due to gastrointestinal diseases attributed to alcohol use in Peru from 2003 to 2016.
To assess and identify changes in the temporal trend in mortality from alcohol-attributable gastrointestinal diseases and their disease burden based on years of life lost (YLL) in Peru. An ecological study of the death records of the Ministry of Health of Peru was conducted from 2003-2016. A gastrointestinal death attributable to alcohol was considered if the basic, intermediate, or final cause of death included ICD-10 codes: K70, K700-4, K709, K292, K852, and K860. Crude and age-adjusted mortality rates were calculated for the general population aged 15 or older and by sex, and YLL. Joinpoint regression analysis was performed to evaluate trends in mortality. There were 11 148 deaths by alcohol-attributable gastrointestinal diseases, being more frequent in males (74.89%), in adults aged 45 years and above (83.67%), living in urban area (69.87%) and the Andes region (60.0%), and in subjects with liver disease (85.98%). Adjusted mortality rates varied from 6.21 (95% CI: 5.78-6.63) in 2003 to 3.95 (95% CI: 3.67-4.22) in 2016. The trend of mortality decreased in the general population (APC: -6.17, 95% CI: -9.9 to -2.2, p=0.007) during the period 2008-2016. Deaths from the causes studied generated 224 545 YLL. A declining trend was found in gastrointestinal deaths attributable to alcohol in the period 2008-2016. The highest mortality occurred in males, individuals aged 45 years and above, living in urban areas and the Andes region.


Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand.
A series of compounds derived from phencyclidine (PCP) was examined in the sigma receptor and PCP receptor binding assays. The derivatives included compounds containing methylene, ethylene or carboxyl ethylene insertion between the cycloalkyl ring and the amine group of PCP. Various phenyl substitutions, cycloalkyl rings and amines of these derivatives were also examined. The methylene and ethylene insertions decreased the compounds' potencies at PCP receptors, whereas they increased the potencies at sigma receptors. The carboxyl ethylene insertion produced compounds with negligible potencies at PCP receptors while possessing high potencies for sigma receptors. One derivative (PRE-084; 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate hydrochloride) had an IC50 of 44 nM in the sigma receptor assay, an IC50 of more than 100,000 nM for PCP receptors and an IC50 higher than 10,000 nM in a variety of other receptor systems. In general, compounds with hydroxy-substituted phenyl groups tended to have decreased potency at sigma receptors, whereas methylphenyl and chlorophenyl substitutions increased potencies. Reduction of cycloalkyl ring size decreased potencies for sigma receptors and quaternized amine groups invariably lowered the compound's potencies. Conformational analysis indicated that PRE-084 fitted onto a pharmacophore model for the sigma ligands. The study describes a new, highly selective ligand for the sigma receptor. The results of this study also confirm distinctly different structural requirements for binding to sigma and PCP receptors and provide a new structural consideration for synthesizing sigma-selective compounds.


Characterization of new RNA polymerase III and RNA polymerase II transcriptional promoters in the Bovine Leukemia Virus genome.
Bovine leukemia virus latency is a viral strategy used to escape from the host immune system and contribute to tumor development. However, a highly expressed BLV micro-RNA cluster has been reported, suggesting that the BLV silencing is not complete. Here, we demonstrate the in vivo recruitment of RNA polymerase III to the BLV miRNA cluster both in BLV-latently infected cell lines and in ovine BLV-infected primary cells, through a canonical type 2 RNAPIII promoter. Moreover, by RPC6-knockdown, we showed a direct functional link between RNAPIII transcription and BLV miRNAs expression. Furthermore, both the tumor- and the quiescent-related isoforms of RPC7 subunits were recruited to the miRNA cluster. We showed that the BLV miRNA cluster was enriched in positive epigenetic marks. Interestingly, we demonstrated the in vivo recruitment of RNAPII at the 3'LTR/host genomic junction, associated with positive epigenetic marks. Functionally, we showed that the BLV LTR exhibited a strong antisense promoter activity and identified cis-acting elements of an RNAPII-dependent promoter. Finally, we provided evidence for an in vivo collision between RNAPIII and RNAPII convergent transcriptions. Our results provide new insights into alternative ways used by BLV to counteract silencing of the viral 5'LTR promoter.


Combined Superior Mesenteric Artery Syndrome and Nutcracker Syndrome in a Young Patient: A Case Report and Review of the Literature.
BACKGROUND Superior mesenteric artery syndrome is the compression of the third portion of the duodenum between the superior mesenteric artery and the aorta causing abdominal pain and vomiting. Nutcracker syndrome is the compression of the left renal vein between the superior mesenteric artery and the aorta causing symptoms related to renal congestion. Both entities, although well described in the literature, are individually rare, and even though they might share a common etiology, their co-existence has been reported in only a few case reports. CASE REPORT An 18-year-old male, previously healthy, presented with postprandial abdominal pain relieved by bilious vomiting that started shortly after he lost weight fasting. Our investigation revealed superior mesenteric artery syndrome as well as a compressed left renal vein. He was started on an enriched fluid diet which was progressed gradually as he regained weight. His left renal vein compression at the time was asymptomatic; it will be followed up for possible resolution after the patient's weight returns to normal. CONCLUSIONS Superior mesenteric artery syndrome is to be suspected in patients with abdominal pain following weight loss. Conservative treatment with a focus on weight regain will cure most cases. Asymptomatic or mildly symptomatic nutcracker syndrome is treated conservatively. For patients requiring intervention, laparoscopic extravascular titanium stent placement seems to be the least invasive promising option today, awaiting further definitive studies.


Immunotherapy of lymphomas.
Lymphoid malignancies typically promote an infiltrate of immune cells at sites involved by the disease. While some of the immune cells present in lymphoma have effector function, the immune system is unable to eradicate the malignant clone. Therapies that optimize immune function therefore have the potential to improve the outcome of lymphoma patients. In this Review, we discuss immunologic approaches that directly target the malignant cell as well as approaches to optimize both the innate and adaptive immune response to the tumor. While many of these therapies have shown single-agent activity, the future will clearly require thoughtful combinations of these approaches.


Functional Brain Imaging Reliably Predicts Bimanual Motor Skill Performance in a Standardized Surgical Task.
Currently, there is a dearth of objective metrics for assessing bi-manual motor skills, which are critical for high-stakes professions such as surgery. Recently, functional near-infrared spectroscopy (fNIRS) has been shown to be effective at classifying motor task types, which can be potentially used for assessing motor performance level. In this work, we use fNIRS data for predicting the performance scores in a standardized bi-manual motor task used in surgical certification and propose a deep-learning framework 'Brain-NET' to extract features from the fNIRS data. Our results demonstrate that the Brain-NET is able to predict bi-manual surgical motor skills based on neuroimaging data accurately ( R2=0.73). Furthermore, the classification ability of the Brain-NET model is demonstrated based on receiver operating characteristic (ROC) curves and area under the curve (AUC) values of 0.91. Hence, these results establish that fNIRS associated with deep learning analysis is a promising method for a bedside, quick and cost-effective assessment of bi-manual skill levels.


Is obesity a risk factor for progressive radiographic knee osteoarthritis?
To examine whether obesity increases the risk of progression of knee osteoarthritis (OA). We used data from the Multicenter Osteoarthritis Study, a longitudinal study of persons with or at high risk of knee OA. OA was characterized at baseline and 30 months using posteroanterior fixed-flexion radiographs and Kellgren/Lawrence (K/L) grading, with alignment assessed on full-extremity films. In knees with OA at baseline (K/L grade 2 or 3), progression was defined as tibiofemoral joint space narrowing on the 30-month radiograph. In knees without OA at baseline (K/L grade 0 or 1), incident OA was defined as the development of radiographic OA at 30 months. Body mass index (BMI) at baseline was classified as normal (<25 kg/m(2)), overweight (25-<30 kg/m(2)), obese (30-<35 kg/m(2)), and very obese (>or=35 kg/m(2)). The risk of progression was tested in all knees and in subgroups categorized according to alignment. Analyses were adjusted for age, sex, knee injury, and bone density. Among the 2,623 subjects (5,159 knees), 60% were women, and the mean +/- SD age was 62.4 +/- 8.0 years. More than 80% of subjects were overweight or obese. At baseline, 36.4% of knees had tibiofemoral OA, and of those, only one-third were neutrally aligned. Compared with subjects with a normal BMI, those who were obese or very obese were at an increased risk of incident OA (relative risk 2.4 and 3.2, respectively [P for trend < 0.001]); this risk extended to knees from all alignment groups. Among knees with OA at baseline, there was no overall association between a high BMI and the risk of OA progression; however, an increased risk of progression was observed among knees with neutral but not varus alignment. The effect of obesity was intermediate in those with valgus alignment. Although obesity was a risk factor for incident knee OA, we observed no overall relationship between obesity and the progression of knee OA. Obesity was not associated with OA progression in knees with varus alignment; however, it did increase the risk of progression in knees with neutral or valgus alignment. Therefore, weight loss may not be effective in preventing progression of structural damage in OA knees with varus alignment.


Health needs of ex-military personnel in the UK: a systematic review and qualitative synthesis.
Despite all local authorities in England signing up to the Armed Forces Covenant, only a small proportion of Joint Strategic Needs Assessments (JSNAs) include detailed consideration of the health of the local ex-military population. This article supports improvements to JSNAs by systematically reviewing published research for evidence of differences in health between the ex-military population and the general public. Systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology for qualitative synthesis of mixed study designs. SCOPUS, PubMed and Google Scholar were searched for published research on health outcomes among UK ex-military populations. All study designs were included. 43 studies met the inclusion criteria. Rates of mental illness and hearing loss are higher among ex-military populations compared with the general public, while rates of cancer among ex-military personnel born after 1960 are lower. Despite high rates of hazardous drinking among serving personnel, rates of alcohol-related harm among ex-military populations are no higher than the general public. There is a subpopulation at increased risk of a range of adverse outcomes. This group is variously identified as younger, male, less educated, more likely to have served in a combat role and/or left service early. This review found evidence of areas of increased and reduced disease burden among ex-military populations. More detailed information on the make-up of the local ex-service population would support more meaningful needs assessments. The Ministry of Defence and local authorities and service providers should work together to support early identification and targeted support for those at the highest risk of adverse outcomes.


Caring for a family member with intellectual disability into old age: Applying the sociocultural stress and coping model to Italian and Greek migrants in Australia.
Little is known about how older parent caregivers from culturally and linguistically diverse (CALD) backgrounds experience caring for their family member with intellectual disability into late life. In-depth semi-structured interviews were carried out with N = 19 family caregivers aged 50-91 from ten Italian and four Greek families. The Sociocultural Stress and Coping Model was used as a framework to interpret their experiences. A number of stressors including the need to make sacrifices, physical and emotional demands, uncertain futures and challenges associated with "the system" were identified. While family members play a key role in providing support, changing values around filial responsibility were evident. Further attention needs to be given to CALD families to address challenges associated with caring for their family member with intellectual disabilities as they age. This study also challenges assumptions that CALD families prefer to keep caring within the family long-term.


Psychiatric symptoms in adolescents: FKBP5 genotype--early life adversity interaction effects.
Psychiatric disorders are multi-factorial and their symptoms overlap. Constitutional and environmental factors influence each other, and this contributes to risk and resilience in mental ill-health. We investigated functional genetic variation of stress responsiveness, assessed as FKBP5 genotype, in relation to early life adversity and mental health in two samples of adolescents. One population-based sample of 909 12-year-old adolescents was assessed using the Life Incidence of Traumatic Events scale and the Strengths and Difficulties Questionnaire. One sample of 398 17-year-old adolescents, enriched for poly-victimized individuals (USSS), was assessed using the Juvenile Victimization Questionnaire and the Trauma Symptom Checklist for Children (TSCC). The FKBP5 rs1360780 and rs3800373 polymorphisms were genotyped using a fluorescence-based competitive allele-specific PCR. Most prominently among poly-victimized older male adolescents, the least common alleles of the polymorphisms, in interaction with adverse life events, were associated with psychiatric symptoms, after controlling for ethno-socio-economic factors. The interaction effect between rs3800373 and adverse life events on the TSCC sub-scales-anxiety, depression, anger, and dissociation-and with the rs1360780 on dissociation in the USSS cohort remained significant after Bonferroni correction. This pattern of association is in line with the findings of clinical and neuroimaging studies, and implies interactive effects of FKBP5 polymorphisms and early life environment on several psychiatric symptoms. These correlates add up to provide constructs that are relevant to several psychiatric symptoms, and to identify early predictors of mental ill-health.


Signal polymorphism in the web-decorating spider Argiope argentata is correlated with reduced survivorship and the presence of stingless bees, its primary prey.
Many spiders, and in particular those in the genus Argiope, spin highly visible web decorations whose function and significance are the subject of spirited debate. In this work, we present data to address two of the competing hypotheses that fuel this controversy. In particular, we examine the relationship between the presence of web decorations and spider survivorship (predator-protection hypothesis) and the relationship between the presence of prey and spider decorating behavior (the prey-attraction hypothesis). Our laboratory studies reveal that the decorating behavior of the spider A. argentata has a genetic component but that the expression of decorating behavior tends to be elicited only when a spider is well fed. Furthermore, our field studies show that in the presence of abundant stingless bees, spider decorating behavior is induced. Nevertheless, our field surveys also suggest that spiders that decorate their webs show reduced survivorship. We propose that the high correlation between web decorating in the presence of stingless bees supports the hypothesis that A. argentata engage in decorating behavior when attracting or targeting specific prey types. However, we also propose that web decorations attract the predators of A. argentata because high-frequency decorators suffer lower survivorship than spiders that decorate moderately or rarely. These findings suggest that spider web decorating behavior is affected by conflicting selection pressures: the positive effect of prey attraction versus the negative effect of predator attraction. Due to the heritable component of decorating behavior, web decorating among A. argentata is likely to be particularly sensitive to the spider's local ecology as well as local patterns of gene flow.


Alcohol, drugs, caffeine, tobacco, and environmental contaminant exposure: reproductive health consequences and clinical implications.
Reproductive function and fertility are thought to be compromised by behaviors such as cigarette smoking, substance abuse, and alcohol consumption; however, the strength of these associations are uncertain. Furthermore, the reproductive system is thought to be under attack from exposure to environmental contaminants, particularly those chemicals shown to affect endocrine homeostasis. The relationship between exposure to environmental contaminants and adverse effects on human reproductive health are frequently debated in the scientific literature and these controversies have spread into the lay press drawing increased public and regulatory attention. Therefore, the objective of the present review was to critically evaluate the literature concerning the relationship between lifestyle exposures and adverse effects on fertility as well as examining the evidence for a role of environmental contaminants in the purported decline of semen quality and the pathophysiology of subfertility, polycystic ovarian syndrome, and endometriosis. The authors conclude that whereas cigarette smoking is strongly associated with adverse reproductive outcomes, high-level exposures to other lifestyle factors are only weakly linked with negative fertility impacts. Finally, there is no compelling evidence that environmental contaminants, at concentrations representative of the levels measured in contemporary biomonitoring studies, have any effect, positive or negative, on reproductive health in the general population. Further research using prospective study designs with robust sample sizes are needed to evaluate testable hypotheses that address the relationship between exposure and adverse reproductive health effects.


Lower visual field advantage for motion segmentation during high competition for selection.
A series of visual enumeration tasks were conducted investigating the role of the dorsal visual stream in motion segmentation. Cortical areas representing the lower visual field have greater connections with the parietal cortex and should therefore show an advantage for processes driven by the dorsal stream (Previc, 1990). We looked for differences in processing displays in the upper versus lower visual field when targets required segmentation from distractors in an enumeration task. In a baseline condition, random configurations of moving and static items were presented briefly (200 ms) to the upper or lower visual field. Fast and efficient enumeration took place both for moving targets and for static targets presented alone; there was no effect of visual field. In contrast, for moving targets, a lower visual field advantage was found when the inclusion of static distractors demanded segmentation by motion. This disappeared at the smaller display sizes when the targets were presented in canonical patterns. The results are consistent with segmentation of moving targets from static distractors being mediated by dorsal regions of the visual cortex, particularly under conditions of high load (non-canonical patterns). These regions show greater sensitivity to the lower visual field and to magnocellular-based input.


Influence of molecular design on radical spin multiplicity: characterisation of BODIPY dyad and triad radical anions.
A strategy to create organic molecules with high degrees of radical spin multiplicity is reported in which molecular design is correlated with the behaviour of radical anions in a series of BODIPY dyads. Upon reduction of each BODIPY moiety radical anions are formed which are shown to have different spin multiplicities by electron paramagnetic resonance (EPR) spectroscopy and distinct profiles in their cyclic voltammograms and UV-visible spectra. The relationship between structure and multiplicity is demonstrated showing that the balance between singlet, biradical or triplet states in the dyads depends on relative orientation and connectivity of the BODIPY groups. The strategy is applied to the synthesis of a BODIPY triad which adopts an unusual quartet state upon reduction to its radical trianion.


Sexual regret in college students.
A questionnaire study was conducted to assess the relationship between sexual regret and sexual behaviors and demographic factors among 348 college-aged students prior to attending an educational program about sexual health issues. Analyses conducted on the portion of the sample who were sexually active (n = 270) indicated that the majority (71.9%, n = 194) has regretted their decision to engage in sexual activity at least once. The most cited reasons for regret by students included their sexual decision making as inconsistent with their morals (37%), an acknowledgment that alcohol influenced their decision (31.7%), the realization they did not want the same thing as their partner (27.9%), the lack of condom use (25.5%), feeling pressure by their partner (23.0%), and their desire to wait until marriage to have sex (15.4%). The only significant sex difference was that women reported regret due to feeling pressured by a partner more often than men. Multiple and logistic regression analyses indicated that the only significant predictor of regret regarding one's sexual decisions was the number of sexual partners. These results demonstrate the need for sexual educators to incorporate sexual regret into their curricula as the phenomenon of regret is more common than pregnancy and sexually transmitted diseases, the usual focus of sexuality education.


Angiogenesis in transgenic models of multistep angiogenesis.
The histopathology and the epidemiology of human cancers, as well as studies of animal models of tumorigenesis, have led to a widely accepted notion that multiple genetic and epigenetic changes have to accumulate for progression to malignancy. Formation of new blood vessels (tumor angiogenesis) has been recognized, in addition to proliferative capabilities and ability to down-modulate cell death (apoptosis), as essential for the progressive growth and expansion of solid tumors. Mice overexpressing activated forms of oncogenes or carrying targeted mutations in tumor suppressor genes have proven extremely useful for linking the function of these genes with specific tumor features such as continuous proliferation, escape from apoptosis, invasion and neo-angiogenesis. The interbreeding of these mice allows for studying the extent of cooperativity between different genetic lesions in disease progression, leading to a greater understanding of multi-stage nature of tumorigenesis.


Experimental drought and heat can delay phenological development and reduce foliar and shoot growth in semiarid trees.
Higher temperatures associated with climate change are anticipated to trigger an earlier start to the growing season, which could increase the terrestrial C sink strength. Greater variability in the amount and timing of precipitation is also expected with higher temperatures, bringing increased drought stress to many ecosystems. We experimentally assessed the effects of higher temperature and drought on the foliar phenology and shoot growth of mature trees of two semiarid conifer species. We exposed field-grown trees to a ~45% reduction in precipitation with a rain-out structure ('drought'), a ~4.8 °C temperature increase with open-top chambers ('heat'), and a combination of both simultaneously ('drought + heat'). Over the 2013 growing season, drought, heat, and drought + heat treatments reduced shoot and needle growth in piñon pine (Pinus edulis) by ≥39%, while juniper (Juniperus monosperma) had low growth and little response to these treatments. Needle emergence on primary axis branches of piñon pine was delayed in heat, drought, and drought + heat treatments by 19-57 days, while secondary axis branches were less likely to produce needles in the heat treatment, and produced no needles at all in the drought + heat treatment. Growth of shoots and needles, and the timing of needle emergence correlated inversely with xylem water tension and positively with nonstructural carbohydrate concentrations. Our findings demonstrate the potential for delayed phenological development and reduced growth with higher temperatures and drought in tree species that are vulnerable to drought and reveal potential mechanistic links to physiological stress responses. Climate change projections of an earlier and longer growing season with higher temperatures, and consequent increases in terrestrial C sink strength, may be incorrect for regions where plants will face increased drought stress with climate change.


Silica, silicosis, and lung cancer: a risk assessment.
To investigate exposure-response relationships for silica, silicosis, and lung cancer. Quantitative review of the literature identified in a computerized literature search. The risk of silicosis (ILO category 1/1 or more) following a lifetime of exposure at the current OSHA standard of 0.1 mg/m(3) is likely to be at least 5-10% and lung cancer risk is likely to be increased by 30% or more. The exposure-response relation for silicosis is nonlinear and reduction of dust exposures would have a greater than linear benefit in terms of risk reduction. Available data suggests that 30 years exposure at 0.1 mg/m(3) might lead to a lifetime silicosis risk of about 25%, whereas reduction of the exposure to 0.05 mg/m(3) might reduce the risk to under 5%. The lifetime risk of silicosis and lung cancer at an exposure level of 0.1 mg/m(3) is high. Lowering exposures to the NIOSH recommended limit if 0.05 mg/m(3) may have substantial benefit.


Mycophenolate mofetil treatment reduces atherosclerosis in the cholesterol-fed rabbit.
Immune/inflammatory responses of arterial vessel wall constituents to lipid metabolic disturbances have been postulated to contribute to the pathogenesis of atherosclerosis. Mycophenolate mofetil (MMF), an antiproliferative agent used in clinical transplantation, has been shown to inhibit smooth muscle cell (SMC) proliferation and decrease the recruitment of monocytes into sites of chronic inflammation. This study was conducted to determine the effect of MMF on atherosclerotic plaque development after cholesterol-induced injury. New Zealand white rabbits were fed a high-cholesterol diet containing 0.5% cholesterol and 8% peanut oil. The experimental group (n = 10) was given MMF (80 mg/kg/day subcutaneously); the control group (n = 10) received placebo injections. The aortas were harvested at 12 weeks for immunohistochemical analyses. SMCs were identified by reactivity with a monoclonal antibody (mAb) to alpha smooth muscle actin. Monocytes/macrophages were detected with mAb RAM 11. Cross-sectional areas of the media and neointima were measured using computer-assisted image analysis. The density of SMCs and macrophage/foam cells within the neointima was calculated by dividing the number of cells by the area of the plaque. Total cholesterol, triglyceride, high density lipoprotein, and low density lipoprotein were significantly increased compared with levels before the initiation of a high-cholesterol diet, but there were no significant differences between the MMF-treated and untreated groups. Neointimal area in aortic tissue sections of the MMF-treated group (0.586 +/- 0.602 mm(2)) was significantly lower when compared with that in control animals (1.082 +/- 0.621 mm(2)) (P < 0.05). The densities of neointimal SMCs and monocytes/macrophages in the control group were 778 +/- 293 and 341 +/- 90 cells/mm(2), respectively. MMF treatment significantly reduced the number of neointimal SMCs (506 +/- 185 cells/mm(2)) (P < 0.05). The number of monocytes/macrophages was also reduced after MMF treatment (260 +/- 124 cells/mm(2)) but not significantly. Our results demonstrate that the administration of MMF significantly reduced neointimal SMC accumulation and plaque development in a hypercholesterolemic model of atherosclerosis.


The cyclin-dependent kinase inhibitor p21 limits murine mesangial proliferative glomerulonephritis.
Mesangial cell (MC) proliferation underlies increased matrix accumulation in glomerulonephritis (GN), and the resolution of MC proliferation occurs largely through apoptosis. Proliferation and apoptosis are controlled by specific cell cycle proteins, where cyclin-dependent kinase (CDK) inhibitors such as p21 bind target cyclin-CDK complexes. However, the role of p21 in acute mesangial proliferative GN is not known. This study was conducted to test the hypothesis that p21 regulates MC proliferation and apoptosis in anti-MC serum-induced GN. Age and sex matched wild-type (p21+/+) and p21-deficient (p21-/-) mice were injected with sheep anti-MC serum. Renal function (BUN, urinary albumin excretion), histology, DNA synthesis (BrdU. Ki-67) and apoptosis (TUNEL) were quantified at day 6 and day 12 (n = 6-8/time point). In p21+/+ mice, anti-MC-serum induced mild MC proliferative GN, and glomerular p21 expression was increased. Renal function was worse in nephric p21-/- mice. PAS and silver staining revealed that p21-/- mice had typical features of MC proliferative GN with focal segmental tuft necrosis, focal mesangiolysis and focal mesangial hypercellularity. Occasional features of podocyte injury (swelling, vacuolization) were noted. Double immunostaining confirmed increased mesangial cell DNA synthesis in nephritic p21-/- mice at day 6. In contrast, there was no difference in glomerular apoptosis in nephritic p21+/+ and p21-/- mice at each time point. Glomerular lesions were accompanied by severe glomerular and tubulointerstitial fibrosis in p21-/- mice. This data shows that the CDK-inhibitor p21 regulates the MC proliferative response to immune-mediated injury. In contrast, p21 does not alter the apoptotic response, resulting in a delayed resolution in nephritic p21-/- mice.