Racism as a stressor for African Americans. A biopsychosocial model.
Various authors have noted that interethnic group and intraethnic group racism are significant stressors for many African Americans. As such, intergroup and intragroup racism may play a role in the high rates of morbidity and mortality in this population. Yet, although scientific examinations of the effects of stress have proliferated, few researchers have explored the psychological, social, and physiological effects of perceived racism among African Americans. The purpose of this article was to outline a biopsychosocial model for perceived racism as a guide for future research. The first section of this article provides a brief overview of how racism has been conceptualized in the scientific literature. The second section reviews research exploring the existence of intergroup and intragroup racism. A contextual model for systematic studies of the biopsychosocial effects of perceived racism is then presented, along with recommendations for future research.


Chloride removal and excitation-contraction coupling in guinea pig ileal smooth muscle.
The effect of extracellular Cl (Cl-o) removal on contractions evoked by a selective muscarinic agonist, cis-2-methyl-4-dimethylaminomethyl 1,3-dioxolane methiodide (CD), and high K+ depolarizations in the isolated guinea pig ileal longitudinal muscle was studied. The replacement of Cl-o with impermeant anions, such as isethionate (Ise-), was found to selectively inhibit a portion of the initial phasic response to K+ and CD, leaving the secondary and sustained tonic responses unchanged. In Ca2+-free solutions, the loss of contractile responses to high K+ was faster and more pronounced in Cl--free compared with Cl--containing solutions. Furthermore, the uptake of Ca2+, as represented by 45Ca2+, from the saline solution was delayed and reduced in Ise--containing Cl-o-free solutions. Replacement of Cl-o with other impermeant anions, such as gluconate and methylsulphate, had a similar action on contractile activity as for Ise-replacement. Cl-o replacement with permeant anions, such as nitrate, however, did not significantly inhibit the phasic response and sometimes increased the tonic response to K+. These results indicate that there is a Cl-o-dependent Ca2+ pool in the guinea pig ileal longitudinal muscle and we speculate that this Cl-o-dependent Ca2+ pool is associated with membrane structures, such as calveolae, which would thus offer a degree of protection to depletion by removal of extracellular Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)


C5-8 brachial plexus root injury: the "T-1 hand".
Classically, C5-7 root injuries of the brachial plexus have been associated with palsies of shoulder abduction/external rotation, elbow flexion/extension, and wrist, thumb, and finger extension. However, current myotome maps generally indicate that C-8 participates in the innervation of thumb and finger extensors. Therefore, the authors have hypothesized that, for palsies of the thumb and finger extensors, the injury should affect the C-5 through C-8 roots. The authors tested their hypothesis in 30 patients with upper-type palsies of the brachial plexus. They traced a correlation between clinical findings and root injury, as documented by CT myelography, direct visualization during surgery, and electrophysiological studies. In C5-8 root injuries, shoulder abduction and external rotation were paralyzed, and in all patients, wrist extensors were paralyzed. However, in 22 of the 30 patients, wrist extension was possible, because of contraction of the extensor digitorum communis and extensor pollicis longus. Wrist flexion and pronation also were preserved. The T-1 root contributed significantly to innervation of the thumb and finger flexors, ensuring 34% grasping and 40% pinch strength relative to the normal side. Hand sensation was largely preserved. Based on the authors' observations, they suspect that the clinical scenario previously attributed to a C5-7 root injury is, in fact, a C5-8 root injury. The authors propose referring to this partial palsy of the brachial plexus as a "T-1 hand."


DNA metabarcoding of cloacal swabs provides insight into diets of highly migratory sharks in the Mid-Atlantic Bight.
The abundances of migratory shark species observed throughout the Mid-Atlantic Bight (MAB) during productive summer months suggest that this region provides critical habitat and prey resources to these taxa. However, the principal prey assemblages sustaining migratory shark biomass in this region are poorly defined. We applied high-throughput DNA metabarcoding to shark feces derived from cloacal swabs across nine species of Carcharhinid and Lamnid sharks to (1) quantify the contribution of broad taxa (e.g., invertebrates, fishes) supporting shark biomass during seasonal residency in the MAB and (2) determine whether the species displayed distinct dietary preference indicative of resource partitioning. DNA metabarcoding resulted in high taxonomic (species-level) resolution of shark diets with actinopterygian and elasmobranch fishes as the dominant prey categories across the species. DNA metabarcoding identified several key prey groups consistent across shark taxa that are likely integral for sustaining their biomass in this region, including Atlantic menhaden (Brevoortia tyrannus), Atlantic mackerel (Scomber scombrus), and benthic elasmobranchs, including skates. Our results are consistent with previously published stomach content data for the shark species of similar size range in the Northwest Atlantic Ocean, supporting the efficacy of cloacal swab DNA metabarcoding as a minimally invasive diet reconstruction technique. The high reliance of several shark species on Atlantic menhaden could imply wasp-waist food-web conditions during the summer months, whereby high abundances of forage fishes sustain a diverse suite of migratory sharks within a complex, seasonal food web.


Recombinant platelet factor 4: a therapeutic, anti-neoplastic chimera?
Angiogenesis plays a pivotal role in many serious and life-threatening disorders (e.g., cancer, atherosclerosis, diabetes, arthritis, psoriasis, nephropathy, and retinopathy) and is regulated by a delicate equilibrium between a variety of pro- and anti-angiogenic factors. Although recombinant platelet factor 4 (PF4) was originally developed and evaluated as a clinical alternative to protamine for heparin neutralization, the current scientific evidence supports a role for this protein and derivative peptides in inhibiting tumor growth and spread, by suppression of tumor-induced neovascularization in many different types of solid tumors. As a heparin-binding tetramer, recombinant PF4 interferes with several steps of endothelial cell proliferation, migration, and angiogenesis, regulates apoptotic death through activation of distinct signal transduction pathways, inhibits growth factor receptor binding, amplifies the inflammatory response of natural killer cells through regulation of cytokines production, and induces and maintains a nonspecific immune response to cancer cells. These biological evidences paved the way for the development and marketing of novel PF4-based angiostatic agents characterized by reduced toxicity and improved bioavailability, thus raising the possibility of an alternative approach for preventing and treating growth and metastasis of tumors. Some PF4-derived molecules such as carboxyl-terminal fragments of recombinant human PF4 and modified and chimeric peptides have already been developed that exhibit stronger anti-angiogenic properties than the parent molecule and may serve as leads for further therapeutic developments. Newer means of delivering of this anti-angiogenic agent are also being attempted, including PF4-bearing polymeric microspheres, vector-mediated PF4 transduction, transgene transfection into oncolytic viruses, and molecular targeting therapy against PF4 and rHuPF4 conjugates. These delivery systems aim to produce high concentrations of the therapeutic agent in a local area for a sustained period, thereby avoiding the typical problems encountered with long-term administration of recombinant proteins.


[Peripheral neuropathy as a presenting form of Cockayne syndrome].
We report a clinical observation of an infant aged 5 months with Cockayne syndrome whose symptomatology included failure to thrive, microcephaly, peripheral neuropathy and elevated level of protein in CSF. More typical signs of this syndrome appeared lately with progeroid facies, photosensitivity and intracranial calcifications that computed tomography revealed at 13 months of age. The early onset of clinical manifestations, the association with peripheral neuropathy, and the high level of protein in CSF are unusual facts that led us to do the differential diagnosis with other demyelinating disorders.


Seeing the body produces limb-specific modulation of skin temperature.
Vision of the body, even when non-informative about stimulation, affects somatosensory processing. We investigated whether seeing the body also modulates autonomic control in the periphery by measuring skin temperature while manipulating vision. Using a mirror box, the skin temperature was measured from left hand dorsum while participants: (i) had the illusion of seeing their left hand, (ii) had the illusion of seeing an object at the same location or (iii) looked directly at their contralateral right hand. Skin temperature of the left hand increased when participants had the illusion of directly seeing that hand but not in the other two view conditions. In experiment 2, participants viewed directly their left or right hand, or the box while we recorded both hand dorsum temperatures. Temperature increased in the viewed hand but not the contralateral hand. These results show that seeing the body produces limb-specific modulation of thermal regulation.


Phase Angle and Postoperative Complications in a Model of Immunonutrition in Patients with Pancreatic Cancer.
The aim of this study was to determine the influence of our own model of immunonutrition on phase angle and postoperative complications. Our goal was to establish modern prehabilitation procedures for patients operated on for pancreatic cancer. Patients with pancreatic cancer who qualified for surgical treatment were divided into two groups. Group I (20 patients; 12 with pancreatic head cancer, 8 with pancreatic tail/body cancer) was given immunonutrition (Impact Oral 3× a day, 237 mL, for 5 days before surgery, and after surgery for an average of 3.5 days). Group II (20 patients; 12 with pancreatic head cancer, 8 with pancreatic tail/body cancer) did not receive immunonutrition. Body weight, body mass index and phase angle were assessed on admission to the hospital, after preoperative immunonutrition, on the third and eighth postoperative days. C-reactive protein and Interleukin-1 α were measured on admission to the hospital, after preoperative immunonutrition, on the eighth postoperative day. Postsurgical complications were assessed via Clavien-Dindo classification. On admission to the hospital, the phase angle was 5.0° (4.70-5.85) in Group I and 5.1° (5.00-6.25) in Group II. After 5 days of using preoperative immunonutrition, it increased statistically significantly (p < 0.02) to 5.35°. In Group I, on the third day after surgery, it decreased statistically significantly (p < 0.001) to 4.65°, and then, increased to 4.85° on the eighth day. In Group II, statistically significant decreases in the phase angle were observed on the third (4.5°; p < 0.002) and eighth (4.55°; p < 0.008) days after surgery. A statistically significant increase in CRP (86.6 mg/dL; p < 0.02) and IL-1α (18.5 pg/mL; p < 0.03) levels was observed on the eighth day after surgery in this group. In Group I, a statistically significant negative correlation (R -0.501106; p < 0.002) of the phase angle after 5 days of preoperative immunonutrition with postoperative complications was observed. This study used our own model of immunonutrition in patients undergoing surgery for pancreatic cancer. The applied model of perioperative IN improved the postoperative course of patients operated on due to pancreatic cancer. Fewer complications were observed in patients in the group receiving IN. Also, the PA value increased after the 5-day preoperative IN, and the use of perioperative IN improved the PA value on the eighth postoperative day compared to the group that did not receive IN. On this day, an increase in inflammatory parameters was also observed in the group that did not receive IN. In addition, PA correlated negatively with complications. The PA can be a useful tool to assess the effectiveness of the applied IN, and thus, to predict the occurrence of postoperative complications. Therefore, there is a further need for studies on larger groups of patients.


Evaluating the Brexit and COVID-19's influence on the UK economy: A data analysis.
The economic landscape of the United Kingdom has been significantly shaped by the intertwined issues of Brexit, COVID-19, and their interconnected impacts. Despite the country's robust and diverse economy, the disruptions caused by Brexit and the COVID-19 pandemic have created uncertainty and upheaval for both businesses and individuals. Recognizing the magnitude of these challenges, academic literature has directed its attention toward conducting immediate research in this crucial area. This study sets out to investigate key economic factors that have influenced various sectors of the UK economy and have broader economic implications within the context of Brexit and COVID-19. The factors under scrutiny include the unemployment rate, GDP index, earnings, and trade. To accomplish this, a range of data analysis tools and techniques were employed, including the Box-Jenkins method, neural network modeling, Google Trend analysis, and Twitter-sentiment analysis. The analysis encompassed different periods: pre-Brexit (2011-2016), Brexit (2016-2020), the COVID-19 period, and post-Brexit (2020-2021). The findings of the analysis offer intriguing insights spanning the past decade. For instance, the unemployment rate displayed a downward trend until 2020 but experienced a spike in 2021, persisting for a six-month period. Meanwhile, total earnings per week exhibited a gradual increase over time, and the GDP index demonstrated an upward trajectory until 2020 but declined during the COVID-19 period. Notably, trade experienced the most significant decline following both Brexit and the COVID-19 pandemic. Furthermore, the impact of these events exhibited variations across the UK's four regions and twelve industries. Wales and Northern Ireland emerged as the regions most affected by Brexit and COVID-19, with industries such as accommodation, construction, and wholesale trade particularly impacted in terms of earnings and employment levels. Conversely, industries such as finance, science, and health demonstrated an increased contribution to the UK's total GDP in the post-Brexit period, indicating some positive outcomes. It is worth highlighting that the impact of these economic factors was more pronounced on men than on women. Among all the variables analyzed, trade suffered the most severe consequences in the UK. By early 2021, the macroeconomic situation in the country was characterized by a simple dynamic: economic demand rebounded at a faster pace than supply, leading to shortages, bottlenecks, and inflation. The findings of this research carry significant value for the UK government and businesses, empowering them to adapt and innovate based on forecasts to navigate the challenges posed by Brexit and COVID-19. By doing so, they can promote long-term economic growth and effectively address the disruptions caused by these interrelated issues.


Triple-negative breast cancer: role of specific chemotherapy agents.
Cytotoxic chemotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC) despite the promise of new targeted and biologic agents. Many studies have shown significant benefit of chemotherapy in the neoadjuvant, adjuvant, and metastatic treatment of TNBC. Neoadjuvant chemotherapy studies have consistently reported higher response rates in TNBC than non-TNBC, and pathologic complete response has been shown to predict improved long-term outcomes for TNBC. Although the specific adjuvant regimens that may be most effective for TNBC are still being determined, third-generation chemotherapy regimens using dose dense or metronomic polychemotherapy are among the most effective tools presently available. The role of specific chemotherapy agents in the treatment of TNBC remains incompletely defined and warrants careful review to ensure that the most effective therapy is delivered while minimizing unnecessary toxicity. Platinum agents have seen renewed interest in TNBC based on a growing body of preclinical and clinical data suggesting encouraging activity. Taxanes and anthracyclines are active in TNBC and remain important agents but have not shown specific benefit over non-TNBC. Capecitabine has limited reported data in TNBC, but some reports suggest differential activity in TNBC compared with hormone receptor-positive breast cancer. TNBC is itself a heterogeneous group in which subgroups such as BRCA1 mutation carriers may have particular sensitivity to platinum agents and relatively less sensitivity to taxanes. Therefore, the identification of additional molecular biomarkers to predict response to specific chemotherapy is required to further improve treatment strategies with the current menu of chemotherapy options and future combinations with targeted therapies.


Postoperative epidural analgesia versus systemic analgesia for thoraco-lumbar spine surgery in children.
Spine surgery may be associated with severe acute postoperative pain. Compared with systemic analgesia alone, epidural analgesia may offer better pain control. However, epidural analgesia has sometimes been associated with rare but serious complications. Therefore, it is critical to quantify the real benefits of epidural analgesia over other modes of pain treatment. To assess the effectiveness and safety of epidural analgesia compared with systemic analgesia for acute postoperative pain control after thoraco-lumbar spine surgery in children. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature on 14 November 2018, together with the references lists of related reviews and retained trials, and two trials registers. We included all randomized controlled trials performed in children undergoing any type of thoraco-lumbar spine surgery comparing epidural analgesia with systemic analgesia for postoperative pain. We applied no language or publication status restriction. We assessed risk of bias of included trials using the Cochrane tool. We analysed data using random-effects models. We rated the quality of the evidence according to the GRADE scale. We included 11 trials (559 participants) in the review, and seven trials (249 participants) in the analysis: 140 participants received epidural analgesia and 109 received systemic analgesia.Most studies included adolescents. Three trials included in the analysis contained some participants older than 18 years. The types of surgery were posterior spinal fusion for idiopathic scoliosis (nine trials), anterior correction for idiopathic scoliosis (one trial), or selective dorsal rhizotomy in children with cerebral palsy (one trial). The mean numbers of vertebrae operated on were between nine and 14.5 and the mean numbers of spinal levels were between three and four and a half. The length of surgery varied between three and six and a half hours.Compared with systemic analgesia, epidural analgesia reduced pain at rest at all time points. At six to eight hours, the mean pain score on a 0 to 10 scale with systemic analgesia was 3.1 (standard deviation 0.7) and with epidural analgesia was -1.32 points (95% confidence interval (CI) -1.83 to -0.82; 4 studies, 116 participants; moderate-quality evidence). At 72 hours, the mean pain score with epidural analgesia was equivalent to a -0.8 point reduction on a 0 to 10 scale (standardized mean difference (SMD) -0.65, 95% CI -1.19 to -0.10; 5 studies, 157 participants; moderate-quality evidence).Return of gastrointestinal functionThere was no difference for nausea and vomiting between groups (risk ratio (RR) 0.87, 95% CI 0.58 to 1.30; 6 studies, 215 participants; low-quality evidence). One study found epidural analgesia with local anaesthetics may have increased the number of participants who had their first flatus within 48 hours (RR 1.63, 95% CI 1.08 to 2.47; 30 participants; very low-quality evidence). Two studies found epidural analgesia with local anaesthetics may have increased the number of participants in whom first bowel movement occurred within 48 hours (RR 11.52, 95% CI 2.36 to 56.26; 60 participants; low-quality evidence). It was uncertain whether epidural analgesia reduced the time to first bowel movement (MD 0.09 days, 95% CI -0.32 to 0.50; 1 study, 60 participants; very low-quality evidence) and time to first liquid ingestion following epidural infusion of an opioid alone or a local anaesthetic plus an opioid (mean difference (MD) -5.02 hours, 95% CI -13.15 to 3.10; 2 studies, 56 participants; very low-quality evidence). Epidural analgesia with local anaesthetics may have increased the risk of having first solid food ingestion within 48 hours (RR 7.00, 95% CI 1.91 to 25.62; 1 study, 30 participants; very low-quality evidence).Secondary outcomesIt was uncertain whether there was a difference in time to ambulate (MD 0.08 days, 95% CI -0.24 to 0.39; 1 study, 60 participants; very low-quality evidence) and hospital length of stay (MD -0.29 days, 95% CI -0.69 to 0.10; 2 studies, 89 participants; very low-quality evidence). Two studies found participants were more satisfied when treated with epidural analgesia (MD 1.62 on a scale from 0 to 10, 95% CI 1.26 to 1.97; 60 participants; very low-quality evidence). It was unclear whether there was a difference in parent satisfaction for epidural analgesia with an opioid alone (MD 0.60, 95% CI -0.81 to 2.01; 1 trial, 27 participants; very low-quality evidence).ComplicationsIt was uncertain whether there was a difference in the risk of complications such as: respiratory depression (risk difference (RD) -0.05, 95% CI -0.16 to 0.05; 4 studies, 126 participants; very low-quality evidence); wound infection (RD 0.01, 95% CI -0.05 to 0.08; 2 trials, 93 participants; very low-quality evidence); epidural abscess (RD 0, 95% CI -0.05 to 0.05; 3 trials, 120 participants; very low-quality evidence); and neurological complications (RD 0.01, 95% CI -0.04 to 0.06; 4 studies, 151 participants; very low-quality evidence). There is moderate- and low-quality evidence that there may be a small additional reduction in pain up to 72 hours after surgery with epidural analgesia compared with systemic analgesia. Two very small studies showed epidural analgesia with local anaesthetic alone may accelerate the return of gastrointestinal function. The safety of this technique in children undergoing thoraco-lumbar surgery is uncertain due to the very low-quality of the evidence. The study in 'Studies awaiting classification' may alter the conclusions of the review once assessed.


Assessment of problematic internet use by the Compulsive Internet Use Scale and the Internet Addiction Test: a sample of problematic and pathological gamblers.
This study aims to analyze psychometric properties and validity of the Compulsive Internet Use Scale (CIUS) and the Internet Addiction Test (IAT) and, second, to determine a threshold for the CIUS which matches the IAT cut-off for detecting problematic Internet use. A total of 292 subjects with problematic or pathological gambling (237 men, 55 women) aged 14-63 years and with private Internet use for at least 1 h per working or weekend day were recruited via different recruitment channels. Results include that both scales were internally consistent (Cronbach's α=0.9) and had satisfactory convergent validity (r=0.75; 95% CI 0.70-0.80). The correlation with duration of private Internet use per week was significantly higher for the CIUS (r=0.54) compared to the IAT (r=0.40). Among all participants, 25.3% were classified as problematic Internet users based on the IAT with a cut-off≥40. The highest proportion of congruent classified cases results from a CIUS cut-off ≥18 (sensitivity 79.7%, specificity 79.4%). However, a higher cut-off (≥21) seems to be more appropriate for prevalence estimation of problematic Internet use.


Maturation changes the excitability and effective connectivity of the frontal lobe: A developmental TMS-EEG study.
The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS-EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS-EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high-density TMS-EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between-group differences in the topography of the TMS-evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS-EEG co-registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders.


Association between mammalian lifespan and circadian free-running period: the circadian resonance hypothesis revisited.
Biological rhythms that oscillate with periods close to 24 h (circadian cycles) are pervasive features of mammalian physiology, facilitating entrainment to the 24 h cycle generated by the rotation of the Earth. In the absence of environmental time cues, circadian rhythms default to their endogenous period called tau, or the free-running period. This sustained circadian rhythmicity in constant conditions has been reported across the animal kingdom, a ubiquity that could imply that innate rhythmicity confers an adaptive advantage. In this study, we found that the deviation of tau from 24 h was inversely related to the lifespan in laboratory mouse strains, and in other rodent and primate species. These findings support the hypothesis that misalignment of endogenous rhythms and 24 h environmental cycles may be associated with a physiological cost that has an effect on longevity.


Transverse effect of Haas and Hyrax appliances on the upper dental arch in patients with unilateral complete cleft lip and palate: a comparative study.
The aim of the present study was to evaluate the transverse effect of rapid maxillary expansion in patients with unilateral complete cleft lip and palate while comparing the Haas and Hyrax appliances. The sample consisted of 48 patients divided into two groups: Group I = 25 patients treated with modified Haas appliance (mean age: 10 years and 8 months); and Group II = 23 patients treated with Hyrax appliance (mean age: 10 years and 6 months). Cast models were taken during pre-expansion and after removal of the appliance, at the end of the retention period. The models were scanned with the aid of the 3 Shape R700 3D scanner. Initial and final transverse distances were measured at cusp tips and cervical-palatal points of maxillary teeth by using the Ortho Analyzer 3D software. The mean expansion obtained between cusp tips and between cervical-palatal points was, respectively: for inter-canine width, 4.80 mm and 4.35 mm with the Haas appliance and 5.91 mm and 5.91 mm with the Hyrax appliance; as for first deciduous molars or first deciduous premolars, the values obtained were 6.46 mm and 5.90 mm in the Haas group, and 7.11 mm and 6.65 mm in the Hyrax group; with regard to first molars, values were 6.11 mm and 5.24 mm in the Haas group, and 7.55 mm and 6.31 mm in the Hyrax group. Rapid maxillary expansion significantly increased the transverse dimensions of the upper dental arch in patients with cleft palate, with no significant differences between the Hass and Hyrax expanders.


"The weather is not good": exploring the menstrual health experiences of menstruators with and without disabilities in Vanuatu.
Menstrual health is essential for gender equality and achieving the sustainable development goals. Though currently lacking, understanding and addressing menstrual health and social related inequalities requires comparison of experiences between menstruators with and without disabilities. We completed a mixed-methods population-based study of water, sanitation and hygiene, disability and menstrual health in TORBA and SANMA Provinces, Vanuatu. Methods included a census, nested case-control study, in-depth interviews (IDIs), focus group discussions (FGDs), PhotoVoice and structured observations. We undertook a population census of 11,000+ households and recruited 164 menstruators with and 169 without disabilities (aged 10-45) into a nested case-control study. 20 menstruators across both groups were selected for the qualitative component. Menstruators with disabilities were five times (adjusted Odds Ratio [aOR] 5.5, 95% Confidence Interval 1.8 - 16.5) more likely to use different bathing facilities to others in the household, nearly twice as likely (1.8, 1.1 - 3.1) to miss social activities, and three times (3.0, 1.6 - 5.7) more likely to eat alone during menstruation. Menstrual restrictions were widespread for all, but collecting water and managing menstrual materials was harder for menstruators with disabilities, particularly those requiring caregivers' support. These factors negatively impacted menstruators with disabilities' comfort, safety and hygiene, yet they reported less interference of menstruation on participation. Negative factors affecting all menstruators disproportionately impact those with disabilities, compounding existing inequalities. Menstruators with disabilities may have reported less interference because they are accustomed to greater participation restrictions than others. Australian Government's Water for Women fund and public donations.


Triple Rule Out Versus Coronary CT Angiography in Patients With Acute Chest Pain: Results From the ACIC Consortium.
This study sought to evaluate the diagnostic yield of triple rule out (TRO) versus coronary computed tomography angiography (CTA) scanning in patients with acute chest pain enrolled in a large statewide registry. Although TRO scans provide simultaneous evaluation of coronary artery disease (CAD), pulmonary embolism (PE), and aortic disease (AD), their use is not well defined. Patients undergoing TRO or coronary CTA at 53 Michigan institutions for acute chest pain (in the emergency department or inpatient setting) in the ACIC (Advanced Cardiovascular Imaging Consortium) were included. Demographic characteristics, scan findings, and image quality parameters were compared between coronary CTA and TRO scans. The primary outcome was diagnostic yield, defined as obstructive CAD (>50% stenosis), PE, or AD; secondary outcomes were radiation dose, contrast volume, and image quality. From July 2007 to September 2013, 12,834 patients underwent computed tomography scanning (TRO, n = 1,555; coronary CTA, n = 11,279). The TRO group had more women (57.1% vs. 47.8%, p < 0.001). Diagnostic yield was similar (TRO, 17.4% vs. coronary CTA, 18.3%; p = 0.37), driven by CAD (15.5% vs. 17.2%, p = 0.093); PE and AD were 1.1% and 0.4% (p = 0.004) and 1.7% and 1.1% (p = 0.046). TRO had higher median radiation (9.1 mSv vs. 6.2 mSv; p < 0.0001) and mean contrast (113 ± 6 ml vs. 89 ± 17 ml; p < 0.0001) doses. Nondiagnostic images were frequent in TRO (9.4% vs. 6.5%; p < 0.0001). In emergency department patients, PE and AD were more often detected on TRO. Among inpatients, there were no differences in overall yield or in that of PE, AD, or CAD. TRO was associated with slightly higher yield of PE and AD, specifically in the emergency department. This benefit comes with higher nondiagnostic image quality, radiation, and contrast doses. Although TRO may be of value in selected patients, its indiscriminate use is not warranted. The appropriate use of TRO needs to be further defined. (Advanced Cardiovascular Imaging Consortium [ACIC]; NCT00640068).


Retinal detachments due to traumatic tears in the pars plana ciliaris.
To describe the clinical features of retinal detachments caused by traumatic tears in the pars plana ciliaris. This study is a retrospective review of five cases of retinal detachments secondary to traumatic breaks limited to the nonpigmented epithelium of the pars plana ciliaris. Four patients had a history of recent closed-globe trauma due to a fist blow and the remaining patient had a history of remote closed-globe trauma. In all cases, the tearing of the pars plana developed in the superonasal quadrant. The low-lying configuration of the detachment and the absence of a retinal break, oral tear, or avulsed vitreous base challenged the ability of the initial examiners to establish the correct diagnosis. Each patient underwent successful surgical reattachment of the retina. Retinal detachments may result from traumatic tears in the nonpigmented epithelium of the pars plana ciliaris. These detachments often do not become clinically manifest for several months or longer following ocular contusion. They tend to be shallow with a smooth and flat surface, which makes diagnosis difficult during routine ophthalmoscopy. Scleral depression is almost always necessary to identify the pars plana tear(s).


Polymorphism of IL10, IL4, CTLA4, and DAO Genes in Cross-Reactive Nonsteroidal Anti-inflammatory Drug Hypersensitivity.
Our aim was to evaluate genetic polymorphism of molecules involved in immunoregulatory/allergic processes in patients who presented with cutaneous hypersensitivity caused by chemically unrelated nonsteroidal anti-inflammatory drugs. Polymorphisms at IL10 (-1082 G>A), IL4 (-589 C>T), CTLA4 (+49A>G), and DAO (+8956 C>G) genes were studied in 55 cases and 97 controls by the polymerase chain reaction-restriction fragment length polymorphism technique. With regard to the polymorphism at IL10 -1082, higher frequencies of the AG genotype (57% vs 39%) and G allele carriers (70% vs 48%) were found among the patients, indicating a risk effect (odds ratio [OR] = 2.56 and P = .01 for AG genotype and OR = 2.52; P = .01 for AG/GG). For the CTLA4 +49 A/G single-nucleotide polymorphism (SNP), AG genotype (31.0%) (P = .02) and G carrier (54.0%) (P = .05) frequencies were found to be significantly lower in the patient group compared with the control group (51.0% and 69.0%, respectively). The SNP DAO +8956 C>G was associated with a strong protective effect, with OR values of 0.83 for CG and 0.11 for GG genotype (P = .04 for the codominant model), suggesting an allele dose effect. The combination of IL10 and DAO SNPs in a multivariate model did not alter the OR values, suggesting independent effects for both SNPs. The results are striking. In conclusion, these results suggest that polymorphisms in regulatory targets of the immune response and in DAO gene could modulate an individual's susceptibility to nonsteroidal anti-inflammatory drug hypersensitivity reactions. Further studies will be necessary to complement our results.


The Development of Patient Scheduling Groups for an Effective Appointment System.
Patient access to care and long wait times has been identified as major problems in outpatient delivery systems. These aspects impact medical staff productivity, service quality, clinic efficiency, and health-care cost. This study proposed to redesign existing patient types into scheduling groups so that the total cost of clinic flow and scheduling flexibility was minimized. The optimal scheduling group aimed to improve clinic efficiency and accessibility. The proposed approach used the simulation optimization technique and was demonstrated in a Primary Care physician clinic. Patient type included, emergency/urgent care (ER/UC), follow-up (FU), new patient (NP), office visit (OV), physical exam (PE), and well child care (WCC). One scheduling group was designed for this physician. The approach steps were to collect physician treatment time data for each patient type, form the possible scheduling groups, simulate daily clinic flow and patient appointment requests, calculate costs of clinic flow as well as appointment flexibility, and find the scheduling group that minimized the total cost. The cost of clinic flow was minimized at the scheduling group of four, an 8.3% reduction from the group of one. The four groups were: 1. WCC, 2. OV, 3. FU and ER/UC, and 4. PE and NP. The cost of flexibility was always minimized at the group of one. The total cost was minimized at the group of two. WCC was considered separate and the others were grouped together. The total cost reduction was 1.3% from the group of one. This study provided an alternative method of redesigning patient scheduling groups to address the impact on both clinic flow and appointment accessibility. Balance between them ensured the feasibility to the recognized issues of patient service and access to care. The robustness of the proposed method on the changes of clinic conditions was also discussed.


Resident smoking in long-term care facilities--policies and ethics.
To characterize smoking behavior, facility policies related smoking, and administrators' views of smoking-related problems in Veterans Affairs nursing home care units nationwide. An anonymous mail survey of long-term care facilities was administered to 106 nursing home supervisors at VA Medical Centers with nursing home care units. The response rate was 82%. Administrators from 106 VA nursing home units reported smoking rates ranging from 5% to 80% of long-term care residents, with an average of 22%. Half of the nursing homes had indoor smoking areas. Frequent complaints from nonsmokers about passive smoke exposure were reported in 23% of the nursing homes. The nursing administrators reported that patient safety was their greatest concern. Seventy- eight percent ranked health effects to the smokers themselves a "major concern," while 70% put health effects to exposed nonsmokers in that category. Smoking in the nursing home was described as a "right" by 59% of respondents and a "privilege" by 67%. Some individuals reported that smoking was both a right and a privilege. Smoking is relatively common among VA long-term care patients. The promotion of personal autonomy and individual resident rights stressed in the Omnibus Budget Reconciliation Act of 1987 may conflict with administrative concerns about the safety of nursing home smokers and those around them.


Cutaneous T-cell lymphoma with CNS involvement: a case series and review of the literature.
Cutaneous T-cell lymphoma (CTCL) is a rare hematologic malignancy that traditionally presents with cutaneous lesions, though metastases are not uncommon in progressive disease. We describe four cases of CTCL with central nervous system (CNS) involvement, detailing the history, pathological characteristics, treatment response, and progression. Median time from initial diagnosis to CNS metastasis was ∼5.4 years (range 3.4-15.5 years) and survival after metastasis was ∼160 days (range 19 days-4.4 years). No patients achieved long-term (>5 years) survival, though some displayed varying degrees of remission following CNS-directed therapy. We conclude that clinicians must be attentive to the development of CNS metastases in patients with CTCL. The growing body of literature on such cases will inform evolving therapeutic guidelines on this rare CTCL complication.


Intercellular Genetic Interaction Between Irf6 and Twist1 during Craniofacial Development.
Interferon Regulatory Factor 6 (IRF6) and TWIST1 are transcription factors necessary for craniofacial development. Human genetic studies showed that mutations in IRF6 lead to cleft lip and palate and mandibular abnormalities. In the mouse, we found that loss of Irf6 causes craniosynostosis and mandibular hypoplasia. Similarly, mutations in TWIST1 cause craniosynostosis, mandibular hypoplasia and cleft palate. Based on this phenotypic overlap, we asked if Irf6 and Twist1 interact genetically during craniofacial formation. While single heterozygous mice are normal, double heterozygous embryos (Irf6 +/- ; Twist1 +/- ) can have severe mandibular hypoplasia that leads to agnathia and cleft palate at birth. Analysis of spatiotemporal expression showed that Irf6 and Twist1 are found in different cell types. Consistent with the intercellular interaction, we found reduced expression of Endothelin1 (EDN1) in mandible and transcription factors that are critical for mandibular patterning including DLX5, DLX6 and HAND2, were also reduced in mesenchymal cells. Treatment of mandibular explants with exogenous EDN1 peptides partially rescued abnormalities in Meckel's cartilage. In addition, partial rescue was observed when double heterozygous embryos also carried a null allele of p53. Considering that variants in IRF6 and TWIST1 contribute to human craniofacial defects, this gene-gene interaction may have implications on craniofacial disorders.


The impact of high-resolution ultrasound in the differential diagnosis of non-hemolytic jaundice.
Because jaundice is a common reason for hospital admission. A fast and correct differential diagnosis is very important to increase treatment efficacy. The aim of our study was to evaluate the impact of the high-resolution ultrasound in this kind of clinical setting. In a prospective study we included 30 patients and we divided them in patients with extrahepatic jaundice and patients with intrahepatic jaundice. We observed a high accuracy of the high-resolution sonography, with a sensitivity of 95% and a specificity of 100% for extrahepatic jaundice, and a sensitivity of 100% and a specificity of 95% for intrahepatic jaundice. We conclude that the high-resolution ultrasound should be used in the very beginning of the diagnostic algorithm for the evaluation of patients with unclear jaundice.


Maternal Lipopolysaccharide Exposure Promotes Immunological Functional Changes in Adult Offspring CD4+ T Cells.
Maternal immune activation (MIA) is a risk factor for autism and schizophrenia. However, how MIA affects offspring immune function remains unknown. To investigate the effect of MIA on the offspring, pregnant C57BL/6J mice were given an intraperitoneal injection of 50 μg/kg lipopolysaccharide (LPS) on gestational day 12.5. Adult LPS-treated offspring were hyper-reactive to LPS, and enhanced tumor necrosis factor-α production was observed. CD4+ T cells from LPS offspring had an elevated percentage of interferon (IFN)-γ(+) CD4+ T cells and interleukin (IL)-17A+ CD4+ T cells in the spleen, IL-17A+ CD4+ T cells in the liver, and CD4+ Foxp3+ T cells in the spleen. LPS offspring CD4+ T cells showed increased proliferation and an enhanced survival rate. DNA microarray analysis of resting LPS offspring CD4+ T cells identified eight up-regulated genes, most of which encoded transcription factors. Quantitative liquid chromatography-mass spectrometry identified 18 up-regulated proteins in resting LPS offspring CD4+ T cells and five up-regulated proteins in activated LPS offspring CD4+ T cells, most of which participated in the PANTHER Gene Ontology metabolic process. Our results showed that MIA to LPS up-regulated proteins involved in metabolic process in CD4+ T cells from LPS offspring that might contribute to the hyperactivated immune response of adult LPS offspring.


70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age.
The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age. MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing. Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]). With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy. European Commission Sixth Framework Programme.


Sun-dried Azolla leaf meal at 10% dietary inclusion improved growth, meat quality, and increased skeletal muscle Ribosomal protein S6 kinase β1 abundance in growing rabbit.
Rapidly growing human populations and the increased need for high nutritive value meat in terms of low fat, high protein, and low sodium content are the driving reasons for the increase in rabbit meat production. However, dietary protein alternatives to sustain rabbit meat production, without competing with humans for strategic crops are needed. Therefore, the current study was conducted to investigate the effect of Azolla leaf meal (ALM) as a dietary protein source on growth performance, meat quality, and abundance and activation of Ribosomal protein S6 kinase β1 (p70S6K1), a downstream target of mammalian target of rapamycin signalling pathway and, thus, a key player in the regulation of protein synthesis and muscle mass. For this purpose, 60 weaned male V-Line rabbits were blocked for the initial BW and randomly allotted into four dietary treatments, with 15 replicate per treatment (n = 15/group) as follows: (1) CON group was fed on basal diet contains 0% of ALM, (2) AZ10 group fed on diet containing 10% ALM, (3) AZ20 group fed on diet containing 20% ALM, and (4) AZ30 group fed on diet containing 30% ALM. Rabbits were raised individually, and the experimental period was 42 days. At the end of the experiment, rabbits were euthanised and blood and skeletal muscle samples were collected. Body weight and BW gain were the highest in AZ10 group (P = 0.01), while feed intake was the highest in AZ30 (P = 0.01), feed conversion ratio was the lowest in AZ10 and highest in AZ30 (P = 0.01). Dressing % was the highest in AZ10 and lowest in AZ30 groups (P = 0.01). Muscle cross-sectional area was low in both AZ20 and AZ30 groups compared to CON (P = 0.01). The lysine concentration of Longissimus lumborum muscle increased (P = 0.03) while isoleucine tended to decrease in AZ10 vs CON (P = 0.09). The phosphorylation ratio of skeletal muscle p70S6K1 increased in AZ10 and AZ20 groups (P = 0.05). Therefore, ALM could be included in a growing rabbit diet, up to 10%, while higher doses negatively alter production performance, meat quality, and feed efficiency of growing rabbits.


Systemic cardiovascular complications in patients with long-standing diabetes mellitus: comprehensive assessment with whole-body magnetic resonance imaging/magnetic resonance angiography.
The primary objective was to evaluate the prevalence of atherosclerotic disease, myocardial infarctions, and cerebrovascular disease in patients with long-standing diabetes using whole-body magnetic resonance imaging (WB-MRI) combined with whole-body magnetic resonance angiography (WB-MRA) and to estimate the cumulative disease burden in a new MRA-based score. The study was approved by the ethics committee and all patients gave informed written consent. Sixty-five patients with long-standing (>10 years) diabetes mellitus without acute symptoms were prospectively evaluated. The patients were clinically assessed and received WB-MRI/WB-MRA containing an examination of the brain, the heart, the arterial vessels (abdominal aorta, the supraaortic, renal, pelvic, and peripheral arteries), and the feet. Prevalence rates were calculated and compared with a healthy control group of 200 individuals after adjustment for age and sex by a logistic regression analysis using exact parameter estimates (Cochran-Mantel-Haenszel-statistics). Finally, an MRA based vessel score (sum of grades of all evaluated vessels divided by the number of vessels; grades range from 1, normal, to 6, complete occlusion) indicative of atherosclerotic disease burden was created for this study. This vessel score's association with clinical and biochemical parameters (age, sex, type of diabetes, diabetes duration, body mass index, blood pressure, smoking, coronary artery disease-status, retinopathy, serum creatinine, hemoglobin A1c test, low density lipoprotein-concentration, medication) was assessed with an age and sex adjusted analysis (generalized linear model). In the diabetic patients, we found prevalence rates of 49% for peripheral artery disease, 25% for myocardial infarction, 28% for cerebrovascular disease, and 22% for neuropathic foot disease. In all vascular beds, at least 50% of the pathologies were previously unknown. Myocardial infarction (P= 0.0002), chronic ischemic cerebral lesions (P = 0.0008), and atherosclerotic disease were significantly more common in diabetic than in control subjects (internal carotid artery: P = 0.006, vertebral artery: P = 0.009, intracerebral vessels: P = 0.02, superficial femoral artery: P = 0.006, anterior tibial artery: P = 0.01, posterior tibial artery: P = 0.02, fibular artery: 0.003). The WB-MRI/WB-MRA-based score showed a significant association with age (P = 0.0008), male sex (P = 0.03), nephropathy (P = 0.006), diabetic retinopathy (P = 0.007), and coronary artery disease status (P = 0.006). Body mass index, blood pressure, hemoglobin A1c test, low density lipoprotein-cholesterol, and medications showed no significant association with the score. Using WB-MRI combined with WB-MRA we found a high prevalence of occult atherosclerotic disease in long-standing diabetic patients. This study shows that the true atherosclerotic burden in these patients is largely underestimated.


Developmental stage-specific epigenetic control of human beta-globin gene expression is potentiated in hematopoietic progenitor cells prior to their transcriptional activation.
To study epigenetic regulation of the human beta-globin locus during hematopoiesis, we investigated patterns of histone modification and chromatin accessibility along this locus in hematopoietic progenitor cells (HPCs) derived from both humans and transgenic mice. We demonstrate that the developmentally related activation of human beta-like globin genes in humans and transgenic mice HPCs is preceded by a wave of gene-specific histone H3 hyperacetylation and K4 dimethylation. In erythroid cells, expression of beta-like globin genes is associated with histone hyperacetylation along these genes and, surprisingly, with local deacetylation at active promoters. We also show that endogenous mouse beta major and human beta-like genes are subject to different epigenetic control mechanisms in HPCs. This difference is likely due to intrinsic properties of the human beta-globin locus since, in transgenic mice, this locus is epigenetically regulated in the same manner as in human HPCs. Our results suggest that a defined pattern of histone H3 acetylation/dimethylation is important for specific activation of human globin promoters during development in human and transgenic HPCs. We propose that this transient acetylation/dimethylation is involved in gene-specific potentiation in HPCs (ie, before extensive chromatin remodeling and transcription take place in erythroid cells).


Analysis of the anatomical tachycardia circuit in verapamil-sensitive atrial tachycardia originating from the vicinity of the atrioventricular node.
Calcium channel-dependent tissue has been suggested to be involved in the circuit of verapamil-sensitive atrial tachycardia originating from the atrioventricular (AV) node vicinity (V-AT), but little information exists. To examine the tachycardia circuit of V-AT, a single extrastimulus was delivered during tachycardia to 10 sites of the intraatrial septum: the earliest atrial activation site; His bundle (HB) site; 3 arbitrarily divided sites on the AV junction extending from the HB site to the coronary sinus ostium (CSOS) (sites S, M, and I); the internal-CSOS, inferior-CSOS, superior-CSOS, posterior-CSOS, and posteroinferior-CSOS in 10 patients with V-AT. The longest coupling interval that reset V-AT and subsequent return cycle were measured. The longest coupling interval at earliest atrial activation site was significantly longer than the longest coupling interval at the HB site, site S, M, and I, internal-CSOS, inferior-CSOS, superior-CSOS, posterior-CSOS, and posteroinferior-CSOS, respectively (P<0.001 for HB site and P<0.0001 for the remaining 8 sites). The return cycle at earliest atrial activation site did not differ from the tachycardia cycle length, whereas those at the remaining 9 sites were significantly longer than tachycardia cycle length (P<0.001). Furthermore, a single extrastimulus delivered from sites inferior to the HB site advanced His potential without resetting V-AT in 7 patients in whom AV block was not observed during tachycardia. Atrial tissue within the Koch's triangle extending from the HB site to posteroinferior-CSOS is not involved in the tachycardia circuit. Verapamil-sensitive atrial tissue close to the AV node but not the AV nodal conducting system forms the tachycardia circuit of V-AT.


Fatal cyclophosphamide cardiomyopathy: its clinical course and treatment.
Acute decompensating cardiomyopathy induced by cyclophosphamide is usually irreversible. To investigate the clinical course and the outcome of therapy, 13 patients (1.7%) with grade III acute cardiomyopathy and hypotension who were treated with ablative transplant regimens between January 1980 and September 1995 were analyzed. Eight of nine patients died of acute fatal restrictive cardiomyopathy with unresponsive hypotension (ARCH), whereas three of four patients who survived the initial episode died of subacute congestive heart failure (SCHF). Acute fatal restrictive cardiomyopathy was characterized with extreme sensitivity to volume overload, myocardial edema and a rapidly fatal course. It was associated with progressive, unresponsive hypotension, reduced left ventricular stroke work index (LVSWI: 29.29 +/- 9.74 g-m/beat/m2) and markedly reduced systemic and pulmonary vascular resistance indices (SVRI: 429.72 +/- 168.84, PVRI: 58.63 +/- 45.08 dyne.sec/cm5.m2). Subacute CHF was identified by myocardial edema, dilated chambers and biventricular pump failure represented by decreases in fractional shortening (FS: 19.5 +/- 4.9%). Of 10 patients who received conventional therapy, nine died and one sustained chronic CHF. One of three patients with ARCH on antioxidant therapy of ascorbic acid and theophylline survived the episode. The data suggests peripheral vascular collapse may also be responsible for fatal ARCH.


THE INSECT V-ATPase, A PLASMA MEMBRANE PROTON PUMP ENERGIZING SECONDARY ACTIVE TRANSPORT: IMMUNOLOGICAL EVIDENCE FOR THE OCCURRENCE OF A V-ATPase IN INSECT ION-TRANSPORTING EPITHELIA.
Active electrogenic K+ transport in insects serves as the energy source for secretion or absorption in gastrointestinal epithelia or for the receptor current in sensory epithelia. In the larval midgut of the tobacco hornworm Manduca sexta, a vacuolar-type proton pump (V-ATPase) and a K+/nH+ antiport represent the functional elements of the potassium pump. Several immunological findings support the hypothesis that active K+ transport in other insect epithelia may also be energized by a V-ATPase. In immunoblots, crude homogenates of sensilla-rich antennae and Malpighian tubules of M. sexta cross reacted with an immune serum directed to the purified plasma membrane V-ATPase from the midgut; the M. sexta midgut V-ATPase cross reacted with polyclonal antibodies to endomembrane V-ATPases from xenic origin. In immunocytochemical investigations of larvae of M. sexta and adults of Antheraea pernyi, monoclonal antibodies to defined subunits of the purified midgut V-ATPase or polyclonal antibodies to xenic endomembrane V-ATPase labelled the sites of active K+ transport: the goblet cell apical membrane in the midgut, the brush border of Malpighian tubules and the apical projections of the auxiliary cells in antennal sensilla. The functional mechanism of a primary H+-pumping V-ATPase and a secondary H+-dependent K+ transport postulated for K+-transporting insect epithelia may be further applicable to active Na+ or Cl- transport and would provide a unifying concept for all ouabain-insensitive electrogenic ion transport in insects. The findings from the midgut investigations, however, are the first instance in which a V-ATPase provides an alternative to the Na+/K+-ATPase in energizing secondary active transport in animal plasma membranes.


Association of Ankle-Brachial Indices With Limb Revascularization or Amputation in Patients With Peripheral Artery Disease.
The prevalence and morbidity of peripheral artery disease (PAD) are high, with limb outcomes including revascularization and amputation. In community-dwelling patients with PAD, the role of noninvasive evaluation for risk assessment and rates of limb outcomes have not been established to date. To evaluate whether ankle-brachial indices are associated with limb outcomes in community-dwelling patients with PAD. A population-based, observational, test-based cohort study of patients was performed from January 1, 1998, to December 31, 2014. Data analysis was conducted from July 15 to December 15, 2017. Participants included a community-based cohort of 1413 patients with PAD from Olmsted County, Minnesota, identified by validated algorithms deployed to electronic health records. Automated algorithms identified limb outcomes used to build Cox proportional hazards regression models. Ankle-brachial indices and presence of poorly compressible arteries were electronically identified from digital data sets. Guideline-recommended management strategies within 6 months of diagnosis were also electronically retrieved, including therapy with statins, antiplatelet agents, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and smoking abstention. Ankle-brachial index (index ≤0.9 indicates PAD; <.05, severe PAD; and ≥1.40, poorly compressible arteries) and limb revascularization or amputation. Of 1413 patients, 633 (44.8%) were women; mean (SD) age was 70.8 (13.3) years. A total of 283 patients (20.0%) had severe PAD (ankle-brachial indices <0.5) and 350 (24.8%) had poorly compressible arteries (ankle-brachial indices ≥1.4); 780 (55.2%) individuals with less than severe disease formed the reference group. Only 32 of 283 patients (11.3%) with severe disease and 68 of 350 patients (19.4%) with poorly compressible arteries were receiving 4 guideline-recommended management strategies. In the severe disease subgroup, the 1-year event rate for revascularization was 32.4% (90 events); in individuals with poorly compressible arteries, the 1-year amputation rate was 13.9% (47 events). In models adjusted for age, sex, and critical limb ischemia, poorly compressible arteries were associated with amputation (hazard ratio [HR], 3.12; 95% CI, 2.16-4.50; P < .001) but not revascularization (HR, 0.91; 95% CI, 0.69-1.20; P = .49). In contrast, severe disease was associated with revascularization (HR, 2.69; 95% CI, 2.15-3.37; P < .001) but not amputation (HR, 1.30; 95% CI, 0.82-2.07; P = .27). Community-dwelling patients with severe PAD or poorly compressible arteries have high rates of revascularization or limb loss, respectively. Guideline-recommended management strategies for secondary risk prevention are underused in the community.


The Influence of Blue Light and the BlsA Photoreceptor on the Oxidative Stress Resistance Mechanisms of Acinetobacter baumannii.
Acinetobacter baumannii is a catalase-positive Gram-negative bacterial pathogen that causes severe infections among compromised patients. Among its noteworthy regulatory mechanisms, this microorganism regulates its lifestyle through the blue light using flavin (BLUF) protein BlsA. This protein regulates a diverse set of cellular processes that include, but are not limited to, motility, biofilm formation, phenylacetic acid metabolism, iron uptake, and catalase activity. We set out to determine how A. baumannii regulates catalase activity and other related oxidative stress phenotypes in response to light. Notably, because A. baumannii ATCC 17978 encodes four catalase homologs - which we refer to as KatA, KatE, KatE2, and KatG - we also aimed to show which of these enzymes exhibit light- and BlsA-dependent activity. Our work not only provides insight into the general function of all four catalase homologs and the impact of light on these functions, but also directly identifies KatE as a BlsA-regulated enzyme. We further demonstrate that the regulation of KatE by BlsA is dependent on a lysine residue that we previously demonstrated to be necessary for the regulation of surface motility. Furthermore, we show that BlsA's five most-C-terminal residues - previously considered dispensable for BlsA's overall function - are necessary for the light-independent and light-dependent regulation of catalase and superoxide dismutase activities, respectively. We hypothesize that these identified critical residues are necessary for BlsA's interaction with protein partners including the transcriptional regulators Fur and BfmR. Together these data expand the understanding regarding how A. baumannii uses light as a signal to control oxidative stress resistance mechanisms that are critical for its pathophysiology.


Leachable diphenylguanidine from rubber closures used in pre-filled syringes: A case study to understand solid and solution interactions with oxytocin.
Leachables derived from multi-component drug-device syringe systems can result in changes to the quality of drug products. Diphenylguanidine (DPG), a leachable released from styrene butadiene rubber syringe plungers, interacts with Oxytocin to form protein-adducts. This study investigated the mechanism and kinetics of this interaction in both solid and solution states through in-vitro tests and spectroscopic methods For solid state interaction, the protein-adducts with DPG were characterized using SEM, XRD, DSC, FTIR, 13C ss NMR, and dissolution analysis. For solution state interaction, LC-HRMS was used to assess stability of Oxytocin solutions in presence of various concentrations of DPG at 25°C and 40°C for 4 weeks. Moreover, molecular docking analysis was used to identify possible molecular configurations of the interaction.Results were consistent with the formation of a new solid state with distorted surface morphology for oxytocin-DPG adducts, in which the oxytocin carbonyl group(s) and the secondary amine groups of DPG interact. This interaction was also confirmed by molecular docking analysis through hydrogen bonding (2.31Å) and Van der Waal attraction (3.14Å). Moreover, LC-HRMS analysis revealed an increase in Oxytocin stability and suppression of Oxytocin dimerization by DPG. A potential reduction in the rate of Oxytocin dissolution from the formed adducts was indicative of its strong association with DPG. Hence, the leaching potential of DPG from rubber closures and plungers should be monitored and controlled to maintain the quality and stability of the pharmaceutical product.


Light signaling as cellular integrator of multiple environmental cues in plants.
Plants being sessile need to rapidly adapt to the constantly changing environment through modifications in their internal clock, metabolism, and gene expression. They have evolved an intricate system to perceive and transfer the signals from the primary environmental factors namely light, temperature and water to regulate their growth development and survival. Over past few decades rigorous research using molecular genetics approaches, especially in model plant Arabidopsis, has resulted in substantial progress in discovering various photoreceptor systems and light signaling components. In parallel several molecular pathways operating in response to other environmental cues have also been elucidated. Interestingly, the studies have shown that expression profiles of genes involved in photomorphogenesis can undergo modulation in response to other cues from the environment. Recently, the photoreceptor, PHYB, has been shown to function as a thermosensor. Downstream components of light signaling pathway like COP1 and PIF have also emerged as integrating hubs for various kinds of signals. All these findings indicate that light signaling components may act as central integrator of various environmental cues to regulate plant growth and development processes. In this review, we present a perspective on cross talk of signaling mechanisms induced in response to myriad array of signals and their integration with the light signaling components. By putting light signals on the central stage, we propose the possibilities of enhancing plant resilience to the changing environment by fine-tuning the genetic manipulation of its signaling components in the future.


An all-consuming case.
This is a case of a 6-month-old child who presented to the local paediatric department with a relatively short history of developmental regression, hypotonia, weight loss, irritability and hepatosplenomegaly. The child then proceeded to spike temperatures up to 39°C. The case demonstrates the logical investigative process involved in such a case and discusses the differential diagnoses at each stage. It also highlights the importance of multi-specialty work in complex cases and the potential consequence of premature closure of diagnosis.


Modification of the Hill technique for repair of hiatal hernia.
The major modification of this technique allows accurate placement of sutures through the median arcuate ligament and eliminates the dissection required to expose the aorta at the origin of the celiac artery. Use of a separate row of sutures to create a sling at the esophagogastric junction maintains the desired intraluminal diameter when the esophagogastric junction is secured to the median arcuate ligament.


Contraction-induced intracellular signals and their relationship to muscle GLUT-4 concentration.
This investigation used a model of increased skeletal muscle contractile activity to evaluate whether the adenylate cyclase-adenosine 3',5'-cyclic monophosphate (cAMP) pathway and/or the high-energy phosphate state of the muscle might be temporally related to the contraction-induced increase in skeletal muscle GLUT-4 protein concentration. Plantaris and gastrocnemius muscles of Sprague-Dawley rats were subjected to 3, 7, 14, or 28 days of chronic low-frequency electrical stimulation (10 Hz, 24 h/day). GLUT-4 protein concentration was slightly reduced after 3 days of electrical stimulation, similar to control values at 7 days and significantly elevated above control at 14 days (53%, P < 0.05) and 28 days (338%, P < 0.05) of stimulation. ATP, creatine phosphate, creatine, and P, were inversely related to GLUT-4 protein concentration. Adenylate cyclase activity increased with electrical stimulation and was significantly related to the increased GLUT-4 protein. cAMP was significantly increased at 14 days of stimulation and remained elevated through 28 days. These results demonstrate that both the adenylate cyclase-cAMP pathway and the high-energy phosphate state of the muscle are temporally related to elevations in skeletal muscle GLUT-4 protein concentration in response to chronic low-frequency electrical stimulation and, as such, suggest that both may comprise a component of the intracellular signal that regulates the contraction-induced increase in skeletal muscle GLUT-4 protein concentration.


Capacity of nano-reactors of AOT micro-emulsions to form and sustain ultra small semiconductor quantum dots.
Microemulsions (MEs) are increasingly being used as nano-reactors for the formation and synthesis of nanoparticles or quantum dots (QDs). In this paper, we study the capacity of aqueous nanoreactors of AOT microemulsions for the formation of ultrasmall semiconductor QDs by fixing w = ([H2O]/[AOT]) and varying the concentration of CdS up to 100 mM. The CdS QDs in the MEs are evaluated using UV-vis spectroscopy, XRD, TEM, and light scattering. Particles are found to be controlled in 8.7 A-11.8 A. The UV-vis spectra are analysed using an accurate tight-binding (TB) approach and effective mass approximation (EMA). The TB method, being much more accurate than the EMA, gives results in good agreement with X-ray diffraction (XRD) and transmission electron microscopy (TEM). XRD reveals that the particles are mostly zinc-blend at low concentrations (> or =20 mM) but a mixture of zinc-blend and wurtzite at higher concentrations (100 mM). High concentrations of CdS are useful to improve the yield while best-utilizing nanoreactors and to give a tight control over size and polydispersity. MEs containing CdS are found to be stable over a month when kept in the dark.


Cross-Protection against MERS-CoV by Prime-Boost Vaccination Using Viral Spike DNA and Protein.
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness and has a high mortality of ∼34%. However, since its discovery in 2012, an effective vaccine has not been developed for it. To develop a vaccine against multiple strains of MERS-CoV, we targeted spike glycoprotein (S) using prime-boost vaccination with DNA and insect cell-expressed recombinant proteins for the receptor-binding domain (RBD), S1, S2, SΔTM, or SΔER. Our S subunits were generated using an S sequence derived from the MERS-CoV EMC/2012 strain. We examined humoral and cellular immune responses of various combinations with DNA plasmids and recombinant proteins in mice. Mouse sera immunized with SΔER DNA priming/SΔTM protein boosting showed cross-neutralization against 15 variants of S-pseudovirions and the wild-type KOR/KNIH/002 strain. In addition, these immunizations provided full protection against the KOR/KNIH/002 strain challenge in human DPP4 knock-in mice. These findings suggest that vaccination with the S subunits derived from one viral strain can provide cross-protection against variant MERS-CoV strains with mutations in S. DNA priming/protein boosting increased gamma interferon production, while protein-alone immunization did not. The RBD subunit alone was insufficient to induce neutralizing antibodies, suggesting the importance of structural conformation. In conclusion, heterologous DNA priming with protein boosting is an effective way to induce both neutralizing antibodies and cell-mediated immune responses for MERS-CoV vaccine development. This study suggests a strategy for selecting a suitable platform for developing vaccines against MERS-CoV or other emerging coronaviruses.IMPORTANCE Coronavirus is an RNA virus with a higher mutation rate than DNA viruses. Therefore, a mutation in S-protein, which mediates viral infection by binding to a human cellular receptor, is expected to cause difficulties in vaccine development. Given that DNA-protein vaccines promote stronger cell-mediated immune responses than protein-only vaccination, we immunized mice with various combinations of DNA priming and protein boosting using the S-subunit sequences of the MERS-CoV EMC/2012 strain. We demonstrated a cross-protective effect against wild-type KOR/KNIH/002, a strain with two mutations in the S amino acids, including one in its RBD. The vaccine also provided cross-neutralization against 15 different S-pseudotyped viruses. These suggested that a vaccine targeting one variant of S can provide cross-protection against multiple viral strains with mutations in S. The regimen of DNA priming/Protein boosting can be applied to the development of other coronavirus vaccines.


'MetaTaal': enhancing complex syntax in children with specific language impairment--a metalinguistic and multimodal approach.
Currently, most research on the effective treatment of morphosyntax in children with specific language impairment (SLI) pertains to younger children. In the last two decades, several studies have provided evidence that intervention for older school-age children with SLI can be effective. These metalinguistic intervention approaches teach grammatical rules explicitly and use shapes and colours as two-dimensional visual support. Reading or writing activities form a substantial part of these interventions. However, some children with SLI are poor readers and might benefit more from an approach that is less dependent on literacy skills. To examine the effectiveness of a combined metalinguistic and multimodal approach in older school-age children with SLI. The intervention was adapted to suit poor readers and targeted the improvement of relative clause production, because relative clauses still pose difficulties for older children with SLI. Participants were 12 monolingual Dutch children with SLI (mean age 11;2). All children visited a special school for children with speech and language disorders in the Netherlands. A quasi-experimental multiple-baseline design was chosen to evaluate the effectiveness of the intervention. A set of tasks was constructed to test relative clause production and comprehension. Two balanced versions were alternated in order to suppress a possible learning effect from multiple presentations of the tasks. After 3 monthly baseline measurements, the children received individual treatment with a protocolled intervention programme twice a week during 5 weeks. The tests were repeated directly post-therapy and at a retention measurement 3 months later. During the intervention programme, the speech therapist delivering the treatment remained blind to the test results. No significant changes were found during the baseline measurements. However, measurement directly post-therapy showed that 5 h of intervention produced significant improvement on the relative clause production tasks, but not on the relative clause comprehension task. The gains were also maintained 3 months later. The motor and tactile/kinesthetic dimensions of the 'MetaTaal' metalinguistic intervention approach are a valuable addition to the existing metalinguistic approaches. This study supports the evidence that grammatical skills in older school-age children with SLI can be remediated with direct intervention using a metalinguistic approach. The current tendency to diminish direct intervention for older children with SLI should be reconsidered.


Adenosine monophosphate-activated protein kinase: a central regulator of metabolism with roles in diabetes, cancer, and viral infection.
Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor activated by metabolic stresses that inhibit catabolic ATP production or accelerate ATP consumption. Once activated, AMPK switches on catabolic pathways, generating ATP, while inhibiting cell growth and proliferation, thus promoting energy homeostasis. AMPK is activated by the antidiabetic drug metformin, and by many natural products including "nutraceuticals" and compounds used in traditional medicines. Most of these xenobiotics activate AMPK by inhibiting mitochondrial ATP production. AMPK activation by metabolic stress requires the upstream kinase, LKB1, whose tumor suppressor effects may be largely mediated by AMPK. However, many tumor cells appear to have developed mechanisms to reduce AMPK activation and thus escape its growth-restraining effects. A similar phenomenon occurs during viral infection. If we can establish how down-regulation occurs in tumors and virus-infected cells, there may be therapeutic avenues to reverse these effects.


Characterization of the PC4 binding domain and its interactions with HNF4alpha.
In the presence of oxidative stress, the hepatocellular inflammatory-redox (IR) state upregulates inducible nitric oxide synthase (iNOS) expression as an anti-oxidant function. In IL-1beta and peroxide treated hepatocytes, we have identified hepatocyte nuclear factor-4alpha (HNF4) and the transcriptional co-activator, PC4, to be essential for upregulation of iNOS transcription in this setting. The co-activator, PC4, facilitates activator-dependent transcription via interactions with basal transcriptional machinery that are independent of PC4-DNA binding. The interaction between HNF4 and PC4 has not been previously characterized. In this study utilizing human HepG2 cells, we demonstrate the critical role for p38 MAP kinase mediated HNF4 Ser158 phosphorylation (P-HNF4-S158), binding of PC4 to P-HNF4-S158 and characterize the functional domain of PC4 required for P-HNF4-S158 binding. Our results indicate that the presence of the IR state enhances PC4-HNF4 binding to upregulate transcription of target hepatocyte genes, such as iNOS.


One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee.
Chondral lesions in athletically active patients cause considerable morbidity, and treatment with existing cell-based therapies can be challenging. Bone marrow has been shown as a possible source of multipotent stem cells (MSCs) with chondrogenic potential and is easy to harvest during the same surgical procedure. To investigate the clinical outcome in a group of active patients with large full-thickness chondral defects of the knee treated with 1-step surgery using bone marrow-derived MSCs and a second-generation matrix. Case series; Level of evidence, 4. From January 2007 to February 2010, 25 patients (average age, 46.5 years) with symptomatic large chondral defects of the knee (International Cartilage Repair Society grade 4) who underwent cartilage transplantation with MSCs and a collagen type I/III matrix were followed up for a minimum of 3 years. The average lesion size was 8.3 cm(2). Coexisting injuries were treated during the same surgical procedure in 18 patients. All patients underwent a standard postoperative rehabilitation program. Preoperative and postoperative evaluations at 1-year, 2-year, and final follow-up included radiographs, magnetic resonance imaging (MRI), and visual analog scale (VAS) for pain, International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm, Marx, and Tegner scores. Seven patients underwent second-look arthroscopic surgery, with 4 consenting to a tissue biopsy. No patients were lost at final follow-up. The average preoperative values for the evaluated scores were significantly improved at final follow-up (P < .001): VAS, 5.4 ± 0.37 to 0.48 ± 0.19; IKDC subjective, 37.92 ± 4.52 to 81.73 ± 2.42; KOOS pain, 61.04 ± 3.95 to 93.32 ± 1.92; KOOS symptoms, 55.64 ± 3.23 to 89.32 ± 2.32; KOOS activities of daily living, 63.96 ± 4.48 to 91.20 ± 2.74; KOOS sports, 34.20 ± 5.04 to 80.00 ± 3.92; KOOS quality of life, 32.20 ± 4.43 to 83.04 ± 3.37; Lysholm, 46.36 ± 2.25 to 86.52 ± 2.73; Marx, 3.00 ± 0.79 to 9.04 ± 0.79; and Tegner, 2.12 ± 0.32 to 5.64 ± 0.26. Patients younger than 45 years of age and those with smaller or single lesions showed better outcomes. The MRI scans showed good stability of the implant and complete filling of the defect in 80% of patients, and hyaline-like cartilage was found in the histological analysis of the biopsied tissue. No adverse reactions or postoperative complications were noted. The treatment of large chondral defects with MSCs is an effective procedure and can be performed routinely in clinical practice. Moreover, it can be achieved with 1-step surgery, avoiding a previous surgical procedure to harvest cartilage and subsequent chondrocyte cultivation.


Toward single cell tattoos: Biotransfer printing of lithographic gold nanopatterns on live cells.
Lithographic nanopatterning techniques like photolithography, electron-beam lithography, and nanoimprint lithography (NIL) have revolutionized modern-day electronics and optics. Yet, their application for creating nano-bio interfaces is limited by the cytotoxic and two-dimensional nature of conventional fabrication methods. Here, we present a biocompatible and cost-effective transfer process that leverages (a) NIL to define sub-300 nm gold (Au) nanopattern arrays, (b) amine functionalization of Au to transfer the NIL-arrays from a rigid substrate to a soft transfer layer, (c) alginate hydrogel as a flexible, degradable transfer layer, and (d) gelatin conjugation of the Au NIL-arrays to achieve conformal contact with live cells. We demonstrate biotransfer printing of the Au NIL-arrays on rat brains and live cells with high pattern fidelity and cell viability and observed differences in cell migration on the Au NIL-dot and NIL-wire printed hydrogels. We anticipate that this nanolithography-compatible biotransfer printing method could advance bionics, biosensing, and biohybrid tissue interfaces.


Alcohol's effects on lipid bilayer properties.
Alcohols are known modulators of lipid bilayer properties. Their biological effects have long been attributed to their bilayer-modifying effects, but alcohols can also alter protein function through direct protein interactions. This raises the question: Do alcohol's biological actions result predominantly from direct protein-alcohol interactions or from general changes in the membrane properties? The efficacy of alcohols of various chain lengths tends to exhibit a so-called cutoff effect (i.e., increasing potency with increased chain length, which that eventually levels off). The cutoff varies depending on the assay, and numerous mechanisms have been proposed such as: limited size of the alcohol-protein interaction site, limited alcohol solubility, and a chain-length-dependent lipid bilayer-alcohol interaction. To address these issues, we determined the bilayer-modifying potency of 27 aliphatic alcohols using a gramicidin-based fluorescence assay. All of the alcohols tested (with chain lengths of 1-16 carbons) alter the bilayer properties, as sensed by a bilayer-spanning channel. The bilayer-modifying potency of the short-chain alcohols scales linearly with their bilayer partitioning; the potency tapers off at higher chain lengths, and eventually changes sign for the longest-chain alcohols, demonstrating an alcohol cutoff effect in a system that has no alcohol-binding pocket.


Multiple genomic alterations on 21q22 predict various TMPRSS2/ERG fusion transcripts in human prostate cancers.
A number of TMPRSS2/ERG fusion transcripts have been reported since the discovery that recurrent genomic rearrangements result in the fusion of TMPRSS2 and ETS family member genes. In this article we present evidence demonstrating that multiple genomic alterations contribute to the formation of various TMPRSS2/ERG transcripts. Using allele-specific analysis of the data generated from the GeneChip 500K SNP array we observed both hemizygous and homozygous deletions occurring at different locations between and within TMPRSS2 and ERG in prostate cancers. The 500K SNP array enabled us to fine map the start and end of each deletion to specific introns of these two genes, and to predict a variety of fusion transcripts, including a new form which was confirmed by sequence analysis of the fusion transcripts in various tumors. We also inferred that translocation is an additional mechanism of fusion for these two genes in some tumors, based on largely diploid genomic DNA between TMPRSS and ERG, and different fusion transcripts produced in these tumors. Using a bioinformatics approach, we then uncovered the consensus sequences in the regions harboring the breakpoints of the deletions. These consensus sequences were homologous to the human Alu-Sq and Alu-Sp subfamily consensus sequences, with more than 80% homology. The presence/absence of Alu family consensus sequence in the introns of TMPRSS2 and ERG correlates with the presence/absence of fusion transcripts of theses two genes, indicating that these consensus sequences may contribute to genomic deletions and the fusion of TMPRSS2 and ERG in prostate cancer.


The formation of the pronephric duct in Xenopus involves recruitment of posterior cells by migrating pronephric duct cells.
Cell migration and cell-cell interactions play important roles in numerous processes during embryogenesis. One of these is the formation of the pronephric (Wolffian) duct (PD), which connects the pronephros to the cloaca. It is currently accepted that in most amphibians the pronephric duct is formed by active migration of the pronephric duct rudiment (PDR) cells along a predetermined pathway. However, there is evidence that in Xenopus, the PD may be formed entirely by in situ segregation of cells out of the lateral mesoderm. In this study, we show, using PDR ablation and Xenopus laevis-Xenopus borealis chimeras, that PD elongation in Xenopus requires both active cell migration and an induced recruitment of cells from the posterior. We also show that PDR cell migration is limited to only a few stages during development and that this temporal control is due, at least in part, to changes in the competence of the PD pathway to support cell migration.


Developmental plasticity in fat patterning of Ache children in response to variation in interbirth intervals: a preliminary test of the roles of external environment and maternal reproductive strategies.
A firm link between small size at birth and later more centralized fat patterning has been established in previous research. Relationships between shortened interbirth intervals and small size at birth suggest that maternal energetic prioritization may be an important, but unexplored determinant of offspring fat patterning. Potential adaptive advantages to centralized fat storage (Baker et al., 2008: In: Trevathan W, McKenna J, Smith EO, editors. Evolutionary Medicine and Health: New Perspectives. New York: Oxford) suggest that relationships with interbirth intervals may reflect adaptive responses to variation in patterns of maternal reproductive effort. Kuzawa (2005: Am J Hum Biol 17:5-21; 2008: In: Trevathan W, McKenna J, Smith EO, editors. Evolutionary Medicine and Health: New Perspectives. New York: Oxford) has argued that maternal mediation of the energetic quality of the environment is a necessary component of developmental plasticity models invoking predictive adaptive responses (Gluckman and Hanson 2004: Trends Endocrinol Metab 15:183-187). This study tested the general hypothesis that shortened interbirth intervals would predict more centralized fat patterning in offspring. If long-term maternally mediated signals are important determinants of offspring responses, then we expected to observe a relationship between the average interbirth interval of mothers and offspring adiposity, with no relationship with the preceding interval. Such a finding would suggest that maternal, endogenous resource allocation decisions are related to offspring physiology in a manner consistent with Kuzawa's description. We observed exactly such a relationship among the Ache of Paraguay, suggesting that maternally mediated in utero signals of postnatal environments may be important determinants of later physiology. The implications of these findings are reviewed in light of life history and developmental plasticity theories and ourability to generalize the results to other populations. Recommendations for further empirical research are briefly summarized.


Accuracy assessment of three-dimensional surface reconstructions of teeth from cone beam computed tomography scans.
The use of three-dimensional (3D) models of the dentition obtained from cone beam computed tomography (CBCT) is becoming increasingly more popular in dentistry. A recent trend is to replace the traditional dental casts with digital CBCT models for diagnosis, treatment planning and simulation. The accuracy of these models was previously assessed through comparing linear physical and radiographical measurements. However, this assessment technique is both observer and landmark dependent. The accuracy of 3D CBCT teeth reconstructions is yet to be reliably measured. To assess the accuracy of 3D CBCT reconstructions of the teeth using a semi-automated and observer-independent method and to assess the influence of field of view (FoV) selection on reconstruction accuracy. Fully dentate upper and lower dry human jaws, placed in a plastic box and immersed in water, were scanned using CBCT with small, medium and large FoV. The teeth were then scanned separately using MicroCT. Cone beam computed tomography and MicroCT 3D teeth models were compared, and mean surface difference was calculated per tooth for each FoV. Mean and (maximum) differences between MicroCT and CBCT were 120 +/- 40 (max. 679) microm, 157 +/- 39 (max. 824) micro and 207 +/- 80 (max. 862) microm for the small, medium and large FoV, respectively. Cone beam computed tomography models were larger than MicroCT because of larger voxel size. Our results indicate that CBCT may provide accurate 3D reconstructions of the teeth that can be useful for some clinical applications.


The synthesis of parasitic cysteine protease and trypanothione reductase inhibitors.
The presence of parasitic cysteine proteases and trypanothione reductase in the parasitic protozoa of the genus Trypanosoma and Leishmania has made these enzymes attractive targets for the development of antitrypanosomal and antileishmanial agents. Furthermore, the presence of cysteine proteases in Plasmodium falciparum has presented additional opportunities for the development of chemical scaffolds that could potentially be utilized against all of the aforementioned parasites. While previous reviews on parasitic cysteine proteases and trypanothione reductase covered various aspects, none emphasized the chemistry behind the synthesis of described inhibitors. This review focuses on recent developments in the synthesis of low-molecular weight inhibitors of these enzymes with a bearing on the human diseases of leishmaniasis, malaria and trypanosomiasis. Only those inhibitors whose synthesis has been described in the open literature during the period 1993-mid 2002 have been highlighted. The review thus excludes what may be in the patent literature. Inhibitors synthesized using combinatorial and/or parallel synthesis chemistry as well as polymer-assisted synthesis methodologies have been deliberately omitted from this review because they are a subject of a separate and focused review.


The effects of feed and intracellular pyruvate levels on the redistribution of metabolic fluxes in Escherichia coli.
In a previous study, an Escherichia coli strain lacking the key enzymes (acetate kinase and phosphotransacetylase, ACK-PTA) of the major acetate synthesis pathways reduced acetate accumulation. The ackA-pta mutant strain also exhibits an increased lactate synthesis rate. Metabolic flux analysis suggested that the majority of excessive carbon flux was redirected through the lactate formation pathway rather than the ethanol synthesis pathway. This result indicated that lactate dehydrogenase may be competitive at the pyruvate node. However, a 10-fold overexpression of the fermentative lactate dehydrogenase (ldhA) gene in the wild-type parent GJT001 was not able to divert carbon flux from acetate. The carbon flux through pyruvate and all its end products increases at the expense of flux through biosynthesis and succinate. Intracellular pyruvate measurements showed that strains overexpressing lactate dehydrogenase (LDH) depleted the pyruvate pool. This observation along with the observed excretion of pyruvate in the ackA-pta strain indicates the significance of intracellular pyruvate pools. In the current study, we focus on the role of the intracellular pyruvate pool in the redirection of metabolic fluxes at this important node. An increasing level of extracellular pyruvate leads to an increase in the intracellular pyruvate pool. This increase in intracellular pyruvate affects carbon flux distribution at the pyruvate node. Partitioning of the carbon flux to acetate at the expense of ethanol occurs at the acetyl-CoA node while partitioning at the pyruvate node favors lactate formation. The increased competitiveness of the lactate pathway may be due to the allosteric activation of LDH as a result of increased pyruvate levels. The interaction between the reactions catalyzed by the enzymes PFL (pyruvate formate lyase) and LDH was examined.


Epidemiology of firesetting in adolescents: mental health and substance use correlates.
Despite high rates of firesetting among community adolescents, little is known about its correlates. This study identifies the mental health and substance use correlates of four firesetting levels in an epidemiological sample of adolescents. Three thousand, nine hundred and sixty-five (3,965) students in grades 7 to 12 were surveyed. Multinomial analyses were used to compare non-firesetters; desisters (lifetime, but no past-year firesetting); low frequency firesetters (once or twice in the past 12 months); and high frequency firesetters (3 + times) on measures of mental health and substance use. Twenty-seven percent of youth reported firesetting during the past year. Of these, 13.7% reported one or two episodes, and 13.5% reported 3 or more episodes. Firesetting was more prevalent among males and among those in high school. Youth who began firesetting before age 10 were more likely to report frequent firesetting during the past year. Compared to non-firesetters, the firesetting groups had elevated risk profiles. Desisters and low frequency firesetters were more likely to report psychological distress, binge drinking, frequent cannabis use, and sensation seeking. Low frequency firesetters also reported higher rates of delinquent behavior, suicidal intent, and low parental monitoring than non-firesetters. High frequency firesetters reported elevated risk ratios for all of these risk indicators plus other illicit drug use. The cumulative number of risk indicators was positively associated with firesetting severity. Firesetting is associated with psychopathology and substance use during adolescence. Findings highlight the need for programs to address the mental health and substance use problems that co-occur with firesetting.