Mortality among male cigar and cigarette smokers in the USA.
Cigars and cigarettes are both smoked, but much less is known about the former's long-term health effects, due to its low prevalence and infrequent collection of cigar information in national surveys. We conducted a follow-up mortality study of cigar-smoking men age 40-79 years in National Health Interview Surveys (NHIS). We used pooled NHIS files linked to the National Death Index to obtain follow-up from year of interview to year of death or December 31, 2015. We developed categories of cigarette and cigar smoking that accommodate dual and former use of both products. We used Cox proportional hazards models, adjusted for age, race/ethnicity, marital status, education, income and region to estimate hazard ratios (HRs, 95% confidence intervals, CI) for mortality from all causes, heart diseases, malignant neoplasms, cerebrovascular disease, chronic lower respiratory diseases and two mutually exclusive categories: smoking-related and other diseases. There were 14,657 deaths from all causes, including 3426 never tobacco users, 3276 exclusive cigarette smokers and 176 exclusive cigar users. The latter had no statistically significant evidence of increased mortality from all causes, heart diseases, malignant neoplasms, cerebrovascular disease, smoking-related diseases or other causes. In contrast, the mortality experience of dual users of cigars and cigarettes and cigar smokers who formerly used cigarettes is similar to exclusive cigarette smokers. This study provides evidence that male cigar smokers age 40 + years had elevated mortality risks. However, after accounting for cigarette smoking and other confounding variables, we found significantly increased mortality only among dual and former users of cigarettes.


Can pacing self-management alter physical behavior and symptom severity in chronic fatigue syndrome? A case series.
Given the lack of evidence in support of pacing self-management for patients with chronic fatigue syndrome (CFS), we examined whether physical behavior and health status of patients with CFS would improve in response to a pacing self-management program. We performed an observational study of pacing self-management in seven CFS patients using a single-case study design. Stages A1 and A2 (7-day assessment periods) of the A1-B-A2 design corresponded to the baseline and posttreatment measurements of physical behavior (real-time activity monitoring) and health status (self-reported measures), respectively. Stage B (3 weeks of treatment) consisted of three individual treatment sessions of pacing self-management. When comparing pre- versus posttreatment data, we found that the patients' ability to perform daily activities and the severity of their symptom complexes were improved (p = 0.043). Concentration difficulties, mood swings, muscle weakness, and intolerance to bright light improved as well. A statistically significant decrease in the mean time spent doing light activity (<3 metabolic equivalents) was observed, but a change in the way physical activity was spread throughout the day was not. We found that 3 weeks of pacing self-management was accompanied by a modest improvement in symptom severity and daily functioning. The outcome of the present study calls for a randomized controlled clinical trial to examine the effectiveness of pacing self-management for people with CFS.


Molecular Pathways and Mechanisms of HER2 in Cancer Therapy.
The oncogene ERBB2 encoding the receptor tyrosine-protein kinase erbB-2 (HER2) is frequently overexpressed or amplified and occasionally mutated in a variety of human cancers. The early discovery of this oncogene, its established oncogenic relevance in diverse cancers, its substantial expression on the surface of cancer cells, and its druggable catalytic activity have made it one of the most pursued targets in the history of cancer drug development. Initiatives targeting HER2 provided the early stimulus for several transformational pharmaceutical technologies, including mAbs, tyrosine kinase inhibitors, antibody-drug conjugates, and others. The seismic impact of these efforts has been felt in treatment of many cancers, including breast, gastroesophageal, lung, colorectal, and others. This impact continues to broaden with increasing indications on the horizon and a plethora of novel agents in development. However, implementation of these therapeutic strategies has been complex. The clinical translation of every one of these classes of agents has been notable for underperformance or overperformance characteristics that have informed new lines of research providing deeper insights into the mechanistic complexities and unrealized opportunities provided by this molecular target. Despite all the successes to date, the preponderance of scientific evidence indicates that the full potential of HER2 as a target for cancer therapeutics is far greater than currently realized, and numerous lines of investigation are ongoing to deepen and broaden the scope of impact of HER2 as a signaling, homing, or immunologic target. In this review, we explore the existing data and evolving paradigms surrounding this remarkable target for cancer therapy.


Minimally Invasive Osteosynthesis of Distal Tibia Fractures using Anterolateral Locking Plate.
Introduction: Plating in distal tibia fractures are associated with higher rate of soft tissue complications. As adequate soft tissue cover is available over anterolateral surface of the tibia, use of anterolateral plate fixation in distal tibia fractures has increased. The purpose of our research is to evaluate the outcomes of anterolateral locking plate fixation in distal tibia fractures using ORIF. Materials and Methods: A retrospective analysis of 25 patients, who had distal tibia fractures and underwent open reduction and anterolateral plating. Bone and soft tissue healing and complications encountered were analysed. Result: Full weight bearing was allowed at an average of 5.4 months (range: 3-12 months) after seeing radiological union. We have observed superficial wound infection in four cases. Two cases had marginal necrosis, two cases had sensory disturbance over dorsolateral aspect of foot and two cases had delayed non-union. Mean length of surgical incision was 9cm (range: 5-12 cm). Conclusion: Open reduction internal fixation of distal tibia fractures with anterolateral plating is a reliable way of fracture fixation and stabilisation with proper surgical technique and aseptic precautions.


Circumferential endoscopic mucosal resection in Barrett's esophagus with high-grade intraepithelial neoplasia or mucosal cancer. Preliminary results in 21 patients.
Treatment by endoscopic mucosal resection (EMR) has been established for early lesions in Barrett's esophagus. However, the remaining Barrett's esophagus epithelium remains at risk of developing further lesions. The aim of this study was to evaluate the efficacy of circumferential endoscopic mucosectomy (circumferential EMR)s in removing not only the index lesion (high-grade intraepithelial neoplasia (HGIN) or mucosal cancer), but also the remaining Barrett's esophagus epithelium. A total of 21 patients were included in the study (11 men, 10 women), who had Barrett's esophagus and either HGIN (n = 12) or mucosal cancer (n = 9). Of the patients, 17/21 were at high surgical risk and five had refused surgery. On the basis of preprocedure endosonography their lesions were classified as T1N0 (n = 19) or T0N0 (n = 2). The lesions and the Barrett's esophagus epithelium were removed by polypectomy after submucosal injection of 10-15 ml of saline; a double-channel endoscope was used in 15/21 cases. Circumferential EMR was performed in two sessions, the lesion and the surrounding half of the circumferential Barrett's esophagus mucosa being removed in the first session. In order to prevent the formation of esophageal stenosis, the second half of the Barrett's esophagus mucosa was resected 1 month later. Complications occurred in 4/21 patients (19 %), consisting of bleeding which was successfully managed by endoscopic hemostasis in all cases. No strictures were observed during follow-up (mean duration 18 months) and endoscopic resection was considered complete in 18/21 patients (86 %). For three patients, histological examination showed incomplete removal of tumor: one of these underwent surgery; two received chemoradiotherapy, and showed no evidence of residual tumor at 18 months' and 24 months' follow-up, respectively. Two patients in whom resection was initially classified as complete later presented with local recurrence and were treated again by EMR. Barrett's esophagus mucosa was completely replaced by squamous cell epithelium in 15/20 patients (75 %). Circumferential EMR is a noninvasive treatment of Barrett's esophagus with HGIN or mucosal cancer, with a low complication rate and good short-term clinical efficacy. Further studies should focus on long-term results and on technical improvements.


Enhancing Behavior Change Technique Coding Methods: Identifying Behavioral Targets and Delivery Styles in Smoking Cessation Trials.
The behavior change technique (BCT) taxonomy v1 is often used in systematic reviews for identifying active components of interventions. Its utility could be enhanced by linking BCTs to specific target behaviors and qualifying BCT delivery style. To determine whether behavioral targets and delivery styles of BCTs can be coded reliably and to determine the utility of coding these characteristics. As part of a large systematic review of 142 smoking cessation trials, two researchers independently coded publicly and privately held intervention and comparator group materials, specifying the behavioral target (quitting, abstinence, medication adherence, or treatment engagement) and delivery style (tailored vs. not tailored; active participation vs. passive receipt) of each BCT. Researchers coded 3,843 BCTs, which were reliably attributed to behavioral targets (AC1 = 0.92, PABAK = 0.91). Tailoring (AC1 = 0.80, PABAK = 0.74) and participation (AC1 = 0.71, PABAK = 0.64) were also coded reliably. There was considerable variability between groups in quitting and abstinence BCTs (ranges: 0-41; 0-18) and in tailoring and participation (ranges: 0-20; 0-32), but less variability for medication adherence and treatment engagement (ranges: 0-6; 0-7). Behavioral targets and delivery styles of BCTs can be reliably identified and occur with sufficient frequency in smoking cessation trials for inclusion in quantitative syntheses (e.g., meta-regression analyses). Systematic reviewers could consider adopting these methods to evaluate the impact of intervention components targeting different behaviors, as well as the benefits of different BCT delivery styles.


[Constructing meanings and possibilities: the incubation team's experience of a supportice undertaking].
The aim of this qualitative study was to analyze the experience of an incubation team in a supportive undertaking regarding mental healthcare clients. Interviews were conducted with seven team members, and the data were analyzed using content data analysis. The analysis revealed four categories: considering incubation as a process - learning and finding the meanings of support; pointing out the easy and difficult aspects in the process of constructing the undertaking; seeing results of the inclusion through work - noticing the clients' improvement; and pointing out the need for changes in the process, expecting greater autonomy of clients and formalization of the undertaking. The experience revealed itself as a new and fulfilling job for the team, allowing for learning, exchanging knowledge and attachment. We identified that the technician plays the role of educator/facilitator of the process. In addition to the simple aspects and the recognition of the relevance of the work in terms of the clients' lives, the team faces challenges in generating satisfactory revenue.


[Infection with HTLV virus type I-II in patients with cervico-uterine cancer in the Yucatan peninsula, Mexico].
Southwestern Japan is an endemic zone with high prevalence of HTLV-I infection. In addition, a relation between cancer of the cervix and this retrovirus has been described. A recent study has demonstrated a low prevalence of HTLV-I/II infection in Yucatan, Mexico. However, cancer of the cervix is the most frequent oncological disease in this region. The objective of this study was to determine the relationship between cancer of the cervix and the HTLV-I/II infection. Sera from 123 patients with cancer of the cervix and 662 healthy women were screened for antibodies against HTLV-I/II by ELISA and agglutination test (PA). Results were confirmed by Western blot (WB). In the confirmed cases the differentiation between HTLV-I and HTLV-II was made by synthetic peptides. Only one woman (0.8%) had positive results in the patients group and two women (0.3%) had reactivity in the control group. In all these cases the antibodies were positive for HTLV-II. The prevalence in the group of patients with cancer of the cervix was similar to that of the control group. We therefore concluded that in Yucatan, Mexico there is no relation between HTLV-I/II infection and cancer of the cervix.


The concepts of critical organ and radiation dose as applied to plutonium.
The concepts of critical organ or tissue and the calculation of radiation dose have been and may well continue to be central to the development of standards for most radionuclides. In the case of plutonium the occupational standard was based on a modification of the direct calculations of maximum permissible annual dose (MPAD) or dose rate but critical organs must still be chosen for different routes of entry and different compounds and for all of the derived standards. Changes in such standards by likely variations in metabolic parameters and models are shown to be significant but not large. Application of the critical organ concept to population exposure standards poses some new problems because the basic MPAD does not distinguish among organs. A simple scaling factor from occupational exposure standards thus is not satisfactory. Use of the concept of dose commitment has many advantages but it is still necessary to select a critical organ and calculate dose. By-passing some of the problems in present practices by using risk-estimates seems unlikely for plutonium at the present time because of the paucity of human effects data and the fact that the animal experiments used quite different dosage regimens from the likely exposure situations to plutonium. A brief comparison is made of radiation and chemical hazard evaluation procedures.


Impact of caloric restriction on peripheral nerve injury-induced neuropathic pain during ageing in mice.
The incidence of peripheral neuropathy development and chronic pain is strongly associated with the arrival of senescence. The gradual physiological decline that begins after the mature stage produces myelin dysregulation and pathological changes in peripheral nervous system, attributed to reduction in myelin proteins expression and thinner myelin sheath. Moreover in elder subjects, when nerve damage occurs, the regenerative processes are seriously compromised and neuropathic pain (NeP) is maintained. We previously demonstrated that caloric restriction (CR) in adult (4 months) nerve-lesioned mice was able to facilitate remyelination and axons regeneration, to have anti-inflammatory action and to prevent NeP chronification. Here, we show CR therapeutic potential on nerve injury-induced neuropathy in mice at the beginning of the senescence (12 months). Long lasting decrease in hypersensitvity induced by peripheral nerve lesion and powerful reduction in proinflammatory circulating agents have been observed. Moreover, our results evidence that CR is able to counteract the ageing-related delay in axonal regeneration, enhancing Schwann cells proliferation and accelerating recovery processes. Differently from adults, it does not affect fibres myelination. In light of a continuous growth in elderly population and correlated health problems, including metabolic disorders, the prevalence of neuropathy is enhancing, generating a significant public cost and social concern. In this context energy depletion by dietary restriction can be a therapeutic option in NeP.


Anti-cardiolipin antibodies in fetal blood and amniotic fluid derived from patients with the anti-phospholipid syndrome.
The aim of this study was to investigate whether, in patients with antiphospholipid syndrome, anticardiolipin antibodies pass from mother to offspring sera and amniotic fluid. Eleven patients with antiphospholipid syndrome (study group) and 11 healthy controls, matched by maternal and gestational age (control group) were prospectively examined for the presence of anticardiolipin antibodies in the cord blood during labour, and amniotic fluid during vaginal or Caesarean delivery. Three neonates (27.3%) in the study group had anticardiolipin antibodies in the cord blood, while none had them in the control group. Anticardiolipin antibodies were detected in the amniotic fluid in six (54.5%) of the study group pregnancies, compared with none in the control group. No adverse neonatal outcome was noted except for significantly lower (P < 0.0006) mean birth weight in the study group. Anticardiolipin antibodies can pass the placenta and be detected in fetal cord blood and amniotic fluid. This finding might be used in the future for the assessment of pregnancies with antiphospholipid syndrome.


Feeling understood for the first time: experiences of participation in rehabilitation after out-of-hospital sudden cardiac arrest.
Survivors of out-of-hospital sudden cardiac arrest (SCA) may suffer from long-term cognitive, psychological, or physical post-arrest consequences impacting and disrupting daily life. To adjust to and manage daily life is critical, and therefore a tailored rehabiliation programme was introduced to the participants. The study aimed to explore the lived experience among cardiac arrest survivors. Data were gathered through six focus group interviews during a cardiac arrest rehabilitation programme. Thirty-three out-of-hospital SCA survivors (8 women and 25 men) participated. Time since cardiac arrest was on average 12-57 months. An exploratory qualitative design inspired by Ricoeur's phenomenological hermeneutics was applied. Two main themes emerged from the analysis and interpretation: (i) a lack of support from the health system in the transition from hospital to daily life; and (ii) feeling understood for the first time. The findings revealed that out-of-hospital SCA survivors experience a knowledge gap struggling for support. Attending the programme, gaining knowledge and experiencing peer support was described as a revelation for them. The findings suggest that out-of-hospital SCA survivors felt understood for the first time when attending a cardiac arrest rehabilitation programme. A post-arrest pathway is needed led by a coordinating cardiac arrest specialist nursing service together with allied healthcare professionals. Focus on hypoxic brain injuries, emotional burdens, and supportive strategies are essential in the transition to daily life. Facilitated peer support is warranted.


Ramucirumab and durvalumab for previously treated, advanced non-small-cell lung cancer, gastric/gastro-oesophageal junction adenocarcinoma, or hepatocellular carcinoma: An open-label, phase Ia/b study (JVDJ).
Emerging evidence supports combining immune checkpoint inhibitors (ICIs) with conventional or targeted therapies to enhance ICI antitumour activity and broaden the spectrum of patients who respond to ICIs. Here, we present the safety and preliminary efficacy of ramucirumab, an anti-VEGFR2 IgG1, plus durvalumab, an anti-PD-L1 IgG1, in previously treated patients with advanced non-small-cell lung cancer (NSCLC), gastric/gastro-oesophageal junction adenocarcinoma (gastric/GEJ), or hepatocellular carcinoma (HCC). A 25-centre, phase Ia/b single-arm, non-randomised, multi-cohort study was undertaken in patients with advanced/metastatic disease, Eastern Cooperative Oncology Group performance status, 0-1, progression on prior therapy, no prior ramucirumab or immunotherapy and any PD-L1 status. Patients received ramucirumab (10 mg/kg) plus durvalumab (1125 mg) intravenously Q3W (NSCLC), or ramucirumab (8 mg/kg) plus durvalumab (750 mg) Q2W (gastric/GEJ, HCC). Phase Ia treatment was found safe for phase Ib expansion; final enrolment was NSCLC (n = 28), gastric/GEJ (n = 29), HCC (n = 28). Grade ≥3 treatment-related adverse events occurred in 32.1%, 37.9% and 42.9% of patients, respectively. The most common were fatigue (35.7%), hypertension (34.5%) and diarrhoea (28.6%), respectively. Two patients died owing to an adverse event; one was treatment-related (hepatitis acute, HCC cohort). Objective response rate was 11% for NSCLC and HCC and 21% for gastric/GEJ. Median progression-free survival and overall survival were, respectively, 2.7 and 11 months in NSCLC; 2.6 and 12.4 months in gastric/GEJ; 4.4 and 10.7 months in HCC, with more prolonged survival in patients with high PD-L1 expression. Ramucirumab/durvalumab exhibited manageable safety. The combination showed antitumour activity in all cohorts, particularly in patients with high PD-L1 expression.


Antimicrobial treatment of febrile neutropenia: pharmacokinetic-pharmacodynamic considerations.
Patients with cancer or hematologic diseases are particularly at risk of infection leading to high morbidity, mortality and costs. Extensive data show that optimization of the administration of antimicrobials according to their pharmacokinetic and pharmacodynamic parameters improves clinical outcome. Evidence is growing that when pharmacokinetic and pharmacodynamic parameters are used to target not only clinical cure but also eradication, the selection resistance is also contained. This is of particular importance in patients with neutropenia in whom increasing rates of drug-resistant Gram-negative bacteria have been reported, particularly Pseudomonas aeruginosa. Based on experimental and clinical studies, pharmacokinetic and pharmacodynamic parameters are discussed in this review for each antibiotic used in febrile neutropenia in order to help physicians improve dosing and optimization of antimicrobial agents.


Virilizing ovarian Leydig cell tumor in a woman with subclinical Cushing syndrome.
To report the case of a patient with a virilizing ovarian Leydig cell tumor and subclinical Cushing syndrome attributable to an adrenal adenoma. Detailed clinical, laboratory, radiologic, and pathologic findings are presented, and the pertinent literature is reviewed. A 49-year-old woman was referred for evaluation of a left adrenal mass (3.0 by 2.4 cm), which had been diagnosed by computed tomographic scan 4 years previously during a work-up for hirsutism. On examination, she had central obesity, facial hirsutism, and male pattern baldness. Work-up showed elevated total and free testosterone levels of 196 ng/dL (reference range, 20 to 70) and 24 pg/mL (1 to 9), respectively. Other results (and reference ranges) were as follows: dehydroepiandrosterone sulfate, 7.5 microg/dL (10 to 221); corticotropin, 12 pg/mL (5 to 50); morning cortisol, 1.4 microg/dL after a 1-mg overnight dexamethasone suppression test; and urine free cortisol, 48.8 microg/24 h (20 to 100). The testosterone level decreased by 14% after a 2-day low-dose dexamethasone suppression test. Findings on transvaginal ovarian ultrasonography and a computed tomographic scan of the pelvis were normal. A laparoscopic adrenalectomy revealed an adrenal adenoma. On the first day postoperatively, the cortisol level was less than 1.0 microg/dL; however, the testosterone level remained elevated. At 6 months postoperatively, a normal result of a cosyntropin stimulation test indicated recovery of the hypothalamic-pituitary-adrenal axis. Bilateral oophorectomy revealed a 1.3-cm right ovarian Leydig cell tumor. Postoperatively, the testosterone level declined to less than 20 ng/dL. To our knowledge, this is the first case report of a virilizing ovarian Leydig cell tumor in a patient with subclinical Cushing syndrome.


A porous porphyrin organic polymer (PPOP) for visible light triggered hydrogen production.
A visible light active porphyrin-based porous organic polymer having high chemical stability and surface area has been synthesized and its ability to influence the photocatalytic activity of large band gap-TiO2 nanoparticles has been tested. The resultant composite shows improved photocatalytic activity as compared to the parent precursors. This study provides insights into the photosensitizing ability of the polymer in addition to its ability to firmly harbor nanoparticles onto its surface.


Dental, Dental Hygiene, and Advanced Dental Students' Use, Knowledge, and Beliefs Regarding Tobacco Products.
Using cigarettes and alternative tobacco products (ATPs) is associated with negative oral health outcomes, and dental health professionals are poised to help patients quit. The aim of this study was to determine dental, dental hygiene, and advanced dental students' use, knowledge, and beliefs about cigarettes and ATPs, including perceptions about their education in tobacco dependence treatment and counseling experience. All 1,783 students enrolled in the dental, dental hygiene, and postdoctoral dental programs at the New York University College of Dentistry were invited to participate in the survey in 2016. A total of 708 students at least partially completed the survey, for a response rate of 39.7%. In the results, 146 of the students (20.1%) reported ever using cigarettes, while 253 (35.7%) reported ever using any ATP. Regarding tobacco use intervention, the students reported they had not received enough training on ATPs, were neutral about cigarettes, and were somewhat confident and not so confident counseling a cigarette smoker or ATP user, respectively. By their fourth year, 77.8% of the dental students reported they had counseled someone to stop smoking cigarettes, but only 40.7% had counseled someone to stop using ATPs. Overall, all groups of students reported feeling more confident and had received more education on interventions for cigarettes than for ATPs (p<0.001). These students reported low confidence in helping people quit tobacco and did not perceive they had received enough training on intervening with patients on use of cigarettes and ATPs. These findings call for a revised tobacco education curriculum for dental, dental hygiene, and advanced dental students, focused on building knowledge and confidence for promoting tobacco dependence treatment.


High level transient expression of the murine coronavirus haemagglutinin-esterase.
We have expressed the murine coronavirus haemagglutinin-esterase protein in a vaccinia virus/T7 RNA polymerase system. The levels of expression observed are significantly higher than those found in virus-infected cells. The expressed protein has both receptor-destroying (esterase) and receptor-binding (haemadsorption) activities. The use of this system will greatly facilitate analysis of the structure-function relationships of this protein.


Scientific and clinical challenges in sepsis.
Advances in intensive care and antibiotics have prevented the spread of some infections, though sepsis mortality rates remain high. With failure of over thirty clinical trials, sepsis remains a scientific and clinical challenge in modern medicine. Sepsis is defined by the clinical signs of a systemic inflammatory response to infection. "Severe sepsis" is when these symptoms are associated with multiple organ dysfunction. These definitions of sepsis may be too broad and common to heterogeneous groups of patients who do not necessarily have the same disorder. This consideration has become especially evident in the clinical trials that have failed to obtain consistent results in similar studies of patients diagnosed with severe sepsis. In these trials, patients with infections caused by different microorganisms, and affecting different organs, have been combined under the general diagnosis of severe sepsis. The situation is analogous to attempting a clinical trial based on the general definition of cancer, combining all patients with tumor independent of the type of malignancy. In this consideration, it would not be very surprising that activated protein C, the only treatment in sepsis approved by the Food and Drug Administration, is projected for use in only a small subset of patients with severe sepsis. This article reviews novel inflammatory molecular aspects and the experimental anti-inflammatory strategies for sepsis, as they may represent particular pathological processes in specific subsets of patients.


Measurement and characteristics of fusion of isolated membrane fractions from maize root tips.
Maize root tips were incubated in vivo with radioactive glucose, choline or diazotized sulphanilic acid. Membrane fractions were prepared from radioactive and non-radioactive roots. The transfer of radioactivity between mixed membrane fractions has enabled a quantitative system to be developed to study in vitro membrane fusion between Golgi apparatus and plasma membrane-rich fractions. Membrane fusion was found to be dependent on time, temperature, Mn2+ and Ca2+. Mn2+ was as effective as Ca2+, other divalent cations had a moderate or no effect. The effect of various substances, including inhibitors of microtubular and microfilament assembly and blocking reagents for sulphydryl group on membrane fusion has been investigated. The process appears to be dependent on the membrane proteins or glycoproteins; trypsinization of mixed membranes prior to the addition of Ca2+ inhibited significantly the fusion process. SDS-polyacrylamide gel electrophoresis of trypsin-treated membranes revealed the selective loss of one particular polypeptide which could play a role in membrane fusion.


Oral candidal carriage in asymptomatic patients.
Interest in the association between oral cancer risk and Candida-associated promotion of mucosal dysplasia continues. However, little is known of the presence and amount of oral yeast in the mouths of healthy patients without mucosal lesions. The purpose of this prospective cross-sectional clinical study was to ascertain the prevalence and degree of carriage of Candida in the oral cavities of a non-cancer population, with reference to a range of parameters affecting the oral environment. Oral rinse samples were collected from a sample of 203 patients attending the Royal Dental Hospital of Melbourne and analysed for the presence and degree of colonization of yeast species that were phenotypically identified as albicans and non-albicans species. Oral yeast carriage was found in 98/203 patients (48.3%), and of these, 83 (84.7%) patients carried C. albicans. There was no statistical difference in carriage when comparing gender, age, or presence of a removable prosthesis. Both smoking and the presence of active carious lesions were found to be positively correlated with the carriage of oral Candida. Individuals who are current smokers are nearly seven times more likely to have oral Candida, and participants with high candidal colonization are more likely to be current smokers. Participants with active carious lesions were also more likely to carry oral Candida.


Functional cis-regulatory modules encoded by mouse-specific endogenous retrovirus.
Cis-regulatory modules contain multiple transcription factor (TF)-binding sites and integrate the effects of each TF to control gene expression in specific cellular contexts. Transposable elements (TEs) are uniquely equipped to deposit their regulatory sequences across a genome, which could also contain cis-regulatory modules that coordinate the control of multiple genes with the same regulatory logic. We provide the first evidence of mouse-specific TEs that encode a module of TF-binding sites in mouse embryonic stem cells (ESCs). The majority (77%) of the individual TEs tested exhibited enhancer activity in mouse ESCs. By mutating individual TF-binding sites within the TE, we identified a module of TF-binding motifs that cooperatively enhanced gene expression. Interestingly, we also observed the same motif module in the in silico constructed ancestral TE that also acted cooperatively to enhance gene expression. Our results suggest that ancestral TE insertions might have brought in cis-regulatory modules into the mouse genome.


Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence for PAPSS2 as a Longevity Gene.
Although there is compelling evidence for a genetic contribution to longevity, identification of specific genes that robustly associate with longevity has been a challenge. In order to identify longevity-enhancing genes, we measured differential gene expression between offspring of long-lived Amish (older than 90 years; cases, n = 128) and spouses of these offspring (controls, n = 121) and correlated differentially expressed transcripts with locations of longevity-associated variants detected in a prior genome-wide association study (GWAS) of survival to age 90. Expression of one of these transcripts, 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2), was significantly higher in offspring versus controls (4×10(-4)) and this association was replicated using quantitative real-time polymerase chain reaction. PAPSS2, a sulfation enzyme located on chromosome 10, is ~80kb upstream of the PAPSS2 transcription start site. We found evidence of cis-expression for the originally reported GWAS SNP and PAPSS2 Monogenic conditions linked to PAPSS2 include andrenocortical androgen excess resulting in premature pubarche and skeletal dysplasias, both of which have premature aging features. In summary, these findings provide novel evidence for PAPSS2 as a longevity locus and illustrate the value of harnessing multiple "-omic" approaches to identify longevity candidates.


Essential roles of HDAC1 and 2 in lineage development and genome-wide DNA methylation during mouse preimplantation development.
Epigenetic modifications, including DNA methylation and histone modifications, are reprogrammed considerably following fertilization during mammalian early embryonic development. Incomplete epigenetic reprogramming is a major factor leading to poor developmental outcome in embryos generated by assisted reproductive technologies, such as somatic cell nuclear transfer. However, the role of histone modifications in preimplantation development is poorly understood. Here, we show that co-knockdown (cKD) of Hdac1 and 2 (but not individually) resulted in developmental failure during the morula to blastocyst transition. This outcome was also confirmed with the use of small-molecule HDAC1/2-specific inhibitor FK228. We observed reduced cell proliferation and increased incidence of apoptosis in cKD embryos, which were likely caused by increased acetylation of TRP53. Importantly, both RNA-seq and immunostaining analysis revealed a failure of lineage specification to generate trophectoderm and pluripotent cells. Among many gene expression changes, a substantial decrease of Cdx2 may be partly accounted for by the aberrant Hippo pathway occurring in cKD embryos. In addition, we observed an increase in global DNA methylation, consistent with increased DNA methyltransferases and UHRF1. Interestingly, deficiency of RBBP4 and 7 (both are core components of several HDAC1/2-containing epigenetic complexes) results in similar phenotypes as those of cKD embryos. Overall, HDAC1 and 2 play redundant functions required for lineage specification, cell viability and accurate global DNA methylation, each contributing to critical developmental programmes safeguarding a successful preimplantation development.


Prevention of oral diseases.
The different types of hard- and soft tissues that are involved in the formation of the oral cavity are subject of numerous diseases. Albeit dental caries and periodontitis comprise the most common oral disease entities, also several premalignant and malignant conditions can occur within the oral cavity. There exists are wide armamentarium for the prevention of both, dental caries and periodontitis. Preventive strategies are even more important regarding oral malignancies since specifically these entities commonly provide only poor prognosis if not treated in early stages. The present contribution aims to present the pathogenic background of the most common oral diseases and the most effective methods for their prevention.


Primary Care and Public Health Collaboration Reports: A Qualitative Review of Integration Aims, Participants, and Success Determinants.
This qualitative review of 57 published case reports aimed to analyze primary care and public health integration efforts in 45 states to summarize collaboration aims, participants, and systemic, organizational, and interactional success determinants. Chronic disease management, maternal and child health, and wellness and health promotion were the most commonly reported aims of collaboration between primary care and public health entities in the United States. Typical participants were government public health structures, health delivery systems, communities, academia, state professional medical associations, and employers and businesses. Systemic, organizational, and interactional determinants included adequate funding, multiple stakeholder engagement, leadership, data and information sharing, capitalization on collaborator resources, community engagement, steering committees, effective communication, regular meetings, shared mission, vision, and goals, previous positive relationships, collaborations, and partnerships. The present study contributes to the body of knowledge of when, where, and under what contextual circumstances collaboration and integration have been perceived as effective. Future research could extrapolate which determinants are more essential than others and focus on how systemic, organizational, and interactional factors are interrelated. To advance the practice of successful integration between primary care and public health entities, longitudinal research is needed to examine the degree of integration and sustainability.


Grain yield and physiological traits of rice lines with the drought yield QTL qDTY12.1 showed different responses to drought and soil characteristics in upland environments.
To improve yield in upland conditions, near-isogenic lines (NILs) of the major-effect drought yield quantitative trait locus qDTY12.1 in rice (Oryza sativa L.) were developed in the background of the upland variety Vandana. These NILs have shown greater water uptake a larger proportion of lateral roots, and higher transpiration efficiency under drought than Vandana, and one NIL (481-B) was selected as having the highest yield. In this study, the NILs were assessed in two greenhouse and 18 upland field trials for their response to drought and different soil textures. Performance of qDTY12.1 NILs was not affected by soil texture but showed a notable response to drought stress severity. The yield advantage of 481-B over Vandana was highest in field trials with intermittent drought stress, in which the mean trial yield was greater than 0.5tha-1, and in the least favourable well watered trial. The effects of qDTY12.1 on water uptake were most apparent under mild to moderate stress but not in very severe drought or well watered treatments, whereas the lateral root and transpiration efficiency responses were observed under a range of conditions. These results highlight the varying response of qDTY12.1 across upland environments and the complexity of multiple mechanisms acting together to confer an effect on rice yield under drought.


Glycoprotein tyrosine phosphorylation in Rous sarcoma virus-transformed chicken embryo fibroblasts.
The level of tyrosine phosphorylation of cellular glycoproteins isolated by wheat germ agglutinin chromatography in cells infected with a variety of kinase-positive/transformation-defective src mutants was examined in an effort to identify cellular membrane proteins whose phosphorylation correlates with phenotypic transformation. We have identified two glycoproteins, with molecular masses of 95 and 135 kilodaltons, whose phosphorylation correlates with morphological transformation, growth in soft agar, and an increase in the rate of 2-deoxyglucose uptake. The strong correlation obtained between transformation and phosphorylation of these proteins suggests that they may be substrates for pp60src which are important in the process of transformation.


Screening for celiac disease in a North American population: sequential serology and gastrointestinal symptoms.
The prevalence of diagnosed celiac disease is <1 in 2,000 in the United States, but screening studies undertaken in European and other populations have revealed a much higher prevalence. The objective of this study was to determine the prevalence of celiac disease and the utility of screening in the general adult population of a geographically isolated area. Serum tissue transglutaminase antibodies (tTG-IgA) were measured in volunteer health-care participants aged ≥ 18 years at the annual Casper, Wyoming, Blue Envelope Health Fair blood draw. Subjects with positive tTG-IgA tests had their endomysial IgA antibodies checked. Double positives were offered endoscopy with small bowel biopsy. All subjects completed a short gastrointestinal (GI) symptom questionnaire. A total of 3,850 residents of the Natrona County had serologic evaluation for celiac disease, 34 of whom tested positive for both tTG and endomysial antibody (EMA) IgA. Excluding three individuals with previous diagnosis of celiac disease, the overall prevalence of positive celiac serology in this community sample was 0.8%. All 31 subjects were offered a small bowel biopsy. Of the 18 biopsied subjects, 17 (94%) had at least partial villous atrophy. Symptoms that were reported by the fair attendees did not predict positivity. Screening for celiac disease was widely accepted in this preventative health-care setting. Undiagnosed celiac disease affects 1 in 126 individuals in this Wyoming community. Most were asymptomatic or had atypical presentations. Serologic testing can readily detect this disease in a general population.


Effect of delta-sleep-inducing peptide on expression of heat shock protein 70 kDa in K562 cells.
For evaluation of the stress-protective influence of delta-sleep inducing peptide we studied its effects on the system of heat-shock proteins in immune cells using the method of flow cytometry. The peptide affected the expression of heat-shock protein 70 kDa in cultured human myeloleukemia K562 cells. Delta-sleep-inducing peptide reduces accumulation of intracellular heat shock proteins 70 kDa in cells cultured under conditions of high density.


Abnormal neurogenesis and cortical growth in congenital heart disease.
Long-term neurological deficits due to immature cortical development are emerging as a major challenge in congenital heart disease (CHD). However, cellular mechanisms underlying dysregulation of perinatal corticogenesis in CHD remain elusive. The subventricular zone (SVZ) represents the largest postnatal niche of neural stem/progenitor cells (NSPCs). We show that the piglet SVZ resembles its human counterpart and displays robust postnatal neurogenesis. We present evidence that SVZ NSPCs migrate to the frontal cortex and differentiate into interneurons in a region-specific manner. Hypoxic exposure of the gyrencephalic piglet brain recapitulates CHD-induced impaired cortical development. Hypoxia reduces proliferation and neurogenesis in the SVZ, which is accompanied by reduced cortical growth. We demonstrate a similar reduction in neuroblasts within the SVZ of human infants born with CHD. Our findings demonstrate that SVZ NSPCs contribute to perinatal corticogenesis and suggest that restoration of SVZ NSPCs' neurogenic potential is a candidate therapeutic target for improving cortical growth in CHD.


Ant-plant sociometry in the Azteca-Cecropia mutualism.
A holistic understanding of superorganism biology requires study of colony sociometry, or the quantitative relationships among growth, nest architecture, morphology, and behavior. For ant colonies that obligately nest within plant hosts, their sociometry is likely intertwined with the plant, which has implications for the evolution, strength, and stability of the mutualism. In the Azteca-Cecropia mutualism, plants provide ants with food rewards and hollow stems for nesting in return for protection from herbivores. Several interesting questions arise when considering ant-plant sociometry: are colony growth and plant growth synchronized? How do colonies distribute themselves within the stem of their host plant? How do plant traits influence worker morphology? How is collective personality related to tree structure, nest organization, and worker morphology? To address these questions, we investigated patterns within and relationships among five major sociometric categories of colonies in the field - plant traits, colony size, nest organization, worker morphology, and collective personality. We found that colony sociometry was intimately intertwined with host plant traits. Colony and plant growth rates were synchronized, suggesting that positive feedback between plant and colony growth stabilizes the mutualism. The colony's distribution inside the host tree tended to follow leaf growth, with most workers, brood, and the queen in the top half of the tree. Worker morphology correlated with plant size instead of colony size or age, which suggests that plant traits influence worker development. Colony personality was independent of colony distribution and tree structure but may correlate with worker size such that colonies with smaller, less variable workers had more aggressive personalities. This study provides insights into how ant-plant structural relationships may contribute to plant protection and the strength of mutualisms.


Adults with Williams syndrome. Preliminary study of social, emotional and behavioural difficulties.
In recent years there has been an upsurge of interest in the study of distinctive patterns of behavioural and psychological characteristics associated with specific, biologically determined, intellectually disabling conditions. This study investigates whether such a profile can be identified in adults with Williams syndrome. Parents and other care-givers were interviewed about the social, emotional and behavioural characteristics of 70 adults with Williams syndrome, aged 19 years to 39 years 9 months. The adults were reported to have high rates of behavioural and emotional difficulties, particularly in terms of poor social relationships, over-friendliness and social disinhibition, preoccupations and obsessions, and high levels of anxiety and distractibility. The findings provide preliminary support for the existence of a specific pattern of behavioural and personality characteristics and associated difficulties in adults with Williams syndrome, which persist from childhood and often require intervention from mental health professionals. Implications for clinical practice are considered.


REM sleep without atonia with REM sleep-related motor events: broadening the spectrum of REM sleep behavior disorder.
To assess the presence of increased REM-related motor activity during sleep, by questionnaires for REM sleep behavior disorder (RBD), in participants with "isolated" REM sleep without atonia (RWA). Two hundred forty-nine patients were consecutively enrolled, with age ≥18 years, sharing bedroom with a roommate, and without a severe health, neurological, or cognitive problem. Motor activity during sleep was assessed by means of the RBD Screening Questionnaire (RBDSQ) and the RBD questionnaire-Hong Kong (RBDQ-HK). A video-polysomnographic recording was obtained and the REM Atonia Index was computed. Thirteen participants were diagnosed to have RBD while the remaining 236 were subdivided into two subgroups: 34 participants with "low" (<0.8) and 202 participants with "high" Atonia Index (≥0.8). RBDSQ and RBDQ-HK were both higher in participants with low Atonia Index than in those with high Atonia Index, as well as number of drugs taken and number of comorbidities. No effect of antidepressant use was found on Atonia Index and a multiple-regression analysis showed that Atonia Index was significantly (inversely) correlated only with the behavioral score obtained with the RBDQ-HK. Our study shows that individuals with isolated RWA have an increased motor activity/behavioral pattern during sleep, although this activity does not allow us to diagnose RBD. Our findings broaden the spectrum of RBD and the condition that we have identified should be better characterized in order to understand its eventual development into fully blown RBD or not.


Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial.
To determine the role of chemotherapy in the multidisciplinary treatment of patients with osteosarcoma, a randomized prospective trial of postoperative adjuvant chemotherapy was begun in 1981. Fifty-nine patients with nonmetastatic classic intramedullary osteosarcoma were randomized; 32 received postoperative adjuvant chemotherapy consisting of high-dose methotrexate, Adriamycin (Adria Laboratories, Columbus, OH), and BCD (bleomycin, cytoxan, actinomycin D), and 27 patients received no adjuvant chemotherapy. At a median follow-up of 2 years, there was a statistically significant improvement in both disease-free and overall survival in those who received adjuvant chemotherapy. In addition, there was no difference in the less than 20% disease-free or overall survival of patients treated in the 1970s who did not receive chemotherapy, as compared with the concurrent nontreatment controls. Therefore, with identical staging procedures, uniform surgical management, and standard pathologic evaluation, postoperative adjuvant chemotherapy definitely improves disease-free and overall survival in patients with osteosarcoma.


Mitochondrial apoptosis-inducing factor is involved in doxorubicin-induced toxicity on H9c2 cardiomyoblasts.
The cardiotoxicity induced by the anti-cancer doxorubicin involves increased oxidative stress, disruption of calcium homeostasis and activation of cardiomyocyte death. Nevertheless, antioxidants and caspase inhibitors often show little efficacy in preventing cell death. We hypothesize that a caspase-independent cell death mechanism with the release of the apoptosis-inducing factor from mitochondria is involved in doxorubicin toxicity. To test the hypothesis, H9c2 cardiomyoblasts were used as model for cardiac cells. Our results demonstrate that z-VAD-fmk, a pan-caspase inhibitor, does not prevent doxorubicin toxicity in this cell line. Doxorubicin treatment results in AIF translocation to the nuclei, as confirmed by Western Blotting of cell fractions and confocal microscopy. Also, doxorubicin treatment of H9c2 cardiomyoblasts resulted in the appearance of 50kbp DNA fragments, a hallmark of apoptosis-inducing factor nuclear effects. Apoptosis-inducing factor knockdown using a small-interfering RNA approach in H9c2 cells resulted in a reduction of doxorubicin toxicity, including decreased p53 activation and poly-ADP-ribose-polymerase cleavage. Among the proteases that could be responsible for apoptosis-inducing factor cleavage, doxorubicin decreased calpain activity but increased cathepsin B activation, with inhibition of the latter partly decreasing doxorubicin toxicity. Altogether, the results support that apoptosis-inducing factor release is involved in doxorubicin-induced H9c2 cell death, which explains the limited ability of caspase inhibitors to prevent toxicity.


SARS-CoV-2 Infection, A Risk Factor for Pituitary Apoplexy? A Case Series and Literature Review.
Introduction: Pituitary apoplexy (PA) is a rare phenomenon, characterized by a hemorrhagic or ischemic event of the pituitary gland, most often in association with a pituitary lesion. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the strain of virus responsible for the internationally recognized global pandemic COVID-19. Multiple clinical manifestations associated with this virus have been described, ranging from asymptomatic, mild flu symptoms to acute respiratory distress syndrome, end-organ failure leading to death. Cases of patients with concomitant COVID-19 infections and PA are being further recognized in the literature, but the causal association between the 2 entities remains speculative. Objectives: The objectives of this case series are 3-fold: to describe additional cases of patients with concomitant COVID-19 infection and PA (1), to review the current evidence regarding this potential complication associated with a COVID-19 infection (2), and to discuss physiopathological hypotheses, treatments, and prognoses of this newly recognized association (3). Method: We conducted an electronic chart review of patients treated for PA with concomitant COVID-19 infection from March 2020 to December 2021. A literature review was performed using MEDLINE, Web of Science, and Embase databases to identify other cases of COVID-19-associated PA. Results: From March 2020 to December 2021, 3 patients presented to our center with PA following a symptomatic COVID-19 infection. Two of these patients developed PA symptoms days following the viral infection, whereas the third patient developed PA after a 2-month period. The 2 first patients were managed surgically because of persistent visual symptoms. Results from our literature review yielded 12 other cases of COVID-19-associated PAs. Conclusions: The association between COVID-19 infection and PA has been increasingly reported in the literature. With the addition of the 3 cases described in our article, a total of 15 cases have been published. Many contributing mechanisms may lead to PA following COVID-19 infection. Coagulopathy is probable major contributing cause responsible for hemorrhage or infarction of the pituitary gland. Our case series provides further arguments that PA may be a direct manifestation of a COVID-19 infection.


Relationship between driver's record and automobile versus child pedestrian collisions.
The purpose of this study was to explain the relationship of a history of driver's violations as a factor in motor vehicle versus child pedestrian injury incidents. A case-control study was conducted utilizing police reports from 1 January 1993, to 30 June 1995, to identify drivers (cases) whose car struck a child pedestrian less than 15 years of age. Controls were randomly selected drivers identified from the license files of the California Department of Motor Vehicles (DMV) who had no record of striking a child pedestrian in the 30 month study period. Two controls per case were selected based on postal code of residence and incident date of case. Prior driver citations, safety violations, license suspension/revocation, and negligent operator points were analyzed from 1 April 1991, to the incident date for cases and controls. Of 327 drivers who met the case definition, 237 (73%) had information on file in the California DMV driver records. Analysis was based on 237 cases and 474 controls. Drivers who hit a child pedestrian were more likely to have had a prior citation, more citations, more safety violations, a suspended or revoked license, or more negligent operator points than drivers who did not hit a child pedestrian in the study period. A positive association exists between the number of citations, safety violations, or negligent operator points and the likelihood that a driver hit a child pedestrian. Drivers with a history of driving infractions represent a high risk source of danger to child pedestrians. Possible routes of intervention include more rigorous sanctions against these drivers, more intensive education of the involved driver regarding pedestrians, higher insurance and monetary penalties, and a need to pursue more rigorously hit-and-run and unlicensed drivers, including modification of driver code violations for such cases.


Ultrastructure of palatal taste buds in the perihatching chick.
Palatal taste buds of perihatching chicks were examined by electron microscopy. Four intragemmal cell types were characterized. 1) Light: with voluminous, electron-lucent cytoplasm containing scattered free ribosomes, rough and smooth endoplasmic reticulum, plump mitochondria, sparse perinuclear filaments, occasional Golgi bodies, and numerous clear and dense-cored vesicles. Clear vesicles sometimes aggregate in a presynaptic-like configuration apposed to an axonal profile. These cells contained large, spherical, uniformly granular nuclei with one nucleolus. 2) Dark: with dense cytoplasm containing filamentous bundles surrounding the nucleus, occasional clear vesicles, centrioles, rough endoplasmic reticulum, and compact mitochrondria. The apical cytoplasm noticeably lacks dense secretory granules. Irregular to lobulated nuclei are densely granular, and contain scattered clumps of chromatin, adhering especially to the inner leaflet of the nuclear membrane, and at least one nucleolus. Cytoplasmic extensions of dark cells envelop other intragemmal cell types and nerve fibers. Light and dark cells project microvilli into the taste pore. 3) Intermediate: contain gradations of features of light and dark cells. 4) Basal: darker than the other intragemmal cell types and confined to the ventral bud region. Putative afferent synapses in relation to light cells, and axo-axonal contacts are described. While the appearance of axo-axonal contacts may be a transient developmental event, other bud features are consonant with observations in adult chickens and suggest that the peripheral gustatory apparatus is mature at hatching in this precocial avian species.


Evaluating institutional fit for the conservation of threatened species.
Recovery and conservation of threatened species require adequate institutional responses. We tested an approach to systematically identify and measure how an institutional framework acknowledges threats and required responses for the recovery of endangered species. We measured institutional functional fit with a drivers-pressure-state-impacts-response (DPSIR) model integrated with a quantitative text mining method and qualitative analysis of statutory instruments to examine regulatory responses that support the recovery of 2 endangered species native to Australia, the bridled nailtail wallaby (Onychogalea fraenata) and the Eastern Bristlebird (Dasyornis brachypterus). The key components of the DPSIR model were present in the institutional framework at statutory and operational levels, but some institutional gaps remained in the protection and recovery of the Eastern Bristlebird, including feral predator control, weed control, and grazing management in some locations. However, regulatory frameworks varied in their geographic scope and the application and implementation of many instruments remained optional. Quantitative text mining can be used to quickly navigate a large volume of regulatory documents, but challenges remain in selection of terms, queries of co-occurrence, and interpretation of word frequency counts. To inform policy, we recommend that quantitative assessments of institutional fit be complemented with qualitative analysis and interpreted in light of the sociopolitical and institutional context.


[Preventive behaviors for the sexual transmission of AIDS, other infections, and pregnancy in high-school students].
To describe preventive behaviors and behavioral intentions related to AIDS sexual transmission, other sexually transmitted diseases and unwanted pregnancies among 10th grade Barcelona students. Cross-sectional study. Stratified random sample from Barcelona secondary schools in 1996. Secondary schools. 981 students at 35 10th grade classrooms. 82% of the students are 15-16 years old. 58% are girls. 16% have had sexual intercourse (boys 18% and girls 14%); among those, 43% of males and 30% of females have had only once sexual intercourse. 78% use always or almost always a condom. 22% of boys and 44% of girls have refused at least an opportunity of unprotected intercourse. Boys feel more confident to buy, carry on and use a condom, however girls feel more confident in convincing their partner and refusing unprotected sex. Among those with sexual experience, partner opinion predicts condom use (boys OR = 30.8 and girls OR = 8.8), as well as partner use (boys OR = 14.2 and girls OR = 15.4). Intention to use condoms with a regular partner is related to the perception of youth normative behaviors (boys OR = 10.9 and girls OR = 4.4) and friends opinion (boys OR = 6.2 and girls OR = 5.4). Condom use with a non regular partner is related also to the perception that its use avoids infections and unwanted pregnancies (boys OR = 9.9 and girls OR = 8.0). Intention to refuse unprotected sex relates, in both genders, to youth normative behaviors and self-efficacy to refuse unprotected intercourse. 16% of the 10th grade students have had a sexual intercourse. Only half part of them use always condom, although it is the contraceptive method more frequently used. Condom use relates mainly to partners opinions and their current use. Intentions to use condoms are associated also to friends opinion and youth social norm perception. Intention to use a condom with non regular partners aims avoiding diseases and unwanted pregnancies.


Occupational and workplace factors associated with low back pain.
The authors discuss the dimensions of the problem of back pain in the context of associated occupational and workplace factors, including a review of epidemiologic studies that have been conducted.


Single-cell cloning of human T-cell lines reveals clonal variation in cell death responses to chemotherapeutics.
Genetic modification of human leukemic cell lines using CRISPR-Cas9 has become a staple of gene-function studies. Single-cell cloning of modified cells is frequently used to facilitate studies of gene function. Inherent in this approach is an assumption that the genetic drift, amplified in some cell lines by mutations in DNA replication and repair machinery, as well as non-genetic factors will not introduce significant levels of experimental cellular heterogeneity in clones derived from parental populations. In this study, we characterize the variation in cell death of fifty clonal cell lines generated from human Jurkat and MOLT-4 T-cells edited by CRISPR-Cas9. We demonstrate a wide distribution of sensitivity to chemotherapeutics between non-edited clonal human leukemia T-cell lines, and also following CRISPR-Cas9 editing at the NLRP1 locus, or following transfection with non-targeting sgRNA controls. The cell death sensitivity profile of clonal cell lines was consistent across experiments and failed to revert to the non-clonal parental phenotype. Whole genome sequencing of two clonal cell lines edited by CRISPR-Cas9 revealed unique and shared genetic variants, which had minimal read support in the non-clonal parental population and were not suspected CRISPR-Cas9 off-target effects. These variants included genes related to cell death and drug metabolism. The variation in cell death phenotype of clonal populations of human T-cell lines may be a consequence of T-cell line genetic instability, and to a lesser extent clonal heterogeneity in the parental population or CRISPR-Cas9 off-target effects not predicted by current models. This work highlights the importance of genetic variation between clonal T-cell lines in the design, conduct, and analysis of experiments to investigate gene function after single-cell cloning.


Pd-catalyzed intramolecular aminohydroxylation of alkenes with hydrogen peroxide as oxidant and water as nucleophile.
A palladium-catalyzed intramolecular aminohydroxylation of alkenes was developed, in which H2O2 was applied as the sole oxidant. A variety of related alkyl alcohols could be successfully obtained with good yields and excellent diastereoselectivities, which directly derived from oxidation cleavage of alkyl C-Pd bond by H2O2. Facile transformation of these products provided a powerful tool toward the synthesis of 2-amino-1,3-diols and 3-ol amino acids. Preliminary mechanistic studies revealed that major nucleophilic attack of water (S(N)2 type) at high-valent Pd center contributes to the final C-O(H) bond formation.


Antagonistic and plant growth promotion of rhizobacteria against Phytophthora colocasiae in taro.
Taro leaf blight caused by Phytophthora colocasiae adversely affects the growth and yield of taro. The management of this disease depends heavily on synthetic fungicides. These compounds, however, pose potential hazards to human health and the environment. The present study aimed to investigate an alternative approach for plant growth promotion and disease control by evaluating seven different bacterial strains (viz., Serratia plymuthica, S412; S. plymuthica, S414; S. plymuthica, AS13; S. proteamaculans, S4; S. rubidaea, EV23; S. rubidaea, AV10; Pseudomonas fluorescens, SLU-99) and their different combinations as consortia against P. colocasiae. Antagonistic tests were performed in in vitro plate assays and the effective strains were selected for detached leaf assays and greenhouse trials. Plant growth-promoting and disease prevention traits of selected bacterial strains were also investigated in vitro. Our results indicated that some of these strains used singly (AV10, AS13, S4, and S414) and in combinations (S4+S414, AS13+AV10) reduced the growth of P. colocasiae (30-50%) in vitro and showed disease reduction ability when used singly or in combinations as consortia in greenhouse trials (88.75-99.37%). The disease-suppressing ability of these strains may be related to the production of enzymes such as chitinase, protease, cellulase, and amylase. Furthermore, all strains tested possessed plant growth-promoting traits such as indole-3-acetic acid production, siderophore formation, and phosphate solubilization. Overall, the present study revealed that bacterial strains significantly suppressed P. colocasiae disease development using in vitro, detached leaf, and greenhouse assays. Therefore, these bacterial strains can be used as an alternative strategy to minimize the use of synthetic fungicides and fertilizers to control taro blight and improve sustainable taro production.


Web-accessible molecular modeling with Rosetta: The Rosetta Online Server that Includes Everyone (ROSIE).
The Rosetta molecular modeling software package provides a large number of experimentally validated tools for modeling and designing proteins, nucleic acids, and other biopolymers, with new protocols being added continually. While freely available to academic users, external usage is limited by the need for expertise in the Unix command line environment. To make Rosetta protocols available to a wider audience, we previously created a web server called Rosetta Online Server that Includes Everyone (ROSIE), which provides a common environment for hosting web-accessible Rosetta protocols. Here we describe a simplification of the ROSIE protocol specification format, one that permits easier implementation of Rosetta protocols. Whereas the previous format required creating multiple separate files in different locations, the new format allows specification of the protocol in a single file. This new, simplified protocol specification has more than doubled the number of Rosetta protocols available under ROSIE. These new applications include pKa determination, lipid accessibility calculation, ribonucleic acid redesign, protein-protein docking, protein-small molecule docking, symmetric docking, antibody docking, cyclic toxin docking, critical binding peptide determination, and mapping small molecule binding sites. ROSIE is freely available to academic users at http://rosie.rosettacommons.org.


Scid mouse model of psoriasis: a unique tool for drug development of autoreactive T-cell and th-17 cell-mediated autoimmune diseases.
In both skin and synovial tissues of psoriatic arthritis (PsA) patients, there are prominent lymphocytic infiltrates localized to the dermal papillae in the skin and the sublining layer stroma in the joint. T-cells, with a predominance of CD4+ lymphocytes, are the most significant lymphocytes in the tissues; in contrast, this ratio is reversed in the epidermis, synovial fluid compartment, and at the enthesis, where CD8+ T-cells are more common. This differential tropism of CD8+ T-cell suggests that the CD8+ T-cells may be driving the immune response in the joint and skin. This is supported by an association with MHC class I. The cytokine network in the psoriatic skin and synovium is dominated by monocyte and T-cell-derived cytokines: IL-1beta, IL-2, IL-10, IFN-gamma, and TNF-alpha. In PsA synovium, higher levels of IFN-gamma, IL-2, and IL-10 have been detected than in psoriatic skin. An analysis of T-cell receptor beta-chain variable (TCRbetaV) gene repertoires revealed common expansions in both skin and synovial inflammatory sites, suggesting an important role for cognate T-cell responses in the pathogenesis of PsA and that the inciting antigen may be identical or homologous between the afflicted skin and synovium. Traditionally, T-cells have been classified as T helper 1 (Th1) or Th2 cells by production of defining cytokines, IFN-gamma and IL-4, respectively. Recently, a new type of T-cell, Th17, has been linked to autoimmune inflammation. T-helper 17 (Th17) cells are a unique effector CD4+ T-cell subset characterized by the production of interleukin (IL)-17. Murine diseases that were previously considered to be pure Th1-mediated responses have been shown to contain mixed populations of Th1 and Th17 cells. Also, in humans, a critical immunoregulatory role of Th-17 cells in infectious and autoimmune diseases has been identified. It has been postulated that IL-17 may be important in psoriasis. Our initial observations demonstrate that IL-17 and its receptor system are important for PsA also. In in vivo and in vitro studies we have demonstrated that IL-17/IL-17R are enriched in skin, synovial tissue, and synovial fluid of psoriatic arthritis patients and Th17 cells are functionally significant in the pathogenesis of psoriasis and psoriatic arthritis. Here we will share our experience of the SCID mouse model of psoriasis in respect to its use in investigating psoriatic diseases and development of immune-based drugs for psoriasis, psoriatic arthritis, and other autoimmune diseases.


Advances in the understanding of dyskeratosis congenita.
Dyskeratosis congenita (DC) is a rare inherited syndrome exhibiting marked clinical and genetic heterogeneity. It is characterised by mucocutaneous abnormalities, bone marrow failure and a predisposition to cancer. Bone marrow failure is the principal cause of premature mortality. Studies over the last 10 years have demonstrated that DC is principally a disease of defective telomere maintenance. All DC patients have very short telomeres and the genetically characterised cases of DC have mutations in six genes which either encode components of the telomerase complex (DKC1, TERC, TERT, NOP10, NHP2) or shelterin (TINF2); these are important in the elongation and protection of the telomeric end, respectively. These advances have led to the recognition of cryptic forms of DC, such as presentations with aplastic anaemia and myelodysplasia. They have also increased our understanding of normal haematopoiesis and provided new insights to the aetiology of some cases of aplastic anaemia and related haematological disorders.


Fluorescent anticytokinins as a probe for binding. Isolation of cytokinin-binding proteins from the soluble fraction and identification of a cytokinin-binding site on ribosomes of tobacco callus cells.
4-Substituted 2-methylthiopyrido[2,3-d]pyrimidines, a series of recently developed anticytokinins, have been found to fluoresce strongly in water and to be useful as probes for binding studies. The binding activity of the soluble proteins and particulate fraction of tobacco callus cells to the biologically most active member of the family, 4-n-butylamino-2-methylthiopyrido[2,3-d]pyrimidine (BAMPP), was studied fluorimetrically. We found that the binding activity is better monitored in terms of saturable binding rather than in terms of the amount of bound ligand, a conventional method used in isolation studies of hormone receptor proteins. Using this technique we isolated two kinds of high-affinity cytokinin-binding proteins from the soluble fraction and identified a high-affinity binding site on ribosomes.


Redox Properties of CeIVDOTA in Carbonated Aqueous Solutions. A Radiolytic and an Electrochemical Study.
The redox chemistry of CeIIIDOTA in cage in carbonate solutions was studied using electrochemistry and radiolysis techniques (continuous radiolysis and pulse radiolysis). Spectroscopic measurements point out that the species present in the solutions at high bicarbonate concentrations are [CeIIIDOTA(CO3)]3- (or less plausible [CeIIIDOTA(HCO3)]2-) with the carbonate (bicarbonate) anion as the ninth ligand versus [CeIIIDOTA(H2O)]- present in the absence of bicarbonate. Electrochemical results show a relatively low increase in the thermodynamic stabilization of the redox couple CeIV/III in the presence of carbonate versus its aqueous analogue. [CeIVDOTA(CO3)]2- and [CeIVDOTA(H2O)], prepared electrochemically, decompose photolytically. However, kept in the dark, both are relatively long lived; [CeIVDOTA(H2O)], though, is orders of magnitude kinetically more stable (a considerably longer half-life). Thus, one concludes that the carbonate species have a different mechanism of decomposition depending also on the presence of dioxygen after its preparation (in deaerated/aerated solutions). The [CeIVDOTA(CO3)]2- species is produced radiolytically by oxidation of the trivalent species by CO3•- with a rate constant, measured using pulse radiolysis, of 3.3 × 105 M-1 s-1. This rate constant is at least 1 order of magnitude smaller than most of the rate constants so far reported for the reaction of CO3•- with transition metal/lanthanide (cerium)/actinide complexes. This result together with the bulkiness of the reactants might suggest an outer-sphere electron transfer rather than the inner-sphere one so far proposed. The lifetime of the tetravalent cerium species obtained radiolytically in the presence of carbonate is shorter than the electrochemical one, suggesting a different conformer involved.


Diffraction with wavefront curvature: a path to unique phase recovery.
Modern X-ray optics is able to produce very tightly focused beams. The size of these focused spots is comparable to the scale of large molecules and therefore to the lattice spacing of crystals of these molecules. In this case, the phase of the illuminating beam may vary on the scale of the lattice and conventional diffraction theory needs to be modified. In this paper, coherent diffraction by non-planar beams is considered and it is shown that it is possible to uniquely recover the phase of the diffraction pattern.


The effect of four-year hypolipidaemic treatment on the intimal thickness of the common carotid artery in patients with familiar hyperlipidaemia.
Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis. We assess the effects of lipid lowering therapy on the progression of early, preintrusive carotid arterial atherosclerosis in high risk patients with familial hyperlipidaemia free of symptomatic cardiovascular disease. Fifty-two patients with familial hyperlipidaemia by were treated by diet and various hypolipidaemic drugs. Eighteen individuals were not taking hypolipidaemic drugs. In a prospective study by B-mode ultrasound we assessed the intima-media thickness of the distal common carotid arterial (CCA) far wall at baseline and after 4 years. In a subgroup of 25 patients with familial hypercholesterolaemia there was a significant decrease in total and LDL cholesterol and reduction in the intima-media thickness (IMT) of the common carotid artery from 0.78+/-0.22 mm to 0.69+/-0.17 mm (p=0.004). In a subgroup of 27 patients with familial combined hyperlipidaemia significant decreases in total and LDL cholesterol and triglycerides were associated with a decrease in the IMT of common carotid. artery from 0.72+/-0.22 mm to 0.67+/-0.15 mm (p=0.044). In 18 individuals, who were not taking hypolipidaemic drugs, there were no significant changes in the levels of cholesterol and triglycerides and in the IMT of the common carotid artery (increase from 0.58+/-0.18 mm to 0.62+/-0.13 mm, p>0.05). Lipid-lowering therapy in patients with familial hyperlipidaemia free of symptomatic cardiovascular disease reverses the progression of early, preintrusive atherosclerosis of the carotid artery. It is a beneficial sign indicating the possibility for atherosclerosis regression.


Rapid Prediction of Bacterial Heterotrophic Fluxomics Using Machine Learning and Constraint Programming.
13C metabolic flux analysis (13C-MFA) has been widely used to measure in vivo enzyme reaction rates (i.e., metabolic flux) in microorganisms. Mining the relationship between environmental and genetic factors and metabolic fluxes hidden in existing fluxomic data will lead to predictive models that can significantly accelerate flux quantification. In this paper, we present a web-based platform MFlux (http://mflux.org) that predicts the bacterial central metabolism via machine learning, leveraging data from approximately 100 13C-MFA papers on heterotrophic bacterial metabolisms. Three machine learning methods, namely Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), and Decision Tree, were employed to study the sophisticated relationship between influential factors and metabolic fluxes. We performed a grid search of the best parameter set for each algorithm and verified their performance through 10-fold cross validations. SVM yields the highest accuracy among all three algorithms. Further, we employed quadratic programming to adjust flux profiles to satisfy stoichiometric constraints. Multiple case studies have shown that MFlux can reasonably predict fluxomes as a function of bacterial species, substrate types, growth rate, oxygen conditions, and cultivation methods. Due to the interest of studying model organism under particular carbon sources, bias of fluxome in the dataset may limit the applicability of machine learning models. This problem can be resolved after more papers on 13C-MFA are published for non-model species.


Responsiveness of the quality of life in late-stage dementia scale to psychotropic drug treatment in late-stage dementia.
We report on the responsiveness of a previously validated quality-of-life scale, the Quality of Life in Late-Stage Dementia scale (QUALID), as an outcome measure in a clinical trial of two psychotropic medications. Secondary analyses were conducted comparing outcome measures used in a randomized double-blind trial of two antipsychotics (olanzapine and risperidone) for the treatment of dementia-related behavioral symptoms. The QUALID was completed for 31 of the patients in addition to several measures of behavior-related dementia symptoms including the Neuropsychiatric Inventory, the Withdrawn Behavior subscale of the Multidimensional Observation Scale for Elderly Subjects, the Mini-Mental State Examination, and the Clinical Global Impression. Measures of safety and adverse effects included the Simpson-Angus Scale and records of specific adverse events. A significant positive relationship was found between QUALID score and improvement in behavioral symptoms, and a negative association was found with adverse medication effects. The QUALID was sensitive to both the treatment effects and the adverse effects of medication in this sample of patients.


Maternal age at child birth, birth order, and suicide at a young age: a sibling comparison.
Previous studies have reported strong associations between birth order, maternal age, and suicide, but these results might have been confounded by socioeconomic and other factors. To control for such factors, we compared suicide risk between siblings and studied how maternal age at child birth and birth order influenced risk in a cohort study of 1,690,306 Norwegians born in 1967-1996 who were followed up until 2008. Using stratified Cox regression, we compared suicide risk within families with 2 or more children in which one died from suicide. Altogether, 3,005 suicides occurred over a mean follow-up period of 15 years; 2,458 of these suicides occurred among 6,741 siblings within families of 2 or more siblings. Among siblings, a higher position in the birth order was positively associated with risk; each increase in birth order was associated with a 46% (adjusted hazard ratio = 1.46, 95% confidence interval: 1.29, 1.66) higher risk of suicide. For each 10-year increase in maternal age at child birth, the offspring's suicide risk was reduced by 57% (adjusted hazard ratio = 0.43, 95% confidence interval: 0.30, 0.62). Our study suggests that confounding due to familial factors is not likely to explain the associations of birth order and maternal age at child birth with suicide risk.


A systems model of exocytic vesicles in Arabidopsis pollen during its germination.
A basic systems model for vesicle trafficking in Arabidopsis pollen tubes was constructed. The model was composed of transcriptome data and differential equations. The transcriptome data revealed some genes controlling vesicle trafficking in the pollen tubes, and the differential equations connected the molecular functions of the gene products. The computed pollen tube growth reasonably agreed with biological samples. Here, I expand the computational prediction into exocytic vesicles during pollen germination, which can be used to examine the accuracy of the systems model with biological samples. The computational analysis of the model predicts that the number of exocytic vesicles changes in an over 10-fold range before the vesicle trafficking system reaches the equilibrium that makes the pollen tube grow logarithmically. SYP125 (syntaxin of plants 125) is highly localized in the pollen tube tip in both the biological sample and systems model. The computational analysis predicts that SYP125 would highly localize in exocytic vesicles temporally before the pollen tube grows logarithmically. These kinetic predictions guide future research directions.


A brief history of nurse anesthesia practice.
Anesthetics have been administered for centuries, from opium poppy and leaches, to today's sophisticated agents and techniques. In the United States, nurses have been delivering safe, professional, cost-effective care for well over 100 years. Nurse anesthetists have weathered the storms of war and politics to become a strong force in the current health care arena. The following is a brief overview of their interesting journey.


The ruthenium(ii)-catalyzed C-H olefination of indoles with alkynes: the facile construction of tetrasubstituted alkenes under aqueous conditions.
An environmentally-friendly and facile protocol for the construction of tetrasubstituted alkenes has been established with Ru(ii)-catalyzed C-H bond functionalizations under mild conditions. The method features the usage of readily available substrates, without external oxidants and additives, 100% atom economy, and excellent regioselectivity, thus enhancing the practicability of this protocol. Moreover, this transformation proceeded smoothly under aqueous conditions and could be extended to the gram scale. N-Methoxyamide, as a directing group (DG), played a vital role in the transformation.


Reaction dynamics at a metal surface; halogenation of Cu(110).
Scanning Tunnelling Microscopy (STM) is opening up a new field of reaction dynamics, followed one-molecule-at-a-time, only recently applied to reaction at a metal surface. Here we combine experiment with theory in studying the motions involved in the successive breaking by electron-induced reaction of the two carbon-halogen bonds, C-Cl or C-I, in physisorbed p-dihalobenzene, to form chemisorbed halogen-atoms and organic residue on Cu(110) at 4.6 K. We characterize the geometry of the physisorbed initial state, p-dichlorobenzene (pDCB) and p-diiodobenzene (pDIB), at the copper surface, as well as the successive final states of both chemisorbed reaction products: electron #1 giving rise to the first halogen-atom and a chemisorbed halophenyl and electron #2 giving a second halogen-atom and a chemisorbed phenylene. The major findings reported are (a) the distance and angular distributions of the chemisorbed reaction products relative to the physisorbed reagent molecule, (b) an approximate ab initio calculation, coupled with classical molecular dynamics (MD), of the repulsion between the products on the excited potential-energy surfaces, pes*, following excitation by electrons #1 or #2, and subsequently MD on the ground-state pes with inclusion of inelastic surface-interaction as a means to understanding the above, (c) observation of the changing dynamics with the chemistry of the halogen-atom, and (d) characterization of the effects of secondary encounters among the reaction products in the constrained space of the more highly localized reaction of pDIB. Item (d) shows clear evidence of high reactivity in surface-aligned collisions with restricted impact parameter, termed Surface Aligned Reaction, SAR, characterized by STM.


Adolescents' perceptions of interpersonal communication, respect, and concern for privacy in an urban tertiary-care pediatric emergency department.
To measure adolescents' perceived overall satisfaction with health care in a pediatric emergency department (PED), identify key factors that contributed to satisfaction, and determine how these factors interacted with length of stay (LOS) and triage acuity. Prospective observational design with a convenience sample of 100 adolescents 13 to 21 years old recruited from the PED between February and June 2007. Participants completed a self-administered 27-item written survey with closed and open-ended items. Survey response rate was 99%. Respondents completed the survey in a mean time of 6.6 minutes (range, 3-12 minutes; SD, 2.0 minutes). Most (95%) reported being satisfied with their overall PED experience, and 91% would recommend the PED to other adolescents. Interpersonal communication and respect correlated significantly with respondents' overall satisfaction. There were no statistically significant differences in overall satisfaction rates by sex, age, socioeconomic status, or ethnicity, or by LOS, triage acuity score, or hospital admission. Most (94%) answered a qualitative survey item that asked how their PED care could be improved with 4 distinct responses: no changes necessary, enhance interpersonal communication, improve comfort of stay, and shorten LOS. Adolescents expressed high levels of satisfaction with their overall PED experience at our institution. Interpersonal communication and respect highly correlated with overall satisfaction. A multicenter study using a similar self-administered survey would further support the relationship between key factors and PED adolescent satisfaction. Utilization of a self-administered survey for adolescent research is feasible in the PED and could be used to improve quality control measures for adolescent care.


Rab14 Overexpression Promotes Proliferation and Invasion Through YAP Signaling in Non-Small Cell Lung Cancers.
Several reports have shown that Rab14 is dysregulated in human cancers suggesting that it is an oncogenic protein closely related to tumorigenesis. However, whether Rab14 plays a role in the development and progression of human non-small cell lung cancer (NSCLC) remains unclear. Rab14 protein levels were examined in 115 cases of NSCLC tissues and 6 cancer cell lines. Rab14 knockdown was performed in H1299 and A549 cell lines. Rab14 plasmid transfection was performed in the LK2 cell line. The biological roles and mechanisms of Rab14 were examined using MTT, colony formation, Matrigel invasion assay, migration assay, cell cycle analysis, Western blotting, and RT-qPCR. We found that Rab14 was upregulated in 65 of 115 lung cancer tissues. Rab14 high expression was significantly correlated with advanced TNM stage and nodal metastasis. Rab14 protein levels were higher in lung cancer cell lines than in normal bronchial cell line. Functionally, Rab14 overexpression increased growth rate, colony formation, invasion/migration ability and cell cycle progression, while Rab14 siRNA decreased the cell proliferation rate, colony numbers and inhibited invasion/migration ability and cell cycle progression. Rab14 upregulated cyclin D1, cyclin E, connective tissue growth factor (CTGF) and downregulated p27 protein and mRNA levels in both A549 and H1299 cell lines, while Rab14 siRNA produced the opposite effects. Further study showed that Rab14 overexpression increased luciferase reporter activity from transcriptional enhanced associate domain (TEAD) protein. Accordingly, Rab14 increased total Yes-associated protein (YAP) and nuclear YAP protein while decreased phosphorylated (p)-YAP and cytoplasmic YAP protein expression. Cycloheximide treatment showed that Rab14 downregulated the level of YAP degradation. Depletion of YAP using siRNA abolished the influence of Rab14 on cyclin D1, cyclin E, and CTGF. YAP knockdown also partly abolished the effects of Rab14 on cell proliferation and invasion. In summary, our data showed that Rab14 is overexpressed in human NSCLC. Rab14 facilitated proliferation and invasion, possibly through regulation of YAP signaling.


Physical mechanisms and biological significance of supramolecular protein self-assembly.
In living cells, chemical reactions of metabolism, information processing, growth and development are organized in a complex network of interactions. At least in part, the organization of this network is accomplished as a result of physical assembly by supramolecular scaffolds. Indeed, most proteins function in cells within the context of multimeric or supramolecular assemblies. With the increasing availability of atomic structures and molecular thermodynamics, it is possible to recast the problem of non-covalent molecular self-assembly from a unified perspective of structural thermodynamics and kinetics. Here, we present a generalized theory of self-assembly based on Wegner's kinetic model and use it to delineate three physical mechanisms of self-assembly: as limited by association of assembly units (nucleation), by association of monomers (isodesmic), and by conformational reorganization of monomers that is coupled to assembly (conformational). Thus, we discuss actin, tubulin, clathrin, and the capsid of icosahedral cowpea chlorotic mottle virus with respect to assembly of architectural scaffolds that perform largely mechanical functions, and pyruvate dehydrogenase, and RING domain proteins PML, arenaviral Z, and BRCA1:BARD1 with regard to assembly of supramolecular enzymes with metabolic and chemically directive functions. In addition to the biological functions made possible by supramolecular self-assembly, such as mesoscale mechanics of architectural scaffolds and metabolic coupling of supramolecular enzymes, we show that the physical mechanisms of self-assembly and their structural bases are biologically significant as well, having regulatory roles in both formation and function of the assembled structures in health and disease.


Opioids, pain, the brain, and hyperkatifeia: a framework for the rational use of opioids for pain.
Opioids have relieved more human suffering than any other medication, but their use is still fraught with significant concerns of misuse, abuse, and addiction. This theoretical article explores the hypothesis that opioid misuse in the context of pain management produces a hypersensitivity to emotional distress, termed hyperkatifeia. In the misuse of opioids, neural substrates that mediate positive emotional states (brain reward systems) are compromised, and substrates mediating negative emotional states (brain stress systems) are enhanced. A reflection and early marker of such a nonhomeostatic state may be the development of opioid-induced hyperkatifeia, defined as the increased intensity of the constellation of negative emotional/motivational symptoms and signs observed during withdrawal from drugs of abuse (derived from the Greek "katifeia" for dejection or negative emotional state) and is most likely to occur in subjects in whom the opioid produces a break with homeostasis and less likely to occur when the opioid is restoring homeostasis, such as in effective pain treatment. When the opioid appropriately relieves pain, opponent processes are not engaged. However, if the opioid is administered in excess of need because of overdose, pharmacokinetic variables, or treating an individual without pain, then the body will react to that perturbation by engaging opponent processes in the domains of both pain (hyperalgesia) and negative emotional states (hyperkatifeia). Repeated engagement of opponent processes without time for the brain's emotional systems to reestablish homeostasis will further drive changes in emotional processes that may produce opioid abuse or addiction, particularly in individuals with genetic or environmental vulnerability.


Mpox and HIV-Collision of Two Diseases.
The global outbreak of mpox has brought renewed attention to a previously neglected disease which is particularly severe in people with underlying untreated HIV co-infection. For this population, the disease is progressive, severe, and often lethal. In this review, we examine the pathogenesis of mpox disease and its collision with co-existent HIV infection and discuss key considerations for management as well as emerging clinical dilemmas and areas for future research. Co-existent untreated HIV infection characterized by severe immunocompromise potentiates the nefarious effects of monkeypox virus infection leading to severe manifestations of mpox. Treating mpox in the context of HIV requires mpox-directed therapies, supportive care, and HIV-specific treatment to restore immune function. Preventative measures for PWH are like those in healthy individuals, but the effectiveness and durability of protection conferred by existing vaccines in PWH remain to be fully characterized. Mpox is an important opportunistic infection in PWH. Clinicians should be aware of the unique features of the disease in this population and approaches to care and management of mpox in PWH.


Modified use of a proximal humeral internal locking system (PHILOS) plate in extra-articular distal-third diaphyseal humeral fractures.
Surgical treatment of extra-articular distal-third diaphyseal humeral fractures is controversial in terms of surgical approach and position of implant. The aim of this study is to evaluate the clinical and radiological outcomes of a modified application of the proximal humeral internal locking system (PHILOS) plate in extra-articular distal-third diaphyseal humeral fractures. A total of 23 patients with extra-articular distal humerus fractures were treated using either open plating or the minimally invasive plate osteosynthesis (MIPO) technique with upside down application of the PHILOS plate. Fracture configuration, number of screws in the distal fragment, and time to union were analysed. Elbow range of motion, Mayo Elbow Performance Score (MEPS), and complications were evaluated at the final follow-up. Fracture union was obtained in all patients at a mean postoperative time of 20.8 ± 2.9 weeks. The mean shortest and longest cortical lengths were 50.7 ± 14.0 mm and 85.2 ± 12.4 mm, respectively. The average number of screws in the distal humeral fragment was 5.6 ± 0.7. No statistically significant correlation was observed between the shortest cortical length and number of screws in the distal fragment (p = 0.224) or between the longest cortical length and the number of screws in the distal humeral fragment (p = 0.956). The average MEPS was 97.6 (range, 75-100). No postoperative complications that required reoperation were occured. A modified anterior application of the PHILOS plate in extra-articular distal-third diaphyseal humeral fracture showed satisfactory outcomes, so it is an alternative when considering the ability to increase plate-screw density with locking screw fixation in a distal humeral fragment. Therapeutic level IV, case series.


Surgical treatment for colic in the foal (67 cases): 1980-1992.
Sixty-seven foals age < 150 days underwent a ventral celiotomy for colic. Of the 67 foals, 51 foals (82%) recovered from anaesthesia and 42 (63%) were subsequently released from the hospital. Three (6%) of the 51 foals were subjected to a repeat celiotomy. Long term follow-up was available on 36 foals. Twenty-nine (57%) of the 51 foals recovered from anaesthesia, were alive at least 2 years following surgery. Adhesions were identified in 8 (17%) of the foals which recovered from general anaesthesia but were subsequently subjected to euthanasia due to recurrent colic. Strangulating lesions were associated with a lower survival rate. Nineteen per cent of foals with strangulating intestinal lesions survived > 2 years following surgery, compared to 69% of foals with nonstrangulating lesions. The age of foals on admission had a significant effect on survival. Only 10% of foals less than 14 days of age survived, compared to 45.8% of foals between age 15 and 150 days.


"There Would Be More Black Spaces": Care/giving Cartographies during COVID-19.
Black geographies, Black feminist anthropology, and related fields have provided substantial evidence attesting to the effects of racially violent spatial practices such as dispossession, racial segregation, mass incarceration, and redlining for the health outcomes and life chances of Black communities and other racialized groups, and conversely, the political and healing potential of placemaking projects. We foreground theory from Black geographies and Black feminist work on care to examine care/giving cartographies at the height of the COVID-19 pandemic. We present findings from semi-structured interviews conducted virtually in 2021 that combined care/giving narratives and counter-mapping with 20 African American residents of Tucson, Arizona, as part of a longer-term community-based placemaking project. Interview data underscore the spatial and discursive pervasiveness of anti-Blackness, including within biomedical spaces of care, and negative effects on health. We argue that narratives centering care/giving alongside practices of counter-mapping are indictments of the institutional structures abetting anti-Black racism as a structuring, spatial logic. [anti-Black racism, COVID-19, caregiving, counter-mapping].