Predictors of the 10 year course of mental health and quality of life for trauma-affected refugees after psychological treatment.
Background: Trauma-affected refugee patients benefit from psychological treatment to different degrees. Only a handful of studies has investigated potential predictors of treatment outcome that could throw light on the great variability in outcomes reported for this group. Such knowledge may be vital to better tailor prevention and treatment efforts to the needs of different individuals and subgroups among these patients. Objective: In a naturalistic and longitudinal study, the aim was to analyse demographics and traumatic exposure as potential predictors of the participants' long-term trajectories of mental health symptoms and quality of life. Method: A group of 54 multi-origin adult refugee patients with complex traumatic exposure, such as armed conflicts, persecution, torture, and childhood adversities, were interviewed face to face over up to 10 years; at therapy admittance, and at varying points in time during and after psychotherapy. Checklists of war-related and childhood trauma, mental health symptoms, and quality of life were included in the interviews. In linear mixed effects analyses, interaction was analysed with potential predictors included separately because of the sample size. Time was modelled as continuous from inclusion into the study. Results: Gender predicted the course of symptoms of post-traumatic stress, anxiety, and depression, and of quality of life in physical health and social relationships. Childhood family violence and experiences of torture predicted the course of depression, whereas the extent of exposure to war-related trauma events and having experienced torture predicted the course of anxiety. Conclusions: The results indicated greater chronicity in male refugees, in refugees who had experienced domestic violence during childhood, in refugees who had experienced torture, and in refugees with more numerous types of potentially traumatic war-related experiences. The findings highlight the need for gender-sensitive research, rehabilitative efforts, and treatment. HIGHLIGHTS In a 10 year longitudinal and naturalistic therapy follow-up study of traumatized refugees, female gender, childhood trauma, war trauma, and torture predicted mental health and quality of life outcomes.Male participants responded less than females to therapy.


Lack of toxicological influences by microsampling (50 µL) from jugular vein of rats in a collaborative 28-day study.
Due to finalization of the ICH S3A Q&A focusing on microsampling, application of microsampling technique to regular non-clinical animal studies is expected for non-clinical safety assessment of pharmaceuticals. In Europe, microsampling from the tail vein or saphenous vein has often been used, whereas sampling from the jugular vein is thought to be more common for non-clinical studies in Japan. Therefore, we assessed the toxicological effects of serial microsampling from the jugular vein of SD rats in a common 28-day study at 4 independent organizations. Fifty microliter sampling was performed at 6 timepoints on day 1 to 2 and 7 timepoints on day 27 to 28 and its toxicological influences on body weight, food consumption, hematological and clinical chemistry parameters, and organ weights (on day 29 for 3 and day 28 for 1 organizations) were evaluated. The serial microsampling was shown to have no or minimal influences on the assessed parameters. The observed statistical differences for the 18 parameters were sporadic and did not appear to be systemically associated with microsampling. However, the sporadic changes were more often observed in females (14/18 parameters) than in males (6/18), suggesting the possibility that female rats were more susceptible to treatment-based influences. The current results indicate that serial 50 μL sampling from the jugular vein of SD rats had no or very slight toxicological effects, suggesting that this microsampling condition is applicable for toxicokinetic evaluation of non-clinical rat toxicity studies.


P53 Expression in benign Breast Disease Development: A Systematic Review.
Benign breast disease (BBD) is one of main breast cancer risk factors. Dysfunctions on p53 protein, which has a genome protective role, have been related to breast cancer developments. However, its role on BBD development is still unclear. A systematic review of literature was proceeded according to PRISMA-P guidelines. PubMed, BVS, MEDLINE and Scholar Google were used as databases, complemented by a manual search in articles references. Articles searches were conducted from May to July 2019 and publications in English, Spanish and Portuguese were selected. P53 expression was set as outcome among women with BBD and were included only articles with good quality according STROBE tools. Data concerning p53 expression frequencies were independently extracted by two review authors, and eligible articles were synthesized. From 12 studies selected for this review, the majority analyzed p53 expression in non-proliferative lesions and general p53 expressions ranged from 0 to 100%. P53 expression was more frequently observed in cases series studies (91.7%) and in studies conducted in Occidental Europe (41.7%). P53 expression was more frequent among tissues with fibrocystic disease (22.5%) and fibroadenoma (22.5%). When compared with all breast tissues types, benign breast disease corresponds to 34.39% of p53 expression. Second outcomes were not evaluated because the heterogeneity observed in selected studies. In addition, more studies considering ethnicity and benign breast disease classification should also be considered for further analysis.


Biomechanical Analysis of Tibial Tuberosity Medialization and Medial Patellofemoral Ligament Reconstruction.
Biomechanical studies are commonly performed to evaluate the influence of medial patellofemoral ligament (MPFL) reconstruction and tibial tuberosity medialization on patellar tracking and patellofemoral contact pressures. The most common method is in vitro simulation of knee function, but computational simulation of knee function and computational reconstruction of in vivo motion can also be utilized. The current review of the biomechanical literature indicates that MPFL reconstruction and tibial tuberosity medialization reduce lateral patellar tracking. Decreased lateral patellofemoral contact pressures have also been noted. For MPFL reconstruction, the most commonly noted biomechanical concerns are graft overtensioning and nonanatomic attachment on the femur leading to overconstraint of the patella and elevated medial contact pressures. For tuberosity medialization, the influence of altered tibiofemoral kinematics on postoperative function is unknown. Future biomechanical studies should emphasize inclusion of anatomic features and tracking patterns related to patellar instability, with comparison between the surgical approaches for continued development of treatment guidelines.


Socioeconomic and early-life factors and risk of being overweight or obese in children of Swedish- and foreign-born parents.
Ethnic minorities/immigrants have differential health as compared with natives. The epidemic in child overweight/obesity (OW/OB) in Sweden is leveling off, but lower socioeconomic groups and immigrants/ethnic minorities may not have benefited equally from this trend. We investigated whether nonethnic Swedish children are at increased risk for being OW/OB and whether these associations are mediated by parental socioeconomic position (SEP) and/or early-life factors such as birth weight, maternal smoking, BMI, and breastfeeding. Data on 10,628 singleton children (51% boys, mean age: 4.8 y, born during the period 2000-2004) residing in Uppsala were analyzed. OW/OB was computed using the International Obesity Task Force's sex- and age-specific cutoffs. The mother's nativity was used as proxy for ethnicity. Logistic regression was used to analyze ethnicity-OW/OB associations. Children of North African, Iranian, South American, and Turkish ethnicity had increased odds for being overweight/obese as compared with children of Swedish ethnicity (adjusted odds ratio (OR): 2.60 (95% confidence interval (CI): 1.57-4.27), 1.67 (1.03-2.72), 3.00 (1.86-4.80), and 2.90 (1.73-4.88), respectively). Finnish children had decreased odds for being overweight/obese (adjusted OR: 0.53 (0.32-0.90)). Ethnic differences in a child's risk for OW/OB exist in Sweden that cannot be explained by SEP or maternal or birth factors. As OW/OB often tracks into adulthood, more effective public health policies that intervene at an early age are needed.


Excessive Smartphone Use is Associated with Depression, Anxiety, Stress, and Sleep Quality of Australian Adults.
Problematic smartphone use has been associated with poorer mental health in different population groups; however, little is known about how levels of smartphone use were associated with mental health outcomes of adults in Australia. Using data from a cross-sectional survey among Australian adults aged 18-59 years (n = 655, Mean = 24.55 [SD = 5.59] years; 66% female), the current study aimed to examine association between problematic smartphone use and different psychological outcomes. Participants completed measures of problematic smartphone use with Mobile Phone Problem Use Scale (MPPUS), mental health outcomes with Depression, Anxiety, and Stress Scale (DASS-21), and Pittsburgh Sleep Quality Index (PSQI), in addition to some socio-demographics. Smartphone use was categorised into three groups: low-moderate, moderate-high, and high-severe. A total of 160 adults (24.4%) reported high-severe smartphone use. Multivariable linear regression analyses showed that smartphone use was inversely associated with psychological outcomes in a dose-dependent manner with high-severe smartphone uses having the most adverse effects. Compared to low-moderate use, average depression score was 3.5 points higher for moderate-high smartphone use (β = 3.51, 95% CI: 1.63-5.40) and 6.9 points higher for high-severe smartphone use (β = 6.91, 95% CI: 4.74-9.07). Similarly, average stress score was 3.4 points higher for moderate-high smartphone use (β = 3.40, 95% CI: 1.75-5.06) and 7.0 points higher for high-severe smartphone use (β = 7.02, 95% CI: 5.11-8.93). Similar association estimates were found for anxiety and sleep quality. Reducing smartphone use has the potential to optimise depression, anxiety, stress, and sleep quality; however, longitudinal research is warranted to establish directionality of the association.


Targeted therapy with low doses of 131I-MIBG is effective for disease palliation in highly refractory neuroblastoma.
Palliative treatment ore remains a significant clinical problem. To retrospectively determine the clinical response to 131I-MIBG therapy at low doses in patients with refractory neuroblastoma. We performed a retrospective chart review of 10 patients with neuroblastoma treated with 1311-MIBG at Rambam Health Care Campus from 1994 to 2012. Clinical data, number of 131I-MIBG courses delivered, toxicities, and clinical responses were reviewed. MIBG scan was performed after each course. Twenty-one courses of 131I-MIBG were delivered to 10 patients (3 girls, 7 boys). Their mean age was 3.8 years (range 1.5-6 years). All patients received several protocols of chemotherapy including the high dose form. Three patients received three courses of 131I-MIBG with a minimum of 6 weeks between each course, five patients received two courses, and two patients received only one course. An objective response to the first course was obtained in nine patients and to the second course in six of eight, and in three children who underwent the third course the pain decreased. One patient has no evidence of disease, four are alive with disease, and five died of the disease. No unanticipated toxicities were observed. Low dose 131I-MIBG is an effective and relatively non-toxic treatment in neuroblastoma disease palliation. Rapid and reproducible pain relief with 131I-MIBG was obtained in most of the children. Treatment with systemic radiotherapy in the form of low dose 131I-MIBG was easy to perform and effective in cases of disseminated neuroblastoma, demonstrating that this primary therapy can be used for palliative purposes.


Stability and resilience of the intestinal microbiota in children in daycare - a 12 month cohort study.
We performed a 12-month cohort study of the stability and resilience of the intestinal microbiota of healthy children in daycare in Denmark in relation to diarrheal events and exposure to known risk factors for gastrointestinal health such as travelling and antibiotic use. In addition, we analyzed how gut microbiota recover from such exposures. We monitored 32 children in daycare aged 1-6 years. Fecal samples were submitted every second month during a one-year observational period. Information regarding exposures and diarrheal episodes was obtained through questionnaires. Bacterial communities were identified using 16S rRNA gene sequencing. The core microbiota (mean abundance > 95%) dominated the intestinal microbiota, and none of the tested exposures (diarrheal events, travel, antibiotic use) were associated with decreases in the relative abundance of the core microbiota. Samples exhibited lower intra-individual variation than inter-individual variation. Half of all the variation between samples was explained by which child a sample originated from. Age explained 7.6-9.6% of the variation, while traveling, diarrheal events, and antibiotic use explained minor parts of the beta diversity. We found an age-dependent increase of alpha diversity in children aged 1-3 years, and while diarrheal events caused a decrease in alpha diversity, a recovery time of 40-45 days was observed. Among children having had a diarrheal event, we observed a 10x higher relative abundance of Prevotella. After travelling, a higher abundance of two Bacteroides species and 40% less Lachnospiraceae were seen. Antibiotic use did not correlate with changes in the abundance of any bacteria. We present data showing that Danish children in daycare have stable intestinal microbiota, resilient to the exposures investigated. An early age-dependent increase in the diversity was demonstrated. Diarrheal episodes decreased alpha diversity with an estimated recovery time of 40-45 days.


Clothing-Mediated Exposures to Chemicals and Particles.
A growing body of evidence identifies clothing as an important mediator of human exposure to chemicals and particles, which may have public health significance. This paper reviews and critically assesses the state of knowledge regarding how clothing, during wear, influences exposure to molecular chemicals, abiotic particles, and biotic particles, including microbes and allergens. The underlying processes that govern the acquisition, retention, and transmission of clothing-associated contaminants and the consequences of these for subsequent exposures are explored. Chemicals of concern have been identified in clothing, including byproducts of their manufacture and chemicals that adhere to clothing during use and care. Analogously, clothing acts as a reservoir for biotic and abiotic particles acquired from occupational and environmental sources. Evidence suggests that while clothing can be protective by acting as a physical or chemical barrier, clothing-mediated exposures can be substantial in certain circumstances and may have adverse health consequences. This complex process is influenced by the type and history of the clothing; the nature of the contaminant; and by wear, care, and storage practices. Future research efforts are warranted to better quantify, predict, and control clothing-related exposures.


Incidence of Subclinical Hypothyroidism and Hypothyroidism in Early Pregnancy.
Untreated and subclinical hypothyroidism (SCH) has been associated with adverse pregnancy complications such as increased risk of miscarriage, hypertension, preeclampsia, and preterm delivery. However, in Sweden, screening for thyroid dysfunction during pregnancy is only recommended for women with a high risk of thyroid disease. Therefore, the aim of this study was to determine the incidence of clinical and SCH in women in the first trimester of pregnancy. In this prospective study, 1298 pregnant women were divided into three groups: one unselected general screening group (n = 611), one low-risk group comprising women without risk factors for thyroid disorder (n = 511), and one high-risk group comprising women with an inheritance or suspicion of thyroid disease or undergoing treatment for thyroid disease (n = 88). Serum was obtained up to gestational week 13, and thyrotropin (TSH) was analyzed. The incidences of thyroid dysfunction in the three screening groups were 9.8% in the general screening group, 9.6% in the low-risk group, and 10.2%, p = 0.948, in the high-risk group. In the women with known hypothyroidism on levothyroxine treatment, 50.6% had serum TSH levels above 2.0 mIU/L. High-risk screening is not useful in predicting which women are at risk of thyroid disease in early pregnancy since ∼10% of women with SCH or hypothyroidism could not be diagnosed in this way.


Differential cytoprotection by glycine against oxidant damage to proximal tubule cells.
Tert-butyl hydroperoxide (tBHP) injured freshly isolated proximal tubules in an Fe-dependent fashion that was ameliorated by a lipophilic antioxidant, diphenyl-p-phenylenediamine (DPPD), but was only minimally affected by glycine. Menadione-induced injury was Fe-independent and was unaffected by DPPD, but was strongly blocked by glycine. Fe was highly toxic when intracellular loading was facilitated by concomitant treatment with hydroxyquinoline (HQ). This toxicity was blocked by DPPD or chelating the Fe, but not by glycine. All of the lesions were characterized by severe depletion of glutathione and other soluble thiols. Menadione induced large increases in protein associated with the Triton-insoluble cytoskeleton and decreases in protein thiol content, consistent with extensive cross linking, but did not increase thiobarbituric acid reactive substances (TBARS). tBHP and HQ + Fe had either no effect or only moderate, delayed effects on cytoskeletal proteins, but induced substantial increases of TBARS. Glycine did not the alter changes in cytoskeletal proteins, thiols, or TBARS produced by any of the agents. Protection against tBHP toxicity by deferoxamine and DPPD was accompanied by substantial suppression of TBARS accumulation. Superimposition of hypoxia during tBHP exposure reduced TBARS accumulation and restored cytoprotective activity to glycine. Thus, in contrast to its consistently strong cytoprotection against a number of other insults, glycine is only variably cytoprotective against oxidant lesions in freshly isolated proximal tubules. Extensive oxidative crosslinking of proteins is compatible with maintenance of glycine cytoprotection against lethal membrane damage. Fe-induced injury to proximal tubules associated with lipid peroxidation as manifested by TBARS formation is a relatively glycine-insensitive insult.


InAs/GaAsSb quantum dot solar cells.
The hybrid structure of GaAs/GaAsSb quantum well (QW)/InAs quantum dots solar cells (QDSCs) is analyzed using power-dependent and temperature-dependent photoluminescence. We demonstrate that placing the GaAsSb QW beneath the QDs forms type-II characteristics that initiate at 12% Sb composition. Current density-voltage measurements demonstrate a decrease in power efficiency with increasing Sb composition. This could be attributed to increased valence band potential in the GaAsSb QW that subsequently limits hole transportation in the QD region. To reduce the confinement energy barrier, a 2 nm GaAs wall is inserted between GaAsSb QW and InAs QDs, leading to a 23% improvement in power efficiency for QDSCs.


Auditory cortical responses in patients with Bell's palsy.
We recorded auditory evoked magnetic responses with a whole-scalp 122-channel SQUID neuromagnetometer in 14 patients with Bell's palsy (9 with left-sided and 5 with right-sided) and in 10 controls. The stimuli were 50-ms 1-kHz tone bursts, delivered first to the left and then to the right ear at interstimulus intervals (ISIs) of 1, 2 and 4 s. In patients, the N100m, the 100-ms response originating in the auditory cortices peaked, on average, 8 ms earlier and the response strengths were, on average, 7 nAm stronger over the contralateral than ipsilateral hemisphere. The response latencies and strengths did not differ significantly from those of controls and there were no significant differences in response latencies and strengths between the stimulation of the affected and healthy side. On average, the response latencies and strengths increased as a function of ISI over both hemispheres both in patients and in controls. These findings suggest that Bell's palsy is an isolated peripheral neuropathy that does not affect the function of the auditory pathways.


Motor skills in children aged 7-10 years, diagnosed with autism spectrum disorder.
This study used the Movement Assessment Battery for Children (M-ABC2) to assess motor skills in children aged 7-10 years with autism (n = 18) in comparison to two groups of age-matched typically developing children; a receptive vocabulary matched group (n = 19) and a nonverbal IQ matched group (n = 22). The results supported previous work, as indicated by a significant general motor impairment in the group with autism. However, sub-analysis of the M-ABC2 revealed that there were only 2 out of 8 subcomponent skills which showed universal significant specific deficits for the autism group; i.e. catching a ball and static balance. These results suggest that motor skill deficits associated with autism may not be pervasive but more apparent in activities demanding complex, interceptive actions or core balance ability.


A cooperative-binding split aptamer assay for rapid, specific and ultra-sensitive fluorescence detection of cocaine in saliva.
Sensors employing split aptamers that reassemble in the presence of a target can achieve excellent specificity, but the accompanying reduction of target affinity mitigates any overall gains in sensitivity. We for the first time have developed a split aptamer that achieves enhanced target-binding affinity through cooperative binding. We have generated a split cocaine-binding aptamer that incorporates two binding domains, such that target binding at one domain greatly increases the affinity of the second domain. We experimentally demonstrate that the resulting cooperative-binding split aptamer (CBSA) exhibits higher target binding affinity and is far more responsive in terms of target-induced aptamer assembly compared to the single-domain parent split aptamer (PSA) from which it was derived. We further confirm that the target-binding affinity of our CBSA can be affected by the cooperativity of its binding domains and the intrinsic affinity of its PSA. To the best of our knowledge, CBSA-5335 has the highest cocaine affinity of any split aptamer described to date. The CBSA-based assay also demonstrates excellent performance in target detection in complex samples. Using this CBSA, we achieved specific, ultra-sensitive, one-step fluorescence detection of cocaine within fifteen minutes at concentrations as low as 50 nM in 10% saliva without signal amplification. This limit of detection meets the standards recommended by the European Union's Driving under the Influence of Drugs, Alcohol and Medicines program. Our assay also demonstrates excellent reproducibility of results, confirming that this CBSA-platform represents a robust and sensitive means for cocaine detection in actual clinical samples.


Occlusal features of Chinese adults in Hong Kong.
The molar relations, overjet and overbite of 201 Hong Kong Chinese adults of mean age 20 years were studied. It was found that 63.7 per cent had Angle Class I, 16.4 per cent had Class II and 19.9 per cent had Class III molar relations. Of the sample studied, 69.7 per cent had normal overjets of two to four mm, 14.9 per cent had increased overjets and 15.4 per cent had reduced or reversed overjets. The most prevalent overbite was zero to one-third of the mandibular central incisor crown length (63.2 per cent of the sample); 31.3 per cent had overbites of one to two thirds of mandibular central incisor crown length; four per cent had overbites of more than two thirds of mandibular incisor crown length; and 1.5 per cent only had open bites.


A comparison of the value of hyoscine butylbromide and glucagon on aorto iliac intravenous digital subtraction.
The diagnostic quality of intravenous subtraction aorto-iliac arteriograms was assessed in 60 patients randomly allocated to receive either hyoscine butylbromide or glucagon as an inhibitor of bowel peristalsis. The examinations in patients receiving hyoscine butylbromide showed statistically significantly less artefact due to bowel movement than those receiving glucagon. Furthermore, glucagon is 20 times more expensive than hyoscine butylbromide. Neither drug produced significant ECG changes or side effects. We conclude that intravenous hyoscine butylbromide should be used routinely, except where specifically contra-indicated, in all patients undergoing IV-DSA of the aorto-iliac segments.


Intracytoplasmic sperm injection and advanced maternal age: Success or treatment failure?
Infertility rate documented in Pakistan is 21.9% with only 25% success rate even after procedures like intracytoplasmic sperm injection (ICSI). This rate is further on the decline with enhancement of female age. We aimed to observe the effect of female age on oocyte parameters and reproductive outcome after ICSI. It was done by retrospective analysis of a quasi- experimental design carried out after approval from "Ethical review board of Islamabad clinic serving infertile couples" from July 2010 to August 2011. The response to ovarian stimulation in (282) females was assessed on the basis of groups, A, B, C and D with age ranges up to 25years; 25.1 to 30years; 30.1 to 35years and >35years, respectively. The outcome was assessed as non-pregnant, preclinical abortion and clinical pregnancy groups on the basis of beta hCG and cardiac activity by trans-vaginal scan. We observed that maximum number of pregnancies 32 (38%) occurred in C group, and least 10 (10%) in group A. There was a statistical reduction in the number of mature and fertilized oocytes as the age advanced from group C to D (p<0.05).This shows that reduction in maturity and fertilization of oocytes with advancement of age recommends early referral of couples to assisted reproductive clinics.


Transcriptional regulation of SUP35 and SUP45 in Saccharomyces cerevisiae.
SUP35 and SUP45 encode translational release factors in the yeast Saccharomyces cerevisiae. In addition, Sup35p is related to the cytoplasmically inherited prion-like phenotype [PSI+]. The vital cellular role of Sup35p and Sup45p prompted us to study the regulation of transcription of the corresponding genes. Since the [PSI] state of the yeast strain affects the abundance of Sup35p and Sup45p, both [PSI+] and [psi-] variants were included in these analyses. It turned out that SUP35 and SUP45 transcript levels are regulated by nutritional changes and stress in a way strikingly similar to those of ribosomal protein genes. The [PSI] state did not influence the respective transcript levels nor their regulation, although HSP12 (as a monitor of general stress-responsive) gene expression appeared to differ in the two variant strains. The transcription activation sites of SUP35 and SUP45 were mapped using deletion analysis of the respective promoter-reporter fusion genes. The UAS in both cases was found to consist of an Abf1p-site and a T-rich element. Also in this respect SUP35 and SUP45 show a notable resemblance with ribosomal protein genes. Evidence was found that SUP35 in addition harbors a potential internal promoter element which became active after progressive 5'-deletion removing the first of the three in-frame ATGs.


Patterns of Response and Progression to Immunotherapy.
Patterns of response and progression to immunotherapy may differ from those observed with drugs such as chemotherapy and molecularly targeted agents. Specifically, some patients experience a response after progression that is retrospectively named pseudoprogression. This phenomenon of pseudoprogression, first reported in patients with melanoma who were treated with ipilimumab, has led to the development of immune-specific related response criteria, such as irRC (immune-related response criteria), irRECIST (immune-related RECIST), and iRECIST (immunotherapy RECIST) that allow continued treatment beyond progression. However, the rate of pseudoprogression has never exceeded 10% of patients across tumor types. Conversely, rapid progressions after immunotherapy, called hyperprogressions, were reported by three different teams in 9% to 29% of patients treated with immunotherapy. Because of the absence of control arms in these studies, it remains to be determined whether these rapid progressions reflect a detrimental effect of immunotherapy in these patients. Finally, preliminary data suggest that immunotherapy might also affect response to subsequent standard therapies. In total, given the rarity of pseudoprogressions across tumor types and the recent description of hyperprogressions, classic RECIST remains a reasonable and rational method to assess response to immunotherapy. Continuation of treatment beyond progression should be proposed only in carefully selected patients whose clinical conditions have improved and who have not experienced severe toxicities. Although there is an urgent need to identify predictive biomarkers of efficacy to immunotherapy, there is an equally urgent need to identify predictive factors of progression or possibly hyperprogression.


Heart transplantation in an infant with Williams-Beuren syndrome and rapidly progressive ischemic cardiomyopathy.
Ischemic cardiomyopathy with resultant refractory HF may occur in patients with WBS, often as the result of coronary involvement with SVAS. The rapid development of arteriopathy at a young age raises concerns regarding transplant candidacy due to progressive stenoses at other arterial sites with potential detrimental impact on long-term heart graft function. We report a 2-month-old male infant diagnosed with mild aortic stenosis during the neonatal period, but subsequently developed rapidly progressive supravalvar and coronary artery stenoses leading to cardiogenic shock due to myocardial ischemia. The presentation led to the diagnosis of WBS. He required prolonged CPR including ECMO therapy. He subsequently underwent LVAD implantation as bridge to transplant and 4 days later heart transplantation. His post-operative course was complicated by prolonged mechanical ventilation and extended intensive care unit and hospital stays. However, at follow-up 18 months post-transplant he continues to have normal graft function with mild, non-progressive residual coarctation of aorta and non-progressive moderately hypoplastic pulmonary arteries.


[The use of tranexamic acid during large joint endoprosthetic surgeries].
The aim of the study is to measure the effectiveness and safety of tranexam acid during hip and knee joint endoprothesis surgeries. Tranexam (Mir-Pharm, Russia) was administered to 45 patients 30 minutes before the surgery in the dose of 10-15 mg/kg and 6 hours after first infusion in the same dose. In the control group (n = 45) Tranexam was not administered. The intraoperative, drain and general blood loss, need of donor blood and dynamics of hematological parameters were assessed. The total number of complications and potential transfusion complications was measured. The use of Tranexam acid allowed lowering the blood loss on all the stages of investigation for more than 50%. The general blood loss in the main group was 693.3 +/- 252.2 ml compared to 1259 +/- 454.6 ml in the control group. A need for donor erythrocytes occurred in 2 cases of the main group, who received the total of 3 doses of allogenic blood. In the control group 26 patients received 57 doses of donor blood. There was no need in donor plasma in the main group. The hemoglobin and hematocrit values were higher in the main group compared to the control group. In both cases there were no tromboembolic or transfusional complications. The potential risk of transfusional complications was lower in the main group. Tranexam acid is an effective and safe blood loss prophylaxis measure during the large joint prosthetic surgeries.


An improved acoustical wave propagator method and its application to a duct structure.
The pseudospectral time-domain method has long been used to describe the acoustical wave propagation. However, due to the limitation and difficulties of the fast Fourier transform (FFT) in dealing with nonperiodic problems, the dispersion error is inevitable and the numerical accuracy greatly decreases after the waves arrive at the boundary. To resolve this problem, the Lagrange-Chebyshev interpolation polynomials were used to replace the previous FFT, which, however, brings in an additional restriction on the time step. In this paper, a mapped Chebyshev method is introduced, providing the dual benefit of preserving the spectral accuracy and overcoming the time step restriction at the same time. Three main issues are addressed to assess the proposed technique: (a) Spatial derivatives in the system operator and the boundary treatment; (b) parameter selections; and (c) the maximum time step in the temporal operator. Furthermore, a numerical example involving the time-domain evolution of wave propagation in a duct structure is carried out, with comparisons to those obtained by Euler method, the fourth-order Runge-Kutta method, and the exact analytical solution, to demonstrate the numerical performance of the proposed technique.


The use of a bone block graft from the chin for alveolar ridge augmentation.
Periodontal disease and tooth loss often leave the patient with an alveolar ridge that is less than adequate for endosseous implant placement. Alveolar bone grafting offers a clinically successful treatment option to regain all or some of this lost bone. This article describes the use of a bone block from the chin for the augmentation of the alveolar ridge. It relates the clinical techniques to the healing process in an effort to better understand the events involved.


The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery.
The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer. Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response.Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol. The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051).


Acetoacetylation of insulin.
Insulin was treated with diketen at pH6.9. The reaction mixture was resolved into four components by DEAE-Sephadex chromatography. The first component was unchanged insulin. The second and third components were shown by end-group analysis to be substituted on phenylalanine B-1 and glycine A-1 respectively. The fourth component was disubstituted on both phenylalanine B-1 and glycine A-1. The in-amino group of lysine B-29 was not involved in the reaction at low reagent concentrations. The purity of these derivatives was checked by their electrophoretic behaviour and by measurement of the rate of their reaction with trinitrobenzenesulphonic acid. The hormonal activity of the derivatives was determined. The effect of the modifications on the hormonal activity and the tertiary structure of insulin is discussed.


Hearing loss in workers exposed to toluene and noise.
In this study we investigated the risk of hearing loss among workers exposed to both toluene and noise. We recruited 58 workers at an adhesive materials manufacturing plant who were exposured to both toluene and noise [78.6-87.1 A-weighted decibels; dB(A)], 58 workers exposed to noise only [83.5-90.1 dB(A)], and 58 administrative clerks [67.9-72.6 dB(A)] at the same company. We interviewed participants to obtain sociodemographic and employment information and performed physical examinations, including pure-tone audiometry tests between 0.5 and 6 kHz. A contracted laboratory certified by the Council of Labor in Taiwan conducted on-site toluene and noise exposure measurements. The prevalence of hearing loss of >or=25 dB in the toluene plus noise group (86.2%) was much greater than that in the noise-only group (44.8%) and the administrative clerks (5.0%) (p<0.001). The prevalence rates were 67.2, 32.8, and 8.3% (p<0.001), respectively, when 0.5 kHz was excluded from the estimation. Multivariate logistic regression analysis showed that the toluene plus noise group had an estimated risk for hearing loss>or=25 dB, 10.9 times higher than that of the noise-only group. The risk ratio dropped to 5.8 when 0.5 kHz was excluded from the risk estimation. Hearing impairment was greater for the pure-tone frequency of 1 kHz than for that of 2 kHz. However, the mean hearing threshold was the poorest for 6 kHz, and the least effect was observed for 2 kHz. Our results suggest that toluene exacerbates hearing loss in a noisy environment, with the main impact on the lower frequencies.


Interdependent Oxidation of Eicosapentaenoic Acid and Docosahexaenoic Acid in Isada Krill Oil Encapsulated with Maltodextrin by Spray-drying.
The major polyunsaturated fatty acids in krill oil extracted from Euphausia pacifica, known as Isada on the Sanriku coast, are eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) acid. A kinetic model was proposed to explain the relationship between the fractions of unoxidized EPA (Y E) and unoxidized DHA (Y D) in the oil spray-dried with maltodextrin and stored at 25, 50, and 70℃. The relationship between Y E and Y D during storage was independent of the temperature and could be expressed using the proposed model. This indicated that the oxidation of EPA and DHA in krill oil was interdependent.


Helicobacter cinaedi bacteremia with cellulitis after ABO-incompatible living-donor liver transplantation: Case report.
Helicobacter cinaedi (H. cinaedi), a Gram-negative spiral-shaped bacterium, is an enterohepatic non-Helicobacter pylori Helicobacter species. We report the first case of H. cinaedi bacteremia with cellulitis after liver transplantation. A 48-year-old male, who had been a dog breeder for 15 years, underwent ABO-incompatible living-donor liver transplantation for hepatitis C virus-induced decompensated cirrhosis using an anti-hepatitis B core antibody-positive graft. The patient was preoperatively administered rituximab and underwent plasma exchange twice to overcome blood type incompatibility. After discharge, he had been doing well with immunosuppression therapy comprising cyclosporine, mycophenolate mofetil, and steroid according to the ABO-incompatible protocol of our institution. However, 7 mo after transplantation, he was admitted to our hospital with a diagnosis of recurrent cellulitis on the left lower extremity, and H. cinaedi was detected by both blood culture and polymerase chain reaction analysis. Antibiotics improved his symptoms, and he was discharged at day 30 after admission. Clinicians should be more aware of H. cinaedi in immunocompromised patients, such as ABO-incompatible transplant recipients.


Which TKI? An embarrassment of riches for chronic myeloid leukemia patients.
With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia, clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid leukemia patients. All of these considerations need to be made in the context of the patient's comorbidities, which may lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of achieving optimal response.


Job lock among survivors of childhood cancer and their spouses post Affordable Care Act implementation: A Childhood Cancer Survivor Study brief report.
It is unknown how common job lock (i.e., staying at job to maintain health insurance) remains among childhood cancer survivors after Affordable Care Act (ACA) implementation in 2010. We examined prevalence of and factors associated with job lock using a cross-sectional survey from the Childhood Cancer Survivor Study (3503 survivors; 942 siblings). Survivor, spousal, and any survivor/spouse job lock were more frequently reported by survivors than siblings. Survivor job lock/any job lock was associated with older age, low income, severe chronic conditions, and debt/inability to pay debt. Job lock remains more common among survivors than siblings after ACA implementation.


Neuronal mitochondrial morphology and transmembrane potential are severely altered by hypothyroidism during rat brain development.
We recently demonstrated that thyroid hormone is an important regulator of mitochondrial gene expression during brain development. To gain further insights into the consequences of this regulation, we have performed functional and structural analysis of brain mitochondria from control and hypothyroid neonatal rats. Flow cytometric analysis showed a significant decrease in the mitochondrial transmembrane potential in hypothyroid animals compared with controls, which was reversed after 48 h, but not after 2 h, of thyroid hormone administration, suggesting that the functional alterations observed are the consequence of changes in mitochondrial gene expression. In addition, band shift studies showed a protein bound to the rat mitochondrial promoter differentially regulated by thyroid state. Electron microscopic analysis of cerebral cortex, striatum, and hippocampus revealed marked differences in the morphology of neuronal mitochondria from control and hypothyroid neonates. Hypothyroid mitochondria presented a decrease in the area of the inner membrane plus cristae in all areas studied, except for the hippocampal CA1 neurons and nonneuronal cell types. The observations reported here provide a basis for the known biochemical action of thyroid hormone on brain development.


Turning points for environmental sustainability: the potential role of income inequality, human capital, and globalization.
Recently, the potential role of social indicators in environmental degradation gets immense attention. Environmental degradation and income inequality are two of the hot topics of debate that anticipate urgent solution. However, income inequality-CO2 emissions nexus has been little investigated in the literature. This study explores the relationship between income inequality and carbon dioxide emission by incorporating globalization and human capital as the determinants of this relationship. The study deploys an innovative technique of dynamic auto-regressive distributive lag simulation to evaluate data covering the period 1980-2015. Findings indicate that unequal distribution of wealth negatively affects carbon emissions. Likewise, the results show that globalization and human capital contribute to environmental degradation. The inclusion of transmission variables validates findings of the study. Policy strategies toward better income distribution and positive externalities of globalization are suggested for sustainability transitions.


Role of deep cloud convection in the ozone budget of the troposphere.
Convective updrafts in thunderstorms prolong the lifetime of ozone (O(3)) and its anthropogenic precursor NOx [nitric oxide (NO) + nitrogen dioxide (NO(2))] by carrying these gases rapidly upward from the boundary layer into a regime where the O(3) production efficiency is higher, chemical destruction is slower, and surface deposition is absent. On the other hand, the upper troposphere is relatively rich in O(3) and NOx from natural sources such as downward transport from the stratosphere and lightning; convective overturning conveys the O(3) and NOx toward the Earth's surface where these components are more efficiently removed from the atmosphere. Simulations with a three-dimensional global model suggest that the net result of these counteractive processes is a 20 percent overall reduction in total tropospheric O(3). However, the net atmospheric oxidation efficiency is enhanced by 10 to 20 percent.


Application and sensitivity testing of a eutrophication assessment method on coastal systems in the United States and European Union.
The Assessment of Estuarine Trophic Status (ASSETS) screening model has been extended to allow its application to both estuarine and coastal systems. The model, which combines elements of pressure, state and response, was tested on four systems: Maryland Coastal Bays and Long Island Sound in the United States and The Firth of Clyde (Scotland) and Tagus Estuary (Portugal) in the European Union. The overall scores were: Maryland Coastal Bays: Bad; Firth of Clyde: Poor; Tagus Estuary: Good. Long Island Sound was modelled along a timeline, using 1991 data (score: Bad) and 2002 data (score: Moderate). The improvement registered for Long Island Sound is a consequence of the reduction in nutrient loading, and the ASSETS score changed accordingly. The two main areas where developments are needed are (a) In the definition of type-specific ranges for eutrophication parameters, due to the recognition that natural or pristine conditions may vary widely, and the use of a uniform set of thresholds artificially penalizes some systems and potentially leads to misclassification; (b) In the definition and quantification of measures which will result in an improved state through a change in pressures, as well as in the definition of appropriate metrics through which response may be assessed. One possibility is the use of detailed research models where different response scenarios potentially produce changes in pressure and state. These outputs may be used to drive screening models and analyze the suitability of candidate metrics for evaluating management options.


The Experience of Working With a Faith Community Nurse Liaison of Care in a Primary Care Practice Among Older Adult Clients and Their Informal Caregiver.
Informal caregivers of older adults aging in place are at risk for adverse health and financial consequences. This descriptive qualitative study explored the experience of working with a faith community nurse (FCN) liaison of care in a Catholic health care system affiliated primary care practice among older adult clients and their informal caregiver. Semistructured face-to-face interviews were conducted with nine older adult client-informal caregiver dyads, three clients, and one caregiver (n = 22). Interviews were audio recorded, transcribed, and analyzed using Braun and Clarke's reflexive thematic analysis method. The analysis generated one overarching theme, I'm Sorry the Study and FCN Visits Are Coming to an End, and two key themes, The FCN Was Always There to Help Us (older adult clients) and The FCN Took the Pressure Off of Caregiving for Awhile (informal caregivers). Participants viewed the FCN as an instrumental member of their health care team and considered prayer and spiritual support offered by the FCN an essential element of care.


Time-dependent degenerative transformations in the lipidome of chalazia.
The aim of this prospective study was to conduct histopathologic and lipidomic analyses of chalazia, in order to evaluate time-dependent changes in the lesion. Samples of surgically excised chalazia were collected over a period of 12 months from 10 patients (mean age 41 years; range, 23-58) with clinically diagnosed chalazia, who underwent scheduled surgery. The ages of chalazia varied from 2 to 28 weeks. To confirm the clinical diagnoses, the morphology of collected tissue samples was evaluated histologically after hematoxylin and eosin staining. The lipids from individual chalazia were analyzed by high-performance liquid chromatography-mass spectrometry and compared with authentic lipid standards and with the lipids of meibum collected from normal controls. We observed gradual, lesion age-dependent transformation of the lipidome of chalazia from an almost normal meibum-like composition to a very different kind of lipidome. A rapid initial increase in the free cholesterol content was followed by a gradual replacement of extremely long chain meibomian-type lipids with a mixture of shorter-chain cholesteryl esters of the C14-C18 family, triacylglycerols, ceramides, phospholipids and sphingomyelins. In addition, a rapid disappearance of wax esters and cholesteryl esters of (1-O)-acyl-omega-hydroxy fatty acids from the lipidome of aging chalazia was observed. Our results are indicative of dramatic, time-dependent changes in the lesion that may involve cholesterol as a trigger and/or a marker of subsequent degeneration of the meibomian lipidome. We hypothesize that early inhibition of these transformations may be useful in reversing the course of the disease.


Regulation of gene activity by dosage compensation at the chromosomal level in drosophila.
Two models of dosage compensation have been tested by the measurement of G6PD and 6PGD enzymatic specific activities in flies hyperploid for regions of the X chromosome. Females duplicated for the proximal half of the X chromosomes (2 1/2 X's) have an increased level of G6PD and a normal level of 6PGD. Females duplicated for the distal half of the X chromosome (2 1/2 X's) have a normal level of G6PD and an increased level of 6PGD. Males bearing duplications of various segments of the X chromosome show control levels of G6PD and 6PGD, except where the duplicated region includes the structural gene for G6PD or 6PGD. These results fail to provide evidence for either the presence of discrete X-linked compensator (regulator) genes reducing the activity of other X-linked genes, or for a factor in limiting supply necessary for the transcription of all the genes on the X chromosome. Superfemales (3 X chromosomes) have the same G6PD and 6PGD activity levels as their diploid sisters. It would appear that the regulation of gene activity by dosage compensation is a chromosomal phenomenon in that the level of activity per gene copy for loci on the X chromosome is modulated in a stepwise fashion according to the total number of X chromosomes present.


Artificial intelligence for dementia research methods optimization.
Artificial intelligence (AI) and machine learning (ML) approaches are increasingly being used in dementia research. However, several methodological challenges exist that may limit the insights we can obtain from high-dimensional data and our ability to translate these findings into improved patient outcomes. To improve reproducibility and replicability, researchers should make their well-documented code and modeling pipelines openly available. Data should also be shared where appropriate. To enhance the acceptability of models and AI-enabled systems to users, researchers should prioritize interpretable methods that provide insights into how decisions are generated. Models should be developed using multiple, diverse datasets to improve robustness, generalizability, and reduce potentially harmful bias. To improve clarity and reproducibility, researchers should adhere to reporting guidelines that are co-produced with multiple stakeholders. If these methodological challenges are overcome, AI and ML hold enormous promise for changing the landscape of dementia research and care. HIGHLIGHTS: Machine learning (ML) can improve diagnosis, prevention, and management of dementia. Inadequate reporting of ML procedures affects reproduction/replication of results. ML models built on unrepresentative datasets do not generalize to new datasets. Obligatory metrics for certain model structures and use cases have not been defined. Interpretability and trust in ML predictions are barriers to clinical translation.


[Case report of a double ano-rectal neoplasia (adenocarcinoma and melanoma)].
The association in a single organ of two neoplasms with different, histogenensis is uncommon. A dual ano-rectal neoplasms, pigmented malignant melanoma in collision with adenocarcinoma is reported, along with a discussion concerning the problems related with primary origin of the melanocytic component.


The chemical uncoupler 2,4-dinitrophenol (DNP) protects against diet-induced obesity and improves energy homeostasis in mice at thermoneutrality.
The chemical uncoupler 2,4-dinitrophenol (DNP) was an effective and widely used weight loss drug in the early 1930s. However, the physiology of DNP has not been studied in detail because toxicity, including hyperthermia and death, reduced interest in the clinical use of chemical uncouplers. To investigate DNP action, mice fed a high fat diet and housed at 30 °C (to minimize facultative thermogenesis) were treated with 800 mg/liter DNP in drinking water. DNP treatment increased energy expenditure by ∼ 17%, but did not change food intake. DNP-treated mice weighed 26% less than controls after 2 months of treatment due to decreased fat mass, without a change in lean mass. DNP improved glucose tolerance and reduced hepatic steatosis without observed toxicity. DNP treatment also reduced circulating T3 and T4 levels, Ucp1 expression, and brown adipose tissue activity, demonstrating that DNP-mediated heat generation substituted for brown adipose tissue thermogenesis. At 22 °C, a typical vivarium temperature that is below thermoneutrality, DNP treatment had no effect on body weight, adiposity, or glucose homeostasis. Thus, environmental temperature should be considered when assessing an anti-obesity drug in mice, particularly agents acting on energy expenditure. Furthermore, the beneficial effects of DNP suggest that chemical uncouplers deserve further investigation for the treatment of obesity and its comorbidities.


Enzyme-linked immunosorbent assay for antibody against the nicotinic acetylcholine receptor in human myasthenia gravis.
Antibody against acetylcholine receptor (AChR) of human skeletal muscle was measured using enzyme-linked immunosorbent assay and found in 23 (74%) of 31 Japanese patients with generalized myasthenia gravis. In 15 patients with generalized myasthenia gravis who had not undergone thymectomy and who were not receiving adrenocorticosteroids, the antibody was found in 13 (87%). Antibody was also found in 13 (54%) of 24 patients with myasthenia gravis against AChR fractions obtained from fetal calf thymus. Based on the subunit structures of the AChR protein, the double precipitation assay using iodine 125-alpha-bungarotoxin is also capable of detecting antibody against the toxin binding site, by cross reactivity. This is among the first reports of experiments in which enzyme-linked immunosorbent assay was used to measure the antibodies in human myasthenia gravis and provides evidence of anti-AChR antibody against antigens from fetal calf thymus.


Demonstration of complex antigenic heterogeneity in a human glioma cell line and eight derived clones by specific monoclonal antibodies.
We have investigated the antigenic heterogeneity of human glioma cells and its correlation with other parameters of tumor cell heterogeneity (karyotype, 2':3' cyclic nucleotide 3'-phosphohydrolase expression, in vitro morphology) using the established human glioma cell line D-54 MG and eight single-cell-derived clones. The panel of antibodies used included 3 previously described heterologous sera raised against human gliomas and lamb oligodendroglia and 10 monoclonal antibodies with demonstrated reactivity for tumors of neuroectodermal origin, human fetal tissue, or human Thy-1. Antigen expression was determined by cell surface radioimmunoassay and peroxidase-antiperoxidase immunohistology. The use of a monoclonal antibody panel composed of ten reagents of varied specificity resulted in the demonstration of highly variable and complex antigenic patterns on the cell surfaces of cloned subpopulations of the human glioma cell line D-54 MG. Only one antigen, human Thy-1, was present on the parent line and all clones; the remaining nine antigens exhibited a distribution unrelated to other predictive parameters of genotypic or phenotypic heterogeneity such as karyotype, 2':3' cyclic nucleotide 3'-phosphohydrolase expression, or in vitro morphology. With the exception of clones 3 and 4, which shared a common antigen profile but exhibited distinctly different in vitro morphological patterns, the detected antigenic profile of each clone was distinct, with the proportion of expressed antigens ranging from 2 of 10 (clone 2) to 10 of 10 (clone 1). The demonstration of distinct, selectively maintained cell subpopulations within a human glioma cell line has direct implications for immunotherapeutic designs.


Gold nanoparticles can induce the formation of protein-based aggregates at physiological pH.
Protein-nanoparticle interactions are of central importance in the biomedical applications of nanoparticles, as well as in the growing biosafety concerns of nanomaterials. We observe that gold nanoparticles initiate protein aggregation at physiological pH, resulting in the formation of extended, amorphous protein-nanoparticle assemblies, accompanied by large protein aggregates without embedded nanoparticles. Proteins at the Au nanoparticle surface are observed to be partially unfolded; these nanoparticle-induced misfolded proteins likely catalyze the observed aggregate formation and growth.


Computational approaches for predicting the binding sites and understanding the recognition mechanism of protein-DNA complexes.
Protein-DNA recognition plays an important role in the regulation of gene expression. Understanding the influence of specific residues for protein-DNA interactions and the recognition mechanism of protein-DNA complexes is a challenging task in molecular and computational biology. Several computational approaches have been put forward to tackle these problems from different perspectives: (i) development of databases for the interactions between protein and DNA and binding specificity of protein-DNA complexes, (ii) structural analysis of protein-DNA complexes, (iii) discriminating DNA-binding proteins from amino acid sequence, (iv) prediction of DNA-binding sites and protein-DNA binding specificity using sequence and/or structural information, and (v) understanding the recognition mechanism of protein-DNA complexes. In this review, we focus on all these issues and extensively discuss the advancements on the development of comprehensive bioinformatics databases for protein-DNA interactions, efficient tools for identifying the binding sites, and plausible mechanisms for understanding the recognition of protein-DNA complexes. Further, the available online resources for understanding protein-DNA interactions are collectively listed, which will serve as ready-to-use information for the research community.


Do macrophages follow the beat of circadian rhythm in TIME (Tumor Immune Microenvironment)?
Advances in cancer research have made clear the critical role of the immune response in clearing tumors. This breakthrough in scientific understanding was heralded by the success of immune checkpoint blockade (ICB) therapies such as anti-programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), as well as the success of chimeric antigen receptor (CAR) T cells in treating liquid tumors. Thus, much effort has been made to further understand the role of the immune response in tumor progression, and how we may target it to treat cancer. Macrophages are a component of the tumor immune microenvironment (TIME) that can promote tumor growth both indirectly, by suppressing T cell responses necessary for tumor killing, as well as directly, through deposition of extracellular matrix and promotion of angiogenesis. Thus, understanding regulation of macrophages within the tumor microenvironment (TME) is key to targeting them for immunotherapy. However, circadian rhythms (24-hour cycles) are a fundamental aspect of macrophage biology that have yet to be investigated for their role in macrophage-mediated suppression of the anti-tumor immune response Circadian rhythms regulate macrophage-mediated immune responses through time-of-day-dependent regulation of macrophage function. A better understanding of the circadian biology of macrophages in the context of the TME may allow us to exploit synergy between existing and upcoming treatments and circadian regulation of immunity.


Detection of highly and minimally leukotoxic Actinobacillus actinomycetemcomitans strains in patients with periodontal disease.
This study examined the prevalence of highly and minimally leukotoxic Actinobacillus actinomycetemcomitans in patients with periodontal disease. Pooled subgingival plaque samples from 136 patients with some form of periodontal disease were examined. Subjects were between 14 and 76 years of age. Clinical examinations included periodontal pocket depth (PD), plaque index (PI) and bleeding index (BI). The obtained plaque samples were examined for the presence of highly or minimally leukotoxic A. actinomycetemcomitans strains by the polymerase chain reaction (PCR). Chi-square and logistic regression were performed to evaluate the results. Forty-seven subjects were diagnosed with gingivitis, 70 with chronic periodontitis and 19 with aggressive periodontitis. According to chi-square there was no significant correlation detected between PD (chi2 = 0.73), PI (chi2 = 0.35), BI (chi2 = 0.09) and the presence of the highly leukotoxic A. actinomycetemcomitans. The highly leukotoxic A. actinomycetemcomitans strains were correlated with subjects that were 28 years of age and younger (chi2 = 7.41). There was a significant correlation between highly leukotoxic A. actinomycetemcomitans and aggressive periodontitis (chi2 = 22.06). This study of a Brazilian cohort confirms the strong association between highly leukotoxic A. actinomycetemcomitans strains and the presence of aggressive periodontitis.


Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.
Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell-cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia, indicating common immunological features across different parts of the nervous system. Our study thus identifies subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.


The impact of CPAP on cardiovascular biomarkers in minimally symptomatic patients with obstructive sleep apnea: a pilot feasibility randomized crossover trial.
Previous, largely uncontrolled studies demonstrated the substantial effects of continuous positive airway pressure ventilation (CPAP) on a variety of physiologic and biochemical markers known to be risk factors for cardiovascular disease in patients with obstructive sleep apnea (OSA). In this pilot crossover study, we assessed (1) the feasibility of using CPAP in a group of minimally symptomatic patients with OSA, assessed through patient compliance and (2) CPAP therapy's effect on biomarkers in these patients. We studied patients with minimal daytime sleepiness who were referred to the University of British Columbia's Hospital Sleep Clinic with suspected OSA and an apnea-hypopnea index (AHI) > 15 events/h. Patients were randomized to either CPAP or no therapy for 4 weeks followed by a washout of 4 weeks, and then a crossover to the other intervention. Fasting morning blood and urine, 24-h blood pressure (BP) measurements, and endothelial function (peak flow-mediated dilation to nitroglycerin-mediated dilation ratio) were assessed before and after each study intervention. Nine adult male and four female patients were studied. Mean (SD) age was 55 (7) years, mean AHI = 27.9/h, mean Epworth Sleepiness Score = 6.8 (11/13 had a score < 10), and mean BMI = 31.1 kg/m(2). Mean compliance with CPAP therapy was 5.53 h/night. Compared to no therapy, potential improvements were observed with CPAP for urinary microalbumin, norepinephrine, and epinephrine to creatinine ratios (decreased by 3.51 mg/mmol, 1.70 nmol/mmol, and 0.95 nmol/mmol, respectively); 24-h BP (systolic decreased by 3.60 mmHg, diastolic by 0.70 mmHg); homeostasis model for insulin resistance score (decreased by 1.11); and endothelial function (increased by 7.4%). However, none of the above differences was significant (p > 0.10). In this pilot study there were potential improvements in a variety of cardiovascular biomarkers with CPAP. CPAP compliance was reasonably good even though patients were not particularly sleepy. Accordingly, larger randomized controlled trials in this area appear feasible and warranted.


Competing iconicities in the structure of languages.
The paper examines the role that iconicity plays in the structuring of grammars. Two main points are argued for: (a) Grammar does not necessarily suppress iconicity; rather, iconicity and grammar can enjoy a congenial relation in that iconicity can play an active role in the structuring of grammars. (b) Iconicity is not monolithic. There are different types of iconicity and languages take advantage of the possibilities afforded by them. We examine the interaction between iconicity and grammar by focusing on the ways in which sign languages employ the physical body of the signer as a rich iconic resource for encoding a variety of grammatical notions. We show that the body can play three different roles in iconic forms in sign languages: it can be used as a naming device where body parts represent body parts; it can represent the subject argument of verbal signs, and it can stand for first person. These strategies interact and sometimes compete in the languages under study. Each language resolves these competitions differently, which results in different grammars and grammatical structures. The investigation of the ways in which grammar and iconicity interact in these languages provides insight into the nature of both systems.


Cell-Based Therapies Used to Treat Lumbar Degenerative Disc Disease: A Systematic Review of Animal Studies and Human Clinical Trials.
Low back pain and degenerative disc disease are a significant cause of pain and disability worldwide. Advances in regenerative medicine and cell-based therapies, particularly the transplantation of mesenchymal stem cells and intervertebral disc chondrocytes, have led to the publication of numerous studies and clinical trials utilising these biological therapies to treat degenerative spinal conditions, often reporting favourable outcomes. Stem cell mediated disc regeneration may bridge the gap between the two current alternatives for patients with low back pain, often inadequate pain management at one end and invasive surgery at the other. Through cartilage formation and disc regeneration or via modification of pain pathways stem cells are well suited to enhance spinal surgery practice. This paper will systematically review the current status of basic science studies, preclinical and clinical trials utilising cell-based therapies to repair the degenerate intervertebral disc. The mechanism of action of transplanted cells, as well as the limitations of published studies, will be discussed.


Distinct Expression and Clinical Significance of Zinc Finger AN-1-Type Containing 4 in Oral Squamous Cell Carcinomas.
Zinc finger AN1-type containing 4 (ZFAND4) has emerged as a promising prognostic marker and predictor of metastasis for patients with oral squamous cell carcinoma (OSCC). However, further validation is fundamental before clinical implementation. Hence, this study evaluated the expression pattern of ZFAND4 protein expression by immunohistochemistry using an independent cohort of 125 patients with OSCC, and correlations with the clinicopathologic parameters and disease outcome. Remarkably, ZFAND4 expression, while negligible in normal epithelium, exhibited two distinct expression patterns in tumors that did not overlap. A gross granular staining was characteristic of the undifferentiated cells at the invasive front of tumors, whereas the most differentiated cells located at the center of the tumor nests showed diffuse non-granular staining. ZFAND4 staining was higher in undifferentiated than in differentiated areas of tumors. High ZFAND4 expression in differentiated cells was significantly associated to well-differentiated (p = 0.04) and non-recurrent tumors (p = 0.04), whereas ZFAND4 expression in undifferentiated cells correlated with tumor location (p = 0.005). No correlations between the ZFAND4 expression and patient survival were found. These data question the clinical relevance of ZFAND4 expression as a prognostic biomarker in OSCC, and also reveal distinct ZFAND4 expression patterns depending on the differentiation areas of tumors that should be evaluated separately.


FreeGaze: A Framework for 3D Gaze Estimation Using Appearance Cues from a Facial Video.
Gaze is a significant behavioral characteristic that can be used to reflect a person's attention. In recent years, there has been a growing interest in estimating gaze from facial videos. However, gaze estimation remains a challenging problem due to variations in appearance and head poses. To address this, a framework for 3D gaze estimation using appearance cues is developed in this study. The framework begins with an end-to-end approach to detect facial landmarks. Subsequently, we employ a normalization method and improve the normalization method using orthogonal matrices and conduct comparative experiments to prove that the improved normalization method has a higher accuracy and a lower computational time in gaze estimation. Finally, we introduce a dual-branch convolutional neural network, named FG-Net, which processes the normalized images and extracts eye and face features through two branches. The extracted multi-features are then integrated and input into a fully connected layer to estimate the 3D gaze vectors. To evaluate the performance of our approach, we conduct ten-fold cross-validation experiments on two public datasets, namely MPIIGaze and EyeDiap, achieving remarkable accuracies of 3.11° and 2.75°, respectively. The results demonstrate the high effectiveness of our proposed framework, showcasing its state-of-the-art performance in 3D gaze estimation.


mTHPC-based photodynamic therapy induction of autophagy and apoptosis in cultured cells in relation to mitochondria and endoplasmic reticulum stress.
Photodynamic therapy (PDT), an approved anticancer treatment, is reported as a potent inducer of programmed cell death (PCD) by both apoptosis and autophagy. The present study investigated the kinetics of both autophagy and caspase activation in MCF-7 cells submitted to mTHPC-PDT upon condition of treatment promoting ER accumulation of mTHPC. Fluence-dependent immediate cytochrome c (cyt C) release followed by caspase-9 and -7 activation at 1 h post-PDT evidenced a mitochondrial oxidative stress triggered by high light doses leading to >90% of cell death. ER oxidative stress was monitored by the induction of the glucose-related protein chaperone GRP78. From 6 h post-PDT, GRP78 induction was accompanied by the conversion of LC3-I into LC3-II, the hallmark of autophagosome formation. The formation of acid vesicles evidenced by fluorescence microscopy was obvious from 22 h post-PDT. Twenty-four hours post-PDT, cyt C release decreased and caspase-9 cleavage disappeared, while the expression of cleaved caspase-7 remained significant. At the same time, the profiles of GRP78, cleaved caspase-7 and LC3-II expression were similar irrespective of light doses. In contrast to an inhibitor of caspase activation Z-VAD-FMK, the use of autophagy inhibitor, Wortmannin, impaired cytotoxicity along with an increase in caspase-7 activation. These results demonstrate a valuable contribution of autophagy to cell death in mTHPC-photosensitized MCF-7 cells.


Effects of tertiary treatment by fungi on organic compounds in a kraft pulp mill effluent.
Pulp and paper mills generate a plethora of pollutants depending upon the type of pulping process. Efforts to mitigate the environmental impact of such effluents have been made by developing more effective biological treatment systems in terms of biochemical oxygen demand, chemical oxygen demand, colour and lignin content. This study is the first that reports an evaluation of the effects of a tertiary treatment by fungi (Pleurotus sajor caju, Trametes versicolor and Phanerochaete chrysosporium and Rhizopus oryzae) on individual organic compounds of a Eucalyptus globulus bleached kraft pulp and paper mill final effluent after secondary treatment (final effluent). The tertiary treatment with P. sajor caju, T. versicolor and P. chrysosporium and R. oryzae was performed in batch reactors, which were inoculated with separate fungi species and monitored throughout the incubation period. Samples from effluent after secondary and after tertiary treatment with fungi were analysed for both absorbance and organic compounds. The samples were extracted for organic compounds using solid-phase extraction (SPE) and analysed by gas chromatography-mass spectrometry (GC/MS). The efficiencies of the SPE procedure was evaluated by recovery tests. A total of 38 compounds (carboxylic acids, fatty alcohols, phenolic compounds and sterols) were identified and quantified in the E. globulus bleached kraft pulp mill final effluent after secondary treatment. Recoveries from the extraction procedure were between 98.2% and 99.9%. The four fungi species showed an adequate capacity to remove organic compounds and colour. Tertiary treatment with R. oryzae was able to remove 99% of organic compounds and to reduce absorbance on 47% (270 nm) and 74% (465 nm). P. sajor caju, T. versicolor and P. chrysosporium were able to remove 97%, 92% and 99% of organic compounds, respectively, and reduce 18% (270 nm) to 77% (465 nm), 39% (270 nm) to 58% (465 nm) and 31% (270 nm) to 10% (465 nm) of absorbance, respectively. The wide variety of organic compounds found in the final effluent must be due to the degradation of E. globulus wood in pulp and paper mill. The concentrations of organic compounds in the final effluent of E. globulus bleached kraft pulp mill were in residual levels maybe due to the secondary treatment. The recovery tests showed the effectiveness of the extraction procedure, and no losses of analyte were suspected in the analytical determinations. Lignin derivatives such as vanilic acid, syringic acid, guaiacol, syringol and phloroglucinol were totally removed by R. oryzae, but the 47% absorbance reduction obtained at 270 nm suggests that these species were not able to complete degradation of lignin macromolecular compounds. The organic compounds (carboxylic acids, fatty alcohols, phenolic compounds and sterols) were removed more efficiently by tertiary treatment with R. oryzae or P. chrysosporium, followed by P. sajor caju and T. versicolor. Regarding the removal of both colour and organic compounds, the tertiary treatment with R. oryzae was the most efficient. In order to reduce the deleterious impacts of paper mill effluents, efforts have been made to develop more effective advanced tertiary treatments. This study may serve as a basis of characterisation, in terms of organic compounds of E. globulus bleached kraft pulp mill final effluent after secondary treatment and as an effort to understand the effects of tertiary treatments with fungi on low concentrations of organic compounds from biological secondary treatment.


Activation of Na+/H+ exchanger is not involved in the PDGF-BB-induced DNA-synthesis in vascular smooth muscle cells.
HOE 694 [(3-methylsulphonyl-4-piperidinobenzoyl)guanidine methanesulphonate] was characterized as a new, potent, non-amiloride inhibitor of the Na+/H+ exchanger. In order to elucidate whether the Na+/H+ exchanger isoform 1 (NHE-1) is involved in the PDGF-BB-induced DNA-synthesis in vascular smooth muscle cells, we investigated the effect of HOE 694 and EIPA on the PDGF-BB-induced DNA synthesis. EIPA (10 microM) inhibited the PDGF-BB-induced stimulation of the Na+/H+ exchanger and the PDGF-BB-induced DNA synthesis in a concentration-dependent manner. HOE 694 (1-50 microM) dose-dependently inhibited the PDGF-BB-induced stimulation of the Na+/H+ exchanger but had no significant effects on DNA-synthesis. Our findings suggest that activation of the Na+/H+ exchanger is not essential for PDGF-BB-induced vascular smooth muscle cell growth.


Single-wavelength phasing strategy for quasi-racemic protein crystal diffraction data.
Racemic protein crystallography offers two key features: an increased probability of crystallization and the potential advantage of phasing centric diffraction data. In this study, a phasing strategy is developed for the scenario in which a crystal is grown from a mixture in which anomalous scattering atoms have been incorporated into only one enantiomeric form of the protein molecule in an otherwise racemic mixture. The structure of a protein crystallized in such a quasi-racemic form has been determined in previous work [Pentelute et al. (2008), J. Am. Chem. Soc. 130, 9695-9701] using the multiwavelength anomalous dispersion (MAD) method. Here, it is shown that although the phases from such a crystal are not strictly centric, their approximate centricity provides a powerful way to break the phase ambiguity that ordinarily arises when using the single-wavelength anomalous dispersion (SAD) method. It is shown that good phases and electron-density maps can be obtained from a quasi-racemic protein crystal based on single-wavelength data. A prerequisite problem of how to establish the origin of the anomalous scattering substructure relative to the center of pseudo-inversion is also addressed.


Insights into the Role of Innate Immunity in Cervicovaginal Papillomavirus Infection from Studies Using Gene-Deficient Mice.
We demonstrate that female C57BL/6J mice are susceptible to a transient lower genital tract infection with MmuPV1 mouse papillomavirus and display focal histopathological abnormalities resembling those of human papillomavirus (HPV) infection. We took advantage of strains of genetically deficient mice to study in vivo the role of innate immune signaling in the control of papillomavirus. At 4 months, we sacrificed MmuPV1-infected mice and measured viral 757/3139 spliced transcripts by TaqMan reverse transcription-PCR (RT-PCR), localization of infection by RNAscope in situ hybridization, and histopathological abnormities by hematoxylin and eosin (H&E) staining. Among mice deficient in receptors for pathogen-associated molecular patterns, MyD88-/- and STING-/- mice had 1,350 and 80 copies of spliced transcripts/μg RNA, respectively, while no viral expression was detected in MAVS-/- and Ripk2-/- mice. Mice deficient in an adaptor molecule, STAT1-/-, for interferon signaling had 46,000 copies/μg RNA. Among mice with targeted deficiencies in the inflammatory response, interleukin-1 receptor knockout (IL-1R-/-) and caspase-1-/- mice had 350 and 30 copies/μg RNA, respectively. Among mice deficient in chemokine receptors, CCR6-/- mice had 120 copies/μg RNA, while CXCR2-/- and CXCR3-/- mice were negative. RNAscope confirmed focal infection in MyD88-/-, STAT1-/-, and CCR6-/- mice but was negative for other gene-deficient mice. Histological abnormalities were seen only in the latter mice. Our findings and the literature support a working model of innate immunity to papillomaviruses involving the activation of a MyD88-dependent pathway and IL-1 receptor signaling, control of viral replication by interferon-stimulated genes, and clearance of virus-transformed dysplastic cells by the action of the CCR6/CCL20 axis.IMPORTANCE Papillomaviruses infect stratified squamous epithelia, and the viral life cycle is linked to epithelial differentiation. Additionally, changes occur in viral and host gene expression, and immune cells are activated to modulate the infectious process. In vitro studies with keratinocytes cannot fully model the complex viral and host responses and do not reflect the contribution of local and migrating immune cells. We show that female C57BL/6J mice are susceptible to a transient papillomavirus cervicovaginal infection, and mice deficient in select genes involved in innate immune responses are susceptible to persistent infection with variable manifestations of histopathological abnormalities. The results of our studies support a working model of innate immunity to papillomaviruses, and the model provides a framework for more in-depth studies. A better understanding of mechanisms of early viral clearance and the development of approaches to induce clearance will be important for cancer prevention and the treatment of HPV-related diseases.


Syndecan-1/CD138 expression in normal myeloid, acute lymphoblastic and myeloblastic leukemia cells.
Stabilization of cell surface antigens and preservation of ultrastructural integrity are important aspects of immunoelectron microscopical studies. In the present study, 4 anti-syndecan-1/CD138 (B-B2, B-B4, MI15, 1D4) monoclonal antibodies (mAbs) were applied in combination with periodatelysine-paraformaldehyde (PLP) fixation and indirect pre-embedding peroxidase electron microscopical immunocytochemistry to analyse the localization and function of these molecules in normal myeloid cells, acute lymphoblastic leukemia (ALL) cells and acute myeloblastic leukemia (AML) cells. One case of normal human bone marrow, 3 cases of untreated AML and 2 cases of untreated ALL were studied. Samples were immediately fixed for 4 h in freshly-prepared PLP fixative in 0.037 mol/L phosphate buffer, pH 7.4, containing 10 mmol/L sodium metaperiodate, 75 mmol/L lysine, and 2% paraformaldehyde. Expression of syndecan-1 was found at the plasma membrane of all cell types. Staining intensity at the membrane of AML cells was stronger than that on the membrane of normal myeloid and ALL cells. We conclude that anti-syndecan-1/CD138 mAbs in combination with the method described here are a suitable tool for detection of cell surface syndecan molecules in cells originating from progenitor cells that can differentiate in both myeloid and lymphoid cells.


Beyond PICO: the SPIDER tool for qualitative evidence synthesis.
Standardized systematic search strategies facilitate rigor in research. Current search tools focus on retrieval of quantitative research. In this article we address issues relating to using existing search strategy tools, most typically the PICO (Population, Intervention, Comparison, Outcome) formulation for defining key elements of a review question, when searching for qualitative and mixed methods research studies. An alternative search strategy tool for qualitative/mixed methods research is outlined: SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type). We used both the SPIDER and PICO search strategy tools with a qualitative research question. We have used the SPIDER tool to advance thinking beyond PICO in its suitable application to qualitative and mixed methods research. However, we have highlighted once more the need for improved indexing of qualitative articles in databases. To constitute a viable alternative to PICO, SPIDER needs to be refined and tested on a wider range of topics.


Ethical dimensions of periviability.
The birth of neonates at the limits of viability, or periviability, poses numerous challenges to health care providers and to systems of care, and the care of these pregnancies and neonates is fraught with ethical controversies. This statement summarizes the ethical principles involved in the care of periviable pregnancies and neonates, and provides expert clinical opinion about the numerous challenges posed by this problem around the world. Topics addressed include a summary of the published experience, an ethical framework, translating neonatal outcome data to the obstetric arena, management as a trial of intervention, referral to tertiary centers, neonatal resuscitation, cesarean delivery for fetal indication, and limits on life-sustaining neonatal treatment.


Range flow in varying illumination: algorithms and comparisons.
We extend estimation of range flow to handle brightness changes in image data caused by inhomogeneous illumination. Standard range flow computes 3D velocity fields using both range and intensity image sequences. Toward this end, range flow estimation combines a depth change model with a brightness constancy model. However, local brightness is generally not preserved when object surfaces rotate relative to the camera or the light sources, or when surfaces move in inhomogeneous illumination. We describe and investigate different approaches to handle such brightness changes. A straightforward approach is to prefilter the intensity data such that brightness changes are suppressed, for instance, by a highpass or a homomorphic filter. Such prefiltering may, though, reduce the signal-to-noise ratio. An alternative novel approach is to replace the brightness constancy model by 1) a gradient constancy model, or 2) by a combination of gradient and brightness constancy constraints used earlier successfully for optical flow, or 3) by a physics-based brightness change model. In performance tests, the standard version and the novel versions of range flow estimation are investigated using prefiltered or nonprefiltered synthetic data with available ground truth. Furthermore, the influences of additive Gaussian noise and simulated shot noise are investigated. Finally, we compare all range flow estimators on real data.


Single nucleotide polymorphism (SNP) discovery and linkage mapping of bovine cytokine genes.
Polymorphic markers at bovine gene loci facilitate the integration of cattle genetic maps with those of humans and mice. To this end, 31 single nucleotide polymorphism (SNP) markers were developed for seven bovine chemokine genes. Loci were amplified from bovine genomic DNA by the polymerase chain reaction, and candidate amplicons were sequenced to determine their identity. Amplified loci from 24 founding parents and select progeny from a beef cattle reference population were sequenced and analyzed for SNPs. SNP haplotype alleles were determined by examining segregation patterns and used to establish the locus position on the bovine linkage map. Loci for growth-related proteins (GRO3, GRO1, and GROX) were clustered with the related CXC chemokine genes, interleukin (IL) 8, and epithelial cell inflammatory protein 1, at 84 cM from the centromeric end of the bovine chromosome (BTA) 6 linkage group. Bovine loci for a cluster of IL8 receptors, a stromal cell-derived factor 1, interferon-gamma, and tumor necrosis factor-alpha were mapped at 90, 55, 59, and 34 cM, respectively, from the centromeric ends of the BTA 2, 28, 5, and 23 linkage groups. The positions of these bovine loci were compared with those of orthologous loci on the human map to refine the boundaries of conserved synteny. These seven loci provide examples of SNP development in which the efficiency was largely dependent on the availability of bovine genomic or cDNA sequence. The polymorphic nature of these SNP haplotype markers suggests that they will be useful for mapping complex traits in cattle, such as resistance to infectious disease.


Impact of patient age on the functional and psychosocial outcomes of orthognathic treatment.
Orthognathic treatment has been demonstrated to enhance oral function and quality of life. In the UK, prior approval criteria have been trialled to govern the provision of orthognathic surgery within the National Health Service (NHS). These include the patient's age and presence of functional concerns. The purpose of this paper was to examine the outcomes of orthognathic treatment with respect to patient age at the start of treatment. This was a retrospective evaluation of a single surgeon's experience of patients treated for dentofacial deformity over a 17-year period. A total of 118 patients completed pre-treatment and post-treatment questionnaires. There were significant improvements (p < 0.001) in reported functional problems, and in Body Satisfaction Scale (BSS), General Health Questionnaire (GHQ-12), and in Anxiety questionnaire scores. There was no difference in outcome when younger and older patients were compared. Orthognathic treatment produced positive functional and psychosocial outcomes irrespective of the patient's age at the start of treatment.


Fermentation of cucumbers brined with calcium chloride instead of sodium chloride.
Waste water containing high levels of NaCl from cucumber fermentation tank yards is a continuing problem for the pickled vegetable industry. A major reduction in waste salt could be achieved if NaCl were eliminated from the cucumber fermentation process. The objectives of this project were to ferment cucumbers in brine containing CaCl(2) as the only salt, to determine the course of fermentation metabolism in the absence of NaCl, and to compare firmness retention of cucumbers fermented in CaCl(2) brine during subsequent storage compared to cucumbers fermented in brines containing both NaCl and CaCl(2) at concentrations typically used in commercial fermentations. The major metabolite changes during fermentation without NaCl were conversion of sugars in the fresh cucumbers primarily to lactic acid which caused pH to decrease to less than 3.5. This is the same pattern that occurs when cucumbers are fermented with NaCl as the major brining salt. Lactic acid concentration and pH were stable during storage and there was no detectable production of propionic acid or butyric acid that would indicate growth of spoilage bacteria. Firmness retention in cucumbers fermented with 100 to 300 mM CaCl(2) during storage at a high temperature (45 degrees C) was not significantly different from that obtained in fermented cucumbers with 1.03 M NaCl and 40 mM CaCl(2). In closed jars, cucumber fermentations with and without NaCl in the fermentation brine were similar both in the chemical changes caused by the fermentative microorganisms and in the retention of firmness in the fermented cucumbers.


[Workplace health promotion: description and preliminary results of ASL of Bergamo integrated].
Interventions for health promotion in the workplace (WHP programs) can improve the health of workers, acting on modifiable risk factors for chronic diseases. The effectiveness of integrated programs of health promotion in companies is well described in literature. Our project was conducted in two mid-sized companies in the province of Bergamo, respectively with 170 and 230 employees. The project issues were in the following areas: tobacco smoke (awareness and support to smoking cessation); nutrition (awareness and practical action on the workplace canteen); physical activity (awareness, information and practical ways of incentives); prevention of road accidents (training and initiatives to promote safety). The analysis of the behaviours and individual risk factors was performed by a questionnaire at the beginning of the project and a year later. 95 initial questionnaires were returned and processed for the company A and 168 for the company B; their results were discussed with company management, the company doctors and workers representatives and allowed the formulation of a "company assessment risk profile" according to the methodology of the Assessment of Health Risks with Feedback (AHRF). There have been training/awareness messages in working hours for all employees on areas of lifestyle and have started work on the canteen, actions to promote road safety, physical activity and interventions to counter the smoking. The effectiveness of group treatments for smoking cessation has been of 55.6% at 3 months and 50% at 6 months (at the present only a company has achieved 6 months of follow up).


Characterization of Mpl mutants using primary megakaryocyte-lineage cells from mpl(-/-) mice: a new system for Mpl structure-function studies.
Mpl is the thrombopoietin (TPO) receptor. The current molecular understanding of how Mpl activation stimulates proliferation of megakaryocyte-lineage cells is based largely on the engineered expression of Mpl in nonmegakaryocyte-lineage cell lines. However, the relevance of these findings to Mpl signaling in primary megakaryocyte-lineage cells remains largely unknown. Therefore, a system was developed to study Mpl function in primary mpl(-/-) megakaryocyte-lineage cells. Expressing avian retroviral receptors on the surfaces of mammalian cells overcomes their natural block to avian retroviral infection; 815 bp of human GPIIb regulatory sequence was used to generate transgenic mice with megakaryocyte-lineage expression of the subgroup A avian leukosis virus receptor, TVA. Avian retroviral infection of unfractionated bone marrow from these mice is restricted to megakaryocyte-lineage cells. The transgenic mice were crossed to an mpl(-/-) background generating GPIIb-tva+mpl(-/-) mice. By using avian retroviruses to express wild-type or mutant Mpl on the surfaces of primary megakaryocyte-lineage cells, it was demonstrated that (1) the 10 membrane-proximal, cytoplasmic amino acids of Mpl are required for TPO-induced proliferation; (2) Y582F mutation confers a proliferative advantage over wild-type Mpl and imparts a constitutive anti-apoptotic signal; (3) truncating the 50 C-terminal Mpl amino acids reduces but does not eliminate TPO-induced mitogen-activated protein kinase activation, yet it does not alter the synergistic effect of stem cell factor on TPO-induced proliferation; and (4) TPO-induced proliferation of early, primary megakaryocyte-lineage cells does not require Stat-5 phosphorylation. The system reported provides an improved approach for Mpl structure-function studies, and the method can be applied to any hematopoietic lineage.


Immunomodulatory Effects of Saccharomyces cerevisiae Fermentation Product Supplementation on Immune Gene Expression and Lymphocyte Distribution in Immune Organs in Broilers.
A study was conducted to evaluate the molecular and cellular immunomodulatory effects of a Saccharomyces cerevisiae fermentation product (Original XPC, Diamond V) in broilers. Our lab has previously demonstrated that broilers fed XPC generate faster and stronger antigen-specific humoral immune responses to Newcastle disease virus (NDV) vaccination. This study aims at investigating the mechanism behind this increased immunocompetence. One-day-old broilers were randomly assigned to one of two treatments: 1.25 kg/ton S. cerevisiae fermentation product (XPC treatment group) or control diet. Birds were vaccinated against NDV on day 1 (B1 strain) and day 21 (LaSota strain) post-hatch. Innate and adaptive immune-related gene expression profiles in central (thymus and bursa of Fabricius) and peripheral (spleen) immune organs were investigated at 14 and 28 days of age by qPCR array. Fold changes larger than 1.2 (P < 0.05) between treated and control were considered significant. Lymphocyte subpopulations in central and peripheral immune organs and blood leukocytes were analyzed by flow cytometry at 14, 21, 28, and 42 days of age. In the spleen, Th1 immune responses and antiviral genes, such as IFN-γ, and its downstream genes signal transducer and activator of transcription (STAT4) and NFκB, were significantly upregulated in the treated group by 14 days of age. In the thymus, genes belonging to different functional groups were influenced at different time points. Cytokine genes associated with lymphocyte maturation, differentiation, and proliferation, such as IL-1R, IL-2, and IL-15 were significantly upregulated in the treated group by 28 days of age. Genes preferentially expressed in the medulla of the thymus and mature thymocytes, such as Myxovirus resistance gene 1, interferon regulatory factor-1, interferon regulatory factor-7, and STAT1, were upregulated in the birds supplemented with XPC. Birds supplemented with XPC had significantly higher percentages of CD3+, CD4+, and CD8+ T-cells in the thymus at day 28 of age, indicating production of more mature T-cells, which was consistent with gene expression results. Results suggest that XPC supplementation primes broilers to become more immunocompetent, without compromising growth performance.