Prognostic Prediction Based on Dynamic Contrast-Enhanced MRI and Dynamic Susceptibility Contrast-Enhanced MRI Parameters from Non-Enhancing, T2-High-Signal-Intensity Lesions in Patients with Glioblastoma.
Few attempts have been made to investigate the prognostic value of dynamic contrast-enhanced (DCE) MRI or dynamic susceptibility contrast (DSC) MRI of non-enhancing, T2-high-signal-intensity (T2-HSI) lesions of glioblastoma multiforme (GBM) in newly diagnosed patients. This study aimed to investigate the prognostic values of DCE MRI and DSC MRI parameters from non-enhancing, T2-HSI lesions of GBM. A total of 76 patients with GBM who underwent preoperative DCE MRI and DSC MRI and standard treatment were retrospectively included. Six months after surgery, the patients were categorized into early progression (n = 15) and non-early progression (n = 61) groups. We extracted and analyzed the permeability and perfusion parameters of both modalities for the non-enhancing, T2-HSI lesions of the tumors. The optimal percentiles of the respective parameters obtained from cumulative histograms were determined using receiver operating characteristic (ROC) curve and univariable Cox regression analyses. The results were compared using multivariable Cox proportional hazards regression analysis of progression-free survival. The 95th percentile value (PV) of Ktrans, mean Ktrans, and median Ve were significant predictors of early progression as identified by the ROC curve analysis (area under the ROC curve [AUC] = 0.704, p = 0.005; AUC = 0.684, p = 0.021; and AUC = 0.670, p = 0.0325, respectively). Univariable Cox regression analysis of the above three parametric values showed that the 95th PV of Ktrans and the mean Ktrans were significant predictors of early progression (hazard ratio [HR] = 1.06, p = 0.009; HR = 1.25, p = 0.017, respectively). Multivariable Cox regression analysis, which also incorporated clinical parameters, revealed that the 95th PV of Ktrans was the sole significant independent predictor of early progression (HR = 1.062, p < 0.009). The 95th PV of Ktrans from the non-enhancing, T2-HSI lesions of GBM is a potential prognostic marker for disease progression.


Brief communication: Orphaned Male Chimpanzees die young even after weaning.
If a social-living animal has a long life span, permitting different generations to co-exist within a social group, as is the case in many primate species, it can be beneficial for a parent to continue to support its weaned offspring to increase the latter's survival and/or reproductive success. Chimpanzees have an even longer period of dependence on their mothers' milk than do humans, and consequently, offspring younger than 4.5-5 years old cannot survive if the mother dies. Most direct maternal investments, such as maternal transportation of infants and sharing of night shelters (beds or nests), end with nutritional weaning. Thus, it had been assumed that a mother's death was no longer critical to the survival of weaned offspring, in contrast to human children, who continue to depend on parental care long after weaning. However, in theory at least, maternal investment in a chimpanzee son after weaning could be beneficial because in chimpanzees' male-philopatric society, mother and son co-exist for a long time after the offspring's weaning. Using long-term demographic data for a wild chimpanzee population in the Mahale Mountains, Tanzania, we show the first empirical evidence that orphaned chimpanzee sons die younger than expected even if they lose their mothers after weaning. This suggests that long-lasting, but indirect, maternal investment in sons continues several years after weaning and is vital to the survival of the sons. The maternal influence on males in the male-philopatric societies of hominids may be greater than previously believed.


Recent update on potential cytotoxicity, biocompatibility and preventive measures of biomaterials used in dentistry.
Dental treatment is provided for a wide variety of oral health problems like dental caries, periodontal diseases, periapical infections, replacement of missing teeth and orthodontic problems. Various biomaterials, like composite resins, amalgam, glass ionomer cement, acrylic resins, metal alloys, impression materials, bone grafts, membranes, local anaesthetics, etc., are used for dental applications. The physical and chemical characteristics of these materials influence the outcome of dental treatment. It also impacts on the biological, allergic and toxic potential of biomaterials. With innovations in science and their positive results, there is also a need for awareness about the biological risks of these biomaterials. The aim of dental treatment is to have effective, yet safe, and long-lasting results for the benefit of patients. For this, it is important to have a thorough understanding of biomaterials and their effects on local and systemic health. Materials used in dentistry undergo a series of analyses before their oral applications. To the best of our knowledge, this is the first and original review that discusses the reasons for and studies on the toxicity of commonly used biomaterials for applications in dentistry. It will help clinicians to formulate a methodical approach for the selection of dental biomaterials, thus providing an awareness for forecasting their risk of toxic reactions.


Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children.
In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children. Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days. The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL). This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.


Multidrug resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but do not enhance drug penetration in brain and testis.
The aim of this study was to assess whether P-glycoprotein (Pgp) inhibitors altered the blood-brain barrier and enhanced vinblastine (VBL) distribution in brain, testis and other Pgp-expressing tissues. Trifluoperazine, cyclosporin A, amiodarone, quinidine, the nifedipine analog Bay K8644 and verapamil were selected among Pgp inhibitors and were administered intraperitoneally 1 hr before an intravenous dose of 10 mg/kg VBL. Trifluoperazine and cyclosporin A were also administered intraperitoneally for 7 days before VBL. VBL and its metabolite O4-deacetylvinblastine were measured in tissues by high-performance liquid chromatography assay. None of the reversing agents (RA) appreciably raised VBL concentrations in brain and testis, whereas all except quinidine significantly enhanced VBL distribution in liver and kidney; the most effective were trifluoroperazine and cyclosporin A. In mice treated with RA and VBL combined, O4-deacetylvinblastine levels in liver and kidney reached either the same or higher levels than in mice treated with VBL alone, indicating that the increase in VBL levels is not due to inhibition of its metabolism. The main conclusions are that (1) inhibitors of Pgp, even at high doses, do not increase the permeability of the blood-brain barrier in mice, suggesting caution in the clinical use of RA combined with antitumor agents for brain tumors; and (2) several RA achieve high enough concentrations to enhance the distribution of VBL in other normal tissues expressing Pgp, thus potentially increasing VBL toxicity.


MCML: Combining physical constraints with experimental data for a multi-purpose meta-generalized gradient approximation.
The predictive power of density functional theory for materials properties can be improved without increasing the overall computational complexity by extending the generalized gradient approximation (GGA) for electronic exchange and correlation to density functionals depending on the electronic kinetic energy density in addition to the charge density and its gradient, resulting in a meta-GGA. Here, we propose an empirical meta-GGA model that is based both on physical constraints and on experimental and quantum chemistry reference data. The resulting optimized meta-GGA MCML yields improved surface and gas phase reaction energetics without sacrificing the accuracy of bulk property predictions of existing meta-GGA approaches.


Myxoma-like features of organizing thrombi in arteries and veins.
Evidence for the development of the cardiac myxoma from organizing thrombi has been presented previously. In this study, many of the features of the myxoma were observed in organizing thrombi in arteries and veins. Individual undifferentiated mesenchymal cells, cords of similar cells, vascular bud-like cellular aggregates, fibroblasts, well-formed vessels, and multiwalled vessels set within a loose, mucoid ground substance were present in the thrombi. These areas resembled the basilar layer of the cardiac myxoma. Cartilage-like cells, like those in the superficial zone of myxomas, were noted in some thrombi, and ossification had occurred rarely. These observations support a thrombogenic origin of the myxoma. Local physical factors may provide the stimulus for varying differentiation of mesenchymal cells in both the peripheral thrombi and the myxoma.


Impaired NK Cell Responses to Pertussis and H1N1 Influenza Vaccine Antigens in Human Cytomegalovirus-Infected Individuals.
NK cells contribute to postvaccination immune responses after activation by IL-2 from Ag-specific memory T cells or by cross-linking of the low-affinity IgG receptor, CD16, by Ag-Ab immune complexes. Sensitivity of NK cells to these signals from the adaptive immune system is heterogeneous and influenced by their stage of differentiation. CD56(dim)CD57(+) NK cells are less responsive to IL-2 and produce less IFN-γ in response to T cell-mediated activation than do CD56(bright) or CD56(dim)CD57(-) NK cells. Conversely, NK cell cytotoxicity, as measured by degranulation, is maintained across the CD56(dim) subsets. Human CMV (HCMV), a highly prevalent herpes virus causing lifelong, usually latent, infections, drives the expansion of the CD56(dim)CD57(+)NKG2C(+) NK cell population, skewing the NK cell repertoire in favor of cytotoxic responses at the expense of cytokine-driven responses. We hypothesized, therefore, that HCMV seropositivity would be associated with altered NK cell responses to vaccine Ags. In a cross-sectional study of 152 U.K. adults, with HCMV seroprevalence rate of 36%, we find that HCMV seropositivity is associated with lower NK cell IFN-γ production and degranulation after in vitro restimulation with pertussis or H1N1 influenza vaccine Ags. Higher expression of CD57/NKG2C and lower expression of IL-18Rα on NK cells from HCMV seropositive subjects do not fully explain these impaired responses, which are likely the result of multiple receptor-ligand interactions. This study demonstrates for the first time, to our knowledge, that HCMV serostatus influences NK cell contributions to adaptive immunity and raises important questions regarding the impact of HCMV infection on vaccine efficacy.


Optical laboratory morphological inspection processor.
Morphological transformations are applied to industrial inspection problems. A real time optical architecture to implement morphological transformations such as erosion, opening, closing, and skeletonization is described and analyzed. The first real time optical laboratory results of erosion and opening are presented for locating string in tobacco.


Differences in family functioning before and during the COVID-19 pandemic: an observational study in Peruvian families.
The COVID-19 pandemic has had a major impact on family relationships, as several families have lost family members due to COVID-19 pandemic and become physically and emotionally estranged due to lockdown measures and critically economic periods. Our study contrasted two hypotheses: (1) family functioning changed notably before and after the COVID-19 pandemic initiation in terms of cohesion, flexibility, communication and satisfaction; (2) balanced families have a greater capacity to strictly comply with quarantine (i.e., social confinement), compared to unbalanced families. We performed an observational study comparing family functioning between two independent groups, evaluated before and during the first wave of the COVID-19 pandemic in Peru. A total of 7,980 participants were included in the study. For the first hypothesis, we found that, during the pandemic, families became more balanced in terms of cohesion (adjusted before-during mean difference or β1 = 1.4; 95% CI [1.0-1.7]) and flexibility (β2 = 2.0; 95% CI [1.6-2.4]), and families were less disengaged (β3 = -1.9; 95% CI [-2.3 to -1.5]) and chaotic (β4 = -2.9; 95% CI [-3.3 to -2.4]). Regarding the second hypothesis, we confirmed that families with balanced cohesion (adjusted prevalence ratio or aPR = 1.16; 95% CI [1.12-1.19) and flexibility (aPR = 1.23; 95% CI [1.18-1.27]) allowed greater compliance with quarantine restrictions; while disengaged (aPR = 0.91; 95% CI [0.88-0.93]) and chaotic families (aPR = 0.89; 95% CI [0.87-0.92]) were more likely to partially comply or not comply with the quarantine. Finally, family communication (aPR = 1.17; 95% CI [1.11-1.24]) and satisfaction (aPR = 1.18; 95% CI [1.11-1.25]) also played a role in favouring quarantine compliance. This new evidence enlightens the family systems theory while informing future interventions for improving compliance with quarantine measures in the context of social confinement.


Persistence of acidosis in alloxan-induced diabetic rats treated with the juice of Asystasia gangetica leaves.
Diabetes mellitus is gradually becoming a global health burden leading to an increase in the search for herbal hypoglycemic agents as alternatives to synthetic ones. Asystasia gangetica is one of the herbs used in folklore system of medicine for managing hypoglycaemia associated with diabetes. The influence of the juice of A. gangetica leaf on alloxan-induced diabetic rats was assessed by treating diabetic rats with 25%, 50% and 75% fresh juice and glibenclamide for 5 weeks. Afterwards, the plasma concentrations of glucose, triacylglycerols, total cholesterol, high-density lipoprotein (HDL) cholesterol, thiobarbituric acid reactive substances and bicarbonate were assayed spectrophotometrically. Treatment of the diabetic rats with the juice significantly (P < 0.05) reduced the elevated plasma levels of glucose to a level not significantly (P > 0.05) different from that of glibenclamide. The juice also significantly (P < 0.05) reduced the plasma lipid peroxidation and improved the lipid profile, as indicated by a significant (P < 0.05) reduction in the total cholesterol: HDL cholesterol ratio. However, there was a significant (P < 0.05) rise in the level of bicarbonate as result of the juice treatment from 28.15 ± 2.82 mmol/l in normal control to 60.83 ± 17.46 mmol/l in diabetic control and to 122.20 ± 34.68 mmol/l, 120.95 ± 35.09 mmol/l and 115.85 ± 11.79 mmol/l in 25%, 50% and 75% juice, respectively. Therefore, this inability of A. gangetica to prevent acidosis detracts from the potential of its usefulness in managing diabetes.


Factors associated with poor outcomes among adults hospitalized for influenza in France: A three-year prospective multicenter study.
Influenza is an important cause of serious illness and death, particularly in elderly and high-risk groups. Aim of this study was to identify factors associated with poor outcomes among adults hospitalized in France for laboratory-confirmed seasonal influenza. Patients hospitalized for influenza were identified in a prospective, multicenter study carried out in French hospitals during three consecutive influenza seasons (2012-2015). Influenza virus infection was confirmed by reverse transcription polymerase chain reaction. Sociodemographic and clinical variables were compared according to the virus type and subtype. Risk factors for complications, intensive care unit (ICU) admission and death were analyzed by backward stepwise logistic regression. The study population consisted of 566 patients, of whom 56% were older than 65 years and 82% had underlying chronic illnesses. Type A influenza viruses infected 422 patients (75%), including subtype H3N2 in 239 patients (57%). The prior vaccine coverage rate was 38%. Complications occurred in 255 patients (45%), consisting mainly of pneumonia (n=143, 30%) and respiratory failure (n=116, 20%). Eighty-three patients (15%) were admitted to an ICU, and the in-hospital mortality rate was 4% (n=21). Sixty-six patients (12%) received oseltamivir. Age over 65 years was the only identified risk factor for complications. Risk factors for ICU admission were an absence of vaccination, no oseltamivir administration before admission, pre-existing chronic respiratory disease, and current smoking. Age over 65 years and ICU admission were risk factors for death. Older individuals and patients with underlying conditions are most at risk of influenza complications. Vaccination and early oseltamivir administration, both of which are recommended for these patients, appear to reduce ICU admissions.


Roles of Surfactants in Oriented Immobilization of Cellulase on Nanocarriers and Multiphase Hydrolysis System.
Surfactants, especially non-ionic surfactants, play an important role in the preparation of nanocarriers and can also promote the enzymatic hydrolysis of lignocellulose. A broad overview of the current status of surfactants on the immobilization of cellulase is provided in this review. In addition, the restricting factors in cellulase immobilization in the complex multiphase hydrolysis system are discussed, including the carrier structure characteristics, solid-solid contact obstacles, external diffusion resistance, limited recycling frequency, and nonproductive combination of enzyme active centers. Furthermore, promising prospects of cellulase-oriented immobilization are proposed, including the hydrophilic-hydrophobic interaction of surfactants and cellulase in the oil-water reaction system, the reversed micelle system of surfactants, and the possible oriented immobilization mechanism.


False-Positive Monospot in a Returning Traveler with Dengue Fever.
The heterophile antibody (Monospot), initial test of choice for Epstein-Barr virus (EBV)-associated infectious mononucleosis, is both sensitive (70-92%) and specific (96-100%). False positives have been demonstrated in cases of viral hepatitis, human immunodeficiency virus, leukemia, lymphoma, pancreatic cancer, systemic lupus erythematosus, and rubella. We present a case of a 46-yr-old male who developed fever, chills, headaches, myalgia, fatigue, and photophobia 1 d after returning from the Philippines. He demonstrated a mild transaminitis and significant thrombocytopenia (12,000 cells/μL). His initial evaluation revealed a positive heterophile antibody test. Without a classic EBV presentation, a fever in returning traveler evaluation was instituted resulting in a positive dengue test by direct fluorescence IgM (8.82 IU) and IgG (7.13 IU), respectively. Both his EBV DNA polymerase chain reaction and IgM by viral capsid antigen were negative. Dengue, an RNA flavivirus, and the dengue antibody have demonstrated cross-reactivity with other flaviviruses including Japanese encephalitis virus, yellow fever virus, West Nile virus, and St. Louis encephalitis. However, EBV is a double-helix DNA herpesvirus and structurally very different. To our knowledge, this is the first reported case of cross-reactivity between dengue and EBV that describes a potential false positive for the heterophile antibody test.


Cellular stress drives pancreatic plasticity.
Controversy has long surrounded research on pancreatic beta cell regeneration. Some groups have used nonphysiological experimental methodologies to build support for the existence of pancreatic progenitor cells within the adult pancreas that constantly replenish the beta cell pool; others argue strongly against this mode of regeneration. Recent research has reinvigorated enthusiasm for the harnessing of pancreatic plasticity for therapeutic application--for example, the transdifferentiation of human pancreatic exocrine cells into insulin-secreting beta-like cells in vitro; the conversion of mouse pancreatic acinar cells to beta-like cells in vivo via cytokine treatment; and the potential redifferentiation of dedifferentiated mouse beta cells in vivo. Here, we highlight key findings in this provocative field and provide a perspective on possible exploitation of human pancreatic plasticity for therapeutic beta cell regeneration.


Radiation reduction during percutaneous coronary intervention: A new protocol with a low frame rate and selective fluoroscopic image storage.
The percutaneous coronary intervention (PCI) procedure is associated with potentially high levels of radiation exposure and therefore increased risk of adverse radiation-induced outcomes, ranging from cataract to malignancy. Frame rate reduction and selective fluoroscopy storage may help reduce radiation exposure. In this study, we evaluated the efficacy of a radiation reduction protocol that uses a lower frame rate and selective storage of fluoroscopic images in terms of its effect on reducing the radiation dose during PCI.The new protocol incorporated a lower frame rate as compared with the conventional protocol, and used selective storage of fluoroscopic images. We reviewed the medical records of patients who underwent PCI under the conventional protocol from January 2013 to December 2013, and compared them with those who underwent PCI with the new protocol from January 2015 to December 2015. The primary endpoint was radiation dose reduction expressed as cumulative air kerma and dose-area product (DAP). The image quality was assessed by 3 independent well-trained cardiologists.One hundred fifty-five patients were enrolled in the conventional protocol group, and 152 were enrolled in the radiation reduction protocol group (total, n = 307). There was no statistical significance in terms of the baseline characteristics, including body mass index. Overall, the radiation reduction protocol group showed a significant reduction in both cumulative air kerma (1634.39 ± 717.95 vs 2074.75 ± 1003.72 mGy, P < .001) and DAP (12344.86 ± 5371.75 vs 15312.19 ± 7136.58 μGy m, P < .001). Image quality was acceptable in both groups.The radiation reduction protocol, which uses a lower frame rate and selective storage of fluoroscopic images, may be an alternative approach to reducing PCI radiation dose.


Susceptibility of the horn fly, Haematobia irritans irritans (Diptera: Muscidae), to insecticides in Brazil.
Since horn fly populations became established throughout Brazil, complaints regarding control failure have increased around the country. A broad survey to evaluate the susceptibility of horn flies to both organophosphate (OP) and pyrethroid insecticides was conducted from October 2000 to April 2003. Bioassays using filter papers impregnated with cypermethrin, permethrin or diazinon were conducted on 154 horn fly populations in 14 states and 78 municipalities. Resistance to cypermethrin, the active ingredient present in most insecticide products for horn fly control in Brazil, was detected in 98.46% of the populations, with resistance ratios (RR) ranging from 2.5 to 719.9. Resistance to permethrin (RRs < 6.3) was found in 96.67% of the populations, despite its lack of use. In general, pyrethroid resistance was detected in 97.18% of the horn fly populations, with frequencies greater than 87% in all regions of the country. The status of susceptibility of horn fly populations in Brazil to insecticides can be characterized by high susceptibility to OPs and widespread resistance to pyrethroids, potentially compromising the efficacy of pyrethroid products in most cases. Although some partial results have previously been presented, a general picture of horn fly susceptibility in Brazil is presented here for the first time.


Influence of Body Mass Index and Albumin on Perioperative Morbidity and Clinical Outcomes in Resected Pancreatic Adenocarcinoma.
Obesity is a known risk factor for PDA and recent reports suggest obesity has a negative impact on clinical outcomes in patients with PDA. Pretreatment body mass index (BMI) and serum albumin (SA) have been shown to be associated with worse overall survival in patients with advanced and metastatic PDA. However, minimal data exists on the impact of BMI and SA on perioperative and long-term clinical outcomes in patients with early-stage resected PDA. Herein, we report on the impact of these variables on perioperative clinical outcomes, overall survival (OS) and disease free survival (DFS) in patients with resected PDA. With IRB approval, we evaluated 1,545 patients with PDA treated at a single institution from 2007-2013 and identified 106 patients who underwent upfront resection with curative intent. BMI and SA were calculated preoperatively and at the time of last clinical evaluation. Influence of preoperative BMI, SA, change in either variable, and influence of other clinical and pathologic variables on perioperative morbidity and mortality was assessed. The impact of these variables on DFS and OS was assessed with cox regression modeling and ANOVA. Actuarial estimates for DFS and OS were calculated using Kaplan-Meier methods. Median follow up time was 16 months (3-89). Mean age was 68 years. Median survival was 14 months (3-65) and median time to recurrence was 11 months (1-79). Length of hospital stay was associated with BMI (p = .023), change in BMI (p = .003) and SA (p = .004). Post-operative transfusion rate was associated with SA (p = .021). There was a strong correlation between BMI change and positive margin (p = .04) and lymph node status (p = .01). On multivariate analysis, change in SA (p = .03) and node positivity (p = .008) were associated with decreased DFS. Additionally, preoperative SA (p = .023), node positivity (p = .026) and poor differentiation (p = .045) were associated with worse OS on multivariate analysis. Low preoperative SA was associated with worse DFS and OS in patients with resected PDA. Lower BMI and SA were associated with longer post-operative hospital stay. Our study is one of the first to describe how pre-operative BMI and SA and post-operative changes in these variables impact clinical and perioperative outcomes. This data supports nutritional status and weight loss as predictors of outcome in resected pancreatic cancer patients and warrants further prospective investigation.


Clinical guideline on adenotonsillectomy: the Italian experience.
Five years after publishing the document on 'The clinical and organizational appropriateness of tonsillectomy and adenoidectomy' in 2003, a multidisciplinary group of experts came together again to update this document and to publish a guideline with grading of evidences and recommendations. Major revisions of the previous document were addressed to: (1) the diagnosis and indications for adenotonsillectomy in presence of OSAS in children, (2) the analysis of advantages of new surgical techniques in terms of effectiveness, costs or the risk of postsurgery bleeding and recurrences, and (3) the efficacy of perioperative management in reducing the incidence and duration of post-operative events. In fact, in the last years, a relevant number of evidence became available on the above-mentioned items making the need for a continuing updating of guidelines tangible. As a premise to the guideline, it is stressed how the previous document impact was prominent: the decrease of total number of tonsillectomy in Italy was evident and accompanied by a decrease of variations in the regional rates. Besides the document contributed to strengthen the multidisciplinary collaboration, especially between pediatricians and otorhinolaryngologists, and to divulge the Evidence-Based Medicine culture.


Selective immunomodulation by the antineoplastic agent mitoxantrone. II. Nonspecific adherent suppressor cells derived from mitoxantrone-treated mice.
Mitoxantrone exerts a potent suppressive influence upon humoral immune responses. The B cell is a likely target for this inhibitory effect, and we have reported evidence supporting this possibility. The impact of mitoxantrone upon T lymphocyte reactivity was assessed as a second mode of action of this novel antineoplastic drug. TH and TS lymphocyte induction were tested in the in vitro anti-sheep erythrocyte response, and a surprising differential effect of mitoxantrone was observed. Helper activity was abrogated and suppressor function was enhanced. In apparent disagreement with this result, mitoxantrone inhibited the in vivo induction of TS cells using trinitrophenylated spleen cells. Macrophages were investigated as potential mediators of these effects upon immunoregulatory function. Replacement of macrophages in mitoxantrone-treated spleen cell preparations by normal adherent cells allowed the induction and complete expression of TH lymphocyte function. Conversely, replacement of mitoxantrone-treated macrophages with normal adherent cells before induction of TS cells failed to generate TS cell function. Thus, TH cells were resistant and TS cells were completely susceptible to mitoxantrone. Furthermore, supplementation of normal TH cell cultures with splenic macrophages from mitoxantrone-treated mice inhibited the induction of helper function. Production of the lymphokines IL 2 and TRF in mitoxantrone-treated mice was normal. This is consistent with the retention of functional TH cells in drug-treated spleens. Macrophages in the spleens of mitoxantrone-treated mice were responsible for the abrogated helper function and the enhanced suppressor activity. Although TS cell induction was directly inhibited by the drug, the effect upon TH cell function was secondary to the action of mitoxantrone-induced suppressor macrophages. Mitogen-stimulated lymphokine production was normal. Thus, mitoxantrone is a selective immunomodulator. The macrophage-mediated suppression of TH cell induction and humoral immunity investigated in spleens from mitoxantrone-treated mice is an intriguing finding that may have significant implications for immunotherapy.


The survival of motor neurons protein determines the capacity for snRNP assembly: biochemical deficiency in spinal muscular atrophy.
Reduction of the survival of motor neurons (SMN) protein levels causes the motor neuron degenerative disease spinal muscular atrophy, the severity of which correlates with the extent of reduction in SMN. SMN, together with Gemins 2 to 7, forms a complex that functions in the assembly of small nuclear ribonucleoprotein particles (snRNPs). Complete depletion of the SMN complex from cell extracts abolishes snRNP assembly, the formation of heptameric Sm cores on snRNAs. However, what effect, if any, reduction of SMN protein levels, as occurs in spinal muscular atrophy patients, has on the capacity of cells to produce snRNPs is not known. To address this, we developed a sensitive and quantitative assay for snRNP assembly, the formation of high-salt- and heparin-resistant stable Sm cores, that is strictly dependent on the SMN complex. We show that the extent of Sm core assembly is directly proportional to the amount of SMN protein in cell extracts. Consistent with this, pulse-labeling experiments demonstrate a significant reduction in the rate of snRNP biogenesis in low-SMN cells. Furthermore, extracts of cells from spinal muscular atrophy patients have a lower capacity for snRNP assembly that corresponds directly to the reduced amount of SMN. Thus, SMN determines the capacity for snRNP biogenesis, and our findings provide evidence for a measurable deficiency in a biochemical activity in cells from patients with spinal muscular atrophy.


Nurses' experience of violence in Alberta and British Columbia hospitals.
This study examined responses to a survey on violence in the workplace from a sample of 8,780 registered nurses practising in 210 hospitals in the Canadian provinces of Alberta and British Columbia. Findings relate to the frequency of violence against nurses, reported as the number of times they experienced a violent incident in the workplace. Nearly half (46%) of those surveyed had experienced 1 or more types of violence in the last 5 shifts worked. Frequency varied by type: emotional abuse 38%, threat of assault 19%, physical assault 18%, verbal sexual harassment 7.6%, sexual assault 0.6%. Further, 70% of those who had experienced violence indicated they had not reported it. Patients constituted the main source of all types of violence. The most prevalent type, emotional abuse, was further explored for its possible determinants. This was also the type of violence most evenly distributed among sources (patients, families, co-workers, physicians). Multiple regression modelling using the individual nurse as the unit of analysis showed the significant predictors of emotional abuse to be age, casual job status, quality of care, degree of hospital restructuring, type of unit, relationships among hospital staff, nurse-to-patient ratios, and violence-prevention measures; using the hospital as the unit of analysis the predictors were found to be quality of care, age, relationships with hospital staff, presence of violence-prevention measures, and province. These findings illustrate important differences in models that use the individual and the institution as the unit of analysis. Implications include targeting prevention strategies not only at the nurse but, perhaps more importantly, at the hospital. Overall, the findings suggest that health-care institutions are not always healthy workplaces and may increasingly be stressful and hazardous ones.


REGγ deficiency promotes premature aging via the casein kinase 1 pathway.
Our recent studies suggest a role for the proteasome activator REG (11S regulatory particles, 28-kDa proteasome activator)γ in the regulation of tumor protein 53 (p53). However, the molecular details and in vivo biological significance of REGγ-p53 interplay remain elusive. Here, we demonstrate that REGγ-deficient mice develop premature aging phenotypes that are associated with abnormal accumulation of casein kinase (CK) 1δ and p53. Antibody array analysis led us to identify CK1δ as a direct target of REGγ. Silencing CK1δ or inhibition of CK1δ activity prevented decay of murine double minute (Mdm)2. Interestingly, a massive increase of p53 in REGγ(-/-) tissues is associated with reduced Mdm2 protein levels despite that Mdm2 transcription is enhanced. Allelic p53 haplodeficiency in REGγ-deficient mice attenuated premature aging features. Furthermore, introducing exogenous Mdm2 to REGγ(-/-) MEFs significantly rescues the phenotype of cellular senescence, thereby establishing a REGγ-CK1-Mdm2-p53 regulatory pathway. Given the conflicting evidence regarding the "antiaging" and "proaging" effects of p53, our results indicate a key role for CK1δ-Mdm2-p53 regulation in the cellular aging process. These findings reveal a unique model that mimics acquired aging in mammals and indicates that modulating the activity of the REGγ-proteasome may be an approach for intervention in aging-associated disorders.


The sounds of cardiac arrest: innovating to obtain an accurate record during in-hospital cardiac arrest.
To obtain an accurate audit during in-hospital cardiac arrest, following recommendations of the Utstein style and measuring time intervals between the different interventions, is difficult. To assess whether the use of an audio recording system during in-hospital cardiac arrest resuscitation allows the register of more items during cardiopulmonary resuscitation. Prospective observational study between January 2008 and December 2009. The population that were included, were hospitalized patients and non-hospitalized patients assisted by a cardiac arrest team, except for critical areas. An audio recording system with a timer was turned on when cardiac arrest team was alerted. Recordings were reviewed to fill in the items recommended by the Utstein style. Time intervals were calculated. Mean number of completed items per patient were compared between recorded and non-recorded cardiac arrest. 119 CA team alerts took place. 64 (53.7%) cases were real CA and 37 (57.8%) of them were properly recorded. A mean number of items per patient in recorded cardiac arrest cases were 18.18 (±3.2) vs. 15.96 (±4.1) in non-recorded cardiac arrest cases (p<0.05). In the recorded cases, mean times were: alert - arrival: 1.23 (±0.95)min; arrival - cardiopulmonary resuscitation initiation: 0.63 (±0.38)min; arrival - first defibrillation: 2.06 (±1.33)min; arrival - intubation: 8.42 (±4.64)min; arrival - first adrenaline: 3.30 (±1.98)min. The audio recording system permits the register of a larger number of items per patient during in-hospital cardiac arrest and allows measurement of time intervals between the different interventions during cardiopulmonary resuscitation.


Phospholipid subclass specific alterations in the passive ion permeability of membrane bilayers: separation of enthalpic and entropic contributions to transbilayer ion flux.
Alterations in phospholipid class, subclass, and individual molecular species contribute to the diversity of biologic membranes, but their effects on membrane passive ion permeability have not been systematically studied. Herein, we developed a simple and efficient fluorescence technique based upon the loss of valinomycin-inducible membrane potential to characterize the passive flux of ions across phospholipid bilayers. Detailed kinetic characterization of ion flux across membrane bilayers composed of discrete chemical entities demonstrated that the class, subclass, and individual molecular species of each phospholipid have substantive effects on membrane passive ion permeability properties. Increasing the degree of unsaturation in either the sn-1 or sn-2 aliphatic chains in phosphatidylcholine markedly enhanced transmembrane ion flux, with over 10-fold differences in the first-order rate constant manifested in molecular species containing four double bonds in comparison to those possessing three double bonds (e.g., kapp = 0.0014 min-1 for 1-octadec-9'-enoyl-2-octadec-9', 12'-dienoyl-sn-glycero-3-phosphocholine (18:1-18:2 phosphatidylcholine) while kapp = 0.021 min-1 for 1,2-dioctadec-9', 12'-dienoyl-sn-glycero-3-phosphocholine (18:2-18:2 phosphatidylcholine)). Moreover, although the apparent first-order rate constants for transmembrane ion flux in vesicles composed of phosphatidylcholine or plasmanylcholine containing palmitate at the sn-1 position and arachidonate at the sn-2 position were similar (kapp = 0.04 min-1 at 22 degreesC for both), the kapp for corresponding vesicles composed of plasmenylcholine was 20-fold less (kapp = 0.002 min-1 at 22 degreesC). Examination of the temperature dependence of passive membrane ion permeability demonstrated that altered ion flux across membranes composed of choline glycerophospholipids was primarily due to entropic effects without substantial changes in the activation energy for ion translocation. For example, Ea = 19.7 +/- 0.5 and 20.7 +/- 0.6 kcal.mol-1 for 1-hexadecanoyl-2-eicosa-5',8',11', 14'-tetraenoyl-sn-glycero-3-phosphocholine (16:0-20:4 phosphatidylcholine) and 1-O-(Z)-hexadec-1'-enyl-2-eicosa-5',8',11', 14'-tetraenoyl-sn-glycero-3-phosphocholine (16:0-20:4 plasmenylcholine), respectively, while their difference in the entropies of activation (DeltaS) was 4.3 +/- 0.5 cal.mol-1.K-1. Collectively, these results identify substantial differences in the membrane passive ion permeability properties of phospholipid classes, subclasses, and molecular species present in biologic membranes of eukaryotic cells and identify entropic alterations as an important contributor to these differences.


[Rationale for implant insertion after enucleation of eyes with uveal melanoma].
Results of retrospective analysis of medical charts of 328 patients after enucleation due to uveal melanoma (UM) are represented. Our study showed that recurrent tumor occurs in 2.44% cases. The main reasons of recurrence are scleral invasion or tumor damage during surgery. After enucleation due to juxtapapillary UM recurrence is rare and occurs after long-term follow-up. Thus after enucleation due to UM implant insertion is possible in case of scleral integrity and absence of macroscopically apparent tumor extension beyond sclera.


[Activation of neutrophils in allergic asthmatics].
Neutrophil chemotactic activity (NCA) and activity of myeloperoxidase (MPO) of the neutrophils in asthmatic patients during attacks and in remission and normal controls were determined. The results showed that NCA and activity of MPO in asthmatic patients during attacks were significantly higher than those in remission and in the controls. There was no difference of either NCA or the activity of MPO between asthmatic patients in remission and the controls. There was definite correlation between NCA and activity of MPO in asthmatic patients during attacks, but no correlation between the asthmatic patients in remission and the controls. The results suggest that chemotaxis and activation of neutrophils by neutrophil chemotactic factor may play an important role in pathophysiology of asthma.


Examination of X chromosome markers in Rett syndrome: exclusion mapping with a novel variation on multilocus linkage analysis.
Rett syndrome is a neurologic disorder characterized by early normal development followed by regression, acquired deceleration of head growth, autism, ataxia, and stereotypic hand movements. The exclusive occurrence of the syndrome in females and the occurrence of a few familial cases with inheritance through maternal lines suggest that this disorder is most likely secondary to a mutation on the X chromosome. To address this hypothesis and to identify candidate regions for the Rett syndrome gene locus, genotypic analysis was performed in two families with maternally related affected half-sisters by using 63 DNA markers from the X chromosome. Maternal and paternal X chromosomes from the affected sisters were separated in somatic cell hybrids and were examined for concordance/discordance of maternal alleles at the tested loci. Thirty-six markers were informative in at least one of the two families, and 25 markers were informative in both families. Twenty loci were excluded as candidates for the Rett syndrome gene, on the basis of discordance for maternal alleles in the half-sisters. Nineteen of the loci studied were chosen for multipoint linkage analysis because they have been previously genetically mapped using a large number of meioses from reference families. Using the exclusion criterion of a lod score less than -2, we were able to exclude the region between the Duchenne muscular dystrophy locus and the DXS456 locus. This region extends from Xp21.2 to Xq21-q23. The use of the multipoint linkage analysis approach outlined in this study should allow the exclusion of additional regions of the X chromosome as new markers are analyzed. This in turn will result in a defined region of the X chromosome that should be searched for candidate sequences for the Rett syndrome gene in both familial and sporadic cases.


Severe Haemophilus influenzae infections.
From May 1973 thorugh April 1974, a total of 83 children with severe Haemophilus influenzae infections were treated in three Denver pediatric hospitals. Although meningitis was the most common clinical manifestation (45 cases), other foci of infection were also noted (pneumonia, 12 cases; cheek cellulitis, eight cases; epiglottitis, eight cases; empyema, seven cases; pericarditis, three cases; arthritis, one case; periorbital cellulitis, one case; and abscess, one case). Nine children had positive blood cultures with H influenzae without an initial detectable focus of infection. Two patients developed clinically apparent sites of infection (osteomyelitis and scalp abscesses).


Tower of London test: a comparison between conventional statistic approach and modelling based on artificial neural network in differentiating fronto-temporal dementia from Alzheimer's disease.
The early differentiation of Alzheimer's disease (AD) from frontotemporal dementia (FTD) may be difficult. The Tower of London (ToL), thought to assess executive functions such as planning and visuo-spatial working memory, could help in this purpose. Twentytwo Dementia Centers consecutively recruited patients with early FTD or AD. ToL performances of these groups were analyzed using both the conventional statistical approaches and the Artificial Neural Networks (ANNs) modelling. Ninety-four non aphasic FTD and 160 AD patients were recruited. ToL Accuracy Score (AS) significantly (p < 0.05) differentiated FTD from AD patients. However, the discriminant validity of AS checked by ROC curve analysis, yielded no significant results in terms of sensitivity and specificity (AUC 0.63). The performances of the 12 Success Subscores (SS) together with age, gender and schooling years were entered into advanced ANNs developed by Semeion Institute. The best ANNs were selected and submitted to ROC curves. The non-linear model was able to discriminate FTD from AD with an average AUC for 7 independent trials of 0.82. The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients.


The Principles of Revised Clinical Guidelines about Palliative Sedation Therapy of the Japanese Society for Palliative Medicine.
Background: When the suffering of a terminally ill patient is intolerable and refractory, sedatives are sometimes used for symptom relief. Objective: To describe the main principles of revised Japanese clinical guidelines about palliative sedation therapy. Design: Consensus methods using the Delphi technique were used. Results: The main principles of the guidelines that were newly defined or developed are as follows: (1) palliative sedation was defined as "administration of sedatives for the purpose of alleviating refractory suffering" (excluding the aim of reducing patient consciousness); (2) palliative sedation was classified according to the method of administration of sedatives: respite sedation versus continuous sedation (including (continuous) proportional sedation and continuous deep sedation); (3) a description of state-of-the-art recommended treatments for difficult symptoms such as delirium, dyspnea, and pain before the symptom was determined as refractory was included; (4) the principle of proportionality was newly defined from an ethical point of view; and (5) families' consent was regarded as being desirable (mandatory in the previous version). Conclusions: We described the main principles of revised Japanese clinical guidelines about palliative sedation therapy. Further consensus building is necessary.


Sulphation of proteochondroitin and 4-methylumbelliferyl beta-D-xyloside-chondroitin formed by mouse mastocytoma cells cultured in sulphate-deficient medium.
Mouse mastocytoma cells were cultured in medium containing [3H]GlcN and concentrations of [35S]sulphate varying from 0.01 to 0.5 mM. Intracellular [35S]sulphate incorporation increased severalfold from the lowest concentrations, reaching a maximum at 0.1-0.2 mM, whereas incorporation of [3H]hexosamine remained constant at all sulphate concentrations. Proteo[3H]-chondroitin [35S]sulphate was isolated and incubated with chondroitin ABC lyase, yielding 35S-labelled and/or 3H-labelled delta Di-0S and delta Di-4S disaccharide products. The increasing percentage of delta Di-4S was consistent with the increasing sulphate incorporation at each higher [35S]sulphate concentration. Examination of proteochondroitin [35S]sulphate size by Sepharose CL-6B chromatography indicated a range consistent with various numbers of glycosaminoglycan chains on the protease-resistant serglycin core protein. Alkali-cleaved chondroitin [35S]sulphate products indicated similar size distributions at all sulphate concentrations with no indication of preferential sulphation being related to smaller or larger size. DEAE-cellulose chromatography of [3H]chondroitin [35S]sulphate glycosaminoglycans indicated a random undersulphation as [35S]sulphate concentration was lowered. Addition of 4-methylumbelliferyl beta-D-xyloside to the cultures resulted in a 2-2.5-fold stimulation of [3H]chondroitin [35S]sulphate synthesis with formation of beta-xyloside-[3H]chondroitin [35S]sulphate which was much smaller, as estimated by Sepharose CL-6B chromatography, than the decreased amount of [3H]chondroitin [35S]sulphate derived from proteo[3H]chondroitin [35S]sulphate. Much higher concentrations of sulphate were necessary to produce sulphation of the beta-xyloside-[3H]chondroitin comparable with that of proteo[3H]-chondroitin, as indicated by chondroitin ABC lyase products and DEAE-cellulose chromatography. The specific radioactivities of the [3H]GalN in the proteo[3H]chondroitin [35S]sulphate and beta-xyloside-[3H]chondroitin [35S]sulphate were calculated from the 3H and 35S c.p.m. of isolated dual-labelled delta Di-4S from each, and indicated that the presence of the beta-xyloside resulted in a dilution of the [3H]GlcN by endogenous GlcN that was 4 times higher than that of cultures lacking the beta-xyloside. The higher sulphate concentrations needed for sulphation of beta-xyloside-chondroitin suggests that the membrane-bound nature of the proteochondroitin acceptor in juxtaposition to a chondroitin sulphate-synthesizing enzyme complex effectively reduces the apparent Km for adenosine 3'-phosphate 5'-phosphosulphate.


Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
The purpose of this study was to assess the effect of persistent organochlorine compounds through the dietary intake of fatty fish from the Baltic Sea on human fertility. Information on time to pregnancy, subfertility, and infertility was collected retrospectively by self-administered questionnaires in 2 cohorts of fishermen's wives from the Swedish east (by the Baltic Sea) and west coasts. In addition to cohort affiliation, current fish consumption and growing up in a fishing village were used as proxies for exposure within the eastcoast cohort. A decreased success (ie, pregnancy) rate and a tendency towards increased subfertility was found for heavy smokers (> or =10 cigarettes/day) in the eastcoast cohort as compared with the westcoast cohort [success rate ratio 0.66, 95% confidence interval (95% CI) 0.49-.89; subfertility odds ratio 1.64, 95% CI 0.91-2.91). However, internal analyses within the eastcoast cohort did not show that growing up in a fishing village or high current fish consumption decreased the success rate. Eastcoast cohort affiliation showed an increased risk for infertility (odds ratio 2.49, 95% CI 1.05-5.92). The present data give some support for a negative association between exposure to persistent organochlorine compounds and fertility among heavy smokers. However, when the proxy exposure measures are also considered, the findings are not consistent. Better individual exposure assessments should be used before more firm conclusions are drawn.


Law enforcement and firearms: understanding firearm ownership and storage habits.
This study seeks to better understand firearm ownership among law enforcement officers (LEO), with the goal of informing future firearm injury and suicide prevention efforts. We describe the frequency and sociodemographic correlates of firearm ownership and storage practices among, and examine the association between suicidal ideation and current firearm storage practices. The present study used data from a large online study (n=6410) and included data from individuals who were currently or previously being employed as an LEO (n=369; M (SD) age=39.2 y (15.8 y), 75.2% male, 66.7% white). Self-report measures were used to assess for firearm ownership, storage habits and suicidal ideation. Descriptive statistics were used to describe the frequency of firearm ownership and logistic regressions were used to examine the extent to which demographic characteristics and suicidal ideation were associated with firearm ownership. Overall, 70.5% (n=261) of the sample reported firearm ownership. LEO who were older had significantly lower odds of reporting firearm ownership. Those who were married and those who reported lifetime suicidal ideation had significantly greater odds of reporting firearm ownership. Whereas firearm-owning LEO who reporting storing a firearm locked had significantly lower odds of reporting lifetime suicidal ideation, those who reported storing a firearm unloaded had significantly greater odds of reporting lifetime suicidal ideation. Findings have important public health implications and can be used to increase adherence with secure storage recommendations. Increasing secure storage may help reduce suicide risk among LEO, a sample at heightened risk for suicide.


Ancient and novel small RNA pathways compensate for the loss of piRNAs in multiple independent nematode lineages.
Small RNA pathways act at the front line of defence against transposable elements across the Eukaryota. In animals, Piwi interacting small RNAs (piRNAs) are a crucial arm of this defence. However, the evolutionary relationships among piRNAs and other small RNA pathways targeting transposable elements are poorly resolved. To address this question we sequenced small RNAs from multiple, diverse nematode species, producing the first phylum-wide analysis of how small RNA pathways evolve. Surprisingly, despite their prominence in Caenorhabditis elegans and closely related nematodes, piRNAs are absent in all other nematode lineages. We found that there are at least two evolutionarily distinct mechanisms that compensate for the absence of piRNAs, both involving RNA-dependent RNA polymerases (RdRPs). Whilst one pathway is unique to nematodes, the second involves Dicer-dependent RNA-directed DNA methylation, hitherto unknown in animals, and bears striking similarity to transposon-control mechanisms in fungi and plants. Our results highlight the rapid, context-dependent evolution of small RNA pathways and suggest piRNAs in animals may have replaced an ancient eukaryotic RNA-dependent RNA polymerase pathway to control transposable elements.


Metabolomic Profiling and Cytotoxic Tetrahydrofurofuran Lignans Investigations from Premna odorata Blanco.
Metabolomic profiling of different Premna odorata Blanco (Lamiaceae) organs, bark, wood, young stems, flowers, and fruits dereplicated 20, 20, 10, 20, and 20 compounds, respectively, using LC-HRESIMS. The identified metabolites (1-34) belonged to different chemical classes, including iridoids, flavones, phenyl ethanoids, and lignans. A phytochemical investigation of P. odorata bark afforded one new tetrahydrofurofuran lignan, 4β-hydroxyasarinin 35, along with fourteen known compounds. The structure of the new compound was confirmed using extensive 1D and 2D NMR, and HRESIMS analyses. A cytotoxic investigation of compounds 35-38 against the HL-60, HT-29, and MCF-7 cancer cell lines, using the MTT assay showed that compound 35 had cytotoxic effects against HL-60 and MCF-7 with IC50 values of 2.7 and 4.2 µg/mL, respectively. A pharmacophore map of compounds 35 showed two hydrogen bond acceptor (HBA) aligning the phenoxy oxygen atoms of benzodioxole moieties, two aromatic ring features vectored on the two phenyl rings, one hydrogen bond donor (HBD) feature aligning the central hydroxyl group and thirteen exclusion spheres which limit the boundaries of sterically inaccessible regions of the target's active site.


Zinc supplements for treating thalassaemia and sickle cell disease.
Haemoglobinopathies, inherited disorders of haemoglobin synthesis (thalassaemia) or structure (sickle cell disease), are responsible for significant morbidity and mortality throughout the world. The WHO estimates that, globally, 5% of adults are carriers of a haemoglobin condition, 2.9% are carriers of thalassaemia and 2.3% are carriers of sickle cell disease. Carriers are found worldwide as a result of migration of various ethnic groups to different regions of the world. Zinc is an easily available supplement and intervention programs have been carried out to prevent deficiency in people with thalassaemia or sickle cell anaemia. It is important to evaluate the role of zinc supplementation in the treatment of thalassaemia and sickle cell anaemia to reduce deaths due to complications. To assess the effect of zinc supplementation in the treatment of thalassaemia and sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 01 February 2013. Randomised, placebo-controlled trials of zinc supplements for treating thalassaemia or sickle cell disease administered at least once a week for at least a month. Two review authors assessed the eligibility and risk of bias of the included trials, extracted and analysed data and wrote the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate. We identified nine trials for inclusion with all nine contributing outcome data. Two trials reported on people with thalassaemia (n = 152) and seven on sickle cell anaemia (n = 307).In people with thalassaemia, in one trial, the serum zinc level value showed no difference between the zinc supplemented group and the control group, mean difference 47.40 (95% confidence interval -12.95 to 107.99). Regarding anthropometry, in one trial, height velocity was significantly increased in patients who received zinc supplementation for one to seven years duration, mean difference 3.37 (95% confidence interval 2.36 to 4.38) (total number of participants = 26). In one trial, however, there was no difference in body mass index between treatment groups.Zinc acetate supplementation for three months (in one trial) and one year (in two trials) (total number of participants = 71) was noted to increase the serum zinc level significantly in patients with sickle cell anaemia, mean difference 14.90 (95% confidence interval 6.94 to 22.86) and 20.25 (95% confidence interval 11.73 to 28.77) respectively. There was no significant difference in haemoglobin level between intervention and control groups, at either three months (one trial) or one year (one trial), mean difference 0.06 (95% confidence interval -0.84 to 0.96) and mean difference -0.07 (95% confidence interval -1.40 to 1.26) respectively. Regarding anthropometry, one trial showed no significant changes in body mass index or weight after one year of zinc acetate supplementation. In patients with sickle cell disease, the total number of sickle cell crises at one year were significantly decreased in the zinc sulphate supplemented group as compared to controls, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (total participants 130), but not in zinc acetate group, mean difference 1.54 (95% confidence interval -2.01 to 5.09) (total participants 22). In one trial at three months and another at one year, the total number of clinical infections were significantly decreased in the zinc supplemented group as compared to controls, mean difference 0.05 (95% confidence interval 0.01 - 0.43) (total number of participants = 36), and mean difference -7.64 (95% confidence interval -10.89 to -4.39) (total number of participants = 21) respectively. According to the results, there is no evidence from randomised controlled trials to indicate any benefit of zinc supplementation with regards to serum zinc level in patients with thalassaemia. However, height velocity was noted to increase among those who received this intervention.There is mixed evidence on the benefit of using zinc supplementation in people with sickle cell disease. For instance, there is evidence that zinc supplementation for one year increased the serum zinc levels in patients with sickle cell disease. However, though serum zinc level was raised in patients receiving zinc supplementation, haemoglobin level and anthropometry measurements were not significantly different between groups. Evidence of benefit is seen with the reduction in the number of sickle cell crises among sickle cell patients who received one year of zinc sulphate supplementation and with the reduction in the total number of clinical infections among sickle cell patients who received zinc supplementation for both three months and for one year.The conclusion is based on the data from a small group of trials,which were generally of good quality, with a low risk of bias. The authors recommend that more trials on zinc supplementation in thalassaemia and sickle cell disease be conducted given that the literature has shown the benefits of zinc in these types of diseases.


Costs of administration, travelling, and productivity losses associated with hospital administration of multiple myeloma drugs in Finland.
To estimate the drug administration, travelling, and productivity costs associated with infusion or subcutaneous proteasome inhibitor (PI) treatments (specifically carfilzomib and bortezomib) for multiple myeloma (MM) patients in Finland. Price tariffs of Finnish hospital districts are used as the basis of invoicing sent to healthcare service payers. A review of these price tariff lists was conducted and obtained data analysed to estimate the mean unit cost of PI administration visit. Travelling costs stratified by areas with different population densities were assessed, based on the national travelling reimbursement register data maintained by the Social Insurance Institution of Finland. Productivity costs due to time spent on administration visits and travelling were estimated based on an expert interview and a spatial healthcare accessibility analysis. Nineteen (95%) of the Finnish hospital districts were included in the review. Relevant unit cost information was found for 15 (75%) of the districts. The mean PI administration cost alone was 270€ (95% CI = 189€-351€) per administration and increased to 371€ when travelling costs were included. Productivity costs added, the mean PI administration costs totalled 405€ for bortezomib and 437€ for carfilzomib. The costing rationale of price tariffs may vary between hospital districts. Productivity costs were estimated conservatively, due to lack of data. The administration of intravenous or subcutaneous PIs to treat MM in healthcare facilities causes significant and potentially avoidable healthcare, travelling, and indirect costs, and they should be included in all health economic evaluations (HEEs). As the cost estimates utilized in this study represent most of central hospitals in the country, they provide useful information for future HEEs. A broader conclusion is that novel oral medications, such as the first oral PI, have a significant potential for reducing administration-related costs of subcutaneous or intravenous PIs.


Pelvic lymphoscintigraphy: contribution to the preoperative staging of rectal cancer.
Preservation of the anal sphincter in surgery for cancer of the distal rectum in an attempt to avoid colostomy has been a main concern of colorectal surgeons. Various proposed procedures contradict oncological principles, especially with respect to pelvic lymphadenectomy. Therefore, prior knowledge of pelvic lymph node involvement is an important factor in choosing the operative technique, i.e., radical or conservative resection. Introduction of ultrasound, computerized tomography, and magnetic resonance have made preoperative study of the area possible. Nevertheless, these resources offer information of an anatomical nature only. Lymphoscintigraphy enables the morphological and functional evaluation of the pelvic area and contributes toward complementing the data obtained with the other imaging techniques. The objective of this prospective study is twofold: to standardize the lymphoscintigraphy technique and to use it to differentiate patients with rectal cancer from those with other coloproctologic diseases. Sixty patients with various coloproctologic diseases were studied prospectively. Ages ranged from 21 to 96 years (average, 51 and median, 55 years). Twenty-six patients were male and 34 were female. Thirty patients had carcinoma of the distal rectum as diagnosed by proctologic and anatomic-pathologic examinations, 20 patients had hemorrhoids, 5 had chagasic megacolon, 2 had diverticular disease, 2 had neoplasm of the right colon, and 1 had ulcerative colitis as diagnosed by proctologic exam and/or enema. The lymphoscintigraphy method consisted of injecting 0.25 mL of a dextran solution marked with radioactive technetium-99m into the right and left sides of the perianal region and obtaining images with a gamma camera. The results were analyzed statistically with a confidence level of 95% (P <.05) using the following statistical techniques: arithmetic and medium average, Fisher exact test, chi-square test corrected for continuity according to Yates, and distribution tables for the number of patients. In rectal cancer, the tracer progresses unilaterally or is absent; in other patients, the progress of the tracer is bilateral and symmetrical, although its progress may be slow. Statistical tests showed with high significance that the agreement index between the clinical diagnosis and the result of the lymphoscintigraphic exam was 93%. Lymphoscintigraphy is a standardized, painless, and harmless test that can be performed in all cases; it differentiates patients with rectal cancer from those with other coloproctological diseases.


Trimming Surface Sugars Protects Histoplasma from Immune Attack.
Dectin-1 is an essential innate immune receptor that recognizes β-glucans in fungal cell walls. Its importance is underscored by the mechanisms that fungal pathogens have evolved to avoid detection by this receptor. One such pathogen is Histoplasma capsulatum, and in a recent article in mBio, Rappleye's group presented data showing that yeasts of this organism secrete a β-glucanase, Eng1, which acts to prune β-glucans that are exposed on the fungal cell surface [A. L. Garfoot et al., mBio 7(2):e01388-15, 2016, http://dx.doi.org/10.1128/mBio.01388-15]. The trimming of these sugars reduces immune recognition through Dectin-1 and subsequent inflammatory responses, enhancing the pathogenesis of H. capsulatum.


Early and rapid targeting of eye-specific axonal projections to the dorsal lateral geniculate nucleus in the fetal macaque.
The emergence of eye-specific axonal projections to the dorsal lateral geniculate nucleus (dLGN) is a well established model system for exploring the mechanisms underlying afferent targeting during development. Using modern tract tracing methods, we examined the development of this feature in the macaque, an Old World Primate with a visual system similar to that of humans. Cholera toxin beta fragment conjugated to Alexa 488 was injected into the vitreous of one eye, and CTbeta conjugated to Alexa 594 into the other eye of embryos at known gestational ages. On embryonic day 69 (E69), which is approximately 100 d before birth, inputs from the two eyes were extensively intermingled in the dLGN. However, even at this early age, portions of the dLGN were preferentially innervated by the right or left eye, and segregation is complete within the dorsalmost layers 5 and 6. By E78, eye-specific segregation is clearly established throughout the parvocellular division of the dLGN, and substantial ocular segregation is present in the magnocellular division. By E84, segregation of left and right eye axons is essentially complete, and the six eye-specific domains that characterize the mature macaque dLGN are clearly discernable. These findings reveal that targeting of eye-specific axonal projections in the macaque occurs much earlier and more rapidly than previously reported. This segregation process is completed before the reported onset of ganglion cell axon loss and retino-dLGN synapse elimination, suggesting that, in the primate, eye-specific targeting occurs independent of traditional forms of synaptic plasticity.


All-optical radiation reaction at 10²¹ W/cm².
Using full-scale 3D particle-in-cell simulations we show that the radiation reaction dominated regime can be reached in an all-optical configuration through the collision of a ~1 GeV laser wakefield accelerated electron bunch with a counterpropagating laser pulse. In this configuration the radiation reaction significantly reduces the energy of the particle bunch, thus providing clear experimental signatures for the process with currently available lasers. We also show that the transition between the classical and quantum radiation reaction could be investigated in the same configuration with laser intensities of 10²³ W/cm².


Tryptophan-96 in cytochrome P450 BM3 plays a key role in enzyme survival.
Flavocytochrome P450 from Bacillus megaterium (P450BM3 ) is a natural fusion protein containing reductase and heme domains. In the presence of NADPH and dioxygen the enzyme catalyses the hydroxylation of long-chain fatty acids. Analysis of the P450BM3 structure reveals chains of closely spaced tryptophan and tyrosine residues that might serve as pathways for high-potential oxidizing equivalents to escape from the heme active site when substrate oxidation is not possible. Our investigations of the total number of enzyme turnovers before deactivation have revealed that replacement of selected tryptophan and tyrosine residues with redox inactive groups leads to a twofold reduction in enzyme survival time. Tryptophan-96 is critical for prolonging enzyme activity, suggesting a key protective role for this residue.


Pseudo-peptides based on methyl cysteine or methionine inspired from Mets motifs found in the copper transporter Ctr1.
Most proteins involved in Cu homeostasis bind to intracellular Cu(I) in stable Cu(S-Cys)x environments, thanks to well-conserved cysteine-rich sequences. Similarly, the Cu(I) transport protein Ctr1, responsible for copper acquisition, binds Cu(I) in Cu(S-Met)3 environments in conserved methionine-rich MXMXXM sequences, referred as Mets motifs. Pseudo-peptides based on a nitrilotriacetic acid scaffold and functionalized with three amino acids bearing thioether side chains, either methyl cysteine in T(1) or methionine in T(2), were synthesized as mimics of the Mets sequences found in Ctr1. These two ligands were obtained with good overall yields from commercial amino acids and demonstrate efficient chelating ability for Cu(I). Only one species, the mononuclear [CuT(1,2)](+) complex, was evidenced by electrospray ionization-mass spectroscopy (ESI-MS) and the circular dichroism signature obtained for the most constrained CuT(1) complex having the shortest side chains showed reorganization of the pseudo-peptide scaffold upon Cu(I) complexation. Considering that thioether functions are neutral sulfur donors, the stability constants measured by competition with ferrozine are quite large: log K ≈ 10.2-10.3. The CuT(1,2) complexes are significantly more stable that those formed with linear peptides, mimicking isolated Mets motifs MXMXXM of the Cu transport protein Ctr1 (log K ≈ 5-6). This may be attributed to the preorganized pseudo-peptide scaffold, which arranges the three neutral sulfur donors toward the metal center. Such moderate affinity Cu(I) chelators are interesting for applications in chelation therapy, for instance, to induce minimum disturbance of Cu homeostasis in Wilson's disease treatments.


Facilitation of neuronal activity in somatosensory and posterior parietal cortex during prehension.
In order to study prehension in a reproducible manner, we trained monkeys to perform a task in which rectangular, spherical, and cylindrical objects were grasped, lifted, held, and lowered in response to visual cues. The animal's hand movements were monitored using digital video, together with simultaneously recorded spike trains of neurons in primary somatosensory cortex (S-I) and posterior parietal cortex (PPC). Statistically significant task-related modulation of activity occurred in 78% of neurons tested in the hand area; twice as many cells were facilitated during object acquisition as were depressed. Cortical neurons receiving inputs from tactile receptors in glabrous skin of the fingers and palm, hairy skin of the hand dorsum, or deep receptors in muscles and joints of the hand modulated their firing rates during prehension in consistent and reproducible patterns. Spike trains of individual neurons differed in duration and amplitude of firing, the particular hand behavior(s) monitored, and their sensitivity to the shape of the grasped object. Neurons were classified by statistical analysis into groups whose spike trains were tuned to single task stages, spanned two successive stages, or were multiaction. The classes were not uniformly distributed in specific cytoarchitectonic fields, nor among particular somatosensory modalities. Sequential deformation of parts of the hand as the task progressed was reflected in successive responses of different members of this population. The earliest activity occurred in PPC, where 28% of neurons increased firing prior to hand contact with objects; such neurons may participate in anticipatory motor control programs. Activity shifted rostrally to S-I as the hand contacted the object and manipulated it. The shape of the grasped object had the strongest influence on PPC cells. The results suggest that parietal neurons monitor hand actions during prehension, as well as the physical properties of the grasped object, by shifting activity between populations responsive to hand shaping, grasping, and manipulatory behaviors.


Avian corneal nerves: co-distribution with collagen type IV and acquisition of substance P immunoreactivity.
Within the avian cornea collagen type IV is preferentially and characteristically localized to the epithelial and endothelial basement membranes. In the present paper, we demonstrate that collagen type IV also is present within the corneal stroma coincident with the development and distribution of corneal nerves indicating that intra-stromal fibers are associated with Schwann cells or an equivalent cell type. We also demonstrate intra-stromal fibers of collagen type IV orthogonal to the epithelial basement membrane. These novel structures are most prominent on the tenth day of development and become progressively less distinct until they are no longer detectable on the eighteenth day of development. Substance P immunoreactivity is prominently expressed by nerves innervating the epithelium. The first substance P immunoreactive nerves are detected on the twelfth day of development, concomitant with the initiation of epithelial innervation and not the extension of nerves through the stroma. Such nerve fibers become more numerous with progressive development and demonstrate extensive association with both basal and superficial epithelial cells. Thus, the avian cornea is richly supplied with substance P primary afferents. The expression of substance P immunoreactivity correlates directly with the initiation of innervation of the corneal epithelium.


Knee extension fatigue attenuates repeated force production of the elbow flexors.
Non-local muscle fatigue has been demonstrated with unilateral activities, where fatiguing one limb alters opposite limb forces. Fewer studies have examined if non-local fatigue occurs with unrelated muscles. The purpose of this study was to investigate if knee extensors fatigue alters elbow flexors force and electromyography (EMG) activity. Eighteen males completed a control and fatiguing session (randomised). Blood lactate was initially sampled followed by three maximal voluntary contractions (MVC) with the elbow flexors and two with the knee extensors. Thereafter, subjects either sat (control) or performed five sets of bilateral dynamic knee extensions to exhaustion using a load equal to the dominant limb MVC (1-min rest between sets). Immediately afterwards, subjects were assessed for blood lactate and unilateral knee extensors MVC, and after 1 min performed a single unilateral elbow flexor MVC. Two minutes later, subjects performed 12 unilateral elbow flexor MVCs (5 s contraction/10 s rest) followed by a third blood lactate test. Compared to control, knee extensor force dropped by 35% (p < 0.001; ES = 1.6) and blood lactate increased by 18% (p < 0.001; ES = 2.8). Elbow flexor forces were lower after the fatiguing protocol only during the last five MVCs (p < 0.05; ES = ∼ 0.58; ∼ 5%). No changes occurred between conditions in EMG. Elbow flexor forces significantly decreased after knee extensors fatigue. The effect was revealed during the later stages of the repeated MVCs protocol, demonstrating that non-local fatigue may have a stronger effect on repeated rather than on single attempts of maximal force production.


The meaning of 'life' and other abstract words: Insights from neuropsychology.
There are a number of long-standing theories on how the cognitive processing of abstract words, like 'life', differs from that of concrete words, like 'knife'. This review considers current perspectives on this debate, focusing particularly on insights obtained from patients with language disorders and integrating these with evidence from functional neuroimaging studies. The evidence supports three distinct and mutually compatible hypotheses. (1) Concrete and abstract words differ in their representational substrates, with concrete words depending particularly on sensory experiences and abstract words on linguistic, emotional, and magnitude-based information. Differential dependence on visual versus verbal experience is supported by the evidence for graded specialization in the anterior temporal lobes for concrete versus abstract words. In addition, concrete words have richer representations, in line with better processing of these words in most aphasic patients and, in particular, patients with semantic dementia. (2) Abstract words place greater demands on executive regulation processes because they have variable meanings that change with context. This theory explains abstract word impairments in patients with semantic-executive deficits and is supported by neuroimaging studies showing greater response to abstract words in inferior prefrontal cortex. (3) The relationships between concrete words are governed primarily by conceptual similarity, while those of abstract words depend on association to a greater degree. This theory, based primarily on interference and priming effects in aphasic patients, is the most recent to emerge and the least well understood. I present analyses indicating that patterns of lexical co-occurrence may be important in understanding these effects.


Implementation of an electronic referral system for outpatient specialty care.
Poor communication between primary care and specialists often leads to delays, inefficiencies and suboptimal patient outcomes. This study examined implementation of an electronic referral system (eReferral) that creates direct communication between primary care providers and specialist reviewers. Semi-structured interviews were conducted to assess factors affecting the success of eReferral implementation; transcripts were analyzed using qualitative methods. Primary and specialty care providers were enthusiastic about the system. Primary care providers had favorable attitudes despite a number of challenges including increased workload due to a shift in tasks from specialists and administrative personnel, poor connectivity, and insufficient hardware. System acceptance was driven by perceptions of improved access to specialty care, better appointment tracking, and improved communication between primary and specialty care providers. Synergy among development processes, implementation practices, and technical factors, including human-centered design, iterative development, a phased rollout, and an intuitive user interface, also fostered uptake of the system.


[Chlorphentermine-induced lipidosis of the cochlea and the cochlear nucleus].
The anoretic drug chlorphentermine induces, after long-term feeding, an accumulation of phospholipids mainly stored in lysosomes. Inner hair cells and nerve running to these cells are especially affected, whereas the outer hair cells and their nerves are less changed. Supporting cells and ganglion cells of the spiral ganglion always exhibit inclusions. Changes in the perikarya of the cochlear nucleus are not so outstanding and are in the scope of the alterations found in other parts of the nervous system. The morphological alterations allow some conclusions about the phospholipid metabolism and the lysosomal capacity of the affected cells. Furthermore, experimental lipidosis is considered as an useful model for inherited lipidosis bearing in mind the different pathogenesis underlying both conditions. Last but not least, the clinical consequence has to be pointed out when treating with drugs having different main effects but the same side effects.


Preparation and investigation the release behaviour of wax microspheres loaded with salicylic acid.
Salicylic acid-beeswax microspheres were prepared by melt dispersion technique. The effects of formulation parameters on the microscopic characteristic, drug loading and cumulative amount of released drug were investigated by experimental design. Results showed that all of the microparticles were spherical with porous surfaces. The average size of microspheres was 24-48 microm, the drug content was in the range of 22-45% and the encapsulation efficiency was 46-93%. Drug loading was influenced by emulsification speed as a main factor. All the microspheres had a burst release initially. The emulsifier concentration did not have a significant effect on drug release. The release behaviour of microspheres conformed best to Korsmeyer-Peppas semi-empirical model and the release of SA from beeswax microspheres was Fickian (n < 0.45).


Sexual abstinence and HIV knowledge in school-going adolescents with intellectual disabilities and non-disabled adolescents in Nigeria.
The study compared sexual practices and predictors of sexual abstinence among adolescent learners with mild/moderate intellectual impairments and their non-disabled peers in Nigeria. This was a comparative, cross-sectional survey that assessed sexual practices of learners with mild/moderate intellectual impairments (N = 300) and non-disabled learners (N = 300), aged 12-19 years, in Oyo State, Nigeria. Data were analysed using SPSS 15.0. Findings indicated that learners with mild/moderate intellectual impairments abstained from sex less than non-disabled adolescents (p = 0.002). Girls with intellectual disabilities were almost four times more likely to report history of rape than non-disabled girls. There was no significant difference between sexually abstinent and sexually experienced learners with intellectual disabilities (p = 0.671) and non-disabled adolescents (p = 0.181) in their mean HIV transmission knowledge scores. Many factors, including being male, social supports and self-efficacy determined sexual abstinence among adolescents. Although sexual abstinence is the recommended HIV-prevention strategy in HIV prevention curriculum in Nigerian schools, findings of this study suggested that sexual abstinence alone may not be effective for adolescent learners with intellectual disabilities. Interventions targeting youth with intellectual disabilities should consider all these factors.


The role of apolipoprotein E in Guillain-Barré syndrome and experimental autoimmune neuritis.
Apolipoprotein E (apoE) is a 34.2 kDa glycosylated protein characterized by its wide tissue distribution and multiple functions. ApoE has been widely studied in lipid metabolism, cardiocerebrovascular diseases, and neurodegenerative diseases like Alzheimer's disease and mild cognitive impairment, and so forth. Recently, a growing body of evidence has pointed to nonlipid related properties of apoE, including suppression of T cell proliferation, regulation of macrophage function, facilitation of lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and modulation of inflammation and oxidation. By these properties, apoE impacts physiology and pathophysiology at multiple levels. The present paper summarizes updated studies on the immunoregulatory function of apoE, with special focus on isoform-specific effects of apoE on Guillain-Barré syndrome (GBS) and its animal model experimental autoimmune neuritis (EAN).


Grey matter alterations in patients with depersonalization disorder: a voxel-based morphometry study.
To our knowledge, no whole brain investigation of morphological aberrations in dissociative disorder is available to date. Previous region-of-interest studies focused exclusively on amygdalar, hippocampal and parahippocampal grey matter volumes and did not include patients with depersonalization disorder (DPD). We therefore carried out an explorative whole brain study on structural brain aberrations in patients with DPD. We acquired whole brain, structural MRI data for patients with DPD and healthy controls. Voxel-based morphometry was carried out to test for group differences, and correlations with symptom severity scores were computed for grey matter volume. Our study included 25 patients with DPD and 23 controls. Patients exhibited volume reductions in the right caudate, right thalamus and right cuneus as well as volume increases in the left dorsomedial prefrontal cortex and right somatosensory region that are not a direct function of anxiety or depression symptoms. To ensure ecological validity, we included patients with comorbid disorders and patients taking psychotropic medication. The results of this first whole brain investigation of grey matter volume in patients with a dissociative disorder identified structural alterations in regions subserving the emergence of conscious perception. It remains unknown if these alterations are best understood as risk factors for or results of the disorder.


Phylogeny, Traits, and Biodiversity of a Neotropical Bat Assemblage: Close Relatives Show Similar Responses to Local Deforestation.
If species' evolutionary pasts predetermine their responses to evolutionarily novel stressors, then phylogeny could predict species survival in an increasingly human-dominated world. To understand the role of phylogenetic relatedness in structuring responses to rapid environmental change, we focused on assemblages of Neotropical bats, an ecologically diverse and functionally important group. We examined how taxonomic and phylogenetic diversity shift between tropical forest and farmland. We then explored the importance of evolutionary history by ascertaining whether close relatives share similar responses to environmental change and which species traits might mediate these trends. We analyzed a 5-year data set (5,011 captures) from 18 sites in a countryside landscape in southern Costa Rica using statistical models that account and correct for imperfect detection of species across sites, spatial autocorrelation, and consideration of spatial scale. Taxonomic and phylogenetic diversity decreased with deforestation, and assemblages became more phylogenetically clustered. Species' responses to deforestation were strongly phylogenetically correlated. Body mass and absolute wing loading explained a substantial portion of species variation in species' habitat preferences, likely related to these traits' influence on maneuverability in cluttered forest environments. Our findings highlight the role that evolutionary history plays in determining which species will survive human impacts and the need to consider diversity metrics, evolutionary history, and traits together when making predictions about species persistence for conservation or ecosystem functioning.


[EGFR tyrosine kinase inhibitors as a targeted therapy for bronchioloalveolar carcinoma of the lung: a case report of a clinically prompt and intensive response and literature review].
Bronchioloalveolar carcinoma (BAC) is an adenocarcinoma belonging to non-small cell lung carcinomas (NSCLC) that, in addition to its morphology and endobronchial spread, presents with certain specific clinical characteristics: greater incidence in women, non-smokers and younger patients, presence of malignant bronchorrhea and lower susceptibility to conventional cytostatic therapies in comparison to other subtypes of NSCLC. On the other hand, nonmucinous type of BAC may show better therapeutic response to targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) erlotinib or gefitinib, as it is 5 times more frequently a carrier of EGFR gene mutations compared to conventional lung adenocarcinomas. We present a case of a 41 years old man, non-smoker for the last 5 years, who was diagnosed with a pneumonic form of nonmucinous bronchioloalveolar carcinoma. Metastases to regional and distant lymph nodes and massive involvement of skeleton with infiltrations in the bone marrow were present at the diagnosis. During the first line palliative chemotherapy with combination regimen of carboplatin and paclitaxel, the disease progressed significantly and the patient's condition deteriorated (performance status (PS) 3, severe dyspnoea at rest, malignant bronchorrhea). Subsequently, administration of erlotinib was initiated based on a series of case studies describing good response of BAC to treatment with EGFR TKI. An evident improvement of the patient's condition was observed as early as 4 days of administration, together with regression of peripheral lymphadenopathy. Nearly complete disappearance of pulmonary infiltrates was observed after 30 days of therapy, with the patient becoming asymptomatic, PS 0. Molecular genetics confirmed the tumour phenotype to be highly responsive to EGFR TKI therapy. The tumour contained EGFR mutation in exon 19 (in-frame L747-753insS deletion) and wild-type K-ras. Disease relapse in the liver occurred 6 months later confirming disease progression. Further treatment remained ineffective despite brief stabilisations of liver enzyme progression following repeated administration of pemetrexed and gefitinib. The patient died 12 months after the diagnosis. Our case confirms the importance of targeted therapy when treating tumours of an appropriate phenotype. Such treatment may have prompt and intensive effect that may reverse the course of the disease even in patients with poor overall health status.


LCR testing for gonorrhoea and chlamydia in population surveys and other screenings of low prevalence populations: coping with decreased positive predictive value.
Nucleic acid amplification tests have facilitated field based STD studies and increased screening activities. However, even with highly specific tests, the positive predictive value (PPV) of such tests may be lower than desirable in low prevalence populations. We estimated PPVs for a single LCR test in a population survey in which positive specimens were retested. The Baltimore STD and Behavior Survey (BSBS) was a population based behavioural survey of adults which included collecting urine specimens to assess the prevalence of gonorrhoea and chlamydial infection. Gonorrhoea and chlamydial infection were diagnosed by ligase chain reaction (LCR). Nearly all positive results were retested by LCR. Because of cost considerations, negative results were not confirmed. Predicted curves for the PPV were calculated for a single testing assuming an LCR test sensitivity of 95%, and test specificities in the range 95.0%-99.9%, for disease prevalences between 1% and 10%. Positive specimens were retested to derive empirical estimates of the PPV of a positive result on a single LCR test. 579 participants age 18-35 provided urine specimens. 20 (3.5%) subjects initially tested positive for chlamydial infection, and 39 (6.7%) tested positive for gonococcal infection. If positive results on the repeat LCR are taken as confirmation of a "true" infection, the observed PPV for the first LCR testing was 89.5% for chlamydial infection and 83.3% for gonorrhoea. This is within the range of theoretical PPVs calculated from the assumed sensitivities and specificities of the LCR assays. Empirical performance of a single LCR testing approximated the theoretically predicted PPV in this field study. This result demonstrates the need to take account of the lower PPVs obtained when such tests are used in field studies or clinical screening of low prevalence populations. Repeat testing of specimens, preferably with a different assay (for example, polymerase chain reaction), and disclosure of the non-trivial potential for false positive test results would seem appropriate in all such studies.


H-Packer: Holographic Rotationally Equivariant Convolutional Neural Network for Protein Side-Chain Packing.
Accurately modeling protein 3D structure is essential for the design of functional proteins. An important sub-task of structure modeling is protein side-chain packing: predicting the conformation of side-chains (rotamers) given the protein's backbone structure and amino-acid sequence. Conventional approaches for this task rely on expensive sampling procedures over hand-crafted energy functions and rotamer libraries. Recently, several deep learning methods have been developed to tackle the problem in a data-driven way, albeit with vastly different formulations (from image-to-image translation to directly predicting atomic coordinates). Here, we frame the problem as a joint regression over the side-chains' true degrees of freedom: the dihedral $\chi$ angles. We carefully study possible objective functions for this task, while accounting for the underlying symmetries of the task. We propose Holographic Packer (H-Packer), a novel two-stage algorithm for side-chain packing built on top of two light-weight rotationally equivariant neural networks. We evaluate our method on CASP13 and CASP14 targets. H-Packer is computationally efficient and shows favorable performance against conventional physics-based algorithms and is competitive against alternative deep learning solutions.


PCR differentiation of commercial yeast strains using intron splice site primers.
The increased use of pure starter cultures in the wine industry has made it necessary to develop a rapid and simple identification system for yeast strains. A method based upon the PCR using oligonucleotide primers that are complementary to intron splice sites has been developed. Since most introns are not essential for gene function, introns have evolved with minimal constraint. By targeting these highly variable sequences, the PCR has proved to be very effective in uncovering polymorphisms in commercial yeast strains. The speed of the method and the ability to analyze many samples in a single day permit the monitoring of specific yeast strains during fermentations. Furthermore, the simplicity of the technique, which does not require the isolation of DNA, makes it accessible to industrial laboratories that have limited molecular expertise and resources.


Hepatopulmonary Syndrome: A Nationwide Analysis of Epidemiological Trends and Outcomes From 2012 to 2018.
This study was designed to determine the epidemiological trends and adverse outcomes of hepatopulmonary syndrome (HPS). This retrospective interrupted trend study analyzed data from the Nationwide Inpatient Sample (NIS) for the years 2012, 2014, 2016 and 2018 to identify adult (≥ 18 years) hospitalizations with a diagnosis of HPS. We highlighted epidemiological trends for HPS. Inpatient mortality, mean length of stay (LOS) and mean total hospital charge (THC) were estimated using multivariate regression trend analysis. We observed an increase in the total number of HPS hospitalizations from 1,565 in 2012 to 2,495 in 2018, with mean age ranging from 55.8 to 58.1 years. There was a trend towards increasing hospitalizations (P-trend < 0.001) with increasing mean age (P-trend = 0.003) for HPS. Whites made up most of the study population. The inpatient mortality for HPS ranged from 12.4% to 12.6%, but there was no statistically significant trend for mortality (P-trend = 0.534) between 2012 and 2018. Additionally, there was no change in both mean LOS (P-trend = 0.545) and mean THC (P-trend = 0.534) for HPS for these years. Hospitalizations and mean age for HPS were on the rise. Inpatient mortality ranged from 12.4% to 12.6%; however, a statistically significant trend for mortality was absent.