Incident Type 2 Diabetes Duration and Cancer Risk: A Prospective Study in Two US Cohorts.
The influence of type 2 diabetes mellitus (T2D) duration on cancer incidence remains poorly understood. We prospectively followed for cancer incidence 113 429 women in the Nurses' Health Study (1978-2014) and 45 604 men in the Health Professionals Follow-up Study (1988-2014) who were free of diabetes and cancer at baseline. Cancer incidences were ascertained by review of medical records. In the multivariable-adjusted model incident, T2D was associated with higher risk of cancers in the colorectum, lung, pancreas, esophagus, liver, thyroid, breast, and endometrium. The pooled hazard ratios (HRs) ranged from 1.21 (95% confidence interval [CI] = 1.06 to 1.38) for colorectal cancer to 3.39 (95% CI = 2.24 to 5.12) for liver cancer. For both composite cancer outcomes and individual cancers, the elevated risks did not further increase after 8 years of T2D duration. The hazard ratio for total cancer was 1.28 (95% CI = 1.17 to 1.40) for T2D duration of 4.1-6.0 years, 1.37 (95% CI = 1.25 to 1.50) for 6.1-8.0 years, 1.21 (95% CI = 1.09 to 1.35) for 8.1-10.0 years, and 1.04 (95% CI = 0.95 to 1.14) after 15.0 years. In a cross-sectional analysis, a higher level of plasma C-peptide was found among participants with prevalent T2D of up to 8 years than those without T2D, whereas a higher level of HbA1c was found for those with prevalent T2D of up to 15 years. Incident T2D was associated with higher cancer risk, which peaked at approximately 8 years after diabetes diagnosis. Similar duration-dependent pattern was observed for plasma C-peptide. Our findings support a role of hyperinsulinemia in cancer development.


Stochastic Reaction Networks Within Interacting Compartments.
Stochastic reaction networks, which are usually modeled as continuous-time Markov chains on [Formula: see text], and simulated via a version of the "Gillespie algorithm," have proven to be a useful tool for the understanding of processes, chemical and otherwise, in homogeneous environments. There are multiple avenues for generalizing away from the assumption that the environment is homogeneous, with the proper modeling choice dependent upon the context of the problem being considered. One such generalization was recently introduced in Duso and Zechner (Proc Nat Acad Sci 117(37):22674-22683 , Duso and Zechner (2020)), where the proposed model includes a varying number of interacting compartments, or cells, each of which contains an evolving copy of the stochastic reaction system. The novelty of the model is that these compartments also interact via the merging of two compartments (including their contents), the splitting of one compartment into two, and the appearance and destruction of compartments. In this paper we begin a systematic exploration of the mathematical properties of this model. We (i) obtain basic/foundational results pertaining to explosivity, transience, recurrence, and positive recurrence of the model, (ii) explore a number of examples demonstrating some possible non-intuitive behaviors of the model, and (iii) identify the limiting distribution of the model in a special case that generalizes three formulas from an example in Duso and Zechner (Proc Nat Acad Sci 117(37):22674-22683 , Duso and Zechner (2020)).


ABCD1 and X-linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models.
X-linked adrenoleukodystrophy (X-ALD) is a phenotypically heterogeneous disorder involving defective peroxisomal β-oxidation of very long-chain fatty acids (VLCFAs), due to mutation in the ABCD1 gene. X-ALD is the most common peroxisomal inborn error of metabolism and confers a high degree of morbidity and mortality. Remarkably, a subset of patients exhibit a cerebral form with inflammatory invasion of the central nervous system and extensive demyelination, while in others only dying-back axonopathy or even isolated adrenal insufficiency is seen, without genotype-phenotype correlation. X-ALD's biochemical signature is marked elevation of VLCFAs in blood, a finding that has been utilized for massive newborn screening for early diagnosis. Investigational gene therapy approaches hold promises for improved outcomes. However, the pathophysiological mechanisms of the disease remain poorly understood, limiting investigation of targeted therapeutic options. Animal models for the disease recapitulate the biochemical signature of VLCFA accumulation and demonstrate mitochondrially generated reactive oxygen species, oxidative damage, increased glial death, and axonal damage. Most strikingly, however, cerebral invasion of leukocytes and demyelination were not observed in any animal model for X-ALD, reflecting upon pathological processes that are yet to be discovered. This review summarizes the current disease models in animals, the lessons learned from these models, and the gaps that remained to be filled in order to assist in therapeutic investigations for ALD.


[Clinical features of patients with the pathological diagnosis of amyloidosis].
Amyloidosis is characterized by the extracellular deposit of an insoluble fibrillar protein that leads to tissue atrophy and necrosis. To report the clinical features of cases of amyloidosis diagnosed in a public hospital in Santiago, Chile, from 2000 to 2004. Retrospective review of all pathology reports of biopsies obtained from 2000 to 2004. In all cases reported as "amyloidosis", the clinical features of such patients were obtained from their medical records. The medical records of 11 patients with amyloidosis were obtained (aged 35 to 71 year old, seven females). Seven had a systemic and four a localized disease. Six patients had primary amyloidosis and in one, it was secondary to a disseminated tuberculosis. Five patients with the generalized disease consulted for anarsarca, three for weight loss and 2 for chronic diarrhea. Patients with localized disease consulted for tonsil enlargement, dysphonia and skin lesions. Five patients with generalized disease had renal involvement and five had cardiac involvement. Three patients had malabsorption. The most common presentation of systemic amyloidosis is anasarca and renal involvement is common.


Triggered release in lipid bilayer-capped mesoporous silica nanoparticles containing SPION using an alternating magnetic field.
We report here the on-command cargo controlled delivery using an alternating magnetic field (AMF) from magnetic silica mesoporous supports capped with a lipid bilayer.


Use of a pediatric parenteral amino acid mixture in a population of extremely low birth weight neonates: frequency and spectrum of direct bilirubinemia.
This retrospective study demonstrates a low frequency of parenteral nutrition-associated direct bilirubinemia within a population of extremely low birthweight neonates (1000 gm or less) exposed to a pediatric amino acid mixture.


Oxfendazole--anthelmintic activity in Egyptian goats artificially infected with gastrointestinal nematodes.
The recently developed benzimidazole anthelmintic, oxfendazole, was tested against artificial nematode infestations in Egyptian goats using oral dosing at 4.5 and 2.8 mg/kg. A 100% clearance of mature and immature Haemonchus contortus, Trichostrongylus axei, Ostertagia circumcincta, Coopera curticei, Bunostomum trigonocephalum and Chabertia ovina was obtained at the 4.5 mg/kg level. Very high levels of clearance against the mature worms were obtained at 2.8 mg/kg but the drug was less effective against immature worms at the lower dose rate. PCV, hemoglobin concentration and total erythrocyte counts declined after infection but became significantly (P less than 0.001) raised in treated animal.


Circular biomanufacturing through harvesting solar energy and CO2.
Using synthetic biology, it is now time to expand the biosynthetic repertoire of plants and microalgae by utilizing the chloroplast to augment the production of desired high-value compounds and of oil-, carbohydrate-, or protein-enriched biomass based on direct harvesting of solar energy and the consumption of CO2. Multistream product lines based on separate commercialization of the isolated high-value compounds and of the improved bulk products increase the economic potential of the light-driven production system and accelerate commercial scale up. Here we outline the scientific basis for the establishment of such green circular biomanufacturing systems and highlight recent results that make this a realistic option based on cross-disciplinary basic and applied research to advance long-term solutions.


Pathogenicity ofFusarium SPP. contributing to the stalk rot of Maize in Poland.
During 1985-1989 a stalk rot of early maturity hybrids of maize was studied in Radzikow (Central Poland). It was found thatFusarium species were dominant on plants with stalk rot symptoms. Spectrum ofFusarium spp. had changed within the years. The most frequently isolated were:F.subglutinans,F.culmorum andF.crookwellense. When the disease developed early in the seasonF.graminearum was also present.Predominant species were examined for their pathogenicity according to the modified method of Molot, Simone (1967). Isolates ofF.graminearum andF.culmorum were found to be strong pathogens,F.crookwellense andF.subglutinans - moderate andF.oxysporum andF.eguiseti were the weak ones.


Relationship between parental attachment styles and suicide in adolescents and adults admitted to an inpatient psychiatric hospital.
Suicide is among one of the leading causes of death in the United States affecting individuals of all ages. We examined the relationship between suicide risk and parental attachment among an inpatient psychiatric sample of 690 adolescents and 1000 adults. Participants completed self-report measures of suicide risk and attachment. We found that both adolescents and adults with insecure (i.e., preoccupied, dismissive, fearful) maternal and paternal attachment are at a significantly higher risk of suicide compared to those with secure maternal and paternal attachment. Adolescents who endorsed a previous suicide attempt (27.2 %) were less likely to have a secure maternal attachment, while adults who endorsed a previous suicide attempt (28.9 %) were less likely to have secure paternal attachment. Our sample had limited racial and ethnic diversity which may limit the generalizability of the results to a broader population. The present study provides evidence of the importance of parental attachment styles as a predictor of suicide-related behaviors across both adolescents and adults who are admitted inpatient. This suggests the importance of utilizing family-based interventions in order to reduce the risk of suicide.


Obstructive renal cysts.
Renal cysts usually are asymptomatic, produce no harm to the kidney and require no treatment once diagnosed. However, an occasional expanding cyst causes progressive obstruction to caliceal or pelvic outflow. Herein is reported observations on 4 patients in whom cysts produced significant obstruction to the pelvic or major caliceal outflow. In 3 cases treatment was by decompression, with resolution of the obstruction. Two requirements must be met for a cyst to obstruct: 1) it must lie at or near the hilus and 2) it must have turgor sufficient to overcome the pressure of the intrapelvic urine. In contrast to most renal cysts those producing significant obstruction require operation.


Ptaquiloside Z, a new toxic unstable sesquiterpene glucoside from the neotropical bracken fern Pteridium aquilinum var. caudatum.
Reversed-phase HPLC fractionation, monitored by brine shrimp bioassay, led to the isolation of a new illudane-type sesquiterpene glucoside, ptaquiloside Z (2), as well as the known bracken carcinogen ptaquiloside (1), from a bioactive aqueous extract of the neotropical bracken fern Pteridium aquilinum var. caudatum (Pteridaceae). The structure of ptaquiloside Z (2) was confirmed by spectroscopic analyses and chemical degradation. Both compounds exhibited similar toxicity (LC50 62.5 micrograms/ml at 24 h and LC50 7.8 micrograms/ml at 48 h) toward brine shrimp.


Implementing a Machine-Learning-Adapted Algorithm to Identify Possible Transthyretin Amyloid Cardiomyopathy at an Academic Medical Center.
Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is a frequently under-recognized cause of heart failure (HF) in older patients. To improve identification of patients at risk for the disease, we initiated a pilot program in which 9 cardiac/non-cardiac phenotypes and 20 high-performing phenotype combinations predictive of wild-type ATTR-CM were operationalized in electronic health record (EHR) configurations at a large academic medical center. Inclusion criteria were age >50 years and HF; exclusion criteria were end-stage renal disease and prior amyloidosis diagnoses. The different Epic EHR configurations investigated were a clinical decision support tool (Best Practice Advisory) and operational/analytical reports (Clarity™, Reporting Workbench™, and SlicerDicer); the different data sources employed were problem list, visit diagnosis, medical history, and billing transactions. With Clarity, among 45 051 patients with HF, 4006 patients (8.9%) had ⩾1 phenotype combination associated with increased risk of wild-type ATTR-CM. Across all data sources, 2 phenotypes (cardiomegaly; osteoarthrosis) and 2 combinations (carpal tunnel syndrome + HF; atrial fibrillation + heart block + cardiomegaly + osteoarthrosis) generated the highest proportions of patients for wild-type ATTR-CM screening. All EHR configurations tested were capable of operationalizing phenotypes or phenotype combinations to identify at-risk patients; the Clarity report was the most comprehensive.


Peripheral endografts for the treatment of traumatic arterial injuries.
Catheter-based endovascular techniques for vascular trauma management are being increasingly reported. Covered stents may be inserted and deployed through a remote site of percutaneous access under local anesthesia and are ideal for treating arterial ruptures and pseudoaneurysms and to seal off arteriovenous communications. Advantages of endovascular stent-graft repair of peripheral traumatic arterial injuries include less blood loss and tissue damage, reduced operative time and morbidity, shortened hospital stay and recovery periods, and reduced healthcare costs. The present report provides an overview of the role of balloon-expandable and self-expandable covered stents in the minimally invasive treatment of various types of traumatic arterial injuries.


Influence of Chirality of Benzimidazole Amine Hybrids on Inhibition of Human Erythrocytes Carbonic Anhydrase I, II and Acetylcholinesterase.
Novel chiral benzimidazole amine hybrids (4a-4d) were synthesized from commercially available amine [(R)- (+)-phenylethylamine, (-) (S)-(-)-phenylethylamine, (-) (R)-(-)-cyclohexylethylamine, (S)-(+)-cyclohexylethylamine] and 2-(chloromethyl)-N-tosyl-1H-benzimidazole. The synthesized compounds (4a-4d) were characterized by IR, NMR, and LC/MS analysis. The inhibitory effect of 4a-4d on human erythrocytes carbonic anhydrase I (hCA-I), II (hCA-II), and acetylcholinesterase (AChE) activity was investigated. For hCA-I, the IC50 values of 4a-4d were found to be 4.895 μM, 1.750 μM, 0.173 μM, and 0.620 μM, respectively, and for hCA-II, the IC50 values of 4a-4d were found to be 0.469 μM, 0.380 μM, 0.233 μM, 0.635 μM, respectively. Furthermore, IC50 values of 4a-4d on AChE were found as 87.5 nM, 100 nM, 26.92 nM, and 100 nM, respectively. In addition, molecular docking analysis was performed to evaluate the affinity of 4a-4d against hCA-I, hCA-II, and AChE and explain their binding interactions.


Use of proliferation rate, p53 staining and perforating elastic fibers in distinguishing keratoacanthoma from hypertrophic lichen planus: a pilot study.
Distinguishing keratoacanthoma (KA) and hypertrophic lichen planus (LP) histopathologically can be difficult, and the challenge is compounded by the tendency of KA to arise in association with hypertrophic LP. In this pilot study, we compared 18 cases each of KA and hypertrophic LP for proliferation index (MIB-1), p53 staining and the presence of perforating elastic fibers (elastic Verhoeff-van Gieson) to determine the utility of these staining modalities in distinguishing KA from hypertrophic LP. Proliferation index in KA compared to hypertrophic LP is 88.2 (mean positive MIB-1 cells/×100 field), SD = 56.6 and 47.3, SD = 68.4, respectively. p53 staining in KA compared to hypertrophic LP is 251 (mean positive cells/×100 field), SD = 117 and 158, SD = 119, respectively. Fifteen of eighteen (83%) keratoacanthomata demonstrate perforating elastic fibers compared to 1/18 (6%) for hypertrophic LP. Proliferation index is not significantly different between KA and hypertrophic LP (p = 0.059). Expression of p53 is increased in KA over hypertrophic LP (p = 0.024). The presence of perforating elastic fibers in KA is significantly different from hypertrophic LP (p < 0.0001) and suggests that elastic Verhoeff-van Gieson staining may be of practical benefit in distinguishing KA from hypertrophic LP in difficult cases.


Preventing unplanned pregnancies.
A two-year study was undertaken in 1975--1976 to plan, implement and evaluate innovatory family planning educational and service delivery pilot projects, among those at-risk in Sydney. The study was done in three stages, described in the three parts of this paper. Part 1 describes the process of analyzing the major factors and outcomes in unplanned pregnancy and determining some characteristics of women experiencing unplanned pregnancies, from abortion and adoption records. The characteristics analyzed are: are, marital status, occupation, socio-economic status, and ethnic group. Part II describes the process of determing acceptable communication channels and services they would use. Twenty-five women were interviewed in each of eight at-risk categories. Recommendations are made about suitable educational methods, and family planning services. Part 3 describes the implementation and evaluation of pilot projects. Four major projects are described: (i) in a two lower socio-economic housing area(s), (ii) among Greek men, (iii) among South Americans, and (iv) in two factories. Recommendations are made about future educational programmes and services.


Birth season and environmental influences on blood leucocyte and lymphocyte subpopulations in rural Gambian infants.
In rural Gambia, birth season predicts infection-related adult mortality, providing evidence that seasonal factors in early life may programme immune development. This study tested whether lymphocyte subpopulations assessed by automated full blood count and flow cytometry in cord blood and at 8, 16 and 52 weeks in rural Gambian infants (N = 138) are affected by birth season (DRY = Jan-Jun, harvest season, few infections; WET = Jul-Dec, hungry season, many infections), birth size or micronutrient status. Geometric mean cord and postnatal counts were higher in births occurring in the WET season with both season of birth and season of sampling effects. Absolute CD3+, CD8+, and CD56+ counts, were higher in WET season births, but absolute CD4+ counts were unaffected and percentage CD4+ counts were therefore lower. CD19+ counts showed no association with birth season but were associated with concurrent plasma zinc status. There were no other associations between subpopulation counts and micronutrient or anthropometric status. These results demonstrate a seasonal influence on cell counts with a disproportionate effect on CD8+ and CD56+ relative to CD4+ cells. This seasonal difference was seen in cord blood (indicating an effect in utero) and subsequent samples, and is not explained by nutritional status. These findings are consistent with the hypothesis than an early environmental exposure can programme human immune development.


Benign hepatic lesions in women taking oral contraceptives.
Four previously unreported cases of benign hepatic cell lesions in young women taking oral contraceptives are described. A brief review of the literature is presented with emphasis on the clinical symptoms, the findings on angiography and radionuclide scan, and the relation of the lesions to oral contraceptives.


Violence in hospitals and burnout among nursing staff.
Nursing staff, especially in violence-prone emergency departments (ED), are at high risk of burnout. Frequently experienced violence is expected to have a strong impact on the nursing staff's burnout. This study aimed to examine the differences in the level of burnout between nursing staff who work in the ED and nursing staff who work in other inpatient departments, and its relationship with violence in various hospitals in Israel. A cross-sectional study that utilized a three-part questionnaire: demographic data, degree of burnout, and frequency occurrence of violence events against nurses. 150 nurses in EDs (N = 75) and inpatient departments (N = 75) were sampled. Significant differences were found between the two groups: Nurses in EDs experienced a higher degree of burnout than nurses in other hospital departments, and the degree of burnout was found to have a positive relationship with exposure to both verbal and physical workplace violence. Nursing staff in EDs could develop a high degree of burnout, and exposure to workplace violence could exacerbate it. The physical and emotional safety of the staff is an important aspect in preventing burnout, and creating a secure work environment.


Better understanding of water quality evolution in water distribution networks using data clustering.
The complexity of water distribution networks raises challenges in managing, monitoring and understanding their behavior. This article proposes a novel methodology applying data clustering to the results of hydraulic simulation to define quality zones, i.e. zones with the same dynamic water origin. The methodology is presented on an existing Water Distribution Network; a large dataset of conductivity measurements measured by 32 probes validates the definition of the quality zones. The results show how quality zones help better understanding the network operation and how they can be used to analyze water quality events. Moreover, a statistical comparison with 158,230 conductivity measurements validates the definition of the quality zones.


Clinical implications of the angiosome model in peripheral vascular disease.
Vascular surgery has seen a revolutionary transformation in its approach to peripheral vascular disease over the last 2 decades, fueled by technological innovation and a willingness by the field to adopt these changes. However, the underlying pathology behind critical limb ischemia and the significant rate of unhealed wounds and secondary amputations despite apparently successful revascularization needs to be addressed. In seeking to improve outcomes, it may be beneficial to examine our approach to vascular disease at the fundamental level of anatomy, the angiosome, to better dictate reperfusion strategies beyond a simple determination of open vs endovascular procedure. We performed a systematic review of the current literature concerning the significance of the angiosome concept in the realm of vascular surgery. The dearth of convincing evidence in the form of prospective trials and large patient populations, and the lack of a consistent, comparable vocabulary to contrast study findings, prevent recommendation of the conceptual model at a wider level for guidance of revascularization attempts. Further well-structured, prospective studies are required as well as emerging imaging strategies, such as indocyanine green dye-based fluorescent angiography or hyperspectral imaging, to allow wider adoption of the angiosome model in vascular operations.


Cardiomyocyte hyperplasia after plasmid-mediated vascular endothelial growth factor gene transfer in pigs with chronic myocardial ischemia.
For over 40 years it has been proposed that cardiomyocyte hyperplasia may occur in hypertrophic human hearts. While this implies that heart myocytes can undergo cytokinesis, evidence of conventional cell division has been exceptionally reported. Recently, we found that gene transfer of vascular endothelial growth factor (VEGF) displays a mitogenic effect on adult cardiomyocytes. In the present study we searched for cardiomyocyte hyperplasia as evidence of VEGF-induced cardiomyocyte cytokinesis. Three weeks after implanting an Ameroid constrictor at the origin of the left circumflex artery, 16 pigs were randomized to receive 10 direct intramyocardial injections of 3.8 mg of plasmid encoding for VEGF (pVEGF) or empty plasmid. Five weeks later, hearts were weighed, myocyte diameter was measured in tissue sections, and myocyte length and nuclei number were studied in isolated myocytes. A resting echocardiogram was performed immediately before reoperation and before sacrifice to evaluate global and regional left ventricular function. Investigators were blinded to the study groups and nature of the injectate until the end of data analysis. No heart weight differences existed between groups. However, in the ischemic myocardium, pVEGF-treated hearts had 22% more cardiomyocytes per unit volume and exhibited significantly more oligonucleated (1 or 2 nuclei) cardiomyocytes than hearts receiving empty plasmid. In pigs with chronic myocardial ischemia, VEGF gene transfer induced cardiomyocyte cytokinesis, as revealed by cardiomyocyte hyperplasia. Our finding extends the previously reported mitogenic effect of VEGF on adult cardiomyocytes and supports the hypothesis that VEGF may have a therapeutic role in diseases characterized by myocardial cell loss.


Neutron radiotherapy for adenoid cystic carcinoma of minor salivary glands.
To examine the efficacy of fast neutron radiotherapy for the treatment of patients with locally advanced, adenoid cystic carcinoma of minor salivary glands and to identify prognostic variables associated with local control, overall survival, and cause specific survival. Eighty-four patients having adenoid cystic carcinoma of minor salivary glands were treated with fast neutron radiotherapy during the years 1985-1994. All patients had either unresectable disease or gross disease remaining after attempted surgical extirpation. Seventeen patients had previously received conventional radiotherapy and their subsequent treatment fields and doses for neutron radiotherapy were modified for critical sites (brainstem, spinal cord, brain). Although the median doses (tumor maximum and tumor minimum) only varied by < or = 10%, treatment portals were substantially smaller in these patients because of normal tissue complication considerations. Twelve patients (13%) had distant metastases at the time of treatment and were only treated palliatively with smaller treatment portals and lower median tumor doses (< or = 80% of the doses delivered to curatively treated patients). Seventy-two patients were treated with curative intent, with nine of these having recurrent tumors after prior full-dose radiotherapy. The median duration of follow-up at the time of analysis was 31.5 months (range 3-115). Sites of disease and number of patients treated per disease site were as follows: paranasal sinus-31; oral cavity-20; oropharynx-12; nasopharynx-11; trachea-6; and other sites in the head and neck-4. The 5-year actuarial local-regional tumor control rate for all patients treated with curative intent was 47%. Patients without involvement of the cavernous sinus, base of skull, or nasopharynx (51 patients) had a 5-year actuarial local-regional control rate of 59%, whereas local-regional control was significantly lower (15%) for patients with tumors involving these sites (p < 0.005). In the latter cases, normal tissue injury considerations precluded delivery of the full dose to the entire tumor. Patients with no history of prior radiotherapy (63 patients) had an actuarial local control rate of 57% at 5 years compared to 18% for those (9 patients) who had been previously irradiated with conventional photons (p = 0.018). Eliminating the dose-limiting factors of prior radiation therapy and/or high risk sites of involvement, the 5-year actuarial local-regional control rate for these 46 patients was 63%, with an actuarial cause specific survival rate of 79%. Lymph node status was a predictor of distant metastasis: 57% of node positive patients developed distant metastases by 5 years compared to 15% of patients with negative nodes (p < 0.0005), and patients who had nodal involvement developed distant metastases sooner than node negative patients (p < 0.0001). The 5-year actuarial overall survival and cause specific survival for the 72 patients treated with curative intent were 59% and 64%, respectively. Fast neutron radiotherapy offers high local-regional control and survival rates for patients with locally advanced, unresectable adenoid cystic carcinomas of minor salivary glands. It should be considered as initial primary treatment for these patients, as well as for other patients in whom surgical extirpation would cause considerable morbidity.


Preventing quality improvement drift: evaluation of efforts to sustain the cost savings from implementing best practice guidelines to reduce unnecessary electrocardiograms (ECGs) during the preadmisison testing evaluation.
Medical professionals commonly fail to follow best practice guidelines. Drift, or a return to previous tendencies, is abundant in healthcare even when guidelines are followed initially. This "drift" was found internally at Temple University Hospital with preoperative electrocardiograms (ECGs). Best-practice guidelines were instituted and followed as a first step, but sustaining performance improvement was the ultimate goal. The objectives are to improve and maintain adherence to published guidelines for preoperative ECG testing at Temple University Hospital in a physician-led, nurse practitioner (NP)-staffed preadmission testing (PAT) clinic. To start this quality improvement (QI) project, a retrospective chart review was completed to determine the number of ECGs performed in PAT at Temple University Hospital in 2017. New guidelines for ordering preoperative ECGs were then implemented, and Plan-Do-Study-Act (PDSA) cycles were performed over 3 years. A repeat retrospective chart review was completed and looked at ECGs ordered from 2018 through 2020. The number of ECGs completed in PAT before and after implementation of the new guidelines was then compared. In addition, the complexity of our surgical patients was estimated by looking at the yearly average American Society of Anesthesiology Physical Health Status (American Society of Anesthesiology [ASA] status) values assigned. Finally, the cost of performing each ECG was calculated, and the cost savings to the hospital over 4 years was determined. The baseline ECG rate for PAT in 2017, 2018, 2019, and 2020 at Temple University Hospital was 54.0 , 20.7, 22.3, and 21.9 %, respectively, which was a statistically significant decrease in ECG performance rate in the years after implementation of the PDSA project. The ASA status average remained constant, demonstrating that while patients' medical diagnoses remained on average the same, reinforced training had been effective in preventing a return to previous liberal ordering tendencies. Over the course of 4 years, the reduction in unnecessary ECGs led to an estimated direct cost savings of $213,000. Self-adoption of best-practice guidelines among clinicians is often poor; however, the barriers to adoption can be overcome with education and individual feedback. Sustaining performance improvement gains is challenging, but possible, as shown by example in one urban, academic teaching hospital's physician-led, NP-staffed outpatient clinic.


[Alzheimer's disease and visual impairment].
Alzheimer disease is the most prevalent cause of cognitive decline in older adults. The typical presentation of Alzheimer disease is memory dysfunction, however, presentations with impairment in other domains may occur. Visual symptoms may be the first manifestation of Alzheimer disease. The purpose of this article is to review the spectrum of visual system disturbances found in Alzheimer disease.


Phosphatidylethanolamine binding protein 1 in vacular endothelial cell autophagy and atherosclerosis.
We previously found that phosphatidylcholine-specific phospholipase C (PC-PLC) was a key inducing element of atherosclerosis, and might negatively regulate human umbilical vein endothelial cell (HUVEC) autophagy. To further investigate the mechanism of PC-PLC action, we initially identified phosphatidylethanolamine binding protein 1 (PEBP1) as a binding partner of PC-PLC by using mass spectrometry (MS, MALDI-TOF/TOF). We found that PEBP1 positively regulated PC-PLC activity in HUVECs, and inhibition of PC-PLC by its inhibitor D609 suppressed PEBP1 expression dramatically. Moreover, both PC-PLC and PEBP1 negatively regulated HUVEC autophagy independently of mammalian target of rapamycin (mTOR). Furthermore, the PEBP1 level was elevated during the development of atherosclerosis, while D609 significantly decreased the upregulated PEBP1 level in apoE(-/-) mice.


Organotins are co-clastogens in a whole mammalian system.
The frequency of micronuclei induced by mitomycin C (MMC) in mouse peripheral reticulocytes was enhanced by treatment with organotins: bis(tri-n-butyltin) oxide (TBTO) and triphenyltin chloride (TPTC). TBTO and TPTC did not themselves induce micronucleated reticulocytes (MNRETs) in mouse peripheral blood. When 50 mg/kg TBTO or 100 mg/kg TPTC was given orally to mice simultaneously with an intraperitoneal (i.p.) administration of 1 mg/kg MMC, however, TBTO and TPTC caused about 55% and 51% increases, respectively, in MMC-induced a synergistic MNRET frequency. Organotin administration 3 or 6 h before and 3 h after MMC injection also caused enhancement of MNRET frequency. These results demonstrate that TBTO and TPTC act as co-clastogens in a whole mammalian system.


Possible association of hepatitis C virus infection with late-onset psoriasis: a hospital-based observational study.
Psoriasis is a chronic inflammatory disease mainly involving the skin and joints, mediated by pro-inflammatory cytokine tumor necrosis factor (TNF)-α. In hepatitis C, continuous inflammation mediated by TNF-α leads to liver cirrhosis and diabetes mellitus. Hence, psoriasis and hepatitis C have pathophysiological factors in common. An epidemiological association between the two conditions has been reported, but no detailed research has yet been performed. Frequency of hepatitis C virus (HCV) infection was assessed in 717 patients with psoriasis and 38 057 with all other dermatological diseases who visited Fukuoka University Hospital in 1998-2011. HCV⁺ and HCV⁻ psoriatic patients were further compared. Frequency of HCV infection was significantly higher in psoriasis (7.5%) than in controls (3.3%) in overall ages. When stratified by age at the first visit, the frequency was significantly higher in patients with psoriasis than in controls aged in their 60s (11.8% vs 6.6%, respectively, P = 0.0215) and 70s (19.5% vs 7.3%, P < 0.0001). HCV⁺ psoriatic patients were significantly older at onset than HCV⁻ ones (median, 54 vs 39 years), stronger male predominance (male/female ratio, 4.4:1), similar family history of psoriasis, higher association of diabetes mellitus and hypertension, and significantly lower body mass index (22.4 ± 2.73 vs 24.2 ± 4.61), in age-stratified (≥ 40 years) analysis. HCV⁺ psoriatic patients were less obese, but still had a higher frequency of diabetes mellitus and hypertension, possibly due to chronic inflammation in the liver and other organs. HCV infection may trigger psoriasis, especially late-onset psoriasis, possibly via overproduction of TNF-α, a common mediator of the two conditions.


Alveolar gas exchange and tissue deoxygenation during exercise in type 1 diabetes patients and healthy controls.
We used near-infrared spectroscopy to investigate whether leg and arm skeletal muscle and cerebral deoxygenation differ during incremental cycling exercise in men with type 1 diabetes (T1D, n=10, mean±SD age 33±7 years) and healthy control men (matched by age, anthrometry, and self-reported physical activity, CON, n=10, 32±7 years) to seek an explanation for lower aerobic capacity (˙VO2peak) often reported in T1D. T1D had lower ˙VO2peak (35±4mlkg(-1)min(-1) vs. 43±8mlkg(-1)min(-1), P<0.01) and peak work rate (219±33W vs. 290±44W, P<0.001) than CON. Leg muscle deoxygenation (↑ [deoxyhemoglobin]; ↓ tissue saturation index) was greater in T1D than CON at a given absolute submaximal work rate, but not at peak exercise, while arm muscle and cerebral deoxygenation were similar. Thus, in T1D compared with CON, faster leg muscle deoxygenation suggests limited circulatory ability to increase O(2) delivery as a plausible explanation for lower ˙VO2peak and earlier fatigue in T1D.


Postconditioning attenuates acute intestinal ischemia-reperfusion injury.
The aim of this study was to test the hypothesis that postconditioning (POC) would reduce the detrimental effects of the acute intestinal ischemia-reperfusion (I/R) compared to those of the abrupt onset of reperfusion. POC has a protective effect on intestinal I/R injury by inhibiting events in the early minutes of reperfusion in rats. Twenty-four Wistar-Albino rats were subjected to the occlusion of superior mesenteric artery for 30 minutes, then reperfused for 120 minutes, and randomized to the four different modalities of POC: (1) control (no intervention); (2) POC-3 (three cycles of 10 seconds of reperfusion-reocclusion, 1 minute total intervention); (3) POC-6 (six cycles of 10 seconds of reperfusion-reocclusion, 2 minutes total intervention); and (4) sham operation (laparotomy only). The arterial blood samples [0.3 mL total creatine kinase (CK) and 0.6 mL malondialdehyde (MDA)] and the intestinal mucosal MDA were collected from each after reperfusion. POC, especially POC-6, was effective in attenuating postischemic pathology by decreasing the intestinal tissue MDA levels, serum total CK activity, inflammation, and total histopathological injury scores. POC exerted a protective effect on the intestinal mucosa by reducing the mesenteric oxidant generation, lipid peroxidation, and neutrophil accumulation. The six-cycle algorithm demonstrated the best protection.


A self-monitoring technique for increasing productivity in multiple media.
During the baseline condition the number of lines written on a word processor and the amount of time spent on studio art were recorded. During Phase I self-recording of the number of lines written were graphed. Additional baseline information was obtained concerning the time spent on studio art. In Phase II both the number of lines written and time spent on art were recorded. Treatment effects were maintained at a 10 months follow-up.


Prevalence of left atrial enlargement and its risk factors in general Chinese population.
Left atrial enlargement (LAE) has been proven to be significantly related to stroke and cardiovascular diseases. In China, few studies related to LAE have been conducted, especially in the general population. To the best of our knowledge, our study is the first to explore the prevalence of LAE and associated risk factors in the general Chinese population. This study included a total of 11,956 subjects aged ≥35 years. All participants completed a questionnaire, and underwent complete physical examination, electrocardiogram (ECG) and echocardiogram. We defined LAE as a LA diameter exceeding 4.0 cm in men and 3.8 cm in women. We conducted a multivariable logistic regression analysis and a linear regression analysis to identify independent factors of LAE. The overall prevalence of LAE was 6.43 % for subjects aged over 35 years. The prevalence of LAE was 6.78 % in women and 6.02 % in men. The major risk factors of LAE were female sex (odds ration [OR]: 1.229, β: 0.197), advancing age (OR: 1.015, β: 0.036), high systolic blood pressure (OR: 2.331, β: 0.185), high body mass index (BMI) (OR: 3.956, β: 0.373), diabetes (OR: 1.498, β: 0.030), high left ventricular myocardial index (OR: 1.003, β: 0.073), and low left ventricular ejection fraction, low heart rate, and low estimated glomerular filtration rate. Additionally, the association between BMI and LAE was the most obvious. Female sex, advancing age, high systolic blood pressure, high BMI, diabetes, high left ventricular myocardial index, low estimated glomerular filtration rate, low left ventricular ejection fraction, and low heart rate were proven to be risk factors of LAE.


The rotation ratios method: a method to describe altered pelvic orientation in sequential radiographs.
A method to describe pelvic rotations between pairs of standard sequential pelvic anteroposterior radiographs based on a pelvic phantom is described in a former study. To expand this method into clinical use based on clinical data. Teardrop distances were measured on 262 pelvic radiographs from 46 patients in a clinical material using a computer program designed to perform measurements on digital radiographs. Anthropometric data recorded from 141 pelvises in an anatomical collection were employed in a computer program designed to simulate radiographs of virtual objects. Virtual rotations of the pelvises were carried out with 4653 virtual radiographs obtained. Virtual radiographic measures were analyzed. A statistically significant difference of 8 mm between mean teardrop distance in females (120 mm) and males (112 mm) was found in the clinical material. A set of formulas describing the relations between differences of two rotation ratios and pelvic rotations were derived. Four simple regression analyses were carried out with the use of virtual measures. Adjusted teardrop distances were implemented. A clinical method to describe pelvic rotations using standard pelvic radiographs was developed.


Viruses with deletions in antiapoptotic genes as potential oncolytic agents.
Replication-selective oncolytic viruses have emerged as a new treatment platform for cancers. However, selectivity and potency need to be improved before virotherapy can become a standard treatment modality. In addition, mechanisms that can be incorporated to enable targeting a broad range of cancer types are highly desirable. Cancer cells are well known to have multiple blocks in apoptosis pathways. On the other hand, viruses have evolved to express numerous antiapoptotic genes to antagonize apoptosis induced upon infection. Viruses with deletions in antiapoptotic genes can therefore be complemented by antiapoptotic genetic changes in cancer cells for efficient replication and oncolysis. In this review, we summarize the recent development of this concept, the potential obstacles, and future directions for optimization.


The role of dendritic cells in neuroblastoma: Implications for immunotherapy.
Neuroblastoma is a solid tumor, which is originated from some neural tissues. The immune system including the innate and adaptive immune system fights against this tumor. Dendritic cells (DCs) play an important role in this way by recognizing tumor antigens and activating specific types of T cells. These cells are derived from monocytes that are induced by inflammatory factors secreted by different cells in the tumor microenvironment (TME). There are different types of DCs, including monocyte-derived DCs (moDC), plasmacytoid DCs (pDC), conventional DCs type 1 and 2 (cDC1 and cDC2), and Langerhans cells. DCs connect the innate and the adaptive part of the immune system and have an important role in anti-tumor immunity. There are some vaccines that involve specific types of DCs, which can be used to prevent neuroblastoma. Also, we can use the combination of inflammatory factors and DCs as a substitute for chemotherapy.


Early pacemaker implantation for transcatheter aortic valve implantation is safe and effective.
Permanent pacemaker (PPM) implantation is a common complication of transcatheter aortic valve implantation (TAVI). The optimum timing of PPM implantation is still unclear as conduction abnormalities evolve and a balance needs to be struck between conservative delays in the hope of conduction recovery and overutilization of pacing. This study aimed to assess the safety and efficacy of early PPM implantation, without an observation period, among TAVI patients. This is a retrospective, observational study of 1398 TAVI patients. Clinical and pacing data were collected at baseline, 30 days and at a median of 15 (4-21) months post-TAVI. Study endpoints included PPM-related complications, pacing utilization and hospital length of stay. One hundred five patients (8.2%) required a PPM, of which 13 were implanted pre and 92 post-TAVI. Seventy-six percent required pacing for either second- or third-degree heart block. Time to implantation for post-TAVI PPM was 1 (0-3) day. Six patients experienced a pacing-related complication- lead displacement (n = 3), hematoma (n = 2), and device infection (n = 1). Pacing utilization defined as pacing >10% of the time or a pacing requirement at the time of the pacing check was demonstrated in 83% of patients. Multivariate analysis revealed complete heart block (CHB) was the only independent predictor of pacing utilization. Hospital length of stay for the post-TAVI PPM group was longer than the group without PPM (4 [2-8] vs. 3 [2-4] days; p < .001). Early PPM implantation in TAVI patients is safe and majority of patients require pacing in the short and mid-term.


Elasticity of fiber meshes from multiblock copolymers influences endothelial cell behavior.
The behavior of endothelial cells is remarkably influenced by the physical and biochemical signals from their surrounding microenvironments. Here, the elasticity of fiber meshes was studied as a design parameter of substrates for endothelial cells in order to modulate angiogenesis. Human umbilical vein endothelial cells (HUVECs) were cultured on electrospun fiber meshes made from polyetheresterurethane (PEEU), differing in their elasticity. Cell morphology, proliferation, migration and angiogenesis of endothelial cells on the degradable substrate meshes were characterized. The aspect ratio of HUVECs cultured on the fiber meshes from PEEU materials increased with increasing stiffness of the materials. HUVECs cultured on fiber meshes with high stiffness (Young's modulus E = 4.5±0.8 MPa) presented a higher proliferation rate and significantly faster migration velocity, as well as higher tube formation capability than the cells cultured on fiber meshes with low stiffness (E = 2.6±0.8 MPa). These results suggested that tuning the fiber meshes' elasticity might be a potential strategy for modulating the formation or regeneration of blood vessels.


Isolation of influenza A viruses from migratory waterfowls in San-in District, Western Japan in winters of 1980-1982.
In the two winters of 1980-1982, we surveyed migratory waterfowl of some species staying in San-in District, Western Japan for influenza virus at a few stations. From November 1980 to April 1981, only two strains of influenza virus, H13N1 and H11N6 subtypes, were isolated from 465 fecal samples from pintails but none from 255 samples from whistling swans nor from 625 black-tailed gulls. From November 1981 to March 1982, 17 viruses were isolated from 1156 fecal samples. Fourteen viruses, 10 H7N3, 2 H1N6 and 2 H3N8, were isolated from 459 feces samples from whistling swans. Two viruses, H13N3 and H13N6 subtypes, were isolated from 425 fecal samples from black-tailed gulls. A strain belonging to H1N3 subtype was isolated from 30 feces samples from mallards but no virus was isolated from 242 samples from pintails.


New Insight on Carbon Dioxide-Mediated Hydrogen Production.
A new approach to hydrogen production from water is described. This simple method is based on carbon dioxide-mediated water decomposition under UV radiation. The water contained dissolved sodium hydroxide, and the solution was saturated with gaseous carbon dioxide. During saturation, the pH decreased from about 11.5 to 7-8. The formed bicarbonate and carbonate ions acted as scavengers for hydroxyl radicals, preventing the recombination of hydroxyl and hydrogen radicals and prioritizing hydrogen gas formation. In the presented method, not yet reported in the literature, hydrogen production is combined with carbon dioxide. For the best system with alkaline water (0.2 m NaOH) saturated with CO2 under UV-C, the hydrogen production amounted to 0.6 μmol h-1 during 24 h of radiation.


Career characteristics and postgraduate education of female dentist graduates of the College of Dentistry at King Saud University, Saudi Arabia.
The aims of this study were to investigate the number of female bachelor of dental surgery graduates who earned postgraduate education degrees from King Saud University, their specialties, degrees of qualification, and countries of graduation. A questionnaire survey was conducted through face-to-face or phone interview among 677 female dentists who graduated from the College of Dentistry at King Saud University between 1984 and 2006. Five hundred forty-five (81%) graduate female dentists responded, of whom 54% had completed postgraduate dental education. In the Saudi Board, 17% had obtained degrees in advanced restorative dentistry, 15% in pediatric dentistry, 14% in advanced general dentistry, 11% in orthodontics, 10% in prosthodontics, 8% in operative dentistry, 5% in endodontics, 5% in periodontics, 3% in oral and maxillofacial surgery, and 11% in other specialties. Fifty-nine percent had master's degrees, 7% had doctorates, 32% had board certificates, and 2% had fellowship certificates. More than half (54%) the female dentists surveyed had pursued postgraduate education. This investigation highlighted the different specialties enrolled by female dentists. Orthodontic post graduate program displayed the highest percentage of interest. Understanding the unavoidable social family needs and the demand for higher education by female dentists provides ideas as more programs should be planned to accommodate the needs of Saudi female dentists. This type of study should be repeated due to the increasing interest of female dentists in higher education.


O2 regulates stem cells through Wnt/β-catenin signalling.
Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (<5% O2) have revealed strong regulatory links between O2 availability and functions of stem and precursor cells. Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O2 gradients. However, the underlying mechanisms remain unclear. Here, we show that hypoxia inducible factor-1α (HIF-1α), a principal mediator of hypoxic adaptations, modulates Wnt/β-catenin signalling in hypoxic embryonic stem (ES) cells by enhancing β-catenin activation and expression of the downstream effectors LEF-1 and TCF-1. This regulation extends to primary cells, including isolated neural stem cells (NSCs), and is not observed in differentiated cells. In vivo, Wnt/β-catenin activity is closely associated with low O2 regions in the subgranular zone of the hippocampus, a key NSC niche. Hif-1α deletion impairs hippocampal Wnt-dependent processes, including NSC proliferation, differentiation and neuronal maturation. This decline correlates with reduced Wnt/β-catenin signalling in the subgranular zone. O2 availability, therefore, may have a direct role in stem cell regulation through HIF-1α modulation of Wnt/β-catenin signalling.


Proteomic analysis reveals oxidative stress response as the main adaptative physiological mechanism in cows under different production systems.
Three groups of cows representing three ranges of welfare in the production system were included in the study: two groups of Bruna dels Pirineus beef cattle maintained under different management systems (good and semiferal conditions) and a group of Alberes cows, a breed that lives in the mountains (hardest conditions). In order to identify new stress/welfare biomarkers, serum from Bruna cows living in both environments was subjected to DIGE labelling, two-dimensional electrophoresis and MALDI-MS or ion trap MS. Identification was achieved for 15 proteins, which mainly belonged to three biological functions, the oxidative stress pathway (glutathione peroxidase (GPx) and paraoxonase (PON-1)), the acute phase protein family (Heremans Schmid glycoprotein alpha2 (α2-HSG)) and the complement system. Biological validation included the Alberes breed. GPx and PON-1 were validated by an enzymatic assay and found to be higher and lower, respectively, in cows living in hard conditions. α2-HSG was validated by ELISA and found to be reduced in hard conditions. Other biomarkers of the redox status were also altered by living conditions: protein carbonyl content, superoxide dismutase (SOD) and glutathione reductase (GR). Our results show that changes in the redox system are the main adaptation of cows living in challenging environmental conditions.


[SARS-CoV-2 incidence, transmission, and containment measures in daycare centers during the COVID-19 pandemic-findings from the Corona Daycare Study].
Daycare centers are of substantial sociopolitical and pedagogical relevance; at the same time, the close contact of children in daycare groups among each other and with employees favors the transmission of infections. In the COVID-19 pandemic, questions arose about how infection events occur in daycare centers, what role daycare children play in the pandemic, and what protective and hygienic measures are implemented in daycare centers. From 06/2020 to 12/2021, we conducted the "Corona Day Care Study," in which we address pedagogical and infection epidemiological topics in a joint approach. In the study, data are collected from different sources. Official reporting data as well as weekly data from daycare centers in the so-called KiTa Register are continuously evaluated. In addition, SARS-CoV‑2 outbreaks in daycare centers are investigated on site by repeated sample collection and interviews. SARS-CoV‑2 infection incidence in daycare centers or in daycare-aged children was very dynamic from 03/2020 to 05/2021. In the second and third pandemic waves, the number of SARS-CoV‑2 outbreaks in daycare centers rose sharply, accompanied by a substantial increase in daycare and group closures. Most recently, the proportion of affected children in outbreaks increased steadily. However, preliminary examinations of SARS-CoV‑2 outbreaks (n = 28) revealed that, on average, only a fraction of daycare contact persons (6.8%) were infected by child index cases. Transmission frequencies differed markedly between the individual daycare centers. The combination of regularly collected reporting and survey data as well as outbreak investigations allows a multilayered monitoring and understanding of infection events in daycare centers; its findings could be incorporated into recommendations for public health measures.


Polymer support synthesis. XII. Derivatization with the 4-decyloxytrityl group as an aid in the affinity chromatography of oligo- and polynucleotides.
In a continuation of previous studies on trityl groups substituted with long alkyl chains as affinity-protecting groups for oligonucleotides, the use of the (4-decyloxyphenyl)diphenylmethyl (DTr) group as an aid in the separation of solid-phase products has been investigated. This substituent, which can be introduced and removed from the 5'-position in a similar manner to the di-p-anisylphenylmethyl group, helps in the purification of deoxypolynucleotides with up to 140 bases. Their retention time was shown to depend not only on the length of the nucleotide chain and alkyl substituent, but also on the elution gradient rate. In oligoribonucleotide synthesis, the DTr group allows the purification of partially protected sequences, which are more stable to enzymatic degradation and, therefore, more suitable for handling and storage.


Pathology of Extranodal Lymphoma.
An overview of the pathology of extranodal lymphoma is presented. The emphasis of this presentation is on the classification system of extranodal lymphomas, including both B-cell and T-cell lymphomas, based on their morphology, phenotype, and molecular alterations.


Assessment of ecotoxicological risks to river otters from ingestion of invasive red swamp crayfish in metal contaminated areas: Use of feces to estimate dietary exposure.
The invasive red swamp crayfish (Procambarus clarkii) has become a major food resource for Eurasian otters (Lutra lutra) in the Iberian Peninsula. Crayfish accumulate large amounts of metals, and hence otters could be at risk of exposure and intoxication through crayfish consumption. We conducted a food safety risk assessment for otters inhabiting two historical mining areas in central Spain affected by lead (Pb) and mercury (Hg) pollution. Estimated daily intakes (EDI) of Pb and Hg were non-invasively calculated from the proportion of crayfish remains and metal levels in otter feces. We considered that the abdominal muscle and the carcass of crayfish differ significantly in relative weight, total metal content and bioavailability of metals to reduce the uncertainty of risk characterization. Fecal concentrations of Hg and Pb in the polluted areas were 1.878 and 6.554 μg/g d. w., respectively (13-fold and 7-fold higher compared to a non-polluted area). EDI of Hg and Pb in the polluted areas were 66.02 and 78.26 μg/kg-day, respectively (14- and 8-fold higher than in the reference area). EDI from the Hg area were above minimum levels susceptible to cause neurotoxicity in mustelids, and 6.3% were above levels susceptible to cause histopathological lessions. In the Pb area, 16.7% of EDI were consistent with levels causing reproductive effects. Metal exposure through crayfish consumption might prevent or slow the recovey of otters in these polluted environments, thus this factor should be considered in management strategies aimed to protect otter populations.


Molecular dermatology comes of age.
Groundbreaking advances on the molecular and cellular physiological and physiopathological skin processes, including the complete sequencing of the genome of several species and the increased availability of gene-modified organisms, paved the way to firmly establishing molecular approaches and methods in experimental, translational, and clinical dermatology. As a result, newly developed experimental ex vivo assays and animal models prove exquisite tools for addressing fundamental physiological cutaneous processes and pathogenic mechanisms of skin diseases. A plethora of new findings that were generated using these experimental tools serve as a strong basis for intense translational research efforts aiming at developing new, specific, and sensitive diagnostic tests and efficient "personalized" therapies with less side-effects. Consequently, a broad array of molecular diagnostic tests and therapies for a wide spectrum of skin diseases ranging from genodermatoses through skin neoplasms, allergy, inflammatory and autoimmune diseases, are already routinely used in the clinical dermatology practice. This article highlights several major developments in molecular experimental and clinical dermatology.


Forearm and finger hemodynamics, blood pressure control, and lipid changes in patients with diabetic hypertension treated with atenolol and prazosin.
Hypertension and diabetes mellitus frequently coexist and are independent risk factors for reduced peripheral perfusion. Antihypertensive medications that reduce blood pressure and improve peripheral perfusion would have advantages in diabetic patients with hypertension. In a randomized, two-placebo period, single-blind, two-way crossover study, we determined finger and forearm blood flow, lipid levels, and blood pressure control in 19 diabetic patients with hypertension, with each atenolol or prazosin and placebo period of 4 weeks' duration. Both drugs reduced blood pressure (sitting: 157/95 to 142/84 mm Hg, atenolol; 155/95 to 138/82 mm Hg, prazosin; standing: 154/94 to 144/84 mm Hg, atenolol; 154/94 to 133/81 mm Hg, prazosin). Lipid levels did not change except that low-density lipoprotein levels fell from 148 to 127 mg/dl with prazosin. Atenolol did not change forearm or finger blood flow or vascular resistance. Prazosin increased blood flow and reduced vascular resistance in both finger and forearm. In conclusion, prazosin has a potentially more appropriate hemodynamic profile than has atenolol in diabetic patients with hypertension.


Incidence and prevalence of insulin-dependent diabetes mellitus in the zero- to 19-years' age-group in Sydney.
A population-based register of cases of insulin-dependent diabetes mellitus in the zero- to 19-years' age-group was established in the Southern Metropolitan Health Region of Sydney. The aims of the register were to provide accurate incidence and prevalence data for comparison with those of studies from elsewhere in the world and to evaluate diabetes services, morbidity and compliance with self-care regimens. This article presents the incidence and prevalence data. In the Southern Metropolitan Health Region, the annual incidence of insulin-dependent diabetes mellitus per 100,000 population who were aged zero to 19 years, rose from 10.3 cases in 1984 to 14.8 cases in 1987, and in the zero- to 14-years' age-group, it rose from 13.6 cases per 100,000 population in 1984 to 19.4 cases per 100,000 population in 1987; the increases were not statistically significant. The prevalence in the zero- to 19-years' age-group was 0.80 cases per 1000 population, and in the zero- to 14-years' age-group, it was 0.74 cases per 1000 population on February 1, 1986. Age-specific incidence rates were calculated for the years 1984-1987. Incidence peaks occurred at the ages of six years, 10 years and 12-13 years.


Fifteen years of experience with antepartum fetal testing.
The introduction of antepartum fetal heart rate testing occurred in the very early 1970s. This article describes the evolution of testing within the Los Angeles County/University of Southern California Medical Center and encompasses a 15-year time period between 1971 and 1985. During this time approximately 200,000 patients were delivered of their infants. Fetal surveillance increased from less than 1% to current levels of 16% of patients. The antepartum fetal death rate was evaluated as a measure of evaluating the usefulness of antepartum testing. The fetal death rate after antepartum testing in selected high-risk patients was significantly less than that found in those patients not tested. The questions that might be raised regarding broader application of this technique and potential benefits are stated.


Reversible inhibition of RNA synthesis and irreversible inhibition of protein synthesis by D-galactosamine in isolated mouse hepatocytes.
The inhibition of RNA synthesis of isolated mouse liver parenchymal cells caused by 10 mM D-galactosamine was reversible, while the inhibition of protein synthesis remained unaltered after the removal of galactosamine. 10(-5)M epinephrine and 10(07)M glucagon have been shown to decrease aminoglycogen formation and thus to reduce the inhibitory effect of galactosamine on protein synthesis (II). However, these hormones did not decrease the inhibition of RNA synthesis. 10 mM D-galactosamine did not effect the nucleoside and amino acid incorporation of isolated non-parenchymal mouse liver cells. The predominant role of aminoglycogen in the inhibition of protein synthesis in galactosamine induced liver injury is discussed.


The Thaumarchaeon N. gargensis carries functional bioABD genes and has a promiscuous E. coli ΔbioH-complementing esterase EstN1.
Biotin is an essential cofactor required for carboxylation and decarboxylation reactions in all domains of life. While biotin biosynthesis in most Bacteria and Eukarya is well studied, the complete pathway for this vitamer in Archaea is still not known. Detailed genome searches indicated the presence of possible bio gene clusters only in Methanococcales and Thaumarchaeota. Therefore, we analysed the functionality of the predicted genes bioA, bioB, bioD and bioF in the Thaumarchaeon Nitrososphaera gargensis Ga2.9 which are essential for the later steps of biotin synthesis. In complementation tests, the gene cluster-encoded N. gargensis bioABD genes except bioF restored growth of corresponding E. coli Rosetta-gami 2 (DE3) deletion mutants. To find out how biotin biosynthesis is initiated, we searched the genome for a possible bioH analogue encoding a pimeloyl-ACP-methylester carboxylesterase. The respective amino acid sequence of the ORF estN1 showed weak conserved domain similarity to this class of enzymes (e-value 3.70e-42). Remarkably, EstN1 is a promiscuous carboxylesterase that complements E. coli ΔbioH and Mesorhizobium loti ΔbioZ mutants for growth on biotin-free minimal medium. Additional 3D-structural models support the hypothesis that EstN1 is a BioH analogue. Thus, this is the first report providing experimental evidence that Archaea carry functional bio genes.


Application of acetone acetals as water scavengers and derivatization agents prior to the gas chromatographic analysis of polar residual solvents in aqueous samples.
The sensitivity of gas chromatography (GC) combined with the full evaporation technique (FET) for the analysis of aqueous samples is limited due to the maximum tolerable sample volume in a headspace vial. Using an acetone acetal as water scavenger prior to FET-GC analysis proved to be a useful and versatile tool for the analysis of high boiling analytes in aqueous samples. 2,2-Dimethoxypropane (DMP) was used in this case resulting in methanol and acetone as reaction products with water. These solvents are relatively volatile and were easily removed by evaporation enabling sample enrichment leading to 10-fold improvement in sensitivity compared to the standard 10μL FET sample volumes for a selection of typical high boiling polar residual solvents in water. This could be improved even further if more sample is used. The method was applied for the determination of residual NMP in an aqueous solution of a cefotaxime analogue and proved to be considerably better than conventional static headspace (sHS) and the standard FET approach. The methodology was also applied to determine trace amounts of ethylene glycol (EG) in aqueous samples like contact lens fluids, where scavenging of the water would avoid laborious extraction prior to derivatization. During this experiment it was revealed that DMP reacts quantitatively with EG to form 2,2-dimethyl-1,3-dioxolane (2,2-DD) under the proposed reaction conditions. The relatively high volatility (bp 93°C) of 2,2-DD makes it possible to perform analysis of EG using the sHS methodology making additional derivatization reactions superfluous.


Quantitative hematoma heterogeneity associated with hematoma growth in patients with early intracerebral hemorrhage.
Early hematoma growth is associated with poor functional outcomes in patients with intracerebral hemorrhage (ICH). We aimed to explore whether quantitative hematoma heterogeneity in non-contrast computed tomography (NCCT) can predict early hematoma growth. We used data from the Risk Stratification and Minimally Invasive Surgery in Acute Intracerebral Hemorrhage (Risa-MIS-ICH) trial. Our study included patients with ICH with a time to baseline NCCT <12 h and a follow-up CT duration <72 h. To get a Hounsfield unit histogram and the coefficient of variation (CV) of Hounsfield units (HUs), the hematoma was segmented by software using the auto-segmentation function. Quantitative hematoma heterogeneity is represented by the CV of hematoma HUs. Multivariate logistic regression was utilized to determine hematoma growth parameters. The discriminant score predictive value was assessed using the area under the ROC curve (AUC). The best cutoff was determined using ROC curves. Hematoma growth was defined as a follow-up CT hematoma volume increase of >6 mL or a hematoma volume increase of 33% compared with the baseline NCCT. A total of 158 patients were enrolled in the study, of which 31 (19.6%) had hematoma growth. The multivariate logistic regression analysis revealed that time to initial baseline CT (P = 0.040, odds ratio [OR]: 0.824, 95 % confidence interval [CI]: 0.686-0.991), "heterogeneous" in the density category (P = 0.027, odds ratio [OR]: 5.950, 95 % confidence interval [CI]: 1.228-28.828), and CV of hematoma HUs (P = 0.018, OR: 1.301, 95 % CI: 1.047-1.617) were independent predictors of hematoma growth. By evaluating the receiver operating characteristic curve, the CV of hematoma HUs (AUC = 0.750) has a superior predictive value for hematoma growth than for heterogeneous density (AUC = 0.638). The CV of hematoma HUs had an 18% cutoff, with a specificity of 81.9 % and a sensitivity of 58.1 %. The CV of hematoma HUs can serve as a quantitative hematoma heterogeneity index that predicts hematoma growth in patients with early ICH independently.


Psychophysics of reading--XIII. Predictors of magnifier-aided reading speed in low vision.
A key clinical problem in low-vision assessment is finding simple measures that are predictive of real-world performance. Our purpose was to determine whether a set of clinical variables could predict how well low-vision subjects read with their magnifiers. The variables were Snellen acuity, presence/absence of central scotomas, clear/cloudy ocular media, age, magnifier type, and score on a standardized test of reading speed (Minnesota Low-vision Reading Test). Forty low-vision subjects identified the magnifier they most "preferred" to use, based on the frequency and length of time used, ease of use, or any other factor considered important by each subject. All subjects were highly experienced with their magnifier (3 months to 21 yr of use). We classified the magnifiers into five categories: (1) standard correction only; (2) hand-held magnifier; (3) spectacle-mounted magnifier; (4) closed-circuit TV; and (5) stand magnifier. Subjects used their preferred magnifiers to read aloud printed paragraphs of about 150 words from which their reading speeds were calculated. By far the best predictor of the magnifier-aided reading speed was the score on the standardized reading test which accounted for 79.7% of the variance. 43.7% of the variance was accounted for by age, and 42.3% by magnifier type. Snellen acuity, central visual field status, and ocular media status were not significantly correlated with magnifier-aided reading speed. We conclude that a standardized clinical reading test can give a valid prediction of the reading speed a low-vision patient is likely to achieve with a magnifier.


Chronic lymphocytic leukemia with a novel der(8;15)(q10;q10) translocation.
A 71-year-old male was found to have chronic lymphocytic leukemia. Cytogenetic study of the leukemic lymphocytes shows a 46,XY,der(8;15)+15. The der(8;15) is a novel chromosomal abnormality in human malignancies. The resulting loss of 8p and trisomy 15q are both unusual chromosomal changes in chronic lymphocytic leukemia.


A Study of the Antitumour Activity of Four Triorganophosphinegold(I) Thiolates: R(3) PAu(SR'), R = Ph, Cy, Et; SR'H = 6-Mercaptopurine and R = Et; SR'H = 6-Thioguanine.
The antitumour activities of four triorganophosphinegold(I) thiolates, R(2)PAu(S'R) [R = Ph, Cy, Et; SR'H = 6-mercaptopurine and R Et; SR'H = 6-thioguanine] against the National Cancer Institute (NCI) panel of 60 cell lines are reported The [Cy(3)PAu(6-MP)] complex proved to be the more cytotoxic of the four complexes tested. For the 6-MP series, an order of cytotoxicity was established such that the activity followed the order R = Cy > Ph > Et. Sub-panel selectivity against the Leukemia cell lines was found for each of [Cy(3) PAu(6-MP)] and [Et(3)PAu(6-TG)].


How to counter the problem of R1 resection in duodenopancreatectomy for pancreatic cancer?
Although duodenopancreatectomy has been standardized for many years, the pathological examination of the specimen was re-described in the last years. In methodical pathological studies up to 85% had an R1 margin.1,2 These mainly involved the posterior und medial resection margin.3 As a consequence we need to optimize and standardize the pathological workup of the specimen and to extend the surgical resection, where possible without risk for the patient. In an instructive video we show the technique of duodenopancreatectomy with emphasis on the dorsal and medial resection margin. Furthermore we show the standardized pathological workup of the specimen, involving the reporting of all the resection margins. To accurately determine R1 status at the posterior and medial resection margin, a close collaboration between pathologist and surgeon is crucial. Pathologists do a standardized workup of the resected specimen with staining of the surfaces and systematic analysis of all the resection margins. Surgeons need to extend the resection of the pancreatic head to the superior mesenteric artery by dorsal dissection.


The effects of mevinolin on the thiol/disulfide exchange between 3-hydroxy-3-methyglutaryl-coenzyme A reductase and glutathione.
The feeding of mevinolin plus cholestyramine to rats results in the production of a form of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR-CM) having thiol/disulfide redox properties different from those of 3-hydroxy-3-methylglutaryl-CoA reductase isolated from animals which had been given only cholestyramine (HMGR-C). The second-order rate constant for the inactivation of HMGR-CM by GSSG is 7-fold slower than for HMGR-C, while the second-order rate constant for the reactivation of oxidized enzyme by GSH is 100-fold slower. However, in the presence of saturating concentrations of both substrates, the rate constants for thiol/disulfide exchange are similar for both forms of the enzyme. HMGR-CM behaves as if a protein-glutathione mixed disulfide having a Kox of 27 +/- 4 is formed at equilibrium. In contrast, HMGR-C has previously been shown to form a protein-protein disulfide (Cappel, R. E., and Gilbert, H. F. (1988) J. Biol. Chem. 263, 12204-12212). Both forms of the enzyme are more difficult to oxidize thermodynamically in the presence of saturating levels of both substrates. For HMGR-CM, NADPH alone has no effect on the equilibrium constant for oxidation, but hydroxymethylglutaryl-CoA alone makes the enzyme approximately twice as difficult to oxidize. Under physiological conditions, HMGR-CM is thermodynamically more difficult to oxidize than HMGR-C. HMGR-C can be converted to HMGR-CM by in vitro treatment with mevinolinate. A direct or indirect interaction of mevinolin with HMGR-C results in some persistent, as yet undefined, structural alteration which inhibits the formation of a protein-SS-protein disulfide upon oxidation by glutathione disulfide.


Receptor activity modifying proteins regulate the activity of a calcitonin gene-related peptide receptor in rabbit aortic endothelial cells.
In Xenopus oocytes with an endogenous calcitonin gene-related peptide (CGRP) receptor, a receptor activity modifying protein (RAMP1) enhancing CGRP stimulated chloride currents of the cystic fibrosis transmembrane regulator was recently cloned [McLatchie, L.M. et al. (1998) Nature 393, 333-339]. Here, transient expression of RAMP1 in rabbit aortic endothelial cells (RAEC) brought about stimulation of cAMP accumulation by human (h) alphaCGRP with an EC50 of 0.41 nM. This was antagonized by a CGRP receptor antagonist alphaCGRP(8-37). Co-expression of RAMP3 together with RAMP1 reduced the maximal cAMP response to h alphaCGRP by 47% (P < 0.05). The cells also express RAMP2 encoding mRNA and an adrenomedullin (ADM) receptor coupled to stimulation of cAMP formation by hADM (EC50 0.18 nM). The latter was antagonized by an ADM receptor antagonist hADM(22-52). In conclusion, expression of a CGRP receptor in RAEC requires RAMP1. The same receptor presumably recognizes ADM making use of endogenous RAMP2. The results reveal competition between the different RAMPs in the regulation of CGRP/ADM receptor activity.


Dual-acting histone deacetylase-topoisomerase I inhibitors.
Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation.


[Effectiveness and hemodynamic mechanism of action of blood pressure lowering by intravenous labetalol in patients with a critical increase in blood pressure].
Labetalol (L) was intravenously given to ten patients with an acute elevation of arterial blood pressure above to 200 to 100 mmHg. Blood pressure was controlled in 9 of 10 patients (less than or equal to 170/100 mmHg) with 50 mg in 4, 100 mg in 4 and 200 mg L in 1 patient. In 9 responders, systolic pressure decreased from 207 +/- 20 to 161 +/- 9, diastolic pressure from 107 +/- 11 to 90 +/- 8, and mean pressure from 140 +/- 11 to 113 +/- 5 mmHg, and all pressures remained at these levels during a 25 min control period. Heart rate decreased significantly from 87 +/- 20 to 69 +/- 11 per min and cardiac index from 3.2 +/- 0.8 to 2.6 +/- 0.61/min x m2. Stroke volume index remained unchanged. Total peripheral resistance and pulmonary artery occlusion pressure were not significantly altered but tended to increase, resulting in a small shift to the right of the ventricular function curve. Pulmonary vascular resistance increased significantly from 236 +/- 108 to 314 +/- 132 dyn x sec x cm-5 and mixed venous oxygen saturation decreased from 70 +/- 5 to 65 +/- 8%. Peripheral resistance was considerably higher and cardiac index lower in patients with a heart rate below 70/min. We conclude that L effectively lowers the arterial blood pressure in hypertensive crisis, but the substance should not be used in patients with heart rates below 70/min, as in this case the beta-blocking effect may supervene resulting in a high-resistance low-output state.


Striatal dopamine transporters and cognitive function in Parkinson's disease.
Idiopathic Parkinson's disease (PD) is characterized by clinical motor symptoms including hypokinesia, rigidity and tremor. In addition to the movement disorder, cognitive deficits are commonly described. In the present study, we applied FP-CIT SPECT to investigate the impact of nigrostriatal dopaminergic degeneration on cognitive function in PD patients. Fifty-four PD patients underwent [123I]FP-CIT SPECT and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) testing. FP-CIT SPECT visualized the density of presynaptic dopamine transporters in both striata, each subdivided into a limbic, executive and sensorimotor subregion according to the atlas of Tziortzi et al (Cereb Cortex 24, 2014, 1165). CERAD testing quantified cognitive function. In the CERAD testing, PD patients exhibited deficits in the domains of semantic memory, attention, visuospatial function, non-verbal memory and executive function. After correction for multiple testing, the performance of the subtests Figure Recall and Trail-Making Test A correlated significantly with FP-CIT uptake into the ipsilateral executive subregion. The performance of the subtest Figure Saving correlated significantly with FP-CIT uptake into the contralateral executive subregion. The significant correlation between cognitive function and density of nigrostriatal dopamine transporters, as assessed by FP-CIT SPECT, indicate that striatal dopaminergic pathways-primarily the executive striatal subregion-are relevant to cognitive processing in PD.


[1,5]-Brook rearrangement: an overlooked but valuable silyl migration to synthesize configurationally defined vinylsilane. The unique steric and electronic effects of geminal bis(silane).
An unusual [1,5]-Brook rearrangement of the lithium alkoxide of geminal bis(silyl) homoallylic alcohol is described. The unique steric and electronic effects of geminal bis(silane) were found to be crucial for promoting this long-range silyl migration, as well as for facilitating the subsequent γ/Z-selective addition of silyl allyllithium with carbonyl compounds to synthesize diverse configurationally defined Z-vinylsilanes.


Altered Callosal Morphology and Connectivity in Asymptomatic Carotid Stenosis.
Carotid stenosis, even in the clinically asymptomatic stage, causes cognitive impairment, silent lesions, and hemispheric changes. The corpus callosum (CC) is crucial for hemispheric cortical integration and specialization. To examine if CC morphology and connectivity relate to cognitive decline and lesion burden in asymptomatic carotid stenosis (ACS). Retrospective, cross-sectional. 33 patients with unilaterally severe (70%) ACS and 28 demographically and comorbidity-matched controls. A publicly available healthy adult lifespan (ages between 18 and 80; n = 483) MRI dataset was also included. A 3.0 T; T1 MPRAGE and diffusion weighted gradient echo-planar imaging sequences. Structural MRI and multidomain cognitive data were obtained. Midsagittal CC area, circularity, thickness, integrity, and probabilistic tractography were calculated and correlated with cognitive tests and white matter hyperintensity. Fractional anisotropy, mean diffusivity (MD), and radial diffusivity were determined from DTI. Independent two-sample t-tests, χ2 tests, Mann-Whitney U, locally weighted scatterplot smoothing (LOWESS) curve fit, and Pearson correlation. A P value < 0.05 was considered statistically significant. Patients with ACS demonstrated significant reductions in callosal area, circularity, and thickness compared to controls. The callosal atrophy was significantly correlated with white matter hyperintensity size (r = -0.629, P < 0.001). Voxel-wise analysis of diffusion measures in the volumetric CC showed that ACS patients exhibited significantly lower fractional anisotropy and higher MD and radial diffusivity in the genu and splenium of the CC than controls. Further lifespan trajectory analysis showed that although the midsagittal callosal area, circularity, and thickness exhibited age-related decreases, the values in the ACS patients were significantly lower in all age groups. Midsagittal callosal atrophy and connectivity reflect the load of silent lesions and the severity of cognitive decline, respectively, suggesting that CC degeneration has potential to serve as an early marker in ACS. 3 TECHNICAL EFFICACY STAGE: 2.


Assessing the use of an infographic on pre-exposure prophylaxis for Wisconsin community pharmacists.
Pre-exposure prophylaxis (PrEP) treatments reduce the risk of contracting human immunodeficiency virus (HIV). However, despite proven effectiveness, PrEP use remains low among populations at risk of contracting HIV. Successful PrEP uptake includes developing partnerships with health care providers to implement PrEP-related tools and interventions. Pharmacists are uniquely positioned health professionals who can provide PrEP services in the community, such as pharmacy-led PrEP clinics, to increase uptake, adherence, and retention. Unfortunately, prior evidence shows that not all pharmacists have enough knowledge about PrEP to provide effective care, resulting in low confidence and discomfort in PrEP-related patient consultations. This study aimed to assess Wisconsin community pharmacists' intentions of utilizing an infographic on PrEP for HIV prevention to educate themselves on PrEP and in consultations with patients starting PrEP. An adaptative survey, using the Theory of Planned Behavior, was conducted to assess pharmacists' intentions by measuring their attitudes, subjective norms, and perceived behavioral control. The Fisher exact tests were performed to examine associations between the 3 theoretical constructs against intentions. Pharmacists reported high intentions of utilizing the infographic to educate themselves (62%) and counsel patients starting PrEP (54%). Their attitudes, subjective norms, and perceived behavioral controls were all significantly associated with their intentions. However, their intentions were reported lower than their attitudes, subjective norms, and perceived behavioral control, suggesting that additional factors may influence intentions that were not measured in this study. The results from this study demonstrate Wisconsin community pharmacists' intentions of using an infographic on PrEP for HIV prevention in practice while measuring their attitudes, subjective norms, and perceived behavioral control. Future research is warranted to explore adapting and using the infographic to better understand its influence in improving pharmacy care among HIV-negative individuals.


A gene-controlling response of bone marrow progenitor cells to granulocyte-macrophage colony stimulating factors.
The production of granulocytes and macrophages from progenitor cells in the bone marrow is controlled, in part, by a family of humoral regulators, termed colony stimulating factors (CSF). We have examined genetic factors controlling this process using in vitro cloning techniques. The inbred mouse strain LP/J showed elevated colony formation (CFU-C) in response to one subtype of CSF (G,M-CSF) compared to other strains of mice examined including the strain C57BL/6J. This variation resulted in a shift to the left of the CFU-C dose-response curve for LP/J. No difference between LP/J and C57BL/6J was seen with another subtype of CSF (CSF-1). Maximal CFU-C response was similar in the two mouse strains with both types of CSF, and mixing experiments with both types of CSF gave the same maximal level of colony formation as the individual CSF. (C57BL/6J X LP/J)F1 progeny exhibited a CFU-C dose-response curve to CSF-2 that was intermediate between the parental types, indicating additive inheritance. Genetic analysis of backcross progeny suggested that the variation in CFU-C response is probably determined by a single primary gene, although the variability of the colony formation assay has complicated interpretation of genetic studies. These results suggest that CSF-1 and G,M-CSF act independently on a single bone marrow progenitor cell population. The properties of the genetic variation for G,M-CSF response are consistent with an alteration in cellular receptors for G,M-CSF.


One drug to treat many diseases: unlocking the economic trap of rare diseases.
There are two major problems with the development of therapies for rare diseases. First, among over 7000 such diseases, the vast majority are caused by genetic defects and/or include neurodegeneration, making them very difficult to treat. Second, drugs for rare diseases, so-called orphan drugs, are extremely expensive, as only a small number of patients are interested in purchasing them. This results in the appearance of a specific economic trap of rare diseases; namely, despite high biomedical, pharmaceutical and technological potential, the development of new orphan drugs is blocked by the economic reality. The purpose of this work was to find a potential solution that might resolve this economic trap of rare diseases. A literature review was conducted, and a hypothesis was formulated assuming that the use of one drug for the treatment of many rare diseases might overcome the economic trap. We provide examples showing that finding such drugs is possible. Thus, a possible solution for the problem of developing orphan drugs is presented. Further preclinical and clinical studies, although neither easy nor inexpensive, should verify whether the hypothesis regarding the possibility of unlocking the economic trap of rare diseases is valid.


Clinical study of recurrence rate and survival time of patients with carcinoma of the breast treated by biopsy excision without any other therapy.
We report the recurrence rate and survival time in 31 patients with carcinoma of the breast who were treated by limited excision of the primary tumour and no other therapy. At three years the overall recurrence rate in the breast was 28%. One patient was found to have systemic disease and two died of other causes. The overall recurrence rate in the breast at five years was 33%. One patient died of disseminated disease at 6 years 4 months.


The humanitarian and outreach ethics charter in ENT. Ethics at the heart of missions.
Humanitarian action, in the broad sense, including global outreach missions by ENT physicians, has been effective for many years. These volunteer missions have not had any specific regulatory framework, be it medical, social or above all ethical. The testimony of ENT physicians in certain "recipient" countries, in particular during the 2017 Paris Congress of the International Federation of Otorhinolaryngological Societies (IFOS), revealed the importance of adequate coordination between "provider" and "recipient" teams. Several ethical reports have been made, but few specifically focused on ENT outreach. The present review is based on feedback from several missions given to the French Society of OtoRhinoLaryngology and Head and Neck Surgery (SFORL) and IFOS, and on a review of the literature. A specific charter of global outreach and humanitarian missions in ENT has been drawn up. This review is essential for optimizing the sharing of knowledge and training in otorhinolaryngology across the world while respecting mandatory sociocultural and ethical rules.


Optimisation of steroid prophylaxis schedules in breast cancer patients receiving docetaxel chemotherapy-a survey of health care providers and patients.
Despite the widespread use of steroid prophylaxis schedules for breast cancer patients receiving docetaxel chemotherapy, questions still exist regarding their optimal use. We surveyed health care providers and patients about their experiences with steroid prophylaxis. Two questionnaires were developed and circulated. One was presented to health care providers (chemotherapy nurses, pharmacists and medical oncologists) involved in the treatment of breast cancer and the second to patients who had received docetaxel chemotherapy for early stage breast cancer. The health care providers' questionnaire was completed by 184 of 698 invitees: 92/171 (53.8 %) chemotherapy nurses, 56/284 (19.7 %) pharmacists and 36/243 (14.8 %) medical oncologists (overall response rate 26.4 %). Two steroid schedules were found to be the most commonly used: dexamethasone 8 mg BID for 6 doses, with either 3 (79 %) or 2 (11 %) doses taken before docetaxel administration. Suboptimal adherence to steroid premedication had been experienced by 98 % (177/181) of practitioners. Despite the presence of local treatment protocols in 65 % (119/183) of practitioners' institutions, 10 different strategies were commonly used when steroid premedication was taken incorrectly. The patients' questionnaire was completed by 72/87 (82.3 %) invitees. Respondents reported correctly taking their premedication 99 % (70/71) of the time. Patients felt steroids frequently caused side effects, the most common being sleep disturbance (35/72 = 49 %) and skin toxicity (16/72 = 22 %). Suboptimal adherence to steroid premedication prior to docetaxel administration is a common clinical challenge. There appears to be discordance between the practitioner and the patient experience. A single, universally accepted and used protocol for both pre- and post-medication and management when premedication is not taken as prescribed could improve adherence.


Responses of nuclear glucose-6-phosphatase to diabetes and to hydrocortisone administered to normal and diabetic rats differ from those of the microsomal enzyme.
The effect of alloxan-diabetes, and of pharmacological doses of hydrocortisone administered to normal and diabetic rats, on carbamyl phosphate:glucose phosphotransferase and D-glucose-6-phosphate phosphohydrolase (EC 188.8.131.52) activities of isolated hepatic nuclei and microsomes were studied by assay at pH 7 in the absence and presence of deoxycholate. Hormonally related alterations both in activity levels and in the activation by the detergent (i.e. latency) of activities of the two cellular structural elements differed significantly. Most strikingly, (a) a 3--4-fold increase in the levels of activities of nuclei was seen in response either to diabetes or to hydrocortisone administered to normal rats whether or not detergent was added to preparations prior to assay; (b) the normally low degree of stimulation by detergent of activities of nuclei was unaltered in diabetes, and (c) administration of the glucocorticoid to diabetic rats decreased activity levels and increased their activation by detergent. Directly contrasting responses were noted with isolated microsomal preparations. Fundamental differences in the enzymes in these two organelle preparations are thus demonstrated. It appears that both synthetic and hydrolytic activities of this enzyme of nuclei may be manifest in the presence of requisite substrates, and that activities of this organelle may become increasingly prominent under certain hormonally perturbed conditions.


Boosting support vector machines for cancer discrimination tasks.
Cancer is a complex disease that is caused by rapid alteration of genes. Prediction of the state of cancer in advance contributes to a better understanding of its mechanism and improves the cancer therapy process. For example, predicting the malignancy of tumors in advance can prevent the development of cancer through the early treatment and clinical management of tumor progression. Despite generation of extensive clinical data obtained from the high-throughput technologies, it is necessary to develop machine learning algorithms to guide the prediction process. In the study, we utilize boosting and develop three computational methods to increase the performance of support vector machines (SVM). The aforementioned methods improve the performance over existing state-of-the-art algorithms, including SVM and xgboost. We evaluate the proposed boosting approach relative to the existing algorithms by using several gene expression data related to oral cancer, breast cancer, pheochromocytomas and paragangliomas, bladder cancer, and gastric cancer. The reported results using several performance measures indicate that algorithms employing the proposed approach outperform algorithms employing the baseline approach.


Intraocular miotics and postoperative inflammation.
Sixty patients scheduled for planned extracapsular cataract extraction with intraocular lens (IOL) implantation were randomly assigned to receive acetylcholine chloride, carbachol, or balanced salt solution (BSS) immediately after IOL placement and at the end of the surgical case. As part of the postoperative evaluation, patients were examined at the first and eighth postoperative day with a Kowa FC-1000 laser flare and cell meter to assess objectively the amount of postoperative inflammation. At day one and day eight, the amount of cell and flare in the carbachol group was significantly greater than in the acetylcholine group or in the BSS control group. The acetylcholine group had significantly less flare than the BSS group at day one; yet there was no difference between the two groups at day eight, nor was there a significant difference in the amount of cells between day one and day eight. It is presumed that the prolonged miosis seen in the carbachol group delays the re-establishment of the blood-aqueous barrier after surgery, causing the inflammatory response.


[Complications in a patient with liver cirrhosis and HCV coinfection during treatment with peginterferon and ribavirin].
Authors present a case of 15-years old girl with liver cirrhosis due to biliary atresia with HCV coinfection with portal hypertension after several episodes of variceal bleeding treated primarily with sclerotherapy and later with transjugular intrahepatic porto-systemic stent shunt. In a patient during the combined peginterferon alfa-2b and ribavirin treatment a decompensation of liver occurred with necessity for liver transplantation.


Lipoxygenases in chronic liver diseases: current insights and future perspectives.
Chronic liver diseases (CLDs) caused by viral infections, alcohol/drug abuse, or metabolic disorders affect millions of people globally and have increased mortality owing to the lack of approved therapies. Lipoxygenases (LOXs) are a family of multifaceted enzymes that are responsible for the oxidation of polyunsaturated fatty acids (PUFAs) and are implicated in the pathogenesis of multiple disorders including liver diseases. This review describes the three main LOX signaling pathways - 5-, 12-, and 15-LOX - and their involvement in CLDs. We also provide recent insights and future perspectives on LOX-related hepatic pathophysiology, and discuss the potential of LOXs and LOX-derived metabolites as diagnostic biomarkers and therapeutic targets in CLDs.


First evidence of in vitro cytotoxic effects of marine microlitter on Merluccius merluccius and Mullus barbatus, two Mediterranean commercial fish species.
Marine litter is composed mainly of plastics and is recognized as a serious threat to marine ecosystems. Ecotoxicological approaches have started elucidating the potential severity of microplastics (MPs) in controlled laboratory studies with pristine materials but no information exists on marine environmental microlitter as a whole. Here, we characterized the litter in the coastal Northern Tyrrhenian sea and in the stomach of two fish species of socio-economic importance, and exposed primary cell cultures of mucosal and lymphoid organs to marine microlitter for evaluating possible cytotoxic effects. An average of 0.30 ± 0.02 microlitter items m-3 was found in water samples. μFT-IR analysis revealed that plastic particles, namely HDPE, polyamide and polypropylene were present in 100% and 83.3% of Merluccius merluccius and Mullus barbatus analyzed, which overall ingested 14.67 ± 4.10 and 5.50 ± 1.97 items/individual, respectively. Moreover, microlitter was confirmed as a vector of microorganisms. Lastly, the apical end-point of viability was found to be significantly reduced in splenic cells exposed in vitro to two microlitter conditions. Considering the role of the spleen in the mounting of adaptive immune responses, our results warrant more in-depth investigations for clarifying the actual susceptibility of these two species to anthropogenic microlitter.