Factors Affecting the Quality of Life of Patients After Kidney Transplantation: A Cross-Sectional Study.
Kidney transplantation is currently the best choice for renal replacement therapy, due to its effect in reducing mortality and improving the quality of life (QoL) of patients with end-stage renal disease. This study aimed to identify factors affecting QoL after kidney transplantation. We conducted a cross sectional study by recruiting patients who had kidney transplantation at Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, from 2018 - 2020. QoL was assessed using the 36-item Short Form Health Survey (SF-36) questionnaire. We evaluated age, sex, body mass index, hemoglobin level, estimated glomerular filtration rate, duration of dialysis before transplantation, history of diabetes, depression, and performance status as factors associated with QoL score. We involved 107 subjects in our study. Depression, hemoglobin level, ECOG performance status, and duration of dialysis were factors affecting the physical component score (R2=0.21). Depression and hemoglobin level were factors affecting the mental component score (R2=0.34 ). Depression, hemoglobin level, and ECOG performance status were factors contributed to the total QoL score (R2=0.41). Factors that contributed to QoL status were depression, ECOG performance status, and hemoglobin levels. This study supported the need for assessment of QoL on regular basis, psychological aspects including depression, as well as other factors that can affect QoL such as performance status and hemoglobin level in patients before and after kidney transplantations.


Maraviroc for previously treated patients with R5 HIV-1 infection.
CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)


Oridonin Triggers Chaperon-mediated Proteasomal Degradation of BCR-ABL in Leukemia.
Inducing degradation of oncoproteins by small molecule compounds has the potential to avoid drug resistance and therefore deserves to be exploited for new therapies. Oridonin is a natural compound with promising antitumor efficacy that can trigger the degradation of oncoproteins; however, the direct cellular targets and underlying mechanisms remain unclear. Here we report that oridonin depletes BCR-ABL through chaperon-mediated proteasomal degradation in leukemia. Mechanistically, oridonin poses oxidative stress in cancer cells and directly binds to cysteines of HSF1, leading to the activation of this master regulator of the chaperone system. The resulting induction of HSP70 and ubiquitin proteins and the enhanced binding to CHIP E3 ligase hence target BCR-ABL for ubiquitin-proteasome degradation. Both wild-type and mutant forms of BCR-ABL can be efficiently degraded by oridonin, supporting its efficacy observed in cultured cells as well as mouse tumor xenograft assays with either imatinib-sensitive or -resistant cells. Collectively, our results identify a novel mechanism by which oridonin induces rapid degradation of BCR-ABL as well as a novel pharmaceutical activator of HSF1 that represents a promising treatment for leukemia.


Hypersensitivity to DNA cross-linking agents associated with up-regulation of glucose-regulated stress protein GRP78.
We have shown previously that NAD/poly(ADP-ribose) polymerase-deficient cells that overexpress Mr 78,000 glucose-regulated stress protein (GRP78) are resistant to topoisomerase II inhibitors, such as etoposide, m-amsacrine, and doxorubicin. However, these cells have been found to be hypersensitive to DNA cross-linking agents, including melphalan, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These observations prompted us to examine whether overexpression of GRP78 is associated with modulation of cytotoxicity of clinically useful DNA-cross-linking agents such as melphalan, BCNU, and cisplatin. We up-regulated GRP78 in V79 Chinese hamster cells by 2-5-fold using two independent approaches that include exposure to 6-aminonicotinamide, or 2-deoxyglucose. Subsequently, these GRP78-overexpressing cells were trypsinized, plated in regular medium without GRP78-inducing agents, and allowed a 5-h attachment time before being treated with melphalan, BCNU, or cisplatin for 1 h to determine clonogenic survivals. In addition, repair of DNA cross-links induced by those agents were determined by alkaline elution assay. Our results show that the GRP78-overexpressing V79 cells are hypersensitive to DNA cross-linking agents compared to the control V79 cells. Furthermore, repair of drug-induced DNA cross-links appears to be considerably slower in these cells relative to that found in control V79 cells. Thus, our results suggest that (a) up-regulation of GRP78 is associated with an impairment of DNA cross-link repair, (b) up-regulation of GRP78 is associated with potentiation of cytotoxicity induced by alkylating and platinating agents, and (c) up-regulation of GRP78 can be considered as a potentially useful tool to modulate the cytotoxicity of clinically useful alkylating and platinating agents.


The role of clinical decision support in pharmacist response to drug-interaction alerts.
With over 100,000 different types of drug-drug interactions health care professionals rely heavily on automated drug-interaction alerts. Substantial variance in drug-interaction alerts yields opportunities for the use of clinical decision support (CDS) as a potential benefit to pharmacists. The purpose of this research was to determine whether decision support during dispensing impacts pharmacist response to drug-interaction alerts. A brief survey was administered to pharmacists in the community consisting of three patient cases, each containing three drug-drug interactions of varying severity. For each interaction, pharmacists were asked how they would respond, one group of pharmacists was randomly assigned to receive CDS while the other group did not. There were no significant differences in pharmacist response to alerts between the two groups. The control group did appear to be more likely to consult a drug reference, but this difference was not significant. While this study did not demonstrate a significant difference, drug-interaction alerts are still an area where improvements could be made. Advancements have the potential to reduce risk to patients and limit unnecessary hospital admissions. This study suggests that this level of clinical decision support has limited impact, but may prove beneficial by reducing the need to consult additional references.


Chronic inhibition of phosphodiesterase 5 with tadalafil affords cardioprotection in a mouse model of metabolic syndrome: role of nitric oxide.
Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and reduce cardiac dysfunction following ischemia/reperfusion (I/R) injury in C57BL/6NCrl-Leprdb-lb/Crl mice with MetS phenotypes. Adult male MetS mice were randomized to receive vehicle solvent or tadalafil (1 mg/kg,i.p.) daily for 28 days and C57BL/6NCrl mice served as healthy wild-type controls. After 28 days, cardiac function was assessed by echocardiography and hearts from a subset of mice were isolated and subjected to 30 min of global ischemia followed by 60 min of reperfusion (I/R) in ex vivo Langendorff mode. Body weight, blood lipids, and glucose levels were elevated in MetS mice as compared with wild-type controls. The dyslipidemia in MetS was ameliorated following tadalafil treatment. Although left ventricular (LV) systolic function was minimally altered in the MetS mice, there was a significant diastolic dysfunction as indicated by reduction in the ratio of peak velocity of early to late filling of the mitral inflow, which was significantly improved by tadalafil treatment. Post-ischemic cardiac function, heart rate, and coronary flow decreased significantly in MetS mice compared to wild-type controls, but preserved by tadalafil treatment. Myocardial infarct size was significantly smaller following I/R, which was associated with higher plasma levels of nitrate and nitrite in the tadalafil-treated MetS mice. In conclusion, tadalafil induces significant cardioprotective effects as shown by improvement of LV diastolic function, lipid profile, and reduced infarct size following I/R. Tadalafil treatment enhanced NO production, which may have contributed to the cardioprotective effects.


A mouse gene (Dgcr6) related to the Drosophila gonadal gene is expressed in early embryogenesis and is the homolog of a human gene deleted in DiGeorge syndrome.
We report the identification of a mouse gene, Dgcr6, which shows high sequence similarity to gonadal (gdl), a Drosophila gene of unknown function. Dgcr6 is the mouse homolog of human DGCR6, previously shown to be deleted in DiGeorge syndrome, a developmental field defect affecting the derivatives of the pharyngeal arches which is associated with 22q11.2 deletions. The Dgcr6 transcript has a 594 nucleotide open reading frame (ORF) encoding 198 amino acids. We previously mapped Dgcr6 to mouse chromosome 16B1-B3, a region known to contain other mouse homologs of genes deleted in DiGeorge syndrome. Expression studies were performed by Northern blotting analysis on mouse embryo and adult tissues and by RNA in situ hybridization on mouse embryo sections. Results show that Dgcr6 transcripts are abundant during mouse embryogenesis, from at least 7 days post coitum. In particular, high expression was detected in the brain, spinal cord and pharyngeal arches. On adult tissues high expression was detected in testis. The function of Dgcr6 is to be determined, but its developmental expression suggests that this gene may play a role in the developmental defects associated with 22q11.2 deletions.


In vitro genotoxic effects of ZnO nanomaterials in human peripheral lymphocytes.
In this study, possible genotoxic effects of zinc oxide (ZnO) nanoparticles were investigated in cultured human peripheral lymphocytes by using chromosome aberrations and micronucleus assays (MN). For this purpose, the cells were treated with ZnO (1, 2, 5, 10, 15 and 20 μg/mL) for 24 and 48 h. In this research, four types of chromosome aberrations were observed as chromatid and chromosome breaks, fragment and dicentric chromosomes. ZnO induced significant increase of the ratio of chromosomal aberrations as well as percentage of abnormal cells at concentrations of 1, 5, 10 and 20 μg/mL in 24 h treatments. In 48 h treatments, while ZnO nanomaterials induced significant increase of the percentage of abnormal cells only at a concentration of 10 μg/mL, and of chromosome aberration per cell in comparison to the control at concentrations of 5 and 10 μg/mL. On the other hand, this material significantly increased the micronuclei frequency (MN) at concentrations of 10 and 15 μg/mL in comparison to the control. Cytokinesis-block proliferation index was not affected by ZnO treatments. It also decreased the mitotic index in all concentrations at 24 h but not at 48 h. The present results indicate that ZnO nanoparticles are clastogenic, mutagenic and cytotoxic to human lymphocytes in vitro at specific concentrations and time periods.


Behavioral Response to HIV/AIDS Prevention Messages Among Students in Selected Universities of Amhara Region, Northwest Ethiopia: An Extended Parallel Process Model.
HIV/AIDS is a global pandemic. Sub-Saharan Africa accounts for two-thirds of the newly HIV-infected cases in the world. Similarly, the prevalence of HIV infections among Ethiopian university students has also increased as HIV prevention was not sufficiently prioritized. In order to decrease the surge of the HIV pandemic, prevention messages that encourage individuals to reduce sexual and risk behaviors still remain a key intervention strategy. Besides this, the behavioral response to HIV prevention messages among Ethiopian universities is not well studied. To assess students' behavioral response to HIV/AIDS prevention messages in selected universities of the Amhara region using an extended parallel process model (EPPM), in 2019. A facility-based cross-sectional study was employed among 423 eligible students from January to February, 2019 using a stratified sampling technique. The dependent variable is response to HIV/AIDS prevention messages (danger control and fear control) which is addressed by EPPM. The model explains the components of threat (perceived susceptibility and perceived severity) and efficacy (response efficacy and self-efficacy). Subtracting wings of threat component score from efficacy wings score gives the critical value. If the critical value had positive scores, it showed responses of danger control; if the critical value was negative, it showed response of fear control. A logistic regression model was fitted to assess the association between the dependent and independent variables. The response rate of this study was 94.6%. Among 400 respondents, 263 (65.8%; 95%CI: 61-70) of them were in the danger control response whereas 137 (34.2%; 95%CI: 30- 39) were in fear control response. Moreover, 200 (50%) of the participants had adequate knowledge and 180 (45%) had a favorable attitude towards HIV/AIDS prevention messages. Danger control response for HIV prevention messages was higher among first-year students (AOR=5.5; 95%CI: 1.5-19) and third-year students (AOR=3.9; 95%CI: 2-14) compared with fifth-year students. Similarly, those students who reside on the campus were 60% times less likely to develop danger control when compared with students who live with their family (AOR=0.4; 95%CI: 0.2-0.9). Besides this, students who had adequate knowledge (AOR=2.6; 95%CI: 1.5-4.5) and students who receive fear-inducer messages (AOR=4.5; 95%CI: 3-25] were more likely to develop danger control responses. Nearly two-thirds of the participants were in the danger control response. Year of study, with whom students currently live, type of message they received, and the knowledge level of respondents were the factors associated with students' response to HIV/AIDS prevention messages. Therefore, the messages must aim at enhancing threat component perception with appropriate efficacy messages to control danger and promote behavioral change.


Immediate posttraumatic seizures: is routine hospitalization necessary?
A recent Internet survey of pediatric neurosurgeons showed that 86% routinely admitted children with immediate posttraumatic seizures (PTS) for a brief period of observation. We wished to determine whether certain children meeting predefined criteria could instead be safely discharged from the emergency room. We reviewed the records of children admitted during the past 5 years with a diagnosis of seizure and head injury. Children with a minor head injury, a PTS occurring within 24 h of injury and no intracranial abnormalities on admission CT scan were included. Children with previous neurological conditions, a history of prior seizures (other than PTS or febrile seizures), a prior history of anticonvulsant use, or intracranial abnormalities on the admission CT scan were excluded. Records were abstracted for child's age, gender, length of admission, previous history of PTS or febrile seizures, mechanism of injury, location of impact, time between impact and PTS, the number, length and type of PTS, Glasgow Coma Score (GCS) on admission, subsequent complications and hospital costs. Seventy-one children met the inclusion criteria. Eleven children presented to the emergency room with prolonged seizures, transient apnea or persistently low GCS and required admission to the intensive care unit (ICU). Among the 60 remaining children with simple PTS, none had further seizures during the follow-up period, and none had significant complications. The average cost of hospitalization was known for 58 children; after excluding the costs for 5 patients who were admitted to the ICU, the average hospital cost amounted to USD 1,615 per patient. Our data suggest that children with isolated minor head injuries and simple PTS who recover fully in the emergency room, whose CT scans show no intracranial abnormalities and who have no prior history of neurological disease, epilepsy or anticonvulsant use are at low risk for recurrent seizures or neurological complications, and could potentially be sent home to a reliable caretaker and a stable home situation. However, because of the limited sample size in this study, the statistical risk of a bad outcome may be as high as 9%; we therefore suggest that much larger studies are potentially needed before this becomes a standard policy.


Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach.
Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols. Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated. A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters. Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.


Dyspareunia, back pain and chronic pelvic pain: the importance of this pain complex in gynecological practice and its relation with grandmultiparity and pelvic relaxation.
The aim of this study was to evaluate the correlation between severe dyspareunia, back pain, dysmenorrhea and chronic pelvic pain (CPP), and the relationship of each pain type with various sociodemographic factors, pelvic relaxation and high parity. Two hundred thirty-five premenstrual individuals were included. The prevalences of CPP, deep dyspareunia, dysmenorrhea and back pain were found to be 80.4, 30.6, 57.0 and 57.4%, respectively. Marriage duration was longer (p < 0. 01) and also parity was higher (p < 0.0001) in CPP cases than controls. However, none of the demographic factors had a significant correlation with dyspareunia, back pain and dysmenorrhea. CPP was correlated with both back pain (r = 0.18, p < 0.005) and dyspareunia (r = 0.19, p < 0.004). However, there was no correlation between back pain and dyspareunia. On the other hand, dysmenorrhea did not show a correlation with any pain types. While grandmultiparity had a significant effect on CPP (p < 0.0001), it did not have a significant effect on other pain types in a MANOVA model. CPP is very often seen in our population and it often makes a pain complex with dyspareunia and back pain. The prevention of grandmultiparity is important to decrease the incidence of CPP.


Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages.
Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women.


Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia.
A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level. Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues. Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.


The Association Among Medication Beliefs, Perception of Illness and Medication Adherence in Ischemic Stroke Patients: A Cross-Sectional Study in China.
To examine the association and the mediating effect among medication beliefs, perception of illness, and medication adherence in ischemic stroke patients. This is a cross-sectional study, 306 ischemic stroke patients recruited from The Second Affiliated Hospital of Harbin Medical University, China between June 2018 and October 2018. The Beliefs about Medications Questionnaire (BMQ) was used to assess a patient's beliefs about medication. The Brief Illness Perceptions Questionnaire (BIPQ) was used to rapidly determine the cognitive and emotional representation of ischemic stroke. Self-reported adherence was assessed using the Medication Adherence Report Scale (MARS). Logistic regression analysis, Pearson correlations, and mediation analysis were used to evaluate the association and mediating effects among medication beliefs, perception of illness, and medication adherence. Overall, 220 (65.48%) participants were non-adherent to their ischemic stroke medications. Non-adherent patients had greater stroke severity (p = 0.031) compared to adherent patients. After adjusting for demographic characteristics, specific concern (odds ratio [OR]: 0.652, 95% confidence interval [CI]: 0.431 to 0.987, p-value [P] = 0.043), and the perception of illness (overall score) (OR: 0.964, 95% CI: 0.944 to 0.985, P = 0.001) were significantly associated with medication adherence in ischemic stroke patients. The mediation analysis showed the significant indirect effects of specific concern, general overuse, and general harm. It suggested that some impacts of medication beliefs have been mediated on medication adherence. Perceived concern about adverse effects of medicines and perception of illness have an influential impact on self-reported medication adherence in ischemic stroke patients. To enhance adherence, patients' beliefs about medication and perceptions of their disease should be reconsidered. Future work should investigate interventions to influence patient adherence by addressing concerns about their ischemic stroke medications and the perception of the disease.


[Submucous turbinate resection].
This article describes the authors' experiences on submucous resection of the turbinate bone in chronic hypertrophic lower turbinates. Similar to the procedure in septoplasties, this surgery preserves the mucosa and its physiological properties. The technique is facilitated by an amazingly low tendency to bleeding. 70 patients were followed up post-operatively. More than 70% reported a marked improvement of nasal breathing. No serious complications were seen.


Clinical and Histological Characteristics of Mycosis Fungoides and Sézary Syndrome: A Retrospective, Single-centre Study of 43 Patients from Eastern Denmark.
Diagnosis of mycosis fungoides and Sézary syndrome can be very challenging. Clinical and histopathological data for patients with mycosis fungoides and Sézary syndrome in Denmark are limited. A retrospective study was performed in Region Zealand, Denmark from 1990 to 2016. A total of 43 patients with mycosis fungoides or Sézary syndrome were identified during the period. At the time of diagnosis the patients' mean age was 64.3 years and 74.5% had early-stage (≤IIA) disease. The mean time from onset of skin disease to diagnosis was 4.4 years. Surprisingly, 43% progressed to a higher disease stage, and risk of disease progression was higher for stage IB than IA (p = 0.01). All cases displayed some degree of epidermotropism and the infiltrates consisted of pleomorphic lymphocytes with a T-helper (CD4+/CD8-) phenotype. This study describes, for the first time, all aspects of clinical and histopathological findings in patients with mycosis fungoides and Sézary syndrome in a well-characterized Danish cohort.


[Importance of the morphofunctional status of APUD cells in the prognosis of duodenal ulcer hemorrhage].
In 24 patients with uncomplicated duodenal ulcer and 40 patients with acute bleeding duodenal ulcer morphofunctional status of the local paraendocrine adjusting system of the duodenal mucous membrane in the periulcer, ulcer and remote zones was studied with histochemical and electron-microscopic techniques. It is established, that ECL- and G-apudocytes hyperplasia and hyperfunction and vice versa D-cells reduction of the number and suppression of the secretory activity are reliable prognostic criteria of duodenal ulcer bleeding.


Berberine enhances gemcitabine‑induced cytotoxicity in bladder cancer by downregulating Rad51 expression through inactivating the PI3K/Akt pathway.
Although gemcitabine (GEM) has been used to treat bladder cancer (BC) for a number of years, severe adverse events or drug resistance frequently develops. A series of drugs have been proved to sensitize patients to GEM and reduce the side effects. The aim of the present study was to evaluate the potential effects of berberine (BER) on GEM‑induced cytotoxicity in BC and to explore the possible underlying mechanisms. T24 and 5637 human BC cell lines were treated with GEM and/or BER before cell proliferation, apoptosis and migration were studied. Oncomine databases and Gene Expression Profiling Interactive Analysis (GEPIA) were used to retrieve RAD51 recombinase (Rad51) mRNA expression. Overexpression plasmid or specific Rad51 small interfering RNA were used to examine the role of Rad51 in drug‑treated BC cells. BC model mice were administered with GEM and/or BER before changes in tumor volume, size and Ki67 expression were assessed. BER enhanced GEM‑induced cytotoxicity, apoptosis and inhibition of migration, whilst attenuating the GEM‑induced upregulation of phosphorylated Akt and Rad51 expression. According to Oncomine and GEPIA analyses, Rad51 was found to be significantly upregulated in BC tissues compared with that in normal tissues, where there was a weak positive correlation between Rad51 and Akt1 expression. Knockdown of Rad51 enhanced GEM‑induced cytotoxicity, whilst overexpression of Rad51 reversed the suppressed cell viability induced by BER and GEM. Inactivation of the PI3K/Akt pathway by LY294002 or BER enhanced GEM‑induced cytotoxicity and downregulated Rad51 expression, whilst overexpression of constitutively active Akt restored Rad51 expression and cell viability that was previously decreased by BER and GEM. BER additively inhibited tumor growth and Ki67 expression when combined with GEM in vivo. These results suggest that BER can enhance GEM‑induced cytotoxicity in BC by downregulating Rad51 expression through inactivating the PI3K/Akt pathway, which may represent a novel therapeutic target for BC treatment.


[Video-EEG monitoring in the diagnosis of epilepsy in children].
This paper analyzes the results of a survey of 785 patients referred to our hospital with a diagnosis of epilepsy. Diagnosis of forms of epilepsy and definition of the localization of epileptogenic focus in patients with focal epilepsy (FE) were performed using the method of video-EEG monitoring. Every fifth patient with suspected ongoing seizures has nonepileptic paroxysms. FE was found in 92,6% of patients in a children's epileptological hospital and about half of them (48,2%) had a frontal localization. The presence of <<generalized>> types of seizures and <<generalized>> epileptiform activity on EEG was the feature of FE at the early age. The discordance of interictal focus and onset zones was observed in 22,8% of cases; 9,4% of patients with FE had more than one cortical area responsible for the generation of epileptic seizures. The localization of the epileptogenic zone can not be reliably established without an analysis of ictal EEG. All these cases are related to the early childhood (0-3 years), which indicates the need for recording multiple seizures (> 5) to identify the epileptogenic zone in this age group. Accuracy and reliability of diagnosis have special value in case of preparation of the patient with FE to surgical treatment.


Ocular localization of mycobacterial lesions in tank-reared juvenile cobia, Rachycentron canadum.
Severe clinical mycobacteriosis with consistent ocular lesion localization was diagnosed in a population of 800 juvenile tank-reared Cobia (Rachycentron canadum) which experienced a sudden increase in mortality approximately 5 months after arriving into Trinidad and Tobago from Florida, USA. Moderate daily mortality (15-20 animals per day) persisted for just over 1 month. Moribund fish displayed circling behaviour and had an open-mouth gape upon death. Fish consistently presented with bilateral exophthalmia, corneal cloudiness and hyphema. Non-branching acid-fast rods were detected in aqueous humour touch preparations. Histological analysis revealed severe bilateral intra-ocular granulomatous responses in all specimens. Mycobacterium sp. was identified using a real-time PCR assay detecting the RNA polymerase β-subunit (rpoB) gene in different tissue samples. Specimens did not present with characteristic granulomatous responses usually seen in viscera. To the best of our knowledge, this represents only the third documentation of piscine mycobacterial infection presenting with only localized ocular lesions, and the second documented case of mycobacteriosis in cobia. It is, however, the first documentation of an ocular presentation of mycobacteriosis in a marine species and is the first documentation of such a presentation in cobia.


Construct Validity of a Measure of Affective Communication in Psychotherapy.
The present study evaluates the psychometric properties of a therapist measure for evaluating the affective communication created between the patient and therapist during the initial stages of treatment. The Affective Communication Questionnaire (ACQ) was administered to a sample of 81 therapists, each rating a single patient, and principal component analysis indicated the measure has coherent dimensions with strong internal consistency. The construct validity of the ACQ was then established in a sample of 16 therapists rating 73 patients diagnosed with Borderline Personality Disorder (BPD). The measure was found to have a strong relationship to the related constructs of transference, countertransference, and affect experience in predicted directions. The measure also was found to have a modest relationship to independent assessments of patient functioning; most notably more negative affect was significantly related to more odd/eccentric (cluster A) and less anxious/fearful (cluster C) personality disorder symptoms, and greater narrative coherence. Differences in affective communication as a function of treatment type were also evaluated. The clinical and research implications of the findings are discussed.


Pharmacoproteomic study of the effects of chondroitin and glucosamine sulfate on human articular chondrocytes.
Chondroitin sulfate (CS) and glucosamine sulfate (GS) are symptomatic slow-acting drugs for osteoarthritis (OA) widely used in clinic. Despite their widespread use, knowledge of the specific molecular mechanisms of their action is limited. The aim of this work is to explore the utility of a pharmacoproteomic approach for the identification of specific molecules involved in the pharmacological effect of GS and CS. Chondrocytes obtained from three healthy donors were treated with GS 10 mM and/or CS 200 μg/mL, and then stimulated with interleukin-1β (IL-1β) 10 ng/mL. Whole cell proteins were isolated 24 hours later and resolved by two-dimensional electrophoresis. The gels were stained with SYPRORuby. Modulated proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF/TOF) mass spectrometry. Real-time PCR and Western blot analyses were performed to validate our results. A total of 31 different proteins were altered by GS or/and CS treatment when compared to control. Regarding their predicted biological function, 35% of the proteins modulated by GS are involved in signal transduction pathways, 15% in redox and stress response, and 25% in protein synthesis and folding processes. Interestingly, CS affects mainly energy production (31%) and metabolic pathways (13%), decreasing the expression levels of ten proteins. The chaperone GRP78 was found to be remarkably increased by GS alone and in combination with CS, a fact that unveils a putative mechanism for the reported anti-inflammatory effect of GS in OA. On the other hand, the antioxidant enzyme superoxide dismutase 2 (SOD2) was significantly decreased by both drugs and synergistically by their combination, thus suggesting a drug-induced decrease of the oxidative stress caused by IL-1β in chondrocytes. CS and GS differentially modulate the proteomic profile of human chondrocytes. This pharmacoproteomic approach unravels the complex intracellular mechanisms that are modulated by these drugs on IL1β-stimulated human articular chondrocytes.


Functional and physical interactions between yeast 14-3-3 proteins, acetyltransferases, and deacetylases in response to DNA replication perturbations.
The highly conserved 14-3-3 proteins participate in many biological processes in different eukaryotes. The BMH1 and BMH2 genes encode the two functionally redundant Saccharomyces cerevisiae 14-3-3 isoforms. In this work we provide evidence that defective 14-3-3 functions not only impair the ability of yeast cells to sustain DNA replication in the presence of sublethal concentrations of methyl methanesulfonate (MMS) or hydroxyurea (HU) but also cause S-phase checkpoint hyperactivation. Inactivation of the catalytic subunit of the histone acetyltransferase NuA4 or of its interactor Yng2, besides leading to S-phase defects and persistent checkpoint activation in the presence of genotoxic agents, is lethal for bmh mutants. Conversely, the lack of the histone deacetylase subunit Rpd3 or Sin3 partially suppresses the hypersensitivity to HU of bmh mutants and restores their ability to complete DNA replication in the presence of MMS or HU. These data strongly suggest that reduced acetyltransferase functionality might account for the S-phase defects of bmh mutants in the presence of genotoxic agents. Consistent with a role of 14-3-3 proteins in acetyltransferase and deacetylase regulation, we find that acetylation of H3 and H4 histone tails is reduced in temperature-sensitive bmh mutants shifted to the restrictive temperature. Moreover, Bmh proteins physically interact, directly or indirectly, with the Esa1 acetyltransferase throughout the cell cycle and with the Rpd3 deacetylase specifically during unperturbed S phase and after HU treatment. Taken together, our results highlight a novel role for 14-3-3 proteins in the regulation of histone acetyltransferase and deacetylase functions in the response to replicative stress.


Thought, perception and delusional infestation.
The authors report a case of delusional infestation in a 45 year-old woman followed in an out-patient setting. A review of published literature about this disorder and its nosological classification over different historical periods and by different authors is performed. Difficulties in separation of the delusion and hallucination symptoms in body phenomena are discussed.


[Relapsing polychondritis associated with myelodysplasia and acute eosinophilic leukemia].
Authors report a case in which relapsing polychondritis had been diagnosed two years before myelodysplastic syndrome developed and terminated in eosinophilic leukemia. The observation that relapsing polychondritis may precede myelodysplasia is not in concordance with some of the previous reports regarding relapsing polychondritis as a paraneoplastic phenomenon of myelodysplastic syndrome. The terminally developed eosinophilic leukemia is not supposed to be a blastic phase of the underlying myelodysplasia, much rather a second malignant process. This opinion may be confirmed by the early presence of blast cells in the myelodysplastic process without eosinophilia. It seems interesting to note that both our patient and his daughter suffered from diseases of autoimmune origin: acquired vitiligo and subacute cutan lupus erythematodes, respectively.


Disseminating nursing knowledge--a guide to writing for publication.
The dissemination of research findings and other forms of nursing knowledge is generally accepted as an element of accountability for professional practice. While an increase in nursing research has been apparent in recent times, there seemingly remains a reluctance for nurses to publish the findings of their work. The identified barriers to writing for publication primarily focus on a lack of confidence in the ability to write in this arena, and uncertainty, apprehension and confusion regarding how exactly to go about writing and submitting a manuscript. The primary aim of this paper is to demystify the process of writing for publication by presenting a guide ranging from selecting the journal, to dealing with the reviewers' comments. Although the available literature includes a number of helpful hints, coverage of all of the relevant aspects in one article could not be located. It is intended that this paper will provide a valuable contribution by encouraging nurses to develop their research findings or other scholarly ideas into a manuscript to be submitted for publication.


Caregivers' role in managing hereditary angioedema and perceptions of treatment-related burden.
Hereditary angioedema (HAE) is a rare genetic disease that results in recurrent, debilitating, and potentially life-threatening swelling episodes in the extremities, genitals, gastrointestinal tract, and upper airway. Patients can experience significant burdens related to their disease. Informal or familial caregivers often support patients with HAE and likely share in the disease-related burdens, although there are limited HAE caregiver-focused reports in the scientific literature. In the United States, we conducted an online survey of adults caring for an individual with HAE to better understand their experiences with the disease and identify psychosocial impacts of providing care for a patient with HAE. Thirty caregivers provided responses to the survey. Most caregivers were family members of the care recipient and many had HAE themselves. Caregivers reported participating in a number of medical-related tasks and experiencing some burdens as a result of caring for a person with HAE.


Obstetric Ultrasound Efficiency and Accuracy Using a Protocol-Based Examination.
Obstetric ultrasound imaging requires the acquisition of a standard set of maternal and fetal images. Our objective was to evaluate the impact of implementation of a protocol-based ultrasound examination on the duration of ultrasound examinations, examination completion, and accuracy of documentation. We conducted a case-cohort study. Obstetric ultrasound examinations performed in the first, second, and third trimesters were reviewed before and after implementation of a protocol-based ultrasound examination. The duration of the ultrasound examination, number of missing required images, and documentation of missing images were abstracted from an image archival system. To account for clustering by sonographer, 3 mixed effects models with a fixed effect for protocol and a random intercept for sonographer were used to evaluate the effect on the total time of the examination, number of missing images, and whether missing images were documented. A total of 100 ultrasound examinations were compared: 50 before and 50 after implementation of the protocol. Statistically significant differences between outcomes before and after protocol implementation were observed for all outcomes. After implementation of the protocol, the average duration of ultrasound examinations decreased by 7.62 minutes (95% confidence interval [CI], 3.57-11.68 minutes); the number of missing images was reduced by 5.81 per examination (95% CI, 4.24-7.39); and proper documentation of missing images increased by 40.24% (95% CI, 22.77%-57.71%). Implementation of a software protocol-based ultrasound examination significantly improved the efficiency and accuracy of obstetric ultrasound examinations in this study.


Tualang Honey Improves Memory and Prevents Hippocampal Changes in Prenatally Stressed Rats.
This study investigated whether the alterations in memory and hippocampus morphology and levels of malondialdehyde (MDA) and N-methyl-D-aspartate (NMDA) receptor in the hippocampus of adult rats after prenatal stress could be prevented by administration of Tualang honey (TH). Twenty-four pregnant rats were randomly grouped into a control group (C), a stress group (S), and a stress group treated with TH. Eight male pups from each group were randomly chosen and they were sacrificed at eight or ten weeks of age following the novel object recognition test. Their brains were removed and histological changes and levels of MDA and NMDA receptors in the hippocampus were determined. The offspring from TH group showed significantly increased preference index (p<0.05) with higher neuronal number compared to S group. A significantly lower level of MDA and NMDA receptors were shown in TH group (P<0.01; P<0.05 respectively) compared to S group. The parameters investigated were not significantly different between C and TH groups. The study has shown that memory alteration, changes in hippocampus histology, MDA and NMDA receptor levels could be prevented by TH administration during prenatal stress. The results suggest the beneficial effects of Tualang honey in prenatally stressed rat offspring.


Renal autotransplantation and partial resection of the ureter for recurrent benign ureteral tumor.
A report of a patient treated by partial resection of the ureter and renal autotransplantation for recurrent benign ureteral tumors and impaired renal function in the contralateral kidney is presented. Autotransplantation of the ipsilateral kidney associated with benign disease of the renal excretory system is recommended even with normal function of the contralateral kidney. Experience with renal homotransplantation has led to excellent technical and functional results from autotransplantation, and use of the procedure is expanding to include treatment of a variety of renal, ureteral, and renovascular pathology. The role of renal autotransplantation in the preservation of functioning renal units is emphasized.


Lumbopelvic pain and sick leave during pregnancy: A comparison of Italy and Norway.
Pregnancy-related lumbopelvic pain is a frequently reported musculoskeletal disorder, but few studies have compared data between countries. Examine prevalence, severity, and sick leave and explore potential risk factors associated with pregnancy-related lumbopelvic pain in Italian women and compare the results to a similar study in Norway, utilizing the same questionnaire. Cross-sectional. Italian (n = 481) and Norwegian women (n = 435) were allocated from two public hospitals in Rome (Fatebenefratelli San Giovanni Calibita-Isola Tiberina) and Oslo (Oslo University Hospital), as well as four antenatal clinics in Modena (Italy). The questionnaire was completed between gestation weeks 32 and 36, addressing women's experiences of pregnancy-related lumbopelvic pain and sick leave in current week, and retrospectively for prepregnancy, first and second trimesters. In Italy and Norway, 39% and 57% of pregnant women reported pregnancy-related lumbopelvic pain, respectively, with 11% and 25% experiencing severe pregnancy-related lumbopelvic pain. Pregnancy-related lumbopelvic pain was associated with sick leave in Norway (p < 0.01), but not in Italy (p = 0.66) at late gestation. In both countries, women with pregnancy-related lumbopelvic pain versus those with no pregnancy-related lumbopelvic pain were more likely to be multiparous (Italy: 40% versus 31%, p = 0.06 and Norway: 53% versus 38%, p < 0.01), and have gestational weight gain above guidelines (Italy: 21% versus 13%, p = 0.02% and Norway: 27% versus 14%, p < 0.01) and previous experience of pregnancy-related lumbopelvic pain (Italy: 15% versus 2%, p < 0.01 and Norway: 31% versus 4%, p < 0.01). Maternal exercise (⩾2 times weekly) was associated with less pregnancy-related lumbopelvic pain (Italy: odds ratio = 0.33, 95% confidence interval = 0.11-1.0, p = 0.05 and Norway: odds ratio = 0.55, 95% confidence interval = 0.29-1.0, p = 0.06). We observed high rates of pregnancy-related lumbopelvic pain in Italy and Norway, with Norwegian women reporting the highest prevalence and severity level. While both countries had similar rates of sick leave in late gestation, an association between pregnancy-related lumbopelvic pain and sick leave was observed among Norwegian women only. Health care providers should be proactive in addressing pregnancy-related lumbopelvic pain through open communication and seeking input from pregnant individuals. However, it is essential to acknowledge that the current evidence on effective treatments remains limited and inconclusive, highlighting the need for further research in this field.


A critical discussion of computer analysis in medical imaging.
Medical imaging has increasingly provided surrogate endpoints in therapeutic trials. This use assumes that the interpretation of the images can be unbiased and reproducible and that the image attributes included in the interpretation are relevant to the mechanism of the trial. The principal motivation for computer analysis is to evaluate an attribute of the image as a metric in an algorithmic manner, independent of observer bias or variability. The metric is expected to reflect change in rough proportion with at least one aspect of the degree of disease or the effectiveness of the therapeutic intervention. If either condition is satisfied, the measure is quantitative. Visual interpretation explicitly or implicitly tends to be based on multiple image attributes. Explicit combination of multiple attributes yields composite scores. To evaluate the risk or probability of disease, they are useful. But the components of the scores can be combined only if they are mathematically isomorphic. For the evaluation of interventions, they are less useful because the effect on one component may be obscured by the lack of effect on other components. This article reviews quantification of air trapping in cystic fibrosis and quantification in general. Validation of any computer analysis can rely on agreement with visual interpreters (on average), they can be derived from first principles, or by agreement with an alternative method that measures the pathophysiological mechanism directly (xenon washout for air trapping). However, in the context of trials, the validation may come from a superior ability to detect objective change and to discriminate between affected and unaffected individuals.


Evaluation of platelet lymphocyte ratio and 90-day mortality in patients with acute exacerbation of chronic obstructive pulmonary disease.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) have high mortality and health care costs. The platelet to lymphocyte ratio (PLR) is a marker of inflammation and has been reported to be elevated in patients with AECOPD compared to stable state. In this study, we sought to evaluate the association of the PLR in patients with AECOPD with 90-day mortality. We conducted a retrospective cohort study of patients admitted to our institution with a primary diagnosis of AECOPD between January 2014 and July 2014. Blood test results on admission were recorded. The primary outcomes were 90-day mortality. One hundred and eighty-one AECOPD patients were considered for the study. Death had occurred in 16 (9%) patients within 90 days of hospital discharge. Univariable analysis identified age, haemoglobin, neutrophil count, and urea level, neutrophil lymphocyte ratio (NLR) and PLR as being associated with increased 90-day mortality. Multivariable logistic regression analysis variables demonstrated that only PLR (P=0.03) was significantly associated with death at 90 days. Receiver operator characteristic analysis identified PLR ≥235 had a sensitivity of 63% and specificity of 74% in predicting 90-day mortality. PLR was ≥235 was also associated with worse survival (days) [mean ± standard deviation (SD): PLR ≥235 vs. PLR <235: 512±358 vs. 626±346, P=0.004]. A PLR ≥235 was significantly associated with 90-day mortality, which may provide prognostic guidance to clinicians.


Mechanisms in Graves Eye Disease: Apoptosis as the End Point of Insulin-Like Growth Factor 1 Receptor Inhibition.
Background: Graves' eye disease, also called Graves' orbitopathy (GO), is a potentially debilitating autoimmune disease associated with retro-orbital inflammation and tissue expansion, involving both fibroblasts and adipocytes, resulting in periorbital edema, worsening proptosis, and muscle dysfunction with diplopia and may ultimately threaten sight. Accumulating evidence has indicated that autoantibodies to the thyrotropin receptor (TSHR), which induce the hyperthyroidism of Graves' disease, also help mediate the pathogenesis of the eye disease in susceptible individuals through TSHR expression on retro-orbital cells. Since it has long been known that the effects of insulin-like growth factor 1 (IGF-1) and thyrotropin are additive, recent clinical trials with a human monoclonal IGF-1 receptor blocking antibody (teprotumumab; IGF-1R-B-monoclonal antibody [mAb]) have demonstrated its ability to induce significant reductions in proptosis, diplopia, and clinical activity scores in patients with GO. However, the molecular mechanisms by which such an antibody achieves this result is unclear. Methods: We have used Li-Cor In-Cell Western, Western blot, and immunohistochemistry to define levels of different proteins in mouse and human fibroblast cells. Proteomic array was also used to define pathway signaling molecules. Using CCK-8 and BrdU cell proliferation ELISA, we have analyzed proliferative response of these cells to different antibodies. Results: We now show that a stimulating TSHR antibody was able to induce phosphorylation of the IGF-1R and initiate both TSHR and IGF-1R signaling in mouse and human fibroblasts. IGF-1R-B-mAb (1H7) inhibited all major IGF-1R signaling cascades and also reduced TSHR signaling. This resulted in the antibody-induced suppression of autophagy as shown by inhibition of multiple autophagy-related proteins (Beclin1, LC3a, LC3b, p62, and ULK1) and the induction of cell death by apoptosis as evidenced by activation of cleaved caspase 3, FADD, and caspase 8. Furthermore, this IGF-1R-blocking mAb suppressed serum-induced perkin and pink mitophagic proteins. Conclusions: Our observations clearly indicated that stimulating TSHR antibodies were able to enhance IGF-1R activity and contribute to retro-orbital cellular proliferation and inflammation. In contrast, an IGF-1R-B-mAb was capable of suppressing IGF-1R signaling leading to retro-orbital fibroblast/adipocyte death through the cell-extrinsic pathway of apoptosis. This is likely the major mechanism involved in proptosis reduction in patients with Graves' eye disease treated by IGF-1R inhibition.


Physical function and performance measures of children and adolescents with Charcot-Marie-Tooth disease.
This study aimed to verify whether there are differences in foot type, physical function, and performance between children and adolescents with Charcot-Marie-Tooth disease (CMT) and their healthy counterparts, and whether an interval of 6 months, from the initial assessment, reveals any significant changes on physical performance and other specific physical measures of the lower limbs. Subjects and Methods: Participants between 6 and 17 years of age, with CMT (CMT group n = 40), were compared to healthy participants (Control group, n = 49). Twenty participants with CMT completed the follow-up. We collected anthropometric, goniometric (ankle and knee), and dynamometric (inversion, eversion, plantar flexors, dorsiflexors, knee, hip extensors) measures, agonist/antagonist ratios, feet alignment (Foot Posture Index - FPI), muscle power (Long Jump), Pediatric Balance Scale (PBS), and 10-meter walk test (10MWT). Results: Compared to Control, CMT showed reduced passive range of motion (ROM), weakness in all evaluated muscles, increased agonist/antagonist ratios, predominance of varus and lower performance (PBS and Long Jump). After 6 months, CMT measures did not change. Conclusion: The cross-sectional analysis showed reduced ROM, strength, power, and distal muscle imbalance, as well as secondary limitations (PBS and 10MWT) in children and adolescents with CMT. These biomechanical and functional alterations did not change at the 6-month follow-up.


Gastric juice in congenital pernicious anemia contains no immunoreactive intrinsic factor molecule: study of three kindreds with variable ages at presentation, including a patient first diagnosed in adulthood.
The mechanism responsible for the isolated intrinsic factor deficiency in congenital pernicious anemia is unknown. A new second-antibody radioimmunoassay capable of recognizing intrinsic factor independent of the molecule's ability to bind added cobalamin was used to study six patients from three kindreds with this disorder. One of the patients was first diagnosed at age 23 because of unusual circumstances in her case; yet the other patients also demonstrated great age variability at presentation of this presumably congenital disorder, even within the same kindred. The radioimmunoassay failed to detect immunoreactive intrinsic factor in any of the six patients, suggesting that elaboration of an abnormal molecule was not the pathogenetic mechanism. An unexpected incidental finding, contrasting with this observation in congenital pernicious anemia, was immunologic evidence that a previously described patient with familial R binder deficiency clearly elaborated an abnormal R binder molecule.


Human- and computer-accessible 2D correlation data for a more reliable structure determination of organic compounds. Future roles of researchers, software developers, spectrometer managers, journal editors, reviewers, publisher and database managers toward artificial-intelligence analysis of NMR spectra.
The introduction of a universal data format to report the correlation data of 2D NMR spectra such as COSY, HSQC and HMBC spectra will have a large impact on the reliability of structure determination of small organic molecules. These lists of assigned cross peaks will bridge signals found in NMR 1D and 2D spectra and the assigned chemical structure. The record could be very compact, human and computer readable so that it can be included in the supplementary material of publications and easily transferred into databases of scientific literature and chemical compounds. The records will allow authors, reviewers and future users to test the consistency and, in favorable situations, the uniqueness of the assignment of the correlation data to the associated chemical structures. Ideally, the data format of the correlation data should include direct links to the NMR spectra to make it possible to validate their reliability and allow direct comparison of spectra. In order to take the full benefits of their potential, the correlation data and the NMR spectra should therefore follow any manuscript in the review process and be stored in open-access database after publication. Keeping all NMR spectra, correlation data and assigned structures together at all time will allow the future development of validation tools increasing the reliability of past and future NMR data. This will facilitate the development of artificial intelligence analysis of NMR spectra by providing a source of data than can be used efficiently because they have been validated or can be validated by future users. Copyright © 2016 John Wiley & Sons, Ltd.


Taste novelty induces intracellular redistribution of NR2A and NR2B subunits of NMDA receptor in the insular cortex.
Taste recognition memory is a process by which animals associate a taste previously experienced with its gastric consequences. Novel taste presentation induces in the insular cortex biochemical modifications that decrease after the taste becomes familiar. Here we show that, in this cortex, consumption of a novel taste produces an increase of the NR2A and NR2B subunits of the NMDA receptor in the detergent resistant membrane (DRM) fraction. This increase did not occur in the adjacent parietal cortex, was not due to a change in the total amount of protein, and is related with the novelty of the stimulus since it was reduced after the taste became familiar. Furthermore, NR2A and NR2B subunits increase in the DRM was blocked by the injection of a muscarinic acetylcholine receptor antagonist. These results suggest that modulation of NMDA receptors in the insular cortex through the increase of its NR2A and NR2B subunits in the DRM is involved in the taste memory formation via a cholinergic process.


Decorrelation-based blood flow velocity estimation: effect of spread of flow velocity, linear flow velocity gradients, and parabolic flow.
In recent years, a new method to measure transverse blood flow, based on the decorrelation of the radio frequency (RF) signals has been developed. In this paper, we investigated the influence of nonuniform flow on the velocity estimation. The decorrelation characteristics of transverse blood flow using an intravascular ultrasound (IVUS) array catheter are studied by means of computer modeling. Blood was simulated as a collection of randomly located point scatterers; moving this scattering medium transversally across the acoustical beam represented flow. First-order statistics were evaluated, and the signal-to-noise ratio from the signals were measured. The correlation coefficient method was used to present the results. Three velocity profiles were simulated: random spread of blood-flow velocity, linear blood-flow velocity gradient, and parabolic blood-flow. Radio frequency and envelope signals were used to calculate the decorrelation pattern. The results were compared to the mean decorrelation pattern for plug blood-flow. The RF signals decorrelation patterns were in good agreement with those obtained for plug blood flow. Envelope decorrelation patterns show a close agreement with the one for plug blood flow. For axial blood flow, there is a discrepancy between decorrelation patterns. The results presented here suggest that the decorrelation properties of an IVUS array catheter for measuring quantitative transverse blood flow probably will not be affected by different transverse blood-flow conditions.


Reactogenicity of COVID-19 vaccine in hemodialysis patients: a single-center retrospective study.
Introduction: Some hemodialysis patients are reluctant to undergo COVID-19 vaccination for the fear of developing adverse events (AEs). The aim of this study was to verify the safety of the mRNA-1273 vaccine in hemodialysis patients. Methods: We conducted a retrospective analysis of in-center hemodialysis patients who underwent mRNA-1273 vaccine from March 1st to April 30th, 2021. All AEs occurring after the first and the second doses were collected and classified as local or systemic. Results: Overall, 126 patients on chronic maintenance dialysis without a prior COVID-19 diagnosis were vaccinated with two doses of mRNA-1273 vaccine. Mean age was 68 (IQR, 54,7-76) years and 53.6% of patients were aged ≥65 years. During the observational period of 68 (IQR, 66-70) days, AEs occurred in 57.9% and 61.9% of patients after the first dose and second dose, respectively. The most common AEs were: injection-site pain (61.9%), erythema (4.8%), itching (4.8%), swelling (16.7%), axillary swelling/tenderness (2.4%), fever (17.5%) headache (7.9%), fatigue (23.8%), myalgia (17.5%), arthralgia (12.7%), dyspnoea (2.4%), nausea/vomiting (7.1%), diarrhoea (5.6%), shivers (4%) and vertigo (1.6%). The rates of local AEs were similar after the first and second doses (P=0.8), whereas systemic AEs occurred more frequently after the second dose (P=0.001). Fever (P=0.03), fatigue (P=0.02) and nausea/vomiting (P=0.03) were significantly more frequent after the second dose of the vaccine. There were no age-related differences in the rate of AEs. Overall, vaccine-related AEs in hemodialysis patients seem to be lower than in the general population. Conclusion: The RNA-1273 vaccine was associated with the development of transient AEs after the first and second doses in patients on chronic maintenance hemodialysis. They were mostly local, whereas systemic AEs were more prevalent after the second dose. Overall, all AEs lasted for a few days, without any apparent sequelae.


[The problem of true and false mutant spots of the mwh type in method of somatic mosaics of Drosophila melanogaster wing cells].
The problem of identification of true and false mutations of the mwh type was studied by means of gamma-irradiation in a test of somatic mosaics of wing cells of D. melanogaster. It was shown that the level of induction of mwh-like structures consisting of two trichomes and of true mwh mutations is the same if the former are located on the wing surface. Apparently, mwh-like structures located on veins should be assigned to morphoses. The necessity of taking into account two-trichome structures in this test is substantiated.


C-terminal truncation impairs glycosylation of transmembrane collagen XVII and leads to intracellular accumulation.
Collagen XVII, a type II transmembrane protein in hemidesmosomes, is involved in the anchorage of stratified epithelia to the underlying mesenchyme. Its functions are regulated by ectodomain shedding, and its genetic defects lead to epidermal detachment in junctional epidermolysis bullosa (JEB), a heritable skin fragility syndrome, but the molecular disease mechanisms remain elusive. Here we used a spontaneously occurring homozygous COL17A1 deletion mutant in JEB to discern glycosylation of collagen XVII. The mutation truncated the distal ectodomain and positioned the only N-glycosylation site 34 amino acids from the newly formed C terminus, which impaired efficient N-glycosylation. Immunofluorescence staining of authentic JEB keratinocytes and of COS-7 cells transfected with the mutant indicated intracellular accumulation of collagen XVII precursor molecules. Cell surface biotinylation and quantification of ectodomain shedding demonstrated that only about 15% of the truncated collagen XVII reached the cell surface. The cell surface-associated molecules were N-glycosylated in a normal manner, in contrast to the molecules retained within the cells, indicating that N-glycosylation of the ectodomain is required for targeting of collagen XVII to the plasma membrane and that reduced accessibility of the N-glycosylation site negatively regulates this process. Functional consequences of the strong reduction of collagen XVII on the cell surface included scattered deposition of cell adhesion molecule laminin 5 into the extracellular environment and, as a consequence of faulty collagen XVII-laminin ligand interactions, aberrant motility of the mutant cells.


Building-related symptoms are linked to the in vitro toxicity of indoor dust and airborne microbial propagules in schools: A cross-sectional study.
Indoor microbial toxicity is suspected to cause some building-related symptoms, but supporting epidemiological data are lacking. We examined whether the in vitro toxicity of indoor samples from school buildings was associated with work-related health symptoms (building-related symptoms, BRS). Administrators of the Helsinki City Real Estate Department selected 15 schools for the study, and a questionnaire on symptoms connected to work was sent to the teachers in the selected schools for voluntary completion. The cellular toxicity of classroom samples was determined by testing substances extracted from wiped indoor dust and by testing microbial biomass that was cultured on fallout plates. Boar sperm cells were used as indicator cells, and motility loss was the indicator for toxic effects. The effects were expressed as the half maximal effective concentration (EC50) at which >50% of the exposed boar sperm cells were immobile compared to vehicle control. Completed symptom questionnaires were received from 232 teachers [median age, 43 years; 190 (82.3%) women] with a median time of 6 years working at their school. Samples from their classrooms were available and were assessed for cellular toxicity. The Poisson regression model showed that the impact of extracts of surface-wiped school classroom dust on teacher work-related BRS was 2.8-fold (95% CI: 1.6-4.9) higher in classrooms with a toxic threshold EC50 of 6µgml-1 versus classrooms with insignificant EC50 values (EC50 >50µgml-1); P<0.001. The number of symptoms that were alleviated during vacation was higher in school classrooms with high sperm toxicity compared to less toxic sites; the RR was 1.9 (95% CI: 1.1-3.3, P=0.03) for wiped dust extracts. Teachers working in classrooms where the samples showed high sperm toxicity had more BRS. The boar sperm cell motility inhibition assay appears promising as a tool for demonstrating the presence of indoor substances associated with BRS.


Role of CD11/CD18 in shear rate-dependent leukocyte-endothelial cell interactions in cat mesenteric venules.
In vivo microscopy was used to assess the relationships among shear rate (and shear stress), leukocyte rolling velocity, and leukocyte adherence in a cat mesentery preparation. Shear rate in individual venules and arterioles of 25-35 microns diameter were varied over a wide range by graded occlusion of an arterial loop. There was a linear decline in leukocyte rolling velocity (Vwbc) as red cell velocity (Vrbc) was reduced. The ratio Vwbc/Vrbc remained constant despite variations in shear stress from 5-25 dyn/cm2. A reduction in shear stress was associated with an increased leukocyte adherence, particularly when Vwbc was reduced below 50 microns/s. Reduction in wall shear rate below 500 s-1 in arterioles allowed 1-3 leukocytes to adhere per 100 microns length of vessel, while venules exposed to the same shear rates had 5-16 adherent leukocytes. In arterioles, leukocyte rolling was only observed at low shear rates. At shear rates less than 250 s-1 leukocyte rolling velocity was faster in arterioles than venules, and the ratio Vwbc/Vrbc for arterioles was 0.08 +/- 0.02, which was fourfold higher than the ratio obtained in venules at similar shear rates. Pretreatment with the CD18-specific antibody (mAb) IB4 increased leukocyte rolling velocity in venules by approximately 20 microns/s at red cell velocities below 2,000 microns/s. mAb IB4 largely prevented the leukocyte adherence to arterioles and venules, and increased the ratio Vwbc/Vrbc observed in venules at low shear elicit a CD18-dependent adhesive interaction between leukocytes and microvascular endothelium, and that differences in shear rates cannot explain the greater propensity for leukocyte rolling and adhesion in venules than arterioles.


[Investigation on field feces in schistosomiasis endemic areas in Jingzhou City].
To understand the status of field feces in Jingzhou City, so as to provide the evidence for improving the control measures to interrupt the transmission routes of schistosomiasis. The distribution of field feces was investigated in 27 schistosomiasis endemic villages in Gong' an, Jianli, Jiangling, Honghu and Shishou counties (cities) from 2010 to 2012. The schistosome positive status of the field feces was surveyed with the hatching method. There were 1366 field feces and the average density was 0.0892 feces per 100 square meters in this survey. The cattle feces, human feces, dog feces and elk feces respectively accounted for 99.71%, 0.07%, 0.15% and 0.07% in the survey. The infection rates of the field feces were 1.46% and 2.42% in the channels and bottomlands, respectively (P > 0.05). The average rate of infected field feces was 3.21% in 2010, 0.36% in 2011, and 1.60% in 2012, and the difference between 2010 and 2012 was not statistically significant (P > 0.05). The main field feces come from cattle, and the main distribution of infected field feces is in channels and bottom-lands. Therefore, the management of cattle and treatment of field feces should be strengthened.


Best Practices for Developing a Diabetes mHealth App.
The widespread use of smartphones in the United States has led to a surge in mHealth apps designed to support people with various health issues. Yet the effectiveness and long-term impacts of these apps still need to be determined. This article presents a case study of the development of MyT1DHero, an mHealth app for people with type 1 diabetes, to identify best practices for app development. We propose four essential best practices based on the insights gained from this case study: incorporating theoretical frameworks, prioritizing user feedback, engaging key stakeholders, and establishing a robust data-collection foundation. These findings have practical implications for researchers and developers seeking to create effective mHealth interventions. Furthermore, we suggest future research directions to advance the development and implementation of innovative health technologies.


Effect of intravenous administration of fluids on packed cell volume, blood pressure, and total protein and blood glucose concentrations in healthy halothane-anesthetized dogs.
To determine the effects of IV administration of fluids on PCV, serum total protein and blood glucose concentrations, and systolic arterial pressure in healthy anesthetized dogs undergoing elective surgical procedures. Prospective, randomized controlled trial. 70 clinically normal dogs. Dogs received i.v. administration of 0, 5, 10, or 15 mL/kg of body weight/h of a polyionic crystalloid solution or 5% dextrose in water. Blood samples were collected before and after administration of medication, prior to anesthetic induction, after anesthetic induction, at the end of the surgical procedure, and 2 hours after surgery to determine PCV and serum total protein and blood glucose concentrations. Blood pressure was measured before and after anesthetic induction and at the end of the surgery. There were not any significant differences in PCV, total protein concentration, or systolic arterial pressure among treatment groups. Hyperglycemia developed in dogs receiving 5% dextrose in water, but resolved 2 hours after discontinuing administration of fluids. Intravenous administration of fluids may not be necessary to maintain normal blood pressure in young, healthy dogs undergoing elective surgery.


Transformation of beta-lycopene cyclase genes from Salicornia europaea and Arabidopsis conferred salt tolerance in Arabidopsis and tobacco.
Inhibition of lycopene cyclization decreased the salt tolerance of the euhalophyte Salicornia europaea L. We isolated a β-lycopene cyclase gene SeLCY from S. europaea and transformed it into Arabidopsis with stable expression. Transgenic Arabidopsis on post-germination exhibited enhanced tolerance to oxidative and salt stress. After 8 and 21 d recovery from 200 mM NaCl treatment, transgenic lines had a higher survival ratio than wild-type (WT) plants. Three-week-old transgenic plants treated with 200 mM NaCl showed better growth than the WT with higher photosystem activity and less H(2)O(2) accumulation. Determination of endogenous pigments of Arabidopsis treated with 200 mM NaCl for 0, 2 or 4 d demonstrated that the transgenic plants retained higher contents of carotenoids than the WT. Furthermore, to compare the difference between SeLCY and AtLCY from Arabidopsis, we used viral vector mediating ectopic expression of SeLCY and AtLCY in Nicotiana benthamiana. Although LCY genes transformation increased the salt tolerance in tobacco, there is no significant difference between SeLCY- and AtLCY-transformed plants. These findings indicate that SeLCY transgenic Arabidopsis improved salt tolerance by increasing synthesis of carotenoids, which impairs reactive oxygen species and protects the photosynthesis system under salt stress, and as a single gene, SeLCY functionally showed no advantage for salt tolerance improvement compared with AtLCY.


[5-Methylcytosine content in erythroleukemic cells of rats after induction with dimethylsulfoxide].
Erythroleucemic cells of rats were induced by DMSO for the terminal erythroid differentiation. The base composition and the 5 MC content of the DNA were analyzed by HPLC and a significant difference between non-induced and induced cells was not found. The analysis of labelled DNA by the restriction enzymes Hha I, Hpa II, and Msp I did not result in a different pattern before and after the induction. These results suggest that the 5 MC content of the DNA does not change during the induced terminal erythroid differentiation.


Branched-chain amino acid supplementation during repeated prolonged skiing exercises at altitude.
This study was conducted to test the hypothesis that a branched-chain amino acid (BCAA) supplementation would minimize changes in body composition and alterations in plasma amino acid profile induced by prolonged exercises at altitude. Twenty-four highly trained subjects participated in six successive sessions of ski mountaineering (6-8 hr duration, altitude 2,500-4,100 m). Twelve subjects took a dietary supplement of BCAA (BCAA group) and 12 took a dietary supplement that was 98% carbohydrate (C group). Body weight decreased in C subjects (-2.1%, p < .01), while the body weight loss recorded in the BCAA group was not statistically significant (-1.2%, NS). Changes in body composition that resulted from repeated skiing exercise at altitude were not significantly minimized by BCAA administration. Peak power output recorded during an incremental bicycle exercise decreased in C subjects but did not change significantly in BCAA subjects. Results of this study demonstrate that neither changes in body composition related to the ski mountaineering program nor muscular performance during isometric contraction was significantly affected by BCAA administration.


Three ethylene-responsive transcription factors in tobacco with distinct transactivation functions.
Ethylene-responsive factors (ERFs) have conserved DNA-binding domains and interact directly with the GCC box in the ethylene-responsive element that is necessary and sufficient for the regulation of transcription by ethylene. ERFs were shown to be localized to nucleus in transient transfection experiments. Transient expression assays using tobacco protoplasts and a heterologous system in yeast were used to examine the transactivation functions of ERFs. ERF2 and ERF4 enhanced the GCC box-mediated transcription of a reporter gene in tobacco protoplasts. When fused to the DNA-binding domain of yeast GAL4, a carboxy-terminal region of ERF2, as well as both amino-terminal and carboxy-terminal regions of ERF4, functioned as a transactivation domain in tobacco protoplasts. The amino-terminal regions of ERF2 and ERF4 functioned as transactivation domains in yeast. In contrast to ERF2 and ERF4, ERF3 reduced the transcription of the reporter gene in tobacco protoplasts, indicating that ERF3 functions as a repressor. Thus, it appears that ERFs exert their regulatory functions in different ways, with ERF2 and ERF4 being activators and ERF3 being a repressor of transcription.


Cyclotetraazocarbazole--a multichromic molecule.
A macrocyclic cyclotetraazocarbazole was prepared. Surprisingly, during the investigation of its photochromic behavior a drastic color change from yellow to green upon irradiation in chlorinated solvents was observed, which was temperature dependent and could also be induced by acid/base addition. With these three inputs an integrated molecular logic gate including an OR, a NOT and an AND function was build.


[Felty's syndrome without splenomegaly. A case report (author's transl)].
A 63 year-old female patient with rheumatoid arthritis and positive rheumatoid serology presented persistent neutropenia without spleen enlargement detectable by either physical or isotopic means. A pattern identical to that described for classical Felty's syndrome was found on determination of the IgG bound to granulocytes by inhibition of the hemolysis of sheep erythrocytes previously incubated with human IgG. Inhibition of hemolysis in the patient was 94 %, 63 %, and 32 % (according to the concentration of granulocytes per mm3), while in the healthy control it was 37.5 %, 30 %, and 0 %, respectively. In spite of the absence of spleen enlargement, the patient was diagnosed as suffering from Felty's syndrome without splenomegaly. The diagnostic and follow-up value of the measurement of IgG bound to granulocytes is emphasized.


Utility of a Model for Predicting the Risk of Sentinel Lymph Node Metastasis in Patients With Cutaneous Melanoma.
A neural network-based model (i31-GEP-SLNB) that uses clinicopathologic factors (thickness, mitoses, ulceration, patient age) plus molecular analysis (31-gene expression profiling) has become commercially available to guide selection for sentinel lymph node (SLN) biopsy in cutaneous melanoma, but its clinical utility is not well characterized. To determine if use of the i31-GEP-SLNB model is associated with clinical benefit when used to select patients for SLN biopsy. This decision-analytic study used data derived from a published external validation study of the i31-GEP-SLNB prediction model. Participants included patients with primary cutaneous melanoma. The primary outcome was the net benefit associated with using the i31-GEP-SLNB model for SLN biopsy selection compared with other selection strategies (SLN biopsy for all patients and SLN biopsy for no patients) at a 5% risk threshold. Analyses were stratified by American Joint Committee on Cancer (AJCC) T category. The reduction in the number of avoidable SLN biopsies and relative utility were also calculated. Compared with other SLN biopsy selection strategies, use of the i31-GEP-SLNB model had greater net benefit for patients with T1b (+0.012), T2a (+0.002), and T2b melanoma (+0.002) but not for those with high-risk T1a (-0.003) disease. The improvement in relative utility was +22% in patients with T1b, +1% in T2a, and +2% in T2b melanoma. Compared with SLN biopsy for all patients, use of the model would equate to a 23% decrease in SLN biopsies among patients with T1b disease without an SLN metastasis with no increase in the number of patients with an SLN metastasis left untreated; among patients with T2a and T2b melanoma, the net decrease in avoidable biopsies compared with SLN biopsy for all was 3% and 4%, respectively. The findings of this decision-analytic study suggest that i31-GEP SLNB has significant potential for risk-stratifying patients with T1b melanoma if using a 5% risk threshold; its role among patients with T1a and T2 melanoma or using other risk thresholds requires further study. A prospective validation study confirming the added clinical benefit and cost-effectiveness of i31-GEP-SLNB compared with free clinicopathologic-based prediction models is needed in patients with T1b melanoma.


Spatial distribution of citizen science casuistic observations for different taxonomic groups.
Opportunistic citizen science databases are becoming an important way of gathering information on species distributions. These data are temporally and spatially dispersed and could have limitations regarding biases in the distribution of the observations in space and/or time. In this work, we test the influence of landscape variables in the distribution of citizen science observations for eight taxonomic groups. We use data collected through a Portuguese citizen science database (biodiversity4all.org). We use a zero-inflated negative binomial regression to model the distribution of observations as a function of a set of variables representing the landscape features plausibly influencing the spatial distribution of the records. Results suggest that the density of paths is the most important variable, having a statistically significant positive relationship with number of observations for seven of the eight taxa considered. Wetland coverage was also identified as having a significant, positive relationship, for birds, amphibians and reptiles, and mammals. Our results highlight that the distribution of species observations, in citizen science projects, is spatially biased. Higher frequency of observations is driven largely by accessibility and by the presence of water bodies. We conclude that efforts are required to increase the spatial evenness of sampling effort from volunteers.


Toxic shock syndrome in Australian children.
There are limited data describing the epidemiology, management and outcomes of children with toxic shock syndrome (TSS), a potentially life-threatening illness. Here, we describe the incidence, clinical features, treatment and outcome of children with staphylococcal and streptococcal TSS in Victoria, Australia. Retrospective chart review of children admitted between 2003 and 2014 to two tertiary paediatric referral centres who fulfilled the Centers for Disease Control and Prevention case definition of TSS. There were 62 cases over the 11-year period; 43 staphylococcal TSS and 19 streptococcal TSS. The majority (46 (74%)) of cases were admitted to an intensive care unit and 44 (71%) required inotropic support. Compared with those with staphylococcal TSS, patients with streptococcal TSS were younger, more unwell and more likely to have residual morbidity. Adjunctive therapy with intravenous immunoglobulin or clindamycin was used in 58 (94%) of cases and fresh frozen plasma was used in 15 (24%). Seven patients received extracorporeal membrane oxygenation. All patients survived. This study highlights the importance of early recognition of TSS and supports rapid tertiary referral and intensive care management, which includes the use of adjunctive therapy with intravenous immunoglobulin and clindamycin.


Tracking Opioid Prescribing Metrics in Washington State (2012-2017): Differences by County-Level Urban-Rural and Economic Distress Classifications.
High-risk opioid prescribing is a critical driver of prescription opioid-related morbidity and mortality. This study explored opioid prescribing patterns across urban-rural and economic distress classifications. Secondarily, this study explored the urban-rural distribution of relevant health services, economic factors, and population characteristics. County-level opioid prescribing metrics were based on quarterly Washington State Prescription Monitoring Program data (2012-2017). Counties were classified using the 2013 National Center for Health Statistics Urban-Rural Classification Scheme for Counties, and Washington State unemployment-based distressed areas. County-level measures from Area Health Resources Files were used to describe the urban-rural continuum. Persistent economic distress was associated with higher-risk opioid prescribing. The large central metropolitan category had lower-risk opioid prescribing metrics than the other 5 urban-rural categories, which were similar to each other and not ordered by degree of rurality. High-risk prescribing declined over time, without notable trend divergence by either urban-rural or economic distress classifications. The most striking urban-rural differences in opioid prescribing metrics were between large central metropolitan and all other categories; thus, we recommend caution when collapsing urban-rural categories for analysis. Further research is needed regarding geographic and economic patterning of opioid prescribing practices, as well as the dissemination of guidelines and best practices across the urban-rural continuum. Finally, the multiple intertwined burdens faced by rural communities-higher-risk prescribing practices, higher opioid morbidity and mortality rates, and fewer resources for primary care, mental health care, alternative pain treatment, and opioid use disorder treatment-must be addressed as an urgent public health priority.


[Main grade of Gleason's 7 score of the surgical sample correlated with biologic progression in patients treated for total prostatectomy].
To analyse the influence of the main grade of Gleason score 7 of the operative specimen correlated with the blood PSA level on the laboratory progression-free survival of patients treated by radical prostatectomy. 331 patients consecutively treated by radical prostatectomy and presenting a Gleason score 7 were analysed. Exclusion criteria were the use of radiotherapy and/or preoperative and/or postoperative endocrine therapy. The main grade (3 or 4), histological stage, and blood PSA level were analysed for their predictive value of laboratory progression-free survival. The mean follow-up was 3.5 years (range: 13.6 to 72.8 months). Laboratory recurrence was defined by a PSA > 0.4 ng/ml. The main grade of Gleason score 7 was 3 in 199 (60%) patients and 4 in 132 (40%) patients with a mean follow-up of 3.6 years. Laboratory progression-free survival rates were 89% and 72% for main grades 3 and 4, respectively (p = 0.03). When the cancer was confined to the prostate, the progression-free survival rates were 96% and 88% for main grades 3 and 4, respectively (p = 0.01). For a PSA < 10 ng/ml, main grade 3 was associated with a better laboratory progression-free survival rate than main grade 4 (p = 0.0007). No difference in terms of laboratory progression was observed in the presence of extraprostatic extension or PSA > 10 ng/ml. A high correlation was observed between the main grade of Gleason score 7 and laboratory progression-free survival. Main grade 3 constituted a factor of better prognosis than main grade 4.


Role of sonography in the diagnosis of retained products of conception.
To present our experience with clinical and sonographic diagnosis of retained products of conception and to evaluate its correlation with histopathologic findings. This was a retrospective study on 156 patients admitted for retained products of conception. Women were referred because of 1 or more of the following: abdominal pain, bleeding, and fever. The status of the cervix was evaluated by bimanual examination. The diagnosis of retained products of conception was made when a sonographic finding of hyperechoic or hypoechoic material was seen in any part of the uterine cavity or the presence of a thickened endometrial stripe greater than 8 mm and an irregular interface between the endometrium and myometrium was found. One hundred twenty-one women (77.6%) were admitted after dilation and curettage for abortion, and 35 (22.4%) were admitted after spontaneous labor. Histopathologic reports confirmed the diagnosis of retained products of conception in 86 (71%) of 121 women in the postabortion group and in 17 (48.5%) of 35 women in the postpartum group. The overall false-positive rate for sonographic diagnosis was 34%. For women after abortion and after delivery, the false-positive rates were 28.9% and 51.5%, respectively. Reliance on common signs and symptoms to diagnose retained products of conception as well as the use of sonography is associated with an unacceptably high false-positive rate, mainly after delivery. A more conservative approach to the treatment of retained products of conception is suggested.


Assessment of safety/risk of chemicals: inception and evolution of the ADI and dose-response modeling procedures.
This article reviews the procedures for the assessment of safety/risk of chemicals to human health. Because the nature and severity of toxicity and the extent of the database vary from chemical to chemical, the assessment is done on a case by case basis. Essentially 5 steps are involved in the assessment: (a) identification of hazards based on appropriate human and animal data; (b) determination of the dose-response relationship of the adverse effects of the chemical; (c) extrapolation of the dose-response data from test subjects to human populations; (d) estimation of the exposure; and (e) assessment of the safety/risk of the chemical under a specified exposure. Emphasis in this article, however, is placed on the extrapolation of the dose-response data to the human situation. The extrapolation is done by the identification of a no-observed-adverse-effect level (NOAEL) and the application of a safety factor, thereby arriving at an acceptable daily intake (ADI). The safety factor is selected on the basis of, inter alia, the severity of the adverse effect and the adequacy of the database. On the other hand, with genotoxic carcinogens, mathematical modeling is used for extrapolation. This is because the effects of genotoxic carcinogens are generally believed to have no threshold. The ADI approach, which involves the identification of a NOAEL, is therefore not applicable. A number of mathematical models have been developed to assess, from the dose-response data, either the risks that may be associated with a specified dose, or the 'virtually safe dose' at a specified risk level. The evolution, application and shortcomings of these procedures and the potential improvements in the ADI approach and in the dose-response characterization based on these mathematical models are also discussed.


Long term modification of cerebellar inhibition after inferior olive degeneration.
The long term effects of inferior olive destruction on the activities of the Purkinje cells and their target neurones in the cerebellar nuclei were studied in the rat. Careful observations were also made of motor behaviour throughout the study. Albino rats were injected with 3-acetylpyridine to produce a neurotoxic destruction of the inferior olive and then were used for acute recording experiments at 1-2 days, 5-7 days, 12-18 days, 35-38 days, 75-97 days and 230-252 days. After degeneration of the inferior olive, there was an initial period lasting for a few days, characterized by a high firing frequency of Purkinje cells associated with a very low level of activity of the neurones in the cerebellar nuclei. During this period, there was a deep depression of motor activity. A period of adaptation follows during the first month, characterized by a slow recovery of the initial firing frequency of the cerebellar units and a gradual recovery of spontaneous locomotion; nevertheless the firing pattern and motor behaviour remain abnormal. From one month on the unit activities disturbances and the motor deficiencies stabilize. The hypothesis is advanced that Purkinje cell inhibition on their target neurones, which increases during the initial period, gradually diminishes during the adaptation time, and then stabilizes to a subnormal state.