Burden of serious harms from diagnostic error in the USA.
Diagnostic errors cause substantial preventable harms worldwide, but rigorous estimates for total burden are lacking. We previously estimated diagnostic error and serious harm rates for key dangerous diseases in major disease categories and validated plausible ranges using clinical experts. We sought to estimate the annual US burden of serious misdiagnosis-related harms (permanent morbidity, mortality) by combining prior results with rigorous estimates of disease incidence. Cross-sectional analysis of US-based nationally representative observational data. We estimated annual incident vascular events and infections from 21.5 million (M) sampled US hospital discharges (2012-2014). Annual new cancers were taken from US-based registries (2014). Years were selected for coding consistency with prior literature. Disease-specific incidences for 15 major vascular events, infections and cancers ('Big Three' categories) were multiplied by literature-based rates to derive diagnostic errors and serious harms. We calculated uncertainty estimates using Monte Carlo simulations. Validity checks included sensitivity analyses and comparison with prior published estimates. Annual US incidence was 6.0 M vascular events, 6.2 M infections and 1.5 M cancers. Per 'Big Three' dangerous disease case, weighted mean error and serious harm rates were 11.1% and 4.4%, respectively. Extrapolating to all diseases (including non-'Big Three' dangerous disease categories), we estimated total serious harms annually in the USA to be 795 000 (plausible range 598 000-1 023 000). Sensitivity analyses using more conservative assumptions estimated 549 000 serious harms. Results were compatible with setting-specific serious harm estimates from inpatient, emergency department and ambulatory care. The 15 dangerous diseases accounted for 50.7% of total serious harms and the top 5 (stroke, sepsis, pneumonia, venous thromboembolism and lung cancer) accounted for 38.7%. An estimated 795 000 Americans become permanently disabled or die annually across care settings because dangerous diseases are misdiagnosed. Just 15 diseases account for about half of all serious harms, so the problem may be more tractable than previously imagined.


Colletotrichum: species, ecology and interactions.
The presentations of the Special Interest Group meeting Colletotrichum: species, ecology and interactions, held on 1 August 2010 during IMC9 in Edinburgh, UK, are outlined. Seven research projects, ranged from systematics and population genetics to host-pathogen interactions and genome projects were presented. The meeting revealed that currently major species complexes in the genus Colletotrichum are being revised and the identities of many pathogens clarified on the basis of molecular phylogenies, and that the genomes of four species are sequenced and decoded providing an enormous amount of data that are used to increase our understanding of the biology of Colletotrichum species.


Impact of the age of diagnosis on the natural history of ulcerative colitis.
Ulcerative colitis (UC) has a recognized phenotypic heterogeneity. Some studies suggest that age at diagnosis may influence features and natural history of the disease. This study aimed to compare patients', disease's and treatment's features between Portuguese patients diagnosed before and after the age of 40-years-old. Retrospective single-center study that included 310 patients with UC, divided in two groups: Those diagnosed before the age of 40-years-old (early onset UC) and those diagnosed later than that (late onset UC). In each group features of the patients (gender, family history, smoking), of the disease (duration, extension, severity, clinical course, hospitalization, extraintestinal manifestations), and of treatment (oral aminosalicylates, systemic steroids or immunomodulators) were analyzed. Statistical analysis was performed using SPSSv22.0. Univariate and multivariate analyses were performed to assess factors associated with early and late onset UC. From the analyzed patients, 207 had UC diagnosed before the age of 40 years old (43.5% men; mean age at diagnosis 29.4 ± 6.9 years) and 103 were diagnosed after that age (61.2% men; mean age at diagnosis 51.8 ± 8.1 years). In the group diagnosed before 40 years old, female gender (p = 0.003), severe disease (p = 0.002), chronic intermittent clinical course (p = 0.026), and hospitalizations (p = 0.001) were significantly more frequent. The use of oral aminosalicylates (p = 0.032), systemic steroids (p = 0.003) and immunomodulators (p = 0.012) were also more common in the early onset UC group. No differences between groups were found in family history, smoking, disease's extension, extraintestinal manifestations, and use of biological agents. Multivariate analysis pointed early onset UC to be significantly associated with female gender (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.08-2.91; p = 0.024), chronic intermittent symptoms (OR, 2.34; 95% CI, 1.17-4.70; p = 0.016), and need of hospitalization (OR, 2.89; 95% CI, 1.46-5.72; p = 0.002). When diagnosed before the age of 40-years-old, UC preferably affects women and manifests as a more severe disease, with more frequent hospitalizations and chronic intermittent symptoms. These facts might have implications in planning timely and individualized future therapeutic strategies.


Non-Orthogonal Multiple Access with One-Bit Analog-to-Digital Converters Using Threshold Adaptation.
In digital communication systems featuring high-resolution analog-to-digital converters (ADCs), the utilization of successive interference cancellation and detection can enhance the capacity of a Gaussian multiple access channel (MAC) by combining signals from multiple transmitters in a non-orthogonal manner. Conversely, in systems employing one-bit ADCs, it is exceedingly difficult to eliminate non-orthogonal interference using digital signal processing due to the considerable distortion present in the received signal when employing such ADCs. As a result, the Gaussian MAC does not yield significant capacity gains in such cases. To address this issue, we demonstrate that, under a given deterministic interference, the capacity of a one-bit-quantized channel becomes equivalent to the capacity without interference when an appropriate threshold value is chosen. This finding suggests the potential for indirect interference cancellation in the analog domain, facilitating the proposition of an efficient successive interference cancellation and detection scheme. We analyze the achievable rate of the proposed scheme by deriving the mutual information between the transmitted and received signals at each detection stage. The obtained results indicate that the sum rate of the proposed scheme generally outperforms conventional methods, with the achievable upper bound being twice as high as that of the conventional methods. Additionally, we have developed an optimal transmit power allocation algorithm to maximize the sum rate in fading channels.


Effect of cell age on erythrocyte fatty acid composition in rats on different dietary regimes.
1. Rat erythrocytes were fractionated into young, mature and old cell fractions by centrifugation. The fatty acid composition of each fraction was determined by gas-liquid chromatography, under four different dietary conditions: with adequate linoleic acid in the diet, with a diet deficient in linoleic acid, and with the deficient diet supplemented with corn oil for 3 and 12 days. 2. Significant differences were observed in the fatty acid composition of cells of different ages on all diets. The pattern of fatty acid distribution depended on the particular acid in question, on its concentration in the total erythrocyte sample and on the nature of the dietary fat. 3. When corn oil was fed to rats that had been fed previously on a deficient diet, the changes in fatty acid composition that occurred depended on the acid and on the cell age. For example, young cells were more active in incorporating palmitic acid and arachidonic acid but incorporated linoleic acid at a slightly lower rate than older cells. 4. These results are believed to indicate the presence in the erythrocyte of transacylases with different specificities, and to show that transacylase activity changes as the cells age.


Repair of anomalous origin of right coronary artery from the pulmonary artery.
Anomalous origin of the right coronary artery from the pulmonary artery is a rare cardiac malformation. Between July 2002 and July 2005, we operated on 4 patients with this defect. There were 2 males and 2 females, aged from 18 months to 42 years. Three patients underwent direct re-implantation of the right coronary artery into the aorta, and one had an intrapulmonary tunnel repair (intrapulmonary artery baffle with an autologous pericardial patch for tunneling to the anomalous right coronary ostium). Cardiopulmonary bypass was used in 2 patients, and an off-pump technique in the other 2. One patient had an atrial septal defect that was closed with an Amplatzer septal occluder through the right atrium under transesophageal echocardiography, without cardiopulmonary bypass. All patients survived and recovered uneventfully. Follow-up ranged from 3 to 39 months (mean, 17 months). All patients were doing well and free from symptoms, with normal exercise tolerance. Surgical correction of anomalous right coronary artery shows good early and midterm results.


Olfactory ensheathing cell tumor arising from the olfactory mucosa.
We report a rare case of olfactory ensheathing cell tumor. A female presented a large soft mass extending medially to the olfactory cleft and laterally to the middle meatus in the left nasal cavity. Imaging studies confirmed a cystic mass extending superiorly into the frontal lobe, indicating that the tumor arouse from the olfactory mucosa. A subtotal resection was achieved through an endoscopic endonasal approach without operative complications. Immunohistochemically constituent cells were diffusely positive for S-100 protein, but olfactory ensheathing cell tumor was diagnosed by negative staining for Leu7 (CD57). This case indicates that olfactory ensheathing cell tumor should be included in differential diagnoses for the olfactory cleft tumors.


Arch reconstruction without circulatory arrest: historical perspectives and initial clinical results.
For many years, deep hypothermic circulatory arrest had been a necessary and unavoidable adjunct to surgical procedures including aortic arch reconstruction in neonates and infants. Despite meticulous investigation of bypass techniques for deep hypothermic circulatory arrest, unfavorable long-term neurologic deficits have been well documented. Currently, several cerebral perfusion techniques are used in neonatal arch reconstruction to avoid circulatory arrest and prevent brain ischemia. The techniques and their initial clinical results are presented and related problems discussed. Currently available circulatory arrest techniques should be avoided in favor of well-established continuous perfusion techniques, even for arch reconstruction.


Advance Care Planning Practice Patterns Before and During a Pandemic.
Introduction: The COVID-19 pandemic resulted in introspection of the United States health care infrastructure, especially with advance care planning (ACP). Methods: This is a retrospective chart review assessing the frequency of ACP discussions and formal documents reflecting ACP wishes in an outpatient palliative medicine (PM) practice. The study site was at University Medical Center New Orleans from pre-COVID-19 surge (November 2019-February 2020) to months during and post-COVID-19 surge (March-April 2020). Results: Results showed an increase in ACP discussions during the post-COVID-19 months. Patients seen during the surge and post-COVID-19 months were more likely to discuss medical power of attorney (odds ratio [OR] = 1.78, p = 0.045) and preferred code status (OR = 2.82, p < 0.001). Conclusion: Our study showed that more ACP discussions were conducted post-COVID-19 versus pre-COVID-19. However, formal documents reflecting these wishes were lacking. These results can help guide ACP use in crisis periods and improve understanding of ACP discussions in an outpatient PM clinic.


Distal pancreatectomy with splenorenal shunt to preserve spleen in a cirrhotic patient.
At pancreatic ductal adenocarcinoma is an aggressive malignancy with a high recurrence rate. Due to its high potentials of local invasion and distant metastasis, surgical resection is the only means for possible long-term survival. Surgical treatment comprises a distal pancreatectomy with or without splenectomy. Surgery has been conventionally contraindicated for patients with cirrhosis and portal vein hepato-biliary hypertension. Splenorenal shunt was first described by Warren and colleagues, to prevent death from bleeding esophageal varices in a patient with a patent portal vein hypertension. A 55-year-old Caucasian woman presented with an incidental pancreatic tumor. In our case, the shunt was necessary to complete the corrective oncological surgery for pancreatic ductal adenocarcinoma. The main difficulty was the presence of portal hypertension due to liver cirrhosis Child A; moreover, preservation of the spleen was mandatory in this patient. We successfully performed a distal pancreatectomy without splenectomy through the help of splenorenal shunt to preserve venous circulation.


Age-related response to mite parasitization and viral infection in the honey bee suggests a trade-off between growth and immunity.
Host age at parasites' exposure is often neglected in studies on host-parasite interactions despite the important implications for epidemiology. Here we compared the impact of the parasitic mite Varroa destructor, and the associated pathogenic virus DWV on different life stages of their host, the western honey bee Apis mellifera. The pre-imaginal stages of the honey bee proved to be more susceptible to mite parasitization and viral infection than adults. The higher viral load in mite-infested bees and DWV genotype do not appear to be the drivers of the observed difference which, instead, seems to be related to the immune-competence of the host. These results support the existence of a trade-off between immunity and growth, making the pupa, which is involved in the highly energy-demanding process of metamorphosis, more susceptible to parasites and pathogens. This may have important implications for the evolution of the parasite's virulence and in turn for honey bee health. Our results highlight the important role of host's age and life stage at exposure in epidemiological modelling. Furthermore, our study could unravel new aspects of the complex honey bee-Varroa relationship to be addressed for a sustainable management of this parasite.


Screening Commercially Available Entomopathogenic Biocontrol Agents for the Control of Aethina tumida (Coleoptera: Nitidulidae) in the UK.
The Small hive beetle, Aethina tumida, is an invasive pest of honey bees. Indigenous to sub-Saharan Africa, it has now become established in North America and Australia. It represents a serious threat to European honey bees. Commercially available entomopathogenic agents were screened for their potential to control beetle larvae. Entomopathogenic fungi investigated had minimal impact. The nematodes Steinernema kraussei and S. carpocapsae provided excellent control with 100% mortality of larvae being obtained. Sequential applications of the nematodes following larvae entering sand to pupate also provided excellent control for up to 3 weeks. The information gained supports the development of contingency plans to deal with A. tumida should it occur in the UK, and is relevant to the management of Small hive beetle where it is already present.


[Craniosynostosis: a review of 14 cases (author's transl)].
Fourteen cases of single and polimalformative craniosynostosis are presented. A Crouzon's syndrome, and Apert's syndrome and a Carpenter's syndrome are included. On the cranial deformities, 7 cases of scaphocephaly, 4 cases of oxycephaly and 3 cases of acrocephaly were diagnosed. The eye abnormalities, the mental retardation and the intracranial hyperpressure symptomatology were analyzed. A lineal descompresive craniectomy was performed in 10 cases. The applied surgical criterium was the appearing of intracranial hyperpressure. The postoperative results upon the clinical symptomatology and the cranial deformity are commented, showing a real improve of the hyperpressure symptoms in all the cases, a correction of the scaphocephalic defect and a lack of effect on those clinical manifestations resulting from the cerebral damming. Finally, the timing of operation is discussed.


Efficient oxygen reduction catalysis by subnanometer Pt alloy nanowires.
The common knowledge is that Pt and Pt alloy nanoparticles (NPs) less than 2 nm are not desirable for oxygen reduction reaction (ORR). However, whether the same trend is expected in Pt-based nanowires (NWs) and nanoplates remains questionable because there is no scalable approach to make such Pt nanostructures. We report a general approach for preparing subnanometer Pt alloy NWs with a diameter of only 4 to 5 atomic layer thickness, ranging from monometallic Pt NWs to bimetallic PtNi and PtCo NWs and to trimetallic PtNiCo NWs. In a sharp contrast to Pt alloy NPs, the subnanometer Pt alloy NWs demonstrate exceptional mass and specific activities of 4.20 A/mg and 5.11 mA/cm2 at 0.9 V versus reversible hydrogen electrode (RHE), respectively, 32.3 and 26.9 times higher than those of the commercial Pt/C. Density functional theory simulations reveal that the enhanced ORR activities are attributed to the catalytically active sites on high-density (111) facets in the subnanometer Pt alloy NWs. They are also very stable under the ORR condition with negligible activity decay over the course of 30,000 cycles. Our work presents a new approach to maximize Pt catalytic efficiency with atomic level utilization for efficient heterogeneous catalysis and beyond.


Factors explaining variance in perceived pain in women with fibromyalgia.
We hypothesized that a substantial proportion of the subjectively experienced variance in pain in fibromyalgia patients would be explained by psychological factors alone, but that a combined model, including neuroendocrine and autonomic factors, would give the most parsimonious explanation of variance in pain. Psychometric assessment included McGill Pain Questionnaire, General Health Questionnaire, Hospital Anxiety and Depression Rating Scale, Eysenck personality Inventory, Neuroticism and Lie subscales, Toronto Alexithymia Scale, and Multidimensional Health Locus of Control Scale and was performed in 42 female patients with fibromyalgia and 48 female age matched random sample population controls. A subgroup of the original sample (22 fibromyalgia patients and 13 controls) underwent a pharmacological challenge test with buspirone to assess autonomic and adrenocortical reactivity to serotonergic challenge. Although fibromyalgia patients scored high on neuroticism, anxiety, depression and general distress, only a minor part of variance in pain was explained by psychological factors alone. High pain score was associated with high neuroticism, low baseline cortisol level and small drop in systolic blood pressure after buspirone challenge test. This model explained 41.5% of total pain in fibromyalgia patients. In population controls, psychological factors alone were significant predictors for variance in pain. Fibromyalgia patients may have reduced reactivity in the central sympathetic system or perturbations in the sympathetic-parasympathetic balance. This study shows that a biopsychosocial model, including psychological factors as well as factors related to perturbations of the autonomic nervous system and hypothalamic-pituitary-adrenal axis, is needed to explain perceived pain in fibromyalgia patients.


Evaluation of a tuberculosis mass survey conducted in the city of Chatham and in Kent County, Ontario, in 1963.
Computer analysis of the results of a mass tuberculosis survey of the population of Chatham city and Kent County, Ontario, was carried out to assess the efficacy of such surveys as a case-finding device. Six cases of active tuberculosis were found during the survey and approximately 50% of the 89,427 inhabitants of Chatham and Kent County were surveyed with radiographs and Heaf skin tests.A follow-up study of the Heaf test conducted in the public school of Wallaceburg detected 70 Heaf-positive children out of a total of 1190. These Heaf-positive children were further tested with a Mantoux test (5 T.U.) and chest radiography. Only 11 children of the original 70 were Mantoux-positive.These findings further support the hypothesis that the Heaf test, as now read, over-reads for M. tuberculosis infections.


[MG7 expression in helicobacter pylori-related gastric diseases].
To determine the influence of Helicobacter pylori (H. pylori) on gastric cancer-related antigen MG7 expression. The H. pylori infection and the expression level of antigen MG7 in gastric mucosa were determined by HE stain, PCR, ELISA and immunohistochemistry in 291 patients with H. pylori-related conditions, among whom 34 were followed-up. No significant difference was found between H. pylori-negative and H. pylori-positive intestinal metaplasia, atrophic gastritis and dysplasia of gastric epithelium in positive rate of antigen MG7 expression. There was significant difference between H. pylori-negative and H. pylori-positive superficial gastritis in the positive rate of MG7 expression (P < 0.05). During follow-up, one of 3 H. pylori-negative cases turned to be H. pylori-positive, and its MG7 expression turned to be higher at the same time. Three of 31 H. pylori-positive patients were discovered as having early gastric cancer, among whom one with antigen MG7 expression (+ + +) was found to have a reduced Mg7 expression accompanied with H. pylori eliminutied after operation. There is correlationship between H. pylori infection and MG7 expression in superficial gastritis. Although the MG7-positive lesions with H. pylori infection shows a benign nature in morphology, they also have the potential risk of developing into gastric cancer. Therefore, they should be followed up, during which special attention should be paid to patients with increased MG7 expression.


Amide Effects in C-H Activation: Noncovalent Interactions with L-Shaped Ligand for meta Borylation of Aromatic Amides.
A new concept for the meta-selective borylation of aromatic amides is described. It has been demonstrated that while esters gave para borylations, amides lead to meta borylations. For achieving high meta selectivity, an L-shaped bifunctional ligand has been employed and engages in an O⋅⋅⋅K noncovalent interaction with the oxygen atom of the moderately distorted amide carbonyl group. This interaction provides exceptional control for meta C-H activation/borylation.


A multidimensional liquid chromatography-tandem mass spectrometry platform to improve protein identification in high-throughput shotgun proteomics.
A new on-line multidimensional system for sequential trapping and individual elution and separation of peptides based on their molecular weight is described. By sequentially using two chemically different trapping columns, a polymethacrylate monolith and a packed C18 one, peptides from complex samples can be on-line trapped and divided into two fractions, containing respectively mainly medium-large peptides and smaller peptides. Then, by means of two switching valves working in parallel, the two fractions were individually separated by reversed phase chromatography. The whole gradient consisted of two subgradients, with the first one dedicated to the separation of smaller peptides and the second one to the separation of larger peptides. Such configuration allowed to identify up to 1476 proteins in a standard E. coli tryptic digest, with improved performance, increased average sequence coverage and reduced single unique peptide identifications compared to a conventional shotgun proteomics configuration comprising only the C18 trapping column and the analytical column.


Vitamin A toxicity and vitamin E deficiency in a rabbit colony.
Vitamin A toxicosis and vitamin E deficiency was diagnosed in a commercial rabbit-breeding colony and was associated with reproductive abnormalities, abortions, and poor survivability of kits in the breeding colony. Paresis and muscular dystrophy were noted in juvenile rabbits. Another group of New Zealand White rabbits from the same commercial colony was used to assess the effect of vitamin E-based therapy on clinical signs, reproduction, and vitamin A and E serum and liver levels. Blood samples were taken before and after dietary changes and vitamin E therapy. Serum vitamin E remained low after feeding a diet containing the recommended levels of vitamin E. Administration of vitamin E for 2 weeks lowered the serum vitamin A levels and increased the vitamin E serum and liver levels. In conclusion, vitamin E therapy appears to be an effective treatment for hypervitaminosis A.


Cost-Utility Analysis of Cancer Prevention, Treatment, and Control: A Systematic Review.
Substantial innovation related to cancer prevention and treatment has occurred in recent decades. However, these innovations have often come at a significant cost. Cost-utility analysis provides a useful framework to assess if the benefits from innovation are worth the additional cost. This systematic review on published cost-utility analyses related to cancer care is from 1988 through 2013. Analyses were conducted in 2013-2015. This review analyzed data from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org), a comprehensive registry with detailed information on 4,339 original cost-utility analyses published in the peer-reviewed medical and economic literature through 2013. There were 721 cancer-related cost-utility analyses published from 1998 through 2013, with roughly 12% of studies focused on primary prevention and 17% focused on secondary prevention. The most often studied cancers were breast cancer (29%); colorectal cancer (11%); and prostate cancer (8%). The median reported incremental cost-effectiveness ratios (in 2014 U.S. dollars) were $25,000 for breast cancer, $24,000 for colorectal cancer, and $34,000 for prostate cancer. The current evidence indicates that there are many interventions that are cost effective across cancer sites and levels of prevention. However, the results highlight the relatively small number of cancer cost-utility analyses devoted to primary prevention compared with secondary or tertiary prevention.


Catalytic degradation of Acid Orange 7 by manganese oxide octahedral molecular sieves with peroxymonosulfate under visible light irradiation.
In this paper, the photodegradation of Acid Orange 7 (AO7) in aqueous solutions with peroxymonosulfate (PMS) was studied with manganese oxide octahedral molecular sieves (OMS-2) as the catalyst. The activities of different systems including OMS-2 under visible light irradiation (OMS-2/Vis), OMS-2/PMS and OMS-2/PMS/Vis were evaluated. It was found that the efficiency of OMS-2/PMS was much higher than that of OMS-2/Vis and could be further enhanced by visible light irradiation. The catalyst also exhibited stable performance for multiple runs. Results from ESR and XPS analyses suggested that the highly catalytic activity of the OMS-2/PMS/Vis system possible involved the activation of PMS to sulfate radicals meditated by the redox pair of Mn(IV)/Mn(III) and Mn(III)/Mn(II), while in the OMS-2/PMS system, only the redox reaction between Mn(IV)/Mn(III) occurred. Several operational parameters, such as dye concentration, catalyst load, PMS concentration and solution pH, affected the degradation of AO7.


Prognosis and longitudinal changes of physical activity in idiopathic pulmonary fibrosis.
Physical activity (PA) is associated with disease severity in idiopathic pulmonary fibrosis (IPF), but longitudinal studies evaluating its prognostic value and changes over time are lacking. We measured PA (steps per day, SPD) in a cohort of 46 IPF-patients (mean age, 67 years; mean FVC, 76.1%pred.) by accelerometry at baseline, recorded survival status during 3 years follow-up and repeated measurements in survivors. We compared the prognostic value of PA to established mortality predictors including lung function (FVC, DLCO) and 6-min walking-distance (6MWD). During follow-up (median 34 months) 20 patients (43%) died. SPD and FVC best identified non-survivors (AUROC-curve 0.79, p < 0.01). After adjustment for confounders (sex, age, therapy), a standardized increase (i.e. one SD) in SPD, FVC%pred. or DLCO%pred. was associated with a more than halved risk of death (HR < 0.50; p < 0.01). Compared to baseline, SPD, FVC, and 6MWD annually declined in survivors by 973 SPD, 130 ml and 9 m, resulting in relative declines of 48.3% (p < 0.001), 13.3% (p < 0.001) and 7.8% (p = 0.055), respectively. While PA predicts mortality of IPF patients similar to established functional measures, longitudinal decline of PA seems to be disproportionally large. Our data suggest that the clinical impact of disease progression could be underestimated by established functional measures.


Oral involvement in primary Sjögren syndrome.
In small studies, investigators have described oral features and their sequelae in primary Sjögren syndrome (PSS), but they have not provided a full picture of the aspects and implications of oral involvement. The authors describe what is, to their knowledge, the first large-scale evaluation to do so. In addition, they report data regarding utilization and cost of dental care among patients with PSS. The authors surveyed patients with primary Sjögren syndrome as identified by their physicians (PhysR-PSS), patient-members of the Sjögren's Syndrome Foundation (SSF-PSS) and control subjects who did not have PSS. They made comparisons between the three groups. Subjects were 277 patients with PhysR-PSS, 1,225 patients with SSF-PSS and 606 control subjects. More than 96 percent of those in the patient groups experienced oral problems. An oral complaint was the initial symptom in more than one-half of the patients. Xerostomia-associated signs and symptoms were common and severe, as evidenced by scores on an inventory of sicca symptoms. These patients' rate of dental care utilization was high, and the care was costly. Oral and dental disease in PSS is extensive and persistent and represents a significant burden of illness. Oral symptoms and signs are common in patients with PSS. Early recognition of the significance of these findings by oral specialists could accelerate diagnosis and minimize oral morbidities.


Evaluation of VITEK matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of anaerobes.
Rapid and adequate identification of anaerobic bacterial species still presents a challenge for most diagnostic laboratories, hindering the selection of appropriate therapy. In this study, the identification capacity of 16S rRNA sequence analysis, VITEK 2 (BioMérieux, Lyon, France) compact analysis and VITEK MS-mediated identification for anaerobic bacterial species was compared. Eighty-five anaerobic bacterial isolates from 11 provinces in China belonging to 14 genera were identified by these three methods. Differences in identification between these three methods were compared. Consistent identification results were obtained for 54 (54/85, 63.5%) isolates by all three methods, the most discordant results being concentrated in Clostridium XI (n = 8) and Bacteroides fragilis (n = 9) clusters. Using the VITEK MS system, 74 (74/90, 82.2%) isolates were identified as single species consistent with 16S rRNA sequence analysis, which was significantly better than the results obtained with VITEK 2 Compact (P < 0.01). Misidentifications by the Vitek 2 Compact and Vitek MS systems were mainly observed in the Clostridium XI (n = 8)and B. fragilis clusters (n = 9). VITEK MS identified anaerobic bacteria even after they had been exposed to oxygen for a week. Identification by the Vitek MS system was more consistent with 16S rRNA sequence analysis than identification by Vitek 2 Compact. Continuous expansion of the VITEK MS database with rare described anaerobic species is warranted to improve both the efficiency and accuracy of VITEK MS identification in routine diagnostic microbiology.


All-polarization-maintaining Er-doped dual comb fiber laser using single-wall carbon nanotubes.
We demonstrated a bi-directional, Er-doped dual comb fiber laser consisting of all-polarization-maintaining fiber devices. Polyimide films in which single-wall carbon nanotubes (SWNTs) were dispersed were used as the in-line saturable absorber. In order to avoid synchronization of the two combs and associated damage to the SWNT film, a two-branch configuration with two SWNT films was employed. Soliton pulses with almost the same optical spectra were generated stably in each direction, and dual comb beats were observed simply by overlapping the two outputs. The repetition frequency was 28 MHz, and the frequency difference was 105-140 Hz. Thanks to the small frequency difference, dual comb beats corresponding to the whole optical spectrum were observed without any overlapping. Fourier transform spectroscopy using the developed dual comb source was examined, and the characteristics of an optical filter were successfully obtained.


Stigmatization and Social Support of Pregnant Women With HIV or Syphilis in Eastern China: A Mixed-Method Study.
Stigmatization and poor social support are challenges faced by individuals living with HIV or sexually transmitted disease, which can have a profound negative impact on their healthcare. Mother-to-child transmission of either HIV or syphilis can lead to adverse maternal and fetal outcomes. The aim of this study was to investigate stigmatization and social support of pregnant women with HIV or syphilis in eastern China. This was an explanatory sequential mixed-method study conducted in Zhejiang province, China in 2019. Stigmatization, social support, and the associated factors toward HIV or syphilis were evaluated using questionnaires. The social support rating scale was used to evaluate social support, where a score <25% was defined as poor social support. A logistic regression model was used to explore the association between stigmatization and poor social support. A total of 448 women (HIV positive, N = 93; syphilis, N = 355) were recruited in this study. Higher stigmatization was observed in pregnant women with HIV compared to those with syphilis (53.76% vs. 24.36%, p < 0.001), and poorer social support was observed in women with HIV compared with those with syphilis (40.86% vs. 19.86%, p < 0.001), with significant distributions of the total social support scores (Z = -1.976, p = 0.048) and scores on objectivity (Z = -2.036, p = 0.042) and subjectivity (Z = -2.500, p = 0.012). Similar social support among HIV or syphilis pregnant women was observed in medical healthcare facilities. In multivariable logistic model analysis, stigmatization (OR adj = 2.927; 95%CI, 1.714-4.996; p < 0.001) and ethnic minority (OR adj = 2.373; 95%CI, 1.113-5.056; p = 0.025) were negatively associated with social support. Interestingly, employment status was associated with improved social support (OR adj = 0.345; 95%CI, 0.180-0.662; p = 0.001). Stigmatization among pregnant women with HIV or syphilis remains high. We demonstrated that stigmatization was a significant predictor of low social support in pregnant women with HIV or syphilis. The support shown in medical facilities was similar toward pregnant women with HIV or syphilis. Implementation of stigmatization eradication and social support strategies targeting pregnant women with HIV or syphilis may therefore improve the dual elimination of mother-to-child transmission service.


[The surgical anatomy of the adjacent lamellae of the thyroid gland and the laryngeal nerves].
Adjacent lamellae are special fasciae packing up organs tumor-proof. We find them on the rectum and similar layers are developed in the throat. Very important for the surgeon is the anterior lamella. Below the recurrent laryngeal nerve is situated. This anterior lamella is a protection for this vulnerable nerve. The recurrent laryngeal nerve may be aberrant in cases of an anomalous right subclavian artery. The knowledge of the anterior adjacent lamellae of the throat is very important for surgery of the goiter and parathyroid glands.


Growth Hormone (GH) and Gonadotropin-Releasing Hormone (GnRH) in the Central Nervous System: A Potential Neurological Combinatory Therapy?
This brief review of the neurological effects of growth hormone (GH) and gonadotropin-releasing hormone (GnRH) in the brain, particularly in the cerebral cortex, hypothalamus, hippocampus, cerebellum, spinal cord, neural retina, and brain tumors, summarizes recent information about their therapeutic potential as treatments for different neuropathologies and neurodegenerative processes. The effect of GH and GnRH (by independent administration) has been associated with beneficial impacts in patients with brain trauma and spinal cord injuries. Both GH and GnRH have demonstrated potent neurotrophic, neuroprotective, and neuroregenerative action. Positive behavioral and cognitive effects are also associated with GH and GnRH administration. Increasing evidence suggests the possibility of a multifactorial therapy that includes both GH and GnRH.


Peripheral insulin parallels changes in insulin secretion more closely than C-peptide after bolus intravenous glucose administration.
The changes in peripheral serum insulin and plasma C-peptide levels and in the insulin secretory rate in response to iv glucose (0.5 g/kg BW) administration were studied in seven normal subjects. Insulin secretory rates were calculated according to a two-compartment model of distribution for C-peptide, using individual C-peptide kinetics calculated from iv bolus injections of biosynthetic human C-peptide. The mean plasma glucose level increased from a fasting level of 5.1 +/- 0.1 (+/- SE) to a peak of 24.0 +/- 1.0 mmol/L at 3 min and reached basal levels 101 +/- 6 min after glucose administration. The mean serum insulin value increased from 50 +/- 12 to a peak of 405 +/- 58 pmol/L at 3 min and then declined to fasting levels 139 +/- 14 min after the stimulus. In contrast, the mean plasma C-peptide level increased from 390 +/- 50 to a peak of 1460 +/- 210 pmol/L at 3 min and only began declining 45 min after glucose administration, reaching fasting levels 191 +/- 15 min after the stimulus. The mean insulin secretory rate increased from 69.8 +/- 19.9 to a peak of 1412.7 +/- 159.1 pmol/min at 3 min (15.3 +/- 2.5-fold elevation over baseline) and reached basal levels 135 +/- 12 min after the stimulus. The clearance of endogenous insulin during the basal period (2.505 +/- 0.365 L/min) and that during the 4 h after the stimulus (2.319 +/- 0.230 L/min) were similar. In conclusion, after bolus iv glucose administration: 1) the insulin secretory rate is more closely represented by changes in peripheral serum insulin than in plasma C-peptide levels; and 2) no change in endogenous insulin clearance occurs.


An enzyme-sensitive PEG hydrogel based on aggrecan catabolism for cartilage tissue engineering.
A new cartilage-specific degradable hydrogel based on photoclickable thiol-ene poly(ethylene glycol) (PEG) hydrogels is presented. The hydrogel crosslinks are composed of the peptide, CRDTEGE-ARGSVIDRC, derived from the aggrecanase-cleavable site in aggrecan. This new hydrogel is evaluated for use in cartilage tissue engineering by encapsulating bovine chondrocytes from different cell sources (skeletally immature (juvenile) and mature (adult) donors and adult cells stimulated with proinflammatory lipopolysaccharide (LPS)) and culturing for 12 weeks. Regardless of cell source, a twofold decrease in compressive modulus is observed by 12 weeks, but without significant hydrogel swelling indicating limited bulk degradation. For juvenile cells, a connected matrix rich in aggrecan and collagen II, but minimal collagens I and X is observed. For adult cells, less matrix, but similar quality, is deposited. Aggrecanase activity is elevated, although without accelerating bulk hydrogel degradation. LPS further decreases matrix production, but does not affect aggrecanase activity. In contrast, matrix deposition in the nondegradable hydrogels consists of aggrecan and collagens I, II, and X, indicative of hypertrophic cartilage. Lastly, no inflammatory response in chondrocytes is observed by the aggrecanase-sensitive hydrogels. Overall, it is demonstrated that this new aggrecanase-sensitive hydrogel, which is degradable by chondrocytes and promotes a hyaline-like engineered cartilage, is promising for cartilage regeneration.


[Mucoviscidosis discovered after the age of 25 years. Review and follow-up of cases of the literature].
We report a case of cystic fibrosis diagnosed in a 27-year-old man complaining of diarrhoea which was present for 2 years. The diagnosis was suspected upon the association of exocrine pancreatic insufficiency, massive hepatic steatosis, pulmonary infiltrates on chest radiograph, and moderate alterations of pulmonary function tests. It was confirmed by positive sweat tests. Study of the cystic fibrosis gene demonstrated a compound heterozygosity for delta F508 deletion and for mutation W1282X. Diagnosis of cystic fibrosis after the age of 25 is a rare event and the 25 hitherto published case reports are analysed after obtention of more detailed information for the authors. The existence of cases of late diagnosis might be explained by genetic heterogeneity.


Biological Effects of Nanoparticles on Macrophage Polarization in the Tumor Microenvironment.
Biological interactions between tumor-associated macrophages (TAMs), cancer cells and other cells within the tumor microenvironment contribute to tumorigenesis, tumor growth, metastasis and therapeutic resistance. TAMs can remodel the tumor microenvironment to reduce growth barriers such as the dense extracellular matrix and shift tumors towards an immunosuppressive microenvironment that protects cancer cells from targeted immune responses. Nanoparticles can interrupt these biological interactions within tumors by altering TAM phenotypes through a process called polarization. Macrophage polarization within tumors can shift TAMs from a growth-promoting phenotype towards a cancer cell-killing phenotype that predicts treatment efficacy. Because many types of nanoparticles have been shown to preferentially accumulate within macrophages following systemic administration, there is considerable interest in identifying nanoparticle effects on TAM polarization, evaluating nanoparticle-induced TAM polarization effects on cancer treatment using drug-loaded nanoparticles and identifying beneficial types of nanoparticles for effective cancer treatment. In this review, the macrophage polarization effects of nanoparticles will be described based on their primary chemical composition. Because of their strong macrophage-polarizing and antitumor effects compared to other types of nanoparticles, the effects of iron oxide nanoparticles on macrophages will be discussed in detail. By comparing the macrophage polarization effects of various nanoparticle treatments reported in the literature, this review aims to both elucidate nanoparticle material effects on macrophage polarization and to provide insight into engineering nanoparticles with more beneficial immunological responses for cancer treatment.


Freud-2/CC2D1B mediates dual repression of the serotonin-1A receptor gene.
The serotonin-1A (5-HT1A) receptor functions as a pre-synaptic autoreceptor in serotonin neurons that regulates their activity, and is also widely expressed on non-serotonergic neurons as a post-synaptic heteroreceptor to mediate serotonin action. The 5-HT1A receptor gene is strongly repressed by a dual repressor element (DRE), which is recognized by two proteins: Freud-1/CC2D1A and another unknown protein. Here we identify mouse Freud-2/CC2D1B as the second repressor of the 5-HT1A-DRE. Freud-2 shares 50% amino acid identity with Freud-1, and contains conserved structural domains. Mouse Freud-2 bound specifically to the rat 5-HT1A-DRE adjacent to, and partially overlapping, the Freud-1 binding site. By supershift assay using nuclear extracts from L6 myoblasts, Freud-2-DRE complexes were distinguished from Freud-1-DRE complexes. Freud-2 mRNA and protein were detected throughout mouse brain and peripheral tissues. Freud-2 repressed 5-HT1A promoter-reporter constructs in a DRE-dependent manner in non-neuronal (L6) or 5-HT1A-expressing neuronal (NG108-15, RN46A) cell models. In NG108-15 cells, knockdown of Freud-2 using a specific short-interfering RNA reduced endogenous Freud-2 protein levels and decreased Freud-2 bound to the 5-HT1A-DRE as detected by chromatin immunoprecipitation assay, but increased 5-HT1A promoter activity and 5-HT1A protein levels. Taken together, these data show that Freud-2 is the second component that, with Freud-1, mediates dual repression of the 5-HT1A receptor gene at the DRE.


A Demonstration of the Uncertainty in Predicting the Estrogenic Activity of Individual Chemicals and Mixtures From an In Vitro Estrogen Receptor Transcriptional Activation Assay (T47D-KBluc) to the In Vivo Uterotrophic Assay Using Oral Exposure.
In vitro estrogen receptor assays are valuable tools for identifying environmental samples and chemicals that display estrogenic activity. However, in vitro potency cannot necessarily be extrapolated to estimates of in vivo potency because in vitro assays are currently unable to fully account for absorption, distribution, metabolism, and excretion. To explore this issue, we calculated relative potency factors (RPF), using 17α-ethinyl estradiol (EE2) as the reference compound, for several chemicals and mixtures in the T47D-KBluc estrogen receptor transactivation assay. In vitro RPFs were used to predict rat oral uterotrophic assay responses for these chemicals and mixtures. EE2, 17β-estradiol (E2), benzyl-butyl phthalate (BBP), bisphenol-A (BPA), bisphenol-AF (BPAF), bisphenol-C (BPC), bisphenol-S (BPS), and methoxychlor (MET) were tested individually, while BPS + MET, BPAF + MET, and BPAF + BPC + BPS + EE2 + MET were tested as equipotent mixtures. In vivo ED50 values for BPA, BPAF, and BPC were accurately predicted using in vitro data; however, E2 was less potent than predicted, BBP was a false positive, and BPS and MET were 76.6 and 368.3-fold more active in vivo than predicted from the in vitro potency, respectively. Further, mixture ED50 values were more accurately predicted by the dose addition model using individual chemical in vivo uterotrophic data (0.7-1.5-fold difference from observed) than in vitro data (1.4-86.8-fold). Overall, these data illustrate the potential for both underestimating and overestimating in vivo potency from predictions made with in vitro data for compounds that undergo substantial disposition following oral administration. Accounting for aspects of toxicokinetics, notably metabolism, in in vitro models will be necessary for accurate in vitro-to-in vivo extrapolations.


Total synthesis of (-)-serotobenine.
The efficient total synthesis of (-)-serotobenine (1) has been achieved by constructing an optically active dihydrobenzofuran ring via a rhodium carbenoid mediated intramolecular C-H insertion reaction, which was developed by our group. Then the possibility of racemization of 1 was investigated using optically active synthetic 1.


GRASP: guided reference-based assembly of short peptides.
Protein sequences predicted from metagenomic datasets are annotated by identifying their homologs via sequence comparisons with reference or curated proteins. However, a majority of metagenomic protein sequences are partial-length, arising as a result of identifying genes on sequencing reads or on assembled nucleotide contigs, which themselves are often very fragmented. The fragmented nature of metagenomic protein predictions adversely impacts homology detection and, therefore, the quality of the overall annotation of the dataset. Here we present a novel algorithm called GRASP that accurately identifies the homologs of a given reference protein sequence from a database consisting of partial-length metagenomic proteins. Our homology detection strategy is guided by the reference sequence, and involves the simultaneous search and assembly of overlapping database sequences. GRASP was compared to three commonly used protein sequence search programs (BLASTP, PSI-BLAST and FASTM). Our evaluations using several simulated and real datasets show that GRASP has a significantly higher sensitivity than these programs while maintaining a very high specificity. GRASP can be a very useful program for detecting and quantifying taxonomic and protein family abundances in metagenomic datasets. GRASP is implemented in GNU C++, and is freely available at http://sourceforge.net/projects/grasp-release.


The impact of a pharmacist-led educational interview on medication adherence of Saudi patients with epilepsy.
To evaluate the effectiveness of a pharmacist-led educational interview in terms of adherence to antiepileptic drug administration among adult patients with epilepsy. Sixty adult patients with epilepsy who fulfilled the inclusion criteria were recruited. A pharmacist-led educational interview was conducted with the intervention group (n=30). Patients in the control group (n=30) were interviewed and contacted 6 weeks after the initial visit without receiving any intervention. Antiepileptic drug adherence was measured during clinic visits, and 6 weeks afterwards using the 8-item Morisky Medication Adherence Scale. This prospective interventional study was conducted between September and December 2013. Only 29 control patients and 27 intervention patients completed the 6 weeks post-intervention adherence measurement. The adherence score average in the intervention group was 5.26±0.98 at baseline and improved to 6.7±0.823 (P<0.0001) after intervention. In the control group, the adherence score average was 5.76±1.806 at baseline and 5.83±1.627 at 6 weeks (P=0.792). While there was no statistically significant difference in adherence score between intervention and control groups at baseline, the post-intervention difference was significant (P=0.024). Our study suggests that pharmacist-led educational interviews had a positive impact on medication adherence in patients with epilepsy.


[Only used unilateral transnasal approach applied endoscopic sinus surgery for pituitary adenomas].
Endoscope-assisted transnasal approach (TNA) for pituitary adenoma is a new alternative for Hardy's surgery (TSS). We performed TNA using only an endoscope through unilateral nostril. In our approach to sphenoid sinus, we apply method of endoscopic sinus surgery (ESS-TNA). We enter the sphenoid sinus directly through the natural ostium and do not brake the nasal septum nor vomer bone. Since September 2004 we had operated on 12 patients by endoscopic TNA. Six were non-functioning adenomas, and 6 were functioning adenomas. We are first to open the ethomoid sinus to make the space for middle concha to be displaced laterally. Secondary, we widen the natural ostium of the sphenoid sinus, retracting the middle concha laterally. The results were compared with those in 10 cases by TSS operated in our institute. Adenoma removal more than 80% was achieved in 58% by endoscopic TNA whereas in 50% by TSS. We had no case with postsurgical infection. Transient DI occurred in 4 cases and 1 case showed permanent. CSF rhinorrhea was seen in the case having small empty sellae in front of adenoma. For this case, we packed the fat tissue at the floor of the sella with endoscope under local anesthesia to close the fistula. Three cases that had hemianopsia before surgery showed the recovery postoperatively. In 6 functional adenoma, postoperative endocrinological examinations showed normalization in 3 cases and improvements in 3 cases. Postsurgical hospitalization days were 11.4 by endoscopic TNA whereas 15.4 by TSS. Our method showed same or better results than TSS in the removal rate and complication rate whereas the postoperative duration of nasal packing and hospitalization days were shorter than TSS.


MicroRNA expression profiles in human CD3+ T cells following stimulation with anti-human CD3 antibodies.
Anti-CD3 therapy can induce immunosuppression by several non mutually exclusive mechanisms that have been proposed to explain the therapeutic effect the administration anti-CD3 mAb, but its immunoregulatory mechanism is still not completely clear. In T cells, microRNAs (miRNAs) regulate several pathways, including those associated with immune tolerance. Here, we report changes in miRNA expression in T cells following treatment with anti-human CD3 antibodies. Peripheral blood mononuclear cells were cultured in the presence of the monoclonal antibody OKT3 or a recombinant fragment of humanized anti-CD3. Following these treatments, the expression profiles of 31 miRNA species were assessed in T cells using TaqMan arrays. Eight of the tested miRNAs (miR-155, miR-21, miR-146a, miR-210, miR-17, miR-590-5p, miR-106b and miR-301a) were statistically significantly up- or down-regulated relative to untreated cells. Stimulation of T cells with anti-human CD3 antibodies alters miRNA expression patterns, including of miRNA species associated with immune regulatory pathways.


PIWI-Interacting RNA-004800 Is Regulated by S1P Receptor Signaling Pathway to Keep Myeloma Cell Survival.
PIWI-interacting RNA (piRNA) is a kind of non-coding single stranded RNA which plays major roles in epigenetic expressions, genome rearrangement, and regulation of gene and protein. Because piRNAs are abnormally expressed in various cancers, they can be used as novel biomarkers and therapeutic targets. However, the roles of piRNAs in cancer cell growth and survival are not well-known. Here, we are the first to provide evidence that PIWI-interacting RNA-004800 (piR-004800) is overexpressed in both exosomes from multiple myeloma (MM) patients' bone marrow supernatant and primary MM cells. The expression level of piR-004800 is positively correlated with the stages of MM, according to the international staging system (ISS). In MM cell lines, downregulation of piR-004800 induced apoptosis and autophagic cell death. This was accompanied by in vitro and in vivo inhibition of cell proliferation. Our previous study shows that sphingosine-1-phosphate receptor (S1PR) signaling pathway plays a crucial part in MM cell proliferation. In this study, we find that S1PR signaling pathway can regulate the PI3K/Akt/mTOR pathway through control of piR-004800 expressions. Taken together our data supports an oncogenic role for piR-004800 in MM, which sheds insight into a new mechanism that may lead to therapeutic targets in MM, an incurable plasma cell neoplasm.


Telomerase-Mediated Self-Assembly of DNA Network in Cancer Cells Enabling Mitochondrial Interference.
The precise control of the artificially induced reactions inside living cells is emerging as an effective strategy for the regulation of cell functions. Nevertheless, the manipulation of the assembly of exogenous molecules into artificial architectures in response to intracellular-specific signals remains a grand challenge. Herein, we achieve the precise self-assembly of deoxyribonucleic acid (DNA) network inside cancer cells, specifically responding to telomerase, and realize effective mitochondrial interference and the consequent regulation of cellular behaviors. Two functional DNA modules were designed: a mitochondria-targeting branched DNA and a telomerase-responsive linear DNA. Upon uptake by cancer cells, the telomerase primer in linear DNA responded to telomerase, and a strand displacement reaction was triggered by the reverse transcription of telomerase, thus releasing a linker DNA from the linear DNA. The linker DNA afterward hybridized with the branched DNA to form a DNA network on mitochondria. The DNA network interfered with the function of mitochondria, realizing the apoptosis of cancer cells. This system was further administered in a nude mouse tumor model, showing remarkable suppression of tumor growth. We envision that the telomerase-mediated intracellular self-assembly of the DNA network provides a promising route for cancer therapy.


Assessment of frequency specific auditory steady-state response using amplitude modulation with 2-order exponential envelope.
This study investigated the performance of Frequency Specific Auditory Steady-State Response (FS-ASSR) detection elicited by the amplitude modulated tone with 2-order exponential envelope (AM2), using objective response detection (ORD) techniques of Spectral F-Test (SFT) and Magnitude Squared Coherence (MSC). ASSRs from 24 normal hearing adults were obtained during binaural multi-tone stimulation of amplitude-modulation (AM) and AM2 at intensities of 60, 45 and 30 dBSPL. The carrier frequencies were 500, 1000, 2000, and 4000 Hz, modulated between 77 and 105 Hz. AM2 achieve FS-ASSR amplitudes higher than AM by 16%, 18% and 12% at 60, 45 and 30 dBSPL, respectively, with a major increase at 500 Hz (22.5%). AMS2PL increased the Detection Rate (DR) up to 8.3% at 500 Hz for 30 dBSPL, which is particularly beneficial for FS-ASSR detection near the hearing threshold. In addition, responses in 1000 and 4000 Hz were consistently increased. The MSC and SFT presented no differences in Detection Rate (DR). False Detection Rate (FDR) was close to 5% for both techniques and tones. Detection times to reach DR over 90% were 3.5 and 4.9 min at 60 and 45 dBSPL, respectively. Further investigation concerning efficient multiple FS-ASSR is still necessary, such as testing subjects with hearing loss.


Systemic immunosuppression fails to suppress cardiac cytokine induction in pressure overload hypertrophy in rats.
Activation of cytokines such as interleukin-6 (IL-6) has been implicated in the pathogenesis of left ventricular dysfunction and hypertrophy since they have been shown to mediate cell proliferation, negative inotropic effects and myocardial hypertrophy. However, the effects of immunosuppressive therapy on cytokines in the treatment of heart failure and hypertrophy are unclear. To test the hypothesis that systemic immunosuppresion may influence serum and myocardial IL-6 and, thereby, may affect progression of myocardial hypertrophy. We studied the effects of chronic treatment with methotrexate (MTx) and with the ACE inhibitor ramipril on IL-6 in rats with pressure overload left ventricular hypertrophy (LVH) due to aortic banding. Animals were treated with either vehicle (n = 6) or methotrexate (MTx 1: 0.3 mg/kg BW/week; MTx 2: 0.9 mg/kg BW/week; i.p.; n = 6 each group) once a week during weeks 4-12 after aortic banding; sham-operated rats served as controls (CTRL; n = 8). During the development of LVH, serum IL-6 was determined by rat-specific ELISA and 12 weeks after aortic banding myocardial IL-6 was measured using a tissue superfusion technique or determining of protein concentration. Aortic banding significantly lowered blood pressure, increased left ventricular weight and resulted in elevated serum IL-6 levels (27.6 +/- 5.1 vs 19.1 +/- 2.3 pg/ml, p < 0.05) compared to CTRL. MTx treatment normalised the initially elevated serum IL-6 levels after 8 weeks of treatment. The significant increase in IL-6 concentration in the superfusate of all aortic banding groups compared to CTRL (< 30%, p < 0.05) was not altered by prior MTx therapy. Accordingly, both doses of MTx failed to prevent LVH progression (1.67 +/- 0.23 g vs. 2.32 +/- 0.31 g, p < 0.05). In contrast, chronic inhibition of the RAAS not only prevents LVH but also reduces myocardial IL-6 concentration (6898 +/- 355 vs. 3073 +/- 366 pg/mg protein, p < 0.05). Pressure overload LVH in rats is characterized by an increase in serum levels of IL-6 as well as myocardial IL-6. Chronic immunosuppressive therapy normalized systemic IL-6 levels, but failed to reduce cardiac IL-6 expression and the progression of LVH, while ACE inhibition is sufficient to modify LVH and thereby normalises myocardial IL-6 expression.


Metabolic Rate and Perceived Exertion of Walking in Older Adults With Idiopathic Chronic Fatigue.
Fatigue is a common complaint in older adults, often not associated with underlying medical conditions. The purpose of this study was to investigate metabolic rate (MR) of walking, walking performance, and perception-based exertion during walking in older adults with and without idiopathic chronic fatigue (ICF). 20 older adults (aged 70.8±4.9 years), reporting 2 SD above normative values of the Functional Assessment of Chronic Illness Therapy-Fatigue scale and without overt health conditions that explained their symptoms, were compared with 25 age-matched older adults (73.2±5.1 years) without fatigue symptoms. Participants walked 400 m at a rapid pace on a 20-m course. On a separate visit, oxygen consumption was measured during treadmill test at standard (40.2 m/min), preferred paces (40-83 m/min) and peak capacity. Ratings of perceived exertion (RPE) were measured at each treadmill stage and after each lap of the 400-m walk test. During the 400-m walk test, individuals with ICF showed lower overall walking speed and reported a steady increase in RPE with no change observed in non-fatigued group (1.63±1.72 vs 0.27±0.68, p < .01). Similar findings on RPE were noted on treadmill test. Gross MR, mass-specific MR, mass-specific net MR, and MR as a percent of peak oxygen consumption of walking were similar between groups during standard, preferred paces and peak capacity on treadmill. This study suggests that ICF in older adults is not related to elevated metabolic cost of walking. Higher RPE without concomitant decreases in performance indicate a potential disconnect between metabolic output and sensations during movement.


Genotype of DNA double-strand break repair gene XRCC7 is associated with lung cancer risk in Taiwan males and smokers.
The present study aimed to evaluate the contribution of X-ray repair cross-complementing group 7 (XRCC7) G6721T (rs7003908) genetic polymorphism and smoking habit on the risk of lung cancer in Taiwanese. In this hospital-based case-control study, association of single nucleotide polymorphism XRCC7 G6721T with lung cancer risk were examined among 358 patients with lung cancer and 716 age- and gender-matched healthy controls. The genetic-lifestyle interaction was also investigated. The results showed that the percentages of TT, GT and GG genotypes for XRCC7 G6721T were differentially distributed as 60.9%, 34.9% and 4.2% in the group of patients with lung cancer and 48.7%, 43.3% and 8.0% in the non-cancer control group, respectively (p=3.6*10(-7)). We further stratified the populations by gender and smoking behavior to investigate their combinatorial effects with XRCC7 G6721T genotype on lung cancer risk. The results showed that the GG genotype of XRCC7 G6721T had a protective effect on lung cancer susceptibility which was obvious among males and smokers (p=2.2×10(-4) and 3.1×10(-4), respectively). The GG and GT genotypes of XRCC7 rs7003908 compared to the TT genotype had a protective effect on lung cancer risk in Taiwan, particularly among males and smokers.


Ripretinib induced skeletal muscle toxicity through mitochondrial impairment in C2C12 myotubes.
Ripretinib is a multikinase inhibitor drug approved in 2020 by the FDA and in 2021 by EMA for use in the treatment of advanced gastrointestinal stromal tumors (GIST) which have not adequately responded to previous treatments with kinase inhibitors. The most common side effects of the drug are myalgia and fatigue, which likely causes interruption of the treatment or reduction of the dose. Skeletal muscle cells highly depend on ATP to perform their functions and mitochondrial damage may play a role in skeletal muscle toxicity induced by kinase inhibitors. However, the molecular mechanism has not been clearly identified in the literature yet. In this study, it has been aimed to elucidate the role of mitochondria in the toxic effect of ripretinib on skeletal muscle using the mouse C2C12 myoblast-derived myotubes. The myotubes were exposed to ripretinib at the range of 1-20 μM concentrations for 24 h. To determine the potential role of mitochondrial impairment in ripretinib-induced skeletal muscle toxicity, intracellular ATP level, mitochondrial membrane potential (MMP), mitochondrial ROS production (mtROS), mitochondrial DNA (mtDNA) copy number, and mitochondrial mass were examined after ripretinib treatment. Furthermore, changes in PGC 1α/NRF 1/NRF 2 expression levels that play a role in mitochondrial biogenesis and mitophagy were investigated. Additionally, the mitochondrial electron transport chain (ETC) enzyme activities were evaluated. Lastly, a molecular docking study was done to see ripretinib's possible interaction with DNA polymerase gamma (POLG) which is important for DNA replication in the mitochondria. According to the findings, ripretinib decreases the ATP level and mtDNA copy number, induces loss of MMP, and reduces mitochondrial mass. The activities of the ETC complexes were inhibited with ripretinib exposure which is in line with the observed ATP depletion and MMP loss. The molecular docking study revealed that ripretinib has inhibitory potential against POLG which supports the observed inhibition of mtDNA. The expression of PGC 1α was reduced in the nuclear fraction indicating that PGC-1α was not activated since the NRF 1 expression was reduced and NRF 2 level did not show significant change. Consequently, mtROS production increased in all treatment groups and mitophagy-related gene expressions and Parkin protein expression level were up-regulated at high doses. In conclusion, mitochondrial damage/loss can be one of the underlying causes of ripretinib-induced skeletal muscle toxicity. However, further studies are needed to confirm the results in vivo.


Observations on the management of failed spinal operations.
A system is presented for the analysis of failure after spinal operations: 1) outright failure; 2) temporary relief; 3) failure in spondylolisthesis; and 4) infections. With this system it is possible to trace the causes of failure and to correct some of them. When they are used as a guide before operation, the recommendations made should help to prevent many failures.


Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families.
Signaling pathway modules are often encoded by several closely related paralogous genes that can have redundant roles and are therefore difficult to analyze by loss-of-function analysis. A typical example is the Wnt signaling pathway, which in mammals is mediated by 19 Wnt ligands that can bind to 10 Frizzled (FZD) receptors. Although significant progress in understanding Wnt-FZD receptor interactions has been made in recent years, tools to generate systematic interaction maps have been largely lacking. Here we generated cell lines with multiplex mutant alleles of FZD1, FZD2, and FZD7 and demonstrate that these cells are unresponsive to canonical Wnt ligands. Subsequently, we performed genetic rescue experiments with combinations of FZDs and canonical Wnts to create a functional ligand-receptor interaction map. These experiments showed that whereas several Wnt ligands, such as Wnt3a, induce signaling through a broad spectrum of FZD receptors, others, such as Wnt8a, act through a restricted set of FZD genes. Together, our results map functional interactions of FZDs and 10 Wnt ligands and demonstrate how multiplex targeting by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 can be used to systematically elucidate the functions of multigene families.-Voloshanenko, O., Gmach, P., Winter, J., Kranz, D., Boutros, M. Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families.


Zn-alpha 2-glycoprotein levels in breast cancer cytosols and correlation with clinical, histological and biochemical parameters.
Zn-alpha 2-glycoprotein (Zn-alpha 2-gp), a protein present at high levels in breast cyst fluid, has been measured in 104 breast tumour cytosols by using an immunoenzymatic assay. Concentrations of Zn-alpha 2-gp ranged from 0 to 23.5 micrograms/mg of total soluble protein, with an average value of 2.4 micrograms/mg. There was no significant correlation between Zn-alpha 2-gp and menopausal status, tumour size or lymph node involvement, or between this protein and biochemical parameters such as oestrogen receptor, cathepsin D or pS2 levels. However, there was a significant association between Zn-alpha 2-gp and histological grade of tumours, with higher Zn-alpha 2-gp levels in well-differentiated tumours (mean 4.6 micrograms/mg) than in moderately (1.8 micrograms/mg) or poorly (0.9 micrograms/mg) differentiated tumours. On the basis of these results, we propose that Zn-alpha 2-gp may be considered as a biochemical marker of differentiation in breast cancer.


Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4μ8C.
Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4μ8C, was originally known as an inositol-requiring enzyme 1 (IRE1) suppressant, but no study has examined its relationship with mast cells and allergic diseases. Therefore, the purpose of this study was to determine whether 4μ8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4μ8C suppressed the degranulation of IgE-mediated mast cells (IC50=3.2μM) and the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) in a dose-dependent manner. 4μ8C also suppressed passive cutaneous anaphylaxis (PCA) in mice (ED50=25.1mg/kg). In an experiment on mast cell signaling pathways stimulated by antigen, the phosphorylation and activation of Syk was decreased by 4μ8C, and phosphorylation of downstream signaling molecules, such as linker for activated T cells (LAT), Akt, and the three MAP kinases, ERK, p38, and JNK, were suppressed. Mechanistic studies showed that 4μ8C inhibited the activity of Lyn and Fyn in vitro. Based on the results of those experiments, the suppressor mechanism of allergic reaction by 4μ8C involved reduced activity of Lyn and Fyn, which is pivotal in an IgE-mediated signaling pathway. In summary, for the first time, this study shows that 4μ8C inhibits Lyn and Fyn, thus suppressing allergic reaction by reducing the degranulation and the production of inflammatory cytokines. This suggests that 4μ8C can be used as a new medicinal candidate to control allergic diseases such as seasonal allergies and atopic dermatitis.


Expression of multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), lung resistance protein (LRP), and breast cancer resistance protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia.
The aim of this prospective study was to analyze the expression of messenger RNA of genes, such as MDR1, MRP1, BCRP, and LRP, implicated in the mechanism of multidrug resistance (MDR) in relation to the response to induction chemotherapy and relapse and these genes' correlation with each other and with pretreatment laboratory and clinical characteristics. We prospectively studied 49 children (26 boys and 23 girls) with acute lymphoblastic leukemia (ALL) (median age, 5.5 years; range, 15 months to 12.5 years) who were treated with the BFM95 chemotherapy protocol. We used bone marrow mononuclear cells from 7 healthy children as controls. The expression of MDR genes and the beta-actin housekeeping gene was detected by the reverse transcription-polymerase chain reaction with the appropriate primers. The mean expression of each MDR gene was significantly higher in the patients than in the control group (P < .01). We found statistically significant correlations between MRP1 and LRP expression and between MRP1 or LRP expression and MDR1 expression (P < .05). High expression for the MDR1 gene was found in 18 patients (36.7%), and their prognoses were significantly worse than those with low expression (event-free survival, 55.56% versus 86.67%; P = .03, log-rank test). Expression of each of the MDR genes was independent of the initial white blood cell count, immunophenotype, National Cancer Institute risk classification, and prednisone response. Interestingly, MDR1 expression was significantly higher at relapse than at diagnosis for 4 sample pairs. Evaluation of MDR1 expression at diagnosis of childhood ALL may contribute to the early identification of patients at risk of treatment failure.


Relationship of Event-Related Potentials to the Vigilance Decrement.
Cognitive fatigue emerges in wide-ranging tasks and domains, but traditional vigilance tasks provide a well-studied context in which to explore the mechanisms underlying it. Though a variety of experimental methodologies have been used to investigate cognitive fatigue in vigilance, relatively little research has utilized electroencephalography (EEG), specifically event-related potentials (ERPs), to explore the nature of cognitive fatigue, also known as the vigilance decrement. Moreover, much of the research that has been done on vigilance and ERPs uses non-traditional vigilance paradigms, limiting generalizability to the established body of behavioral results and corresponding theories. In this study, we address concerns with prior research by (1) investigating the vigilance decrement using a well-established visual vigilance task, (2) utilizing a task designed to attenuate possible confounding ERP components present within a vigilance paradigm, and (3) informing our interpretations with recent findings from ERP research. We averaged data across electrodes located over the frontal, central, and parietal scalp. Then, we generated waveforms locked to the onset of critical low-frequency or non-critical high-frequency events during a 40 min task that was segregated into time blocks for data analysis. There were three primary findings from the analyses of these data. First, mean amplitude of N1 was greater during later blocks for both low-frequency and high-frequency events, a contradictory finding compared to past visual vigilance studies that is further discussed with respect to current interpretations of the N1 in visual attention tasks. Second, P3b mean amplitude following low-frequency events was reduced during later blocks, with a later onset latency. Third and finally, the decrease in P3b amplitude correlated with individual differences in the magnitude of the vigilance decrement, assessed using d'. The results provide evidence for degradations of cognitive processing efficiency brought on by extended time on task, leading to delayed processing and decreased discriminability of critical stimuli from non-critical stimuli. These conclusions are discussed in the context of the vigilance decrement and corresponding theoretical accounts.


Sialadenitis following I-131 therapy for thyroid carcinoma: concise communication.
During a 4-yr period, ten of 87 patients (11.5%) who received therapeutic doses of radioactive iodine (I-131) for thyroid carcinoma developed acute and/or chronic sialadenitis involving the parotid (five patients) or submandibular (four patients) glands, or both (one patient). Nine of the 10 patients had received prior I-131 therapy; the precipitating I-131 dose varied between 10 and 164 mCi. Onset of symptoms occurred between 1 day and 6 mo following therapy and the duration varied from 3 wk to 21/2 yr. This complication occurs more often than has been appreciated.


Dmrt1 expression in response to estrogen treatment in a reptile with temperature-dependent sex determination.
Dmrt1 has been implicated as an important factor in sex determination in all classes of vertebrates, including reptiles with temperature-dependent sex determination (TSD). Specifically, early embryonic expression of Dmrt1 appears to be an integral part of normal testicular development in vertebrates. Recently, a number of TSD studies have placed Dmrt1 expression at the top of a short list of putative temperature-sensitive events for TSD. Dmrt1 expression has been shown to be up-regulated at male-producing temperatures during the thermosensitive period (TSP) of several TSD reptile species. An interesting finding in Dmrt1 studies of fish and amphibians has been that in species where exogenous steroids can stimulate sex reversal, Dmrt1 expression can also be manipulated by these steroid treatments. In the current study, we examine the effects of exogenous 17beta-estradiol treatment on Dmrt1 expression at male-producing temperature (26 degrees C) in a reptile with TSD, the red-eared slider turtle, Trachemys scripta. Previous studies have demonstrated that exogenous estrogens can stimulate sex reversal (at male-producing temperatures) in this species of turtle. In the current study, T. scripta embryos that received estradiol treatment displayed a significant decrease in Dmrt1 expression during the TSP, while embryos in the control group (no estradiol treatment) showed significant increases in Dmrt1 expression during the TSP. Furthermore, the pattern of Dmrt1 expression for the estradiol-treated group was similar to the pattern we previously reported for Dmrt1 at female-producing temperature (31 degrees C). These findings indicate that exogenous estrogen is acting at or before the Dmrt1 event in the sex determination/sex differentiation cascade of T. scripta. Further, the results are consistent with the hypothesis that exogenous estrogen could be exerting its feminizing effect by down-regulating the expression of Dmrt1.


Transmission Line-Planning Method Based on Adaptive Resolution Grid and Improved Dijkstra Algorithm.
An improved Dijkstra algorithm based on adaptive resolution grid (ARG) is proposed to assist manual transmission line planning, shorten the construction period and achieve lower cost and higher efficiency of line selection. Firstly, the semantic segmentation network is used to change the remote sensing image into a ground object-identification image and the grayscale image of the ground object-identification image is rasterized. The ARG map model is introduced to greatly reduce the number of redundant grids, which can effectively reduce the time required to traverse the grids. Then, the Dijkstra algorithm is combined with the ARG and the neighborhood structure of the grid is a multi-center neighborhood. An improved method of bidirectional search mechanism based on ARG and inflection point-correction is adopted to greatly increase the running speed. The inflection point-correction reduces the number of inflection points and reduces the cost. Finally, according to the results of the search, the lowest-cost transmission line is determined. The experimental results show that this method aids manual planning by providing a route for reference, improving planning efficiency while shortening the duration, and reducing the time spent on algorithm debugging. Compared with the comparison algorithm, this method is faster in running speed and better in cost saving and has a broader application prospect.


A copula-based set-variant association test for bivariate continuous, binary or mixed phenotypes.
In genome wide association studies (GWAS), researchers are often dealing with dichotomous and non-normally distributed traits, or a mixture of discrete-continuous traits. However, most of the current region-based methods rely on multivariate linear mixed models (mvLMMs) and assume a multivariate normal distribution for the phenotypes of interest. Hence, these methods are not applicable to disease or non-normally distributed traits. Therefore, there is a need to develop unified and flexible methods to study association between a set of (possibly rare) genetic variants and non-normal multivariate phenotypes. Copulas are multivariate distribution functions with uniform margins on the [0, 1] interval and they provide suitable models to deal with non-normality of errors in multivariate association studies. We propose a novel unified and flexible copula-based multivariate association test (CBMAT) for discovering association between a genetic region and a bivariate continuous, binary or mixed phenotype. We also derive a data-driven analytic p-value procedure of the proposed region-based score-type test. Through simulation studies, we demonstrate that CBMAT has well controlled type I error rates and higher power to detect associations compared with other existing methods, for discrete and non-normally distributed traits. At last, we apply CBMAT to detect the association between two genes located on chromosome 11 and several lipid levels measured on 1477 subjects from the ASLPAC study.


Risk assessment, fitness cost, cross-resistance, and mechanism of tetraniliprole resistance in the rice stem borer, Chilo suppressalis.
The rice stem borer (RSB), Chilo suppressalis, a notorious rice pest in China, has evolved a high resistance level to commonly used insecticides. Tetraniliprole, a new anthranilic diamide insecticide, effectively controls multiple pests, including RSB. However, the potential resistance risk of RSB to tetraniliprole is still unknown. In this study, the tetraniliprole-selection (Tet-R) strain was obtained through 10 continuous generations of selection with tetraniliprole 30% lethal concentration (LC30 ). The realized heritability (h2 ) of the Tet-R strain was 0.387, indicating that resistance of RSB to tetraniliprole developed rapidly under the continuous selection of tetraniliprole. The Tet-R strain had a high fitness cost (relative fitness = 0.53). We established the susceptibility baseline of RSB to tetraniliprole (lethal concentration at LC50 = 0.727 mg/L) and investigated the resistance level of 6 field populations to tetraniliprole. All tested strains that had resistance to chlorantraniliprole exhibited moderate- to high-level resistance to tetraniliprole (resistance ratio = 27.7-806.8). Detection of ryanodine receptor (RyR) mutations showed that the Y4667C, Y4667D, I4758M, and Y4891F mutations were present in tested RSB field populations. RyR mutations were responsible for the cross-resistance between tetraniliprole and chlorantraniliprole. Further, the clustered regularly interspaced palindromic repeats (CRISPR) / CRISPR-associated protein 9-mediated genome-modified flies were used to study the contribution of RyR mutations to tetraniliprole resistance. The order of contribution of a single RyR mutation to tetraniliprole resistance was Y4667D > G4915E > Y4667C ≈ I4758M > Y4891F. In addition, the I4758M and Y4667C double mutations conferred higher tetraniliprole resistance than single Y4667C mutations. These results can guide resistance management practices for diamides in RSB and other arthropods.


Blood and organ donation patterns of trauma surgeons.
Allogenic blood product transfusion and organ donation are critical components of modern medicine. However, only 5 per cent of the eligible population donate blood and only 53 per cent declare themselves organ donors. Trauma surgeons have an intimate exposure to these needs and their personal donation patterns may reflect this knowledge. A 14 question survey about personal blood and organ donation was sent to 635 members of the American Association for the Surgery of Trauma by e-mail. Seventy-eight per cent of respondents have donated blood and 86 per cent of those donors have done so repeatedly. However, 83 per cent of respondents have not given blood in the past year. Medical reasons were the most common reason cited for inability to donate (45%). With regard to organ donation, 90 per cent of respondents have filled out the organ donation section on their driver's license and 89 per cent have discussed organ donation with their family. The rates of blood and organ donation are higher than the rates of the general population. Trauma surgeons are likely to be blood and organ donors. Their intimate knowledge of the importance of donation plays a role. Personal medical conditions that restrict donation were, among respondents, a more common cause of failure to donate than were time constraints.


Use of ancrod in acute or progressing ischemic cerebral infarction.
Ancrod has been used in Europe for over 15 years for peripheral vascular disease, deep vein thrombosis, and central retinal venous thrombosis, and in patients at risk for thromboembolism. In a double-blind, randomized, placebo-controlled study at University Hospitals in Cincinnati, 20 acute cerebral infarction patients received a series of IV infusions of ancrod (ten) or placebo (ten) for seven days. Early fibrinolysis with a small decrease in fibrinogen was observed, and d-dimers were elevated at four hours, indicating early clot lysis. At three months, patients with moderate to severe strokes (less than 40 on the Scandinavian Stroke Scale) in the ancrod group showed average improvement by a factor of 3 over the placebo group. No bleeding, abnormal laboratory results, or deaths occurred, but ancrod was discontinued in one patient who had seizures. As a result of this study, a double-blind multicenter international clinical trial to further assess the safety and effectiveness of ancrod is being planned.


[Conservative treatment of elbow dislocations].
Ligamentous injuries following dislocations of the elbow joint are a primary indication for nonsurgical treatment. The principles of closed reduction are longitudinal traction of the forearm, followed by flexion. The period of immobilization in a plaster cast should be decided on an individual basis. For elbows that show no tendency to redislocate, immobilization for no more than 1 week should suffice. For elbows with a tendency to redislocate 2-3 weeks' immobilization is recommended. Radiological follow-up shows a high percentage of degenerative changes, i.e. subchondral sclerosis, osteophytosis, periarticular calcification, irregularities in the epicondyles. In addition to slight degenerative changes, there are few subjective complaints and functional impairments. Now evidence has been found to recommend primary surgical treatment of ligamentous injuries associated with dislocation of the elbow.


Investigation of the Effect of PEG Detoxification on Diphtheria Vaccine.
Immunization has been considered a successful global health program that saves many persons' lives each year. The vaccines reduce the risk of getting the disease by building immunity in the body. Therefore, the constant availability of essential vaccines is an important factor in community health. One of the most important vaccines is the diphtheria vaccine, which is usually used as Multivalent diphtheria-tetanus-pertussis (DTP) combination vaccines. The production of this vaccine takes about 45 days, from the initial bacterial culture to the end of toxin production. However, the production of this vaccine can be optimized in case the production stages are carried out under normal conditions. In this study, a significant amount of impurities was removed after washing with phosphate buffer saline, and the toxin was then purified by Sephadex G-50. In this method, the toxin was concentrated to be stored in a smaller space (this removes the concerns for the provision of a suitable space). Another problem with the diphtheria vaccine is that it is reversible after detoxification of the toxin using formaldehyde. For this reason, it is suggested to use MPEG for detoxification, which will produce more stable covalent bonds between PEG and the first type of amine groups in the toxin chain. Tests were performed to evaluate factors, such as in vivo cytotoxicity, lack of edemas formation, the neutralizing activity of serum from guinea pigs immunized with the diphtheria toxoid inactivated with MPEG, and the immunogenic activity of the purified and modified toxin. Comparison of this PEG detoxification toxoid with the standard toxoid produced in Razi Vaccine and Serum Institution, Karaj, Iran, showed that washing with PBS and purification with Sephadex G-50 was an efficient method. The stability and reversibility of the toxoid approved by MPEG were acceptable. Therefore, the results of animal tests showed that the obtained product was stable and caused no wound or necrosis in the tested animals.


[Cardioprotective effect of levcromakalim in isolated guinea pig heart preparations].
The aim of present work was to study the cardioprotective effect of the potassium channel opener levcromakalim at a low concentration (0.3 microM) which does not depress heart rate and left ventricular developed pressure. For the determination of the protection against 10 or 20 min duration of hypoxia (95% N2 + 5% CO2) in isovolumically-perfused Langendorff heart preparations of guinea-pigs biochemical parameters (ATP, phosphocreatine, lactate and glycogen) were used. Under normoxic (95% O2 + 5% CO2) conditions 0.3 microM levcromakalim has not changed myocardial high energy phosphates, glycogen, lactate and the hypoxia induced decrease in ATP and phosphocreatine. The 10 min hypoxia induced increase in lactate and decrease in glycogen have--slightly but not significantly--been moderated and when the duration of hypoxic perfusion has lasted 20 min, this protection became significant. It is supposed that the preservation of glycogen stores induced by levcromakalim may contribute to the decrease of intracellular acidosis evoked by hypoxia. Therefore--in such experimental condition-, this mechanism may constitute the biochemical basis of cardioprotective effect of levcromokalim.


The addition of bleomycin and dose-escalated ifosfamide to the combination of cisplatin plus ifosfamide does not improve survival in advanced or recurrent cervical carcinoma.
Twenty patients with advanced or recurrent cervical cancer were treated with bleomycin 30 U, ifosfamide 5 g/m2, and cisplatin 50 mg/m2 (BIP) every 28 days in a phase II trial. The primary purpose of this study was to compare response rate, survival, and toxicity of this regimen with results obtained in a similar group of patients treated with cisplatin 1 mg/kg per week for six courses followed by cisplatin, 20 mg/m2, plus ifosfamide 1.2 g/m2 daily for 3 days every 28 days. Four of 17 evaluable patients (23.5%) treated with BIP demonstrated a response to therapy (complete response 11.7%; partial response 11.7%). The median duration of response was 8.5+ months (range, 6+ to 24 months). These data do not differ significantly (P = 0.76) from a response rate of 27.5% among patients treated with cisplatin plus ifosfamide (PI). A significant (P = 0.003) increase in myelotoxicity was observed among patients treated with BIP versus those treated with PI. The median survival of patients treated with BIP of 13.5+ months (range, 8+ to 24 months) does not differ significantly from the median survival of 9+ months (3 to 26+ months) among patients treated with PI. The addition of bleomycin and dose-escalated ifosfamide did not significantly improve response rate or survival among patients with advanced or recurrent cervical cancer and resulted in a significant increase in myelotoxicity.


STUDIES ON THE ISOLATION OF METAPHASE CHROMOSOMES.
A method for the isolation of metaphase chromosomes from mouse L1210 leukemia cells has been developed. Cells, arrested at metaphase with colchicine, were exposed to hypotonic solution and the pH was then adjusted to 5.6 to stabilize the chromosomes. The metaphase figures were subsequently disrupted and the chromosomes isolated by a series of differential centrifugations in sucrose. The isolated chromosomes were well preserved, as judged by morphological criteria. The effect of various enzymes and chemical agents on the isolated chromosomes was studied. Chymotrypsin, trypsin, and deoxyribonuclease caused a marked disintegration of the chromosomes, whereas treatment with pepsin and ribonuclease induced no significant morphological alterations.


Self-disclosure, feedback, and outcome in long-term inpatient psychotherapy groups.
Process and outcome measures were compared in two long-term psychotherapy groups. Measures of Self-Disclosure and Feedback were based on analysis of videotaped sessions by use of Bales's SYMLOG three-axial system. These measures were then combined to form a measure of Interpersonal Work. High Interpersonal Work scores, both in early sessions and throughout treatment, predicted better outcome for individual members at 18-month follow-up. Interpersonal Work scores in later group sessions were not related to outcome. Findings suggest that early sessions are a critical time for members to develop a working style in the group. Members who fail to do so have a less successful outcome even if their working styles improve in later sessions.


Fathers' narratives of reducing and quitting smoking.
Despite much attention on women's efforts to reduce or stop smoking during pregnancy and postpartum, less attention has been directed to fathers' experiences in modifying their smoking. Using narrative methods, interviews with 29 new fathers were examined to identify different ways in which men approached reducing or quitting smoking. Four storylines were identified: the cold turkey storyline framed quitting smoking as a snap decision with no need for support or smoking cessation aids; the planned reduction storyline focused on building up reasons to quit and developing detailed strategies to enhance the likelihood of success; the baby as the patch storyline dramatised how the baby displaced the need to smoke, increased motivation for cessation and enhanced success; and, finally, a story of forced reduction that highlighted difficulties with smoking cessation for a highly addicted smoker and the tension and conflict this created in his relationship with his partner. Common to all the storylines was the men's reluctance to rely on smoking cessation resources; instead, self-reliance, willpower, and autonomy figured more prominently in their narratives. The findings from this study support developing gender-sensitive tobacco reduction interventions for fathers who smoke.


Hospice Family Caregivers' Uncertainty, Burden, and Unmet Needs in Prospective Audio Diaries.
Hospice cancer caregivers' (HCCs') burden and unmet needs are well documented in the literature through retrospective, standardized self-report surveys. Hospice cancer caregiver daily experiences of burden and unmet needs are rarely captured within a real-time context. The purpose of this secondary data analysis was to characterize HCCs' day-to-day burden and unmet needs with prospective HCC (N = 50) audio diary data between hospice enrollment and patient death. Uncertainty theory provided a framework for analysis. Diaries were transcribed, analyzed deductively and inductively, and organized thematically. Uncertainty in day-to-day experiences was an important driver of HCC burden and unmet needs. Unmet needs included unclear/unmet expectations regarding hospice care team support; not understanding the extent of HCC role and involvement; and communication challenges with hospice team members. Sources of HCCs' burden were dissonance between how they "should" feel and how they actually felt; feeling alone/having no outlet to express feelings; concerns about their own health and subsequent patient impact; and feeling helpless/occupying a liminal space. Uncertainty surrounding HCCs' experiences encompassed interactions with hospice care teams and the nature of end-of-life caregiving with symptom management, the dying process, and the HCC role. Hospice care teams can respond to uncertainty through assessment, understanding, and recognition of the daily context of HCCs.


Possible Contribution of Alpha2,6-Sialylation to Luteolysis in Cows by Inhibiting the Luteotropic Effects of Galectin-1.
The corpus luteum (CL) is essential for establishing pregnancy. If pregnancy does not occur during the estrous cycle, luteolysis is induced by prostaglandin (PG) F2alpha secreted from the uterus. Galectin-1, a beta-galactose-binding protein, is expressed in the functional CL of cows and increases the viability of bovine luteal steroidogenic cells (LSCs) by modifying the functions of membrane glycoproteins. The binding of galectin-1 to glycoproteins is blocked by alpha2,6-sialylation of the terminal galactose residues of glycoconjugates, which is catalyzed by a sialyltransferase (ST6Gal-I). However, the physiological role of alpha2,6-sialic acid in bovine CL is unclear. The level of alpha2,6-sialylation of the bovine CL was higher during the regressed-luteal stage than in other luteal stages. Lectin histochemistry revealed that alpha2,6-sialylated glycoconjugates were localized to luteal endothelial cells throughout the estrous cycle. In addition, alpha2,6-sialylated glycoconjugates concentrated to the membrane of LSCs during the regressed-luteal stage. PGF2alpha treatment for 72 h enhanced the expression of ST6Gal-I mRNA and the level of alpha2,6-sialylated glycoproteins in mid-LSCs. The level of alpha2,6-sialylated glycoproteins of late-stage LSCs (Days 15-17 after ovulation) was higher than that of mid-stage LSCs (Days 8-12 after ovulation), and galectin-1 increased the viability of mid-LSCs but not that of late-stage LSCs. Furthermore, galectin-1 increased the viability of late-LSCs when alpha2,6-sialic acid residues were removed by neuraminidase. The overall findings suggest that alpha2,6-sialylation stimulated by PGF2alpha contributes to luteolysis by inhibiting the luteotropic effects of galectin-1 in bovine CL.