EUS‑FNA combined with an intracapsular injection of antibiotics and ethanol for posterior mediastinal cyst: A case report.
Mediastinal cysts are rare benign lesions and their diagnosis and treatment remain difficult and controversial. The development of endoscopic ultrasound (EUS) has broadened the horizon for the precise treatment of diseases. The present study reports the case of a 53-year-old male hospitalized with chest pain. All imaging findings, including computed tomography, magnetic resonance imaging and EUS, indicated a benign cystic mass in the posterior mediastinum. The posterior mediastinal cyst was treated with EUS-guided fine-needle aspiration combined with an intracapsular injection of antibiotics and ethanol, and the results indicated no mediastinal infection after the puncture and no recurrence after 3 months of follow-up. The present study provides a new method for diagnosing and treating mediastinal cysts.


Validity of a decision tree for predicting active pulmonary tuberculosis.
The recent outbreaks of multidrug-resistant strains of M. tuberculosis in health care facilities has increased concern over its transmission in health care facilities. Isolation has been recommended for all patients suspected to have tuberculosis even though the feasibility and the cost of this recommendation can be substantial. We have developed a classification tree using clinical and radiographic data from 277 isolation episodes in patients admitted between August 1992 and March 1994 who required isolation for suspicion of tuberculosis. The classification tree was developed with a sensitivity and negative predictive value of 100% by binary recursive partitioning to predict those patients who are unlikely to require isolation. The predictor variables were upper zone disease on chest radiograph, a history of fever, weight loss, and CD4 count. The tree was validated in a separate cohort of 286 isolation episodes between April 1994 and December 1995. In this validation cohort, no erroneous prediction was made of not isolating a patient with active pulmonary tuberculosis. The classification tree had a sensitivity of 100% (95% confidence interval [CI]: 92.5 to 100%), a specificity of 48.1% (95% CI: 43.8 to 52.4%), and a negative predictive value of 100% (95% CI: 98.5 to 100%). We estimate that the use of the tree could have reduced the number of patients requiring isolation by more than 40% without increasing the risk of cross infection.


Calcium- and cyclic AMP-dependent chloride secretion in human colonic epithelia.
Three stable epithelial cell lines (HCA-7, HCA-7-Col 1 and HCA-7-Col 3) all derived from the same human adenocarcinoma have been cultured on collagen-coated Millipore filters. These epithelial monolayers have been used to record short circuit current (SCC) in response to of secretagogues. Similar monolayers, but grown on plastic dishes, were used for measurements of tissue cyclic AMP. Lysylbradykinin, applied to either side of the monolayers, increased SCC in HCA-7 cells but had little effect on the other two lines. The responses showed rapid desensitization, which could be prevented by cooling to 4 degrees C. Responses to kinin were not significantly attenuated by piroxicam, an inhibitor of cyclo-oxygenase. Other secretagogues, vasoactive intestinal polypeptide (VIP) and carbachol also increased SCC in monolayers. The responses to VIP were greatest in HCA-7-Col 1 monolayers while responses were virtually absent in HCA-7-Col 3. A similar profile was seen with carbachol except that responses of HCA-7 and HCA-7-Col 1 monolayers were more equal. With one exception the responses to VIP and carbachol showed sidedness, acting only from the basolateral side. The effects of the secretagogues were inhibited by piretanide, a loop diuretic, applied basolaterally. It is presumed that SCC responses represent electrogenic chloride secretion. Treatment with forskolin increased SCC in HCA-7 and HCA-7-Col 1 monolayers with little effect in HCA-7-Col 3. Nevertheless cyclic AMP levels were elevated most in HCA-7-Col 3 and least in HCA-7-Col 1 monolayers, in reciprocal relationship to the functional response. A23187 increased SCC when applied to HCA-7 and HCA-7-Col 3 monolayers with little effect on HCA-7-Col 1. The differential responses of the three human cell lines provide unique opportunities to discover the functional responsibilities of entities involved in the chloride secretory process. HCA-7-Col 3 cells which generate high levels of cyclic AMP in response to forskolin but which fail to show a substantial chloride secretory response may be a useful model of some disease conditions.


Importance of active layer freeze-thaw cycles on the riverine dissolved carbon export on the Qinghai-Tibet Plateau permafrost region.
The Qinghai-Tibet Plateau (QTP) is experiencing severe permafrost degradation, which can affect the hydrological and biogeochemical processes. Yet how the permafrost change affects riverine carbon export remains uncertain. Here, we investigated the seasonal variations of dissolved inorganic and organic carbon (DIC and DOC) during flow seasons in a watershed located in the central QTP permafrost region. The results showed that riverine DIC concentrations (27.81 ± 9.75 mg L-1) were much higher than DOC concentrations (6.57 ± 2.24 mg L-1). DIC and DOC fluxes were 3.95 and 0.94 g C m-2 year-1, respectively. DIC concentrations increased from initial thaw (May) to freeze period (October), while DOC concentrations remained relatively steady. Daily dissolved carbon concentrations were more closely correlated with baseflow than that with total runoff. Spatially, average DIC and DOC concentrations were positively correlated with vegetation coverage but negatively correlated with bare land coverage. DIC concentrations increased with the thawed and frozen depths due to increased soil interflow, more thaw-released carbon, more groundwater contribution, and possibly more carbonate weathering by soil CO2 formed carbonic acid. The DIC and DOC fluxes increased with thawed depth and decreased with frozen layer thickness. The seasonality of riverine dissolved carbon export was highly dependent on active layer thawing and freezing processes, which highlights the importance of changing permafrost for riverine carbon export. Future warming in the QTP permafrost region may alter the quantity and mechanisms of riverine carbon export.


Effectiveness of early identification and electronic interventions for teens with risk factors for the development of heart disease and diabetes: Phase II findings.
Serum and physical risk factors for the development of heart disease and diabetes are detectable long before adulthood. The purpose of this two-part study was to assess the prevalence and associations of these risk factors in teens and determine the effectiveness of a customizable two-part electronic education program on minimizing identified risks. Data were collected from teens (n = 168) from two high schools (one urban and one rural) in the mid-Atlantic region. After baseline data were collected, the two-part electronic education program was initiated. Serum and physical risk factors were rechecked at 12-week intervals, and results were analyzed. Significant serum and physical risk factor associations were identified and remained present among teens over the course of the study. High-density lipoproteins showed significant, steady improvement. Low-density lipoproteins were positively associated with body mass index, diastolic blood pressure, and thyroid-stimulating hormone level. Although serum and physical risk factors are identifiable in teens, routine screening of this age group and younger is not an established standard of care. Health care providers need effective, innovative methods to counteract these risks. Through increased awareness of the presence of risk factors in young patients, advanced nurse practitioners may implement earlier interventions to counteract these risks.


Urban residence, neighborhood poverty, race/ethnicity, and asthma morbidity among children on Medicaid.
Although poor-urban (inner-city) areas are thought to have high asthma prevalence and morbidity, we recently found that inner cities do not have higher prevalent pediatric asthma. Whether asthma morbidity is higher in inner-city areas across the United States is not known. This study sought to examine relationships between residence in poor and urban areas, race/ethnicity, and asthma morbidity among children with asthma who are enrolled in Medicaid. Children aged 5 to 19 enrolled in Medicaid in 2009 to 2010 were included. Asthma was defined by at least 1 outpatient or emergency department (ED) visit with a primary diagnosis code of asthma over the 2-year period. Urbanization status was defined at the county level and neighborhood poverty at the zip-code level. Among children with asthma, logistic models were created to examine the effects of urbanization, neighborhood poverty, and race/ethnicity on rates of asthma outpatient visits, ED visits, and hospitalizations. This study included 16,860,716 children (1,534,820 with asthma). Among children enrolled in Medicaid, residence in inner-city areas did not confer increased risk of prevalent asthma in either crude or adjusted analyses, but it was associated with significantly more asthma-related ED visits and hospitalizations among those with asthma in crude analyses (risk ratio, 1.48; 95% CI, 1.24-1.36; and 1.97; 95% CI, 1.50-1.72, respectively) and when adjusted for race/ethnicity, age, and sex (adjusted risk ratio, 1.23; 95% CI, 1.08-1.15; and 1.62; 95% CI, 1.26-1.43). Residence in urban or poor areas and non-Hispanic black race/ethnicity were all independently associated with increased risk of asthma-related ED visits and hospitalizations. Residence in poor and urban areas is an important risk factor for asthma morbidity, but not for prevalence, among low-income US children.


Oxidative stress, antioxidants, and lipid profile in the serum and saliva of individuals with coronary heart disease: is there a link with periodontal health?
Oxidative stresses and dyslipidemia are an important risk factor in the development of coronary atherosclerotic complications like angina pectoris and myocardial infarction. The aim of this study was to find the relationship between the salivary lipid profile, lipid peroxidation and antioxidants and the periodontal health status of patients with acute coronary heart disease (CHD). Forty patients who had experienced a recent attack of angina pectoris or myocardial infarction and another 40 noncardiac patients matched for age, sex and residence (control) were recruited. The lipid profile level, lipid peroxidation and antioxidant status were measured in the serum and saliva of all participants together with lactate dehydrogenase (LDH) and C-reactive protein. The studied parameters were then correlated with the periodontal status of the participant using the Clinical Periodontal Sum Score (CPSS). A multiple linear regression was used to assess the net effect of each set of independent variables on the outcome variable using SPSS-21. A P value ≤0.05 was considered statistically significant. Salivary total cholesterol, triglycerides, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, malondialdehyde, uric acid, superoxide dismutase and LDH levels increased with the upper tertile of the CPSS, while salivary high-density lipoprotein-cholesterol decreased with the upper tertile of the CPSS. Periodontal health status could be considered as an independent risk factor for acute CHD.


[The expression of vegf in rat fracture reparative callus].
The present study has determined the histological changes, VEGF (Vascular endothelial growth factor) mRNA alternative expressions and VEGF mRNA levels in chondrogenic-callus, osteogenic-callus and total callus by histology, RT-PCR and Northern blot during rat fracture repair. The results showed that the cellular events of intramembranous ossification, chodrogenesis and endochondral ossification appeared in the callus simultaneously and sequentially. The VEGF mRNAs were expressed in the osteogenic-callus and the chondrogenic-callus, and the strongest expressions were VEGF120 and VEGF164 mRNA. The VEGF mRNA levels in the total callus increased with time after fracture. Take together, these findings suggest that osteogenesis-derived VEGF may play a potential role to modulate the differentiation process of osteogenic and chondrogenic cells during fracture repair.


Positive Outcomes of Optimizing Student-Preceptor Continuity in a Traditional Block Clerkship.
Student-preceptor discontinuity during 3rd-year clerkships limits the quality and quantity of supervision, teaching, and feedback. Although longitudinal integrative clerkships increase continuity and are associated with improved student and preceptor experience, they require schoolwide curricular reform. Alternative innovations enhancing student-preceptor relationships within the constraints of a traditional block clerkship may demonstrate similar benefits. We piloted a continuity-enhanced general pediatric ambulatory schedule during 2 consecutive clerkship blocks in 2013. Students in the continuity-enhanced model (n = 29) were assigned 1-3 primary clinic preceptors, whereas those in the traditional model (n = 30) worked with 5-8. Data were gathered from student assessments and anonymous student and preceptor surveys. We used t and Fisher's exact tests to compare the two groups and performed thematic analysis of free-text survey comments. Our school utilizes a block clerkship model with approximately 30 students rotating through the pediatric clerkship every 8 weeks. During the 3-week ambulatory portion, students spend 8 half days in the general pediatric ambulatory clinic. At the conclusion of each clinic, attendings completed brief student evaluation cards. Traditionally, student and attending schedules were created independently, resulting in transient supervisory relationships and dissatisfaction with clinical engagement, feedback, and evaluation. Seventy-three percent (43/59) of the students completed the survey. Ten general ambulatory attendings collectively completed 87.5% (35/40) of the monthly surveys. Continuity students received significantly more narrative evaluation comments (10.6 vs. 5.8, p <. 001) from general ambulatory clinic attendings and were more likely to have at least one general ambulatory clinic attending endorse being able to provide meaningful feedback and evaluation (n = 29, 100% vs. n = 20, 66.7%, p <. 001). Continuity students were also more likely to endorse being able to ask at least one of these attendings for a letter of recommendation (71.4% vs. 9.1%, p <. 001) and to have at least one general ambulatory clinic attending endorse being able to provide a meaningful letter of recommendation if asked (62.1% vs. 3.3%, p <. 001). Students (88.4%) and attendings (85.7%) preferred the continuity-enhanced schedule. The most frequent theme of both student and attending free-text survey remarks were relationships and assessment. Intentional scheduling of clerkship students to enhance preceptor continuity resulted in significant positive outcomes echoing the relationship-based educational benefits of longitudinal clerkships, particularly in regards to student assessment and feedback. Clerkship directors and other medical educators should consider implementing small changes within block clerkships to maximize student-preceptor continuity.


[Isolated replacement of the tricuspid valve with a bioprosthesis. Apropos of 22 cases in Abidjan].
The authors reviewed the operative and function results of 24 isolated tricuspid valve replacements with bioprostheses in 22 patients. The patient population was young (average age 15 +/- 8 years). The surgical indication was massive tricuspid regurgitation due to chronic parietal endocarditis in 19 cases and to bacterial endocarditis in 3 cases. Tricuspid valve replacement was associated with 19 right ventricular endocardectomies, 2 direct closures of ventricular septal defects, 2 Wooler mitral valvuloplasties and 1 pericardectomy. The operative mortality was 13.5% and the secondary mortality 13.5%. Of the 16 survivors, 13 are in the NYHA Class I with no regular medical therapy. Their cardiothoracic ratio has slightly decreased. Two patients have permanent atrial fibrillation, and 12 have acquired definitive complete right bundle branch block. Eight of these patients had significant improvement of atrial and right ventricular pressures, of Yu's index and cardiac index at postoperative catheterisation. Three of the 16 patients developed progressive calcific degeneration of their bioprostheses. They are among the 6 patients who have been followed up for more than 3 years. There was no mortality at reoperation. Isolated tricuspid valve replacement by bioprosthesis was chosen despite the young age of these patients because of the disadvantages of mechanical prostheses which are associated with a much higher mortality related to incarceration and thrombosis of the prosthesis. The relatively high operative and secondary mortality in this series of isolated tricuspid valve replacement compared to mitral, aortic or micro-aortic valve replacement, is related to the gravity of the underlying causal pathology.


Relief of pain following intravesical capsaicin in patients with hypersensitive disorders of the lower urinary tract.
We have extended our earlier observations on pain relief produced by intravesical instillation of capsaicin (10 microM in saline) in patients with hypersensitive disorders of the lower urinary tract. Patients in group A (n = 15) received intravesical capsaicin on days 0, 14 and 28: on each occasion the drug produced a warm or burning sensation, reduction in bladder capacity and a delayed, transient improvement or disappearance of symptoms. Patients in group B (n = 5) received intravesical capsaicin (10 microM at cystometry) 3 times on day 0. The initial sensation of warmth was experienced on each occasion, indicating that no significant desensitisation has been produced by the first instillation. Clinical improvement similar to that found in group A was observed. Three patients (group C) received warm saline (42 degrees C) at cystometry. This produced a pricking sensation, no change at cystometry and no subjective clinical improvement. Apart from the initial sensation of warmth, no patient in group A or B experienced side effects, either local or systemic. These findings confirm that intravesical instillation of capsaicin has a beneficial effect on patients with hypersensitive bladder disorders. Counter-irritation rather than desensitisation of primary afferents could be a possible mechanism of action. Further studies are needed to establish whether the intravesical administration of capsaicin or capsaicin-like agents represents a new form of treatment for relief of bladder pain.


Prevention of stricture development after corrosive esophageal burn with a modified esophageal stent in dogs.
We sought to test the feasibility and technical ease of a newly designed nitinol-based modified esophageal stent and its effects on preventing postcaustic stricture in mongrel dogs and to try to explain the result at the molecular level. Twenty-four dogs were included in this controlled study. Stenosis index (wall thickness/intraluminal diameter), pathologic features, hydroxyproline quantities, esophageal compliance, and biomechanics were compared between the injured but unstented and stented dogs. Transforming growth factor beta1, Sma/Mad (Smad)3, and Smad7 mRNA expression and protein levels in esophageal tissue were detected by means of reverse transcriptase-polymerase chain reaction and Western blotting, respectively. The modified esophageal stent was able to be placed and retrieved successfully and conveniently and was not only intact but there was also no macroscopic esophageal mucosal injury after the stent removal 4 months later. In comparison with the injured but unstented group, esophageal compliance, biomechanics, and the stenosis index were significantly better in the stented group. Histopathologic study revealed that collagen bundles were thinner and its orientation tended toward a regular and parallel pattern. Transforming growth factor beta1 and Smad3 mRNA expression and protein levels increased and Smad7 mRNA expression and protein levels decreased significantly in esophageal tissue in the stented group. These variables showed no statistically significant difference 2 months after stent removal. The modified esophageal stent might be a promising stent in preventing stricture formation after corrosive esophageal burns clinically.


Publications on ultrasound-guided thermal ablation for thyroid nodules from 2000 to 2022: a bibliometric analysis.
Thyroid nodules are increasingly treated with minimally invasive surgery. Thermal ablation could efficiently treat patients with benign thyroid nodules, recurrent thyroid cancer, and low-risk papillary thyroid carcinoma. This research aims to explore the research field of thermal ablation for thyroid nodules using bibliometric analysis. The web of science core collection (WoSCC) database was utilized from its inception to 1 October 2022, to collect research articles and reviews on ultrasound-guided thermal ablation for thyroid nodules. We applied the R package 'bibliometrix' to summarize the main findings, calculate the occurrences of the top keywords and visualize the international collaboration networks. The co-authorship and co-occurrence analyses were conducted with VOSviewer software. CiteSpace was used to identify the top references and keywords with the highest citation bursts. A total of 820 publications from 32 countries were retrieved. The annual number of related publications showed an increasing trend. China, Italy, and Korea were the most contributing countries. The University of Ulsan College of Medicine in Korea was the most productive institution, and Jung Hwan Baek published the maximum number of articles. The International Journal of Hyperthermia was the most productive journal. 'Papillary thyroid micro-carcinoma (PTMC)' and 'association guideline' were the most frequently used keywords in the field of thermal ablation for thyroid nodules, which indicated the potential hot research topics and frontiers in the future. This bibliometric study conducts a comprehensive analysis of publications on thermal ablation for thyroid nodules, which aids investigators in discovering potential research directions.


Design and implementation of an electronic data recording and processing system for physics quality control checks in external beam radiotherapy.
Quality control (QC) of external beam radiotherapy equipment ensures that commissioning performance is maintained. Paper based data recording is still used for QC, but this is resource intensive in terms of data calculation and processing. Electronic systems of data recording have many advantages; for example, they facilitate the analysis of data on a regular basis, allowing the user to examine the "health" of each machine; they help review and audit local frequencies of each check and can possibly predict component failure. They also allow for secure calculation of results and automatic charting for routine trend analysis. Initially, data recording at our centre was paper-based for daily, weekly and monthly checks. This paper system has been successfully replaced with an electronic system for QC data recording and processing for linear accelerators and superficial units. The system makes use of personal digital assistants and networked laptops for online recording of data, and networked desktop PCs for offline work. The systems of data recording have been designed using the power of macros within Microsoft Excel, which automatically calculate each QC parameter and charts the data recorded for long-term analysis of trends. As of the beginning of 2006, these systems have been fully implemented. The benefits of implementing such a system are numerous, for example, central storage, backup and archiving of data, for greater security and reducing operator errors in calculations. Other benefits are discussed within the paper. In the future, we hope to develop similar systems of data recording for QC checks on other radiotherapy equipment.


Pharmacokinetics of MDL 26479, a novel benzodiazepine inverse agonist, in normal volunteers.
MDL 26479 is a new drug undergoing clinical evaluation for the treatment of depression and for memory loss associated with Alzheimer's disease. As part of a dose tolerance trial, the single- (SD) and multiple-dose (MD) pharmacokinetics of MDL 26479 were evaluated in healthy male volunteers. SDs ranging from 2 to 465 mg, and doses of 30, 60, and 120 mg administered twice daily for 28 d, were examined. Serial blood samples were collected for up to 48 h. Plasma MDL 26479 concentrations were determined by HPLC. Plasma MDL 26479 concentration versus time profiles increased rapidly, followed by multiexponential decline. Time to maximum plasma concentration increased over the 230-fold SD range from 0.5 to 3.8 h. Maximum concentrations and areas under the concentration versus time curves increased disproportionately with dose. Apparent oral clearance estimates decreased from 52.9 to 13.8 Lh-1. MD pharmacokinetic parameters for doses from 30 to 120 mg were consistent with those observed following SD, thus indicating that SD pharmacokinetics are predictive of MD. SD and MD terminal half-life estimates were similar and independent of dose.


Plasmon induced hot carrier generation in a pyridine@Au20 composite.
Using time-dependent density functional theory calculations, we have investigated the generation of hot carriers (HCs) in a system comprising a pyridine molecule and a tetrahedral Au20 plasmonic cluster. Our findings indicate that the decay of the localized surface plasmon resonance (LSPR) induced in the pyridine@Au20 system by a laser pulse facilitates the direct transfer of hot electrons from the occupied states of the Au20 cluster to the unoccupied molecular orbitals of pyridine. Notably, we have identified that the interparticle gap distance between the Au20 cluster and the pyridine molecule plays a critical role in controlling the generation of HCs. By precisely controlling the interaction between the plasmonic cluster and the molecule, we can effectively manipulate the energy distribution of the generated HCs. These insights have the potential to drive advancements in the development of more efficient systems for plasmonic catalysis.


Indirect fluorescent antibody technic for demonstration of serum antibody in dengue hemorrhagic fever cases.
One hundred eighty-three sera from two groups of children with dengue hemorrhagic fever and 37 control sera were examined for antibody against dengue virus by an indirect immunofluorescent method. When the reciprocal titer of 16 or higher was used as the diagnostic level, positive tests could be obtained in 80% of Group I and 100% of Group II sera after 3--6 days of fever. Positive tests were obtained in 100% of both groups after the first week of fever. There was no false-positive among the control sera. Preparation of the antigen is relatively easy, and the antigen may be stored for at least 3 months. The immunofluorescent method is rapid and simple, and is recommended for routine detection of serum antibody in dengue hemorrhagic fever.


Radiofrequency catheter ablation using cooled electrodes: impact of irrigation flow rate and catheter contact pressure on lesion dimensions.
Irrigation of radiofrequency current (RF) ablation reduces the risk of thrombus formation. The aim of this study was to investigate the impact of different irrigation catheter flow rates and contact pressures from the catheter on the development of lesion dimension and thrombus formation. A thigh muscle preparation was achieved in six sheep to create a cradle that was filled and perfused with heparinized blood (250 mL/min, 37 C degrees). RF ablation (30 s, 30 W) was initially performed with three different irrigation flow rates (5 mL/min, 10 mL/min, and 20 mL/min) and a perpendicular position (0.1 N contact pressure) of the irrigated ablation catheter ("Sprinklr," Medtronic, Inc., Minneapolis, MN, USA). The next lesions were induced with constant contact pressure of 0.05 Newton (N); 0.1 N; 0.3 and 0.5 N and a parallel or perpendicular orientation of the catheter, respectively. A constant irrigation flow of 10 mL/min was maintained during these RF applications. Cross sections of the lesions were investigated with regard to maximal depth and maximal diameter at and below the surface. During high flow irrigation (20 mL/min) the surface diameter was significantly smaller (0.63 +/- 0.1 cm) compared to irrigation flowrates of 5 mL/min (0.88 +/- 0.2 cm) and 10 mL/min (1 +/- 0.1 cm). Thrombus formation was not observed during any RF application. Only in perpendicular catheter orientations with a contact pressure of 0.5 N were significantly deeper lesions (0.85 +/- 0.12 cm) induced compared to 0.05 N (0.55 +/- 0.02 cm), 0.1 N (0.7 +/- 0.01 cm) and 0.3 N (0.67 +/- 0.01 cm) contact pressure. There was no significant difference in lesion depth with different flow rates. Irrigated RF ablation even with low flow rates and high catheter contact pressure prevented thrombus formation at the electrode. Smaller lesion diameters have been created with high irrigation flow rates. The deeper lesion created with high catheter contact pressure might be caused by a greater power transmission to the tissue.


It's all in your head - how anticipating evaluation affects the processing of emotional trait adjectives.
Language has an intrinsically evaluative and communicative function. Words can serve to describe emotional traits and states in others and communicate evaluations. Using electroencephalography (EEG), we investigate how the cerebral processing of emotional trait adjectives is modulated by their perceived communicative sender in anticipation of an evaluation. 16 students were videotaped while they described themselves. They were told that a stranger would evaluate their personality based on this recording by endorsing trait adjectives. In a control condition a computer program supposedly randomly selected the adjectives. Actually, both conditions were random. A larger parietal N1 was found for adjectives in the supposedly human-generated condition. This indicates that more visual attention is allocated to the presented adjectives when putatively interacting with a human. Between 400 and 700 ms a fronto-central main effect of emotion was found. Positive, and in tendency also negative adjectives, led to a larger late positive potential (LPP) compared to neutral adjectives. A centro-parietal interaction in the LPP-window was due to larger LPP amplitudes for negative compared to neutral adjectives within the 'human sender' condition. Larger LPP amplitudes are related to stimulus elaboration and memory consolidation. Participants responded more to emotional content particularly when presented in a meaningful 'human' context. This was first observed in the early posterior negativity window (210-260 ms). But the significant interaction between sender and emotion reached only trend-level on post hoc tests. Our results specify differential effects of even implied communicative partners on emotional language processing. They show that anticipating evaluation by a communicative partner alone is sufficient to increase the relevance of particularly emotional adjectives, given a seemingly realistic interactive setting.


Statins and myocardial hypertrophy.
Cardiac hypertrophy is a physiological adaptive response by the heart to pressure overload. However, after prolonged periods, this initial adaptive response becomes maladaptive, leading to increased mortality and morbidity from heart failure. Recently, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been shown to inhibit cardiac hypertrophy by cholesterol-independent mechanisms. Statins block the isoprenylation and activation of members of the Rho guanosine triphosphatase (GTPase) family, such as RhoA and Rac1. Since Rac1 is a requisite component of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is a major source of reactive oxygen species (ROS) in cardiovascular cells, the ability of statins to inhibit Rac1-mediated oxidative stress makes an important contribution to their inhibitory effects on cardiac hypertrophy.


CE-LIF-MS n profiling of oligosaccharides in human milk and feces of breast-fed babies.
Mixtures of the complex human milk oligosaccharides (HMOs) are difficult to analyze and gastrointestinal bioconversion products of HMOs may complicate analysis even more. Their analysis, therefore, requires the combination of a sensitive and high-resolution separation technique with a mass identification tool. This study introduces for the first time the hyphenation of CE with an electrospray mass spectrometer, capable to perform multiple MS analysis (ESI-MS(n)) for the separation and characterization of HMOs in breast milk and feces of breast-fed babies. LIF was used for on- and off-line detections. From the overall 47 peaks detected in off-line CE-LIF electropherograms, 21 peaks could be unambiguously and 11 peaks could be tentatively assigned. The detailed structural characterization of a novel lacto-N-neo-tetraose isomer and a novel lacto-N-fucopentaose isomer was established in baby feces and pointed to gastrointestinal hydrolysis of higher-Mw HMOs. CE-LIF-ESI-MS(n) presents, therefore, a useful tool which contributes to an advanced understanding on the fate of individual HMOs during their gastrointestinal passage.


Unexpected clinical sequelae of Gitelman syndrome: hypertension in adulthood is common and females have higher potassium requirements.
Gitelman syndrome (GS) is a rare inherited disorder caused by mutations in SLC12A3, encoding the thiazide-sensitive transporter NCCT (sodium chloride co-transporter) in the distal tubule. It is characterized by renal potassium (K) and magnesium (Mg) wasting, relative hypotension and hypocalciuria. However, there is phenotypic variability and long-term studies are scarce. We retrospectively assessed clinical and genetic characteristics, and electrolyte requirements, in a cohort of 36 patients with genetically proven GS. The 21 males and 15 females were of median age 39.5 years, range 17-66 years. Six were diagnosed in childhood. Among the 72 mutant alleles, 41 different sequence alterations were identified, of which 13 were previously unreported. Surprisingly, 44% (n = 16) of the cohort has developed hypertension (13 males, 3 females, P = 0.019; median age 53 versus 57 years, P = 0.95). One was already hypertensive by age 23 years. Currently normotensive patients were significantly younger: median 37 versus 55 years (P = 0.005). Hypertensive patients were more likely to harbour mutations in the C-terminal half of the NCCT protein (P = 0.016). Females required more K (median 128 versus 72 mmol/day; P = 0.01) but not Mg. Those with exon 26 and/or at least one destructive mutation had higher K requirements than those with neither: 108 versus 72 mmol (P = 0.016) and a tendency towards higher Mg needs: 30 versus 7.4 mmol (P = 0.07). Our findings suggest that the development of secondary hypertension may be an expected feature of the ageing GS population despite the obligate salt wasting that characterizes the disorder. We hypothesize that this may be related to chronic secondary hyperaldosteronism. The apparently more severe phenotype in women may be related to the effects of female sex hormones on expression or function of NCCT.


miR-148a-3p regulates adipocyte and osteoblast differentiation by targeting lysine-specific demethylase 6b.
Recent emerging studies of miRNAs in mesenchymal stem cell commitment toward adipocyte and osteoblast provide new insights for the understanding of the molecular basis of adipogenesis and osteogenesis. The current study revealed that miR-148a-3p was altered in primary cultured marrow stromal cells and established stromal ST2 line after adipogenic and/or osteogenic treatment. Supplementing miR-148a-3p activity inhibited cell growth and induced ST2 to differentiate into mature adipocytes. Conversely, inactivation of the endogenous miR-148a-3p suppressed ST2 to fully differentiate. By contrast, supplementation of the miR-148a-3p blunted osteoblast differentiation. Lysine-specific demethylase 6b (Kdm6b), a recently identified regulator of osteoblast differentiation was shown to be a direct target of miR-148a-3p by using the luciferase assay. Overexpression of Kdm6b attenuated miR-148a-3p stimulation of adipogenic differentiation. Taken together, our study provides evidences that miR-148a-3p reciprocally regulates adipocyte and osteoblast differentiation through directly targeting Kdm6b.


[Strategies to Optimise R0 Resection for Hilar Cholangiocarcinoma].
Retrospective analyses have shown a 20-40 % incidence of R1 resection in hilar cholangiocarcinoma, which therefore represents a significant issue to be addressed. We have reviewed the literature on the impact of R1 resection in hilar cholangiocarcinomas and on possible surgical options to increase the rate of complete tumour resections. To minimise the rate of R1 resections a preoperative risk assessment concerning the predisposed anatomic locations is required. During planning of the surgical strategy, liver function plays a central role prior to right-sided hemihepatectomies. Due to the loss of a high amount of functional liver parenchyma, contralateral portal vein embolisation is often used prior to right trisectionectomies. For left-sided hepatectomies the management of the right hepatic artery is fundamental. The right hepatic artery has a very close contact to the tumour region, although arterial invasion is rarely seen. However, the risk of manifest or occult R1 resection is relatively high along the right artery. In selected cases an arterial resection might be considered, but this increases the risk of postoperative complications. Arterial resection might be performed either via direct anastomosis or by using an interposition graft. As reserve procedures preoperative embolisation of the hepatic artery without reconstruction or an arterialisation of the portal vein are available. However, the latter two procedures come along with an increased rate of biliary complications. In selected lymph-node negative patients with irresectable hilar cholangiocarcinoma liver transplantation might be considered. Despite significant advances in surgical technique, R1 resection remains a problem, which is aggravated by the lack of evidence-based adjuvant measures.


Brain microdialysate, CSF and plasma pharmacokinetics of ligustrazine hydrochloride in rats after intranasal and intravenous administration.
The aim of this work was to investigate the pharmacokinetics of ligustrazine hydrochloride (LZH) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal (10 mg/kg) or intravenous administration (10 mg/kg) in male Sprague-Dawley rats. Plasma, CSF and cerebral cortex microdialysates were collected at timed intervals for the measurement of LZH by a quick and sensitive HPLC-UV method. LZH entered the brain quickly following both routes of administration. No significant difference was observed between the AUCCSF or cortex /AUCplasma ratio of LZH after intranasal administration (38.4%, 17.4%) and that after intravenous injection (45.9%, 19.9%). The drug targeting index (DTI) was 0.85 and 0.91 in the CSF and cortex, respectively. In conclusion, LZH is rapidly absorbed into the systemic circulation following intranasal administration. There is no direct pathway for LZH transport from the nasal cavity to the brain. The rapidity and magnitude of LZH penetration into the brain indicate that intranasal administration of this agent is a promising alternative to intravenous administration.


The incidence of membrane perforation during sinus floor elevation using sonic instruments: a series of 40 cases.
This study reports the incidence of complications and sinus membrane perforations when using sonic instruments to prepare the lateral window osteotomy for maxillary sinus augmentation. The charts of 33 consecutive patients (40 sinuses) were reviewed. Sinus membrane perforations were reported in 7 cases (17.5% of procedures), with 3 perforations occurring during preparation of the osteotomy window (7.5% of procedures). Postoperatively, 2 cases of sinus infection (5%) and 2 cases of flap dehiscence (5%) were recorded. This study demonstrates that elevation of the sinus floor with a combination of hand and sonic instruments is feasible and safe, with a limited incidence of complications.


Making Health Research Matter: A Call to Increase Attention to External Validity.
Most of the clinical research conducted with the goal of improving health is not generalizable to nonresearch settings. In addition, scientists often fail to replicate each other's findings due, in part, to lack of attention to contextual factors accounting for their relative effectiveness or failure. To address these problems, we review the literature on assessment of external validity and summarize approaches to designing for generalizability. When investigators conduct systematic reviews, a critical need is often unmet: to evaluate the pragmatism and context of interventions, as well as their effectiveness. Researchers, editors, and grant reviewers can implement key changes in how they consider and report on external validity issues. For example, the recently published expanded CONSORT figure may aid scientists and potential program adopters in summarizing participation in and representativeness of a program across different settings, staff, and patients. Greater attention to external validity is needed to increase reporting transparency, improve program dissemination, and reduce failures to replicate research.


Serum interleukin-18 levels as a predictor for patients with genetic dysfunction of cytochrome P450 2C19 in dual antiplatelet therapy with clopidogrel.
P2Y12 reaction unit (PRU) is an index of platelet activity upon treatment with clopidogrel. In spite of suitable P2Y12 reactions in dual antiplatelet therapy (DAPT) with clopidogrel after percutaneous coronary intervention (PCI), cardiovascular events actually occur in some patients, possibly due to a genetic dysfunction of cytochrome P450 2C19 (CYP2C19), which is a major metabolic enzyme of clopidogrel. As testing the CYP2C19 phenotypes to predict such patients may lack general versatility in daily clinical practice, the aim of this study was to examine whether measuring the blood levels of some cytokines in patients showing desirable PRUs in DAPT with clopidogrel could be a substitute for testing the CYP2C19 phenotypes. We analyzed relationships among PRU, serum levels of 51 cytokines, and CYP2C19 phenotypes in 22 patients receiving DAPT with aspirin and clopidogrel after PCI. Seventeen, 18, and 19 of 22 patients indicated PRU ≤ 208, PRU ≤ 230, and PRU ≤ 262, respectively. Approximately 60% of the patients had a genetically metabolic dysfunction of CYP2C19, and the serum levels of interleukin-18 were independently increased in those patients (p = 0.024 in patients with PRU ≤ 208, p = 0.021 with PRU ≤ 230, and p = 0.020 with PRU ≤ 262). The area under the curves in plot receiver operating characteristics curves for the serum levels of interleukin-18 were 0.94, 0.96, and 0.90 in the non-extensive metabolizer patients with PRU ≤ 208, PRU ≤ 230, and PRU ≤ 262, respectively. The serum levels of interleukin-18 may be a predictor to diagnose patients who receive undesirable DAPT with clopidogrel, possibly due to the genetic dysfunction of CYP2C19 in spite of suitable P2Y12 reactions after PCI.


The Korean Hepatitis C Virus Care Cascade in a Tertiary Institution: Current Status and Changes in Testing, Link to Care, and Treatment.
The care cascade for hepatitis C virus (HCV) infection is impeded by multiple barriers, including suboptimal anti-HCV testing, link to care, and diagnosis. We explored the changes in the care cascade of HCV for the past 20 years and its current status in a large cohort from a tertiary referral center. We analyzed 1,144,468 patients who had anti-HCV testing between January 2001 and June 2020. Metrics related to the care cascade of HCV infection and the long-term prognosis of patients were explored. The seroprevalence of anti-HCV positivity was 1.8%, with a recent decreasing trend. In all, 69.9% of anti-HCV positive patients performed HCV RNA testing, with a 65.7% positivity. Patients who did not have HCV RNA testing were older and more likely to have a non-hepatocellular carcinoma malignancy, normal alanine aminotransferase level, and good liver function. Linkage times for HCV RNA testing from the anti-HCV positivity and for antiviral treatment from HCV diagnosis decreased, notably after 2015, when highly efficacious oral antiviral treatment was introduced to Korea. The average treatment uptake rate was 35.4%, which increased to 38.9% after 2015. Of the 5,302 patients analyzed for long-term prognosis, the annual incidences of hepatocellular carcinoma were 1.02 or 2.14 per 100 person-years in patients with or without a sustained virological response, respectively. The care cascade of HCV infection has been suboptimal for the past 20 years, despite the recent changes. More effort should be made to increase HCV RNA testing and treatment uptake.


Pharmacokinetic/pharmacodynamic drug evaluation of benralizumab for the treatment of asthma.
In many severe asthmatics, eosinophils cause inflammation and airways hyperresponsiveness, resulting in frequent exacerbations, impaired lung function, and reduced quality of life. Interleukin-5 (IL-5) is a key cytokine for eosinophil growth, differentiation, recruitment, activation, and survival. Anti-IL-5-based therapies (mepolizumab and reslizumab are humanized monoclonal antibodies (hmAbs) that recognize free IL-5, benralizumab is a hmAb directed at the α subunit of the IL-5R) target the IL-5-signaling in eosinophilic asthma. Areas covered: The pharmacodynamic/pharmacokinetic profile of benralizumab and how it provided indications that permitted optimization of the design and timelines of the pivotal trials are described. Expert opinion: Benralizumab has the advantage over other anti-IL-5 therapies to target the IL-5Rα itself. Afucosylation enhances its interaction with its binding site and facilitates its pharmacological activity. Other benefits of benralizumab are fast (within 24 h) depletion of peripheral blood eosinophils, potent suppressive activity of bone marrow eosinophils and eosinophil precursors, tissue eosinophil apoptosis regardless of the presence of eosinophil survival factors and even at low IL-5R densities. The fact that benralizumab is dosed subcutaneously and is equally effective when given every eight weeks instead than every four weeks provides patients with convenience of self-administration and make it appealing for patients who dislike injections.


A highly potent and selective farnesyltransferase inhibitor ABT-100 in preclinical studies.
Ras mutation has been detected in approximately 20-30% of all human carcinomas, primarily in pancreatic, colorectal, lung and bladder carcinomas. The indirect inhibition of Ras activity by inhibiting farnesyltransferase (FTase) function is one therapeutic intervention to control tumor growth. Here we report the preclinical anti-tumor activity of our most advanced FTase inhibitor (FTI), ABT-100, and a direct comparison with the current clinical candidates. ABT-100 is a highly selective, potent and orally bioavailable FTI. It broadly inhibits the growth of solid tumors in preclinical animal models. Thus, ABT-100 is an attractive candidate for further clinical evaluation. In addition, our results provide plausible insights to explain the impressive potency and selectivity of ABT-100. Finally, we have demonstrated that ABT-100 significantly suppresses the expression of vascular endothelial growth factor (VEGF) mRNA and secretion of VEGF protein, as well as inhibiting angiogenesis in the animal model.


Awareness Among Transgender and Nonbinary Adults of the Otolaryngologist's Role in Providing Gender-Affirming Care Services.
To assess transgender and nonbinary adults' awareness of Otolaryngologists' (ENT) and speech-language pathologists' (SLP) ability to perform various face, neck, and voice procedures for gender-affirming purposes. Cross-sectional survey. Online, from February to May 2022. We developed a list of nonsurgical and surgical gender-affirming face, neck, and voice procedures. We asked transgender and nonbinary (TNB) adults which procedures from this list they knew could be performed by specially-trained ENTs or SLPs for gender-affirmation and which listed procedures they knew existed as gender-affirming treatment before the survey. We assessed awareness of ENTs' and SLPs' ability for each procedure across gender identity using Fisher exact tests. We examined if demographic or socioeconomic factors were associated with the total number of gender-affirming procedures participants knew ENTs or SLPs could perform using univariable linear regression. TNB adults (N = 234) generally knew these procedures existed as gender-affirming treatment (64%-93%). However, TNB adults were largely unaware these gender-affirming procedures could be performed by specially-trained ENTs or SLPs (53% or less), especially procedures unrelated to the voice, neck, and nose (26% or less). Knowledge of ENTs' and SLPs' ability was similar across gender identity for most procedures. Total number of procedures known that ENTs or SLPs could perform did not differ by demographic/socioeconomic factors (p > .05). These findings suggest transgender and nonbinary individuals may not know to seek Otolaryngologists or SLP when desiring gender-affirming face, neck, or voice care. Increased efforts are needed to promote awareness of Otolaryngology's role in providing gender-affirming care.


Measurement of beam profiles by terahertz sensor card with cholesteric liquid crystals.
We demonstrate a sensor card with cholesteric liquid crystals (CLCs) for terahertz (THz) waves generated from a nonlinear crystal pumped by a table-top laser. A beam profile of the THz waves is successfully visualized as color change by the sensor card without additional electronic devices, power supplies, and connecting cables. Above the power density of 4.3 mW/cm2, the approximate beam diameter of the THz waves is measured using the hue image that is digitalized from the picture of the sensor card. The sensor card is low in cost, portable, and suitable for various situations such as THz imaging and alignment of THz systems.


Telescopic Overdenture: A Case Report.
This report describes the case of a 68 year old female patient who presented with the chief complaint of difficulty in chewing and poor aesthetics due to missing teeth. The patient was interested in saving the remaining natural teeth and desired minimal tissue coverage from the prosthesis. After consideration of all the factors involved, it was deemed advisable to resort to a palate free maxillary telescopic complete denture and a mandibular removable partial denture. Considering the age of the patient and the cost involved, implant supported prosthesis was ruled out as a treatment option for the patient. A telescopic denture was chosen as a favourable treatment option since it overcomes many of the problems posed by conventional complete dentures like progressive bone loss, lower stability and retention, loss of periodontal proprioception and low masticatory efficiency. It also provides minimal tissue coverage and better distribution of forces. Evaluation of occlusion, esthetics, phonetics and comfort after 24 hours, 1 week and 1 month of treatment showed that the patient was happy with the prosthesis and was able to speak and chew well. Telescopic overdentures have better retention and stability as compared to conventional complete dentures. They improve the chewing efficiency, patient comfort and also decrease the alveolar bone resorption. As such they are an excellent alternative to conventional complete denture treatment.


Impact of biochemical failure classification on clinical outcome: a secondary analysis of Radiation Therapy Oncology Group 9202 and 9413.
Biochemical failure (BF) after radiation therapy is defined on the basis of a rising prostate-specific antigen (PSA) level (A1 failure) or any event that prompts the initiation of salvage androgen-deprivation therapy without PSA failure (A2). It was hypothesized that A2 failure may have a different prognosis. Data for 2799 eligible patients from Radiation Therapy Oncology Group (RTOG) 9202 and RTOG 9413 were analyzed. BF was defined according to the 1997 American Society for Therapeutic Radiology and Oncology consensus definition as A1 for PSA failure or as A2 for the start of salvage hormone therapy before 3 consecutive PSA rises. Rates of all-cause mortality (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.5-2.0; P < .0001) and distant metastasis (DM; HR, 1.6; 95% CI, 1.3-2.0; P < .0001) were greater with A2 failure. The 5-year overall survival (OS) rates were 88.2% and 74.6% for A1 and A2, respectively (P < .0001), and the DM rates were 15.7% and 29.0%, respectively (P < .0001). The DM rate was greater at 5 years for A2 patients with DM as the first sign of failure versus patients with other A2 failures (87.3% vs 11.7%, P < .001), and this also correlated with worse OS at 5 years: 81.1% for A2 failure without DM and 52.8% with DM (P < .001). After the removal of patients with DM, the difference between A1 and A2 BF persisted for OS (P = .002) but not for DM (P = .16) CONCLUSIONS: These results suggest that patients with rising PSA levels alone have less risk than those with A2 failures; although DM was the largest contributor of adverse risk to A2 failure, it did not account for all excess risk in A2 failure.


The application and prospects of 3D printable microgel in biomedical science and engineering.
Three-dimensional (3D) bioprinting technology is one of the most advanced techniques currently applied in tissue engineering and regenerative medicine and has developed rapidly in the past few years. Despite many breakthroughs, there are still several challenges of 3D bioprinting technology awaiting to be addressed, and one of them is the urgency of optimizing bioinks (natural or synthetic hydrogel), which are critical elements in 3D bioprinting, for specific properties. Different from traditional hydrogels, microgels, which are a new type of bioink, are micron-sized gels with excellent mechanical and biological properties, which make them great candidates for applications in 3D bioprinting. Different from the dense and limited pore size of traditional hydrogels, the pore structure of microgel is adjustable, enabling better cell loading before 3D bioprinting, and the printed pores are conducive to the exchange of metabolic substances and cell migration. The "bottom-up" modular microgel has stronger customizable characteristics, and it can freely adjust its mechanical properties, such as hardness, toughness, and rheological properties. In this review, we review the application of microgels in the field of biomedicine and discuss the future development of microgels in 3D bioprinting.


[Efficacy of Flectron-eartags (cypermethrin) for control of midges (Culicoides) as the vectors of bluetongue virus in cattle: field studies and biossays].
When in 2006 infection with bluetongue for the first time occurred in Germany the registered and already against flies and tabanids in cattle proofed Flectron ear tags were used against the blood feeding vector midges (Culicoides) also. However, the efficacy against gnats was not yet proofed. The efficacy of 1 and 2 ear tags (1,067 g cypermethrin per ear tag) per animal was investigated in North Germany with 237 heifers and dairy cows. Midges were caught in suction light traps close to the cattle on pasture or became trapped by mouth operated aspirators directly at the skin of the animal bodies. Within 12,051 specimens of midges 12 species of Culicoides could be identified. On grasslands 3 species, C. obsoletus, C. pulicaris and C. dewulfi were found to be dominant. These 3 species are also known to be vectors of BTV. The toxic efficacy was found for 14 days with 1 ear tag and up to 21 days with 2 ear tags. This duration of efficacy was confirmed in the laboratory with hair clippings from the dorsal line and the ventral abdomen (bioassay). In accordance with workers in the U.S.A. it is concluded that insecticide-impregnated ear tags will reduce the number of biting midges, and by this way the risk of infection with BTV in herds of treated cattle will be reduced as well as in other cattle of a particular region. It is concluded that ear tags are of considerable value as part of an integrated control program for BT, e.g. vaccination.


Air gun injury to the pericardium in a 9-year-old boy.
The authors present the case of a 9-year-old boy who sustained a gunshot injury to the pericardium by an air gun. The penetrative wound to the pericardium was, according to the performed pre-operative diagnostic methods, initially believed to be a penetrative wound into the cardiophrenic angle of the left pleural cavity. The stabilized patient was indicated for an extraction of the projectile through a left anterior minithoracotomy, during which the projectile was found and successfully removed from the pericardium. The limits of pre-operative assessment, optimal treatment procedures, and surgical approaches in pediatric patients with gunshot injuries to the chest and heart are discussed.


GSH-depleting metal-polyphenol-network nanoparticles with dual enzyme activities induce enhanced ferroptosis.
Ferroptosis is a non-apoptotic form of regulated cell death. The efficiency of ferroptosis is restrained in the tumor microenvironment (TME) by overexpression of glutathione (GSH) and insufficient production of hydrogen peroxide (H2O2). In this work, theranostic nanoparticles Ce-aMOFs@Fe3+-EGCG, termed MEFs, are developed by coating uniform Ce-based amorphous metal-organic frameworks (Ce-aMOFs) with epigallocatechin gallate (EGCG) and Fe3+. Fe3+ is chelated by the adjacent phenol hydroxyl groups in EGCG. In the tumor cell interior, overexpressed GSH and weak acidic medium degrade the coating to release Fe3+ and EGCG accompanied by exposure of Ce-aMOFs. Fe3+ and EGCG consume GSH along with turning Fe3+ into Fe2+. Ce-aMOFs act as a nanozyme possessing dual-enzymatic activities, i.e. superoxide dismutase (SOD)- and phosphatase-like activities. In the TME, Ce-aMOFs catalyze the conversion of endogenous superoxide (O2˙-) into H2O2, and Fe2+ catalyzes H2O2 to generate toxic hydroxyl radicals (˙OH), which may further induce tumor cell death through ferroptosis. In addition, the phosphatase-like activity of Ce-aMOFs may sustainably dephosphorylate NADPH and effectively inhibit intracellular biosynthesis of GSH. Therefore, MEFs ensure down-regulation of intracellular GSH levels and up-regulation of oxidative pressure, which enhance the ferroptosis effect.


Assessment of pathogenicity and tissue distribution of infectious bronchitis virus strains (Italy 02 genotype) isolated from moroccan broiler chickens.
Avian infectious bronchitis (IB) is one of the most important viral diseases of poultry, affecting chickens of all ages and causing major economic losses in poultry flocks. Mass vaccination is conducted in Morocco using a vaccine against Massachusetts, which is the most dominant serotype; however no information about the pathogenesis and tissue distribution of the Moroccan Italy 02 genotype was reported. 40 one-day-old specific pathogen free chickens were divided randomly into four groups. Group1, 2 and 3 were inoculated intra oculo-nasally with 103.5 EID50 of Italy02 viruses, and group 4 was kept as control. Chickens in each group were monitored for 14 days post-infection (pi). Chickens in all infected groups showed severe respiratory signs, which most of them have been reproduced on 2dpi, with varying times of appearance and disappearance. The infected birds appeared lethargic, reluctant to move, with specific respiratory clinical signs and macroscopic lesions. However no nephritis lesions or mortality were recorded in all groups. The specific histological lesions finding in all infected birds, exhibited tracheal lesions with mucosal thickening, hyperplasia of the surface epithelium, mononuclear inflammatory cell infiltrate of lamina propria. Primary and secondary bronchi, epithelial hyperplasia and mononuclear inflammatory cell infiltrate of the lamina propria were also observed. Tracheal lesions developed in all infected birds, confirm the ability of the three tested strains to induce respiratory disease. The results at 14 dpi also revealed that all strains were able to induce serological response. Virus re-isolation from infected organs and amplification of the viral RNA by real-time PCR proved the presence of the virus in lung and trachea of infected chicks. Neither re-isolation nor significant viral RNA detection were detected in the kidney. The results demonstrated that the three strains Italy02 genotype emerging in Moroccan poultry farms have a wide distribution for respiratory system, without kidney damage and without causing mortality.


The clinical diagnosis of subcutaneous tear of the Achilles tendon. A prospective study in 174 patients.
A study to determine the sensitivity, specificity, and positive and negative predictive values of several clinical diagnostic tests of subcutaneous Achilles tendon rupture was performed during a 13-year period. There were 174 patients with clinical diagnosis of unilateral complete subcutaneous Achilles tendon tear and 28 patients with unilateral suspected but no actual Achilles tendon tear. The following tests were used: palpation, calf squeeze, Matles, Copeland, and O'Brien. Palpation of the gap was the least sensitive clinical test with the patient awake (0.73), increasing to 0.81 when the test was performed under anesthesia; the Copeland and O'Brien tests showed a sensitivity of 0.8. Both the calf squeeze and Matles tests were significantly more sensitive than the other tests (0.96 and 0.88, respectively; 0.022 < P < 0.05). All tests showed a high positive predictive value, with no statistically significant difference between the various tests. In the 28 patients with no evidence of a subcutaneous Achilles tendon tear on imaging, the tests showed a high capability to detect that the Achilles tendon was intact (gap palpation specificity, 0.89; calf squeeze test specificity, 0.93; Matles test specificity, 0.85). Whichever tests were performed, at least two of them were positive for a subcutaneous tear of the Achilles tendon in all patients in this study.


Low molecular weight storage material in infantile ceroid lipofuscinosis (CLN1).
The identification of the genetic defect in CLN1 as a palmitoyl-protein thioesterase deficiency initiated a search for the lysosomal storage material. Pulse-chase labelling of fibroblasts and lymphoblastoid cell lines with [35S]cysteine revealed the presence of lipid [35S]cysteine material in CLN1 fibroblasts and not in controls, CLN2 or CLN3 patients or other patients with lipidosis. A single band comigrated with the acylcysteine standard and labelling with [3H]palmitate showed a band of material which eluted from the silicic acid column with the phospholipid fraction and which co-migrated with the lipid-[35S]cysteine band. The storage material is tentatively identified as palmitoylcysteine.


Tackling upper respiratory tract infections.
URTIs are the most common reason for general practice consultations. On average adults suffer two to three such infections per year. When assessing a patient with a URTI in general practice it is important to recognise which patients may require antibiotics, further investigations and/or hospital referral. NICE recommends immediate antibiotics or further investigation and/or management in the following patients who are at risk of complications: Systemically very unwell. Features suggestive of serious illness and complications. Pre-existing comorbidities Older than 65 years with acute cough and two or more of the following, or older than 80 years with acute cough and one or more of the following: hospitalisation in the previous year; diabetes; history of congestive heart failure; current use of oral glucocorticoids. Antibiotics should also be considered for patients with three or more Centor criteria. In other cases (acute otitis media, acute sore throat/pharyngitis/acute tonsillitis, common cold, acute rhinosinusitis or acute cough/acute bronchitis) NICE advocates a no prescribing or delayed prescribing strategy. Most URTIs are self-managed. Patients who do seek consultations often benefit from reassurance, education and instructions for symptomatic home treatment.


Reduction in the incidence and severity of collagen-induced arthritis in DBA/1 mice, using exogenous dehydroepiandrosterone.
This study examined the effect of exogenous dehydroepiandrosterone (DHEA) on the onset, incidence, and severity of collagen-induced arthritis (CIA). DHEA was administered subcutaneously prior to arthritis induction in DBA/1 mice, and the severity of the subsequent arthritis was monitored. Serum levels of total IgG and IgG isotype-specific anti-murine type II collagen were measured. Repeated administration of DHEA during arthritis induction delayed the onset and decreased the severity of arthritis in male and female DBA/1 mice. DHEA failed to have an observable effect on established arthritis. IgG isotype autoantibody levels were found to be decreased in the sera of DHEA-treated mice. Administration of exogenous DHEA offered protection against the development of CIA. These data support the results of human studies in which low DHEA levels have been identified as a potential risk factor for the development of rheumatoid arthritis. These findings also highlight DHEA as a potential therapy worthy of further investigation.


Contracting and chaining to improve the performance of a college golf team: improvement and deterioration.
Recent work with operant procedures in sports has shown that feedback, reinforcement, and chaining can be effective techniques in improving performance. In many cases, however, a problem remains in getting the participants to practice the appropriate responses. In the present study, 14 college golfers were put on successive contingency contracts over three weeks to go through the Total Golf chaining-mastery program of Simek and O'Brien. Rewards consisted of activities such as spots on the starting team and the opportunity to play better courses as well as tangible rewards such as new golf balls. After the first two weeks of training, through 19 steps backward from the green, the mean of three posttraining rounds for these 14 golfers was 3.4 strokes lower than the mean of their three rounds at baseline. At this point, the coach did not follow through with the rewards promised in the second contract. Having been placed on extinction, only three of the 14 players followed through on the third contract. In this return to baseline-like condition an average increase of over two strokes for the team as a whole was noted. The number of steps of the chain mastered in practice and the difference between mean scores at baseline and the last measurement period correlated .86, indicating that 74% of the improvement in golf scores was accounted for by performance on the mastery chain.


Bronchoalveolar lavage eosinophilia associated with Pneumocystis carinii pneumonitis in AIDS patients. Comparative study with non-AIDS patients.
Lower pulmonary tract cell populations collected by bronchoalveolar lavages (BAL) were evaluated in three groups of immunocompromised patients: HIV infected patients with Pneumocystis carinii (PC) pneumonitis (n = 22), or pneumonitis not related to PC (n = 29), and non-HIV-infected, immunocompromised patients with a PC pneumonitis (n = 18). In AIDS patients with PC pneumonitis, the cell populations were 59.3 +/- 4.5 percent alveolar macrophages (AM), 19.6 +/- 2.5 percent lymphocytes, 14.6 +/- 4.4 percent polymorphonuclear cells (PMN), and 10.3 +/- 3.6 percent eosinophils. In HIV-infected patients without PC pneumonitis, they were 76.5 +/- 3.3 percent AM, 13 +/- 2.1 percent lymphocytes, 9.2 +/- 0.3 percent PMN, and 0.6 +/- 0.2 percent eosinophils, and in non-HIV-infected, immunocompromised patients with PC pneumonitis, they were 43.9 +/- 5.7 percent AM, 30.2 +/- 4.3 percent lymphocytes, 20.4 +/- 4.7 percent PMN, and 0.9 +/- 0.4 percent eosinophils. The most striking finding was a marked BAL eosinophilia in AIDS patients with PC pneumonitis. The significance of this particular cellular pulmonary response to PC is not clear, and its consequences on the lung structures and/or PC require evaluation.


Statins and their increased risk of inducing diabetes.
Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes (NOD) in randomized controlled trials and meta-analyses. This review provides an update based on recent outstanding evidence on the statin effect on the risk of diabetes. It also describes mechanisms potentially explaining adverse effects of statins on glucose homeostasis. PubMed was searched for original articles and reviews published from January 2010 (inclusive) to May 2015 (inclusive), which include the Search terms statins, diabetes, glucose, and insulin. NOD risk seems to be more relevant with high-intensity rather than with low-intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes. It appears that statins adversely affect glucose homeostasis in parallel with their 3-hydroxy-3-methylglutaryl-coenzyme A inhibition capacity. It was suggested that lipophilic statins are more diabetogenic than the hydrophilic ones. Mechanisms explaining statin diabetogeneicity include impaired insulin secretion by pancreatic β cells together with increased insulin resistance of various tissues. The CV outcome benefits from statin use outweigh the diabetes menace. However, patients at risk for the development of diabetes should be prescribed statins with caution.


[The problem of rehabilitation of children cerebral palsy].
The paper is devoted to the problem of early diagnosis and correction of development of children with perinatal lesion of the nervous system. Early rehabilitation treatment in children cerebral palsy (CCP) is necessary due to the plasticity of the child's brain and its universal ability to compensate for disturbed functions as well as due to the fact that the first two years of life are optimal for maturation of the speech functional system. Evidence for the differentiation of early, chronic and residual studies of CCP is presented. The authors emphasize the role of the pathology of the functional antigravitation system in the formation of motor-reflex disorders. Possibilities of pathogenetic treatment in each stage of disease are considered.


The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine.
The hypoxia-inducible factor (HIF)-1alpha and the HIF-like factor (HLF) transcription factors are regulated at multiple levels including protein stabilization, nuclear import, and activation of transactivation, resulting in recruitment of coactivators such as the cAMP-response element-binding protein (CREB)-binding protein (CBP)/p300 and SRC-1. During low oxygen tension these proteins modulate a network of genes that are necessary for angiogenesis, erythropopoiesis, and glycolysis. We report here that the C-terminal transactivation domain of HLF is phosphorylated on multiple sites and that phosphorylation on threonine 844 of HLF is necessary for the transcriptional activation function of the protein independently of the hypoxia condition. Importantly, using the mammalian two-hybrid system we demonstrate that a substitution of threonine 844 to an alanine decreased the enhanced transcriptional activation function mediated by CBP/p300.


Counterimmunoelectrophoretic studies of serum prostatic acid phosphatase.
A counterimmunoelectrophoretic (CIEP) assay for the specific determination of prostatic acid phosphatase (PAP) is described. PAP was obtained from benign human prostatic tissue and a specific antiserum to this enzyme was produced in rabbits and goats. The lowest detectable activity of PAP was at 0.3 IU/l or 4 ng./0.1 ml. This CIEP method was compared to a standard biochemical method (Roy) on a wide spectrum of prostatic and nonprostatic disease. Nonprostatic malignancies and other disorders associated with hyperacidphosphatasemia by the biochemical method were found to be nonreactive for PAP by CIEP. Patients under treatment with various stages of prostatic carcinoma showed comparable elevations by both methods (35%). In untreated patients, the CIEP was statistically most sensitive in stage A (39% by CIEP and 14% by chemical).


A case study of pure word deafness: modularity in auditory processing?
AL, a woman with an acquired disturbance of auditory processing beginning in the second decade, was originally diagnosed as having pure word deafness. Recent analysis with a wide range of stimuli suggests that her comprehension deficit also extends to a subset of musical and non-verbal environmental sounds. The perceptual demands of the different auditory stimuli appear to account for part of the apparent material specificity. Additionally, over the years, the presumed temporal lobe cortical pathology has been supplemented by a mild to moderate, peripheral low-frequency hearing loss and evidence of dysfunction in lower level auditory processing pathways. The current peripheral dysfunction closely resembles cases recently labeled as auditory neuropathy. The diagnosis of pure word deafness should not be based on a limited set of auditory stimuli; additionally, a careful assessment using modern audiological techniques should be performed to evaluate peripheral auditory functions.


Nonstereoselective aspects of propranolol pharmacodynamics.
Twenty years after its discovery, the beta-adrenergic blocking agent propranolol continues to interest pharmacologists and clinicians. Its therapeutic profile has extended to areas beyond the purview of the cardiovascular system, and its ocular and central nervous system effects have been well documented. In addition, it still remains a very good pharmacological tool to map out the adrenergic beta-receptors in the body, and stereoisomers of propranolol and other beta-blockers serve as valuable agents to distinguish between the effects related to beta-adrenoceptors and those which are not. The primary purpose of this review is to summarize the evidence indicating that beta-adrenergic blocking agents lack stereoselectivity in some of their effects, including several of considerable therapeutic importance. Because many pharmacological actions of propranolol followed a nonsteroselective pattern, the involvement of beta-adrenoceptors in them was questioned and this led to the search for alternate mechanisms to explain these effects. Studies with propranolol and some related drugs indicated the involvement of a cholinergic mechanism in their antiarrhythmic, ocular hypotensive and some central effects. Also, a presynaptic inhibitory effect at the skeletal neuromuscular junction has been suggested to explain the benefical effect of propranolol and other beta-blockers in tremor. Biochemical studies with these drugs revealed their inhibitory action on the cholinesterase enzyme in blood and other tissues like myocardium and brain. It is thus hypothesized that modulation of cholinergic neurotransmission by propranolol could explain some of its nonstereoselective actions and open new vistas in propranolol pharmacodynamics.


Analytical Methods for Metformin Estimation.
Metformin is a widely prescribed oral anti-hyperglycemic agent used in the management of non-insulin dependent diabetes mellitus (NIDDM) or type II diabetes. This article accentuates various analytical methods viz. HPLC, HPTLC, spectrophotometric, electrochemical, capillary electrophoresis and LC-MS for the estimation of metformin in pharmaceutical formulations and in biological matrices.


Mode of action towards oligopeptides and proteins of hydrolase H, a high-molecular-weight aminoendopeptidase from rabbit skeletal muscle.
The mode of action towards oligopeptides and proteins of hydrolase H purified from rabbit skeletal muscle was studied. The presence of protamine or alpha-N-benzoylarginine p-nitroanilide (an endopeptidase substrate) changed both the Km and V values of the enzyme towards Leu-beta-naphthylamide (an aminopeptidase substrate). This indicates that the binding site for an endopeptidase substrate is different from that for an aminopeptidase substrate. Hydrolase H as an aminopeptidase displayed broad specificity. The enzyme hydrolyzed various dipeptides readily except the dipeptides containing Pro or an amino acid with a hydrophobic beta-branched chain at the NH2 terminus. Pro and Val at the NH2 terminus of tripeptides were also difficult to release, whereas Ile and Val of tetrapeptides were easily released in contrast with those of dipeptides. The longer the peptide chain of Glyn (n = 2, 3, 4), the more susceptible was it to hydrolase H. Hydrolase H behaved as an endopeptidase only towards protamine among the proteins tested. The other proteins, casein, bovine serum albumin, myofibrils, troponin, hemoglobin, sarcoplasmic proteins, and myoglobin were probably attacked only by the aminopeptidase activity of the enzyme.


Impaired plasma nitric oxide availability and extracellular superoxide dismutase activity in healthy humans with advancing age.
This study is aimed to verify the modifications of extracellular superoxide dismutase (EC-SOD) activity and its potential involvement on the mechanism responsible for the impairment of plasma nitric oxide (NO) availability occurring with advancing age in healthy humans. For this purpose, plasma samples were drawn from 40 healthy men, aged 20-92 years, in fasting state and used for measurements of stable end-product nitrite/nitrate (NOx), as expression of NO availability, EC-SOD activity, thiobarbituric acid reactive substances (TBARS) as marker of lipid peroxidation, Trolox equivalent antioxidant capacity (TEAC) as a measure of plasma total antioxidant capacity, and in vitro susceptibility of low density lipoprotein (LDL) to copper-mediated oxidation, evaluated as lag time. As indicated by our results, advancing age was significantly related to decreased plasma values of NOx (r = -0.877, P < 0.001), EC-SOD activity (r = -0.888, P < 0.001), TEAC (r = -0.647, P < 0.001) and lag time (r = -0.621, P < 0.001) as well as to an increased plasma amount of TBARS (r = 0.858, P < 0.001). NOx plasma level resulted independently predicted by EC-SOD activity and age. EC-SOD activity, in turn, was determined by age and TEAC. Taken together, findings of the present study give further insight into the mechanism related to age-associated endothelial dysfunction, indicating that the decreased EC-SOD activity may be involved in the progressive reduction of plasma NO availability with advancing age through the age-related impairment of oxidant/antioxidant balance.


Time-limited psychiatric hospitalization of children: a model and three-year outcome.
Current emphasis on reducing length of hospital stay has stimulated a review of the philosophical, clinical, and administrative approaches to brief psychiatric hospitalization of children. A model of time-limited hospitalization on an eight-bed children's unit was designed to stabilize the patients and triage them back to appropriate levels of community aftercare within 28 days. Clinical and administrative strategies used to facilitate this process included a community-based case manager for each patient, focused clinical intervention, and strong parent involvement. The treatment model was generally successful in meeting the goals of hospitalization. Of 212 admissions over three years, 37 percent of the patients at discharge continued to need complex, multi-modal treatments, and 63 percent were referred for less intensive outpatient care.


Evolutionary dynamics and the phase structure of the minority game.
We show that a simple evolutionary scheme, when applied to the minority game (MG), changes the phase structure of the game. In this scheme each agent evolves individually whenever his wealth reaches the specified bankruptcy level, in contrast to the evolutionary schemes used in the previous works. We show that evolution greatly suppresses herding behavior, and it leads to better overall performance of the agents. Similar to the standard nonevolutionary MG, the dependence of the standard deviation sigma on the number of agents N and the memory length m can be characterized by a universal curve. We suggest a crowd-anticrowd theory for understanding the effect of evolution in the MG.


Beta-tricalcium phosphate delivery system for bone morphogenetic protein.
An aggregate of biodegradable beta-tricalcium phosphate and bone morphogenetic protein (BMP/TCP) induces the differentiation of cartilage within eight days, cartilage and woven bone within 12 days, and lamellar bone, including bone marrow, within 21 days. The yield of new bone from a 1-mg dose was more than 12 times greater from the TCP/BMP than from the BMP alone. Whether TCP acts as a slow-release delivery system, potentiates the activity of BMP, or serves to distribute BMP in a favorable three-dimensional pattern requires further investigation.


The emerging role of proteolysis in mitochondrial quality control and the etiology of Parkinson's disease.
Mitochondria are highly dynamic organelles that are important for many diverse cellular processes, such as energy metabolism, calcium buffering, and apoptosis. Mitochondrial biology and dysfunction have recently been linked to different types of cancers and neurodegenerative diseases, most notably Parkinson's disease. Thus, a better understanding of the quality control systems that maintain a healthy mitochondrial network can facilitate the development of effective treatments for these diseases. In this perspective, we will discuss recent advances on two mitochondrial quality control pathways: the UPS and mitophagy, highlight how new players may be contributing to regulate these pathways. We believe the proteases involved will be key and novel regulators of mitochondrial quality control, and this knowledge will provide insights into future studies aimed to combat neurodegenerative diseases.


Current guidelines for the management of celiac disease: A systematic review with comparative analysis.
Wheat and other gluten-containing grains are widely consumed, providing approximately 50% of the caloric intake in both industrialised and developing countries. The widespread diffusion of gluten-containing diets has rapidly led to a sharp increase in celiac disease prevalence. This condition was thought to be very rare outside Europe and relatively ignored by health professionals and the global media. However, in recent years, the discovery of important diagnostic and pathogenic milestones has led to the emergence of celiac disease (CD) from obscurity to global prominence. These modifications have prompted experts worldwide to identify effective strategies for the diagnosis and follow-up of CD. Different scientific societies, mainly from Europe and America, have proposed guidelines based on CD's most recent evidence. To identify the most recent scientific guidelines on CD, aiming to find and critically analyse the main differences. We performed a database search on PubMed selecting papers published between January 2010 and January 2021 in the English language. PubMed was lastly accessed on 1 March 2021. We distinguished guidelines from 7 different scientific societies whose reputation is worldwide recognized and representative of the clinical practice in different geographical regions. Differences were noted in the possibility of a no-biopsy diagnosis, HLA testing, follow-up protocols, and procedures. We found a relatively high concordance between the guidelines for CD. Important modifications have occurred in the last years, especially about the possibility of a no-biopsy diagnosis in children. Other modifications are expected in the next future and will probably involve the extension of the non-invasive diagnosis to the adult population and the follow-up modalities.


Role of STN1 and DNA polymerase α in telomere stability and genome-wide replication in Arabidopsis.
The CST (Cdc13/CTC1-STN1-TEN1) complex was proposed to have evolved kingdom specific roles in telomere capping and replication. To shed light on its evolutionary conserved function, we examined the effect of STN1 dysfunction on telomere structure in plants. STN1 inactivation in Arabidopsis leads to a progressive loss of telomeric DNA and the onset of telomeric defects depends on the initial telomere size. While EXO1 aggravates defects associated with STN1 dysfunction, it does not contribute to the formation of long G-overhangs. Instead, these G-overhangs arise, at least partially, from telomerase-mediated telomere extension indicating a deficiency in C-strand fill-in synthesis. Analysis of hypomorphic DNA polymerase α mutants revealed that the impaired function of a general replication factor mimics the telomeric defects associated with CST dysfunction. Furthermore, we show that STN1-deficiency hinders re-replication of heterochromatic regions to a similar extent as polymerase α mutations. This comparative analysis of stn1 and pol α mutants suggests that STN1 plays a genome-wide role in DNA replication and that chromosome-end deprotection in stn1 mutants may represent a manifestation of aberrant replication through telomeres.


Differential colocalization of Islet-1 and estrogen receptor alpha in the murine preoptic area and hypothalamus during development.
Estrogen receptor (ER) expression and regulation is vital to the correct functioning of the neuroendocrine brain. Islet-1 (Isl-1) is a LIM homeodomain-containing transcription factor that has been implicated in neuronal differentiation, is located in the hypothalamus, and can alter ER function in vitro. We have determined that Isl-1 is localized in several regions of the hypothalamus, including the ER rich areas of the ventromedial nucleus (VMH), the preoptic area, and the anterior hypothalamus. Using double-label immunocytochemistry, we examined the overlap between immunoreactive ERalpha and Isl-1 in these different hypothalamic brain regions. In the developing brain, almost 100% of VMH cells that contain immunoreactive ERalpha also contain Isl-1. However, in older animals, the percentage of double-label cells decreased below 70%. This change is due to a decrease in the number of cells containing Isl-1, because there was no difference in the number of ERalpha-containing cells. By contrast, in more anterior regions of the hypothalamus, cells containing both Isl-1 and ERalpha were less common, with the two populations adjacent to each other, rather than overlapping. These data suggest that, although Isl-1 and ERalpha can interact, they are not always found in the same cells and that regulation of ERalpha function is not under the same control in the VMH, preoptic area, and the anterior hypothalamus.


Postnatal delayed exacerbation of dural sinus malformation associated with brainstem cavernous malformations: A case report.
Dural sinus malformation (DSM) is a rare paediatric vascular malformation characterised by abnormal dilation of the posterior dural sinus. Owing to its rarity, the pathophysiology of DSM has not been fully elucidated. We report a case of prenatally diagnosed DSM with an unusual clinical course. We detected DSM in a male foetus in the 26th week of gestation by using foetal ultrasonography. Although the DSM regressed during the foetal stage and the arteriovenous shunt was insignificant in the neonate, the shunt rapidly developed four months after birth. The neonate also had postnatal de novo brainstem cavernous malformation (CM), which also developed rapidly, supposedly due to the aggravated venous hypertension resulting from the DSM. We successfully treated the aggravated shunts by endovascular transarterial and transvenous embolisation six times over two years and, subsequently, the clinical condition and the size of the brainstem CM became stable. The DSM and CM seemed to have a metameric origin. Such aberrant cases could help to further the understanding of DSM.


Determination of mercury in fish tissue using a minianalyzer based on cold vapor atomic absorption spectrometry at the 184.9 nm line.
A sensitive method was proposed and optimized for the determination of total mercury in fish tissue by using wet digestion, followed by cold vapor atomic absorption spectrometry (CVAAS) at the main resonance line of mercury (184.9 nm). The measurements were made using a new type of a non-dispersive mercury minianalyzer. This instrument was initially designed and built for atmospheric mercury-vapor detection. For determining mercury in aqueous samples, the minianalyzer was linked with a mercury/hydride system, Perkin Elmer Model MHS-10. To check the method, the analyzed samples were spiked with a standard solution of mercury. The recoveries of mercury spiked to wet fish tissue were >90% for 0.5 - 0.8 g samples. The results showed a better sensitivity (about 2.5 times higher) when using the mercury absorption line at 184.9 nm compared with the sensitivity obtained by conventional CVAAS at 253.7 nm.


Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors.
The Drosophila immune system discriminates between various types of infections and activates appropriate signal transduction pathways to combat the invading microorganisms. The Toll pathway is required for the host response against fungal and most Gram-positive bacterial infections. The sensing of Gram-positive bacteria is mediated by the pattern recognition receptors PGRP-SA and GNBP1 that cooperate to detect the presence of infections in the host. Here, we report that GNBP3 is a pattern recognition receptor that is required for the detection of fungal cell wall components. Strikingly, we find that there is a second, parallel pathway acting jointly with GNBP3. The Drosophila Persephone protease activates the Toll pathway when proteolytically matured by the secreted fungal virulence factor PR1. Thus, the detection of fungal infections in Drosophila relies both on the recognition of invariant microbial patterns and on monitoring the effects of virulence factors on the host.


[An introduction to the Institute of History of Medicine in Medical School of Johns Hopkins University].
The Institute of History of Medicine in Medical School of Johns Hopkins University is a well-known institute in the world. It includes the department of history of medicine, a historic collection, a library of history of medicine and an Editorial Board of the Bulletin of History of Medicine, embodying the tasks of teaching, researching and publication. The faculty members are active and outstanding in lots of fields of history of medicine. It leads the latest research on history of medicine with extensive research scope and active academic activities.


Longer trinucleotide repeats of androgen receptor are associated with higher testosterone and low oxytocin levels in diabetic premature ejaculatory dysfunction patients.
Despite its worldwide high occurrence, the obscurity regarding the description, epidemiology and management of premature ejaculation remains provocative. It is well established that male premature ejaculatory dysfunction is an increasing problem due to spontaneous ejaculation across a variety of general and clinical subjects. The main goal of this study was to determine the relationships between trinucleotide repeats of the androgen receptor (AR), sex steroids, and pituitary hormones with sexual function in men with type 2 diabetes mellitus (DM) and reported with acquired premature ejaculation (PE). A total of 150 normal and 250 PE + DM subjects were enrolled in this study. Each subject was invited to fill out an elaborative questionnaire to acquire precise selective information regarding BMI, duration of PE + DM, self-reported Intra-Vaginal Ejaculatory Latency Time (IELT), sexual and mental health status by using the premature ejaculation diagnostic tool (PEDT) and Beck Depression Inventory-II (BDI-II). Pearson's correlation analysis was used to analyze the relationship between clinical, hormonal, and genetic variables. Ward's minimum variance cluster analysis and principal component analysis were used for evaluation of dependence between genetic, clinical, and demographic parameters. The patients who have the lowest number of (≤21) (CAG)n repeats have higher serum oxytocin levels (114.2 pg/ml; n = 54, 43.2%) than the controls (69.18 pg/ml; n = 22, 17.6%) and the patients with the highest (≥26) number of (CAG)n repeats (62.9 pg/ml; n = 108, 43.2%).On the other hand, patients who have the highest numbers of (CAG)n repeats (≥26) have higher serum testosterone (6.1 ng/ml; n = 108, 43.2% of cohort) lower prolactin (3.01 ng/ml; n = 108, 43.2% of cohort) levels than the controls and patients with the lowest numbers (≤21) of (CAG)n repeats and their TSH (1.53 mIU/L, P < 0.05) levels are lower than those of controls. In the Pearson correlation model, self-estimated IELT demonstrated significantly negative correlation with both (CAG)n and (GCC)n repeats (r = - 0.16, p = 0.0001; r = - 0.19, p = 0.0001) respectively. These repeats have positive correlation with PEDT (r = 0.28, p = 0.0001: r = 0.24, p = 0.0001, whole model) and inversely correlated with BDI-II (r = - 0.25, p = 0.0001). This study indicates that androgen receptor polymorphism modulates the endocrine effect on ejaculatory reflex and depends strongly on its "cofactors". Moreover, our results also confirmed an association between long tri-nucleotide repeats of androgen receptor, sex steroids, pituitary, and thyroid hormones in relation to acquired premature ejaculatory dysfunction in diabetic patients. However, endocrine regulation of PE reflex is a complex phenomenon that requires further investigation.


In vitro vasorelaxing activity of suloctidil.
The vasorelaxing effect of suloctidil was evaluated in isolated rat and rabbit aorta and in isolated rabbit mesenteric and saphenous artery. Suloctidil inhibited contractions induced by increasing extracellular calcium in depolarized arteries, mainly in a competitive way. In the rat aorta, the pA2 value was 7.50 for suloctidil, while pA2 values of 9.96, 7.90 and 8.10 were obtained for nifedipine, cinnarizine and verapamil, respectively. Suloctidil more potently inhibited calcium-induced contractions in small arteries (mesenteric and saphenous artery), than in the aorta. Suloctidil also reduced the tonic component of the responses to norepinephrine. In contrast to the effects on calcium-induced contractions, the effects of suloctidil on norepinephrine-induced responses was mainly noncompetitive. In addition, and unlike cinnarizine and verapamil, high concentration of suloctidil also reduced the phasic component of contractile responses to norepinephrine. Furthermore, unlike nifedipine, verapamil, diltiazem and cinnarizine, suloctidil was devoid of a negative inotropic effect in spontaneously beating guinea-pig atria. In conclusion, suloctidil behaves as a Ca2+-channel blocker in arteries and displays an additional mode of action that could include receptor-operated Ca2+-channels or an intracellular site of action. In addition, suloctidil was found to affect small arteries more than the aorta, and not to affect the atria.


The voltage-gated Na+ channel NaVBP has a role in motility, chemotaxis, and pH homeostasis of an alkaliphilic Bacillus.
The prokaryotic voltage-gated Na(+) channel, NaChBac, is one of a growing channel superfamily of unknown function. Here we show that Na(V)BP, the NaChBac homologue encoded by ncbA in alkaliphilic Bacillus pseudofirmus OF4, is a voltage-gated Na(+) channel potentiated by alkaline pH. Na(V)BP has roles in motility, chemotaxis, and pH homeostasis at high pH. Reduced motility of bacteria lacking functional Na(V)BP was reversed by restoration of the native channel but not by a mutant Na(V)BP engineered to be Ca(2+)-selective. Motile ncbA mutant cells and wild-type cells treated with a channel inhibitor exhibited behavior opposite to the wild type in response to chemoeffectors. Mutants lacking functional Na(V)BP were also defective in pH homeostasis in response to a sudden alkaline shift in external pH under conditions in which cytoplasmic [Na(+)] is limiting for this crucial process. The defect was exacerbated by mutation of motPS, the motility channel genes. We hypothesize that activation of Na(V)BP at high pH supports diverse physiological processes by a combination of direct and indirect effects on the Na(+) cycle and the chemotaxis system.


Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine.
The thienopyridine derivatives ticlopidine and clopidogrel are inhibitors of ADP-induced platelet aggregation. Pharmacological activity of these prodrugs depends on cytochrome P450 (P450)-dependent oxidation to the active antithrombotic agent. In this study, we investigated the interaction potential of clopidogrel and ticlopidine by using human liver microsomes and recombinantly expressed P450 isoforms. Both clopidogrel and ticlopidine inhibited CYP2B6 with highest potency and CYP2C19 with lower potency. Clopidogrel also inhibited CYP2C9, and ticlopidine also inhibited CYP1A2, with lower potency. Inhibition of CYP2B6 was time- and concentration-dependent, and as shown by dialysis experiments, it was irreversible and dependent on NADPH, suggesting a mechanism-based mode of action. Inactivation was of nonpseudo-firstorder type with maximal rates of inactivation (K(inact)) for clopidogrel and ticlopidine in microsomes (recombinant CYP2B6) of 0.35 (1.5 min(-1)) and 0.5 min(-1) (0.8 min(-1)), respectively, and half-maximal inactivator concentrations (KI) were 0.5 microM (1.1 microM) for clopidogrel and 0.2 microM (0.8 microM) for ticlopidine. Inhibition was attenuated by the presence of alternative active site ligands but not by nucleophilic trapping agents or reactive oxygen scavengers, further supporting mechanism-based action. A chemical mechanism is discussed based on the known metabolic activation of clopidogrel and on the finding that hemoprotein integrity of recombinant CYP2B6 was not affected by irreversible inhibition. These results suggest the possibility of drug interactions between thienopyridine derivates and drug substrates of CYP2B6 and CYP2C19.