Venetoclax: a promising repurposed drug against SARS-CoV-2 main protease.
Global health care emergency caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) demands urgent need to repurpose the approved pharmaceutical drugs. Main protease, Mpro of SARS-CoV-2 draws significant attention as a drug target. Herein, we have screened FDA approved organosulfur drugs (till 2016) and our laboratory synthesized organosulfur and organoselenium compounds (L1-L306) against Mpro-apo using docking followed by classical MD simulations. Additionally, a series of compounds (L307-L364) were chosen from previous experimental studies, which were reported to exhibit inhibitory potentials towards Mpro. We found several organosulfur drugs, particularly Venetoclax (FDA approved organosulfur drug for Leukemia) to be a high-affinity binders to the Mpro of SARS-CoV-2. The results reveal that organosulfur compounds including Venetoclax preferentially bind (non-covalently) to the non-catalytic pocket of the protein located in the dimer interface. We found that the ligand binding is primarily favoured by ligand-protein van der Waals interaction and penalized by desolvation effect. Interestingly, Venetoclax binding alters the local flexibility of Mpro and exerts pronounced effect in the C-terminal as well as two loop regions (Loop-A and Loop-B) that play important roles in catalysis. These findings highlighted the importance of drug repurposing and explored the non-catalytic pockets of Mpro in combating COVID-19 infection in addition to the importance of catalytic binding pocket of the protein.Communicated by Ramaswamy H. Sarma.


Investigation of Drug-Polymer Compatibility Using Chemometric-Assisted UV-Spectrophotometry.
A simple chemometric-assisted UV-spectrophotometric method was used to study the compatibility of clindamycin hydrochloride (HC1) with two commonly used natural controlled-release polymers, alginate (Ag) and chitosan (Ch). Standard mixtures containing 1:1, 1:2, and 1:0.5 w/w drug-polymer ratios were prepared and UV scanned. A calibration model was developed with partial least square (PLS) regression analysis for each polymer separately. Then, test mixtures containing 1:1 w/w drug-polymer ratios with different sets of drug concentrations were prepared. These were UV scanned initially and after three and seven days of storage at 25 °C. Using the calibration model, the drug recovery percent was estimated and a decrease in concentration of 10% or more from initial concentration was considered to indicate instability. PLS models with PC3 (for Ag) and PC2 (for Ch) showed a good correlation between actual and found values with root mean square error of cross validation (RMSECV) of 0.00284 and 0.01228, and calibration coefficient (R²) values of 0.996 and 0.942, respectively. The average drug recovery percent after three and seven days was 98.1 ± 2.9 and 95.4 ± 4.0 (for Ag), and 97.3 ± 2.1 and 91.4 ± 3.8 (for Ch), which suggests more drug compatibility with an Ag than a Ch polymer. Conventional techniques including DSC, XRD, FTIR, and in vitro minimum inhibitory concentration (MIC) for (1:1) drug-polymer mixtures were also performed to confirm clindamycin compatibility with Ag and Ch polymers.


A study of morbidity pattern among prostitutes attending a municipal clinic in Pune.
The findings of the present study revealed that out of 200 prostitutes attending a clinic for various ailments, 81.50% were suffering from sexually transmitted diseases (STD) thus posing a potential risk of transmitting these diseases to their clients. Syphilis was found to be the commonest STD afflicting 36.80% of the respondents, the next common being the chancroid (31.28%); 5.52% of the respondents were found to be suffering from concomitant venereal infections. The other important communicable diseases with which some respondents were found to be afflicted, included--tinea infection (3 cases), scabies (2 cases), leprosy (2 cases), pulmonary tuberculosis (4 cases) and upper respiratory tract infection [3 cases). Thus, the prostitutes remain an undisputed potential source of infection not only of STDs but also several other communicable diseases. Therefore, their continuous surveillance, early diagnosis, appropriate treatment and subsequent follow-up should be meticulously carried out. On the other hand the public, particularly the sexually promiscuous individuals must be imparted vigorous health education to avoid exposure to this source.


Modelling time-varying risk factors of tooth loss: Results from joint model compared with extended Cox regression model.
To illustrate the use of joint models (JMs) for longitudinal and survival data in estimating risk factors of tooth loss as a function of time-varying endogenous periodontal biomarkers (probing pocket depth [PPD], alveolar bone loss [ABL] and mobility [MOB]). We used data from the Veterans Affairs Dental Longitudinal Study, a longitudinal cohort study of over 30 years of follow-up. We compared the results from the JM with those from the extended Cox regression model which assumes that the time-varying covariates are exogenous. Our results showed that PPD is an important risk factor of tooth loss, but each model produced different estimates of the hazard. In the tooth-level analysis, based on the JM, the hazard of tooth loss increased by 4.57 (95% confidence interval [CI]: 2.13-8.50) times for a 1-mm increase in maximum PPD, whereas based on the extended Cox model, the hazard of tooth loss increased by 1.60 (95% CI: 1.37-1.87) times. JMs can incorporate time-varying periodontal biomarkers to estimate the hazard of tooth loss. As JMs are not commonly used in oral health research, we provide a comprehensive set of R codes and an example dataset to implement the method.


Membrane-bound complement regulatory activity is decreased on vaccinia virus-infected cells.
Decay accelerating factor (DAF), membrane cofactor protein (MCP), complement receptor 1 and mouse Crry are cell surface-bound complement regulatory proteins capable of inhibiting C3 convertase activity on cell membranes, and therefore provide a substantial protection from attack by homologous complement activated either by the classical or by the alternative pathway. Decrease in complement regulatory activity might lead to spontaneous complement deposition and subsequent cell injury. MoAb 5I2 can inhibit the complement regulatory activity of molecules on rat cells, resulting in deposition of homologous complement. The antigen recognized by 5I2 MoAb in rats is homologous to mouse Crry. Fifteen to 20 h after infection with vaccinia virus, in vitro cultured KDH-8 rat hepatoma cells show a strong decrease in expression of Crry-like antigen, and proved to be sensitive to complement deposition when 1:5 diluted normal rat serum was added to the culture medium as a source of complement. Addition of complement to the cultured KDH-8 cells infected with a very low dose of vaccinia virus (1 plaque-forming unit (PFU)/1000 cells) substantially reduced spreading of virus infection in the cell culture, while inactivation of complement by heat or zymosan treatment abrogated the protective effect.


Acupuncture Treatment for Acute Ankle Injury in the Emergency Department: A Preliminary Case Report.
Acupuncture is an ancient medical treatment that is increasingly attracting the interest of the public. It is a complementary therapy that is widely used for management of pain, especially chronic discomfort caused by migraine, low-back pain and osteoarthritis of the knee(¹⁻³). The evidence base for the effectiveness of acupuncture and its clinical applications is controversial, and although its efficacy and safety in the management of acute pain have been demonstrated, the quality of this modality is still questionable. The present study reports a case of acute ankle injury, which was treated with acupuncture. A 33-year-old man presented with acute twisted ankle injury. He had pain with swelling around the ankle, and he was experiencing difficulty in walking. His clinical diagnosis was acute ankle sprain with severe pain. Several drug treatments are used for pain control, but in this case, we used acupuncture. After treatment, his pain diminished significantly with a decrease in VAS pain level from 8 to 4 in 20 minutes. At follow-up after one month, we found no skin infection in this case.


Association Between Age and Complications After Outpatient Colonoscopy.
There are insufficient data describing the incidence and risk factors of postcolonoscopy complications in older individuals. To assess the association between older age (≥75 years) and the risk of postcolonoscopy complications. This population-based retrospective cohort study included adults (≥50 years) undergoing outpatient colonoscopy between April 2008 and September 2017, identified from Ontario administrative databases. Individuals with inflammatory bowel disease and hereditary colorectal cancer syndromes were excluded. The study population was subdivided into a colorectal cancer screening-eligible cohort (patients aged 50-74 years) and an older cohort (patients aged ≥75 years). The statistical analysis was conducted from December 2018 to September 2019. Older age (≥75 years). The primary outcome was postcolonoscopy complications, defined as the composite of hospitalization or emergency department visits in the 30-day period after the outpatient colonoscopy. Secondary outcomes included incidence of surgically treated colorectal cancer and all-cause mortality at 30 days. Independent variables associated with postcolonoscopy complications were also assessed. The study sample included 38 069 patients; the mean (SD) age was 65.2 (10.1) years, there were 19 037 women (50.0%), and 27 831 patients (73.1%) underwent a first colonoscopy. The cumulative incidence of complications was 3.4% (1310 patients) in the overall population, and it was higher in individuals aged 75 years or older (515 of 7627 patients [6.8%]) than in screening-eligible cohort (795 of 30 443 patients [2.6%]) (P < .001). Independent risk factors for postcolonoscopy complications were age 75 years or older (odds ratio [OR], 2.3; 95% CI, 2.0-2.6), anemia (OR, 1.4; 95% CI, 1.2-1.7), cardiac arrhythmia (OR, 1.7; 95% CI, 1.2-2.2), congestive heart failure (OR, 3.4; 95% CI, 2.5-4.6), hypertension (OR, 1.2; 95% CI, 1.0-1.5), chronic kidney disease (OR, 1.8; 95% CI, 1.1-3.0), liver disease (OR, 4.7; 95% CI, 3.5-6.5), smoking history (OR, 3.2; 95% CI, 2.4-4.3), and obesity (OR, 2.3; 95% CI, 1.2-4.2). The number of previous colonoscopies was associated with a lower risk of complications (OR, 0.9; 95% CI, 0.7-1.0). The incidence of surgically treated colorectal cancer was higher in the older cohort than the screening-eligible cohort (119 patients [1.6%] vs 144 patients [0.5%]; P < .001). All-cause mortality rates were 0.1% overall (39 patients) and 0.1% (19 patients) for individuals aged 50 to 74 years and 0.2% (20 patients) for those aged 75 years and older (P < .001). In this population-based cohort study of individuals living in southern Ontario, age of 75 years and older was associated with a higher risk of 30-day postprocedure complications after outpatient colonoscopy. These findings suggest that the decision to perform a colonoscopy should be carefully considered in patients older than 75 years, especially in the presence of comorbidities. Further studies are needed to better understand the benefits of invasive procedures as opposed to less invasive approaches for colorectal cancer screening and surveillance among older patients.


Examination of Matching Methods, Sparse Effects, and Limitations in a Nationwide Database Study on Alzheimer's Disease.
Akada et al. conducted a nationwide database study on patients with Alzheimer's disease, examining risk factors and outcomes over 3 years. A significant association emerged between decreased daily activities and hip fractures. However, the odds ratio was 1.95 (with p = 0.020) may be inaccurate in men, considering the wide 95% confidence interval (1.12-3.51). Possible influencing factors include an inappropriate outcome variable, sparse-data bias, collinear covariates, and comorbidities. Moreover, exact propensity-score matching would be more efficient than nested matching. Limitations include potential recall bias in measuring daily activities and limited applicability of cause-effect relationships in a national database study.


Prevalence of airflow obstruction in nonsmoking older individuals using different spirometric criteria: the AGES Reykjavik Study.
The prevalence and characteristics of airway obstruction in older individuals varies widely with the definition used. We used a random sample of never smoking older population in Iceland to compare the prevalence and clinical profile of subjects diagnosed with Chronic Obstructive Pulmonary Disease (COPD) based on different spirometric criteria. The study uses data from the Age, Gene/Environment Susceptibility-Reykjavik Study, comprising survivors from the Reykjavik Study. Procedures included standardized questionnaires and pre-bronchodilator spirometry for measurement of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Total of 495 individuals (150 men and 345 women) met study criteria. Mean age 77 years (range 66-92 years) using fixed ratio (FEV1/FVC < 70%) up to 29% of the population were diagnosed with COPD Stage I. The prevalence of COPD increased with age. Only 7 among 495 (1.4%) were diagnosed with COPD using FEV1/FVC LLN and FEV1 LLN. Application of the GOLD criteria for diagnosis of COPD in older lifelong never smoking subjects identifies a substantial number of non-symptomatic subjects as having COPD. If airway obstruction is defined by FEV1/FVC and FEV1 being below the LLN using appropriate reference equations, only very few non-smoking older individuals fulfill the criteria for COPD.


Time-dependent phenomena in the potential response of ion-selective electrodes treated by the Nernst-Planck-Poisson model. 1. Intramembrane processes and selectivity.
The variability of selectivity coefficients, resulting from potential changes over time and the concentration ratio of primary to interfering ions, impedes many practical applications of ion-selective electrodes (ISEs). Existing theoretical interpretations of ISE selectivity are restricted by severe assumptions, such as steady state and electroneutrality, which hinder theorizing on this problem. For this reason, for the first time, the Nernst-Planck-Poisson equations are used to predict and visualize the selectivity variability over time and the concentration ratio. Special emphasis is placed on the non-Nernstian response in the measurements with liquid-ion-exchanger- and neutral-carrier-based ISEs. The conditions under which measured selectivity coefficients are true (unbiased) are demonstrated.


[Penetrating injuries of the heart and great vessels].
Between January 1975 and June 2000 565 patients with thoracic injuries were treated at our institution. 116 of them had penetrating thoracic traumas and 42 injuries of the heart and great vessels. Study includes two groups of patients: hemodynamic stable and hemodynamic unstable ones. Different algorithms of management, techniques, treatment and prognosis are described. In the group of hemodynamic unstable patients the emergency surgical treatment had to be performed sometimes even without the benefit of any radiological imaging method. Mortality rate of patients having reached the hospital equated 23.8%. The surgical treatment results were better in the past decade because of improvement in prehospital care and higher quality of emergency medical system. The possibility of fast transportation allowed a higher percentage of critically injured patients to reach the hospital alive.


Dihydrorhodamine 123 is superior to 2,7-dichlorodihydrofluorescein diacetate and dihydrorhodamine 6G in detecting intracellular hydrogen peroxide in tumor cells.
Dihydrorhodamine 123 (DHR 123), 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA), and dihydrorhodamine 6G (DHR 6G) were evaluated as probes for detecting cellular hydrogen peroxide levels in SPC-A-1 lung adenocarcinoma cells. Imaging techniques and fluorescence-activated cell scan were used in the study of the probe responses. Obvious green fluorescence was established after a 25-min exposure. After staining with MitoTracker Orange CM-H2TMRos (a probe for mitochondria) and the abovementioned probes simultaneously, only the DHR 123 and DHR 6G groups exhibited legible green fluorescence in the mitochondrial regions. Furthermore, the DHR 6G group exhibited weaker fluorescence intensity. When 100 microM H2O2 was added to SPC-A-1 cells loaded with these probes, the intracellular fluorescence increased rapidly and significantly. Our results suggest that DHR 123 is superior for the instantaneous detection of cellular hydrogen peroxide in SPC-A-1 cells.


A systematic review of Bisphenol A "low dose" studies in the context of human exposure: a case for establishing standards for reporting "low-dose" effects of chemicals.
Human exposure to the chemical Bisphenol A is almost ubiquitous in surveyed industrialized societies. Structural features similar to estrogen confer the ability of Bisphenol A (BPA) to bind estrogen receptors, giving BPA membership in the group of environmental pollutants called endocrine disruptors. References by scientists, the media, political entities, and non-governmental organizations to many toxicity studies as "low dose" has led to the belief that exposure levels in these studies are similar to humans, implying that BPA is toxic to humans at current exposures. Through systematic, objective comparison of our current, and a previous compilation of the "low-dose" literature to multiple estimates of human external and internal exposure levels, we found that the "low-dose" moniker describes exposures covering 8-12 orders of magnitude, the majority (91-99% of exposures) being greater than the upper bound of human exposure in the general infant, child and adult U.S. Population. "low dose" is therefore a descriptor without specific meaning regarding human exposure. Where human exposure data are available, for BPA and other environmental chemicals, reference to toxicity study exposures by direct comparison to human exposure would be more informative, more objective, and less susceptible to misunderstanding.


Pathologic characteristics of second breast cancers after breast conservation for ductal carcinoma in situ.
The number of women diagnosed with ductal carcinoma in situ (DCIS) is increasing. Although many eventually develop a second breast cancer (SBC), little is known about the characteristics of SBCs. The authors described the characteristics of SBC and examined associations between the pathologic features of SBC and index DCIS cases. Women were identified in the National Comprehensive Cancer Network Outcomes Database who were diagnosed with DCIS from 1997 to 2008 and underwent lumpectomy and who subsequently developed SBC (including DCIS or invasive disease that occurred in the ipsilateral or contralateral breast). The Fisher exact test and the Spearman test were used to examine associations between the pathologic characteristics of SBC and index DCIS cases. Among 2636 women who underwent lumpectomy for DCIS, 150 (5.7%) experienced an SBC after a median of 55.5 months of follow-up. Of these 150 women, 105 (70%) received adjuvant radiotherapy, and 50 (33.3%) received tamoxifen for their index DCIS. SBCs were ipsilateral in 54.7% of women and invasive in 50.7% of women. Among the index DCIS cases, 60.6% were estrogen receptor (ER)-positive, and 54% were high grade, whereas 77.5% of SBCs were ER-positive, and 48.2% were high grade. Tumor grade (P = .003) and ER status (P = .02) were associated significantly between index DCIS and SBC, whereas tumor size was not (P = .87). After breast conservation for DCIS, SBC in either breast exhibited pathologic characteristics similar to the index DCIS, suggesting that women with DCIS may be at risk for developing subsequent breast cancers of a similar phenotype.


Synthesis and central nervous system activities of certain fluorine-containing 3-substituted indol-2-ones.
Several fluorine-containing 3- aroylmethyl -3-hydroxyindol-2-ones (4a-g), 3- aroylmethyleneindol -2-ones (5a-g) and 3- aroylmethylindol -2-ones (6a-g) were synthesized from the corresponding fluorine-containing indole-2,3-diones and appropriate ketones. The compounds were characterized by spectral studies. Representative compounds of each series were tested on mice for CNS activities, viz. analgesic and anticonvulsant and the effects were also observed against amphetamine-induced stereotypy, on conditioned avoidance response and on potentiation of pentobarbitone sodium hypnosis. Of the compounds examined, the greatest degree of activity was observed in 3- aroyl - methyleneindol -2-ones with a pronounced unsaturation in the system.


Chronic Subdural Hematoma in Women.
Sex differences in various diseases recently have been recognized as an important factor in the approach to more efficient preventive and therapeutic medicine. We clarified sex differences in the clinical characteristics of chronic subdural hematoma (CSDH) by comparing men and women with CSDH, as there is a well-known male predominance in the prevalence of CSDH. Clinical factors and computed tomography findings were investigated retrospectively in 490 consecutive patients admitted to our hospital between 2006 and 2015 who were diagnosed with CSDH. On univariate analysis, women were significantly older than men (P < 0.05). In women, premorbid impaired activities of daily living, consciousness disturbance, acute-to-chronic subdural hematoma, and death as outcomes at discharge were significantly more frequent than in men (P < 0.05). In contrast, women had less frequent instances of good recovery and less alcohol intake (P < 0.05). Multivariate analysis demonstrated female sex as an independent predictor of consciousness disturbance at admission. Female sex also was identified as a predictor of death at discharge. We demonstrated sex differences in the clinical characteristics of CSDH. In the future, management of patients with CSDH with regard to sex differences in disease characteristics could be expected to improve the outcomes of women, which have been worse than in men.


A quantitative stereological study of the area of cortical surface in the monkey, pig and cat cerebrum.
An unbiased stereological method (the 'vertical section') has been available since the 1980s for the area estimation of an arbitrary surface. Using this methodology, the ratio of the inner (folded) cerebral cortical surface area, to that of the outer surface, was estimated to be about 2 in Man. We have used the same morphometric techniques to study the cerebrum of seven monkeys, six pigs and six cats. The results demonstrated that the ratios were similar in monkeys (1.22 +/- 0.21, SD) and pigs (1.00 +/- 0.22), and that both were significantly larger than the ratio in cats (0.71 +/- 0.18).


Exercise intensities modulate ACE2/MasR/eNOS pathway in male Wistar rat's lung.
Specific exercise intensities could improve lung vascular function by increasing nitric oxide (NO). The ACE2/MasR/eNOS axis is one of the pathways facilitating NO synthesis. This study examines the effect of different intensities of aerobic training on the ACE2/MasR/eNOS axis and histology of lung muscular arteries. Male Wistar rats were used in this study and randomized into control and exercise groups receiving low-, moderate-, and high-intensity training. The training was conducted for 30 min daily, five times a week, for 8 weeks. We observed that different exercise intensities affect the ACE2/MasR/eNOS pathway differently. Compared to control, high-intensity aerobic exercise significantly increased ACE2, Mas receptor (MasR), and eNOS mRNA expressions (p < 0.01). Moderate-intensity exercise significantly increased MasR and eNOS mRNA expressions compared to the control (p < 0.05), and this intensity also increased ACE2 mRNA but not significantly. Low-intensity exercise increased ACE2, MasR, and eNOS mRNA expressions but not significantly. Low-, moderate-, or high-intensity exercises reduced the medial wall thickness of the lung muscular arteries but not significantly. In conclusion, high-intensity exercise may induce NO synthesis in the lung by increasing mRNA expression of ACE2, MasR, and eNOS without decreasing the medial wall thickness of the muscular artery. Thus, high-intensity exercise may be the optimal intensity to improve NO synthesis and vascular function in the lung.


Changes in plasma growth hormone (GH) and secretion patterns of GH and luteinizing hormone in buffaloes (Bubalus bubalis) during growth.
To assess the changes of plasma growth hormone (GH) and secretion patterns of GH and luteinizing hormone (LH) during growth in buffaloes, six growing female Murrah buffalo calves (mean age 6+/-0.9 months and body weight 66+/-6 kg) were selected. Plasma samples were collected twice a week for 52 weeks for GH and LH assay. To examine for pulsatile secretion samples were collected at 15 minutes interval for 9 hr at weeks 6 and 42 for GH and LH measurements. Plasma progesterone was also estimated in twice-a-week samples to assess whether any of the buffalo had begun ovarian cyclicity. The body weight of all animals was recorded at weekly interval. Plasma GH concentration decreased (P < 0.01) only up to week 29 and showed an increasing trend (P < 0.01) thereafter. The ratio of plasma GH to body weight declined (P < 0.01) throughout the entire experimental period. Plasma GH showed a declining trend only up to when the animals attained 155 kg body weight and thereafter showed an increasing trend (P < 0.01). Plasma GH revealed distinct pulsatile patterns of release, with a mean of 6 and 5 pulses in the 6-week and 42-week samples, respectively. The plasma LH concentrations around the 42-week time period were significantly higher (P < 0.01) than at the 6-week time period, and they exhibited pulsatility. No animal reached puberty until the end of the experiment. In summary, plasma GH levels have a definite pattern of change during growth and patterns of secretion of plasma GH and LH also have a relation with body weight in this species of animal.


[Significance and course of a cold agglutinin in Eperythrozoon suis infection of swine].
After infection with Eperythrozoon suis, pigs began to produce cold agglutinins of immunoglobulin type IgM, that because of the similarity between the pathogenic antigen and antigen on the erythrocyte membrane caused agglomeration. The progression of this cold agglutinin was measured with an enzyme immunoassay especially invented for this purpose, and compared with serum-IgM, agglutination strength, pathogenic effect as well as number of erythrocytes in the blood. The cold agglutinin extracted from the erythrocyte membrane at 40 degrees C showed, in comparison to the initial figures, a higher level (1259 micrograms/ml) at 6 days after the illness peak, reaching its maximum (2435 micrograms/ml) at 12 days. Similar results were achieved at lower extraction temperatures (22 degrees C, 0 degree C). A high correlation could be shown between the levels of IgM and of cold agglutinin, as well as the parallel increase in the agglutination strength of the blood. At the time of maximal pathogenic effect, no agglutination of blood was observed. The number of erythrocytes decreased in acute phases of an attack to a constant mean of 2.32 Mill./microliters of blood and then increased, at the same rate as the cold agglutinin level decreased, almost reaching normal values. These experiments confirm the fact that an organism following an infection with Eperythrozoon suis, begins to produce cold agglutinins. Due to structural similarities between the pathogen and the erythrocyte antigen the cold agglutinin causes temperature dependent agglutination.(ABSTRACT TRUNCATED AT 250 WORDS)


[Serogrouping of Escherichia coli from urinary tract infections (author's transl)].
Serological grouping with 44 anti-O-sera was performed on 215 E. coli strains isolated from urine of patients with significant bacteriuria. 95 strains (44.2%) were typable, 34 strains (15.8%) proved to be rough strains, and 86 strains (40%) were untypbale. The O-groups 2, 6, 9 and 75 were found to be more frequent in patients with chronic pyelonephritis. Among pregnant women with asymptomatic bacteriuria a typical frequency was not observed.


Regulator of Chromosome Condensation 1-Domain Protein DEK47 Functions on the Intron Splicing of Mitochondrial Nad2 and Seed Development in Maize.
In flowering plants, mitochondrial genes contain approximately 20-26 introns. Splicing of these introns is essential for mitochondrial gene expression and function. Recent studies have revealed that both nucleus- and mitochondrion-encoded factors are required for intron splicing, but the mechanism of splicing remains largely unknown. Elucidation of the mechanism necessitates a complete understanding of the splicing factors. Here, we report the identification of a regulator of chromosome condensation 1 (RCC1)-domain protein DEK47 that is required for mitochondrial intron splicing and seed development in maize. Loss of function in Dek47 severely arrests embryo and endosperm development, resulting in a defective kernel (dek) phenotype. DEK47 harbors seven RCC1 domains and is targeted to mitochondria. Null mutation of DEK47 causes a deficiency in the splicing of all four nad2 introns, abolishing the production of mature nad2 transcript and resulting in the disassembly and severely reduced activity of mitochondrial complex I. In response, the expression of the alternative oxidase AOX2 is sharply increased in dek47. These results indicate that Dek47 is required for the splicing of all the nad2 introns in mitochondria, and essential for complex I assembly, and kernel development in maize.


Animal models of cancer pain.
Modern cancer therapies have significantly increased patient survival rates in both human and veterinary medicine. Since cancer patients live longer they now face new challenges resulting from severe, chronic tumor-induced pain. Unrelieved cancer pain significantly decreases the quality of life of such patients; thus the goal of pain management is to not only to alleviate pain, but also to maintain the patient's physiological and psychological well-being. The major impediment for developing new treatments for cancer pain has been our limited knowledge of the basic mechanisms that drive cancer pain and the lack of adequate animal cancer pain models to study the molecular, biochemical and neurobiological pathways that generate and maintain cancer pain. However this situation has recently changed with the recent development of several novel animal models of cancer pain. This review will focus on describing these animal models, many of them in rodents, and reviewing some of the recent information gained from the use of these models to investigate the basic mechanims that underlie the development and maintenance of cancer pain. Animal models of cancer pain can be divided into the following five categories: bone cancer pain models, non-bone cancer pain models, cancer invasion pain models, cancer chemotherapeutic-induced peripheral neuropathy models, and spontaneous occurring cancer pain models. These models will be important not only for enhancing our knowledge of how cancer pain is generated, but more importantly for the development of novel therapeutic regimes to treat cancer pain in both domestic animals and humans.


Fever in the neurosurgical patient.
Patients with central nervous system trauma frequently have fevers while in the neurosurgical intensive care unit. Temperature elevations in the neurosurgical patient often cause much diagnostic confusion, and little is written that assists the critical care team in arriving at a proper etiologic diagnosis for the fever. This article discusses the common causes of temperature elevations in neurosurgical patients, such as central fever, wound infection, nosocomial pneumonia, posterior fossa syndrome, line sepsis, urosepsis, and drug fever. The recognition of central fevers, posterior fossa syndrome, and drug fevers is particularly important in neurosurgical patients to avoid inappropriate and potentially dangerous treatment with unnecessary antimicrobial therapy. Clinical and laboratory clues provide the clinician with a diagnostic approach to fever in the neurosurgical intensive care setting.


Towards a human proteome atlas: high-throughput generation of mono-specific antibodies for tissue profiling.
A great need exists for the systematic generation of specific antibodies to explore the human proteome. Here, we show that antibodies specific to human proteins can be generated in a high-throughput manner involving stringent affinity purification using recombinant protein epitope signature tags (PrESTs) as immunogens and affinity-ligands. The specificity of the generated affinity reagents, here called mono-specific antibodies (msAb), were validated with a novel protein microarray assay. The success rate for 464 antibodies generated towards human proteins was more than 90% as judged by the protein array assay. The antibodies were used for parallel profiling of patient biopsies using tissue microarrays generated from 48 human tissues. Comparative analysis with well-characterized monoclonal antibodies showed identical or similar specificity and expression patterns. The results suggest that a comprehensive atlas containing extensive protein expression and subcellular localization data of the human proteome can be generated in an efficient manner with mono-specific antibodies.


Incidence of bilateral Marcus Gunn jaw-wink.
This case report describes the unusual finding of bilateral Marcus Gunn jaw-wink. Only a few bilateral jaw-wink patients have been published as case reports. The authors dispute this notion as portrayed in the literature that a bilateral wink is a rare entity. A thorough review of prior case series on congenital ptosis and jaw-wink demonstrates that bilateral involvement is more common than previously thought. A supplemental video shows the classic action of lateral pterygoid contraction causing ipsilateral eyelid retraction.


Genomic O island 122, locus for enterocyte effacement, and the evolution of virulent verocytotoxin-producing Escherichia coli.
The locus of enterocyte effacement (LEE) and genomic O island 122 (OI-122) are pathogenicity islands in verocytotoxin-producing Escherichia coli (VTEC) serotypes that are associated with outbreaks and serious disease. Composed of three modules, OI-122 may occur as "complete" (with all three modules) or "incomplete" (with one or two modules) in different strains. OI-122 encodes two non-LEE effector (Nle) molecules that are secreted by the LEE type III secretion system, and LEE and OI-122 are cointegrated in some VTEC strains. Thus, they are functionally linked, but little is known about the patterns of acquisition of these codependent islands. To examine this, we conducted a population genetics analysis, using multilocus sequence typing (MLST), with 72 VTEC strains (classified into seropathotypes A to E) and superimposed on the results the LEE and OI-122 contents of these organisms. The wide distribution of LEE and OI-122 modules among MLST clonal groups corroborates the hypothesis that there has been lateral transfer of both pathogenicity islands. Sequence analysis of a pagC-like gene in OI-122 module 1 also revealed two nonsynonymous single-nucleotide polymorphisms that could help discriminate a subset of seropathotype C strains and determine the presence of the LEE. A nonsense mutation was found in this gene in five less virulent strains, consistent with a decaying or inactive gene. The modular nature of OI-122 could be explained by the acquisition of modules by lateral transfer, either singly or as a group, and by degeneration of genes within modules. Correlations between clonal group, seropathotype, and LEE and OI-122 content provide insight into the role of genomic islands in VTEC evolution.


The attenuation effect in timing: counteracting dual-task interference with time-judgment skill training.
A basic finding in the time-perception literature is an interference effect in dual-task conditions involving concurrent timing and distractor tasks. Dual-task conditions typically cause time judgments to become less accurate than single-task conditions in which subjects judge time alone. Previous research (Brown, 1998 Psychological Research 61 71-81; Brown and Bennett, 2002 Psychological Research 66 80-89) has shown that practice on the distractor task reduces interference, a phenomenon called the attenuation effect. The present research was designed to determine whether practice on the time-judgment task would produce a similar result. In experiment 1, subjects reproduced 6-14 s intervals in a series of practice trials. Some subjects received feedback regarding the accuracy of each response and others received no feedback. Subsequent testing under dual-task (timing + digit memory) conditions showed that feedback training reduced interference. In experiment 2, the practice trials included both single-task and dual-task conditions. Later tests showed that feedback training eliminated the interference effect. The results highlight the role of attentional resources, the transfer of skills, and compensatory decision processes in time-judgment skill training.


Perioperative post graduate education.
This article describes post-graduate perioperative education in Australia at the Australian Catholic University and St. Vincent's Public Hospital: The Graduate Certificate in Perioperative Practice. The Australian Catholic University operates from eight campuses along the east coast of Australia. There are approximately 9000 students along with 1000 staff. The University consists of major faculties that all have clear relevance to the workplace-namely Arts and Sciences, Education and Health Sciences. Qualifications are offered at Certificate of Doctoral level studies in the areas of business, education, ethics, human movement, management, information systems, music, nursing, religion, social work and theology.


Wave-vortex interaction.
We present an experimental study of the effect of an electromagnetically generated vortex flow on parametrically amplified waves at the surface of a vertically vibrated fluid layer. The underlying vortex flow, generated by a periodic Lorentz force, creates spatiotemporal fluctuations that nonlinearly interact with the standing surface waves. We measure the power spectral density of the surface wave amplitude and we characterize the bifurcation diagram by recording the subharmonic response of the surface to the external vibration. We show that the parametric instability is delayed in the presence of spatiotemporal fluctuations due to the vortex flow. In addition, the dependence of the amplitude of the subharmonic response on the distance to the instability threshold is modified. This shows that the nonlinear saturation mechanism of the waves is modified by the vortex flow.


Characterization of the expression of the Cek8 receptor-type tyrosine kinase during development and in tumor cell lines.
Cek8 is a receptor-type tyrosine kinase gene that was identified by screening a 10 day chicken embryo library with a DNA probe corresponding to the related kinase Cek4 (Sajjadi & Pasquale, 1993). Here we report the characterization of the Cek8 protein and its expression in embryonic tissues and tumor cell lines. The 120 kd Cek8 protein is detected early in embryogenesis, is developmentally regulated and preferentially, but not exclusively, expressed in neural tissues. In the stage 24 chick embryo, Cek8 immunoreactivity is prominent in the spinal cord and spinal nerves. At embryonic day 6, Cek8 expression becomes concentrated to the ventral portion of the spinal nerves, suggesting a role in axonogenesis of specific subsets of neurons. Cek8 is expressed in nearly all of the tumor cell lines examined, including cell lines derived from tumors of the central nervous system. Although the phosphorylation on tyrosine of Cek8 during development is moderate or undetectable, Cek8 is substantially phosphorylated on tyrosine (and thus presumably activated) in many of the transformed cell lines. Because of its high frequency of expression in tumor cell lines, Cek8 differs from previously investigated Eph-related kinases. However, as we show, Cek8 is not unique among the Eph-related kinases: another member of the Eph subclass, Cek5, has similar patterns of expression and phosphorylation in tumor cells. Based on its binding to a variety of lectin columns, Cek8 contains complex N-linked oligosaccharides. Cross-linking of Cek8 molecules on the cell surface with wheat germ agglutinin caused their rapid phosphorylation on tyrosine. Autophosphorylation on tyrosine is typically the first step in the activation of a receptor tyrosine kinase by a ligand.


Two cases of late-onset drug-induced lupus erythematosus caused by ticlopidine in elderly men.
We have experienced two cases of drug-induced lupus erythematosus caused by ticlopidine in the last three years. Both were late-onset cases (1 and 4 years) that occurred in elderly men (76 and 81 years old). The common features were fever, arthralgia, myalgia, serositis, and the presence of anti-histone autoantibodies. Because ticlopidine is widely used in elderly people with ischemic vascular disease, ticlopidine-induced lupus should be considered when patients taking ticlopidine present lupus-like symptoms.


Larval myogenesis in Echinodermata: conserved features and morphological diversity between class-specific larval forms of Echinoidae, Asteroidea, and Holothuroidea.
The myogenesis of class-specific larval forms of three classes belonging to the phylum Echinodermata (Echinoidae, Asteroidea, and Holothuroidea) was investigated via gross-anatomy and comparative morphology of larval muscles. Using staining with phalloidin and antibodies against the muscle proteins, with subsequent CLSM and 3D imaging, we have examined myogenesis in the larvae from the gastrula stage to pre-metamorphosis larval stages. We have shown that temporal and spatial expression of muscle proteins is similar in echinoidea and asteroidea larvae but differs in holothuroidea larvae at early developmental stages. New insights regarding the protein composition of maturing muscular fibrils during development in echinoderm larvae were detected. The first differentiating muscle structures in all tested classes have been found to be circular esophageal muscles that are associated with larval feeding. During early differentiation of echinoderm larval muscle cells, we observed that the expression patterns of the muscle proteins were not uniform but with a characteristic diffuse distribution, which is typical for smooth muscle. An unusual pattern of expression of the muscle proteins was detected in larval sphincters: the thick muscle proteins were first expressed during the early developmental stages, whereas F-actin appeared at later stages. In addition, paired star-shaped muscles were revealed in the mature Echinoidae plutei, but were absent in the Asteroidea, and Holothuroidea larvae. All tested species of Echinodermata exhibited both conserved features of muscle morphology during development indicating a common life history strategy and a planktonic habitat, and also an extensive morphological diversity representing specific anatomical adaptations during development.


Quorum sensing molecules production by nosocomial and soil isolates Acinetobacter baumannii.
Acinetobacter species remain alive in hospitals on various surfaces, both dry and moist, forming an important source of hospital infections. These bacteria are naturally resistant to many antibiotic classes. Although the role of the quorum sensing system in regulating the virulence factors of Acinetobacter species has not been fully elucidated, it has been reported that they play a role in bacterial biofilm formation. The biofilm formation helps them to survive under unfavorable growth conditions and antimicrobial treatments. It is based on the accumulation of bacterial communication signal molecules in the area. In this study, we compared the bacterial signal molecules of 50 nosocomial Acinetobacter baumannii strain and 20 A. baumannii strain isolated from soil. The signal molecules were detected by the biosensor bacteria (Chromobacterium violaceum 026, Agrobacterium tumefaciens A136, and Agrobacterium tumefaciens NTL1) and their separation was determined by thin-layer chromatography. As a result, it has been found that soil-borne isolates can produce 3-oxo-C8-AHL and C8-AHL, whereas nosocomial-derived isolates can produce long-chain signals such as C10-AHL, C12-AHL, C14-AHL and C16-AHL. According to these results, it is possible to understand that these signal molecules are found in the infection caused by A. baumannii. The inhibition of this signaling molecules in a communication could use to prevent multiple antibiotic resistance of these bacteria.


[An electron microscopic histochemical study on the localization of sialic acids in human trabecular meshwork].
The localization of sialic acids in human trabecular meshworks of normal eyes, primary open angle glaucoma (POAG) eyes, congenital glaucoma eyes, and juvenile glaucoma eyes was investigated using biotinyl lectin (LPA, SSA, MAM) and avidin-gold electron microscopic histochemistry. Gold particles were detectable in fine fibrils underneath Schlemm's canal and collagen fibers of normal, POAG, congenital glaucoma, and juvenile glaucoma eyes equally. Many gold particles were detected especially in fine fibrils and basal membrane (compact tissue) 3 microns underneath Schlemm's canal. The present study indicated that extracellular matrices of congenital glaucoma and juvenile glaucoma contained sialic acids and that this may be related to the ocular hypertension of these diseases.


Nucleoside and nucleobase transporters of primary human cardiac microvascular endothelial cells: characterization of a novel nucleobase transporter.
Levels of cardiovascular active metabolites, like adenosine, are regulated by nucleoside transporters of endothelial cells. We characterized the nucleoside and nucleobase transport capabilities of primary human cardiac microvascular endothelial cells (hMVECs). hMVECs accumulated 2-[3H]chloroadenosine via the nitrobenzylmercaptopurine riboside-sensitive equilibrative nucleoside transporter 1 (ENT1) at a V(max) of 3.4 +/- 1 pmol.microl(-1).s(-1), with no contribution from the nitrobenzylmercaptopurine riboside-insensitive ENT2. Inhibition of 2-chloroadenosine uptake by ENT1 blockers produced monophasic inhibition curves, which are also compatible with minimal ENT2 expression. The nucleobase [3H]hypoxanthine was accumulated within hMVECs (K(m) = 96 +/- 37 microM; V(max) = 1.6 +/- 0.3 pmol.microl(-1).s(-1)) despite the lack of a known nucleobase transport system. This novel transporter was dipyridamole-insensitive but could be inhibited by adenine (K(i) = 19 +/- 7 microM) and other purine nucleobases, including chemotherapeutic analogs. A variety of other cell types also expressed the nucleobase transporter, including the nucleoside transporter-deficient PK(15) cell line (PK15NTD). Further characterization of [3H]hypoxanthine uptake in the PK15NTD cells showed no dependence on Na(+) or H(+). PK15NTD cells expressing human ENT2 accumulated 4.5-fold more [3H]hypoxanthine in the presence of the ENT2 inhibitor dipyridamole than did PK15NTD cells or hMVECs, suggesting trapping of ENT2-permeable metabolites. Understanding the nucleoside and nucleobase transporter profiles in the vasculature will allow for further study into their roles in pathophysiological conditions such as hypoxia or ischemia.


Factors affecting the depth of cure of UV-polymerized composites.
Knoop hardness measurements of UV-polymerized dental composites showed that, at a certain depth below the surface, the degree of cure rapidly decreases. The depth of cure was found to be critically dependent on the UV source and exposure time used. A theoretical model was derived which was in quantitative accord with the results.


Hypomethylation and reactivation of the asparagine synthetase gene induced by L-asparaginase and ethyl methanesulfonate.
Successful chemotherapeutic treatment of drug-responsive cancers can be compromised by the acquisition of drug resistance. Standard remission induction therapy for childhood acute lymphoblastic leukemia includes L-asparaginase, since the leukemic cells lack asparagine synthetase (AS) activity and require exogenous asparagine. We have used the Chinese hamster ovary cell line N3, which lacks AS activity, as a model to examine a novel mechanism involved in the development of drug resistance in acute lymphoblastic leukemia. Expression of AS in Chinese hamster ovary cells is associated with hypomethylation in the 5' region of the gene. Activation of AS in concert with hypomethylation occurs spontaneously at a frequency of about 10(-6); we have found that treatment with the hypomethylating drug 5-azacytidine induces a reversion frequency of 10(-2). To investigate the possibility that chemotherapeutic drugs induce similar changes, the asparagine auxotrophic cell line N3 was treated with the chemotherapeutic agents L-asparaginase, vincristine, and 1-beta-D-arabinofuranosylcytosine and with the mutagen ethyl methanesulfonate. Both L-asparaginase and ethyl methanesulfonate increased the frequency of reversion to asparagine prototrophy to about 10(-5), whereas vincristine and 1-beta-D-arabinofuranosylcytosine had no such effect. Asparagine prototrophy correlated with the demethylation of CpG sites in the 5' region of the AS gene and with the appearance of AS mRNA in revertants. In addition to the specific effect seen with the AS gene, L-asparaginase and ethyl methanesulfonate induced global reductions in methylation of up to 25 and 10%, respectively. The ability of chemotherapeutic drugs to inhibit DNA methylation and thereby activate previously silent genes may enable them to promote the aggressiveness of cancers in vivo, including the expression of drug resistance.


Dopaminergic medication normalizes aberrant cognitive control circuit signalling in Parkinson's disease.
Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease, but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in Parkinson's disease by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 ms resolution) functional MRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 Parkinson's disease patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signalling in frontoparietal-basal ganglia circuits in Parkinson's disease patients OFF medication. Importantly, aberrant signalling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in Parkinson's disease patients. These findings were specific to causal signalling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signalling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in Parkinson's disease. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in Parkinson's disease patients OFF medication. However, dopaminergic medication in Parkinson's disease patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.


[Nicolas Andry and orthopedics].
The publication of "Orthopédie" by Andry in 1741 promoted a comprehensive approach to children's deformities, introducing both a new word and a twisted tree emblem, which now delineate a modern speciality. A brief appreciation of Andry's book and stormy career focusses on the limitations of his work, which was written for parents. The etymological constraints of orthopaedy are noted, its suggested rivals discussed and the unsatisfactory adaptations of the word in English high-lighted. "Orthopaedics", a deformed adjective used as a noun, and "pediatric orthopaedics" are defective absurdities which could be remedied by a new, accurate and all-embracing noun "orthosurgery".


[Removal of the kidney following in situ perfusion].
Kidneys of potential donors undergoing sudden cardiac arrest are generally not gathered because the warm ischemia time is too long until nephrectomy. A rapid in situ cold perfusion technique was developed to preserve kidneys in 21 brain-dead patients after cardiac arrest not responding to cardiac resuscitation. In 7 of the 21 potential donors, the in situ perfusion was unsuccessful. In 14 other subjects this technique permitted to save 15 transplantable kidneys; 1 month after grafting, the renal function was similar to that observed in kidneys gathered in living patients. The in situ perfusion technique allows to increase by nearly 10% the efficacy of kidney gathering.


Suppression of dyskinesias in advanced Parkinson's disease. I. Continuous intravenous levodopa shifts dose response for production of dyskinesias but not for relief of parkinsonism in patients with advanced Parkinson's disease.
We characterized the clinical dose-response curves for relief of parkinsonism and production of dyskinesias as a function of plasma levodopa and 3-O-methyldopa levels in six patients with advanced Parkinson's disease (PD) and fluctuating responses to oral levodopa/carbidopa. Dose response to ramped intravenous levodopa infusion was measured after overnight drug withdrawal on two occasions: first after chronic, intermittent oral levodopa/carbidopa, and second after 3 to 5 days of continuous intravenous levodopa. Continuous intravenous levodopa shifted the dyskinesia dose-response curve to the right, reduced maximum dyskinesia activity, but did not significantly alter dose response for relief of parkinsonism. Improvement in dyskinesia was apparent by the second day of continuous levodopa, during which ratios of plasma dopa/3-O-methyldopa remained constant. Our results support the hypothesis that relief of parkinsonism and production of dyskinesia by levodopa occur by separate mechanisms.


Aesthetic reconstruction of retroauricular keloid: Creating a keystone flap from the mastoid-helix area.
Advances in aesthetic rhinoplasty using conchal cartilage grafts have led to a high occurrence of retroauricular keloids. The purpose of this study is to introduce our surgical experiences using a keystone flap in retroauricular keloids following conchal cartilage grafts. The present study is a retrospective review of patients with pathologically confirmed retroauricular keloids following conchal cartilage grafts. These cases were surgically excised and we covered the defect with a keystone flap followed by one-time steroid injection at postoperative day 14 and silicone gel sheeting application for 3 months. Treatment outcome was recorded as recurrence or non-recurrence. In all patients, a follow-up period of minimum 12 months was required. Of these patients, 90.0% had successful treatment of their auricular keloids, whereas 10.0% had recurrences. The postoperative course was uneventful. In conclusion, our aesthetic reconstruction using a keystone flap created from the mastoid-helix area is a useful treatment strategy in terms of retroauricular keloids following conchal cartilage grafts.


Assessment of Institutional Implementation Research Capacity of the National Institutes of Health D43 Network.
Implementation science enhances the efficient practice of solutions from research to real-world application. Low- and lower- to middle-income countries may benefit significantly from implementation research given their limited resources. The National Institutes of Health Fogarty International Center D43 network consists of partnerships between foreign and U.S.-based institutions and aims to strengthen global health research. This paper assesses the D43 network's implementation research focus and training capacity. A survey was distributed to 387 program directors of ongoing and completed D43 projects. Preliminary results show 51.7% of respondents describe "increasing implementation research capacity" as a "high priority." Only 24.8% of faculty in implementation science received formal training, and 60.3% of D43 programs lacked an implementation research training program. Results show there is an increasing need for implementation research but that more can be done to develop implementation research capacity and training. The low response rate of 18% is a limitation of this study.


Extensive thrombosis after COVID-19 vaccine: cause or coincidence?
A 62-year-old Caucasian female patient presented with abdominal pain, vomiting and fever 1 day after administration of COVID-19 vaccine. Bloodwork revealed anaemia and thrombocytosis. Abdominal CT angiography showed a mural thrombus at the emergence of the coeliac trunk, hepatic and splenic arteries, and extensive thrombosis of the superior and inferior mesenteric veins, splenic and portal veins, and the inferior vena cava, extending to the left common iliac vein. The spleen displayed extensive areas of infarction. Aetiological investigation included assessment of congenital coagulation disorders and acquired causes with no relevant findings. Administration of COVID-19 vaccine was considered a possible cause of the extensive multifocal thrombosis. After reviewing relevant literature, it was considered that other causes of this event should be further investigated. Thrombosis associated with COVID-19 vaccine is rare and an aetiological relationship should only be considered in the appropriate context and after investigation of other, more frequent, causes.


Delayed dopamine treatment of segmental small intestinal ischaemia in the rat.
Two groups of rats were subjected to segmental ischaemia of the small intestine for 2 h. According to our previous findings such ischaemia causes impairment of the central circulation as well as of the splanchnic blood flow. Dopamine treatment was initiated 30 or 90 min after the establishment of ischaemia. In the 30-min group cardiac output increased and the blood flow was normalized in those parts of the small intestine where the arteries were not ligated (the non-occluded parts). This result corresponds well to our previous observations when dopamine treatment was started immediately after the establishment of ischaemia. In the 90-min group cardiac output was not affected. Again the intestinal blood flow was normalized in the non-occluded parts. In both groups the pancreatic circulation was impaired.


Technique of skeletal navigation for localizing solitary pulmonary nodules.
We herein detail a novel method of skeletal navigation for localizing small solitary pulmonary nodules of 8-30 mm size and at a distance of less than 15 mm from visceral pleura. Thirty-four lesions found in 29 patients were successfully localized. All 34 target nodules first underwent wedge resections, and there were no cases of technical failure of the present method. This technique incurs no additional cost and complications as caused by other localization approaches. Additionally, this approach provides a backup method in cases of mark displacement.


Tetrandrine inhibits migration and invasion of human renal cell carcinoma by regulating Akt/NF-κB/MMP-9 signaling.
Renal cell carcinoma (RCC) is known as one of the most lethal malignancies in the urological system because of its high incidence of metastasis. Tetrandrine (Tet), a traditional Chinese herbal medicine, exerts a potent anti-cancer effect in a variety of cancer cells. However, the anti-metastatic effect of Tet and its possible mechanism in RCC is still unclear. The present study revealed that Tet significantly suppressed the migration and invasion of RCC 786-O and 769-P cells in vitro. Mechanistically, the protein levels of matrix metalloproteinases 9 (MMP-9), phosphorylated PI3K, PDK1, Akt and NF-κB were markedly reduced after Tet treatment. Moreover, co-treatment with LY294002 (PI3K inhibitor) could further enhance the Tet-inhibited migration and invasion, and the NF-κB and MMP-9 protein levels were further decreased. Similar results were observed after PDTC (NF-κB inhibitor) co-treatment. Conversely, SC79, an Akt activator, could partially reverse the anti-metastatic effects of Tet, accompanied by the restoration of NF-κB and MMP-9 protein levels. In conclusion, the current results indicated that Tet inhibited migration and invasion of RCC partially by regulating Akt/NF-κB/MMP-9 signaling pathway, suggesting that Tet may be a potential therapeutic candidate against metastatic RCC.


[Prevalence of hepatitis G virus infection in a cohort of hemophilic HIV positive patients].
We analysed the prevalence of hepatitis G virus (HGV) infection in HCV+/HIV+ hemophilic patients determining HGV viremia in plasma by polymerase chain reaction (PCR). The overall prevalence of HGV infection was 13.51%. Viremia by HGV was more frequent in younger patients. Two subgroups of patients were considered taking into account prognosis of HIV disease progression. The prevalence of HGV infection was significantly higher in those with better prognosis and low risk of evolution to AIDS. The results suggest that HGV infection may slow disease progression, directly or indirectly.


Neanderthal-Derived Genetic Variation Shapes Modern Human Cranium and Brain.
Before their disappearance from the fossil record approximately 40,000 years ago, Neanderthals, the ancient hominin lineage most closely related to modern humans, interbred with ancestors of present-day humans. The legacy of this gene flow persists through Neanderthal-derived variants that survive in modern human DNA; however, the neural implications of this inheritance are uncertain. Here, using MRI in a large cohort of healthy individuals of European-descent, we show that the amount of Neanderthal-originating polymorphism carried in living humans is related to cranial and brain morphology. First, as a validation of our approach, we demonstrate that a greater load of Neanderthal-derived genetic variants (higher "NeanderScore") is associated with skull shapes resembling those of known Neanderthal cranial remains, particularly in occipital and parietal bones. Next, we demonstrate convergent NeanderScore-related findings in the brain (measured by gray- and white-matter volume, sulcal depth, and gyrification index) that localize to the visual cortex and intraparietal sulcus. This work provides insights into ancestral human neurobiology and suggests that Neanderthal-derived genetic variation is neurologically functional in the contemporary population.


Studies on proteolytic activity and function of the thyroid gland in rats administered excess iodide.
Thyroid auto-proteolytic activity in rats increased significantly only after several weeks of treatment with 1 mg iodide per day. Iodide added in vitro did not activate thyroid auto-proteolysis, nor was inhibition observed. Thyroid proteolytic activity was also tested using 131I-labelled heat-inactivated thyroid homogenate from control rats as substrate. Significantly increased proteolytic activity was again demonstrated in thyroid glands from rats on excess iodide for several weeks. The increased proteolytic activity is therefore probably not due to a decreased proteolytic resistance of thyroglobulin in the iodide-treated rats. Increased synthesis or decreased degradation of thyroid proteolytic enzymes is a more likely explanation for this phenomenon. These findings are at variance with those of some previous studies showing decreased proteolytic activity in thyroid glands from rats administered excess iodide. Since the rats remained euthyroid the increased auto-proteolysis, which occurred quite late, was considered an unexpected finding and it is at present not certain whether this is related to the successful adaptation. Treatment with iodide did not alter the thyroid and hypophyseal weight or histology. Serum free thyroxine level and thyrotropin concentration were also unaffected by excess iodide. The adaptation of the imtact rat thyroid to prolonged and excess iodide intake seems to occur without the assistance of an altered thyrotrophin secretion.


Decacationic [70]Fullerene Approach for Efficient Photokilling of Infectious Bacteria and Cancer Cells.
Photodynamic inactivation of pathogenic bacteria and cancer cells by novel water-soluble decacationic fullerene monoadducts, C60[>M(C3N6+C3)2] and C70[>M(C3N6+C3)2], were investigated. In the presence of a high number of electron-donating iodide anions as parts of quaternary ammonium salts in the arm region, we found that C70[>M(C3N6+C3)2] produced more highly reactive HO• radical than C60[>M(C3N6+C3)2], in addition to singlet oxygen (1O2). This finding offers an explanation of the preferential killing of Gram-positive and Gram-negative bacteria by C60[>M(C3N6+C3)2] and C70[>M(C3N6+C3)2], respectively. The hypothesis is that 1O2 can diffuse more easily into porous cell walls of Gram-positive bacteria to reach sensitive sites, while the less permeable Gram-negative bacterial cell wall needs the more reactive HO• to cause real damage.


A Rare Anatomical Variation in the Pedicle of Anterolateral Thigh (ALT) Flap.
Free anterolateral thigh (ALT) flap finds its place in the front row among the soft-tissue flaps used for complex reconstruction of various defects. Its versatile tissue component and ease of harvesting with minimal donor site morbidity made it a popular flap. However, its variable vascular anatomy alerts the reconstructive surgeon to remain aware of the common variation and vigilant with regard to unusual variation. Commonly described variations are about the origin and course of pedicle and perforators. There are rare reports regarding the presence of double arteries and single vein in the flap pedicle. Here, the authors describe these unusual anatomical variations in the pedicle of ALT flap, with two arteries and one vein, and discuss the surgical implication of the same.


Laboratory tests in patients treated with isotretinoin: occurrence of liver and muscle abnormalities and failure of AST and ALT to predict liver abnormality.
Current laboratory monitoring may not be optimal. A retrospective chart review was performed on thelaboratory results of 246 patients who were treated with isotretinoin for acne over a 9-year period. Tests obtained were CBC, lipid panel, AST, ALT, CK, GGT,and C-reactive protein. Thirty-five patients had an elevated AST and 35 of these had an elevated CK; 32 had an elevated ALT and 11 of these had an elevated CK. Thirteen patients had an elevated GGT; in 5 this was the only abnormality, whereas 8 had a GGT elevation accompanied by an elevated AST or ALT. Two had an elevated GGT and an elevated CK with normal AST and ALT. Fifty-two patients had a single episode of elevated CK, of which 22 were female. However, 57 had multiple CK elevations and only one was female. Thirty-five patients had CK elevations <2 times normal; 38 had levels between 2 and 3 times normal, 18 had levels between 3 and 4 times normal, and 18 had levels greater than 4 times normal. We suggest that ALT and AST are not useful for monitoring isotretinoin therapy and that GGT and CK may be of greater value in managing patients.


Isolation of Cryptococcus gattii from a Castanopsis argyrophylla tree hollow (Mai-Kaw), Chiang Mai, Thailand.
The pathogenic yeast Cryptococcus gattii was isolated from a tree hollow of a Castanopsis argyrophylla King ex Hook.f. (Fagaceae) in Chiang Mai, Thailand. Molecular characterization with amplified fragment length polymorphism analysis and multi-locus sequence typing showed that this isolate belonged to genotype AFLP4/VGI representing C. gattii sensu stricto. Subsequent comparison of the environmental isolate with those from clinical samples from Thailand showed that they grouped closely together in a single cluster.


Frequent relapses in a child with nephrotic syndrome due to PLEVA.
A seven-year-old boy with nephrotic syndrome presented with a frequent rash along with relapse of nephrotic syndrome. Clinical and histological features were suggestive of pityriasis lichenoides et varioliformis acuta (PLEVA). Treatment of the condition with doxycycline led to the cure of the lesions as well as the relapses.


[Pain management with herbal antirheumatic drugs].
Herbal antirheumatics are indicated in painful inflammatory and degenerative rheumatic diseases. Their mechanism of action is broader than that of synthetic antirheumatics. Particular preparations from Devils's Claw with 50 to 100 mg of harpagoside in the daily dosage as well as a particular willow bark extract with 120 to 240 mg salicin in the daily dosage proved efficacy in a number of clinical studies including confirmatory ones. Exploratory studies indicate that these herbal antirheumatics were not inferior to the selective COX-2 inhibitor rofecoxib when treating acute exacerbations of chronic low back pain. For the proprietary nettle root extract IDS23 promising in vitro/in vivo results indicate an anti-inflammatory effect, however there are only 2 open uncontrolled clinical studies available and the proof of efficacy is still missing. Safety data in order to recommend use during pregnancy and lactation are only available for the herbal combination product Phytodolor prepared from aspen, ash and goldenrod. In principle, blackcurrent leaf with not less than 1.5% flavonoids may be an appropriate antirheumatic. Likewise, the seed oils of blackcurrent, evening primrose and borage offering at least 1 to 3 g gammalinolenic acid/day are recommendable. In case superiority versus placebo has been established, proprietary herbal antirheumatics should be administered before the conventional analgesics due to the lower incidence of adverse events.


[Comparative evaluation of zono- and tomography in the differential diagnosis of small spherical formations in the lungs].
A comparative analysis of zono - and tomography in 69 patients with minor peripheral cancer of the lung (26), tuberculoma (24), hamartoma (19) was performed. Zonography was shown to improve differential diagnosis between them. However, its importance is limited and helps to better visualize changes of the lung tissue around the formations, "a path" outgoing to the pulmonary radix and chest wall, and to detect the enlarged intrathoracic lymph nodes. Tomography is of greater informative value for the evaluation of the skialogical features of the formations and pleural changes. The combined use of zono - and tomography results in a better detection of different pathological lung formations of small sizes and changes in the pulmonary tissue enhancing the efficacy of differential radiodiagnosis between them.


Strategies used by older adults to maintain or restore attributed dignity.
Dignity has been linked to the well-being of older adults. However, little is known about how older adults respond to perceived threats to their dignity. Nineteen community-dwelling older adults were interviewed regarding how they maintained their dignity. Grounded theory methods were used to identify (a) the characteristics of situations in which the dignity of older adults was threatened; (b) strategies used by older adults to defend their dignity; (c) variation in those strategies in relation to individual characteristics; and (d) similarities or differences among strategies used by community-dwelling and hospitalized older adults. Three types of strategies (i.e., introspective, interactive, and active) were identified. Although all individuals used all three types of strategies, each participant had a dominant style. Community-dwelling older adults exhibited greater breadth in their responses than their hospitalized counterparts. Understanding the strategies used by community-dwelling older adults with chronic health problems to maintain dignity may help health care providers develop interventions to protect the dignity of older adults.


Development of pH-responsive polymer and citrate aqueous two-phase system for extractive bioconversion of cefprozil.
A pH-responsive aqueous two-phase system (pH-ATPS) has been developed by sodium citrate and a recyclable pH-responsive polymer PADB6.8 that can response to the change of pH values. Phase separation mechanism is studied through Low field-NMR. All variables affecting the phase separation are evaluated. Phase characteristics (viscosity, density, interfacial tension) and phase separation kinetic are studied for understanding of separation process and operational parameters in applications. This pH-ATPS has the characters of low interfacial tension, high recovery leading efficient mass transfer and low cost. The proposed system can be used as a mild medium for extractive bioconversion with low cost. We applied this pH-ATPS in extractive bioconversion of cefprozil. Cefprozil is partitioned towards the polymer-rich phase while the substrates tended to be partitioned in the salt-rich phase. Extractive bioconversion of cefprozil in this pH-ATPS can improve yield of the enzymatic process and reduce the product hydrolysis in optimal conditions. The maximal conversion yield of cefprozil in the studied system is 91.0%.


[Mediators of inflammation and of antimicrobial activity secreted by macrophages (author's transl)].
Macrophages are highly differentiated mononuclear phagocytes which originate from stem cells of the bone marrow. The secretory potential of these cells has been recognized in recent years. Major secretory products comprise lysosomal enzymes, complement proteins, prostaglandins and interferon. Secretion of lysosomal hydrolases and proteinases is most prominent in macrophages stimulated in vivo or in vitro (Fig. 4). Lysosomal enzyme secretion may be an important factor in the induction and maintenance of inflammatory reactions. Complement (C) proteins secreted by macrophages belong to the classical activation unit (C1, C4 and C2), alternative activation unit (C3, B, D, P) and to the group of delayed-acting C proteins (Fig. 7). Therefore macrophages produce at local sites the C component C3 from which biologically active C3 fragments (C3a, C3b, C3e) can be generated. These C3 fragments mediate inflammatory and cytotoxic reactions and also promote phagocytic processes (Fig. 6). Cleavage of secreted C3 into the active fragments may occur by enzymes derived from both C activation units or by secreted lysosomal proteinases (Fig. 8). Stimulated macrophages also synthesize and release prostaglandins. These compounds which have inflammatory as well as antiinflammatory effects (Fig. 12) may play an important regulatory role in inflammatory processes. Interferon has been also recognized as a secretory product of macrophages. This substance supports antimicrobial resistance by its phagocytosis-increasing effect and its antiviral activity. The secretory function of macrophages as well as the biological effects of secreted mediators are highly susceptible to modulation. Thus, C3 fragments stimulate the secretion of lysosomal enzymes (Fig. 6) whereas prostaglandins inhibit their release (Fig. 12). The inflammatory reactions induced by lysosomal enzymes may be further increased by the generation of C3b which stimulates additional lysosomal enzyme release (Fig. 4). These and other examples suggest that endogenous control mechanisms may have a strong influence on the secretory function of macrophages as well as on the biological activity of secreted mediators.


Activation of the kallikrein-kinin system in premature infants with respiratory distress syndrome (RDS).
Plasma prekallikrein levels, kallikrein activity and antikallikrein levels were investigated in nine premature infants with respiratory distress syndrome (RDS) and six premature infants without. Plasma prekallikrein and kallikrein were determined with a chromogenic substrate measuring amidolytic activity. Antikallikrein was measured with a functional assay. In infants with severe RDS, prekallikrein levels were significantly reduced (median 58% of initial values (p less than 0.01) about 48 hours after onset of symptoms. In infants with moderate RDS prekallikrein level was reduced less, while in babies without RDS there were no significant changes in prekallikrein levels the first 5-7 days of life. Antikallikrein levels did not change significantly in any babies. The results suggest that the kallikrein-kinin system might be involved in RDS. This could explain several features of this syndrome such as hypotension and edema. Furthermore the findings show that homeostatic functions are altered in this disease, and they suggest that other cascade systems as the coagulation, fibrinolytic and complement system may be involved as well. The findings emphasize that trauma might be a significant pathogenetical factor for development of this syndrome and indicate that RDS is not simply a biochemical disease with lack of surfactant as the only pathogenetic factor.


Studies on the induction of the interleukin-6 promoter in cell lines of human and simian origin.
In a number of eukaryotic cell types, the promoter of the interleukin-6 (IL-6) gene is inducible by several agents. We studied this inducibility in two human (MG63 and HeLa H21) and four simian cell lines (BSC-1, AP8, CV-1 and VERO). Furthermore, we also investigated whether this inducibility was maintained when a heterologous gene was placed under control of the human IL-6 promoter. As a heterologous gene we used the Simian Virus 40 (SV40) large T antigen, because of its stimulatory effects on SV40-based expression vectors. For the human cell lines tested, we observed that this gene was equally well induced and controlled as the endogenous IL-6 gene. In contrast, the aforementioned simian cell lines were only slightly inducible for IL-6 production; moreover, after transfection with the IL-6 promoter--SV40 T antigen gene construct, a continuous, low level of expression was found, even in those lines which only showed a low (CV-1) or no (BSC-1) endogenous IL-6 background. This apparent difference between the human and simian cells analyzed does not reflect a species specificity, but presumably is related to a different differentiation state of these cells. Furthermore, the IL-6 gene induction could be correlated with activation of the required transcription factor NF-kappa B.


Risk Factors of Asymptomatic Neurocognitive Impairment in People Living with HIV in an Indian Cohort.
Background Asymptomatic neurocognitive impairment (ANI) in people living with HIV (PLWH) can lower quality of life, reduce drug compliance, increase unemployment, and reduce life expectancy. Objective This study was aimed to identify risk factors of ANI in PLWH in an Indian cohort and explore the usefulness of Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment Score (MoCA) as screening tools. Methods PLWH under follow-up at an antiretroviral treatment center who were 18 to 60 years were included in this study. Patients were excluded if they had any cognitive symptoms, previous history of any central nervous system (CNS) pathology, or any systemic illness. Included patients were subjected to domain wise standardized neuropsychological battery. Six domains were screened including language, attention, speed, memory, sensory motor skills, and executive. Abnormal dysfunctional scores in at least two domains were taken as suggestive of ANI. The two groups thus created, ANI and normal cognition, were evaluated for differences. Variables evaluated as risk factors included age, sex, handedness, education, presence of at least one vascular risk factor, duration of disease, biochemical profile, cluster of differentiation 4 (CD4) count (both current and nadir) HIV viral load, and use of antiretroviral therapy (ART) and its CNS penetration effectiveness (CPE). MMSE and MoCA were also done in all patients. Statistical Analysis Regression analysis was used to find out significant variables. MMSE and MoCA scores were correlated using Spearman's correlation coefficient. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were also determined Results Three hundred and eighty-four patients were included out of which 185 (48%) had ANI. In the multivariate regression analysis, female sex with odds Ratio (OR) of 1.89 (95% confidence interval [CI]: 1.21-2.79, p < 0.01), education below 10 years with OR = 2.43 (95% CI: 1.56-3.80, p < 0.01) and presence of at least one vascular risk factor with OR = 2.52 (95% CI: 1.67-3.80, p < 0.01) were found to be significant. Both MMSE and MoCA had a high PPV (0.99 and 0.97, respectively) but poor NPV (0.64 and 0.75) below a score of 25 with MoCA scoring slightly better. Both, MMSE and MoCA correlated well with each other. Conclusion Nearly half of our patients had ANI, despite being on ART. Majority of patients were on ART with CPE > 7 and had relatively preserved immune status. Female HIV patients with at least one vascular risk factor and less than 10 years of formal education were found to be at risk for ANI. MMSE and MoCA are not good screening tools to identify this condition.


Accumulation of photofrin in lesions of airway stenosis rabbit models.
Airway stenosis in childhood is resistant to conventional treatments. Endoscope-assisted photodynamic therapy (PDT) is a potent candidate for the therapeutic modality owing to the easy approach to the tracheal lesion and low degree of invasiveness. The aim of the present study was to examine whether a photosensitizer preferentially accumulates in the lesion of airway stenosis in order to explore the possible applicability of PDT. The tracheal mucosa of rabbits was scraped off, and the rabbits were intravenously administered with Photofrin. The tissue concentration of Photofrin was quantitatively measured by fluorometric analysis. Granulation formation was seen in the mucosa-deprived lesion, causing airway stenosis. Photofrin concentration in the granulation tissue was four-fold higher than that in the intact trachea and 10-fold higher than that in the liver, spleen, skin and muscle. Photofrin preferentially accumulated in the lesion of airway stenosis. A preliminary experiment on PDT using transtracheal illumination showed an amelioration of airway stenosis, resulting in reduction in respiratory stridor.


A rare presentation of aplasia cutis congenita after feto-reduction in a trichorionic-triamniotic pregnancy.
Aplasia cutis congenita (ACC) is rare skin disorder of newborns that has been linked to both assisted reproductive technology (ART) and feto-reduction procedures. ACC is characterized by well-demarcated lesions that are devoid of all skin layers. Group-V ACC presents with a distinctive and symmetrical distribution pattern. It is thought to result from an insult to the fetus after concomitant twin demise and is almost exclusively reported in monochorionic gestations.A 41-year-old female with an in vitro fertilization (IVF) assisted tri-chorionic gestation subsequently underwent selective feto-reduction of Fetus C. The patient delivered two pre-term neonates secondary to pre-eclampsia. The initial exam of Twin B showed extensive, well-demarcated, symmetrical areas devoid of any skin over the anterior and lateral trunk, extending up the lateral thoracic walls. Chest and abdominal viscera were visible through a thin fibrous membrane. The skin defects were managed conservatively with twice-daily dressings of Aquaphor, and Vaseline gauze. The areas of aplasia slowly contracted, though residual scarring was noted. After four weeks in the NICU, most of the areas were healed.ACC in multi-fetal pregnancies is a rare, but well-described complication. This is, to our knowledge, the first reported case in a tri-chorionic IVF gestation after feto-reduction. With increased incidence of ART-associated pregnancies and the use of feto-reduction for higher order gestations, this may become more common. Neonates often require specialized intensive care. Conservative management usually will suffice, although surgical grafting may be required. Physicians should be aware of this condition and counsel their feto-reduction patients of the risk.


Selective cyclooxygenase-2 (COX-2) inhibition reduces proteinuria in renal patients.
Renoprotection is predicted by the antiproteinuric efficacy of a pharmacological agent. Non-steroidal anti-inflammatory drugs (NSAIDs) interfering non-selectively in the prostaglandin system have strong antiproteinuric potency without reduction of systemic blood pressure. The effect of the selective COX-2 inhibitor rofecoxib in proteinuric patients is unknown, granted recently reported detrimental effects in non-renal patients. Short-term effects of rofecoxib on proteinuria and blood pressure as compared to NSAID and RAAS blockade were studied. Sixteen stable patients [mean proteinuria 4.4 g/ day; MAP 103 mmHg)] were included after a wash-out period. Hydrochlorothiazide 12.5 mg QD was given throughout. Additional blood pressure control was ensured by non-RAAS blocking antihypertensive agents. Patients received rofecoxib 25 mg QD, 50 mg QD and indomethacin 75 mg BID in randomized order for 4 weeks. Thereafter, a subset of the included patients (n = 11) received lisinopril 40 mg QD for 6 weeks preceded by a wash-out period. Rofecoxib exerted a dose-dependent antiproteinuric effect. As compared to rofecoxib 25 and 50 mg, indomethacin was more effective [-18, -28 versus -49% (n = 16; P < 0.05)]. As compared to rofecoxib 50 mg, lisinopril was more effective [-21 versus -51% (n = 11; P < 0.05)]. No significant blood pressure changes were observed after rofecoxib and indomethacin, whereas lisinopril had a significant antihypertensive effect. Selective COX-2 inhibition reduces proteinuria without reduction of systemic blood pressure, pointing towards a specific renal effect, and may serve as a novel non-hypotensive adjunct antiproteinuric treatment.


Self-immolative dendrimer biodegradability by multi-enzymatic triggering.
New self-immolative dendritic molecules have been designed and synthesized. The dendrons are built with a multi-enzymatic triggering mechanism, which initiates their biodegradation through a self-immolative chain fragmentation to release a reporter group from the focal point. The dendritic backbone is constructed from polycarbamate linkages, which are stable to hydrolysis and enhance the dendrons' solubility in water. The degradation can readily take place under physiological conditions on enzymatic triggering.


Steroid receptors in two types of rabbit skeletal muscle.
Radiolabeled synthetic steroid hormones and a charcoal adsorption assay were used to identify cytosolic androgen, glucocorticoid, and estrogen receptors in skeletal muscle from rabbits. The presence of the receptors was verified by saturation analysis showing low-capacity, high-affinity binding for the steroid-receptor complexes, specific for each class of steroids. The concentration of androgen and estrogen receptors were of the same magnitude, whereas the corresponding value for the glucocorticoid receptor was about tenfold higher. Comparisons of fast-twitch (the gastrocnemius/plantaris complex) and slow-twitch (soleus) muscles revealed that the latter contained higher concentrations (expressed per g of tissue wet weight) of glucocorticoid and estrogen receptors, but not of androgen receptor. Expressed per mg of soluble protein, the slow-twitch muscle contained higher concentrations of all three receptors, but when related to the concentrations of all three receptors, but when related to the concentration of DNA, only the concentration of estrogen receptor was higher in the slow-twitch muscle. Different response of the two fiber types to direct action of steroid hormones can hence be expected. The fast-twitch muscle contained a higher concentration of soluble protein, whereas the slow-twitch muscle contained higher concentration of DNA, resulting in lower protein/DNA ratio, i.e., smaller "cell units," in the latter muscle.


Combined Diffusion Tensor Imaging and Apparent Transverse Relaxation Rate Differentiate Parkinson Disease and Atypical Parkinsonism.
Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms.


Bacterial flora of leg ulcers in patients admitted to Department of Dermatology, Poznań University of Medical Sciences, during the 1998-2002 period.
Venous leg ulcers are an important cause of morbidity in a significant percentage of the world population. The percentage of leg ulceration, either active or healed, in the European population is about 1%-2%. The aim of this study was to analyze the rate of colonization and qualitative composition of the bacterial flora isolated from leg ulcers in patients admitted to Dermatology Department, Poznań University of Medical Sciences, during the 1998-2002 period, with special reference to the infection risk factors. Bacteriological diagnosis of 175 wound swabs was performed in compliance with compulsory laboratory methods. In 173 positive results, the predominant culture composition included Staphylococcus aureus (56.57%), Pseudomonas aeruginosa (37.14%), Enterococcus faecalis (22.29%), Proteus mirabilis (13.71%) and Escherichia coli (12.57%). There was a significant increase in the incidence of Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli, along with a decrease in the incidence of Staphylococcus aureus isolation during the study period. The rate of yeast-like fungi strains, mainly Candida albicans, recorded in culture composition showed a systematic increase. Changes in the qualitative and quantitative composition of bacterial flora, presence of multiple isolates, and concomitant diseases that may influence the characteristics of leg ulcer disease were closely monitored.


Long-term treatment of elderly individuals with emotional disturbances: an open study with citalopram.
In the present open study, the long-term safety, tolerability, and efficacy of citalopram in the treatment of elderly people with emotional disturbances were studied. One hundred twenty-three elderly patients with symptoms of depression-anxiety were included. Most of the patients (76%) were demented. Fifty-two patients completed a 12-month treatment. Irritability, depressed mood, anxiety, restlessness, and fear-panic were significantly reduced. The severity of illness from baseline to Month 9 was rated as significantly improved. The side effects were infrequent and mostly mild.


Outcomes at 2 years of age after repeat doses of antenatal corticosteroids.
We previously reported the results of a randomized, controlled trial showing that repeat doses of antenatal corticosteroids reduced the risk of respiratory distress syndrome and serious neonatal morbidity. However, data have not been available regarding longer-term effects of this treatment. Women who had received an initial course of corticosteroid treatment 7 or more days previously were randomly assigned to receive an intramuscular injection of corticosteroid (11.4 mg of betamethasone) or saline placebo; the dose was repeated weekly if the mother was still considered to be at risk for preterm delivery and the duration of gestation was less than 32 weeks. We assessed survival free of major neurosensory disability and body size of the children at 2 years of corrected age. Of the 1085 children who were alive at 2 years of age, 1047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P=0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P=0.04). Administration of repeat doses of antenatal corticosteroids reduces neonatal morbidity without changing either survival free of major neurosensory disability or body size at 2 years of age. (Current Controlled Trials number, ISRCTN48656428 [controlled-trials.com].).


Fear-avoidance beliefs about back pain in patients with acute LBP.
We aimed to assess fear-avoidance beliefs in patients with acute low back pain (LBP) and to identify features of patients and general practitioners (GPs) associated with patients' fear-avoidance beliefs. A cross-sectional study conducted in primary care practice in France. A total of 709 GPs completed a self-administered questionnaire assessing fear-avoidance beliefs [the Fear-Avoidance Beliefs Questionnaire (FABQ)] and 2,727 patients with acute LBP completed a self-administered questionnaire assessing pain, perceived handicap and disability (on the Quebec Back Pain Disability Scale) and fear-avoidance beliefs (on the FABQ). Patients' FABQ mean scores were 16.8+/-5.0 for physical activities (FABQ Physical) and 19.5+/-10.9 for occupational activities (FABQ Work). From multivariate analysis, the following factors were associated with patients' FABQ Phys and Work scores: having a GP with a high rating on the FABQ Phys (P=0.0001 and 0.02 for FABQ Phys and Work, respectively), no sport practice (vs. occasional: P=0.0003 and 0.03; vs. usual/competition: P=0.0001 and 0.004), disability score (Quebec) (P=0.0001 for both FABQ scores), and pain intensity (P=0.0012 and 0.0013). High levels of fear-avoidance beliefs occur early in LBP patients, and key messages on this topic should probably be delivered at a very early stage of the disease.


Quantifying fatigue risk in model-based fatigue risk management.
The question of what is a maximally acceptable level of fatigue risk is hotly debated in model-based fatigue risk management in commercial aviation and other transportation modes. A quantitative approach to addressing this issue, referred to by the Federal Aviation Administration with regard to its final rule for commercial aviation "Flightcrew Member Duty and Rest Requirements," is to compare predictions from a mathematical fatigue model against a fatigue threshold. While this accounts for duty time spent at elevated fatigue risk, it does not account for the degree of fatigue risk and may, therefore, result in misleading schedule assessments. We propose an alternative approach based on the first-order approximation that fatigue risk is proportional to both the duty time spent below the fatigue threshold and the distance of the fatigue predictions to the threshold--that is, the area under the curve (AUC). The AUC approach is straightforward to implement for schedule assessments in commercial aviation and also provides a useful fatigue metric for evaluating thousands of scheduling options in industrial schedule optimization tools.