Multiscale entropy of laser Doppler flowmetry signals in healthy human subjects.
The cardiovascular system (CVS) regulation can be studied from a central viewpoint, through heart rate variability (HRV) data, and from a peripheral viewpoint, through laser Doppler flowmetry (LDF) signals. Both the central and peripheral CVSs are regulated by several interacting mechanisms, each having its own temporal scale. The central CVS has been the subject of many multiscale studies. By contrast, these studies at the level of the peripheral CVS are very recent. Among the multiscale studies performed on the central CVS data, multiscale entropy has been proven to give interesting physiological information for diagnostic purposes. However, no multiscale entropy analysis has been performed on LDF signals. The authors' goal is therefore to propose a first multiscale entropy study of LDF data recorded in healthy subjects. The LDF signals recorded in the forearm of seven healthy subjects are processed. Their period sampling is T=50 ms, and coarse-graining scales from T to 23T are studied. Also, for validation, the algorithm is first tested on synthetic signals of known theoretical multiscale entropy. The results reveal nonmonotonic evolution of the multiscale entropy of LDF signals, with a maximum at small scales around 7T and a minimum at longer scales around 18T, singling out in this way two distinctive scales where the LDF signals undergo specific changes from high to low complexity. This also marks a strong contrast with the HRV signals that usually display a monotonic increase in the evolution of the multiscale entropy. Multiscale entropy of LDF signals in healthy subjects shows variation with scales. Moreover, as the variation pattern observed appears similar for all the tested signals, multiscale entropy could potentially be a useful stationary signature for LDF signals, which otherwise are probe-position and subject dependent. Further work could now be conducted to evaluate possible diagnostic purposes of the multiscale entropy of LDF signals.


Plasma lipoproteins, apoproteins and cardiovascular disease in type 2 diabetic patients. A nine-year follow-up study.
To evaluate the role of lipoprotein abnormalities as risk factors for macroangiopathy in Type 2 diabetes. This prospective nine-year follow-up study involved 113 Type 2 diabetic patients (50 men and 63 women, mean age 66.9 +/- 9.9 years), 37 of whom had clinical signs of coronary heart disease (CHD) and cerebrovascular disease (CVD) at baseline. During the follow-up, 32 patients died: 17 of CHD, five of CVD, and 10 of non-vascular causes. The patients who died because of vascular disease were more frequently smokers, and had baseline symptoms of vascular disease; they were also significantly different from the other patients insofar as they were older, and had higher fasting plasma glucose levels, lower fasting C-peptide levels, and lower apoprotein (apo) AII, apo CII, apo CIII and apo E levels. Univariate analysis showed that baseline symptoms of vascular disease, current smoking, age, high fasting plasma glucose levels, low fasting C-peptide levels, and low apo AII, apo CII, apo CIII and apo E levels [but not cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol or qualitative low-density lipoprotein or HDL abnormalities] were associated with cardiovascular mortality. Multivariate analysis showed that only age, smoking, glycated hemoglobin (HbA1c) and fasting C-peptide levels were significant independent determinants of macrovascular death. In Type 2 normolipidemic diabetic patients, only age, smoking, HbA1c and fasting C-peptide levels are independent vascular risk factors. The differences in apo concentrations between patients with and without vascular disease may reflect qualitative abnormalities in plasma lipoproteins related to vascular disease.


Assessment of natural radiation exposure and radon exhalation from building materials in Greece.
In controlling the natural radiation exposure for the residents of dwellings, it is necessary to determine the levels of natural radioactivity (external exposure) and radon exhalation rate (internal exposure) from building materials. Using a high-resolution gamma ray spectrometry system, the activity concentration of natural radionuclides was measured. The radon exhalation rate was measured by hermetically closing the sample in a container and following the radon activity growth as a function of time. Three different methods were applied in order to find the most appropriate, i.e. that with the less uncertainty for the less exposure time. Typical building materials were analyzed in order to examine the external and internal exposures. In addition, the total annual effective dose was evaluated for the residents of a typical Greek dwelling.


Increased long-term mortality with plasma transfusion after coronary artery bypass surgery.
Patients undergoing cardiac surgery often require transfusions of red blood cells, plasma and platelets. These components differ widely in both indications for use and composition. However, from a statistical point of view there is a significant colinearity between the components. This study explores the relation between the transfusion of different blood components and long-term mortality. A retrospective single-centre study was performed including 5,261 coronary artery bypass grafting patients, excluding patients receiving more than eight units of red blood cells, those suffering early death (7 days) and emergency cases. Patients were followed up for a period of up to 7.5 years. A broad spectrum of potential risk factors was analysed using Cox proportional hazards survival regression. Non-significant risk factors were removed by step-wise elimination, and transfusion of red blood cells, plasma and platelets was forced to remain in the model. The transfusion of red blood cells was not associated with decreased long-term mortality (HR = 1.007, p = 0.775), whereas the transfusion of plasma was associated with decreased long-term survival (HR = 1.060, p < 0.001), and the transfusion of platelets was associated with increased long-term survival (HR = 0.817, p = 0.011). The risk associated with transfusion of plasma was mainly attributed to patients receiving large amounts of plasma. All hazard ratios are per unit of blood product transfused. No association was found between the transfusion of red blood cells and mortality during the study period. However, transfusion of plasma was associated with increased mortality while transfusion of platelets was associated with decreased mortality during the study period.


Partial chest wall radiation therapy for positive or close surgical margins after modified radical mastectomy for breast cancer without lymph node metastasis.
Whole-breast radiation therapy after breast-conserving surgery can control local recurrence with a long-term survival rate equivalent to that of radical mastectomy for patients with early breast cancer. However, the significance of radiation therapy for patients with positive/close margins after mastectomy remains controversial. Following radical mastectomy, no residual breast parenchyma remains, and thus radiation therapy of the entire chest wall may represent overtreatment in the patients, especially those without lymph node metastasis (N0). We therefore implemented partial chest wall radiation therapy for patients with N0 breast cancer and positive and/or close margins after mastectomy. A total of 22 patients with N0 status but positive/close margins underwent partial chest wall radiation therapy to irradiate the predetermined clinical target volume, which had margins of at least 2 cm medial, lateral, superior, and inferior to the primary tumor bed. With reference to chest wall thickness, 4-10-MV photons or 5-8-MeV electrons with/without a bolus were delivered. The total dose was 50-66 Gy. We compared the results with those from 18 nonradiation therapy patients using Pearson's χ2 test. All patients in the partial chest wall radiation therapy group achieved good local control despite having a significantly higher proportion of positive margins (77.3%) compared with the nonradiation therapy group (27.8%) (P = 0.002). Both groups showed 100% recurrence- and disease-free survival. Partial chest wall radiation therapy may offer recurrence- and disease-free survival without local recurrence in N0 mastectomy patients with positive/close surgical margins.


Treatment of early stages of mycosis fungoides with narrowband ultraviolet B. A clinical, histological and molecular evaluation of results.
Narrowband ultraviolet B (UVB) phototherapy is increasingly used in mycosis fungoides (MF). We report on the results obtained in a prospective series of early MF patients receiving this therapeutic regimen. In total, 22 patients were treated. Therapeutic results were evaluated on clinical, histological and molecular levels. Patients were then submitted to a clinical follow-up. The cumulative number of treatments ranged from 22 to 48 (mean: 29). A complete clinical remission (CCR) was obtained in 18/22 patients, and a partial clinical remission in 4 cases. Complete or partial histological responses were achieved in 9/15 (all in CCR) and 4/15 patients, respectively. The molecular response was evaluated in 12 patients, and a disappearance of the dominant T cell clone in the skin was obtained in only 3 cases. After 4-48 months of follow-up (mean 20.1 months), 7/18 patients in CCR (39%) relapsed. Narrowband UVB phototherapy is a well-tolerated treatment of early-stage MF, and its efficiency is maximal in very early stages (Ia). Even though clinical results seem very similar to PUVA through indirect and tentative comparisons with historical series, relapses tend to occur earlier than with PUVA, especially when an incomplete histological or molecular response was achieved.


Cell mediated PPD specific cytotoxicity against human monocyte targets: III. Cellular typing with CTLs restricted by class II HLA antigens.
The HLA-restriction specificity of a set of Cytotoxic T-Lymphocytes (CTLs) derived from 20 different individuals and with specificity for antigenic components in Purified Protein Derivative of tuberculin (PPD) were examined against a panel of 50 unrelated target cell donors. PPD pulsed monocytes were used as antigen presenting target cells. CTLs were generated by Interleukin-2 (IL-2) expansion of in vitro PPD activated Peripheral Blood Mononuclear Cells (PBM). The results confirm our previous finding that PPD-specific CTLs are restricted by HLA-class II - and not by class I antigens. The 20 CTLs used together provide reliable cellular typing reagents for the antigens HLA-DR2, -3, -4 and -7 and less so for the antigens HLA-DR1 and -5. In contrast, sharing between CTL- and target cell donors of HLA-DRw6 and -w8 correlates poorly to PPD-specific cytotoxicity. A few consistent exceptional patterns were observed. In one case lack of lysis in spite of HLA-DR antigen sharing could be explained by a split of HLA-DR2 into a normal and a short variant. Positive reactions in combinations, where no HLA-DR antigens are shared, were only few and evenly distributed among CTLs. Thus our findings indicate that our bulk CTLs predominantly contain clones restricted by determinants strongly associated to the serologically defined HLA-DR antigens.


[Clinical approach to herpesviruses. A composite overview].
This review article describes the lesions due to herpesviruses: herpes simplex, chickenpox, herpes zoster (shingles), and infections due to cytomegalovirus and Epstein-Barr virus. Based on current literature, clinical signs, diagnostic methods and therapeutic possibilities are given for each type of infection. B virus infections of humans are also briefly described.


Potential role of urinary angiotensinogen in predicting antiproteinuric effects of angiotensin receptor blocker in non-diabetic chronic kidney disease patients: a preliminary report.
Many chronic kidney disease (CKD) patients have persistent overt proteinuria despite angiotensin receptor blocker (ARB) treatment. This study investigated whether the initial difference in intrarenal renin-angiotensin system activity measured with urinary angiotensinogen would affect the antiproteinuric effects of ARB. Between September 2005 and September 2008, in 50 non-diabetic proteinuric CKD patients not taking renin-angiotensin system inhibitors, the urinary protein/creatinine ratio (P/Cr), angiotensinogen/creatinine ratio (AGT/Cr), plasma renin and aldosterone were measured before starting valsartan, and were followed for 18 months. Patients were divided into three groups according to their initial urinary AGT/Cr. The urinary P/Cr was lower in the low angiotensinogen group, but similar in the high and extremely high angiotensinogen groups (1.3±0.38 vs 2.0±0.92 vs 2.2±0.78). In all groups, the urinary P/Cr was decreased most for the first 6 months. The urinary P/Cr reduction at 6 months was greatest in the high angiotensinogen group (-24.2% vs -46.2% vs -16.4%). The urinary AGT/Cr was decreased most in the high angiotensinogen group. Renal functional deterioration was attenuated in the high angiotensinogen group compared with the extremely high angiotensinogen group. The antiproteinuric effects of ARB were different according to the initial urinary angiotensinogen levels. These results suggest the potential value of the initial urinary AGT/Cr for predicting the therapeutic effect of ARB in proteinuric non-diabetic CKD patients.


[Pseudotumor cerebri secondary to dural sinus thrombosis: pediatric case report].
Pseudotumor cerebri is a relatively common neurologic syndrome in adolescence. In most cases, etiology is idiopathic, but it may have serious complications, such as blindness, that are related to increased intracranial pressure. The aim of this article is to emphasize the differential diagnosis of pseudotumor cerebri, with special attention to treatable etiologies. We report a case of an 12 year-old adolescent who presented with diplopia and headache 9 days after right-sided otitis media and mastoiditis. Head computerized tomography was normal, but brain magnetic resonance imaging demonstrated thrombosis of ipsilateral transverse and sigmoid sinuses, which responded promptly to early anticoagulation. The conclusion is that magnetic resonance imaging is essential for patients with a clinical diagnosis of pseudotumor cerebri in order to exclude treatable causes, such as dural sinus thrombosis.


Bronchioloalveolar carcinoma.
This review focuses on aspects of bronchioloalveolar carcinoma (BAC) in which it differs importantly from other forms of non-small-cell lung cancer. BAC is a form of adenocarcinoma with unique clinical, radiological, and epidemiological features. With the notable exception of a lower likelihood of a positive positron-emission tomographic (PET) scan in BAC, staging, diagnosis, and treatment are largely the same as for other histological subtypes of lung cancer. However, additional treatment options exist that are equivalent, if not more effective, for many patients with BAC. The diagnosis of BAC should be reserved for those tumors meeting the 1999/2004 criteria set forth by the World Health Organization. Revised nomenclature proposed by an expert consensus panel may change how this disease is viewed. Additional clinical trials are needed on patients with BAC, employing strict definitions and enrollment criteria to allow the results to be applied to appropriate patient populations.


Cooperativity between the 3' untranslated region microRNA binding sites is critical for the virulence of eastern equine encephalitis virus.
Eastern equine encephalitis virus (EEEV), a mosquito-borne RNA virus, is one of the most acutely virulent viruses endemic to the Americas, causing between 30% and 70% mortality in symptomatic human cases. A major factor in the virulence of EEEV is the presence of four binding sites for the hematopoietic cell-specific microRNA, miR-142-3p, in the 3' untranslated region (3' UTR) of the virus. Three of the sites are "canonical" with all 7 seed sequence residues complimentary to miR-142-3p while one is "non-canonical" and has a seed sequence mismatch. Interaction of the EEEV genome with miR-142-3p limits virus replication in myeloid cells and suppresses the systemic innate immune response, greatly exacerbating EEEV neurovirulence. The presence of the miRNA binding sequences is also required for efficient EEEV replication in mosquitoes and, therefore, essential for transmission of the virus. In the current studies, we have examined the role of each binding site by point mutagenesis of the seed sequences in all combinations of sites followed by infection of mammalian myeloid cells, mosquito cells and mice. The resulting data indicate that both canonical and non-canonical sites contribute to cell infection and animal virulence, however, surprisingly, all sites are rapidly deleted from EEEV genomes shortly after infection of myeloid cells or mice. Finally, we show that the virulence of a related encephalitis virus, western equine encephalitis virus, is also dependent upon miR-142-3p binding sites.


Amphiphilic polysaccharide nanoballs: a new building block for nanogel biomedical engineering and artificial chaperones.
Enzymatically synthesized glycogen (ESG), a highly branched (1→4)(1→6)-linked α-glucan, is a new monodisperse spherical hyperbranched nanoparticle (molecular weight, 10(6)-10(7); diameter, 20-30 nm), polysaccharide nanoball. Amphiphilic ESG nanoballs were synthesized by introducing a cholesterol group to enzymatically synthesized glycogen (CHESG). CHESG assembled into a structure containing a few molecules to form cluster nanogels (approximately 35 nm in diameter) in water. The cluster nanogels were dissociated by the addition of cyclodextrin (CD) to form a supramolecular CHESG-CD nanocomplex due to complexation with the cholesterol group and CD. The CHESG nanogel showed high capacity for complexation with proteins, and the CHESG-CD nanocomplex showed high chaperone-like activity for thermal stabilization of enzymes. CHESG has great potential to become a new building block for nanogel biomedical engineering and to act as an artificial chaperone for protein engineering.


Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer.
Most trials with Immune Checkpoint Inhibitors (ICIs) for Non-Small Cell Lung Cancer (NSCLC) included only small subgroups of patients aged ≥65. As NSCLC is often diagnosed in patients aged ≥70, real-world data about efficacy and safety of immunotherapy (IO) in elderly patients are essential. We retrospectively collected data about all patients with advanced NSCLC treated with IO at our Institution between April 2013 and March 2019. The patients were stratified for age as follows: <70 year-old, 70-79 year-old, ≥80 year-old. Chi-square test was used to compare qualitative variables. Survival was estimated with Kaplan-Meier method. Log-rank test was used to compare curves. Multivariate analyses were performed with Cox model. We reviewed 290 cases, with a median age of 67 (range: 29-89). Patients aged<70, 70-79 and ≥80 year-old were 180, 94 and 16, respectively. Clinical/pathological variables were uniformly distributed across age classes, except for a higher rate of males (p 0.0228) and squamous histology (p 0.0071) in the intermediate class. Response Rate (RR) was similar across age groups (p 0.9470). Median Progression Free Survival (PFS) and Overall Survival (OS) did not differ according to age (p 0.2020 and 0.9144, respectively). Toxicity was comparable across subgroups (p 0.6493). The only variables influencing outcome were performance status (PS) (p < 0.0001 for PFS, p 0.0192 for OS), number of metastatic sites (p 0.0842 for PFS, p 0.0235 for OS) and IO line (p < 0.0001 for both PFS and OS). Advanced age was not associated to a reduced efficacy of IO in our case series. Furthermore, no toxicity concern emerged even among the eldest pts. To our opinion, ICIs should be considered irrespective of age, provided an optimal PS at baseline. Of note, IO is often the only therapeutic option applicable to these cases considering the toxicity of chemotherapy.


Diastereomeric mixture of calophyllic acid and isocalophyllic acid stimulates glucose uptake in skeletal muscle cells: involvement of PI-3-kinase- and ERK1/2-dependent pathways.
The diastereomeric mixture of calophyllic acid and isocalophyllic acid (F015) isolated from the leaves of Calophyllum inophyllum was investigated for the metabolic effect on glucose transport in skeletal muscle cells. In L6 myotubes, F015 dose-dependently stimulated glucose uptake by increasing translocation of glucose transporter4 (GLUT4) to plasma membrane without affecting their gene expression. The effects on glucose uptake were additive to insulin. Inhibitors analyses revealed that F015-induced glucose uptake was dependent on the activation of phosphatidylinositol-3-kinase (PI-3-K) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), while independent to the activation of 5'AMP-activated kinase (AMPK). F015 significantly increased the phosphorylation of AKT, AS160 and ERK1/2, account for the augmented glucose transport capacity in L6 myotubes. Furthermore, F015 improved glucose tolerance and enhanced insulin sensitivity in skeletal muscle of dexamethasone-induced insulin resistant mice. Our findings demonstrate that F015 activates glucose uptake in skeletal muscle cells through PI-3-K- and EKR1/2-dependent mechanisms and can be a potential lead for the management of diabetes and obesity.


Synthesis of [11C]salicylic acid and related compounds and their biodistribution in mice.
For in vivo measurement of the hydroxyl radical (.OH), we synthesized [11C]salicylic acid, [11C]O-acetylsalicylic acid and [11C]2-methoxybenzoic acid by carboxylation of 2-bromomagnesiumanisol using [11C]CO2. The radiochemical yield of [11C]salicylic acid, [11C]O-acetylsalicylic acid and [11C]2-methoxybenzoic acid calculated from trapped [11C]CO2 in a liquid argon cooled stainless tube was 7.3 +/- 1.6, 5.2 and 10.2 +/- 1.7% (decay corrected), respectively. The uptake of 11C tracers by mouse brain was 0.46, 0.32, and 0.46% dose/g tissue, respectively, at 10 min post injection and presented washout patterns thereafter.


The use of laparoscopy as a primary diagnostic and therapeutic method in penetrating wounds of lower thoracal region.
Diagnostic laparoscopy (DL) was found to be a sensitive and specific method that reduced the incidence of negative or nontherapeutic laparotomy in patients having penetrating abdominal trauma. Twenty-two patients with penetrating trauma of the lower thoracal region were evaluated by DL at the Emergency Department of the Istanbul Medical Faculty to decide on either laparotomy or conservative treatment. There were 7 (31.8%) female and 15 (68.2%) male patients. Mean age was 26.5 (2146) years. Three (13.6%) patients had gunshot wounds and 19 (86.4%) stab injuries. No peritoneal penetration was detected by DL in 11 (50%) patients, and none of these patients later required laparotomy. Of the remaining 11 patients who had peritoneal penetration, diaphragmatic laceration was detected in 9 (81.8%). Nineteen patients (86.4%) avoided nontherapeutic laparotomy. The specificity and sensitivity of DL were 100% in lower thoracal penetrating trauma. The positive diagnostic value and negative predictive value for peritoneal penetration were found to be 100%. The positive predictive value for therapeutic laparotomy and negative predictive value for nontherapeutic laparotomy were 100% as well. All patients who underwent only DL was discharged within 24 hours. There were no mortality or morbidity. Mean follow-up period was 13 months, and no associated complication was encountered during this time.


Reverse cholesterol transport in familial hypercholesterolemia.
Familial hypercholesterolemia is characterized by a major elevation in circulating LDL-cholesterol levels, cholesterol deposition within the arterial wall and an increased risk of premature coronary artery disease. The reverse cholesterol transport (RCT) is now considered as a key process that protects against development of atherosclerosis. The major antiatherogenic action of HDL particles is intimately linked to their determinant role in RCT pathway. However, the steady-sate of HDL-cholesterol levels does not represent the optimal marker to evaluate the efficiency of the RCT in all circumstances. By using ex-vivo systems for the evaluation of the efficacy of RCT a strong inverse relationship between HDL efflux capacity from macrophages and atherosclerosis progression has been demonstrated. Low HDL-C phenotype observed in familial hypercholesterolemia patients is associated with defective capacities of HDL particles to mediate major steps of the centripetal movement of cholesterol from peripheral cells to feces. However, current available treatment used to reduce LDL-C to therapeutic goals does not correct altered functions of HDL particles in humans. In the context of familial hypercholesterolemia, a growing body of evidence suggests that impaired efficacy of the RCT pathway contributes significantly to the progression of atherosclerosis.


Ependymoblastoma in a Japanese Black heifer.
An 18-month-old, Japanese Black heifer had ananastasia over a two-week period. The heifer was euthanized and necropsied. Grossly, a brown and soft mass was found in the left cerebellar hemisphere, which originated from the fourth ventricle in the pons. Multiple papillary masses were also found on the wall of the fourth ventricle. There was massive dilatation of the cerebral aqueduct, and also in the third and lateral ventricles. Histologically, the neoplastic cells formed numerous ependymoblastic rosettes and perivascular pseudorosettes. In the fourth ventricle, the normal ependymal cells were replaced by papillary proliferation of the neoplastic cells. Ultrastructually, the neoplastic cells had a feature differentiating to the ependymal cell showing a few basal bodies in the cytoplasm and connecting to adjacent cells with junctional complexes. We diagnosed the present case as ependymoblastoma with its origins in the fourth ventricle.


Insulinogenic indices from insulin and C-peptide: comparison of beta-cell function from OGTT and IVGTT.
A frequently used index of beta-cell function from the OGTT is the insulinogenic index, IGI. However, there is still some controversy about its validity. In a group of 145 women with different degrees of glucose tolerance, we compared IGI to the corresponding index with C-peptide, DeltaCP(30)/DeltaG(30), which better describes beta-cell function. We also validated both indices with measurements of beta-cell function derived from IVGTT. IGI strongly correlated (R = 0.82, P < 0.0001) with DeltaCP(30)/DeltaG(30). Both IGI and DeltaCP(30)/DeltaG(30) correlated significantly with the corresponding index from IVGTT, though IGI correlation was stronger (IGI: R = 0.67, P < 0.0001; DeltaCP(30)/DeltaG(30): R = 0.56, P < 0.0001). Also indices derived from areas under the curve of insulin, glucose and C-peptide were analyzed. Finally, we compared IGI to similar indices with samples at 60, 90 and 120 min, more often available than that at 30 min. We conclude that IGI is an acceptable index of beta-cell function, as also mirrored by DeltaCP(30)/DeltaG(30). However, the weaker correlation of the C-peptide index with the more accurate index from the IVGTT suggests that it should be used with caution. The index at 60 min can be used as surrogate of IGI, but not the indices at 90 and 120 min.


Infant with thanatophoric dwarfism in triplet pregnancy.
The case of a Japanese female infant with thanatophoric dwarfism, a triplet, is reported. The diagnosis was made at 18 weeks' gestation. Triplets were delivered at 30 weeks' gestation by cesarean section. Two infants, both males, were normal; the female with dwarfism died of respiratory distress 34 min after delivery. This is the first known case of one fraternal triplet being affected by thanatophoric dwarfism.


Analysis of 15q11.2 CNVs in an Indian population with schizophrenia.
Copy number variants (CNVs) of 15q11.2 yielded conflicting reports on their association with schizophrenia (SZ), indicating the need for replication studies. Because there are no 15q11.2 CNV studies on Indian patients, we began by testing 307 SZ patients and 359 age- and sex-matched controls from South India. Using an improved multiplex ligation probe amplification, six deletions were found in patients and three in controls (p = 0.31), whereas one duplication was found in patients and three in controls (p = 0.63). Analysis of families of two patients and two controls with deletions indicated that the mutations were de novo. In conclusion, there seems to be no significant difference in the frequencies of 15q11.2 CNVs among the controls and patients studied here. Future studies involving a larger number of controls and patients are expected to provide better clarity on the relationship between 15q11.2 CNVs and SZ patients from India.


Wherein lies the truth? Assessment of agreement between parent proxy and child respondents.
The epidemiological study of diseases of childhood presents a special situation in that the principal respondent is almost always a person other than the index. Use of proxy respondents in paediatric epidemiology has been little studied compared with the use of surrogate respondents for adults. Agreement between responses from children and their parents to identical questions about the children was assessed in a case-control study of childhood melanoma in Queensland, Australia. Weighted kappa and log-linear modelling techniques were used to measure agreement for ordinal data. Highest agreement was found for reports of unchanging physical characteristics such as eye colour (kappa = 0.88), hair colour (kappa = 0.76), and for history of residing on a farm (kappa = 0.84). Moderate agreement was seen for density of facial freckling (kappa = 0.62), propensity to sunburn (kappa = 0.46) and tanning ability (kappa = 0.47). Variables with low levels of agreement between parent proxy and child respondents included density of freckling on the shoulders (kappa = 0.28) and degree of moliness of the skin at age 5 years (kappa = 0.24). Agreement did not vary according to age or sex of the children. Log-linear modelling was performed to determine the type and magnitude of components of agreement. Agreement between responses from children and parent proxies depends largely upon the type of information sought, rather than characteristics of the respondents.


Clinical significance of antibiotic endotoxin-releasing properties in trauma patients.
To test the hypothesis that antibiotics leading to greater endotoxin release are associated with greater mortality in septic trauma patients. Post hoc analysis of data from a previously conducted prospective, randomized, multicenter study designed to evaluate the efficacy of interferon gamma in preventing infection and death in trauma patients. Nine level I trauma centers. Severely injured trauma patients at high risk for sepsis. Eighty percent (N = 334) of the enrolled patients developed some manifestation of gram-negative sepsis, defined by the administration of gram-negative specific antibiotics. The in-hospital mortality rate of patients who received penicillin-binding protein 3/tumor necrosis factor (PBP3/TNF)-specific antibiotics associated with the greatest degree of endotoxin release and TNF production (PBP3/TNF group, n = 78: aztreonam, ceftazidime, and cefotaxime sodium) was compared with that of patients not receiving these agents (non-PBP3/TNF group, n = 256). Mortality in the PBP3/TNF group (17%) was higher than in the non-PBP3/TNF group (8%, P = .02). The two groups were similar in their mean (+/- SD) Injury Severity Scores (34 +/- 9), ages (31 +/- 12 years), and initial degree of bacterial contamination. Antibiotics that are associated with greater release of endotoxin and production of TNF are also associated with greater mortality in septic trauma patients. Decisions regarding antibiotic administration may need to consider the endotoxin-releasing properties of antibiotics in addition to their antibacterial sensitivity spectrum. Prospective studies of the effect of endotoxin-releasing properties of antibiotics on mortality are warranted.


An isolated aneurysm of the thigh anterolateral branch of the greater saphenous vein in a young patient presenting as an inguinal hernia.
We report the first case of isolated aneurysm of the anterolateral branch of the greater saphenous vein in a 24-year-old man. The aneurysm was initially confused with an inguinal hernia. The patient referred with a respiratory distress due to a pulmonary embolism. The Doppler ultrasounds permitted to clarify the diagnosis. The aneurysm was removed en block under local anaesthesia. Surgeons should be aware to consider a venous aneurysm in the differential diagnosis of an inguinal mass. Indeed, due to its potential risk or embolism, the surgical treatment is mandatory.


A stochastic SIR model on a graph with epidemiological and population dynamics occurring over the same time scale.
We define and study an open stochastic SIR (Susceptible-Infected-Removed) model on a graph in order to describe the spread of an epidemic on a cattle trade network with epidemiological and demographic dynamics occurring over the same time scale. Population transition intensities are assumed to be density-dependent with a constant component, the amplitude of which determines the overall scale of the population process. Standard branching approximation results for the epidemic process are first given, along with a numerical computation method for the probability of a major epidemic outbreak. This procedure is illustrated using real data on trade-related cattle movements from a densely populated livestock farming region in western France (Finistère) and epidemiological parameters corresponding to an infectious epizootic disease. Then we exhibit an exponential lower bound for the extinction time and the total size of the epidemic in the stable endemic case as a scaling parameter goes to infinity using results inspired by the Freidlin-Wentzell theory of large deviations from a dynamical system.


Crystalline-state guest-exchange and gas-adsorption phenomenon for a "soft" supramolecular porous framework stacking by a rigid linear coordination polymer.
A 1D rigid, linear coordination polymer, (4,4'-bipyridine)(2-pyridylsulfonate)copper, has been applied for the controlled-assembly of a new porous host that generates 1D channels by an interdigitated packing through the recognition of hydrogen bonding and pi-pi stacking interactions. The porous structure is architecturally robust when it reversibly uptakes water molecules and exchanges guest small molecules (MeOH, i-PrOH) from solution as determined by single-crystal-to-single-crystal transformation studies. Moreover, the open-channel solid displays irreversible benzene and toluene vapor sorption behaviors attributed to a widening of the channel cross-section that fetters the larger guest molecules, resulting from the dynamic, "soft" supramolecular framework.


Simulation-optimization model for production planning in the blood supply chain.
Production planning in the blood supply chain is a challenging task. Many complex factors such as uncertain supply and demand, blood group proportions, shelf life constraints and different collection and production methods have to be taken into account, and thus advanced methodologies are required for decision making. This paper presents an integrated simulation-optimization model to support both strategic and operational decisions in production planning. Discrete-event simulation is used to represent the flows through the supply chain, incorporating collection, production, storing and distribution. On the other hand, an integer linear optimization model running over a rolling planning horizon is used to support daily decisions, such as the required number of donors, collection methods and production planning. This approach is evaluated using real data from a blood center in Colombia. The results show that, using the proposed model, key indicators such as shortages, outdated units, donors required and cost are improved.


Electromechanical coupling, uncoupling, and ventricular function in patients with bundle branch block: a tissue-Doppler echocardiographic study.
Left bundle branch block (LBBB) is associated with impaired left ventricular (LV) function and increased morbidity and mortality, especially in patients with structural heart diseases. The mechanisms are poorly understood. Subjects with isolated LBBB (n=20), right bundle branch block (RBBB, n=20), and controls (C, n=20) were studied with standard two-dimensional (2D), and color-encoded tissue-Doppler echocardiography (TDE). Inter- and intraventricular systolic and diastolic coordination were assessed from the TDE velocity profiles. LV function was assessed by 2D echocardiography, by TDE-derived peak systolic velocities, and the atrioventricular (AV) plane displacement. Subjects with LBBB had longer electromechanical delays and longer isovolumic relaxation times than did the C and RBBB groups (P <0.001). For the LBBB subjects compared with the RBBB and C groups, ejection times were shorter, peak systolic velocities and AV plane displacements were lower, they had larger LV end-systolic volumes and lower LV ejection fraction (all P <0.001), and the atrial contribution to A-V plane displacement was higher (P <0.01). There were no differences in diastolic or filling times among the groups. In patients with LBBB, delayed regional electromechanical coupling and uncoupling leads to generalized intra- and interventricular asynchrony, thereby explaining the depressed regional and global LV functions. Assessment of the electromechanical coupling and uncoupling processes and their consequences on cardiac function in patients with BBB and structural heart diseases may be possible using TDE.


[Twinkling artifact in color Doppler ultrasonography: pictorial essay].
The "twinkling" artifact is a color-flow sonographic artifact presenting as a rapidly changing color encoding behind a strongly reflecting structure. Recently, "twinkling" artifact has been described behind calcifications in various tissues, urinary and gallbladder stones, encrustated indwelling ureteral stents, strongly reflecting orbital structures and an intracranial microcoil. It is important to recognize this artifact as it could lead to misdiagnosis of vascular flow within a tissue. "Twinkling" artifact could be considered as an additional sonographic feature in the diagnosis of urinary and bile duct stones and encrustated indwelling ureteral stents. "Twinkling" artifact could also play a role in detecting the morphology or biochemical composition of urinary stones.


Investigation and treatment for iron deficiency in heart failure: the unmet need in Lower and Middle Income Countries.
Frank iron deficiency has been associated with a wide range of cardiac and pulmonary abnormalities including non-ischaemic cardiomyopathy. Iron deficiency anaemia and isolated iron deficiency are well-defined adverse prognostic factors in non-ischaemic cardiac failure. Furthermore, iron-deficient patients in chronic heart failure with a serum ferritin of <100 μg/l or <300 μg/l with reduced transferrin saturation of <20%, who were given intravenous iron showed improved clinical outcomes. Iron deficiency with or without anaemia affects over a quarter of the world's population, but the impact of iron deficiency in heart failure and the effective management of iron deficiency in heart failure in Lower and Middle Income Countries (LMICs) is not well described. Heart failure in African cohorts occurs at a younger age than in North America and Europe and is more likely to be due to hypertension. Recent studies suggest that iron deficiency anaemia, which is very common in heart failure patients in Africa, and iron deficiency are independently associated with a poor prognosis in heart failure. Preliminary data suggest that iron deficiency in patients with heart failure can be treated with oral iron, with significant beneficial effects on haematological and physiological variables. Cost may prohibit the use of intravenous iron on a large scale in LMICs and optimal regimes to treat iron deficiency in heart failure patients with oral iron therapy remain to be defined.


What really drives chemical reactions on contact charged surfaces?
Although it is known that contact-electrified polymers can drive chemical reactions, the origin of this phenomenon remains poorly understood. To date, it has been accepted that this effect is due to excess electrons developed on negatively charged surfaces and to the subsequent transfer of these electrons to the reactants in solution. The present study demonstrates that this view is incorrect and, in reality, the reactions are driven by mechanoradicals created during polymer-polymer contact.


Bioequivalence evaluation of two flutamide preparations in healthy female subjects.
In the present study two different preparations containing 250 mg flutamide (3'-trifluoromethyl-4'-nitro-2-methyl-propionylanilide, CAS 13311-84-7) were compared in 20 female subjects. The trial was performed in a randomized two-way cross-over design. Each subject received one tablet with 250 mg flutamide in each period. The two treatment periods were separated by a wash-out phase of 7 days. Blood samples were obtained just before dosing and 18 times during the subsequent 36 h. The plasma concentrations of flutamide, 2-hydroxyflutamide and trifluoromethylnitroaniline were determined by HPLC with UV-detection. Due to the low plasma levels of the parent drug flutamide, the data of the pharmacologically active metabolite 2-hydroxyflutamide (CAS 52806-53-8) were used for bioequivalence assessment. The following mean values were obtained after administration of the test and reference preparation respectively: Flutamide: AUC0-36 = 95.82 ng.h/ml vs 93.33 ng.h/ml, Cmax = 44.78 ng/ml vs 38.73 ng/ml, tmax = 1.71 h vs 1.66 h, 2-hydroxyflutamide: AUC0-infinity = 6090.73 ng.h/ml vs 6068.83 ng. h/ml, Cmax = 772.74 ng/ml vs 779.84 ng/ml, tmax = 2.21 h vs 2.17 h, t1/2 = 8.21 h vs 8.32 h, trifluoromethylnitroaniline: AUC0-infinity = 1771.87 ng.h/ml vs 1701.44 ng.h/ml, Cmax = 173.36 ng/ml vs 171.32 ng/ml, tmax = 2.74 h vs 2.63 h, t1/2 = 10.75 h vs 9.83 h. The two preparations proved to be bioequivalent.


Collimator design for single photon emission tomography.
We discuss recent trends in collimator design and technology, with emphasis on theoretical and practical issues of importance for single photon emission tomography (SPET). The well-known imaging performance parameters of parallel-hole collimators are compared with those of fan-beam collimators, which have enjoyed considerable success in recent years, particularly for brain SPET. We review a simplistic approach to the collimator optimization problem, as well as more sophisticated "task-dependent" treatments and important considerations for SPET collimator design. Practical guidance is offered for understanding trade-offs that must be considered for clinical imaging. Finally, selective comparisons among different SPET systems and collimators are presented for illustrative purposes.


Prenatal diagnosis of vascular anomalies.
Vascular anomalies are diagnosed prenatally with increasing frequency. The authors reviewed a group of children treated at their center who had an abnormal prenatal diagnosis to determine (1) fetal age at which the vascular anomaly was detected, (2) general diagnostic accuracy, and (3) impact on ante- and postnatal care. Their findings are compared with reported cases and series. The authors clarify appropriate terminology and underscore the need for interdisciplinary participation of specialists in the field of vascular anomalies. Patients referred during prenatal life and children with a history of abnormal antenatal findings seen at our vascular anomalies center during a 1-year period (September 1999 through August 2000) were included in this study. The fetal age at diagnosis, pre- and postnatal diagnoses, antenatal course, and neonatal outcome were obtained from the parents, through chart reviews, and through telephone interviews with the treating obstetricians. Twenty-nine patients with vascular anomalies were identified: 17 had a correct prenatal diagnosis, and 12 had an incorrect diagnosis, an overall diagnostic accuracy of 59%. Capillary-lymphatic-venous malformations (CLVM) most often were correctly diagnosed (67%), followed by lymphatic malformation (LM, 62%) and hemangioma (59%). In the infants who received correct diagnoses in utero, there were no fetal deaths and there was no neonatal morbidity. Maternal steroids were administered for a fetus with an intrahepatic hemangioma and deteriorating cardiac function, with subsequent stabilization and successful delivery of a healthy neonate. Among infants with incorrect diagnoses, there was 1 postnatal death, 1 case of erroneous gender assignment, 1 case of unnecessary fetal surgical intervention, 1 unnecessary neonatal laparotomy, and 1 delay in diagnosis of a malignancy. Cesarean section was done for 65% of correctly diagnosed cases, (including 2 ex utero intrapartum [Exit] procedures) and for 33% of incorrectly diagnosed cases. Most diagnoses were made during the mid- to late second trimester and third trimester; only 4 cases (14%) were detected before 20 weeks. In this series, accurate diagnosis optimized antenatal care by providing an opportunity for planning deliveries, for pharmacologic fetal intervention in 1 case, and for appropriate parental counselling. Inaccurate diagnosis was associated with significantly increased morbidity and mortality. Finally, the intrauterine diagnosis of LM should be distinguished from posterior nuchal translucency, an obstetric term applied to fetal lymphatic abnormalities detected in the first and second trimesters that do not manifest as postnatal LM.


[Antidotes to novel direct oral anticoagulants].
During the last 10 years, several novel direct oral anticoagulants (NOACs) have entered the clinical arena and were registered in the Russian Federation for use in patients presenting with atrial fibrillation, venous thrombosis, and pulmonary artery thromboembolism. NOACs are classified into two groups: direct thrombin inhibitor (notably dabigatran) and factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban). Their disadvantage is lack of specific antidotes in case of an emergency situation (injury, infarction, stroke requiring thrombolysis, urgent operation). The review contains the data on the existing therapeutic regimens of treating haemorrhage on the background of taking these coagulants. This is followed by analysing the present-day results of clinical trials aimed at working out pharmaceutical agents (andexanet alpha, idarucizumab, aripazine) being antidotes to direct thrombin inhibitor and the factor Xa inhibitors. Administration of these agents makes it possible to reverse coagulation and minimize the aftermaths of haemorrhage in patients taking these drugs, in emergency situations.


Determination of the type and quantity of sialic acid in the egg jelly coat of the sea urchin Paracentrotus lividus using capillary LC-ESI-MS/MS.
Sialic acid is a terminal sugar of carbohydrate chains that participates in numerous biological events. Recent studies have explored the mechanism of carbohydrate-mediated fertilisation to understand the biochemistry of fertilisation, although the type and quantity of sialic acid and the role of sialic acid during fertilisation remain unknown. Echinoderm fertilisation in particular has been studied extensively, yet our understanding of the mechanisms of carbohydrate-mediated fertilisation and the role of sialic acid remains incomplete. In this study, we characterised the sialic acid types in the egg jelly coat of the sea urchin, Paracentrotus lividus, using the sensitive analytical system capillary liquid chromatography electro-spray ionisation tandem mass spectrometry (capLC-ESI-MS/MS). First, we isolated the egg jelly coat and released its sialic acid using acid treatment. These sialic acids were derivatised with 1,2-diamino-4,5-methylenediaoxy-benzene dihydrochloride (DMB) and injected into the capLC-ESI-MS/MS system. When compared with standards, we identified twelve different types of sialic acid according to their retention times and collision-induced dissociation fragments. The mass spectral data revealed that Neu5Gc, Neu5Ac, Neu5GcS, and Neu5Gc9Ac were the predominant types of sialic acid in the sea urchin jelly coat, with Neu5Gc being the most abundant. Other types of sialic acid detected included Neu5AcS, Neu5Gc7,9Ac2, Neu5,9Ac2, Neu5Gc8Ac, Neu5Gc7Ac, Neu5,7Ac2, Neu5Gc8,9Ac2, and Neu5,8Ac2. The types and quantities of sialic acid that we detected in the egg jelly coat will aid in the discovery of new sialic acid-specific receptors on the sperm membrane.


Preparative Separation of High-Purity Dihydroartemisinic Acid from Artemisinin Production Waste by Combined Chromatography.
In order to make full use of artemisinin production waste and thus to reduce the production cost of artemisinin, we developed an efficient and scalable method to isolate high-purity dihydroartemisinic acid from artemisinin production waste by combining anion-exchange resin with silica-gel column chromatography. The adsorption and desorption characteristics of dihydroartemisinic acid on 10 types of anion-exchange resin were investigated, and the results showed that the 717 anion-exchange resin exhibited the highest capacity of adsorption and desorption to dihydroartemisinic acid. Adsorption isotherms were established for the 717 anion-exchange resin and they fitted well with both Langmuir and Freundlich model. Dynamic adsorption and desorption properties of 717 anion-exchange resin were characterized to optimize the chromatographic conditions. Subsequently, the silica-gel column chromatography was performed and dihydroartemisinic acid with a purity of up to 98% (w/w) was obtained. Finally, the scale-up experiments validated the preparative separation of high-purity dihydroartemisinic acid from industrial waste developed in the present work. This work presented for the first time an isolation of dihydroartemisinic acid with a purity of 98% from Artemisia annua (A. annua) by-product, which adds more value to this crop and has the potential to lower the prices of anti-malarial drugs.


Effect of uterine lavage on neutrophil counts in postpartum dairy cows.
Subclinical endometritis affects approximately 30% of lactating dairy cows, causing significant economic losses to the dairy industry. Yet, there is no efficient treatment available for this condition. The present study examines the effect of uterine lavage in clinically normal cows with sterile saline solution at 30 days in milk (DIM) on the percentage of polymorphonuclear cells (PMNs) detected with endometrial cytology as an indicator of subclinical endometritis. It was hypothesized uterine lavage would be a technique to reduce the number of PMNs in the uterus, and hence be beneficial for cows affected by subclinical endometritis. Cytology samples were taken by low-volume flushing from 50 Holstein Friesian cows on 30 and 40 DIM. On Day 30, cows were clinically examined and randomly assigned into a treatment and control group. In the treatment group, the cytology sampling on Day 30 was immediately followed by uterine lavage with 500-600 mL of sterile physiological saline (35-40°C). Cytology sampling was repeated in all cows at 40 DIM. Lactation numbers >2, peripheral progesterone concentrations >1 ng/mL and uterine lavage at 30 DIM all were significantly associated with lesser PMN percentages at 40 DIM (P=0.0041; 0.0187 and 0.0043, respectively). Uterine lavage might, therefore, be a useful and practical method to decrease the number of PMNs in the uterus of cattle. Results from the current study can be used as preliminary data for designing in depth therapeutic protocols for treatment of subclinical endometritis in cattle.


[Anesthetic management of two patients with amyotrophic lateral sclerosis (ALS)].
We experienced anesthetic management of two cases of amyotrophic lateral sclerosis (ALS). Case 1. A 46-year-old woman underwent emergency operation for ileus. Abdominal muscle relaxation and analgesia were obtained by combined spinal and epidural anesthesia. To avoid prolongation of muscle relaxation, awake intubation without muscle relaxants was performed. After the operation, she awoke smoothly and was extubated without any complications. Case 2. A 65-year-old woman underwent emergency operation for gastric fistula malfunction. We performed anesthetic management only with epidural anesthesia. During and after the operation, she was in good general condition and had no pain. For the patients with ALS, prolongation of muscle relaxation and residual neuromuscular block effect may cause difficult tracheal extubation and postoperative respiratory complications. We observed carefully the condition of the patients with ALS, and were able to choose the minimum invasive anesthetic methods for each case.


Effect of Eriobotrya japonica seed extract on 5-fluorouracil-induced mucositis in hamsters.
In this study, we investigated the effects of an Eriobotrya japonica seed extract (ESE) on mucositis using a 5-fluorouracil (5-FU)-induced mucositis hamster model. This model was prepared by intraperitoneally administering 90 mg/kg of 5-FU to hamsters on Day 1, scratching 1 cm(2) of the left cheek pouch of hamsters with a wire brush on Days 2, 3, and 4, and intraperitoneally administering 60 mg/kg of 5-FU on Day 5. Mucositis was evaluated based on the mucositis score at the mucositis site, left cheek pouch thickness, histological findings on HE staining, and plasma lipid peroxide levels. On Day 10, the mucositis score and left cheek pouch thickness in the ESE group were significantly lower than those in the tap water group. Histologically, the two groups showed a defect of the cheek pouch epithelium on Day 6. On Day 10, epithelial injury and bacterial infection were noted in the tap water group. However, in the ESE group, similar findings were not observed. On Day 6, the plasma lipid peroxide level in the tap water group was significantly higher than that in the normal group. In the ESE group, the plasma lipid peroxide level was significantly lower than that in the tap water group. These results suggest that ESE is useful for treating chemotherapy-induced mucositis.


Major histocompatibility complex binding and T cell recognition of a viral nonapeptide containing a minimal tetrapeptide.
The primary immune response of cytotoxic T lymphocytes in H-2d and H-2q mice to infection with lymphocytic choriomeningitis virus is directed mostly towards the common major T cell epitope of amino acids 112-132 on the viral nucleoprotein (NP). The molecules responsible for presentation of the T cell epitope NP112-132 are in both haplotypes the MHC class I L antigens (Ld, Lq). Truncations of the amino and carboxy termini of the NP 112-132 sequence revealed the nonapeptide RPQASGVYM (NP118-126) as a most effective peptide antigen, but even the tetrapeptide GVYM was recognized by CTL of both haplotypes in a class I antigen-restricted specificity. When tyrosine (Y) or methionine (M) were substituted with alanine, CTL recognition of the altered nonamer required 10(6) to 10(8) times higher peptide concentrations and in one case (Y----A on Ld) the peptide was not recognized at all. Up-modulation of the expression of Ld and Lq class I antigens as measured by flow cytometry correlated with the ability to present the peptide antigens. The only exception was peptide NP118-126 (M----A), which was recognized by T cells on L-Ld and L-Lq target cells but failed to up-regulate Ld and Lq antigens.


Effect of follicle stimulating hormone on female Catla catla (Ham.).
The exogenously administered FSH in Catla catla clearly reveals that a dose of 0.2 mg and 0.4 mg of FSH does not have any marked effect on the ovary, but the vitellogenesis begins with a further dose of 0.2 mg of the same. A rapid accumulation of yolk is recorded in the primary oocytes with a total dose of 0.8 mg of FSH, however, this much hormone is not enough for the spawning. The latter has been recorded with 1.0 mg of FSH which swifts with a dose of 1.2 mg of FSH. The number of mature follicle declines with 1.4 mg of FSH whereas no empty follicle is seen with the same treatment. With each addition of 0.2 mg of FSH upto 2.0 mg the number of oogonia and primary oocytes increases while maturing and mature follicles show a downward tendency.


Examination of the role of CSF-1 independence in myc retrovirus induced monocyte tumorigenesis.
These studies were initiated as an attempt to estimate the number and nature of genetic changes that are required in addition to c-myc deregulation during monocyte tumorigenesis, and to determine whether the oncogenic changes that can be created in vitro resemble the actual changes that occur in vivo. We found that superinfecting myc-immortalized monocytes with a colony stimulating factor-1 (CSF-1) expressing retrovirus strongly promoted tumorigenesis, whereas granulocyte/macrophage-CSF (GM-CSF) and v-fms retroviruses, or the spontaneous acquisition of CSF-1 independence did so only moderately. In addition myc-infected monocytes isolated from mice at a stage prior to tumor formation are more tumorigenic than in vitro myc-immortalized monocytes, but they were still largely CSF-1 dependent, and were not as tumorigenic as reinnoculated tumor cells. In the simplest model only two oncogenic activations are required for monocyte/macrophage transformation, immortalization of the cells with c-myc and deregulation of the CSF-1 gene. However, not all mechanisms that result in loss of CSF-1 dependence lead to full tumorigenicity, suggesting that in vivo tumorigenesis may involve multiple secondary events including growth factor independence.


Dysautonomia and Clinical Outcome in Vegetative State.
Abstract A dramatic disorder tentatively attributed to diencephalic-hypothalamic damage or dysfunction, dysautonomia affects recovery from brain injury. Its incidence, correlation with etiology, and relevance as a predictor of outcome were retrospectively surveyed in 333 patients in vegetative state (VS) for more than 2 weeks at admission. Outcome was assessed according to the Glasgow Outcome Scale (GOS). Data were treated statistically by multivariate analyses. Dysautonomia occurred in 26.1% of patients, with greater incidence among post-traumatic (31.9%) than non-traumatic (15.8%) patients. Outcome was worse among non-traumatic than post-traumatic patients irrespective of dysautonomia, and worst among non-traumatic patients with dysautonomia. Dysautonomia proved common among patients in VS (with incidence depending on etiology and age) and influenced the patients' outcome through mechanisms still to be defined, but conceivably mediated by diencephalic-hypothalamic unbalance.


[TREATMENT OF SCARS IN THE 21ST CENTURY].
Abnormal scars are a common complication of the wound healing process, associated with aesthetic, functional and psychological morbidities. The constant development of our understanding of the pathophysiology of scars has led to the development of different treatment modalities and protocols. Treatment during the early stages of wound healing is considered scar prevention and is associated with better cosmetic results than older mature scars. Several studies have demonstrated optimal results with therapeutic protocols combining different treatment modalities, the most important of them being laser technology. Every scar is unique and requires a customized approach and a combination of modalities to achieve the most aesthetic outcome.


Uterus didelphys with unilateral imperforate hemivagina and ipsilateral renal agenesis.
Eight patients with a double uterus, unilateral vaginal obstruction, and ipsilateral renal agenesis are described. The most common clinical presentation was that of the onset of pelvic pain and dysmenorrhea, in association with the finding of a pelvic mass. In seven patients, a window was created between two vaginae by transvaginal route. In one patient, the blind vagina with hematocolpos and attending uterus were extirpated by an abdominal approach. The postoperative courses were uncomplicated in all patients. A greater awareness of this syndrome should lead to accurate diagnosis. Excision of the obstructing vaginal septum offers a complete relief of symptoms while preserving reproductive capacity.


Risk factors associated with small bowel adenocarcinoma in Crohn's disease: a case-control study.
It is well established that Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). The data concerning SBA risk factors in CD are scanty. The aim of this study was to identify them. In 11 French centers affiliated with the GETAID (Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif), we identified 29 patients with CD and SBA. Eighty-seven CD controls without SBA recruited in a single center were matched to the cases for sex, age, duration, and CD site. A conditional logistic regression, taking into account the matching between cases and controls, was performed. In univariate analysis, the cases had had significantly less small bowel resection and received prolonged treatment with salicylates (more than 2 yr), less often than the controls (odds ratio, OR [95% confidence interval, CI] 0.07 [0.01-0.32] and 0.29 [0.10-0.82], respectively). In multivariate analysis, both associations remained significant (OR 0.04 [0.01-0.28], P= 0.001; OR 0.16 [0.03-0.79], P= 0.02, respectively). This study suggests that small bowel resection and prolonged salicylates use may protect against SBA in CD patients.


Imaging membrane potential in dendrites and axons of single neurons.
This review focuses on the use of imaging techniques to record electrical signaling in the fine processes of neurons such as dendrites and axons. Voltage imaging began with the use and development of externally applied voltage-sensitive dyes. With the introduction of internally applied dyes and advances in detection technology, it is now possible to record supra-threshold action potential responses, as well as sub-threshold synaptic potentials, in fine neuronal processes including dendritic spines. The development of genetically coded sensors, as well as variants of laser scanning microscopy such as second harmonic generation, offers promise for further advances in this field. Through the use and further development of these methods, optical imaging of membrane potential will continue to be a valuable tool for investigators wishing to explore the electrical events underlying single neuronal computation.


Proteome changes induced by c-myb silencing in human chronic myeloid leukemia cells suggest molecular mechanisms and putative biomarkers of hematopoietic malignancies.
To shed light on the molecular mechanisms associated with aberrant accumulation of c-Myb in chronic myeloid leukemia, comparative proteomic analysis was performed on c-myb RNAi-specifically silenced K562 cells, sampled on a time-course basis. 2D-DIGE technology highlighted 37 differentially-represented proteins that were further characterized by nLC-ESI-LIT-MS/MS and validated by western blotting and qRT-PCR analysis. Most of the deregulated proteins were related to protein folding, energy/primary metabolism, transcription/translation regulation and oxidative stress response. Protein network analysis suggested that glycolysis, gluconeogenesis and protein ubiquitination biosynthesis pathways were highly represented, confirming also the pivotal role of c-Myc. A specific reduced representation was observed for glyceraldehyde-3-phosphate-dehydrogenase and α-enolase, suggesting a possible role of c-Myb in the activation of aerobic glycolysis. A reduced amount was also observed for stress responsive heat shock 70kDa protein and 78kDa glucose-regulated protein, previously identified as direct targets of c-Myb. Among over-represented proteins, worth mentioning is the chromatin modifier chromobox protein homolog 3 that contributes to silencing of E2F- and Myc-responsive genes in quiescent G0 cells. Data here presented, while providing novel insights onto the molecular mechanisms underlying c-Myb activity, indicate potential protein biomarkers for monitoring the progression of chronic myeloid leukemia. Myeloid leukemia is a malignant disease of the hematopoietic system in which cells of myeloid lineages accumulate to an undifferentiated state. In particular, it was shown that an aberrant accumulation of the c-Myb transcriptional factor is associated with the suppression of normal differentiation processes promoting the development of the hematopoietic malignancies. Many efforts have been recently made to identify novel genes directly targeted by c-Myb at a transcriptome level. In this work, we originally describe a differential proteomic approach to facilitate the comprehension of the regulation of the protein networks exerted by c-Myb. Our study reveals a complex network of proteins regulated by c-Myb. The functional heterogeneity of these proteins emphasizes the pleiotropic role of c-Myb as a regulator of genes that are crucial for energy production and stress response in leukemia. In fact, variations in glyceraldehyde-3-phosphate-dehydrogenase and α-enolase suggest a possible role of c-Myb in the activation of aerobic glycolysis. Moreover, significant differences were found for heat shock 70kDa protein and 78kDa glucose-regulated protein known as direct c-Myb targets. This work highlights potential protein biomarkers to look into disease progression and to develop translational medicine approaches in myeloid leukemia.


Outpatient instruction for individuals with COPD.
Educating individuals with COPD is an important part of their overall medical and nursing management. Due to the debilitating nature of the disease, care must be exercised to offer programs that meet the participants' individual needs. Classes should be offered at a convenient time and place. To facilitate discussion, class size should be kept small. Family members and significant others should be encouraged to attend the classes to reinforce what is taught in class and to provide support and encouragement. Finally, measuring outcomes is important in order to demonstrate the overall effectiveness of the program; however, instruments used to measure effectiveness must be simple, easy to administer, and complete. Helping individuals manage their COPD presents a real challenge to nurses. A well-designed educational program is one cost-effective measure that can meet this challenge.


Gene expression in human alcoholism: microarray analysis of frontal cortex.
Changes in brain gene expression are thought to be responsible for the tolerance, dependence, and neurotoxicity produced by chronic alcohol abuse, but there has been no large scale study of gene expression in human alcoholism. RNA was extracted from postmortem samples of superior frontal cortex of alcoholics and nonalcoholics. Relative levels of RNA were determined by array techniques. We used both cDNA and oligonucleotide microarrays to provide coverage of a large number of genes and to allow cross-validation for those genes represented on both types of arrays. Expression levels were determined for over 4000 genes and 163 of these were found to differ by 40% or more between alcoholics and nonalcoholics. Analysis of these changes revealed a selective reprogramming of gene expression in this brain region, particularly for myelin-related genes which were down-regulated in the alcoholic samples. In addition, cell cycle genes and several neuronal genes were changed in expression. These gene expression changes suggest a mechanism for the loss of cerebral white matter in alcoholics as well as alterations that may lead to the neurotoxic actions of ethanol.


The inspiratory work of breathing during assisted mechanical ventilation.
We quantified the mechanical work of breathing in six normal subjects during assisted mechanical ventilation. Using two volume-cycled ventilators of different design, we investigated the influence of minute ventilation (VE) and machine settings of trigger sensitivity and flow during CO2-driven hyperventilation to moderate and high levels (12-24 L/min). Work estimates were derived from plots of esophageal and airway pressure against inflation volume. Peak flow and trigger sensitivity were important determinants of the energy expended, and for each combination of machine settings the work done by the subject per liter of ventilation increased with VE. During assisted ventilation the subject expended energy equivalent to 33-50 percent of the work of passive inflation, even under the most favorable conditions of VE, sensitivity and flow. Under the least favorable conditions of VE, sensitivity and flow, the subject's inspiratory work of breathing substantially exceeded the energy needed by the ventilator to inflate the passive thorax. These observations imply that exertion of the respiratory muscles continues throughout inflation during assisted mechanical ventilation and call attention to the possibility that inappropriate selection of ventilatory mode or machine settings may contribute to respiratory muscle fatigue and dyspnea.


Photoexcitation effect on the adsorption of hazardous gases on silica surface.
There is very little scientific understanding of photoexcitation effect on the adsorption properties of adsorbent. The adsorption of four hazardous gases (SARIN (propan-2-ylmethylphospho-nofluoridate), methyl dichlorophosphate (MDCP), trimethyl phosphate (TMP) and hydrogen sulfide (H2S)) on silica surface is taken as target sample in this work. The adsorption energy order (MDCP<SARIN<TMP) in the ground state is consistent with the strength order of intermolecular hydrogen bond (inter-HB) between hydroxyl group of silica surface and hazardous gas, and the desorption order of the three gases in previous reports. However, with the adsorption energy increase of MDCP and the decrease of SARIN and TMP, this order changes remarkably to SARIN<TMP<MDCP after photoexcitation to excited state by absorbing shortwave ultraviolet irradiation. This change is opposite to the inter-HB weakening of MDCP in the first excited (S1) state and the strengthening of TMP and SARIN in the second excited (S2) state. This opposite change is caused by formation of intermolecular charge transfer state of MDCP and local excitation of SARIN and TMP. The H2S is dissociated after photoexcitation to the S1 state. This work presents photoexcitation as a new standard for the design and detection of adsorption properties of adsorbent for its striking effect on adsorption behaviors.


Youth violence trajectories and proximal characteristics of intimate partner violence.
Analyses first examined the developmental course of intimate partner violence (IPV), beginning with trajectories of youth violence. We then examined potential mediators of prior youth violence trajectories in models predicting later IPV perpetration as an outcome. Potential mediators include risks associated with the individual (e.g., current alcohol and drug use and mental health diagnosis), characteristics of a perpetrator's partner (e.g., use of alcohol/drugs and history of antisocial behavior), and aspects of the surrounding community (e.g., neighborhood norms favorable to violence and drug use). Data are from the Seattle Social Development Project, a longitudinal study of over 800 individuals followed from elementary school to young adulthood (age 24). Findings suggest that both chronic and late-increaser patterns of youth violence elevated the likelihood of later IPV perpetration. Partial mediation effects of the relation between youth violence and IPV were found for variables related to one's partner and the surrounding community. Individual characteristics of the perpetrator were not uniquely predictive of IPV when measured as a risk index and modeled along with other risk factors. Findings indicate that the risk of IPV could be lessened by addressing earlier forms of violence and by intervening to reduce risks within and across domains of influence.


Survey of the cosmetic use of lasers and other strong optical radiation sources.
A survey was undertaken regarding the extent to which optical radiation is used in cosmetic treatments and the compliance with national regulations. Questionnaires were sent to 65 clinics, and 23 of these were later inspected. Only one of 41 class 4 lasers had been reported to the authorities according to the regulations prior to the survey. Among sources other than lasers, intense pulsed light (IPL) sources were the most frequent. Although qualified health personnel should be in charge of the treatment, it was observed that 30% of the clinics did not fulfil this requirement. Deviations with respect to personnel training, availability of written procedures, protective equipment and warning signs were frequently observed. The results give rise to concern about the safety of patients and employees.


A multicenter study on HLA and autoimmunity in Japanese patients with early-onset insulin-dependent diabetes mellitus (IDDM): the JDS Study.
The Japan Diabetes Society (JDS) conducted a multicenter study on HLA and autoimmunity in Japanese patients with early-onset insulin-dependent diabetes mellitus (IDDM). HLA, immunoglobulin heavy-chain complex (Gm), properdin factor B (BF), and glyoxalase of erythrocytes (GLO) were typed, and organ-specific autoantibodies including islet cell antibodies (ICA) were assayed in 159 IDDM patients and their relatives and in 258 healthy Japanese subjects. The HLA-DRw9 phenotype and HLA-Bw61/DRw9 haplotype were significantly increased among the patients with autoantibodies other than ICA, whereas the DR4 phenotype and Bw54/DR4 haplotype were significantly increased in those without the autoantibodies. The DR4 phenotype was significantly increased in the patients with autoimmune thyroid diseases. The relative risk of the HLA-DRw9/DR4 genotype was highest among all DR genotypes. The Gm phenotype of g and gft were significantly increased in the patients with the autoantibodies. The BF-F phenotype was significantly decreased in the patients either with or without the autoantibodies. There was no association of GLO types with IDDM. The prevalence of ICA among IDDM patients was decreased with duration of IDDM. No significant association was found between the prevalence of ICA and sex, age at onset, or HLA type. On the other hand, the prevalence of the autoantibodies was not significantly changed with duration of the disease, and was significantly higher in females than in males.


Expression and significance of calreticulin in human osteosarcoma.
As one of the endoplasmic reticulum proteins, calreticulin (CRT) plays a significant role in the body, and it has been used by many researchers as a target for anti-tumor therapy. The main purpose of the present study was to study expression of CRT of human osteosarcoma, and analyze the distinctions between normal and tumor tissues, pre- and post-chemotherapy patients, and metastatic and non-metastatic tumors in respect to this expression. Immunofluorescent staining was used in order to investigate expression of CRT in diverse tissues. The whole RNA and proteins were extracted from the crushed tissues and used in the reverse transcription polymerase chain reaction (RT-PCR) and western blotting analysis. The present study detected expression of CRT in patients with osteosarcoma and revealed a higher expression level in normal tissues surrounding tumors compared with tumor tissues, in the non-metastasis group compared with the metastasis group, and in the chemotherapy group compared with the non-chemotherapy group. These results could indicate a brand-new biological marker which may be applied to estimate the features and prognosis of osteosarcoma.


Blocking action of intracellularly injected neuraminidase on central synapses in vivo.
The effect of neuraminidase on synaptic transmission was studied at cholinergic and noncholinergic contacts in the buccal and cerebral ganglion of Ap]lysia. The amplitudes of monosynaptic unitary postsynaptic potentials generated by intracellular stimulation of identified presynaptic neurones were measured as indication for the efficacy of synaptic transmission. Neuraminidase was either intrasomatically injected into a presynaptic neurone, or the whole ganglion was incubated with the enzyme. Intrasomatic injection of the enzyme resulted in complete failure of synaptic transmission. This effect occurred independently of the transmitter used. The synaptic failure was presynaptic in origin. The biophysical characteristics of an injected neurone, particularly the amplitude and propagation of its action potential, did not appear to be affected by neuraminidase. Synaptic transmission and biophysical membrane properties were unaffected by extracellular neuraminidase. We conclude that the synaptic blockade is due to the enzyme's action inside the presynaptic nerve ending. It seems most likely that neuraminidase cleaves sialic-acid-containing-compounds associated with the nerve terminal surface membrane, probably thus causing failure of transmitter release.


Bcl-2 down-regulation is a novel mechanism of paclitaxel resistance.
Taxanes act by inhibiting microtubule dynamics; in this study, we have investigated mitochondria as an additional target of taxanes. We incubated isolated mitochondria in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. Results showed that they rapidly induced the loss of deltapsim after stimulation of the respiratory state. To evaluate the binding of [14C]paclitaxel to isolated mitochondria, mitochondrial proteins were precipitated yielding 18.6 +/- 2.1 cpm/microg of protein. After stimulation of the respiratory state, binding of [14C]paclitaxel increased up to 163.2 +/- 46.7 cpm/microg of protein. CPM values after Bcl-2 immunoprecipitation was 62.8-fold higher than those of the control antibody, thereby indicating the involvement of Bcl-2 in paclitaxel binding. Then, we established a panel of A2780 cell lines resistant to increasing doses of paclitaxel alone or to high doses of paclitaxel/cyclosporin A (A2780 TC cells). In both cases, Bcl-2 expression was consistently down-regulated, whereas levels of other members of the Bcl-2 family, such as Bax and Bcl-x, did not change in paclitaxel-resistant cell lines. When A2780TC cells were stably transfected with a Bcl-2 construct, paclitaxel sensitivity was partially restored, thereby supporting a direct role of Bcl-2 down-regulation in the maintenance of drug-resistance. Finally, we examined Bcl-2 by immunohistochemistry in a small subset of ovarian cancer paclitaxel-resistant patients and we noticed that the protein is down-regulated in this clinical setting with respect to the expression levels found in drug-sensitive tumors. These findings demonstrate that Bcl-2 is an additional intracellular target of taxanes and that its down-regulation is involved in taxane resistance.


Preterm delivery in Ilorin: multiple and teenage pregnancies as major aetiological factors.
This study reports the aetiological factors responsible for 291 preterm births among 5019 deliveries at the University of Ilorin Teaching Hospital (UITH) during a 12-month period. It was found that although preterm babies made up 5.8% of all deliveries, they were responsible for 42% perinatal deaths. Important aetiological factors predisposing to preterm delivery included multiple pregnancy in 41.2% and primiparity in 23.4%. One-fifth of the primiparous were teenage mothers. Other factors included premature rupture of membrane, antepartum haemorrhage, grandmultiparity and eclampsia. It is suggested that early identification, monitoring and intervention in these high risk groups will improve gestational duration thereby reducing morbidity and mortality associated with preterm deliveries.


Grape seed and skin extract protects against arsenic trioxide induced oxidative stress in rat heart.
Arsenic is a metalloid found in water, soil, and air from natural and anthropogenic sources, and is commonly found in inorganic as well as organic forms. The clinical use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL) is limited by its cardiotoxic side effects. Grape seed and skin extract (GSSE) is a polyphenolic mixture with antioxidant properties. This study aimed to evaluate the protective effect of GSSE on arsenic-induced cardiac oxidative stress and injury. Animals exposed to 2.5 mg/kg As2O3 for 21 days exhibited a relevant increase in heart lipoperoxidation, protein carbonylation, and inflammation, as well as a drop in the activity of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx). In addition, As2O3 disturbed heart lipidemia and lipase activity, transition metals distribution and the associated enzymes, intracellular mediators such as calcium and the associated calpain activity, as well as myocardial architecture. Treatment with 4 g/kg GSSE protected against most of the deleterious effects provoked by As2O3. Our data suggest that GSSE has the potential to protect against As2O3-induced cardiotoxicity.


Cutting edge: DNA polymerases mu and lambda are dispensable for Ig gene hypermutation.
Mutations arising in Ig V genes during an immune response are most likely introduced by one or several error-prone DNA polymerases. Many of the recently described nonreplicative DNA polymerases have an intrinsic fidelity compatible with such an activity, the strongest candidates being polymerase (pol) eta, pol iota, pol zeta, and pol mu. We report in this work that mice inactivated for either of the two polymerases related to pol beta (i.e., pol mu and pol lambda) are viable and fertile and display a normal hypermutation pattern.


Early T cell response in the central nervous system in canine distemper virus infection.
The initial demyelinating lesions in canine distemper virus (CDV) infection develop during a period of severe immunosuppression in the absence of inflammation. In vitro and in vivo studies suggest that early demyelination is due to directly virus-induced oligodendroglial changes. In the present spatiotemporal study in experimentally CDV-infected dogs we observed diffuse up-regulation of T cells throughout the central nervous system (CNS) and T cell invasion in early demyelinating lesions. Invasion of T cells in the CNS occurred despite severe immunosuppression and without any perivascular cuffing. However, the major fraction of invading T cells correlated with sites of viral replication and coincided with the demonstration of an early immune response against the nucleocapsid protein of CDV. Activation of microglial cells was thought to have elicited the migration of T cells to the CNS by secretion of chemokines: marked IL-8 activity was found in the CSF of dogs with acute lesions. In areas of early demyelination, large numbers of CD3+ cells accumulated in the tissue in the absence of any morphological sign of inflammation. Whether the T cells at lesion sites contribute to the development of acute demyelination remains uncertain at this stage. Antiviral cytotoxicity was not apparent since viral clearance in demyelinating lesions is only effective when B cells and concurring antiviral antibody production appeared in the subacute and chronic inflammatory stage of the disease. CD3+ cells appear to persist for several weeks after infection since they were also found in recovered dogs that did not develop demyelination. Accumulation of immune cells, including a significant proportion of resting T cells (CD45RA+) in the CNS in the early stages of the disease may facilitate the later development of the intrathecal immune response and associated immunopathological complications.


Molecular characterization of the Pri3 gene encoding a cysteine-rich protein, specifically expressed during fruiting initiation within the Agrocybe aegerita complex.
Coding and regulating sequences of Pri3 (a novel gene specifically expressed in both nucleus types of dikaryons during fruiting initiation) were compared within nine strains of the Agrocybe aegerita complex originating from Europe, Asia and Latin America. Highly homologous coding sequences were found; and the 95-amino-acid-long PRI3 deduced proteins all shared eight cysteines and eight glycines, a putative signal peptide suggesting an extra-cellular localization, a protein kinase C site (T(70)) and a cAMP-dependent kinase site (S(74)). The PRI3 proteins presented no significant homologies with already known proteins and constitute a new class of small cysteine-rich proteins. Within the 5' uncoding regions, two leader introns and a putative upstream regulating sequence resembling the QA1-F activator site were highly conserved. Comparison of the gene sequences within the A. aegerita complex suggested a divergent evolution of the European and Asian/Latin American groups of genes.


The current state, challenges and perspectives of MR-PET.
Following the success of PET/CT during the last decade and the recent increasing proliferation of SPECT/CT, another hybrid imaging instrument has been gaining more and more interest: MR-PET. First combined, simultaneous PET and MR studies carried out in small animals demonstrated the feasibility of the new approach. Concurrently, some prototypes of an MR-PET scanner for simultaneous human brain studies have been built, their performance is being tested and preliminary applications have already been shown. Through this pioneering work, it has become clear that advances in the detector design are necessary for further optimization. Recently, the different issues related to the present state and future prospects of MR-PET were presented and discussed during an international 2-day workshop at the Forschungszentrum Jülich, Germany, held after, and in conjunction with, the 2008 IEEE Nuclear Science Symposium and Medical Imaging Conference in Dresden, Germany on October 27-28, 2008. The topics ranged from small animal MR-PET imaging to human MR-BrainPET imaging, new detector developments, challenges/opportunities for ultra-high field MR-PET imaging and considerations of possible future research and clinical applications. This report presents a critical summary of the contributions made to the workshop.


An olmesartan medoxomil-based treatment algorithm is effective in achieving 24-hour BP control in patients with type 2 diabetes mellitus, regardless of age, race, sex, or severity of hypertension: subgroup analysis of the BENIFICIARY study.
Hypertension often occurs concomitantly with diabetes mellitus, such that >50% of adults with type 2 diabetes have hypertension. These individuals are at a greater risk of developing renal and cardiovascular disease. The currently recommended BP goal of <130/80 mmHg for patients with type 2 diabetes is achieved in only 37.5% of treated patients with diabetes and hypertension. The antihypertensive efficacy of olmesartan medoxomil (OM) ± hydrochlorothiazide (HCTZ) was investigated in prespecified subgroups (age <65/≥65 years, Blacks/non-Blacks, males/females, or stage 1/stage 2 hypertension) of patients with hypertension and type 2 diabetes enrolled in an open-label, single-arm study (n = 192). Patients started treatment with OM 20 mg/day and were uptitrated at 3-week intervals to OM 40, OM/HCTZ 40/12.5, and OM/HCTZ 40/25 mg/day if BP was ≥120/70 mmHg. The primary endpoint was the change in mean 24-hour ambulatory SBP from baseline to week 12, assessed by mean 24-hour ambulatory BP monitoring. Secondary endpoints included changes in mean 24-hour ambulatory DBP, mean daytime ambulatory BP, mean nighttime ambulatory BP, and mean office seated BP, and the proportions of patients achieving prespecified ambulatory BP targets. This was a multicenter study (24 sites) that took place between November 2006 and November 2007 in the US. BP reductions were significant (p < 0.0001) and similar among subgroups of patients with type 2 diabetes. Following dose titration to OM/HCTZ 40/25 mg/day, similar proportions of patients in the age, race, and sex subgroups (approximately 60-64% across these subgroups) achieved an ambulatory BP target of <130/80 mmHg. A larger proportion of patients with type 2 diabetes and stage 1 hypertension achieved this same goal compared with patients with stage 2 hypertension (75% vs 46.3%). The combination of OM/HCTZ was well tolerated in all patient subgroups irrespective of age, race, sex, or hypertension severity. In this open-label study, OM/HCTZ combination therapy was efficacious and well tolerated in subgroups of patients with diabetes and hypertension. [Clinical Trials Registry Number: NCT00403481].


Modeling dermatophytosis in reconstructed human epidermis: A new tool to study infection mechanisms and to test antifungal agents.
Dermatophytosis is a superficial fungal infection of keratinized structures that exhibits an increasing prevalence in humans and is thus requesting novel prophylactic strategies and therapies. However, precise mechanisms used by dermatophytes to adhere at the surface of the human epidermis and invade its stratum corneum are still incompletely identified, as well as the responses provided by the underlying living keratinocytes during the infection. We hereby report development of an in vitro model of human dermatophytosis through infection of reconstructed human epidermis (RHE) by arthroconidia of the anthropophilic Trichophyton rubrum species or of the zoophilic Microsporum canis and Arthroderma benhamiae species. By modulating density of arthroconidia in the inoculum and duration of exposure to such pathogens, fungal infection limited to the stratum corneum was obtained, mimicking severe but typical in vivo situation. Fungal elements in infected RHE were monitored over time by histochemical analysis using periodic-acid Schiff-staining or quantified by qPCR-detection of fungal genes inside RHE lysates. This model brings improvements to available ones, dedicated to better understand how dermatophytes and epidermis interact, as well as to evaluate preventive and therapeutic agents. Indeed, miconazole topically added to RHE was demonstrated to inhibit fungal infection in this model.


Frequency of Daily Tooth Brushing and Development of any Type of Malignancy.
The aim of this study was to evaluate the association between the frequency of daily tooth brushing and the development of any type of malignancy. We conducted a retrospective longitudinal study, including all adult participants who underwent health check-ups. Primary outcome was the development of any type of malignancy, compared to the frequency of daily tooth brushing, adjusting for potential confounders. A total of 71,449 participants were included and 5,025 participants developed a certain type of malignancy. Not brushing everyday (Odds Ratio (OR)=1.52, 95% Confidence Interval (CI)=1.03-2.25) and brushing once a day (OR=1.25, 95%CI=1.16-1.35) had significantly higher ORs for the outcome than brushing after every meal, although those who brushed once to twice a day had significantly lower OR (OR=0.78, 95%CI=0.72-0.83). As the frequency of daily tooth brushing increased, except for brushing after every meal, the development of all types of malignancies decreased.


High-performance liquid chromatographic determination of histamine in biological samples after derivation with o-phthalaldehyde.
A high-performance liquid chromatographic (HPLC) method for the determination of histamine in tissues, based on precolumn derivation with o-phthalaldehyde, is described. Trichloroacetic acid extracts of rat brain, but not of rat stomach or of rat peritoneal mast cells, had to be cleaned-up by a chromatographic step before HPLC. The extracts were allowed to react with o-phthalaldehyde at pH 12.5 and -20 degrees C for 12 h, followed by acidification to pH 2.0. HPLC was performed on a reverse-phase column with isocratic elution using sulfuric acid in methanol as solvent system. A fluorescence detection system was used; excitation was set at 353 nm and emission was read at 451 nm. One chromatographic run was completed in 20 min. The detection limit with the conventional procedure was 1.5 ng histamine per sample, with a scaled-down procedure it was 250 pg per sample. With extracts of rat gastric mucosa the within-run variation was 2.7% and the day-to-day variation 4.5%.


[Quality parameters of cryoprecipitates from stored blood preservation].
The investigations of a series of 281 cryoprecipitates produced from blood stored at 10 degrees C for 12-18 hours resulted in equal values as compared with those preparations from a control group of 53 preparations which had been prepared from blood maximally stored for 4 hours. Thus, international experiences could be confirmed. An improvement in the quality of erythrocyte concentrates simultaneously produced can be regarded as an additional advantage with respect to the formation of microaggregates during the time the stored blood can be made use of.


Use of non-verbal communication skills to improve nursing care.
This article describes non-verbal communication (NVC), its nursing assessment and its use with people who have a learning disability. A nursing diagnosis of altered non-verbal communication is outlined and a new wellness diagnosis is proposed of potential for enhanced non-verbal communication. The use and encouragement of non-verbal communication with people who have limited verbal comprehension is discussed. Nurses are considered an important focus for change; for enhancing a person's non-verbal skills, for improving their learning environment and for ultimately improving their social development.


Characterization of protein-adjuvant coencapsulation in microparticles for vaccine delivery.
Protein antigens encapsulated as vaccines in poly[(rac-lactide)-co-glycolide] (PLGA) microparticle carriers can induce immune responses. The intensity and directions of this response can be controlled by coloading the microparticles with immunomodulatory adjuvants, e.g., muramyl dipeptide (MDP) as adjuvant combined with ovalbumin (Ova) as protein antigen. In this study, methodologies for an individual quantification of both encapsulated substances should be reported, which comprise (i) a separation process to isolate and determine MDP as intact molecule and (ii) a simultaneous degradation of both analytes with subsequent specific quantification of Ova fragments. It was shown that coloading of both substances resulted in a substantially reduced encapsulation efficiency of MDP. This illustrates that correct conclusions on dose-response relationships in future vaccination studies can only be drawn, if a selective method for adjuvant and protein quantification will be applied.


Ratiometric Upconversion Luminescence Nanoprobe with Near-Infrared Ag2S Nanodots as the Energy Acceptor for Sensing and Imaging of pH in Vivo.
A luminescence resonance energy transfer (LRET) system was successfully developed using near-infrared (NIR) Ag2S nanodots (NDs) as the energy acceptors and upconversion nanoparticles (UCNPs) as the energy donors. The system possessing the properties of NIR excitation (980 nm) and NIR emission (795 nm) was used for the ratiometric detection and bioimaging of pH in tumor cells and zebrafish. Glutathione and mercaptopropionic acid (MPA) co-modified Ag2S NDs (GM-Ag2S NDs) were prepared by ligand exchange with an excellent pH-responsive property over a pH range of 4.0 to 9.0. The NIR GM-Ag2S NDs were covalently grafted with silica coated UCNPs, and an efficient LRET platform was developed via modulation of the thickness of the silica coating. Due to the LRET process between UCNPs and GM-Ag2S NDs, a ratiometric luminescence nanoprobe with the properties of NIR excitation-NIR emission was constructed for pH biosensing and bioimaging. On the basis of high contrast bioimaging, the nanoplatform can distinguish between tumor and normal tissue in the zebrafish model.


Inhibitory effect of 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection.
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) was evaluated for its inhibitory effect on hepadnavirus replication in three different cell systems, i.e., human hepatoma cell lines HepG2 2.2.15 and HB611 (transfected with human hepatitis B virus (HBV)) and primary cultures of duck hepatocytes infected with duck hepatitis B virus (DHBV). PMEA inhibited HBV release from HepG2 2.2.15 cells and HB611 cells at a 50% inhibitory concentration (IC50) of 0.7 and 1.2 microM, respectively. Intracellular viral DNA synthesis was inhibited at concentrations equivalent to those required to inhibit virus release from the cells. DHBV secretion from duck hepatocytes was inhibited by PMEA at an IC50 of 0.2 microM. HBsAg secretion was inhibited by PMEA in a concentration-dependent manner in HB611 cells and DHBV-infected duck hepatocytes but not HepG2 2.2.15 cells. The 50% cytotoxic concentration, as measured by inhibition of [3H-methyl]deoxythymidine incorporation was 150 microM for the two human hepatoma cell lines and 40 microM for the duck hepatocyte cultures. In a pilot experiment PMEA was found to reduce the amounts of DHBV DNA in the serum of Pekin ducks.


Primidone-induced catatonic schizophrenia.
The authors report the case of a severely retarded, 19-year-old female (treated with primidone 250 mg tid since age 12) who was admitted with visual and auditory hallucinations. After four days of continuing hallucinations, she went into classic catatonic schizophrenia. Upon examination, her primidone serum level was found to be well above the normal therapeutic range. The primidone dosage was decreased, and symptoms subsided as serum levels returned to normal.


Structure and reactivity in the non-mevalonate pathway of isoprenoid biosynthesis.
The function, structure and mechanism of two Escherichia coli enzymes involved in the non-mevalonate route of isoprenoid biosynthesis, 2C-methyl-D-erythritol 4-phosphate cytidylyltransferase and 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, are reviewed. Comparisons of each with enzymes from microbial pathogens highlight important conservation of sequence suggestive of similarities in secondary structure, subunit folds, quaternary structure and active sites. Since both enzymes are validated drug targets, the models provide templates for structure-based design of anti-microbial agents targeting a number of serious human diseases.