Mitochondrial complex I in the network of known and unknown facts.
The mitochondrial respiratory chain consists of five multi-subunit complexes embedded in the inner mitochondrial membrane. Complex I is the largest and most complicated proton pump of the respiratory chain encoded by both the mitochondrial and nuclear genomes. In this minireview, attention is given to recent knowledge on the structure, catalytic properties, supramolecular organisation of complex I and its possible role in the triggering of apoptosis.


In vitro characterization of L-type calcium channels and their contribution to firing behavior in invertebrate respiratory neurons.
L-type calcium channel activity has been associated with a number of cytoplasmic responses, including gene transcription and activation of calcium-dependent enzymes, yet their direct contribution to the electrical activities of neurons has remained largely unexplored. Here we report the cloning and functional characterization of a molluscan L-type calcium channel homologue, LCa(v)1, and investigate its role in coordinating neuronal firing patterns. The LCav1 channel exhibits many hallmarks of vertebrate L-type channels in that it is high-voltage activated, slowly inactivating, and dihydropyridine sensitive and displays calcium-dependent inactivation in recording solutions with standard EGTA concentrations. We show that despite comprising less than approximately 20% of the total whole cell current in identified Lymnaea respiratory network neurons, the L-type channels are essential for maintaining rhythmic action potential discharges without being involved in synaptic release. Our data therefore suggest an important role of L-type calcium channels in maintaining rhythmical pattern activity underlying breathing behavior in Lymnaea.


Signal transducer and activator of transcription 3 (STAT3) promoter methylation and expression in pituitary adenoma.
Pituitary adenoma (PA) is a benign brain tumor that can cause neurological, endocrinological and ophthalmological aberrations. Till now there is a need to identify factors that can influence the tumor invasiveness and recurrence. The aim of this study was to evaluate the associations between the signal transducer and activator of transcription 3 (STAT3) promoter methylation, mRNA expression and the invasiveness or recurrence of PAs and patient clinical characteristics. Study participants comprised of 102 subjects with a diagnosis of PA: 54 functioning and 48 non-functioning, 58 invasive and 30 non-invasive PAs and 14 relapses. The bisulfite treatment of tumor DNA and methylation-specific polymerase chain reaction (MS-PCR) method was used to determine the STAT3 gene promoter methylation. For the STAT3 mRNA expression, the first-strand cDNA was produced from total RNA by using reverse transcriptase and quantitative real-time PCR (qRT-PCR) was performed. In 10.78% (11/102) of PA tissues STAT3 gene promoter was methylated. A gender of male and patient group older than 60 years were significantly associated with reduced STAT3 mRNA expression (Mann-Whitney test, p = 0.025, p = 0.047, respectively). However, no more statistical differences were found between STAT3 promoter methylation, mRNA expression and patient clinical characteristics or PA invasiveness or recurrence. Further investigations are needed to clarify the influence of STAT3 gene promoter methylation and mRNA expression changes in PAs.


A comparative assessment of the factor structures and psychometric properties of the GHQ-12 and the GHQ-20 based on data from a Finnish population-based sample.
The General Health Questionnaire (GHQ) is a self-report questionnaire designed to identify psychological distress. Psychometric properties of two versions of GHQ-12 and GHQ-20 were assessed in a large population-based sample of Finnish twins, ages 22 to 27 (n= 4580). Participants were randomized into two subgroups, namely Twin1 (n= 2294) and Twin2 (n= 2286). The GHQ-12 data were assessed using Confirmatory Factor Analysis (CFA). The factor structure of the GHQ-20 was first assessed with Exploratory Factor Analysis (EFA) in the Twin1 dataset, and the results obtained were then subjected to CFA in Twin1 and Twin2 datasets. The CFA of the GHQ-12 indicated that the best fit and the simplest solution were provided by the three-factor solution in both subpopulations. Analyses of the GHQ-20 suggested that the four-factor structure was superior to the three-factor model. This result is also theoretically justifiable. Compared to the 12-item version, GHQ-20 provides additional fourth factor of anhedonia, suggesting some discriminative power.


ALDH1A1 Gene Expression and Cellular Copper Levels between Low and Highly Metastatic Osteosarcoma Provide a Case for Novel Repurposing with Disulfiram and Copper.
Aldehyde dehydrogenase 1A1 (ALDH) is a cancer stem cell marker highly expressed in metastatic cells. Disulfiram (Dis) is an FDA-approved antialcoholism drug that inhibits ALDH and has been studied as a candidate for drug repurposing in multiple neoplasia. Dis cytotoxicity in cancer cells has been shown to be copper-dependent, in part due to Dis's ability to function as a bivalent metal ion chelator of copper (Cu). The objectives of this research were to test ALDH expression levels and Cu concentrations in sarcoma patient tumors and human osteosarcoma (OS) cell lines with differing metastatic phenotypes. We also sought to evaluate Dis + Cu combination therapy in human OS cells. Intracellular Cu was inversely proportional to the metastatic phenotype in human OS cell lines (SaOS2 > LM2 > LM7). Nonmetastatic human sarcoma tumors demonstrated increased Cu concentrations compared with metastatic tumors. qPCR demonstrated that ALDH expression was significantly increased in highly metastatic LM2 and LM7 human OS cell lines compared with low metastatic SaOS2. Tumor cells from sarcoma patients with metastatic disease displayed significantly increased ALDH expression compared with tumor cells from patients without metastatic disease. Serum Cu concentration in canine OS versus normal canine patients demonstrated similar trends. Dis demonstrated selective cytotoxicity compared with human multipotential stromal cells (MSCs): Dis-treated OS cells demonstrated increased apoptosis, whereas MSCs did not. CuCl2 combined with Dis and low-dose doxorubicin resulted in a superior cytotoxic effect in both SaOS2 and LM7 cell lines. In summary, ALDH gene expression and Cu levels are altered between low and highly metastatic human OS cells, canine samples, and patient tumors. Our findings support the feasibility of a repurposed drug strategy for Dis and Cu in combination with low-dose anthracycline to specifically target metastatic OS cells.


Establishing a common language for lumbar transforaminal epidural steroid injections.
Patients presenting to spine surgeons for lumbar radiculopathy often undergo initial conservative treatment including medications, therapy, and lumbar transforaminal epidural steroid injections. Despite a growing number of spinal injections performed, there is a lack of available data regarding the occurrence of wrong-site injections. However, when examined, the discrepancies between ordering level and level of epidural steroid injection performed are immense. To aid with this issue, we propose that instead of ordering a lumbar transforaminal epidural steroid injections at a given level, it should be ordered to address a specific nerve root with laterality. This has the potential to reduce wrong-site procedures and improve patient outcomes. Retrospective chart review of 60 patients at a private orthopaedic spine practice under the care of spine surgeons or physician assistants over a 1-year period. The progress note, injection order form, procedure note, and procedural fluoroscopy were reviewed. If there were inconsistencies between one or more of these steps, it was deemed a failure. Results were analyzed to assess for any differences in outcomes between the two groups. We calculated our sample size prior to the study and powered it at 90%; descriptive statistics, Chi-square, Fisher's exact test, Student's t-test, and Wilcoxon rank sum tests were used where appropriate utilizing SAS v9.4. Thirty-seven patients (37/60, 61.6%) were considered a failure. There were no failures when ordering an S1 nerve root injection. We identified one wrong-site procedure and one wrong-level order that was identified and corrected by the interventionalist. There were multiple inconsistencies identified at various steps in the injection ordering process. This indicates a need to standardize the language used in this process to avoid wrong-site procedures. There were no inconsistencies in ordering an S1 injection, likely because this injection could only be ordered at the nerve root. It is also critical to utilize and save a localization film to ensure accuracy and accountability. We propose indicating the affected nerve root in all cases rather than the level of disc pathology would avoid confusion.


The utility of midtrimester ultrasound assessment of the subcutaneous space in predicting cesarean wound complications.
To evaluate the association between cesarean wound complications and thickness of the subcutaneous space within the anterior abdomen at the midtrimester fetal anatomical survey. In this case-control study, cases were identified using an ICD9 code for wound complications of cesarean delivery. For each case, we identified the woman with the next consecutive midtrimester ultrasound who had a cesarean delivery without a wound complication, matched on age and race, as the control. A blinded investigator measured subcutaneous space at three distinct suprapubic levels in the midsagital plane. Of 7228 women with a cesarean delivery, 123 (1.7%) had a wound complication. Seventy-nine cases were eligible. Midline suprapubic subcutaneous thickness did not differ between cases and controls at the superior, middle or inferior locations (p ≥ 0.35). Body mass index was moderately correlated with ultrasound-derived measurements (r ≥ 0.63; p < 0.001). The incidence of vertical skin incision, stapled skin closure and classical hysterotomy differed between groups (p ≤ 0.046). There was no significant increase in wound complication risk with increasing subcutaneous space thickness, even after adjustment (p ≥ 0.34). Prenatal ultrasound can quantify the subcutaneous space. Vertical skin incision, stapled wound closure, and a classical hysterotomy were associated with cesarean wound complication, but midtrimester subcutaneous thickness was not.


Minimal Residual Disease (MRD) Detection with Translocations and T-Cell Receptor and Immunoglobulin Gene Rearrangements in Adult Acute Lymphoblastic Leukaemia Patients: A Pilot Study.
Monitoring minimal residual disease has become increasingly important in clinical practice of ALL management. Break-point fusion regions of leukaemia related chromosomal aberrations and rearranged immunoglobulin (Ig) and T cell-receptor (TCR) genes, which can be detected by polymerase chain reaction (PCR), are used as leukaemia specific markers in genetic studies of MRD. A total of 31 consecutive patients with newly diagnosed ALL were screened for eligibility criteria. Of those 26 were included in the study. One patient with partial response following induction therapy and four patients who were lost to follow-up after induction were excluded from the study; thus 21 patients were evaluated for MRD. Chromosomal aberrations were detected in 5 (24%) of the patients and were used for MRD monitoring. Three patients had t(9;22) translocation, the other 2 had t(4;11) and t(1;19). MRD-based risk stratification of the 16 patients analysed for Ig/TCR rearrangements revealed 3 low-risk, 11 intermediate-risk and 2 high-risk patients. MRD monitoring is progressively getting to be a more important predictive factor in adult ALL patients. As reported by others confirmed by our limited data there is a good correlation between MRD status and clinical outcome in patients receiving chemotherapy. The pilot-study presented here is the first that systematically and consecutively performs a molecular MRD monitoring of ALL patients in Turkey.


Zinc Oxide-Doped Antibacterial Soda Lime Glass Produced as a Glass Container.
The aim of this study is to produce and characterize glass materials, which have an enhanced antibacterial property by the conventional melting method. Container glass compositions including different amounts of zinc oxide (ZnO) (5.0, 7.5, and 10.0%) were prepared and melted to be able to obtain the antibacterial glass. The Release and antibacterial tests, which were performed after the melting process, showed that the glass doped with 5% ZnO was the most appropriate composition according to test results (99.82% Escherichia coli inactivation) and its raw materials' costs. Physical, thermal, and mechanical properties such as thermal expansion coefficient (86.1 × 10-7/°C), density (2.523 g/cm3), refractive index (1.5191), hardness (596 kg/mm2), and elastic modulus (5.84 GPa) of the glass doped with 5% ZnO were determined, and the results showed that the obtained antibacterial glass sample is suitable to be used as a glass container. HighTemperature Melting Observation System studies were performed on the produced antibacterial glass composition, and it was found that the antibacterial glass can be produced in soda lime glass furnaces without changing any furnace design and production parameters. This antibacterial glass can be a remarkable product for the pharmaceutical and food industries.


Effectiveness of a 5-year school-based intervention programme to reduce adiposity and improve fitness and lifestyle in Indian children; the SYM-KEM study.
Non-randomised non-blinded school-based intervention study. Two schools in the cities of Pune and Nasik, India. The intervention group comprised children attending a Pune school from 7-10 years until 12-15 years of age. Two control groups comprised children of the same age attending a similar school in Nasik, and children in the Pune intervention school but aged 12-15 years at the start of the study. A 5-year multi-intervention programme, covering three domains: physical activity, diet and general health, and including increased extracurricular and intracurricular physical activity sessions; daily yoga-based breathing exercises; making physical activity a 'scoring' subject; nutrition education; healthier school meals; removal of fast-food hawkers from the school environs; and health and nutrition education for teachers, pupils and families. Body mass index (BMI), waist circumference, physical fitness according to simple tests of strength, flexibility and endurance; diet; and lifestyle indicators (time watching TV, studying and actively playing). After 5 years the intervention children were fitter than controls in running, long jump, sit-up and push-up tests (p<0.05 for all). They reported spending less time sedentary (watching TV and studying), more time actively playing and eating fruit more often (p<0.05). The intervention did not reduce BMI or the prevalence of overweight/obesity, but waist circumference was lower than in the Pune controls (p=0.004). It was possible to achieve multiple health-promoting changes in an academically competitive Indian school. These changes resulted in improved physical fitness, but had no impact on the children's BMI or on the prevalence of overweight/obesity.


Bisphenol A impairs the memory function and glutamatergic homeostasis in a sex-dependent manner in mice: Beneficial effects of diphenyl diselenide.
Bisphenol A (BPA) is a compound integrated in commodities, which consequently increases the human exposure to this toxicant. The deleterious effects of BPA exposure during periods of brain development have been documented mainly concerning the impairment in memory functions. Diphenyl diselenide (PhSe)2, an organoselenium compound, shows protective/restorative effects against memory deficits in experimental models. Thus, this study investigated the effects of (PhSe)2 on the memory impairments induced by BPA exposure to male and female mice and the possible involvement of glutamatergic system in these effects. Three-week-old male and female Swiss mice received BPA (5mg/kg), intragastrically, from 21st to 60th postnatal day. After, the animals were intragastrically treated with (PhSe)2 (1mg/kg) during seven days. The mice performed the behavioral memory tests and the [3H] glutamate uptake and NMDA receptor subunits (2A and 2B) analyses were carried out in the hippocampus and cerebral cortex of mice. The results demonstrated that the BPA exposure induced impairment of object recognition memory in both sexes. However, it caused impairments in spatial memory in female and in the passive avoidance memory in male mice. Besides, BPA caused a decrease in the [3H] glutamate uptake and NMDA receptor subunit levels in the cortical and hippocampal regions depending on the sex. Treatment with (PhSe)2 reversed in a sex-independent manner the behavioral impairments and molecular alterations. In conclusion, BPA had a negative effect in different memory types as well as in the glutamatergic parameters in a sex-dependent manner and (PhSe)2 treatment was effective against these alterations.


Evaluation of an automatic intraluminal edge detection technique for intravascular ultrasound images.
Intravascular ultrasound (IVUS) imaging enables detailed analysis and precise measurements of vascular cross-sections. However, to achieve a reduction in the existing level of observer variability requires the development of quantitative IVUS. We have developed a fully automatic intraluminal edge detection technique, based on adaptive active contour models and called ADDER (adaptive damping dependent on echographic regions) that allows the quantitation of the intraluminal cross-sectional area (ICSA). Using a 30-MHz mechanically rotated transducer mounted at the tip of a 3.5-F catheter, 58 normal and pathologic arterial segments (from coronary, renal, splenic, iliac, and carotid arteries) were imaged in vitro. These images were analyzed by 2 experts, E1 and E2, who manually traced the intraluminal contour twice for each image, as well as with ADDER. Intra-observer variabilities for ICSAs were found to be excellent (-1.454 +/- 3.51% for E1, 0.96 +/- 5.4% for E2). The inter-observer variability was 2.1 +/- 4.3%. The success factor for ADDER was 89%. Its intra-observer variability was null, as the method always finds a unique contour. The correlation between the automatically detected ICSA and the manual ICSA was: r = 0.99 (y = 1.03x + 0.89 mm2). Morphometric variations between manually and automatically traced contours, analyzed by the centerline method, were 100 +/- 140 mm on average. In conclusion, the ADDER automatic contour detection applied to IVUS images is robust and characterized by small systematic and random errors; therefore, quantitative IVUS is a useful tool in clinical research trials.


Pulse pressure amplification and its determinants.
Pulse pressure (PP) amplification expressed as the peripheral-to-central PP ratio has gained importance in the assessment of cardiovascular phenotypes and cardiovascular risk. The aim of the present study was to assess the relationship between PP amplification, large vessel parameters and peripheral blood pressure (BP) to gain insights into the amplification phenomenon. Peripheral BP, central BP and carotid-femoral pulse wave velocity (cfPWV) were assessed using the OMRON M6, SphygmoCor and Complior devices, respectively, in 741 adults attending the hypertension outpatient clinic. Analysis of covariance, partial correlations and multiple linear regression models were performed to assess the relationship between PP amplification, peripheral BP and cfPWV. PP amplification was inversely related to BP group. Women showed lower PP amplification than men (1.24 ± 0.18 and 1.35 ± 0.18, respectively, p < 0.001). Age, female gender and mean arterial pressure were inversely associated with PP amplification (p < 0.001), whereas heart rate and body mass index showed positive associations (p < 0.001 and p = 0.049, respectively). cfPWV was a predictor of PP amplification in men but not in women (p = 0.006 and p = 0.424, respectively). PP amplification is related to BP: the higher the BP, the lower the PP amplification. Gender, age and body composition have a significant impact on PP amplification.


Gastric epithelioid haemangioendothelioma.
Epithelioid haemangioendothelioma (EHE) is a rare tumour of vascular origin, characterised by celular proliferation, endotelial, epitelioid or hystiocitoid. It may develop in any organ, but it is more common in lung and liver. Surgery is the recommended treatment; however, in case of a potentially benign situation, an expectant attitude should be adopted. The case reports a 71-year-old female who underwent a laparotomy for a colonic adenocarcinoma. During surgery, a polypoid lesion in the dependency of the gastric wall was found incidentally, which was removed. Histopathology and immunohistochemical analysis confirmed the diagnosis of EHE. Gastric vascular neoplasms represent about 0.9-3.3% of all gastric tumours. Usually have a good prognosis, but due to the borderline biological behaviour of these tumours, it is important to have a detailed clinical evaluation at follow-up of these patients.


Racial differences in end-of-life planning: why don't Blacks and Latinos prepare for the inevitable?.
I evaluate the extent to which ethnic disparities in advance care planning reflect cultural and religious attitudes and experience with the painful deaths of loved ones. Data are from a sample of 293 chronically ill older adults who are seeking care at one of two large medical centers in urban New Jersey. Blacks and Hispanics are significantly less likely than Whites to have a living will, a durable power of attorney for health care (DPAHC), and to have discussed their end of life treatment preferences. Multivariate analyses reveal that the Black-White gap in advance care planning is largely accounted for by Blacks' belief that God controls the timing and nature of death. The Hispanic-White gap is partially accounted for by the belief that one's illness negatively affects one's family. Ethnic disparities are starkest for living will and DPAHC use, and less pronounced for discussions. Implications for policy and practice are discussed.


Spontaneous uterine rupture at 22 weeks' gestation in a multipara with previous hysteroscopic resection of fibroid.
A 34-year-old multiparous woman presented at 22(+6) weeks' gestation with severe abdominal pain which preceded a mechanical fall down the stairs. On admission, fetal movements were felt and fetal heart rate was detected by Doppler ultrasound. Over the course of 12 h, although she maintained her vital signs, repeat laboratory and radiological investigations suggested sinister intra-abdominal pathology. Subsequently, fetal movements and heart rate ceased and the patient began to decompensate. A CT scan confirmed uterine rupture. Subsequent emergency laparotomy revealed a 2 l haemoperitoneum and lifeless fetoplacental unit in the abdominal cavity. It is postulated that this rupture occurred as a rare yet life-threatening complication of a hysteroscopic resection of fibroid that the patient underwent 1 year previously. There are no known published cases of a spontaneous uterine rupture following a hysteroscopic procedure at such an early gestation. The patient made a full physical recovery.


Clinical and radiological features in relation to urinary excretion of lipoarabinomannan in Ethiopian tuberculosis patients.
We have previously reported on the diagnostic potential of urinary lipoarabinomannan (LAM) detection in active tuberculosis (TB). In this study, we identified clinical and radiological parameters that were significantly associated with urine LAM positivity in a clinical sample of 931 patients attending a TB control center in Addis Ababa, Ethiopa. These parameters were attributed weights and used in a diagnostic score (DS) system. Using urinary LAM as a reference, this DS system showed a sensitivity of 65.4% and a specificity of 82.9%. The positive and negative predictive values were 56.8% and 87.4%, respectively. HIV or other coinfections or deficiencies may have blurred the clinical manifestations of pulmonary TB (PTB) and thereby contributed to the relatively high number of false-positive DS results obtained. Although additional markers may be required to improve the sensitivity of the DS system, the relatively high specificity of this simple approach may be of some practical use in the field. Thus, in PTB-suspected, DS-negative cases, the likelihood of ongoing PTB is < 20%.


Using bivariate models to understand between- and within-cluster regression coefficients, with application to twin data.
In the regression analysis of clustered data it is important to allow for the possibility of distinct between- and within-cluster exposure effects on the outcome measure, represented, respectively, by regression coefficients for the cluster mean and the deviation of the individual-level exposure value from this mean. In twin data, the within-pair regression effect represents association conditional on exposures shared within pairs, including any common genetic or environmental influences on the outcome measure. It has therefore been proposed that a comparison of the within-pair regression effects between monozygous (MZ) and dizygous (DZ) twins can be used to examine whether the association between exposure and outcome has a genetic origin. We address this issue by proposing a bivariate model for exposure and outcome measurements in twin-pair data. The between- and within-pair regression coefficients are shown to be weighted averages of ratios of the exposure and outcome variances and covariances, from which it is straightforward to determine the conditions under which the within-pair regression effect in MZ pairs will be different from that in DZ pairs. In particular, we show that a correlation structure in twin pairs for exposure and outcome that appears to be due to genetic factors will not necessarily be reflected in distinct MZ and DZ values for the within-pair regression coefficients. We illustrate these results in a study of female twin pairs from Australia and North America relating mammographic breast density to weight and body mass index.


Modeling Study of the Dynamics of Kinesin-14 Molecular Motors.
Kinesin-14s constitute a subfamily of the large superfamily of adenosine triphosphate-dependent microtubule-based motor proteins. Kinesin-14s have the motor domain at the C-terminal end of the peptide, playing key roles during spindle assembly and maintenance. Some of them are nonprocessive motors, whereas others can move processively on microtubules. Here, we take budding yeast Cik1-Kar3 and human HSET as examples to study theoretically the dynamics of the processive kinesin-14 motor moving on the single microtubule under load, the dynamics of the motor coupled with an Ndc80 protein moving on the single microtubule, the dynamics of the motor moving in microtubule arrays, and so on. The dynamics of the nonprocessive Drosophila Ncd motor is also discussed. The studies explain well the available experimental data and, moreover, provide predicted results. We show that the processive kinesin-14 motors can move efficiently in microtubule arrays toward the minus ends, and after reaching the minus ends, they can stay there stably, thus performing the function of organizing the microtubules in the bipolar spindle into polar arrays at the spindle poles.


Mesenchymal stem cells are resistant to carbon ion radiotherapy.
Mesenchymal stem cells (MSCs) participate in regeneration of tissues damaged by ionizing radiation. However, radiation can damage MSCs themselves. Here we show that cellular morphology, adhesion and migration abilities were not measurably altered by photon or carbon ion irradiation. The potential for differentiation was unaffected by either form of radiation, and established MSC surface markers were found to be stably expressed irrespective of radiation treatment. MSCs were able to efficiently repair DNA double strand breaks induced by both high-dose photon and carbon ion radiation. We have shown for the first time that MSCs are relatively resistant to therapeutic carbon ion radiotherapy. Additionally, this form of radiation did not markedly alter the defining stem cell properties or the expression of established surface markers in MSCs.


Sustained improvement in urticaria pigmentosa and pruritus in a case of indolent systemic mastocytosis treated with cladribine.
Systemic mastocytosis (SM) is a myeloproliferative disorder, characterized by a clonal proliferation of abnormal mast cells accumulating in internal organs and sometimes in the skin, leading to cutaneous and systemic symptoms. Mutations within the gene KIT, which encodes the receptor tyrosine kinase (KIT) on mast cells, is found in most patients with SM. We report a case of a 62-year-old woman presenting with a pruritic rash on her limbs and trunk. Several years later she developed gastrointestinal symptoms, associated with raised serum tryptase. Skin and bone marrow biopsies confirmed a diagnosis of SM, initially presenting with urticaria pigmentosa. Responses to multiple therapies, including potent topical steroids, oral antihistamines, phototherapy and the tyrosine kinase inhibitor, nilotinib, were inadequate. Treatment with cladribine (2-chlorodeoxyadenosine) produced a marked and sustained reduction in her symptoms and serum tryptase level.


Histopathologic and molecular characterization of BAP-1-inactivated melanoma.
BRCA1-associated protein 1 (BAP-1) is a deubiquitylase that functions as a tumor suppressor, regulating multiple cellular processes including cell cycle control, differentiation, cell death, and DNA repair. BAP-1-inactivated melanocytic tumors (BIMTs) have recently been described and are characterized by epithelioid cytomorphology, are often clonal in appearance, and typically do not recur or show malignant transformation on follow-up. To describe the histopathologic and molecular characterization of five cases of BAP-1-inactivated cutaneous malignant melanomas. The archives at two separate institutions were retrospectively searched for tumors classified as melanoma with loss of BAP-1 via immunohistochemistry. Five cases were identified. These cases were classified as malignant melanoma based on cytomorphology, immunohistochemistry, and ancillary molecular testing. The clinical demographics were recorded, along with the histomorphologic features of each case. Genomic analysis for all cases was performed via OncoScan. The five reviewed cases consisted of two females and three males ranging from 67 to 74 years in age. Molecular characterization of each case was performed using OncoScan. Microarray assay showed that there was a complete deletion of 3p in all cases, BRAF V600E mutation in two cases, NRAS missense variant in one case, and loss of 9p in three cases. All cases showed malignant copy number alterations. Herein we describe five cases of BAP-1-inactivated melanomas confirmed by histomorphology and immunohistochemistry, all of which show malignant copy number profiles including loss of 3p. In addition, we provide a case of a likely BIMT showing progression to BAP-1-inactivated melanoma on a 16-year follow-up.


Multiconfiguration Self-Consistent Field Study on Formonitrile Imine and N-Substituted Nitrile Imines HCN2-R: Energy Component Analysis of the Pseudo-Jahn-Teller Effect.
Stable geometrical structures for formonitrile imine (1) and N-substituted nitrile imines HCN2-R (R = Li, BeH, BH2, CH3, CN, CCH, C6H5, NH2, OH, and F) (2-11) were examined by using the multiconfiguration self-consistent-field (MCSCF) method followed by second-order configuration interaction (SOCI) calculations and second-order multiconfiguration quasi-degenerate perturbation theory (MCQDPT2) calculations, together with the aug-cc-pVTZ basis sets. The results show that 1 suffers a pseudo-Jahn-Teller (JT) distortion from a linear C∞v structure to a C1 structure via a planar bent Cs structure. Each of the others is found to undergo pseudo-JT distortion from a symmetrical structure to a planar bent Cs structure for 2, 3, and 7 and to a C1 structure for 4, 5, 6, 8, 9, 10, and 11. At the stationary structures of 1-11, the structural characteristics were briefly discussed in terms of allenic and propargylic. To elucidate the nature of pseudo-JT distortions, energy component analyses were carried out at the MCSCF+SOCI level of theory at all of the stationary structures for the relevant molecules. In most of the molecules examined, pseudo-JT stabilizations were classified into two groups, one in which the stability arises from a lowering of the energy of the attractive term Ven and the other in which the stability results from a lowering of the energy of the repulsive terms Vnn and Vee. In addition to the above two groups, it was also found that the following three groups are responsible for the pseudo-JT stabilizations in a certain stage of the structural changes. Namely, one is a lowering of the energy of the term Vee observed in 6, another is a lowering of the energy of the terms Vee and Ven observed in 9-11, and the other is a lowering of the energy of the terms Ven and Vnn observed in 10. These energetic behaviors were accounted in terms of an elongation or a contraction of the molecular skeleton, a migration of electrons from one part of the molecule to other parts, and the combined effects arising from these two factors.


Nutrition Assessment in Crohn's Disease using Anthropometric, Biochemical, and Dietary Indexes: A Narrative Review.
Malnutrition is common in patients with Crohn's disease and negatively influences immunity and quality of life. The optimal tools for nutrition assessment in patients with Crohn's disease are not clearly defined and lead to variations in practice. With this review, we aimed to appraise the existing evidence for nutrition assessment of patients with Crohn's disease compared with healthy controls and provide a comprehensive guide with relevant measures applicable to clinical practice. A literature search using Medline, Embase, and Scopus from inception to October 1, 2018, was conducted. Forty-one articles that assessed body composition, muscle strength, micronutrient status and/or dietary intake in adults with Crohn's disease compared with an age- and sex-matched healthy individuals were included. There were heterogeneous findings on nutritional status in patients with Crohn's disease compared with healthy controls. Only one article reported a clinically significant difference for body mass index; however, significant deficits in fat mass, fat-free mass, and muscle strength were observed in patients with Crohn's disease compared with healthy controls, with more pronounced differences with increasing disease activity and length of diagnosis. Most research reported significantly lower serum micronutrients in patients with Crohn's disease compared with healthy controls. Half of studies measuring micronutrient intake reported lower intakes in patients with Crohn's disease compared with healthy controls. Fruit and vegetable intake was also lower in patients with Crohn's disease. Difficulties characterizing the type and prevalence of malnutrition exist due to the heterogeneous nature of Crohn's disease and warrants continued investigation. As a result of this review, we advocate that a nutrition assessment should include more parameters than weight and body mass index.


Clinical and Radiographic Evaluation of OsseoSpeed EV Implants.
To evaluate the survival rate (primary outcome) and the marginal bone loss (secondary outcome) of the OsseoSpeed EV Implants (Astra Tech Implant System, Dentsply Sirona Implants; hereinafter EV implants) used in a wide range of clinical scenarios and followed up to 8 years in a nonuniversity setting. All EV implants consecutively placed from 2013 to 2021 in a private dental clinic were included, and medical and radiologic records were retrospectively investigated. Independent reviewers collected 11 data types as potential influencing variables and measured the mesial and distal marginal bone levels to the nearest 0.5 mm on available radiographs, either panoramic or periapical. Tables of descriptive statistics were made at implant and patient levels. Univariate and multiple Cox regression models were adjusted for clustering effects and determined the hazard ratio (HR) and odds ratio (OR) for each independent variable collected. The study sample consisted of 597 EV implants and 235 patients. During a mean follow-up of 42.1 ± 23 months (range: 10 to 94 months), 44 implants were lost (7.4%)-34 early (5.7%) and 10 late (1.7%)-in 38 patients (16.1%). The overall survival rate (SR) was 92.6% (CI: 90.5% to 94.7%), and the proportion of patients with all their implants surviving was 83.8% (CI: 79.1% to 88.5%). At the end of the study, the probability of survival of an implant that did not fail early was 98.2% (CI: 97.1% to 99.3%). Implant-level analysis identified two significant variables: implant diameter (HR 0.37, P = .009**) and immediate postextraction placement (HR 2.35, P = .025*). At the patient level, bruxism (OR = 3.29; P = .009**), history of periodontitis (OR = 2.18, P = .030*), and the number of implants placed (OR = 1.43; P = .001**) were found to be statistically significant. After removing dropouts and early failures from a sample of 528 implants, 412 (78%) had a marginal bone loss (MBL) ≤ 0 mm at the end of the observation time, and 106 surviving implants (22%) showed a mean MBL of 1.42 ± 1.08 mm (range: 0.25 to 6.75 mm). An overall medium-term SR of the EV implants was 92.6%. Four of five EV implants showed a mid-term MBL ≤ 0 mm, and 91.86% of implants completed the observation period with an MBL < 2 mm. Thus, the EV implant system was shown to be a valid alternative for routine use in a nonuniversity setting. Clinicians should remember that there is no 100% implant survival in everyday practice and that bruxism, periodontitis, narrow-diameter implants, and immediate placement are risk factors for a higher failure rate.


Socioeconomic status and other factors associated with HIV status among OVC in Democratic Republic of Congo (DRC).
Orphans and vulnerable children (OVC) are a high-risk group for HIV infection, particularly in Sub-Saharan Africa. This study aims to portray the socioeconomic profile of OVC and examine the association of household and parent/guardian characteristics with the HIV status of OVC. For this quantitative retrospective study, we obtained data from ICAP/DRC for a total of 1,624 OVC from households enrolled for social, financial, and clinical services between January 2017 and April 2020 in two provinces of the Democratic Republic of Congo, Haut-Katanga and Kinshasa. We computed descriptive statistics for OVC and their parents' or guardians' characteristics. We used the chi-square test to determine bivariate associations of the predictor variables with the dichotomous dependent variable, HIV positivity status. To analyze the association between these independent variables and the dichotomous dependent variable HIV status after controlling for other covariates, we performed firth's logistic regression. Of the OVC included in this study, 18% were orphans, and 10.9% were HIV+. The chi-square analysis showed that among parents/guardians that were HIV+, a significantly lower proportion of OVC (11.7%) were HIV+ rather than HIV- (26.3%). In contrast, for parents/guardians with HIV- status, 9.0% of OVC were HIV-negative, and 11.7% of OVC were OVC+. The firth's logistic regression also showed the adjusted odds of HIV+ status were significantly lower for OVC with parents/guardians having HIV+ status themselves (AOR, 0.335; 95% CI, 0.171-0.656) compared with HIV-negative parents/guardians. The adjusted odds of HIV+ status were significantly lower for OVC with a monthly household income of < $30 (AOR, 0.421; 95% CI, 0.202-0.877) compared with OVC with a monthly household income > $30. Our results suggest that, with the exception of a few household and parent/guardian characteristics, the risk of HIV+ status is prevalent across all groups of OVC within this study, which is consistent with the existing body of evidence showing that OVC are in general vulnerable to HIV infection. With a notable proportion of children who are single or double orphans in DRC, HIV+ OVC constitute a high-risk group that merits customized HIV services. The findings of this study provide data-driven scientific evidence to guide such customization of HIV services.


Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. IV. Role of LV vagal afferents.
The negative chronotropic action and the time to peak effect (t(p)) of ATP and its related analogs [2-methylthio-ATP (2-MeSATP), alpha,beta-methylene-ATP (alpha,beta-mATP), and beta,gamma-methylene-ATP (beta,gamma-mATP)] as well as ADP, AMP, and adenosine were determined in anesthetized dogs. Intra-right atrium (RA) and intra-left main coronary artery (LM) ATP markedly suppressed sinus node automaticity. ATP induced a much greater response when administered into the LM than into the RA. The t(p) of ATP administered at the former site was much shorter than that at the latter site. Intra-LM adenosine had either no effect or a relatively very small effect, and its t(p) was significantly longer than that of intra-LM ATP. Bilateral cervical vagotomy either abolished or markedly attenuated the effect of intra-RA and intra-LM ATP; under these conditions, the actions of ATP and adenosine and their t(p) values became similar. The structure-function cascade of intra-LM ATP and its analogs was alpha,beta-mATP > 2-MeSATP > ATP > or = beta,gamma-mATP > ADP >> AMP = 0. The P2X-purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid markedly attenuated the negative chronotropic action of all purine nucleotides. It was concluded that 1) ATP triggers a cardiocardiac vagal depressor reflex by stimulating vagal afferent nerve terminals in the LV myocardium and 2) this action is mediated by P2X-purinoceptors.


Changes in the drug treatment of anxiety disorders.
One of the major changes in the clinical treatment of anxiety has been the substitution of benzodiazepines for less safe sedative-hypnotic drugs. A second major change has been the finding that antidepressants suppress panic attacks. The evidence for this is reviewed in this paper. It appears that panic anxiety is qualitatively different from other kinds of anxiety; this has important implications for diagnosis and treatment. Other clinical issues presented in this symposium are a review of benzodiazepine and new, non-benzodiazepine anxiolytic drugs, the treatment of separation anxiety, and the relationship of mitral valve prolapse to anxiety. Further advances are likely to depend both on our understanding of benzodiazepine and gamma-aminobutyric acid receptors and on drug models for inducing anxiety. The fact that antidepressants suppress panic attacks, and the ability to produce panic attacks in the laboratory opens up a number of possibilities for the investigation of the physiological basis of panic attacks. All of these topics are taken up in this symposium.


Correlation between severity of sleep apnea and upper airway morphology based on advanced anatomical and functional imaging.
Determination of the apnea hypopnea index (AHI) as a measure of the severity of obstructive sleep apnea/hypopnea syndrome (OSAHS) is a widely accepted methodology. However, the outcome of such a determination depends on the method used, is time consuming and insufficient for prediction of the effect of all treatment modalities. For these reasons more methods for evaluating the severity of OSAHS, based on different imaging modalities, have been looked into and recent studies have shown that anatomical properties determined from three-dimensional (3D) computed tomography (CT) images are good markers for the severity of the OSAHS. Therefore, we correlated anatomical measurements of a 3D reconstruction of the upper airway together with flow simulation results with the severity of OSAHS in order to find a combination of variables to indicate the severity of OSAHS in patients. The AHI of 20 non-selected, consecutive patients has been determined during a polysomnography. All patients also underwent a CT scan from which a 3D model of the upper airway geometry was reconstructed. This 3D model was used to evaluate the anatomical properties of the upper airway in OSAHS patients as well as to perform computational fluid dynamics (CFD) computations to evaluate the airflow and resistance of this upper airway. It has been shown that a combination of the smallest cross-sectional area and the resistance together with the body mass index (BMI) form a set of markers that predict very well the severity of OSAHS in patients within this study. We believe that these markers can be used to evaluate the outcome of an OSAHS treatment.


Exploring sex differences for acute ischemic stroke clinical, imaging and thrombus characteristics in the INTERRSeCT study.
Women, especially following menopause, are known to have worse outcomes following acute ischemic stroke. One primary postulated biological mechanism for worse outcomes in older women is a reduction in the vasculoprotective effects of estrogen. Using the INTERRseCT cohort, a multicentre international observational cohort studying recanalization in acute ischemic stroke, we explored the effects of sex, and modifying effects of age, on neuroradiological predictors of recanalization including robustness of leptomeningeal collaterals, thrombus burden and thrombus permeability. Ordinal regression analyses were used to examine the relationship between sex and each of the neuroradiological markers. Further, we explored both multiplicative and additive interactions between age and sex. All patients (n = 575) from INTERRseCT were included. Mean age was 70.2 years (SD: 13.1) and 48.5% were women. In the unadjusted model, female sex was associated with better collaterals (OR 1.37, 95% CIs: 1.01-1.85), however this relationship was not significant after adjusting for age and relevant comorbidities. There were no significant interactions between age and sex. In a large prospective international cohort, we found no association between sex and radiological predictors of recanalization including leptomeningeal collaterals, thrombus permeability and thrombus burden.


Predicting SSRI-Resistance: Clinical Features and tagSNPs Prediction Models Based on Support Vector Machine.
A large proportion of major depressive patients will experience recurring episodes. Many patients still do not response to available antidepressants. In order to meaningfully predict who will not respond to which antidepressant, it may be necessary to combine multiple biomarkers and clinical variables. Eight hundred fifty-seven patients with recurrent major depressive disorder who were followed up 3-10 years involved 32 variables including socio-demographic, clinical features, and SSRIs treatment features when they received the first treatment. Also, 34 tagSNPs related to 5-HT signaling pathway, were detected by using mass spectrometry analysis. The training samples which had 12 clinical variables and four tagSNPs with statistical differences were learned repeatedly to establish prediction models based on support vector machine (SVM). Twelve clinical features (psychomotor retardation, psychotic symptoms, suicidality, weight loss, SSRIs average dose, first-course treatment response, sleep disturbance, residual symptoms, personality, onset age, frequency of episode, and duration) were found significantly difference (P< 0.05) between 302 SSRI-resistance and 304 SSRI non-resistance group. Ten SSRI-resistance predicting models were finally selected by using support vector machine, and our study found that mutations in tagSNPs increased the accuracy of these models to a certain degree. Using a data-driven machine learning method, we found 10 predictive models by mining existing clinical data, which might enable prospective identification of patients who are likely to resistance to SSRIs antidepressant.


[Abdomino-thoracoscopic esophagus resection--an animal experiment study].
Based on animal trials the presented study results describe a method of abdomino-thoracoscopic oesophagectomy for the treatment of oesophageal carcinoma of the middle and lower third. Technical details and the advantages of the surgical procedure, including the avoidance of thoracotomy and the practicability of the thoracoscopic dissection of the oesophagus are shown. Problems exist in the salvage of the specimen, especially in the transcervical passage of the tumorbearing oesophageal part. A final evaluation of the importance of the minimally invasive techniques in oesophageal surgery should not be given until the results of clinical studies are available.


Changing presentation of cutaneous malignant melanoma.
The incidence of cutaneous malignant melanoma is rapidly increasing in Denmark like in other Northern and Western European countries. Our objective was to investigate the characteristics of current patients suffering from cutaneous malignant melanoma. We evaluated patient and tumour characteristics in a cross-sectional study based on data from the Danish Melanoma Register. We included all patients diagnosed with cutaneous malignant melanoma in Healthcare Region Zealand in 2012 and 2013. We identified 520 patients with invasive cutaneous malignant melanoma. More females than males suffered from cutaneous malignant melanoma. Furthermore, females were younger than males, and the anatomical distribution of malignant melanoma varied between the genders. Outcome of sentinel lymph node biopsy was associated with tumour thickness. When comparing findings in our study with earlier Danish studies, we see a trend towards an increase in age at diagnosis. Furthermore, tumour thickness is decreasing and the topical distribution of cutaneous malignant melanoma in females changes towards a male pattern. none. The study has been approved by the Danish National Data Protection Agency.


Microbial biotransformation of bioactive and clinically useful steroids and some salient features of steroids and biotransformation.
Steroids are perhaps one of the most widely used group of drugs in present day. Beside the established utilization as immunosuppressive, anti-inflammatory, anti-rheumatic, progestational, diuretic, sedative, anabolic and contraceptive agents, recent applications of steroid compounds include the treatment of some forms of cancer, osteoporosis, HIV infections and treatment of declared AIDS. Steroids isolated are often available in minute amounts. So biotransformation of natural products provides a powerful means in solving supply problems in clinical trials and marketing of the drug for obtaining natural products in bulk amounts. If the structure is complex, it is often an impossible task to isolate enough of the natural products for clinical trials. The microbial biotransformation of steroids yielded several novel metabolites, exhibiting different activities. The metabolites produced from pregnenolone acetate by Cunning hamella elegans and Rhizopus stolonifer were screened against tyrosinase and cholinesterase showed significant inhibitory activities than the parent compound. Diosgenin and its transformed sarsasapogenin were screened for their acetyl cholinesterase and butyryl cholinesterase inhibitory activities. Sarsasapogenin was screened for phytotoxicity, and was found to be more active than the parent compound. Diosgenin, prednisone and their derivatives were screened for their anti-leishmanial activity. All derivatives were found to be more active than the parent compound. The biotransformation of steroids have been reviewed to a little extent. This review focuses on the biotransformation and functions of selected steroids, the classification, advantages and agents of enzymatic biotransformation and examines the potential role of new enzymatically transformed steroids and their derivatives in the chemoprevention and treatment of other diseases. tyrosinase and cholinesterase inhibitory activities, severe asthma, rheumatic disorders, renal disorders and diseases of inflammatory bowel, skin, gastrointestinal tract.


Decoupling biogeochemical records, extinction, and environmental change during the Cambrian SPICE event.
Several positive carbon isotope excursions in Lower Paleozoic rocks, including the prominent Upper Cambrian Steptoean Positive Carbon Isotope Excursion (SPICE), are thought to reflect intermittent perturbations in the hydrosphere-biosphere system. Models explaining these secular changes are abundant, but the synchronicity and regional variation of the isotope signals are not well understood. Examination of cores across a paleodepth gradient in the Upper Cambrian central Missouri intrashelf basin (United States) reveals a time-transgressive, facies-dependent nature of the SPICE. Although the SPICE event may be a global signal, the manner in which it is recorded in rocks should and does vary as a function of facies and carbonate platform geometry. We call for a paradigm shift to better constrain facies, stratigraphic, and biostratigraphic architecture and to apply these observations to the variability in magnitude, stratigraphic extent, and timing of the SPICE signal, as well as other biogeochemical perturbations, to elucidate the complex processes driving the ocean-carbonate system.


Task-related, low-frequency task-residual, and resting state activity in the default mode network brain regions.
The hypothesis of a default mode network (DMN) of brain function is based on observations of task-independent decreases of brain activity during effort as participants are engaged in tasks in contrast to resting. On the other hand, studies also showed that DMN regions activate rather than deactivate in response to task-related events. Thus, does DMN "deactivate" during effort as compared to resting? We hypothesized that, with high-frequency event-related signals removed, the task-residual activities of the DMN would decrease as compared to resting. We addressed this hypothesis with two approaches. First, we examined DMN activities during resting, task residuals, and task conditions in the stop signal task using independent component analysis (ICA). Second, we compared the fractional amplitude of low-frequency fluctuation (fALFF) signals of DMN in resting, task residuals, and task data. In the results of ICA of 76 subjects, the precuneus and posterior cingulate cortex (PCC) showed increased activation during task as compared to resting and task residuals, indicating DMN responses to task events. Precuneus but not the PCC showed decreased activity during task residual as compared to resting. The latter finding was mirrored by fALFF, which is decreased in the precuneus during task residuals, as compared to resting and task. These results suggested that the low-frequency blood oxygen level-dependent signals of the precuneus may represent a useful index of effort during cognitive performance.


The visible human project®: From body to bits.
In the middle 1990's the U.S. National Library sponsored the acquisition and development of the Visible Human Project® data base. This image database contains anatomical cross-sectional images which allow the reconstruction of three dimensional male and female anatomy to an accuracy of less than 1.0 mm. The male anatomy is contained in a 15 gigabyte database, the female in a 39 gigabyte database. This talk will describe why and how this project was accomplished and demonstrate some of the products which the Visible Human dataset has made possible. I will conclude by describing how the Visible Human Project, completed over 20 years ago, has led the National Library of Medicine to a series of image research projects including an open source image processing toolkit which is included in several commercial products.


A Data-Rich Longitudinal Wellness Study for the Digital Age: Fixing a Broken Medical System Requires Data About Each Patient.
We live in an age of plentiful information, collected continuously by pervasive gadgetry, distributed through digital and social networks, and mined deeply by ever-more-powerful analytics systems. And yet, one of the things we know the least about is our bodies. When it comes to our own health, we are driving blindly. Modern medicine has clearly been remarkably successful, as evidenced by continually growing life expectancies. For example, the number of people 65 and older in the United States has seen a steady increase over the last century, rising from 3.1 million in 1900 to 41.4 million as of 2011-and is expected to grow to 80 million by 2040. Concurrently, the number (and fraction) of people suffering from chronic conditions is also growing, from 44.7% in 1995 to 47.7% in 2015-and expected to rise to over 49% by 2030 [1]. According to the U.S. Centers for Disease Control and Prevention, the vast majority of healthcare costs (86%) are spent on treating and managing chronic disease. Indeed, the medical field today focuses almost entirely on care after illness: modern medicine is largely reactive, waiting until the system fails before taking action. While the field of dentistry has fully embraced regular preventive evaluation and treatment with great success, most other medical fields have yet to do so. Yearly physical evaluations are recommended, but they rely on very limited data collection. As long as there are no symptoms, current standard medical practice largely foregoes testing (laboratory, imaging, etc.) as a screening method to detect disease before it manifests itself.


The epidemiological profile of rubella and congenital rubella syndrome in the United States, 1998-2004: the evidence for absence of endemic transmission.
In 1969, the United States established its national rubella vaccination program. With the success of the program, 32 years later, reports of rubella reached record low numbers. To assess the achievement of elimination of rubella and congenital rubella syndrome (CRS) in the United States, 7 epidemiological criteria were used. Rubella cases reported to the National Notifiable Diseases Surveillance System from 1998 through 2004 and CRS cases reported to the National Congenital Rubella Syndrome Registry from 1998 through 2004 were analyzed. During 1998-2000, the median number of reported rubella cases was 272, whereas, during 2001-2004, the median number reported was 13. The incidence of rubella decreased significantly, from 0.1/100,000 population in 1998 to 0.005/100,000 population in 2004. Since 2001, 5 infants with CRS have been reported--3 were born in 2001, 1 was born in 2003, and 1 was born in 2004. The epidemiological evidence strongly supports the claim that rubella is no longer endemic in the United States. To prevent future rubella outbreaks and CRS cases, current strategies must be maintained.


Arginine and citrulline for the treatment of MELAS syndrome.
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of manifestations. In addition to impaired energy production, nitric oxide (NO) deficiency occurs in MELAS syndrome and leads to impaired blood perfusion in microvasculature that can contribute to several complications including stroke-like episodes, myopathy, and lactic acidosis. The supplementation of NO precursors, L-arginine and L-citrulline, increases NO production and hence can potentially have therapeutic utility in MELAS syndrome. L-citrulline raises NO production to a greater extent than L-arginine; therefore, L-citrulline may have a better therapeutic effect. The clinical effect of L-citrulline has not yet been studied and clinical studies on L-arginine, which are limited, only evaluated the stroke-like episodes aspect of the disease. Controlled studies are still needed to assess the clinical effects of L-arginine and L-citrulline on different aspects of MELAS syndrome.


Process theory as a framework for comprehensive psychodynamic formulations.
In this article, we have proposed a method for developing integrative psychiatric formulations based on process theory, as contrasted to eclectic attempts to combine separate, often disparate, theories. Congruent with chaos theory and "far from equilibrium" thermodynamics, process theory proposes that normal development and psychopathology are creative processes open to chance, choice, and meaningful coincidences and governed by harmonious and conflictual interactions between opposites. We have illustrated our method by discussing a case, previously described by Perry, Cooper, and Michels (1987) from three psychoanalytic perspectives. We interpret this case to result from a possible neuroamine depletion, poor family life, social defects, and habitual conflictual/depressive patterns of interaction.


Physiological relevance of covalent protein modification by dietary isothiocyanates.
Isothiocyanates (ITCs), naturally occurring in abundance in cruciferous vegetables, are the most well-studied organosulfur compounds having an electrophilic reactivity. ITCs have been accepted as major ingredients of these vegetables that afford their health promoting potentials. ITCs are able to modulate protein functions related to drug-metabolizing enzymes, transporters, kinases and phosphatases, etc. One of the most important questions about the molecular basis for the health promoting effects of ITCs is how they modulate cellular target proteins. Although the molecular targets of ITCs remains to be validated, dietary modulation of the target proteins via covalent modification by ITCs should be one of the promising strategies for the protection of cells against oxidative and inflammatory damage. This review discusses the plausible target proteins of dietary ITCs with an emphasis on possible involvement of protein modification in their health promoting effects. The fundamental knowledge of ITCs is also included with consideration of the chemistry, intracellular behavior, and metabolism.


Monoclonal antibodies specific for carcinoembryonic antigen and produced by two hybrid cell lines.
Spleen cells from mice immunized with purified carcinoembryonic antigen (CEA), an important tumor marker of human carcinomas, were fused with the mouse myeloma cell line P3-NSI/1-Ag4. Out of the 400 hybrids obtained, 2 secreted antibodies reacting specifically with two different antigenic determinants present on CEA molecules. They were cloned and established as permanent hybridoma cell lines. These antibodies, which have relatively high-affinities and can be produced in unlimited amounts, will be useful both for the immunochemical characterization of CEA and as a standard reagent for the identification of this antigen in human tissues and body fluids.


Liver growth retardation in corticosteroid-treated neonatal mice.
This study examined the influence of triamcinolone hexacetonide on the growth and nucleic acid synthesis in the liver of neonatal mice. Following a single dose of the hormone the synthesis of DNA was significantly depressed, a feature that lasted for 72 hours. Thereafter an almost full recovery took place and by 144 hours no significant differences existed between hormone-treated livers and their nontreated controls. The above inhibitory effect was dose-dependent and was specific to steroids with glucocorticoid activity. A markedly different response was noted in regard to RNA synthesis. Hormone-treated livers revealed an initial increase in the uptake of 3H-uridine and RNa synthesis but later on revealed a significant decrease in the incorporation of uridine resulting in a marked reduction in the tissue's content of RNA. Concomitantly, the hormone increased significantly the protein content of the liver. It thus became clear that glucocorticoid hormones possess both a significant inhibitory effect upon the proliferative activity of neonatal hepatocytes and interfere with the latters' protein synthetic machinery, thereby affecting the normal growth of the liver at its critical period of growth and development.


Antitumor activity of bis-indole derivatives.
This paper reports the synthesis of compounds formed by two indole systems separated by a heterocycle (pyridine or piperazine). As a primary screening, the new compounds were submitted to the National Cancer Institute for evaluation of antitumor activity in the human cell line screen. The pyridine derivatives were far more active than the piperazine derivatives. For the study of the mechanism of action, the most active compounds were subjected to COMPARE analysis and to further biological tests including proteasome inhibition and inhibition of plasma membrane electron transport. The compound bearing the 5-methoxy-2-indolinone moiety was subjected to the first in vivo experiment (hollow fiber assay) and was active. It was therefore selected for the second in vivo experiment (human tumor xenograft in mice). In conclusion we demonstrated that this approach was successful, since some of the compounds described are much more active than the numerous, so far prepared and tested 3-indolylmethylene-2-indolinones.


Early, patient-initiated treatment of herpes labialis with topical 10% acyclovir.
To determine whether topical acyclovir in polyethylene glycol could reduce the severity of herpes simplex labialis if applied immediately after onset of a recurrence, 10% acyclovir in polyethylene glycol ointment or polyethylene glycol alone was prospectively dispensed to 352 patients in a double-blind, randomized trial. Sixty-nine subjects initiated treatment in the prodrome (57%) or erythema (43%) stage and were followed by clinical and virological criteria. The healing time (6.0 days), maximum lesion area (42 mm2), vesicle or ulcer formation (91%), and maximum lesion virus titer (4.8 log10 PFU) in the drug recipients were not reduced in comparison with those who received the vehicle (5.2 days, 30 mm2, 75%, and 4.5 log10 PFU, respectively). Topical acyclovir in polyethylene glycol was ineffective for the treatment of herpes labialis despite an optimum therapeutic opportunity.


Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats.
There is evidence for the existence of functional interactions between nicotine and cannabinoids and opioid compounds in adult experimental animals. However, there is scarce information about these relationships in young animals. In the present study we evaluated short and long-term effects of a subchronic nicotine treatment [0.4 mg/kg daily i.p. injections from postnatal day (PND) 34 to PND 43], upon hippocampal and striatal cannabinoid-CB(1) and mu-opioid receptors in Wistar rats of both genders. Rats were sacrificed 2 h after the last nicotine injection (short-term effects, PND 43) or one month later (long-term effects, PND 75). Hippocampal and striatal cannabinoid CB(1) and mu-opioid receptors were quantified by Western blotting. The subchronic nicotine treatment induced a region-dependent long-lasting effect in cannabinoid CB(1) receptor: a significant increase in hippocampal cannabinoid CB(1) receptors and a significant decrease in striatal cannabinoid CB(1) receptors, with these effects being similar in males and females. With respect to mu-opioid receptors, subchronic nicotine induced a significant down-regulation in hippocampal and striatal mu-opioid receptors in the long-term, and within the striatum the effects were more marked in adult males than in females. The present results indicate that juvenile nicotine taking may have implications for the endocannabinoid and endogenous opioid function and for the behaviors served by those systems, this includes possible modification of the response of adults to different psychotropic drugs, i.e. cannabis and morphine/heroin when taken later in life.


[Expression of S100-labeled dendritic cells in glottic squamous cell carcinoma and its correlation to prognosis].
Dendritic cells (DCs) are the most important antigen-presenting cells, and can synthesize and secrete S100 protein. This study was designed to investigate the expression of S100-labeled DCs in glottic squamous cell carcinoma, and analyze its correlation to the prognosis. The expression of S100-labeled DCs in peritumoral tissues of 111 specimens of gllotic squamous cell carcinoma was detected by immunohistochemistry; 17 specimens of normal tissues were used as control. The correlation of S100-labeled DCs expression to prognosis of the 111 patients was evaluated. The positive rates of S100-labeled DCs were 51.35% (57/111) in peritumoral tissues of gllotic squamous cell carcinoma, and 0 in normal tissues. The 5-year survival rate was significantly higher in S100-positive group than in S100-negative group (72.31% vs. 53.91%, P=0.030). The glottic squamous cell carcinoma patients with obvious infiltration of S100-labeled DCs may achieve good prognosis.


Promises and Challenges of Microalgal Antioxidant Production.
The exploration of natural antioxidants for nutraceuticals and pharmaceuticals industries has recently increased. This communication aims to grasp the relevance of microalgae in the panorama of natural antioxidant molecules supply to industrial applications as alternatives and/or complements to those typically used from higher plants. Microalgal richness in antioxidant compounds and scavenging ability compared to higher plants is discussed in the context of microalgal biodiversity. We mainly focus on families of powerful antioxidant compounds that have been scarcely investigated in microalgae, such as phenolic compounds, sterols, or vitamins, discussing the promise and challenges of microalgae as providers of health benefits, for instance, through their use as functional food ingredients.


Decline in Mental Health in the Beginning of the COVID-19 Outbreak Among European Older Adults-Associations With Social Factors, Infection Rates, and Government Response.
Governments across the world have deployed a wide range of non-pharmaceutical interventions (NPI) to mitigate the spread of COVID-19. Certain NPIs, like limiting social contacts or lockdowns, had negative consequences for mental health in the population. Especially elder people are prone to mental illnesses during the current pandemic. This article investigates how social factors, infections rates, and stringency of NPIs are associated with a decline in mental health in different European countries. Data stem from the eighth wave of the SHARE survey. Additional data sources were used to build macro indicators for infection rates and NPIs. Two subsamples of persons with mental health problems were selected (people who reported being depressed, n = 9.240 or nervous/anxious, n = 10.551). Decline in mental health was assessed by asking whether depressive symptoms or nervousness/anxiety have become worse since the beginning of the COVID-19 outbreak. For each outcome, logistic regression models with survey-design were used to estimate odds ratios (OR), using social factors (age, gender, education, living alone, and personal contacts) and macro indicators (stringency of NPIs and infection rates) as predictors. Higher age was associated with a lower likelihood of becoming more depressed (OR 0.87) or nervous/anxious (OR 0.88), while female gender increased the odds of a decline in mental health (OR 1.53 for being more depressed; OR 1.57 for being more nervous/anxious). Higher education was only associated with becoming more nervous/anxious (OR 1.59), while living alone or rare personal contacts were not statistically significant. People from countries with higher infection rates were more likely to become more depressed (OR 3.31) or nervous/anxious (OR 4.12), while stringency of NPIs showed inconsistent associations. A majority of European older adults showed a decline in mental health since the beginning of the COVID-19 outbreak. This is especially true in countries with high prevalence rates of COVID-19. Among older European adults, age seems to be a protective factor for a decline in mental health while female gender apparently is a risk factor. Moreover, although NPIs are an essential preventative mechanism to reduce the pandemic spread, they might influence the vulnerability for elderly people suffering from mental health problems.


[Brachytherapy for prostate cancer: high dose rate or low-dose rate?].
Low-dose brachytherapy for prostate cancer was actually proposed in the first years of the XXth century. Its modern version (iodin 125 or palladium 103 permanent implants) now benefits from some 15 years of experience in a few pioneer centers, with very satisfactory results in term of efficacy/toxicity ratio. More recently, a high-dose rate (HDR) prostate brachytherapy technique has been introduced. Initially utilized essentially as a "boost" irradiation combined with external radiotherapy, it is now being proposed by some authors as a monotherapy for selected localized prostate cancers. Although sophisticated radiobiological models have been proposed to compare those two dose-rates, they are not considered to be valid and reliable enough to compare such different irradiation schemes (A low-dose rate irradiation lasting several months vs a few high-dose fractions given in a few days). When it comes to the implantation techniques, it seems that most of the technical problems which arose for both schemes have been solved, and that the experience of a given team is now much more important than the technique itself. Clinical results cannot be reliably compared so far, the follow-up of the patients treated by HDR brachytherapy being usually shorter, and the patients treated with HDR usually presenting with more advanced lesions. Radioprotection features are very different, with no accident reported for low-dose rate implants. For HDR no irradiation is given at all to the staff and family during a normal application, but one has to face the threat of manipulating high activity sources, with a few accidents or incidents reported in the literature. Financial studies show that for more than 20-30 patients treated in a year, HDR is more economical, although a decrease in the cost of the seeds could change the picture. In conclusion, for low-risk localized prostate cancer, it does not appear reasonable to give up using a low-dose rate technique, which proved to be both efficient and poorly toxic. This actually corresponds to the recent GEC-ESTRO recommendations. For the other patients, a dose escalation is appealing: this could be performed using brachytherapy (LDR or HDR), with or without hormonotherapy. Several trials are ongoing or will be activated very soon to try and answer.


An observational study substantiating the statistical significance of cardiopulmonary exercise with laboratory tests during the acute and subacute phases of center and home-based cardiac rehabilitation.
Cardiac rehabilitation (CR) can improve clinical indicators in patients with cardiovascular diseases. The literature reports a 20% reduction in all-cause mortality and a 27% reduction in heart-disease mortality following CR. Although its clinical efficacy has been established, there is uncertainty whether center-based (CBCR) is more effective than home-based (HBCR) programs in acute and subacute phases. We aimed to verify significant differences in their effectiveness for the improvement of cardiopulmonary function by analyzing cardiopulmonary exercise (CPX) with laboratory tests following both CR programs.A single-center cohort study of 37 patients, recently diagnosed with underlying cardiovascular diseases, underwent CBCR(18) and HBCR(19). CBCR group performed a supervised exercise regimen at the CR center, for 1 hour, 2 to 3 days a week, for a total of 12 to18 weeks. HBCR group completed a self-monitored exercise program at home under the same guidelines as CBCR. Participants were evaluated by CPX with laboratory tests at 1- and 6-month, following the respective programs.There was no statistical significance in clinical characteristics and laboratory findings. Pre-post treatment comparison showed significant improvement in VO2/kg, minute ventilation/carbon dioxide production slope, breathing reserve, tidal volume (VT), heart rate recovery, oxygen consumption per heart rate, low-density lipoprotein (LDL), LDL/HDL ratio, total cholesterol, ejection fraction (EF) (P < .05). CBCR approach showed greater improvement with significance in VO2/kg, metabolic equivalents, and EF on between groups analysis (P < .05).The time effect of CPX test and laboratory data showed improvement in cardiopulmonary function and serum indicators for both groups. VO2/kg, metabolic equivalents, and EF were among the variables that showed significant differences between groups. In the acute and subacute phases of 1 to 6 months, the CBCR group showed a greater cardiac output improvement than the HBCR group.


[S-(+)-Ketamine and circulation].
The S-(+) isomer of ketamine has about twice the analgesic potency of the clinically used racemic mixture. Therefore, the known side effects may be reduced when one-half of the usual dose is administered. Several prospective, randomised, and double-blinded studies have been performed to assess whether the S-(+) isomer of ketamine is superior to the racemic mixture with respect to circulatory side effects. Studies in young, healthy volunteers showed that heart rate (HR) and arterial blood pressure (ABP) rise significantly after injection of 2 mg/kg ketamine racemate and 1 mg/kg S-(+) isomer without any significant difference between groups. In the study of Doenicke et al. plasma levels of adrenaline (A) were higher in the racemate group, whereas no difference was found in elevated plasma levels of noradrenaline (NA). Premedication with midazolam blunted major haemodynamic changes. The investigation of Adams et al. confirmed that HR and ABP rise significantly after injection of 2 mg/kg ketamine racemate and 1 mg/kg S-(+) isomer without any significant difference between groups. In this study, no differences were found between groups concerning elevated plasma levels of A and NA. A further study in healthy volunteers also showed comparable haemodynamic changes following i.m.injection of 1.0 mg/kg ketamine racemate or 0.5 mg/kg S-(+) isomer without any significant difference between groups. In a previous clinical study including 40 elderly patients undergoing elective orthopaedic surgery, total intravenous anaesthesia (TIVA) was performed with S-(+)-ketamine or ketamine racemate as an analgesic compound. For induction of TIVA, patients received 0.1 mg/kg midazolam and 1 mg/kg S-(+)-ketamine or 2 mg/kg racemic ketamine, respectively. Throughout surgery, a continuous infusion of 2 mg/kg per hour S-(+)-ketamine or 4 mg/kg racemic ketamine was administered. Three patients in the racemate group showed severe arterial hypertension after induction of anaesthesia and were withdrawn from the study. In both groups plasma A and NA levels as well as HR and ABP increased significantly. In our own randomised, double-blinded study, haemodynamic effects of 2 mg/kg S-(+)-ketamine and 4 mg/kg ketamine racemate, respectively, were investigated in 14 patients undergoing elective aorto-coronary bypass surgery. In both groups HR and ABP significantly increased in 3 patients, each although all patients were deeply sedated with midazolam. One patient in the S-(+)-ketamine group showed severe arterial hypertension and tachycardia after induction of anaesthesia and was withdrawn from the study. With respect to haemodynamic changes, the pharmacodynamic effects of ketamine racemate and S-(+)-ketamine are comparable. Therefore, it can be concluded that neither ketamine nor S-(+)-ketamine should be used in patients who suffer, e.g., from arterial hypertension and coronary artery disease.


The Ebola outbreak: effects on HIV reporting, testing and care in Bonthe district, rural Sierra Leone.
Setting: All public health facilities in Bonthe District, rural Sierra Leone. Objective: To compare, in the periods before and during the Ebola virus disease outbreak, 1) the submission and completeness of monthly human immunodeficiency virus (HIV) reports, and 2) the uptake of HIV testing and care for pregnant women and the general population. Design: A cross-sectional study using routine programme data. Results: Of the 627 HIV reports expected in each period, 406 (65%) were submitted in the pre-Ebola period and 376 (60%) during the Ebola outbreak (P = 0.08), of which respectively 318 (78%) and 335 (89%) had complete information (P < 0.001). In the pre-Ebola period, 5012 pregnant women underwent testing for HIV, of whom 25 were HIV-positive, compared to 4254 during the Ebola period, of whom 21 were HIV-positive (P < 0.001). Of those who were HIV-positive, respectively 14 (56%) and 21 (100%) received antiretroviral prophylaxis or antiretroviral therapy (ART) (P < 0.001). In the general population, 5770 persons underwent HIV testing pre-Ebola vs. 3095 in the Ebola period (P < 0.001); of those who tested positive for HIV, respectively 62% (33/53) and 81% (33/41) were started on ART (P = 0.06). Conclusion: There was suboptimal reporting on HIV/acquired immune-deficiency disease syndrome activities before and during the Ebola virus disease outbreak. HIV testing decreased during the Ebola outbreak, while the uptake of prevention of mother-to-child transmission and ART increased. Pre-emptive actions are needed to maintain the levels of HIV testing in any future outbreak.


[Endoscopic microwave coagulation therapy for locally recurrent nasopharyngeal carcinoma].
Management of locally recurrent nasopharyngeal carcinoma (NPC) is difficult. External beam re-irradiation could cure some patients but might cause severe radiation injury. This study was to evaluate the clinical value of endoscopic microwave coagulation therapy as salvage treatment for locally recurrent NPC. Between Aug. 1994 and Apr. 2005, 55 patients with locally recurrent NPC (stage rT1) were treated with endoscopic microwave coagulation therapy. Local progression-free and overall survival were observed. The median follow-up was 102.1 months (range, 22.4-153.9 months). The median time from last irradiation to recurrence was 22.1 months (range, 6.5-125.6 months). Five patients had local failure. The 5-year local progression-free and overall survival rates were 90.7% and 93.6%, respectively. No patient had intraoperative complications. One patient had nasopharyngeal necrosis after operation, and was healed after one month. Endoscopic microwave coagulation therapy is effective without severe complications in locally recurrent NPC patients. It is a minimally invasive therapy for recurrent NPC.


PAX-9 polymorphism may be a risk factor for hypodontia: a meta-analysis.
To evaluate the association between paired box 9 (PAX9) gene polymorphisms and tooth agenesis in isolated humans, we performed a comprehensive meta-analysis. We examined 6 case-control studies, with a total of 855 hypodontia cases and 1201 healthy controls. The G allele and G carrier (AG + GG) of A1031G were positively associated with hypodontia susceptibility. Similarly, the T allele and T carrier (CT + TT) of C912T and rs12881240 in the PAX9 gene also indicated an increased risk of hypodontia. In addition, the C allele and C carrier (CG + CC) of 718C, IVS2-109, rs4904210, and rs7143727 showed no significant association with oligodontia. The G allele and G carrier (AG + GG) of IVS2-41 in the PAX9 gene were not related factors. Interestingly, the genotype (AG + GG) of IVS2-54 in the PAX9 gene may be a protective factor for oligodontia (odds ratio = 0.21, 95% confidence interval = 0.07-0.63, P = 0.005). However, no significant differences were found in the allele frequency of IVS2-54 in the PAX9 polymorphism between controls and subjects with sporadic tooth agenesis. In conclusion, our meta-analysis results revealed 4 genetic sites of the PAX9 gene involved in hypodontia cases, of which 3 sites may be risk factors and 1 may have a protective role.


Post-Traumatic Osteoarthritis in Mice Following Mechanical Injury to the Synovial Joint.
We investigated the spectrum of lesions characteristic of post-traumatic osteoarthritis (PTOA) across the knee joint in response to mechanical injury. We hypothesized that alteration in knee joint stability in mice reproduces molecular and structural features of PTOA that would suggest potential therapeutic targets in humans. The right knees of eight-week old male mice from two recombinant inbred lines (LGXSM-6 and LGXSM-33) were subjected to axial tibial compression. Three separate loading magnitudes were applied: 6N, 9N, and 12N. Left knees served as non-loaded controls. Mice were sacrificed at 5, 9, 14, 28, and 56 days post-loading and whole knee joint changes were assessed by histology, immunostaining, micro-CT, and magnetic resonance imaging. We observed that tibial compression disrupted joint stability by rupturing the anterior cruciate ligament (except for 6N) and instigated a cascade of temporal and topographical features of PTOA. These features included cartilage extracellular matrix loss without proteoglycan replacement, chondrocyte apoptosis at day 5, synovitis present at day 14, osteophytes, ectopic calcification, and meniscus pathology. These findings provide a plausible model and a whole-joint approach for how joint injury in humans leads to PTOA. Chondrocyte apoptosis, synovitis, and ectopic calcification appear to be targets for potential therapeutic intervention.


Lowest transition state for the chirality-determining step in Ru((R)-BINAP)-catalyzed asymmetric hydrogenation of methyl-3-oxobutanoate.
A systematic search for transition state (TS) structures of the chirality-determining elementary step in a RuCl(2)-((R)-BINAP)-catalyzed asymmetric hydrogenation reaction was performed by using the anharmonic downward distortion following method. As many as 68 TS structures were found for the elementary step because of the complexity of its potential energy surface caused by the introduction of bulky ligands in BINAP for high selectivity. We were able to determine the lowest TS structures for each enantiomer among the 68 TSs, and one for the (R)-type product was found to be the more stable in agreement with the experiment. From a comparison of the lowest TSs for each enantiomer, a "lock-and-key" motif at the TS structure was discovered to be the origin of the high selectivity in the reaction.


Higher-order factor analysis of an instrument with dichotomous data.
This article reports the use of higher-order factor analysis to examine the underlying dimensions of an instrument designed to measure community acceptance of nurse practitioners/physician's assistants. The instrument consisted of both dichotomous and Likert scale items. Use of factor analysis with dichotomous data is controversial. Higher-order factor analysis provides a potential solution to this dilemma. Following initial factor analysis using maximum likelihood extraction with oblique rotation, the factor correlation matrix was factored to obtain second order factors. The second order factors were interpreted using the factor pattern matrix and examining correlations of individual survey items with the second order factors. This procedure provides additional factorial validity of the underlying uni- and multidimensional concepts related to acceptance of NPs and PAs in rural settings: knowledge, competence, access, and trust.


Haemodynamic effects of intravenous nimodipine following aneurysmal subarachnoid haemorrhage: implications for monitoring.
Nimodipine is widely used in patients with aneurysmal subarachnoid haemorrhage for the prevention and treatment of delayed ischaemic neurological deficits. Intravenous nimodipine has significant vasodilatory properties and may compromise the achievement of haemodynamic targets in patients who receive hypertensive hypervolaemic haemodilution therapy. We have studied 22 patients who received postoperative therapy with intravenous nimodipine and show that in a substantial minority (29%) hypotension was not reversed by simple volume loading or low doses of inotropes. Formal haemodynamic assessment in these patients showed widely varying haemodynamic variables, with differences in the need for inotropic and vasopressor therapy. We conclude that optimal haemodynamic management in this subgroup of patients will require the use of pulmonary artery catheterisation.


Heideggerian phenomenological hermeneutics: Working with the data.
It is one thing to read about the methodology and methods of Heideggerian hermeneutic phenomenological research, the ontic description. It is quite another thing to be faced with an interview transcript. This article draws on a study that asked doctoral students about their experience of doing such research. How did they become "phenomenological/hermeneutic" in their thinking and writing? What helped them to find their way? We offer this article as a means of letting others learn from our own experiences. We support our insights with the writings of Heidegger and Gadamer to show the methodological congruence that is essential to Heideggerian phenomenological hermeneutic research.


TRIF, and TRIF-interacting TLRs differentially modulate several adenovirus vector-induced immune responses.
The use of Adenovirus (Ad)-based vectors has proven to be a useful platform for the development of gene therapy and vaccine protocols. The immunological mechanisms underlying these properties need to be identified and understood to foster safer, more efficacious use of this important gene transfer platform. Our recent studies have confirmed an important role for MyD88 dependent toll-like receptor (TLR) pathways as mediators of these responses. In this study, we confirm that TLR3, TLR4 and TRIF (TIR-domain-containing adapter-inducing interferon-beta) can also have augmentative or inhibitory roles during Ad-induced immune responses. Importantly, our studies revealed that TLR4 acts to suppress several aspects of the Ad-induced innate immune response, a finding not previously reported for this TLR in any model system. In addition, using MyD88 and TRIF double knockout mice, we demonstrate that the MyD88 and TRIF adaptor proteins can play either additive or redundant roles in mediating certain aspects of Ad vector-induced innate and adaptive immune responses. Furthering this complexity, our model system strongly suggests that non-TLR based systems must not only exist, but also have a significant role to play during Ad vector-mediated induction of adaptive immune responses.


Left ventricular function during exercise testing and training.
Left ventricular function (LVEF) deteriorates during incremental exercise (GXT) in patients with ischemia (+ISCH). Left ventricular (LV) functional response during steady-state exercise, typical of that used in exercise training, are unknown. We compared LVEF in patients with documented coronary heart disease (CHD) who either had (+) or did not have (-) ISCH, and in healthy volunteers (CONTROL) during GXT and steady state. First pass RNA was performed during upright cycle GXT at rest (R), at the ventilatory threshold (VT), and at maximal exercise (Max); and during steady state at the workload associated with VT after 10, 20, and 30 min of exercise. RNA allowed measurement of ejection fraction (EF) and wall motion (WM); ISCH was mild, angina being relieved by momentary reductions in workload during steady state. Although +ISCH demonstrated the expected deterioration in LV function during GXT (decreased EF, abnormal WM)(EF = 58 to 56 to 54%), there was no evidence for progressive deterioration of LV function during steady state despite the presence of mild ISCH (56 to 56 to 54 to 54%). In -ISCH and CONTROL there were normal responses of EF during GXT (43 to 51 to 51% and 59 to 65 to 61%) and steady state (43 to 51 to 53 to 51% and 59 to 65 to 68 to 69%). We conclude that mild ischemia may be tolerated during steady-state exercise at levels consistent with exercise training without progressive deterioration of LV function.


Health services utilization in adult acquired major upper-limb amputees: a population-based survey.
To increase knowledge of health services utilization and related factors in adult acquired major upper-limb amputees. Population-based cross-sectional study conducted in Norway. Two hundred and twenty four adult acquired major upper-limb amputees (57.4% response rate). Mean age was 53.7 years, 83.5% were men and mean post-amputation time was 24.0 years. Data were collected by postal questionnaires. Amputation-related health services utilization, perceived benefit and unmet needs were reported and associations between these factors and background factors were estimated by multivariate logistic regression analyses. Reported health services utilization was relatively low. The reported benefit of utilized services was generally high. For several non-utilized services, considerable unmet needs for utilization were reported. Several background factors were significantly associated with different aspects of the services examined. A considerable discrepancy between reported pain and utilization of specified pain treatments was noted. The findings of this study suggest that several health services available to acquired major upper-limb amputees should be strengthened. Establishing routines to ensure access to optimal, individualized rehabilitation may prevent disability. We recommend additional, longitudinal studies to further assess the need for mental health care and pain treatment in acquired major upper-limb amputees.


Endothelin-1 and ETA/ETB receptor protein and mRNA: expression in normal and vascularized human corneas.
Neovascularization of the cornea causes blindness and increases the risk of immune rejections after keratoplasty. The purpose of this study was to investigate involvement of the potent angiogenic growth factor endothelin (ET)-1 and its receptors, ETA and ETB, in corneal neovascularization. ET-1, ETA, and ETB receptor protein expression was evaluated in nonvascularized and vascularized human corneas by immunohistochemistry. Epithelial ET-1 protein expression of both groups was compared using a semiquantitative scoring system. Double immunofluorescence was used to colocalize ETA and ETB receptor with CD31. In situ hybridization and immunoelectron microscopy analyzed ET-1 and its receptors in normal and vascularized corneas. Nonvascularized corneas displayed ET-1 and ETA/ETB receptor protein and mRNA in epithelial and some corneal endothelial cells. ETA more than ETB receptors were expressed on some keratocytes. In vascularized corneas, ET-1 and ETA/ETB receptor expression was found in the endothelial lining of new blood vessels (as shown by CD31-colocalization). ET-1 protein expression was significantly increased in the epithelium of vascularized corneas (P < 0.001). Immunogold localized ET-1 and its receptors to the nuclear/perinuclear space and to the luminal side of endothelial cells of new blood vessels. In corneal neovascularization, ET-1 protein and mRNA expression is upregulated in epithelial cells. Together with ET-1, ETA, and ETB receptor expression on endothelial cells of ingrown new blood vessels, this points to an involvement of ET-1 and its receptors in corneal angiogenesis. As potent ETA and ETB receptors are available, the endothelin system may represent an additional target for corneal antiangiogenic therapy.


Evolution of the yeast protein interaction network.
To study the evolution of the yeast protein interaction network, we first classified yeast proteins by their evolutionary histories into isotemporal categories, then analyzed the interaction tendencies within and between the categories, and finally reconstructed the main growth path. We found that two proteins tend to interact with each other if they are in the same or similar categories, but tended to avoid each other otherwise, and that network evolution mirrors the universal tree of life. These observations suggest synergistic selection during network evolution and provide insights into the hierarchical modularity of cellular networks.


The nature and structure of supervision in health visiting with victims of child sexual abuse.
Part of a higher research degree to explore professional practice. To explore how health visitors work with victims of child sexual abuse and the supervision systems to support them. To seek the views and experiences of practising health visitors relating to complex care in order to consider the nature and structure of supervision. The research reported in this paper used a qualitative method of research and semi-structured interviews with practising health visitors of varying levels of experience in venues around England. Qualitative research enabled the exploration of experiences. Identification of the need for regular, structured, accountable opportunities in a 'private setting' to discuss whole caseload work and current practice issues. Supervision requires a structured, formalized process, in both regularity and content, as a means to explore and acknowledge work with increasingly complex care, to enable full discussion of whole caseloads. Supervision is demonstrated as a vehicle to enable the sharing of good practices and for weak practices to be identified and managed appropriately. Supervision seeks to fulfil the above whilst promoting a stimulating, learning experience, accommodating the notion that individuals learn at their own pace and bring a wealth of human experience to the service. The size of the study was dictated by the amount of time available within which to complete a research master's degree course primarily in the author's own time, over a 2-year period. The majority of participants volunteered their accounts in their own time. For others I obtained permission from their employers for them to participate once they approached me with an interest in being interviewed. This research provides a model of supervision based on practitioner views and experiences. The article highlights the value of research and evidence-based information to enhance practice accountability and the quality of care. Proactive risk management can safeguard the health and safety of the public, the practitioner and the organization.