[Insertion and removal of the intraaortic balloon pumping].
Intraaortic balloon pumping (IABP) is the most popular circulatory assist device. Although insertion and removal of IABP has proved to be a safer technique, a significant number of pitfalls have been seen. On the basis of our experience, we make several recommendations that may facilitate safer insertion and removal of IABP. Careful insertion and removal by experienced hands of cardiovascular surgeons should minimize complications.


N,N-acetals as N-acyliminium ion precursors: synthesis and absolute stereochemistry of epiquinamide.
A stereoselective synthesis of (+)-epiquinamide is presented in combination with determination of the absolute configuration of the natural product. Key steps in the sequence involved chemoenzymatic formation of an enantiomerically pure cyanohydrin, reductive cyclization to the corresponding cyclic N,N-acetal, and subsequent conversion into a suitable N-acyliminium ion precursor to enable construction of the second ring.


Solvent-free and room temperature synthesis of 3-arylquinolines from different anilines and styrene oxide in the presence of Al2O3/MeSO3H.
A highly efficient, simple and environmentally friendly synthesis of 3-arylquinolines has been developed in the presence of Al2O3/MeSO3H via one-pot reaction of anilines and styrene oxide. This methodology provides very rapid access to 3-arylquinolines in good to excellent yields under solvent-free conditions at room temperature in air.


COVID-19 in Hospitalised Children and Adolescents: Review of the First Pandemic Year at Vilnius University Hospital Santaros Klinikos.
Since the start of the pandemic with SARS-CoV-2 virus, very little data was known about clinical features and outcomes of COVID-19 in children and adolescents not only in Lithuania, but also in other European countries. This study was started in collaboration with 82 participating healthcare institutions across 25 European countries, using a well-established research network-the Paediatric Tuberculosis Network European Trials Group (ptbnet). This multinational, multicentre cohort study was performed during the first wave of the pandemic, between April 1 and April 24, 2020. Each participating country was allowed to continue further research individually encompassing brighter time limits and using the same methodology. We present here data of children hospitalised at Vilnius University Hospital Santaros Klinikos (VUH SK) during the first year of the pandemic. We included all paediatric patients with PCR confirmed SARS-CoV-2 infection who were hospitalised at VUH SK. The study was performed between March 12, 2020 and March 12, 2021. A standardised data collection spreadsheet was used to record epidemiological, clinical and treatment data. A total of 104 patients were included in the study. The median age of participants was 5 years (IQR 1.0-11.0, range 0-17 years). Males accounted for 50 (48%) of all patients. The average duration of hospitalisation was 3 days. Ten (9.6%) patients had pre-existing medical conditions. Among all hospitalised patients 16 (15%) were asymptomatic, 5 (4.8%) were treated in intensive care unit (ICU). The most common symptoms among COVID-19 patients were pyrexia 71 (68%) followed by upper respiratory tract infection 49 (47%) and gastrointestinal symptoms 33 (32%). Among the entire cohort only 3 (3%) patients required oxygen support, but none of them was started on continuous positive airway pressure (CPAP), mechanical ventilation or extracorporeal membrane oxygenation (ECMO). None of the patients admitted to ICU needed inotropic support. There was no fatal outcome. Our data indicate that COVID-19 may affect children of any age. The COVID-19 disease was usually mild in hospitalized children and adolescents. The most common clinical findings of COVID-19 were pyrexia and symptoms of upper respiratory tract infection. Severe COVID-19 disease cases when oxygen support or treatment in ICU was required were very rare. No patient received antiviral drugs for Covid-19 treatment. There was no fatal outcome due to COVID-19 in our study population.


[Osteogenic exostosis of the capitate bone. Case report and review of the literature].
The occurrence of an osteochondroma in the carpus is very rare and its excision is indicated in the case of significant symptoms or change in its appearance. The diagnosis is often made in adulthood due to the onset of a functional problem even though development of the tumour occurs during skeletal growth. We report the case of a 38 year old patient, with no antecedent trauma, who presents with simultaneous exostoses on the dorsal and palmar surfaces of the capitate, which has not been previously described in the literature. The existence of a bipolar lesion extending anteriorly and posteriorly in the carpus is a possibility which may not be apparent and renders plain radiograph insufficient in the investigation of such a lesion. CT scan and MRI scan are indispensable in the investigation of this kind of carpal lesions, allowing better visualization of the base of the tumour, the expansion of the tumour and relation to the neighbouring soft tissues and the presence of malignant degeneration.


Waiting Room Education in a Community Health System: Provider Perceptions and Suggestions.
The increasing burden of chronic diseases in the United States presents a major challenge to the nation's primary care systems, so improving the efficacy and efficiency of patient education is an important goal. Understanding the current perspectives, practices, and needs of primary care providers should guide innovation towards this end. As a part of the authors' ongoing quality improvement work, a short internet survey was an effective method of enhancing this understanding in one health care system. With a response rate of 24.6 %, the survey revealed that primary care waiting rooms in the health system studied are not conceived of or used by providers as spaces to engage patients in health education. To change this, providers suggested using both printed and technological methods for delivering health information, primarily related to medications, diabetes, and healthy lifestyle practices. Common barriers to improvement cited by providers included diverse language and literacy backgrounds in the patient population, as well as difficulty sustaining change due to infrastructural and administrative barriers. These results suggest steps for development, implementation, and investigation of new educational interventions for patients in the local primary care context.


Cell Therapies in Cardiomyopathy: Current Status of Clinical Trials.
Because the human heart has limited potential for regeneration, the loss of cardiomyocytes during cardiac myopathy and ischaemic injury can result in heart failure and death. Stem cell therapy has emerged as a promising strategy for the treatment of dead myocardium, directly or indirectly, and seems to offer functional benefits to patients. The ideal candidate donor cell for myocardial reconstitution is a stem-like cell that can be easily obtained, has a robust proliferation capacity and a low risk of tumour formation and immune rejection, differentiates into functionally normal cardiomyocytes, and is suitable for minimally invasive clinical transplantation. The ultimate goal of cardiac repair is to regenerate functionally viable myocardium after myocardial infarction (MI) to prevent or heal heart failure. This review provides a comprehensive overview of treatment with stem-like cells in preclinical and clinical studies to assess the feasibility and efficacy of this novel therapeutic strategy in ischaemic cardiomyopathy.


[Angiopoietins predict long-term outcomes after aneurysmal subarachnoid hemorrhage during an early period].
To evaluate the association between serum levels of angiopoietins (Ang) during an early period (within 72 h) and clinical outcomes after aneurysmal subarachnoid haemorrhage (aSAH). This prospective study was conducted at Department of Neurosurgery, Tianjin Medical University General Hospital. Blood samples from 37 aSAH patients were collected at 8 h (or < 8 h), 24 h, 72 h after an onset of SAH. The serum levels of Ang-1, Ang-2 and Tie-2 were measured by enzyme-linked immunosorbent assay (ELISA). They were followed up for 3 months by Glasgow outcome score extended (GOSE). Those with GOSE > 5 were counted as a good outcome while those with GOSE ≤ 5 had a poor outcome. A total of 37 patients with aSAH and 39 healthy controls (HC) were enrolled. The aSAH patients showed a significant rise of Ang-1 within 8 h as compared with HC. The outcomes were good (n = 15) and poor (n = 22). Serum Ang-1 at 8 h (or < 8 h), 24 h and 72 h in good outcomers showed significantly higher than that in poor outcomers [(52 ± 24) vs (37 ± 17) mg/L, (62 ± 26) vs (45 ± 17) mg/L, (107 ± 27) vs (72 ± 18) mg/L]. The serum level of Ang-1 at 8 h and 24 h was one of independent risk factors for aSAH patients by multiariable Logistic regression analysis [adjected OR (95% CI) 1.095 (1.015-1.181) and 1.109 (1.016-1.211)] (P < 0.05). High serum level of Ang-1 during an early period (within 72 h) was associated with good outcomers (r = 0.627, P < 0.001). The serum levels of angiopoietins are significantly altered in aSAH patients, especially higher in good outcomers. And abnormal levels of angiopoietins may affect early brain injury (EBI) after SAH, structural integrity and recovery of blood-brain barrier (BBB) and long-term outcomes in aSAH patients.


Overturning the diagnosis of child abuse.
Three cases, one of bullous impetigo, one of a Mongolian spot, and one of constriction of the toe by a hair, were mistakenly diagnosed as cases of child abuse. The diagnosis of child abuse is not usually simple and requires a careful evaluation of the injuries and the family if cases are not to be either overlooked or overdiagnosed.


Pet Owners and Antibiotics: Knowledge, Opinions, Expectations, and Communication Preferences.
Despite the important role of antimicrobial use in companion animals in the global challenge presented by antimicrobial resistance (AMR), very few studies have quantified pet owner factors that can contribute to suboptimal veterinary antimicrobial use. We conducted an online survey of pet owners, asking about their experiences with veterinarians, their opinions on antibiotic use and knowledge of antibiotics, and their communication preferences regarding judicious prescribing. Just over half (54%) of the 558 pet owners had received antibiotics for their pet at their last non-routine veterinary consultation and most owners were happy (83%) with the antibiotic prescribing decision of their veterinarian. A quarter (25%) indicated that they had been surprised, disappointed or frustrated when a veterinarian had not given their pet antibiotics; 15% had explicitly requested them. Owners placed a higher priority on their pet receiving the most effective treatment than on treatment being cheap or convenient. Most respondents recognized the limitations of antibiotic therapy and the risks associated with antibiotic use, but 50% believed the risks were confined to the treated animal; only a minority was aware of inter-species transfer of bacteria. Pet owners indicated that they would find judicious prescribing messages focused on the direct risks of antibiotics to their pet more compelling than those about public health. Our findings suggest that veterinary communications about responsible antibiotic use should focus on pet owners' priorities and address or bypass their gaps in understanding regarding antibiotic resistance.


Are Aortic Root and Ascending Aorta Diameters Measured by the Pediatric versus the Adult American Society of Echocardiography Guidelines Interchangeable?
Ascending aorta diameters have important clinical value in the diagnosis, follow-up, and surgical indication of many aortic diseases. However, there is no uniformity among experts regarding ascending aorta diameter quantification by echocardiography. The aim of this study was to compare maximum aortic root and ascending aorta diameters determined by the diastolic leading edge (DLE) and the systolic inner edge (SIE) conventions in adult and pediatric patients with inherited cardiovascular diseases. Transthoracic echocardiograms were performed in 328 consecutive patients (260 adults and 68 children). Aorta diameters were measured twice at the root and ascending aorta by the DLE convention following the 2015 American Society of Echocardiography (ASE) adult guidelines and the SIE convention following the 2010 ASE pediatric guidelines. Comparison of the diameters measured by the two conventions in the overall population showed a non-significant underestimation of the diameter measured by the SIE convention at root level of 0.28 mm (CI -1.36; 1.93) and at tubular ascending aorta level of 0.17 mm (CI -1.69; 2.03). Intraobserver and interobserver variability were excellent. Maximum aorta diameter measured by the leading edge convention in end-diastole and the inner edge convention in mid-systole had similar values to a mild non-significant underestimation of the inner-to-inner method that permits them to be interchangeable when used in clinical practice.


Topography mapping of whole body adipose tissue using A fully automated and standardized procedure.
To obtain quantitative measures of human body fat compartments from whole body MR datasets for the risk estimation in subjects prone to metabolic diseases without the need of any user interaction or expert knowledge. Sets of axial T1-weighted spin-echo images of the whole body were acquired. The images were segmented using a modified fuzzy c-means algorithm. A separation of the body into anatomic regions along the body axis was performed to define regions with visceral adipose tissue present, and to standardize the results. In abdominal image slices, the adipose tissue compartments were divided into subcutaneous and visceral compartments using an extended snake algorithm. The slice-wise areas of different tissues were plotted along the slice position to obtain topographic fat tissue distributions. Results from automatic segmentation were compared with manual segmentation. Relatively low mean deviations were obtained for the class of total tissue (4.48%) and visceral adipose tissue (3.26%). The deviation of total adipose tissue was slightly higher (8.71%). The proposed algorithm enables the reliable and completely automatic creation of adipose tissue distribution profiles of the whole body from multislice MR datasets, reducing whole examination and analysis time to less than half an hour.


NMR studies of ligand binding.
NMR spectroscopy is an established tool in drug discovery, but its strength is commonly regarded to be largely confined to the early stages of hit discovery and fragment based drug design, where NMR offers unique capabilities of characterizing the binding modes of ligand molecules that bind sufficiently weakly to be in rapid exchange between bound and free state. Here we, first, provide a meta-review of recent reviews on NMR studies of ligand binding and, second, review recent progress towards NMR characterization of the ligand binding mode in stable protein-ligand complexes, with particular emphasis on the global positioning system (GPS) approach enabled by paramagnetic lanthanide tags.


Influence of adherent and effective antiretroviral therapy use on human papillomavirus infection and squamous intraepithelial lesions in human immunodeficiency virus-positive women.
The impact of highly active antiretroviral therapy (HAART) on the natural history of human papillomavirus (HPV) remains uncertain following conflicting reports. Prior studies, however, did not consider patients' adherence to their regimens or HAART effectiveness (viral suppression). Human immunodeficiency virus (HIV)-positive women (N = 286) who initiated HAART during follow-up in a prospective cohort were assessed semiannually for HPV infection (by polymerase chain reaction) and squamous intraepithelial lesions (SILs). Adherence was defined as use of HAART as prescribed > or = 95% of the time, and effective HAART was defined as suppression of HIV replication. The prevalence, incident detection, and clearance of HPV infection and/or SILs before versus after HAART initiation were compared (using women as their own comparison group). HAART initiation among adherent women was associated with a significant reduction in prevalence (odds ratio, 0.60 [95% confidence interval {CI}, 0.44-0.81]; P = .001), incident detection of oncogenic HPV infection (hazard ratio [HR], 0.49 [95% CI, 0.30-0.82]; P = .006), and decreased prevalence and more rapid clearance of oncogenic HPV-positive SILs (HR, 2.35 [95% CI, 1.07-5.18]; P = .03). Effects were smaller among nonadherent women. The associations of HPV infection and/or SILs with HAART effectiveness were fairly similar to those with HAART adherence. Effective and adherent HAART use is associated with a significantly reduced burden of HPV infection and SILs; this may help explain why rates of cervical cancer have not increased during the HAART era, despite greater longevity.


Posterior Reversible Encephalopathy in Sepsis-Associated Encephalopathy: Experience from a Single Center.
Sepsis-associated encephalopathy (SAE) is frequently encountered in sepsis and is often accompanied by neuroimaging findings indicating ischemia, hemorrhage, and edema. Posterior reversible encephalopathy syndrome (PRES) has been vastly underrecognized in previously reported cohorts of patients with sepsis and SAE. Our aim was to determine the prevalence and distinguishing clinical, neuroimaging, and electroencephalography features of PRES in SAE. In this prospective observational study, patients with radiologically identified PRES were selected from a consecutively enrolled cohort of 156 patients with SAE and assessed for neurological outcome using the extended Glasgow Outcome Scale for 12 months. Patients with SAE and PRES and other types of brain lesions were compared in terms of clinical and diagnostic workup features. Fourteen of 156 patients (8.9%) were determined to be radiologically compatible with PRES, whereas 48 patients displayed other types of acute brain lesions. Patients with PRES often showed lesions in atypical regions, including frontal lobes, the corpus callosum, and the basal ganglia. Source of infection was mostly gram-negative bacteria originating from pneumonia or intraabdominal infections. Patients with PRES were not different from other patients with SAE with brain lesions in terms of features of sepsis and neurological outcome. However, patients with PRES showed increased prevalence of seizures and intraabdominal source of infection. PRES is highly prevalent in SAE, often encompasses unusual brain regions, and usually presents with generalized seizures. Patients with SAE and PRES do not appear to have distinguishing clinical and diagnostic workup features. However, generalized seizures may serve as warning signs for presence of PRES in patients with SAE.


Neurocognitive mechanisms underlying value-based decision-making: from core values to economic value.
VALUE PLAYS A CENTRAL ROLE IN PRACTICALLY EVERY ASPECT OF HUMAN LIFE THAT REQUIRES A DECISION: whether we choose between different consumer goods, whether we decide which person we marry or which political candidate gets our vote, we choose the option that has more value to us. Over the last decade, neuroeconomic research has mapped the neural substrates of economic value, revealing that activation in brain regions such as ventromedial prefrontal cortex (VMPFC), ventral striatum or posterior cingulate cortex reflects how much an individual values an option and which of several options he/she will choose. However, while great progress has been made exploring the mechanisms underlying concrete decisions, neuroeconomic research has been less concerned with the questions of why people value what they value, and why different people value different things. Social psychologists and sociologists have long been interested in core values, motivational constructs that are intrinsically linked to the self-schema and are used to guide actions and decisions across different situations and different time points. Core value may thus be an important determinant of individual differences in economic value computation and decision-making. Based on a review of recent neuroimaging studies investigating the neural representation of core values and their interactions with neural systems representing economic value, we outline a common framework that integrates the core value concept and neuroeconomic research on value-based decision-making.


In hypercholesterolemia, lower peripheral monocyte count is unique among the major predictors of atherosclerosis.
Many studies have shown that enhanced monocyte adherence is an important factor in the initiation of atherosclerosis. Because the relationships between circulating monocyte count and atherosclerosis or its major predictors have received little attention, we conducted this study with the aim of clarifying these relationships. The study included 409 men and women who underwent a carotid artery duplex study and white blood cell analysis (Sysmex Cell Counter) during a 2-day health check at our hospital in 1994. We found no correlation between preexisting carotid atherosclerosis and monocyte count. After adjustment for age and sex, hypercholesterolemia, among the major predictors of atherosclerosis, showed a unique correlation with both lower monocyte count and percentage (P < .001, P < .0001, respectively), whereas smoking was correlated with a higher monocyte count (P < .001). There was a slight but nonsignificant increase in monocyte count in hypertension, diabetes, and hypertriglyceridemia. Our results imply that: (1) hypercholesterolemia has a strong, peripheral monocyte-reducing effect, probably due to direct enhancement of monocyte adhesion to the endothelium, which subsequently initiates the atherosclerotic process, and (2) the mechanisms of other predictor(s)-induced atherosclerosis may be quite different from that of hypercholesterolemia. Another possible explanation for the inverse correlation between monocyte count and serum cholesterol level is that decreased monocyte levels might lead to hypercholesterolemia because of decreased uptake of cholesterol from the plasma by less monocyte-derived macrophages. The reasons why preexisting carotid atherosclerosis did not correlate with monocyte count are also discussed.


Quantitative determination of dynamical properties using coherent spatial frequency domain imaging.
Laser speckle imaging (LSI) is a fast, noninvasive method to obtain relative particle dynamics in highly light scattering media, such as biological tissue. To make quantitative measurements, we combine LSI with spatial frequency domain imaging, a technique where samples are illuminated with sinusoidal intensity patterns of light that control the characteristic path lengths of photons in the sample. We use both diffusion and radiative transport to predict the speckle contrast of coherent light remitted from turbid media. We validate our technique by measuring known Brownian diffusion coefficients (D(b)) of scattering liquid phantoms. Monte Carlo (MC) simulations of radiative transport were found to provide the most accurate contrast predictions. For polystyrene microspheres of radius 800 nm in water, the expected and fit D(b) using radiative transport were 6.10E-07 and 7.10E-07 mm²/s, respectively. For polystyrene microspheres of radius 1026 nm in water, the expected and fit D(b) were 4.7E-07 and 5.35 mm²/s, respectively. For scattering particles in water-glycerin solutions, the fit fractional changes in D(b) with changes in viscosity were all found to be within 3% of the expected value.


Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions.
Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors.


Development of a dermatological image atlas with worldwide access for the continuing education of physicians.
We constructed a dermatological image database as a telemedicine tool for clinical, histopathological and scientific use. The database contained about 1300 clinical images from the 40,000 slides in our archive, to provide a general overview of dermatological diseases and to cover basic student education. Some of the images were made available on the Internet through the World Wide Web system in the middle of 1994. This paper describes the architecture and components of the image database, which was designed for international access and submission of data. It allowed combined searches according to diagnosis, location and appearance of skin lesions, as well as on-screen visualization of the resulting images.


Genetic analysis of sixteen autosomal STR loci in three Tunisian populations from Makthar, Nabeul and Sousse.
Due to its strategic location, Tunisia witnessed the succession and influence of many civilisations throughout history. However, the majority of studies carried out on Tunisia are focussed on Barbarian ethnicity. To estimate genetic diversity and genetic structure of three Tunisian populations using autosomal STRs. 278 individuals were analysed for sixteen STRs. Allele frequencies and statistical parameters were determined. The studied populations showed genetic affinity with geographically close populations. AMOVA showed no genetic difference between the Tunisian populations. Nevertheless, the variance between the populations of the same group was significant, reflecting their heterogeneity even though they came from the same geographical area, and had the same ethnicity and complex demographic history. Our results strongly supported the application of autosomal genetic markers in anthropological and forensic studies. The analyses conducted at the 15-loci level provide the resolution to assess the phylogenetic relationships among the populations examined and other geographically targeted worldwide populations, while the results resulting from the 10-loci studies provide an understanding of the relationships and origins of the North African populations. Furthermore, the current report demonstrates that the battery of autosomal STRs reported are useful, providing the power of discrimination for forensic and paternity analyses.


Hox in space: gene cluster regulation linked to folding of chromatin.
The spatial folding of chromatin has been proposed to be involved in the regulation and coordination of gene expression. The mammalian Hox gene clusters form a particularly interesting case of coordinated gene regulation. Within each Hox cluster, the linear order of the genes closely reflects their temporal and anatomical expression pattern. This striking phenomenon suggests that the overall structure of the Hox clusters is important for their regulation. Recent studies employing chromatin conformation capture techniques indicate that Hox clusters adopt a remarkable spatial configuration, in which active and inactive genes are segregated into two distinct chromatin compartments. Here we discuss the possible underlying mechanisms and regulatory roles of this spatial compartmentalization.


A reflection on health and disease amid COVID-19 pandemic.
Coronavirus disease 2019 pandemic is persisting for more than a year and it's still far from being controlled. It is making a big impact not only on physical illness but also on mental and social aspects. In this situation, we need to reflect on current medical society's view of disease and health. The dominant paradigm in contemporary medicine is the reductionist view of disease and the biomedical model of health. As a result, the healthcare system seems to be more focused on virus eradication than on patient care. We need to look back on this position in view of humanities and ethics and broaden our perspective to an ecological view of disease and the sociomedical model of health. The quarantine and health care policy also needs to be re-built with more focus on patient care.


Association of Vitamin D Receptor Gene Polymorphisms with Chronic Periodontitis in a Population in Western Romania.
Recent data indicate that gene polymorphisms, e.g. those of vitamin D-receptor (VDR), are associated with an increased susceptibility to chronic periodontitis (CP). This study investigated whether VDR gene polymorphism is associated with chronic periodontitis in a population in Western Romania, by determining the prevalence of the BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236) and FokI (rs2228570) genotypes and comparing the CP group with a periodontally healthy group. This case-control study included 53 patients with CP and 47 healthy patients. VDR polymorphisms were genotyped using real-time polymerase chain reaction (PCR). The associations between VDR polymorphisms and CP were determined using logistic regression models, adjusted for patient age and serum level of Vitamin D. We found a statistically significant association between the single nucleotide polymorphism (SNP) rs2228570 (FokI) and CP. Compared with subjects having the Thymine-Thymine (TT) genotype, those with the Cytosine-Cytosine (CC) variant were 19 times more likely to have the disease (adjusted odd ratio [OR]: 19.58; 95% confidence interval [CI]: 2.67 - 198.92) and with the Thymine-Cytosine (TC) variant, 8 times more likely (adjusted OR: 7.86; 95% CI: 1.29 - 61.56). Also, for the SNP rs1544410 (BsmI), compared with the Adenine-Adenine (AA) genotype, the Adenine-Guanine (AG) variant had an increased risk of periodontal disease (crude OR: 3.76; 95% CI: 1.15 - 13.80). This case-control study of a Western Romanian population shows an association between vitamin D receptor (VDR) polymorphisms (FokI and BsmI) and CP susceptibility.


[In vitro analysis of the effect of cyclic loading on the fracture resistance of teeth restored with different post and core systems].
This study aims to compare the fracture resistance of teeth restored with different post and core systems by cyclic loading test and to predict long-term effects. A total of 15 recently extracted mandibular premolars without crowns were endodontically treated. The teeth were randomly divided into three groups with five teeth in each group. Group A, teeth restored with cast metal post and core. Group B, teeth with fiber post and resin core. Group C, teeth with resin filling. All of the teeth were restored with full-cast metal crowns. The specimens were exposed to 300,000 cyclic loadings in a cyclic loading machine and 1,000 thermal cycles between 5 and 55 °C. All of the samples were loaded in AG-IS mechanical testing machine with a compressive load until fracture occurred. The fracture load and the fracture mode of each tooth were recorded. The fracture resistance in group B and C were higher than that of the cast metal post and core restoration (P < 0.05). Repairable fractures were observed in group B and C, whereas unrestorable and catastrophic fractures were found in group A. Fiber post and resin filling is a good choice to restore endodontically treated teeth.


The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy.
The objective of this study was to determine the role of A-Kinase Anchoring Protein (AKAP)-Lbc in the development of heart failure, by investigating AKAP-Lbc-protein kinase D1 (PKD1) signaling in vivo in cardiac hypertrophy. Using a gene-trap mouse expressing a truncated version of AKAP-Lbc (due to disruption of the endogenous AKAP-Lbc gene), that abolishes PKD1 interaction with AKAP-Lbc (AKAP-Lbc-ΔPKD), we studied two mouse models of pathological hypertrophy: i) angiotensin (AT-II) and phenylephrine (PE) infusion and ii) transverse aortic constriction (TAC)-induced pressure overload. Our results indicate that AKAP-Lbc-ΔPKD mice exhibit an accelerated progression to cardiac dysfunction in response to AT-II/PE treatment and TAC. AKAP-Lbc-ΔPKD mice display attenuated compensatory cardiac hypertrophy, increased collagen deposition and apoptosis, compared to wild-type (WT) control littermates. Mechanistically, reduced levels of PKD1 activation are observed in AKAP-Lbc-ΔPKD mice compared to WT mice, resulting in diminished phosphorylation of histone deacetylase 5 (HDAC5) and decreased hypertrophic gene expression. This is consistent with a reduced compensatory hypertrophy phenotype leading to progression of heart failure in AKAP-Lbc-ΔPKD mice. Overall, our data demonstrates a critical in vivo role for AKAP-Lbc-PKD1 signaling in the development of compensatory hypertrophy to enhance cardiac performance in response to TAC-induced pressure overload and neurohumoral stimulation by AT-II/PE treatment.


Dispersion of the Vancomycin Resistance Genes vanA and vanC of Enterococcus Isolated from Nile Tilapia on Retail Sale: A Public Health Hazard.
Although normally regarded harmless commensals, enterococci may cause a range of different infections in humans, including urinary tract infections, sepsis, and endocarditis. The acquisition of vancomycin resistance by enterococci (VRE) has seriously affected the treatment and infection control of these organisms. VRE are frequently resistant to all antibiotics that are effective treatment for vancomycin-susceptible enterococci, which leaves clinicians treating VRE infections with limited therapeutic options. With VRE emerging as a global threat to public health, we aimed to isolate, identify enterococci species from tilapia and their resistance to van-mediated glycopeptide (vanA and vanC) as well as the presence of enterococcal surface protein (esp) using conventional and molecular methods. The cultural, biochemical (Vitek 2 system) and polymerase chain reaction results revealed eight Enterococcus isolates from the 80 fish samples (10%) to be further identified as E. faecalis (6/8, 75%) and E gallinarum (2/8, 25%). Intraperitoneal injection of healthy Nile tilapia with the eight Enterococcus isolates caused significant morbidity (70%) within 3 days and 100% mortality at 6 days post-injection with general signs of septicemia. All of the eight Enterococcus isolates were found to be resistant to tetracycline. The 6/6 E. faecalis isolates were susceptible for penicillin, nitrofurantoin, gentamicin, and streptomycin. On the other hand 5/6 were susceptible for ampicillin, vancomycin, chloramphenicol, and ciprofloxacin. The two isolates of E. gallinarum were sensitive to rifampicin and ciprofloxacin and resistant to vancomycin, chloramphenicol, and erythromycin. Molecular characterization proved that they all presented the prototypic vanC element. On the whole, one of the two vancomycin resistance gene was present in 3/8 of the enterococci isolates, while the esp virulence gene was present in 1/8 of the enterococci isolates. The results in this study emphasize the potential role that aquatic environments are correlated to proximity to anthropogenic activities in determining the antimicrobial resistance patterns of Enterococcus spp. recovered from fish in the river Nile in Giza, Elmounib, Egypt as a continuation of our larger study on the reservoirs of antibiotic resistance in the environment.


[Clinical Observation of Erlotinib in the Treatment of Advanced Non-small Cell Lung Cancer: A Report of 92 Eases.].
Erlotinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase, has been approved effective in local advanced or metastatic non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the efficacy and safety of erlotinib for the treatment of advanced NSCLC. Ninety-two patients with advanced NSCLC who had failed or not tolerated or refused chemotherapy received 150 mg oral doses of erlotinib once daily until the disease progression or intolerable toxicity. Among the 92 NSCLC patients, 2 patient got complete response (2.2%), 22 partial response (23.9%), 48 stable disease (52.2%) and 20 progressive disease (21.7%). The overall response rate and the disease controlled rate of erlotinib was 26.1% (24/92) and 78.3% (72/92), respectively. The response rate of erlotinib were significantly higher in rash and ECOG 0-1 than no rash and ECOG >= 2. The disease controlled rate of erlotinib was significantly higher in female and non-smokers than male and smokers (P<0.05). The response rate of erlotinib did not show significant differences within pathological type or previous treatment. The most common side effects were rash and diarrhea with 84.8% and 31.5%, respectively, but usually were mild. Erlotinib is effective and safe in the treatment of advanced NSCLC patients.


Atmospheric Organic Nitrogen Deposition in Strategic Water Sources of China after COVID-19 Lockdown.
Atmospheric nitrogen deposition (AND) may lead to water acidification and eutrophication. In the five months after December 2019, China took strict isolation and COVID-19 prevention measures, thereby causing lockdowns for approximately 1.4 billion people. The Danjiangkou Reservoir refers to the water source in the middle route of South-to-North Water Diversion Project in China, where the AND has increased significantly; thus, the human activities during the COVID-19 period is a unique case to study the influence of AND to water quality. This work monitored the AND distribution around the Danjiangkou Reservoir, including agricultural, urban, traffic, yard, and forest areas. After lockdown, the DTN, DON, and Urea-N were 1.99 kg · hm-2 · month-1, 0.80 kg · hm-2 · month-1, and 0.15 kg · hm-2 · month-1, respectively. The detected values for DTN, DON, and Urea-N in the lockdown period decreased by 9.6%, 30.4%, and 28.97%, respectively, compared to 2019. The reduction in human activities is the reason for the decrease. The urban travel intensity in Nanyang city reduced from 6 to 1 during the lockdown period; the 3 million population which should normally travel out from city were in isolation at home before May. The fertilization action to wheat and orange were also delayed.


Antisense expression of the peptide transport gene AtPTR2-B delays flowering and arrests seed development in transgenic Arabidopsis plants.
Previously, we identified a peptide transport gene, AtPTR2-B, from Arabidopsis thaliana that was constitutively expressed in all plant organs, suggesting an important physiological role in plant growth and development. To evaluate the function of this transporter, transgenic Arabidopsis plants were constructed expressing antisense or sense AtPTR2-B. Genomic Southern analysis indicated that four independent antisense and three independent sense AtPTR2-B transgenic lines were obtained, which was confirmed by analysis of the segregation of the kanamycin resistance gene carried on the T-DNA. RNA blot data showed that the endogenous AtPTR2-B mRNA levels were significantly reduced in transgenic leaves and flowers, but not in transgenic roots. Consistent with this reduction in endogenous AtPTR2-B mRNA levels, all four antisense lines and one sense line exhibited significant phenotypic changes, including late flowering and arrested seed development. These phenotypic changes could be explained by a defect in nitrogen nutrition due to the reduced peptide transport activity conferred by AtPTR2-B. These results suggest that AtPTR2-B may play a general role in plant nutrition. The AtPTR2-B gene was mapped to chromosome 2, which is closely linked to the restriction fragment length polymorphism marker m246.


TREFOIL FACTOR FAMILY 1 EXPRESSION CORRELATES WITH CLINICAL OUTCOME IN PATIENTS WITH RETINOBLASTOMA.
Correlation of trefoil factor family 1 (TFF1) expression in retinoblastoma tumors with different clinical parameters to evaluate a potential involvement of TFF1 in tumor development and progression. A representative cohort of 59 enucleated eyes from individual patients with retinoblastoma was analyzed for its TFF1 expression profile by immuno staining and real-time PCR. Trefoil factor family 1 expression was correlated with demographics, laterality, tumor-node-metastasis stage, International Classification of Retinoblastoma, tumor differentiation level, and treatment. According to our analysis, increased TFF1 expression significantly correlates with unilateral tumors diagnosed in older children and with poorly differentiated tumors and higher tumor-node-metastasis stages. This retrospective study reveals that unilateral tumors at a higher clinical tumor-node-metastasis stage and poorly differentiated tumor cells express significantly higher levels of TFF1 than those of differentiated tumors at lower tumor-node-metastasis stages. Besides, TFF1 expression correlates with the age of the patients at the time of tumor diagnosis. Our data indicate that TFF1 expression levels are potentially useful additional markers in the classification of tumor staging and prognosis of patients with retinoblastoma.


Neuropsychiatric sequelae of cerebral malaria in Vietnam veterans.
Approximately 250,000 Vietnam veterans suffered cerebral malaria, an illness that often results in damage to subcortical white matter and fronto-temporal areas of neocortex. Case reports dating back 2500 years indicate that survivors of cerebral malaria show depression, poor memory, personality change, and irritability/violence. The purpose of the present study was to compare the neuropsychiatric status of Vietnam veterans who had suffered cerebral malaria in the remote past (i.e., 1966 to 1969) with that of Vietnam veterans wounded in combat who had not suffered malaria or other neurological conditions. Findings indicate that cerebral malaria results in multiple, major, substantially underappreciated neuropsychiatric symptoms in Vietnam veterans, including poor dichotic listening, "personality change," depression, and, in some cases, partial seizure-like symptoms. Findings strongly suggest that history of malaria should be considered in any medical, psychological, or psychiatric workup of a Vietnam War veteran because a positive response could result in substantial changes in diagnosis and treatment.


Amphiphilic Fluorinated Block Copolymer Synthesized by RAFT Polymerization for Graphene Dispersions.
Despite the superior properties of graphene, the strong π⁻π interactions among pristine graphenes yielding massive aggregation impede industrial applications. For non-covalent functionalization of highly-ordered pyrolytic graphite (HOPG), poly(2,2,2-trifluoroethyl methacrylate)-block-poly(4-vinyl pyridine) (PTFEMA-b-PVP) block copolymers were prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization and used as polymeric dispersants in liquid phase exfoliation assisted by ultrasonication. The HOPG graphene concentrations were found to be 0.260⁻0.385 mg/mL in methanolic graphene dispersions stabilized with 10 wt % (relative to HOPG) PTFEMA-b-PVP block copolymers after one week. Raman and atomic force microscopy (AFM) analyses revealed that HOPG could not be completely exfoliated during the sonication. However, on-line turbidity results confirmed that the dispersion stability of HOPG in the presence of the block copolymer lasted for one week and that longer PTFEMA and PVP blocks led to better graphene dispersibility. Force⁻distance (F⁻d) analyses of AFM showed that PVP block is a good graphene-philic block while PTFEMA is methanol-philic.


Complete mitochondrial genome of Sebastes hubbsi (Scorpaenidae, Scorpaeniformes) from the East Sea, Korea.
Hybrids of Sebastes hubbsi, considered a valid species, have been found in the ocean. To examine the basic characteristics of mitochondrial DNA, we analysed the complete mitogenome of S. hubbsis using next-generation sequencing. The complete mitogenome was 16,453 bp in length and comprised 13 protein-coding genes (PCGs), 2 rRNAs, 22 tRNAs and 1 control region. The complete mitochondrial DNA had 27.9% A, 26.7% T, 17.2% G and 28.3% C, showing a slight AT bias (54.5%). The start codon of all PCGs was ATG, except COX1 (GTG). The stop codons in the PCGs were mainly TAA, except ND1 and ND3 (TAG), ND4 (AGA) and Cytb (incomplete termination codon, T). The tRNAs had a typical cloverleaf structure, except tRNA(Ser (AGY)) which lacked the DHU arm. The complete mitogenome of S. hubbsi can be used for hybridization or on-going speciation studies within allied species in the Scorpaenidae.


[Factor decomposition of the differences in life expectancy: a Hungarian method].
"The author shows the Hungarian method of decomposition according to factors causing differences in life expectancies. He uses abridged mortality tables by causes of death of Hungary's male and female population in 1972-1973 and 1982....[The author explains that] the significant increase in the difference between males' and females' average life expectancies at birth can be explained primarily with the ever increasing differences in life expectancies of the victims of various causes of death shifted in favour of females." (SUMMARY IN ENG AND RUS)


Preformed Messenger RNAs and Early Wheat Embryo Germination.
Wheat (Triticum aestivum L.) embryo homogenates have been fractionated into three cell fractions from which RNA was extracted and assayed for mRNA content by in vitro translation and by [(3)H]polyuridylic acid hybridization. In dry embryos the preformed mRNAs are distributed equally between a rapidly sedimenting "pellet" fraction and a cytoplasmic "ribosomal/subribosomal" fraction. During germination 25 to 40% of the total mRNA becomes polyribosomal. The remaining 60 to 75% is retained in the pellet and ribosomal/subribosomal fractions.To compare the nucleotide sequences of the different mRNA fractions, cDNAs were transcribed from polyribosomal (A+) RNA of 40-minute imbibed embryos and from total A(+) RNA of dry embryos, and the ability of these cDNAs to hybridize with the more prevalent classes of mRNA from the different cell fractions was analyzed. The results suggest that there is no significant difference between the preformed mRNAs that move into polyribosomes and those remaining in the nonpolyribosomal fractions. In addition there appears to be no difference between the mRNAs of polyribosomes from embryos germinated for 45 minutes and 5 hours. Between 5 hours and 2 days, however, there is a considerable change in the mRNA composition of the embryos. We conclude for the prevalent classes of message, that the preformed mRNAs of the wheat embryo are not involved in temporal regulation of early development but that they function primarily to allow a rapid resumption of growth upon exposure of the embryo to water.


Screening and brief interventions for hazardous and harmful alcohol use among patients with active tuberculosis attending primary public care clinics in South Africa: results from a cluster randomized controlled trial.
In 2008 the World Health Organization (WHO) reported that South Africa had the highest tuberculosis (TB) incidence in the world. This high incidence rate is linked to a number of factors, including HIV co-infection and alcohol use disorders. The diagnosis and treatment package for TB and HIV co-infection is relatively well established in South Africa. However, because alcohol use disorders may present more insidiously, making it difficult to diagnose, those patients with active TB and misusing alcohol are not easily cured from TB. With this in mind, the primary purpose of this cluster randomized controlled trial was to provide screening for alcohol misuse and to test the effectiveness of brief interventions in reducing alcohol intake in those patients with active TB found to be misusing alcohol in primary public health care clinics in three districts in South Africa. Within each of the three provinces targeted, one district with the highest TB burden was selected. Furthermore, 14 primary health care facilities with the highest TB caseload in each district were selected. In each district, 7 of the 14 (50%) clinics were randomly assigned to a control arm and another 7 of the 14 (50%) clinics assigned to intervention arm. At the clinic level systematic sampling was used to recruit newly diagnosed and retreatment TB patients. Those consenting were screened for alcohol misuse using the Alcohol Use Disorder Identification Test (AUDIT). Patients who screened positive for alcohol misuse over a 6-month period were given either a brief intervention based on the Information-Motivation-Behavioural Skills (IMB) Model or an alcohol use health education leaflet. Of the 4882 tuberculosis patients screened for alcohol and agreed to participate in the trial, 1196 (24.6%) tested positive for the AUDIT. Among the 853 (71%) patients who also attended the 6-month follow-up session, the frequency of positive screening results at baseline/follow-up were 100/21.2% for the AUDIT (P < 0.001) for the control group and 100/16.8% (P < 0.001) for the intervention group. The intervention effect on the AUDIT score was statistically not significant. The intervention effect was also not significant for hazardous or harmful drinkers and alcohol dependent drinkers ( 7-40), alcohol dependent drinkers and heavy episodic drinking, while the control group effect was significant for hazardous drinkers ( 7-19) (P = 0.035). The results suggest that alcohol screening and the provision of a health education leaflet on sensible drinking performed at the beginning of anti-tuberculosis treatment in public primary care settings may be effective in reducing alcohol consumption. PACTR201105000297151.


Functional magnetic resonance imaging of the cervical spinal cord during thermal stimulation across consecutive runs.
The spinal cord is the first site of nociceptive processing in the central nervous system and has a role in the development and perpetuation of clinical pain states. Advancements in functional magnetic resonance imaging are providing a means to non-invasively measure spinal cord function, and functional magnetic resonance imaging may provide an objective method to study spinal cord nociceptive processing in humans. In this study, we tested the validity and reliability of functional magnetic resonance imaging using a selective field-of-view gradient-echo echo-planar-imaging sequence to detect activity induced blood oxygenation level-dependent signal changes in the cervical spinal cord of healthy volunteers during warm and painful thermal stimulation across consecutive runs. At the group and subject level, the activity was localized more to the dorsal hemicord, the spatial extent and magnitude of the activity was greater for the painful stimulus than the warm stimulus, and the spatial extent and magnitude of the activity exceeded that of a control analysis. Furthermore, the spatial extent of the activity for the painful stimuli increased across the runs likely reflecting sensitization. Overall, the spatial localization of the activity varied considerably across the runs, but despite this variability, a machine-learning algorithm was able to successfully decode the stimuli in the spinal cord based on the distributed pattern of the activity. In conclusion, we were able to successfully detect and characterize cervical spinal cord activity during thermal stimulation at the group and subject level.


Time-dependent alterations in mRNA expression of brain neuropeptides regulating energy balance and hypothalamo-pituitary-adrenal activity after withdrawal from intermittent morphine treatment.
Chronic stressors alter brain function and may leave traces after their relief. We used intermittent morphine treatment to examine the relationships between stress-induced changes in energy balance and hypothalamo-pituitary-adrenal (HPA) activity and the recovery thereafter. We studied the effects of morphine injections on energy balance, hormones and fat stores, brain neuropeptide expression, and the ACTH and corticosterone responses to restraint 12 hr after the final injection and 8 d later during recovery. Weight gain, food intake, and caloric efficiency decreased at morphine onset, and these were maintained throughout the morphine injections. At 12 hr, fat stores, leptin, insulin, and testosterone concentrations were reduced. Subsequently, body weight gain and food intake increased and caloric efficiency was above control during the final days. By the eighth recovery day, fat stores and peripheral hormones were no longer depressed. At 12 hr, an over-response of CRF mRNA to restraint occurred in the hypothalamus, similar to the facilitated ACTH and corticosterone responses. On day 8, the hypothalamic CRF mRNA response to restraint was still facilitated, opposite to inhibited ACTH responses. Hypothalamic CRF mRNA correlated highly with mesenteric fat weight in morphine-treated rats. We conclude that there is a prolonged recovery from chronic stressors involving interrelated changes in energy balance and HPA activity. Nonetheless, 8 d after withdrawal from morphine, rats still display facilitated central stress responses, similar to the HPA symptoms described in posttraumatic stress disorder patients. Repeated partial withdrawal associated with intermittent morphine treatment, compounded by complete withdrawal associated with termination of the treatment, is likely required for these metabolic and HPA derangements.


Intrafractional target motions and uncertainties of treatment setup reference systems in accelerated partial breast irradiation.
This study investigated the magnitude of intrafractional motion and level of accuracy of various setup strategies in accelerated partial breast irradiation (APBI) using three-dimensional conformal external beam radiotherapy. At lumpectomy, gold fiducial markers were strategically sutured to the surrounding walls of the cavity. Weekly fluoroscopy imaging was conducted at treatment to investigate the respiration-induced target motions. Daily pre- and post-RT kV imaging was performed, and images were matched to digitally reconstructed radiographs based on bony anatomy and fiducial markers, respectively, to determine the intrafractional motion magnitudes over the course of treatment. The positioning differences of the laser tattoo- and the bony anatomy-based setups compared with those of the marker-based setup (benchmark) were also determined. The study included 21 patients. Although lung exhibited significant motion, the average marker motion amplitude on the fluoroscopic image was about 1 mm. Over a typical treatment time period, average intrafractional motion magnitude was 4.2 mm and 2.6 mm based on the marker and bony anatomy matching, respectively. The bony anatomy- and laser tattoo-based interfractional setup errors, with respect to the fiducial marker-based setup, were 7.1 and 9.0 mm, respectively. Respiration has limited effects on the target motion during APBI. Bony anatomy-based treatment setup improves the accuracy relative to that of the laser tattoo-based setup approach. Since fiducial markers are sutured directly to the surgical cavity, the marker-based approach can further improve the interfractional setup accuracy. On average, a seroma cavity exhibits intrafractional motion of more than 4 mm, a magnitude that is larger than that which is otherwise derived based on bony anatomy matching. A seroma-specific marker-based approach has the potential to improve treatment accuracy by taking the true inter- and intrafractional motions into consideration.


Prosurvival role of JAK/STAT and Akt signaling pathways in MPP+-induced apoptosis in neurons.
In the present study the role of JAK/STAT and Akt in apoptosis was evaluated in cerebellar granule cells after treatment with the mitochondrial toxin MPP(+). Firstly, we evaluated the role of the prosurvival Akt pathway in MPP(+)-induced apoptosis and found that MPP(+) rapidly reduced the phosphorylation of Akt at Ser473. Since PTEN is an upstream regulator of Akt, its inhibition with bpV(pic) (1-30 μM) should activate Akt, however, it did not attenuate CGC cell death mediated by MPP(+) but protected CGC from apoptosis mediated by S/K deprivation. We also demonstrated that after the treatment with the complex I inhibitor, the expression levels of STAT1 increased and the levels of STAT3 decreased at the time points tested (0.5-8h). Meanwhile, pharmacological inhibition of the JAK/STAT pathway with AG490 (10-40 μM) was neuroprotective, probably due to its antioxidant properties, the Jak2-inhibitor-II potentiated MPP(+) neurotoxicity. Collectively, our data indicate that the treatment of CGC with the neurotoxin MPP(+) decreased two prosurvival pathways: STAT3 and Akt. Meanwhile Akt activation, using a PTEN inhibitor, did not play a prominent role in neuroprotection; loss of STAT3 could be a signal pathway involved in neuroprotection against the Parkinsonian neurotoxin MPP(+).


An unusual cause of duodenal perforation due to a lollipop stick.
Children have a natural tendency to explore objects with their mouths; this can result in the swallowing of foreign objects. Most ingested foreign bodies pass uneventfully through the gastrointestinal tract. However, some foreign bodies cause obstruction or perforation of the gastrointestinal tract, requiring surgical intervention. Perforation of the gastrointestinal tract may be associated with considerable morbidity and mortality. The most common sites of intestinal foreign body perforation are the ileocecal and rectosigmoid regions. Foreign body perforation of the duodenum is relatively uncommon. We report the first Korean case of duodenal perforation by an ingested 8-cm lollipop stick. Lollipops are popular with the children and fairly accessible to them, as most parents are not aware of their potential harm. Pediatric clinicians should be aware of the risks associated with lollipop stick ingestion. Our report also describes the feasibility and safety of laparoscopic diagnosis and management of pediatric patients with peritonitis induced by the ingestion of foreign bodies.


Stroke and atherothrombosis: an update on the role of antiplatelet therapy.
Atherothrombosis is responsible for most acute ischemic manifestations of atherosclerotic disease, including stroke. Individuals with evidence of atherothrombotic disease in one vascular bed have a significant risk of recurrence and show increased vulnerability over time for other manifestations elsewhere in the vasculature. Ischemic event rates for asymptomatic patients with multiple atherothrombotic risk factors appear to be similar to those in patients with documented cardiovascular disease. For example, diabetes mellitus and obesity are found at alarmingly high rates in patients with prior cardiovascular events, including stroke or transient ischemic attacks. Antiplatelet therapy is a key component of atherothrombotic event prevention. The results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) study showed that while dual antiplatelet therapy with aspirin and clopidogrel may not play a role in primary prevention, post hoc analysis alluded to the possibility of benefit for dual antiplatelet therapy in certain populations of stroke patients. We examined current recommendations for the prevention of atherothrombotic events, focusing on the role of oral antiplatelet agents in patients with ischemic stroke.


Pathway-specific, species, and sub-type counterscreening for better GPCR hits in high throughput screening.
G protein-coupled receptors represent one of the largest families of drug targets. Time and cost may be saved if GPCR modulators are assessed in terms of signaling pathway selectivity, species selectivity, and selectivity against closely-related family members early in the drug discovery process, perhaps even at the stage of high-throughput screening. Examples are given of how these kinds of selectivity have been addressed during screening.


Effects of foot orthoses on gait patterns of flat feet patients.
Although foot orthotics are widely prescribed for the treatment of flatfoot, the biomechanical effects of such devices are not yet fully clear. Accordingly, this study conducted an experimental investigation to evaluate the effects of orthoses on the gait patterns of patients with flatfoot during level walking. Eleven adults with flatfoot deformities were recruited. For each participant, kinematic and kinetic data were measured under three test conditions, i.e. walking barefoot, walking with shoes, and walking with shoes and insoles. During each test, the participants' gaits patterns were recorded and analyzed using a motion analysis system, two Kistler force plates and EVaRT software. The results showed that walking with shoes and insoles and walking with shoes conditions increased the peak ankle dorsiflexion angle and moment, and also reduced the peak ankle plantarflexion angle and moment. Furthermore, walking with shoes and insoles and walking with shoes conditions increased the peak knee varus moment. The effects of the orthoese on knee and hip were minimal and no significant differences were observed between walking with shoes and insoles and walking with shoes. The results suggested that the foot insoles and shoes developed in this study might benefit the ankle joint in patients with flat feet. In view of the minimal changes between walking with shoes and insoles and walking with shoes, further studies may be required to clarify the interaction between the foot and the insole/shoe.


[Objectivity, reproducibility and validity of 3D ultrasound in dermatology].
Recently it has become possible to visualize the three-dimensional (3D) architecture of sonographic structures using high-resolution ultrasound above 20 MHz (Dermascan C, Denmark; DUB 20, Germany). We studied the objectivity, reproducibility, and validity of these two 3D analysis systems on 22 skin tumors. To validate both systems, we compared the sonometric and histometric volume in 4 tumors. The objectivity was calculated by repeated evaluation of the volume on the same serial B-scan sections at 3-month intervals. The two-dimensional B-scans and 3D images exhibited similar characteristics. Volumetric evaluations were reproducible with both systems (variation coefficient < or = 9.9%), when the applicator was oriented longitudinal to the body axis. By changing the orientation, the coefficient increased up to 58.1% (DUB 20). Sonometric and histometric volumes of a phantom model and of the tumors exhibited small deviations in the Dermascan C (< or = 8.1%) and in some tumors large deviations in the DUB 20 (< or = 93.1%). We can conclude that the 3D sonography is a reproducible method, which can be used to evaluate the volume of skin tumors and metastases under chemotherapy or radiotherapy. We suggest in particular to use the in-vivo tumor volume as a prognostic parameter for the malignant melanoma.


Immunologic abnormalities in hemodialysis patients: improvement after pyridoxine therapy.
8 male patients undergoing maintenance hemodialysis were studied to determine the effect of administering supplements of pyridoxine hydrochloride, 50 mg/day for 3-5 weeks, on tests of immune function. In the 3 patients who initially had abnormal nitroblue tetrazolium reduction tests, the values returned to normal with therapy (p less than 0.05). The generation of chemotactic factors from plasma was defective in all evaluated patients and improved after pyridoxine therapy in 4 of 5 patients (p less than 0.01). The lymphocyte subpopulations changed with a rise in the populations of null cells after supplementation with pyridoxine. In addition, lymphocyte transformation in response to mitogens improved in the 3 patients who initially showed low values in these assays. The improvements occurred with pyridoxine therapy even though some patients who responded had no evidence for vitamin B6 deficiency before therapy, as indicated by a normal erythrocyte glumatic-pyruvic transaminase index. We conclude that several parameters of immune function are improved with pyridoxine supplementation. Studies are necessary to establish the minimum daily intake of pyridoxine which will maintain improved values of these tests of immune function in hemodialysis patients.


Remodeling as metaphor: sex offenders' perceptions of the treatment process.
The perceptions of 43 adult male sex offenders were examined to generate a grounded theory of the sexual abuse treatment process. Methodology included interviews, direct observations, and record analysis. Constant comparative analysis was used to collect and analyze data concurrently. The offenders use remodeling as a metaphor for their treatment process; they remodel themselves, their relationships, and their environment, but the foundations of offending are ever present. The remodeling process involves falling apart, taking on, tearing out, rebuilding, doing the upkeep, and moving on. Remodeling as a metaphor offers a concrete, visual, individualized, and safe way to address the treatment process of sex offenders.


Forensic approach to an archaeological casework of "vampire" skeletal remains in Venice: odontological and anthropological prospectus.
During the years 2006-2007, the Archeological Superintendent of Veneto (Italy) promoted a research project on mass graves located on Nuovo Lazzaretto in Venice, where the corpses of plague deaths were buried during the 16th and 17th centuries. The burials were of different stages and are believed to be the remains of plague victims from the numerous outbreaks of pestilence, which occurred between the 15th and 17th centuries. Among the fragmented and commingled human bones, an unusual burial was found. The body was laid supine, with the top half of the thorax intact, arms parallel to the rachis axis, the articulations were anatomically unaltered. Both the skull morphology and the dimensions of the caput omeris suggest the body was a woman. A brick of moderate size was found inside the oral cavity, keeping the mandible wide open. The data collected by the anthropologist were used to generate a taphonomic profile, which precluded the positioning of the brick being accidental. Likewise, the probability of the brick having come from the surrounding burial sediment was rejected, as the only other inclusions found were bone fragments from previous burials in the same area. The data collected by the odontologist were employed for age estimation and radiological dental assessment. The forensic profile was based conceptually on the "circumstances of death" and concluded that the positioning of the brick was intentional, and attributed to a symbolic burial ritual. This ritual confirms the intimate belief held at those times, between the plague and the mythological character of the vampire.


Evaluation of a novel ultra-sensitive nanoparticle probe-based assay for ricin detection.
A gold nanoparticle (GNP) probe-based assay (GNPA) modified from the bio-barcode assay (BCA) was developed for ultrasensitive detection of ricin, a potential biothreat agent. In the GNPA, a chain of ricin was captured by a GNP probe coated with polyclonal antibodies and single-stranded signal DNA. A magnetic microparticle (MMP) probe coated with ricin A chain monoclonal antibody was then added to form an immuno-complex. After being magnetically separated, the immuno-complex containing the single-stranded signal DNA was characterized by PCR and real-time PCR. A detection limit of 10(-2) fg/ml was determined for the ricin A chain; this is eight orders of magnitude more sensitive than that achieved with an ELISA and two orders more sensitive than that obtained with the BCA. The coefficients of variation (CV) of the intra- and inter-assay values ranged from 3.82-6.46%. The results here show that this novel assay is an ultrasensitive method for detection of ricin proteins and may be suitable for the ultrasensitive detection of other proteins.


Squeezing flow viscometry for nonelastic semiliquid foods--theory and applications.
In most conventional rheometers, notably the coaxial cylinders and capillary viscometers, the food specimen is pressed into a narrow gap and its structure is altered by uncontrolled shear. Also, most semiliquid foods exhibit slip, and consequently the measurements do not always reflect their true rheological properties. A feasible solution to these two problems is squeezing flow viscometry where the specimen, practically intact and with or without suspended particles, is squeezed between parallel plates. The outward flow pattern mainly depends on the friction between the fluid and plates or its absence ("lubricated squeezing flow"). Among the possible test geometries, the one of constant area and changing volume is the most practical for foods. The test can be performed at a constant displacement rate using common Universal Testing Machines or under constant loads (creep array). The tests output is in the form of a force-height, force-time, or height-time relationship, from which several rheological parameters can be derived. With the current state of the art, the method can only be applied at small displacement rates. Despite the method's crudeness, its results are remarkably reproducible and sensitive to textural differences among semiliquid food products. The flow patterns observed in foods do not always follow the predictions of rheological models originally developed for polymer melts because of the foods' unique microstructures. The implications of these discrepancies and the role that artifacts may play are evaluated in light of theoretical and practical considerations. The use of squeezing flow viscometry to quantify rheological changes that occur during a product's handling and to determine whether they are perceived sensorily is suggested.


Clinical Predictors of Response to Baclofen in the Treatment of Alcohol use Disorder: Results from the BacALD Trial.
To examine clinical predictors of treatment response to baclofen in patients with alcohol use disorder (AUD). Data from a randomised controlled trial (RCT) (N = 104), in which AUD patients received placebo or baclofen (30 mg/day or 75 mg/day) for 12 weeks, were analysed to determine predictive effects of the following four clinical characteristics: alcoholic liver disease (ALD), baseline alcohol consumption, craving and anxiety. Treatment outcomes included: (i) time to lapse and (ii) time to relapse. For both outcome measures, baclofen, irrespective of dose, was more effective when alcohol consumption was higher at baseline. Relative to placebo, baclofen increased time to first lapse in patients with higher baseline alcohol consumption (HR = 0.459, 95% CI = 0.219-0.962, P < 0.05). Similarly, baclofen increased time to first relapse in patients with higher alcohol consumption at baseline (HR = 0.360, 95% CI = 0.168-0.772, P < 0.05). There were no predictive effects of other baseline characteristics on time to lapse nor time to relapse. Directly comparing high dose of baclofen (75 mg/day) with low dose of baclofen (30 mg/day) revealed no differences with regards to predictors of baclofen response. Baclofen, relative to placebo, was more effective when alcohol consumption was higher at baseline.


Combining treatment modalities for tetracycline-discolored teeth.
Tetracycline-discolored teeth that are to be restored by porcelain laminate veneers present a clinical challenge. Successfully bleaching such teeth prior to veneering will permit the clinician and technician to overcome the technical difficulties associated with masking dark teeth. This article describes a combined treatment modality in which the teeth are bleached after the preparation for porcelain laminate veneers.


Laminin in traumatized peripheral nerve: basement membrane changes during degeneration and regeneration.
The changes in Schwann cell basement membrane associated with degeneration and regeneration during 50 weeks after transection of rat sciatic nerve were studied immunohistochemically with antibodies to laminin. In half of the animals, regeneration was prevented by suturing the nerve stumps aside, whereas in the rest spontaneous regeneration was allowed. Axonal regeneration was monitored with anti-neurofilament protein antibodies. In control nerves, basement membranes surrounding Schwann cells were visualized as circular, laminin-positive structures within the endoneurium. By 8 weeks after transection, Schwann cells had formed columns which were laminin-positive throughout their cross-sectional area and indistinguishable from basement membrane zones in both non-regenerating and regenerating nerves. As axons repopulated the distal stump, the normal shape of Schwann cell basement membrane tubes was slowly restored in freely regenerating nerves. In non-regenerating nerves, however, a striking atrophy of Schwann cell columns was observed. Regenerating axons were only seen inside laminin-positive tubular structures in all phases after 8 weeks in regenerating nerves. On the other hand, restoration of normal shape in laminin-positive basement membrane zones was coincident with appearance of axons in the distal stump, but it did not take place in chronically degenerating nerves. The results show that chronic degeneration leads to an atrophy of Schwann cell columns and results in a decrease in laminin immunoreactivity associated with them.


[Guidance for the obstetrician encountering a multiple pregnancy].
A retrospective review of multiple birth of higher order delivered at the Obstetric Clinic of University of Rome "La Sapienza" from 1982-1991 was performed. Comparison was made between this group (study group) and other published data. Since 1982 there has been more liberal use of abdominal delivery. Of the 25 multiple pregnancies, 17 were delivered by cesarean section (CS) and 8 by vaginal delivery. The corrected mortality rate in the study group was 19.2% (5/26) for vaginal delivery and 17.5% (10/57) for CS. Indication for CS was: elective (35%), fetal (18%) and maternal (47%). The main neonatal complications resulted from prematurity, and maternal noted complication were post-partum hemorrhage necessitating hysterectomy in one patient. The preferable mode of delivery cannot be stated dogmatically.


18F-FDG PET/CT Monitoring of Response to Programmed Death Protein 1 Blockade in Metastatic Basal Cell Carcinoma.
A 73-year-old woman with history of metastatic basal cell carcinoma presented with a large spinal mass demonstrating a high mutational burden of 111 mutations/Mb. She underwent T12 corpectomy and T10-L3 posterior spinal fusion followed by adjuvant radiation. After 2 years of surveillance, FDG PET/CT and a contrast-enhanced MRI revealed recurrence, prompting salvage therapy with the hedgehog signaling pathway inhibitor, sonidegib, which only transiently stabilized the disease. An off-label treatment with the programmed death protein 1 inhibitor, pembrolizumab, was initiated. Serial FDG PET/CT showed gradual decline in tumor metabolism over the next 12 months, leading to complete metabolic response.


A Mountain or a Plateau? Hematological Traits Vary Nonlinearly with Altitude in a Highland Lizard.
High-altitude organisms exhibit hematological adaptations to augment blood transport of oxygen. One common mechanism is through increased values of blood traits such as erythrocyte count, hematocrit, and hemoglobin concentration. However, a positive relationship between altitude and blood traits is not observed in all high-altitude systems. To understand how organisms adapt to high altitudes, it is important to document physiological patterns related to hypoxia gradients from a greater variety of species. Here, we present an extensive hematological description for three populations of Sceloporus grammicus living at 2,500, 3,400, and 4,300 m. We did not find a linear increase with altitude for any of the blood traits we measured. Instead, we found nonlinear relationships between altitude and the blood traits erythrocyte number, erythrocyte size, hematocrit, and hemoglobin concentration. Erythrocyte number and hematocrit leveled off as altitude increased, whereas hemoglobin concentration and erythrocyte size were highest at intermediate altitude. Additionally, lizards from our three study populations are similar in blood pH, serum electrolytes, glucose, and lactate. Given that the highest-altitude population did not show the highest levels of the variables we measured, we suggest these lizards may be using different adaptations to cope with hypoxia than lizards at low or intermediate altitudes. We discuss future directions that research could take to investigate such potential adaptations.


[Treatment of premature ovarian failure by bushen huoxue recipe combined estrogen and progesterone: a clinical research].
To observe the clinical efficacy of bushen huoxue recipe (BHR) combined estrogen and progesterone in treating premature ovarian failure (POF), and to explore an effective treatment program of POF by integrative medicine. Totally 265 POF patients were randomly assigned to 3 groups, i.e., Group I (86 cases, treated by BHR),Group II (88 cases,treated by conjugated estrogens and medroxyprogesterone acetate), and Group III (91 cases,treated by BHR +conjugated estrogens and medroxyprogesterone acetate). The therapeutic course for each group was 6 months. The main symptoms (including menstrual cycle, hectic fever, night sweat, vaginal dryness, and low libido), laboratory indices [including follicle stimulating hormone (FSH), luteotropic hormone (LH), estradiol (E2), and inhibin B (INH-B)], B-ultrasound indicators (including endometrial thickness, ovarian volume, and antral follicle count), and adverse reactions were observed in the three groups at the end of treatment and 6 months after treatment. Compared with before treatment, the main symptoms, laboratory indices, and B-ultrasound indicators were statistically improved in the three groups at the end of treatment and 6 months after treatment (P <0.05, P <0.01). Better effects were obtained in Group III in improving symptoms of the menstrual cycle, vaginal dryness, and low libido, lowering levels of FSH and LH, elevating levels of E2and INH-B, and ameliorating the endometrial thickness, the ovarian volume, and the antral follicle count (P <0.05, P <0.01). No obvious adverse reaction occurred in the three groups. BHR combined estrogen and progesterone showed better clinical efficacy than use of BHR or estrogen/progesterone alone, indicating it was an effective treatment program for POF.


Rapid fabrication of large-area colloidal crystal monolayers by a vortical surface method.
We have developed a simple approach for rapidly fabricating large-scale colloidal crystal arrays on substrates. Latex particles were first assembled into a close-packed monolayer on a vortical water surface; the monolayer was then transferred onto substrates by a withdrawer. Such an assembly method is conceptually similar to the Langmuir-Blodgett (L-B) methods for film deposition but does not require an L-B trough. The samples exhibit a large-scale periodic feature based on optical microscopy and scanning electron microscopy observations and diffract the laser beam, acting as crystals. This newly developed technique is timesaving, widely accessible, and applicable to large particles (up to 2 microm). It promises to be useful in nanofabrication.


Relative speed of onset of the antidepressant effect of maprotiline.
In a double-blind clinical trial conducted in general practice, maprotiline was compared with amitriptyline. Thirty-three of 40 patients completed the trial, 19 on maprotiline and 14 on amitriptyline. The Hamilton Depression Rating Scale was administered on days, 0, 7, 14, and 21, and a global rating scale of improvement was administered on day 21. Although there were significant reductions in the Hamilton scores by day 21 in both groups, with no significant difference between the compounds, maprotiline produced significantly greater improvement by day 7 than did amitriptyline. A review of published double-blind clinical amitriptyline or imipramine for treatment of depression supports our finding that maprotiline has a faster onset of action than the standard tricyclic antidepressants.


Bronchospasm in obese patients undergoing elective laparoscopic surgery under general anesthesia.
Existing data suggest that obesity correlates with airway hyper-reactivity. However, the incidence of bronchospasm during bariatric surgery in obese patients has not been well studied. This was a prospective observational study comparing 50 obese versus 50 non obese patients undergoing elective laparoscopic surgery over a 2 year period. Bronchospasm was detected clinically by auscultation and was confirmed by measuring peak airway pressure during mechanical ventilation. Blood gases were measured at predetermined time intervals intraoperatively. Categorical variables were analyzed using Fisher's exact test, while numerical variables within and between groups were compared using repeated measures general linear model. The incidence of bronchospasm was significantly higher in obese compared to non obese patients (P = 0.027). Peak airway pressures and blood gases differed significantly when comparing non obese patients versus obese patients without bronchospasm versus obese patients with bronchospasm. Hypoventilation resulting in gradual increase of arterial PaCO2 was noted in all groups during surgery. The incidence of bronchospasm is higher in obese patients compared to non obese patients undergoing elective laparoscopic surgery. Airway pressures and blood gas values in obese patients are somewhere between values in non obese patients and values in patients with bronchospasm, thereby implying that obesity is associated with a state where bronchial smooth muscles are not fully relaxed. Consideration of increased airway reactivity in obese patients undergoing laparoscopic surgery is important for improved patient care and uneventful anesthetic course.


Interleukin-6 and Interleukin-10 Gene Polymorphisms in Patients with Chronic Periodontitis and Response to Treatment after 3 Years.
The aim of this study was to investigate whether genetic susceptibility to chronic periodontitis, conferred by the presence of the IL-6 -572GG genotype or the IL-10 -592A allele, influences the outcomes following a non-surgical periodontal therapy (NSPT)over a long period of time. Thirty-seven chronic periodontitis patients were divided into two groups according to genotype as susceptible (SCP) and non-susceptible (NSCP). All subjects were clinically evaluated at baseline and 3 years following NSPT. Blood samples were collected at baseline from the individuals who fulfilled the inclusion criteria. All participants received NSPT from a single periodontist who was blind to the genotype status of each patient. A statistical analysis was performed by comparing the variables between groups using the Mann-Whitney U test and between baseline and 3 years for each group using the Wilcoxon test. The mean age of the population was estimated to be 47.68±8.64 years and it included 51.4% females, 48.6% smokers, and 45.9% alcohol consumers. Following a genetic analysis, 70.3% of patients were homozygous carriers of the IL-6 -572G (IL-6 SCP), and 46.0% of them were carriers of the IL-10 -592A allele (IL-10 SCP). NSPT reduced all studied parameters (probing depth, attachment loss, bleeding on probing, percentage of sites with 4-6mm and ≥7mm pocket depth and attachment loss) to all participants, but the treatment outcome was not associated with the genotype. The SCP and NSCP individuals showed similar clinical parameters at baseline and at 3 years. Within the limitations of this 3-year prospective cohort study in Caucasians diagnosed with chronic periodontitis, individuals susceptible to periodontal disease as determined by the presence of the IL-6 -572GG genotype or the IL-10 -592A allele showed similar treatment outcome following NSPT.


[Early detection and intervention in childhood and adolescent psychoses].
Research into schizophrenic disorders increasingly focusses on the early stage of the disease (prodrome). Experience in rehabilitation treatment and relapse prevention have led to new diagnostic and treatment strategies before the onset of schizophrenia that could contribute to disease prevention. The present article reports on the latest research results. From the point of view of medical practice negative symptoms and cognitive dysfunctions play a major role in the assessment of prodromal signs. Psychosocial and psychotherapeutic interventions are available for treating patients in the prodromal phase. But so far, there has not been sufficient data to recommend the use of antipsychotics before the onset of schizophrenia.


Behavioural analysis of swarming mosquitoes reveals high hearing sensitivity in Anopheles coluzzii.
Mosquitoes of many species mate in station-keeping swarms. Mating chases ensue as soon as a male detects the flight tones of a female with his auditory organs. Previous studies of hearing thresholds have mainly used electrophysiological methods that prevent the mosquito from flying naturally. The main aim of this study was to quantify behaviourally the sound level threshold at which males can hear females. Free-flying male Anopheles coluzzii were released in a large arena (∼2 m high×2 m×1 m) with a conspicuous object on the ground that stimulated swarming behaviour. Males were exposed to a range of natural and synthetic played-back sounds of female flight. We monitored the responses of males and their distance to the speaker by recording changes in their wingbeat frequency and angular speed. We show that the mean male behavioural threshold of particle velocity hearing lies between 13 and 20 dB sound particle velocity level (SVL) (95% confidence interval). A conservative estimate of 20 dB SVL (i.e. <0.5 µm s-1 particle velocity) is 12-26 dB lower than most of the published electrophysiological measurements from the Johnston's organ. In addition, we suggest that (1) the first harmonic of a female's flight sound is sufficient for males to detect her presence, (2) males respond with a greater amplitude to single-female sounds than to the sound of a group of females and (3) the response of males to the playback of the flight sound of a live female is the same as to that of a recorded sound of constant frequency and amplitude.


Enterochromaffin-like tumour cells in the diffuse but not the intestinal type of gastric carcinomas.
Gastrin may play a role in gastric carcinogenesis, as indicated by an increased frequency of gastric carcinomas in patients with pernicious anaemia and the fact some human gastric cancer cell lines carry the gastrin receptor. Recently, it has been shown that the acid-stimulatory effect of gastrin may be solely mediated by histamine release from the enterochromaffin-like (ECL) cell, on which gastrin has a specific trophic effect. We therefore found it of interest to examine human gastric carcinomas for the presence of ECL tumour cells by using silver staining and chromogranin immunohistochemistry. We found evidence of ECL cell-derived tumour cells in 40% of the diffuse gastric carcinomas but no such tumour cells in the intestinal type of gastric carcinoma. This may suggest that diffuse gastric carcinomas, like malignant gastric tumours of the mastomys, are in fact malignant ECLomas.


Validation of alternating Kernel mixture method: application to tissue segmentation of cortical and subcortical structures.
This paper describes the application of the alternating Kernel mixture (AKM) segmentation algorithm to high resolution MRI subvolumes acquired from a 1.5T scanner (hippocampus, n = 10 and prefrontal cortex, n = 9) and a 3T scanner (hippocampus, n = 10 and occipital lobe, n = 10). Segmentation of the subvolumes into cerebrospinal fluid, gray matter, and white matter tissue is validated by comparison with manual segmentation. When compared with other segmentation methods that use traditional Bayesian segmentation, AKM yields smaller errors (P < .005, exact Wilcoxon signed rank test) demonstrating the robustness and wide applicability of AKM across different structures. By generating multiple mixtures for each tissue compartment, AKM mimics the increased variation of manual segmentation in partial volumes due to the highly folded tissues. AKM's superior performance makes it useful for tissue segmentation of subcortical and cortical structures in large-scale neuroimaging studies.


[Evaluation of an immunoradiometric assay for succinylated ACTH].
A new immunoradiometric assay for succinylated ACTH using 3 monoclonal antibodies has been developed by Immunotech (I-IRMA). It was compared to a commercial immunoradiometric assay of ACTH (Nichols Institute, N-IRMA). The functional sensitivity of I-IRMA assay was estimated at 1.5 ng/L. The comparison of both methods on plasma samples withdrawn at 8 h from 47 normal subjects showed a good correlation coefficient (r = 0.83; P < 0.001). The 24-hours secretion profiles obtained by both methods were similar in 14 normal subjects. Nevertheless, the I-IRMA mean values were about 30% lower than the corresponding N-IRMA values. This difference increased to 50% when the ACTH concentrations were low, as it the case at 24 h or during the dexamethasone suppression test. During insulin hypoglycemia stimulation test, the two procedures gave similar values. Both methods applied to a pathologic population gave similar result to those obtained on normals. In 10 patients bearing corticotroph adenomas, the profiles of ACTH secretions during 24 h were similar using both methods. The I-IRMA values were lower about 30% than N-IRMA values during the base state or after the 8 mg-dexamethasone suppression test. This difference was also observed in 6 patients with corticotroph insufficiency. In conclusion, the comparison of N-IRMA and I-IRMA methods showed the validity of the new succinylated-ACTH assay which is more efficient in the lower range of ACTH concentration. This significant decrease in the sensitivity threshold may be useful in the establishment of the cure criteria in Cushing disease.


Fractal analysis of perfusion imaging in synovitis: a novel imaging biomarker for grading inflammatory activity based on assessing angiogenesis.
The mutual and intertwined dependence of inflammation and angiogenesis in synovitis is widely acknowledged. However, no clinically established tool for objective and quantitative assessment of angiogenesis is routinely available. This study establishes fractal analysis as a novel method to quantitatively assess inflammatory activity based on angiogenesis in synovitis. First, we established a pathophysiological framework for synovitis including fractal analysis of software perfusion phantoms, which allowed to derive explainability with a known and controllable reference standard for vascular structure. Second, we acquired MRI datasets of patients with suspected rheumatoid arthritis of the hand, and three imaging experts independently assessed synovitis analogue to Rheumatoid Arthritis MRI Scoring (RAMRIS) criteria. Finally, we performed fractal analysis of dynamic first-pass perfusion MRI in vivo to evaluate angiogenesis in relation to inflammatory activity with RAMRIS as reference standard. Fractal dimension (FD) achieved highly significant discriminability for different degrees of inflammatory activity (p<0.01) in software phantoms with known ground-truth of angiogenic structure. FD indicated increasingly chaotic perfusion patterns with increasing grades of inflammatory activity (Spearman's ρ=0.94, p<0.001). In 36 clinical patients, fractal analysis quantitatively and objectively discriminated individual RAMRIS scores (p≤0.05). Area under the receiver-operating curve was 0.84 (95% CI 0.7 to 0.89) for fractal analysis when considering RAMRIS as ground-truth. Fractal analysis additionally identified angiogenesis in cases where RAMRIS underestimated inflammatory activity. Based on angiogenesis and perfusion pathophysiology, fractal analysis non-invasively enables comprehensive, objective and quantitative characterisation of inflammatory angiogenesis with subjective and qualitative RAMRIS as reference standard. Further studies are required to establish the clinical value of fractal analysis for diagnosis, prognostication and therapy monitoring in inflammatory arthritis.


[Assessment of the changes in autonomic nervous function during head up tilt test in syncopal patients using spectral analysis of heart rate variability].
To study the pathological mechanism of vasovagal syncope, spectral analysis of heart rate variability was used to evaluate the changes of autonomic function during head up tilt test in patients with unexplained syncope. 27 patients with recurrent episodes of unexplained syncope underwent 70 degrees head up tilt test. Spectral analysis was used to assess the changes in autonomic function before tilt testing, immediately after tilting, just before the occurrence of syncope or at the end of the test, during the syncope period or at the end of the test and after testing in supine rest. At the same time, haemodynamic changes were recorded. Spectral power in very low frequency (VLF, 0.003 - 0.04 Hz), low frequency (LF, 0.04 - 0.15 Hz) and high frequency (HF, 0.15 - 2.00 Hz) were computed with Fast Fourier Transform analysis, and LF and HF were normalized: LF norm = 100 x LF/(TP-VLF) and HF norm = 100 x HF/(TP-VLF). 12 patients (mean age 40 +/- 10 years) showed a negative response and 15 patients (mean age 37 +/- 9 years) showed a positive response. Both systolic and diastolic blood pressure decreased in all the patients [(118.00 +/- 10.42-->81.00 +/- 12.36) mm Hg, P < 0.01 and (76.00 +/- 8.40-->52.00 +/- 10.95) mm Hg, P < 0.01] and heart rate decreased in 8 patients (53%). No significant difference in all the indices of spectral analysis was observed in supine position between the subjects with positive and negative test results. LF norm in both the groups did not alter during the entire tilt procedure. The decreased HF norm and increased LF/HF persisted throughout head up tilt test in the negative patients. In the positive patients, similar patterns of changes were observed before the occurrence of positive symptoms, and during the occurrence of the symptoms. HF norm abruptly rose (10.47 +/- 4.04-->32.95 +/- 10.48) and obviously exceeded that before tilt testing (23.44 +/- 4.20-->32.95 +/- 10.48, P < 0.05) and LF/HF dropped (3.28 +/- 0.39-->1.07 +/- 0.31, P < 0.01). At supine rest just after test, all the indices in both groups came back. In the supine position, autonomic function is similar between positive and negative subjects. Positive patients have a different pattern of response to the tilting test. The pathological mechanism leading to vasovagal syncope appears to be related with the abrupt and excessive increase of vagal activity.


A small regulatory element from chromosome 19 enhances liver-specific gene expression.
Tissue-specific promoters for gene therapy are typically too big for adeno-associated virus (AAV) vectors; thus, the exploration of small effective non-viral regulatory elements is of particular interest. Wild-type AAV can specifically integrate into a region on human chromosome 19 termed AAVS1. Earlier work has determined that a 347 bp fragment (Chr19) of AAVS1 has promoter and transcriptional enhancer activities. In this study, we further characterized this genetic regulation and investigated its application to AAV gene therapy in vitro and in vivo. The Chr19 347 bp fragment was dissected into three regulatory elements in human embryonic kidney cells: (i) TATA-independent promoter activity distributed throughout the fragment regardless of orientation, (ii) an orientation-dependent insulator function near the 5' end and (iii) a 107 bp enhancer region near the 3' end. The small enhancer region, coupled to the mini-CMV promoter, was used to drive the expression of several reporters following transduction by AAV2. In vivo data demonstrated enhanced transgene expression from the Chr19-mini-CMV promoter cassette after tail vein injection primarily in the liver at levels comparable to the chicken beta-actin promoter and higher than the liver-specific TTR promoter (>2-fold). However, we did not observe this increase after muscle injection, suggesting tissue-specific enhancement. All of the results support identification of a small DNA fragment (347 bp) from AAV Chr19 integration site capable of providing efficient and enhanced liver-specific transcription when used in recombinant AAV vectors.


The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism.
Serum calcium levels are regulated by the action of parathyroid hormone (PTH). Major drivers of PTH hypersecretion and parathyroid cell proliferation are the hypocalcemia and hyperphosphatemia that develop in chronic kidney disease patients with secondary hyperparathyroidism (SHPT) as a result of low calcitriol levels and decreased kidney function. Increased PTH production in response to systemic hypocalcemia is mediated by the calcium-sensing receptor (CaR). Furthermore, as SHPT progresses, reduced expression of CaRs and vitamin D receptors (VDRs) in hyperplastic parathyroid glands may limit the ability of calcium and calcitriol to regulate PTH secretion. Current treatment for SHPT includes the administration of vitamin D sterols and phosphate binders. Treatment with vitamin D is initially effective, but efficacy often wanes with further disease progression. The actions of vitamin D sterols are undermined by reduced expression of VDRs in the parathyroid gland. Furthermore, the calcemic and phosphatemic actions of vitamin D mean that it has the potential to exacerbate abnormal mineral metabolism, resulting in the formation of vascular calcifications. Effective new treatments for SHPT that have a positive impact on mineral metabolism are clearly needed. Recent research shows that drugs that selectively target the CaR, calcimimetics, have the potential to meet these requirements.