Global DNA methylation is influenced by smoking behaviour.
The level of epigenetic DNA methylation is an important factor in the pathogenesis of various human diseases. As smoking may influence DNA methylation, we investigated the effect of smoking habits on global DNA methylation in 298 genomic DNA samples (73 fathers, 69 mothers and 156 offspring). We did not find a direct effect of smoking on global DNA methylation. However, there was an association of the offspring's DNA methylation with paternal DNA methylation that was strongest if both had never smoked (R2corr=0.41, Beta=0.68, p=0.02) and completely vanished if the offspring smoked or had ever smoked. These findings suggest an association between smoking behaviour and global DNA methylation, which may be of importance for a wide range of diseases.


Method for measuring brain tissue pressure. Response to alteration in pCO-2 systemic blood pressure, and middle cerebral artery occlusion.
The authors report a method for measuring total local brain tissue pressure (BTP) using a miniature catheter transducer stereotaxically introduced into the white matter of the cat's cerebrum. Quantitative rapid phasic pressure changes were satisfactorily demonstrated. Due to some drift of baseline of the transducers and inability to perform in vivo calibration, reliable long-term quantitative pressure measurements sometimes could not be studied. The BTP from each cerebral hemisphere and the cisternal pressure (CP) were monitored during alterations of pCO-2 and systemic blood pressure, and distilled H20 injection prior to and after right middle cerebral artery (MCA) ligation. The catheter transducers functioned well on chronic implantation for up to 6 weeks. Compared to the chronically implanted catheters, acutely implanted catheters responded identically except for drift. The response of intracranial pressure and CP to MCA occlusion, alterations in pCO2, and systemic blood pressure were similar. No BTP gradients appeared in response to MCA ligation, hypercapnia, hypertension, or progressive swelling of the resulting infarction.


High-Frame-Rate Synthetic Aperture Ultrasound Imaging Using Mismatched Coded Excitation Waveform Engineering: A Feasibility Study.
Mismatched coded excitation (CE) can be employed to increase the frame rate of synthetic aperture ultrasound imaging. The high autocorrelation and low cross correlation (CC) of transmitted signals enables the identification and separation of signal sources at the receiver. Thus, the method provides B-mode imaging with simultaneous transmission from several elements and capability of spatial decoding of the transmitted signals, which makes the imaging process equivalent to consecutive transmissions. Each transmission generates its own image and the combination of all the images results in an image with a high lateral resolution. In this paper, we introduce two different methods for generating multiple mismatched CEs with an identical frequency bandwidth and code length. Therefore, the proposed families of mismatched CEs are able to generate similar resolutions and signal-to-noise ratios. The application of these methods is demonstrated experimentally. Furthermore, several techniques are suggested that can be used to reduce the CC between the mismatched codes.


Outgrowth of human fibroblast aggregates on a substratum triggers a wide variety of morphogenetic properties in the cells.
Twenty-four-hour-old aggregates of human diploid skin fibroblasts are allowed to attach to a glass or plastic substratum. As a result of this attachment the cells in the aggregate demonstrate rapid and generalized changes in cell shape, cell surface and cytoplasm ultrastructure and in their ability to incorporate [3H]thymidine. Within 24 h they grow out on the substratum to attain the regular monolayer configuration. During the process of leaving the aggregate for the substratum a great number of different morphogenetic properties are displayed by the cells, resembling the properties of embryonic or epithelial cells. The simultaneous occurrence of this great variety of cell shape and cell surface changes, many of them unusual for fibroblasts, as well as the concurrent formation of organized cytoplasmic structures - microfilaments, microtubules - at localized areas of the cells, makes this system a potentially useful tool in the study of cell behaviour.


A signal detection-based confidence-similarity model of face matching.
Face matching consists of the ability to decide whether two face images (or more) belong to the same person or to different identities. Face matching is crucial for efficient face recognition and plays an important role in applied settings such as passport control and eyewitness memory. However, despite extensive research, the mechanisms that govern face-matching performance are still not well understood. Moreover, to date, many researchers hold on to the belief that match and mismatch conditions are governed by two separate systems, an assumption that likely thwarted the development of a unified model of face matching. The present study outlines a unified unequal variance confidence-similarity signal detection-based model of face-matching performance, one that facilitates the use of receiver operating characteristics (ROC) and confidence-accuracy plots to better understand the relations between match and mismatch conditions, and their relations to factors of confidence and similarity. A binomial feature-matching mechanism is developed to support this signal detection model. The model can account for the presence of both within-identities and between-identities sources of variation in face recognition and explains a myriad of face-matching phenomena, including the match-mismatch dissociation. The model is also capable of generating new predictions concerning the role of confidence and similarity and their intricate relations with accuracy. The new model was tested against six alternative competing models (some postulate discrete rather than continuous representations) in three experiments. Data analyses consisted of hierarchically nested model fitting, ROC curve analyses, and confidence-accuracy plots analyses. All of these provided substantial support in the signal detection-based confidence-similarity model. The model suggests that the accuracy of face-matching performance can be predicted by the degree of similarity/dissimilarity of the depicted faces and the level of confidence in the decision. Moreover, according to the model, confidence and similarity ratings are strongly correlated. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Population-based survival data for brain tumors in Korea.
Primary brain tumors are relatively uncommon but particularly lethal cancers. Although survival is useful for monitoring the effects of early cancer detection and treatment, there are few population-based estimates of survival for subjects with brain tumors, especially in Asian countries. Using the Korea National Cancer Incidence Database, 4,721 newly diagnosed cases of histologically confirmed malignant primary brain tumors from 1999 to 2004 were analyzed for observed survival. For trend analyses of glioblastomas, we included 2,751 glioblastoma cases diagnosed between 1999 and 2007. We compared survival by age group and histological type by use of the Kaplan-Meier method. For all ages and all brain tumor types in Korea, five-year survival was 37.5 %. For each histological type of brain tumor survival of pediatric and younger adult populations was much better than that of older adults. Five-year survival for glioblastoma, astrocytoma, anaplastic astrocytoma, and oligodendroglioma was 8.9, 51.6, 25.2, and 73.5 %, respectively. Two-year survival for glioblastoma increased from 18.6 % for cases diagnosed in 1999-2001 to 21.3 % for cases diagnosed in 2002-2004 and to 24.7 % for cases diagnosed in 2005-2007. These results may help clinicians and patients to assess long-term prognoses for brain tumors, and the data presented here could serve as master control data set for single-arm clinical trials, especially in Asian populations.


Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial.
Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217 , February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015-001625-16, Sept 2015).


Cerebrotendinous xanthomatosis associated with immune thrombocytopenia.
Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease inherited in a autosomal recessive way. CTX is characterised by childhood-onset cataract, adolescent to young adult-onset tendon xanthomas and adult-onset progressive neurological dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs and seizures). Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon and the neck tendons. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration and decreased chenodeoxycholic acid. Long-term treatment of individuals with CTX with chenodeoxycholic acid (CDCA) normalises bile acid synthesis, normalises plasma and cerebrospinal fluid concentration of cholestanol, and improves neurophysiological findings. Inhibitors of 3-hydroxy 3-methyl glutaryl coenzyme A reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle symptoms.


Naltrexone and alcohol effects on craving for cigarettes in heavy drinking smokers.
Naltrexone has been extensively studied for the treatment of alcohol use disorder. However, less is known about the effects of naltrexone on smoking outcomes in the context of alcohol use among East Asian individuals who have been suggested to differ in response to alcohol and to naltrexone. The present study is a secondary analysis that used a double-blind placebo-controlled design (n = 31) to examine the (a) effects of alcohol on basal craving for cigarettes, (b) effects of naltrexone on cigarette craving and alcohol craving during alcohol administration, and (c) relationship between craving for alcohol and cigarettes. Heavy drinking smokers of East Asian descent completed two counterbalanced intravenous alcohol administration sessions, one after taking naltrexone (50 mg) for five days and one after taking a placebo for five days. Self-reported subjective craving for cigarettes and for alcohol was recorded during each experimental session. Craving for cigarettes and alcohol increased significantly throughout the intravenous alcohol administration. A significant breath alcohol concentration (BrAC) × Medication interaction revealed that naltrexone blunted cigarette craving during alcohol administration, compared to placebo. Naltrexone significantly reduced craving for alcohol during alcohol administration in this group of heavy drinking smokers. Alcohol craving significantly predicted cigarette craving, however this effect did not vary across rising alcohol administration or by medication. These findings demonstrate that naltrexone reduces the urge to smoke and to drink during alcohol administration. Clinical studies are needed to further ascertain whether naltrexone may be of benefit to this distinct subgroup of heavy drinking smokers. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Surface analysis methods of biomaterials used in oral surgery: literature review.
Titanium is the most frequently used biomaterial in oral surgery because of its positive physical and chemical properties. Clinical studies proved that the properties of titanium can be improved by surface modification techniques. To study the surface of biomaterials, the positive effects of the coatings, the response of the organism (corrosion resistance, physical and chemical stability, the thickness of various coatings, biocompatibility), one must choose and use the adequate analytical method for one's goal. In this article, the authors present the most frequently used analytical methods for the study of the surface morphology and composition of biomaterials. Also, they outline the advantages and disadvantages of specific analytical methods and the field where they are used.


Dental infection control at the year 2000. Accomplishment recognized.
Health care providers have strived to address the many elements necessary to achieve effective infection control. Historical progress in microbiology and hospital asepsis provided the foundation for advances in dental preventive practices. Evidence supporting the application of current practices includes a long history of scientific and clinical investigations, technological advances in equipment and materials, and periodic publication of updated recommendations by professional health care organizations. The routine application of precautions such as multiple aseptic procedures, latex gloves, masks, protective eyewear, clinic coats, automated instrument decontamination devices, time-efficient heat sterilization modalities, chemical disinfectants, waste management procedures and single-use disposable items have created a safer environment for dental personnel and patients alike.


Temporal dynamics of bird community composition: an analysis of baseline conditions from long-term data.
Numerous anthropogenic activities threaten the biodiversity found on earth. Because all ecological communities constantly experience temporal turnover due to natural processes, it is important to distinguish between change due to anthropogenic impact and the underlying natural rate of change. In this study, we used data sets on breeding bird communities that covered at least 20 consecutive years, from a variety of terrestrial ecosystems, to address two main questions. (1) How fast does the composition of bird communities change over time, and can we identify a baseline of natural change that distinguishes primeval systems from systems experiencing varying degrees of human impact? (2) How do patterns of temporal variation in composition vary among bird communities in ecosystems with different anthropogenic impacts? Time lag analysis (TLA) showed a pattern of increasing rate of temporal compositional change from large-scale primeval systems to disturbed and protected systems to distinctly successional systems. TLA slopes of <0.04 were typical for breeding bird communities with natural turnover, while communities subjected to anthropogenic impact were characterised by TLA slopes of >0.04. Most of the temporal variability of breeding bird communities was explained by slow changes occurring over decades, regardless of the intensity of human impact. In most of the time series, medium- and short-wave periodicity was not detected, with the exception of breeding bird communities subjected to periodic pulses (e.g. caterpillar outbreaks causing food resource peaks).


Guidelines on the management and prevention of prediabetes.
Pandemic obesity and diabetes mellitus (DM), particularly type-2 DM (T2DM) now has become a serious threat for people worldwide. The International Diabetes Federation (IDF) suggests that the prevalence of DM in the world is 1.9% and it has made DM as the 7th leading cause of death worldwide. It has been estimated that the prevalence of diabetes between 1994 and 2010 was projected as much as 215.6 milion people; however an evaluation in 2007 revealed that the number of diabetic patients has reached 246 million people and it has been concerned that the number would increase in 2025 reaching more than 300 million people. Patients with DM may have various complilcations, including macrovascular diseases (heart disease, stroke and peripheral vascular disease) and microvascular diseases (retinopathy, neuropathy and nephropathy). Complications of DM have started early before the diagnosis of DM has been made. About 50% of patients have alreadly had one chronic complication at the time of diagnosis. Therefore, it is necessary to have a guideline on management of prediabetes condition associated with prevention of chonic complication and cardiovascular risk of diabetes. The guideline is expected to improve the skills of health care professionals in recognizing prediabetes condition, identifying people at high risk for diabetes and providing an appropriate management so that the incidence and complication of DM can be reduced.


Preoperative left atrial volume index is associated with postoperative outcomes in mitral valve repair for chronic mitral regurgitation.
To assess determinants of left atrial reverse remodeling after mitral valve repair and to evaluate the impact of preoperative left atrial volume on postoperative outcomes. We reviewed the records of 720 patients who underwent mitral valve repair from September 2008 to July 2015 and had preoperative measurement of left atrial volume index. We analyzed the association of preoperative left atrial volume index on early and late outcomes, and determined which baseline characteristics are associated with left atrial reverse remodeling, as measured by changes in left atrial volume index in 512 patients who had at least 1 postoperative measurement. The median (interquartile range) preoperative left atrial volume index was 54.0 (44.0-66.0) mL/m2. Preoperative left atrial volume index, age, body mass index, and atrial fibrillation were independently associated with the degree of left atrial reverse remodeling over the follow-up period. Reverse remodeling was greatest in patients with higher baseline left atrial volume index (P < .001), but less reverse remodeling was observed in patients with advanced age (P < .001), preoperative atrial fibrillation (P < .001), and extreme values of body mass index (P = .004), although these effects were moderately attenuated when limiting the analysis to 6-month follow-up. Secondary analysis demonstrated marginally significant effects of preoperative left atrial volume index on risks of early postoperative atrial fibrillation (P = .030) and late mortality (P = .077) after adjusting for age and sex. In patients with degenerative mitral valve regurgitation who had mitral valve repair, preoperative left atrial volume index was associated with extent of left atrial reverse remodeling, risk of early postoperative atrial fibrillation, and late mortality. The majority of reverse remodeling occurs within the first month after operation and is greatest in younger patients.


Writing about testing worries boosts exam performance in the classroom.
Two laboratory and two randomized field experiments tested a psychological intervention designed to improve students' scores on high-stakes exams and to increase our understanding of why pressure-filled exam situations undermine some students' performance. We expected that sitting for an important exam leads to worries about the situation and its consequences that undermine test performance. We tested whether having students write down their thoughts about an upcoming test could improve test performance. The intervention, a brief expressive writing assignment that occurred immediately before taking an important test, significantly improved students' exam scores, especially for students habitually anxious about test taking. Simply writing about one's worries before a high-stakes exam can boost test scores.


Outcomes following chronic obstructive pulmonary disease presentations to emergency departments in Alberta: a population-based study.
Chronic obstructive pulmonary disease (COPD) is a complex, multisystem disorder that often results in exacerbations requiring emergency department (ED) management. Following an exacerbation and discharge from the ED, reassessment and management adjustment with a health care provider are recommended to re-establish control of the disease. To describe outcomes of all COPD presentations to EDs made by adults in Alberta including the time spent in the ED and the physician visits following the ED visit. Provincial administrative databases were used to obtain all ED encounters for COPD during six fiscal years (1999 to 2005). The information extracted included demographics, ED visit timing, and acute and subacute outcomes (physician visits up to 365 days after discharge for all 7302 discharged individuals during a one-year period). Data analysis included descriptive summaries and survival curves. There were 85,330 ED visits for acute COPD, of which 67% were discharged from the ED. Median ED length of stay was longer in large urban areas (Calgary: 5 h 9 min; Edmonton: 4 h 58 min) than in other regions of Alberta (1 h 17 min). Admissions resulted from 32% of visits and varied among regions; however, few were admitted to the intensive care unit (1%) or died (0.1%). Following discharge, the median time to first follow-up with a physician was 13 days; however, only 40% of patients had follow-up visits in the first seven days. Repeat ED visits within seven days occurred in 5.7% of discharged patients, while 25.6% of discharged patients had repeat ED visits within 365 days of discharge. More than 30% of COPD ED visits resulted in admission; regional variation was significant. Moreover, discharged patients experienced delayed follow-up and often required repeat ED visits. Interventions to improve reassessment and reduce COPD-related repeat ED visits should be explored.


The role of speech fidelity in the irrelevant sound effect: Insights from noise-vocoded speech backgrounds.
The Irrelevant Sound Effect (ISE) is the finding that background sound impairs accuracy for visually presented serial recall tasks. Among various auditory backgrounds, speech typically acts as the strongest distractor. Based on the changing-state hypothesis, speech is a disruptive background because it is more complex than other nonspeech backgrounds. In the current study, we evaluate an alternative explanation by examining whether the speech-likeness of the background (speech fidelity) contributes, beyond signal complexity, to the ISE. We did this by using noise-vocoded speech as a background. In Experiment 1, we varied the complexity of the background by manipulating the number of vocoding channels. Results indicate that the ISE increases with the number of channels, suggesting that more complex signals produce greater ISEs. In Experiment 2, we varied complexity and speech fidelity independently. At each channel level, we selectively reversed a subset of channels to design a low-fidelity signal that was equated in overall complexity. Experiment 2 results indicated that speech-like noise-vocoded speech produces a larger ISE than selectively reversed noise-vocoded speech. Finally, in Experiment 3, we evaluated the locus of the speech-fidelity effect by assessing the distraction produced by these stimuli in a missing-item task. In this task, even though noise-vocoded speech disrupted task performance relative to silence, neither its complexity nor speech fidelity contributed to this effect. Together, these findings indicate a clear role for speech fidelity of the background beyond its changing-state quality and its attention capture potential.


Results after vitrectomy in diabetes.
Eighteen eyes in seventeen patients with diabetic retinopathy were operated on using the vitreous infusion-suction cutter. All had severe loss of vision due to retinal detachment or vitreous hemorrhage, or both. Thirteen eyes had a significant improvement in vision. The surgical management and postoperative problems are described. The results suggest that this technique is useful in selected cases of blindness caused by diabetes.


A Y-shaped bifurcation-dedicated stent for the treatment of de novo coronary bifurcation lesions: an IVUS analysis from the BRANCH trial.
The aim of this IVUS substudy was to assess the efficacy of the Y-shaped Medtronic bifurcation-dedicated stent (BDS) for the treatment of de novo coronary bifurcated lesions. In the BRANCH trial, post-procedure IVUS was performed in 45 patients. IVUS was available in both branches in 19 lesions and only the main branch (MB) in 26 lesions. IVUS analysis included four distinct locations: proximal MB, bifurcation site, distal MB, and side branch (SB). Lumen symmetry was calculated as minimum/maximum lumen diameters. The quantity of isolated stent struts across the SB ostium was used to assess inadequate strut apposition to the carina resulting in partial jailing of the SB orifice. A minimum stent area (MSA) <4 mm2 was found in 0% of proximal and distal MB, and in 15.4% of SB. In SB, MSA was located mainly at mid or distal segments (84.6%), rather than at the SB ostium. Eccentric stent expansion and edge dissection were seen primarily at proximal MB. Isolated struts were seen in only 20.9% of SB ostia with a minimum length of 0.7±0.4 mm. Implantation of BDS resulted in adequate stent dimensions and strut apposition at the carina and SB ostium. ClinicalTrials.gov Identifier: NCT00607321.


Loss of skeletal muscle mass can be predicted by sarcopenia and reflects poor functional recovery at one year after surgery for geriatric hip fractures.
Hip fractures in the elderly impact negatively on functional dependence, and carry great social costs and morbidity. We assessed the decline in muscle mass and functional outcomes following hip fracture surgery . Thirty patients with a hip fracture (mean age: 80.8 years) were assessed using dual-energy X-ray absorptiometry and reassessed for changes in body composition 1 year after hip surgery. Baseline demographic data, sarcopenia, and bone mineral density were recorded. Body mass index (BMI), handgrip strength, appendicular skeletal muscle mass (ASM), total body fat percentage, and responses to questionnaires measuring quality of life and activities of daily living (ADL) before injury and 1 year after hip surgery were analyzed to identify changes. Associations with changes in ADL or quality of life were analyzed with time-variant independent variables. Significant losses in ADL were identified at the 1-year follow-up, at which time only 43% of patients had regained their preinjury ADL status. Additionally, the participants had lost an average of 4.63% of ASM. ASM loss was significantly higher in patients with baseline sarcopenia than in those without (mean loss: 9.18% and 1.15%, respectively). When confounders were controlled for, a greater loss of ASM and handgrip strength and larger increase in BMI were associated with greater decrease in ADL 1 year after hip surgery. Geriatric hip fracture patients may experience a significant loss of muscle mass, associated with impaired functional recovery 1 year after hip surgery, highlighting a potential treatment target of maintaining muscle mass to improve prognosis in these patients.


The quest for living-related kidney donors for children with end-stage renal disease.
In a pediatric renal transplant program that actively seeks living-related kidney donors, we achieved a living donor rate of 55% in 119 children. This approximates the national average but is less than an idealized goal. For black children, the living-donor transplant rate was 41%, a disconcertingly low rate. In an attempt to define factors that negatively affected living-related donor availability, we analyzed our evaluation process by distinct phases (interview, histocompatibility testing and medical evaluation). We classified our families on the basis of locale (urban, suburban and rural), family unit (two or less parents, adult sibs or other relatives presenting at interview) and economic status (designating only economic-disadvantaged and other). While histoincompatibility is predictably a negative factor, the negative impacts of medical illness in the donor pool, economic disadvantage and single parent family are striking and cumulative. Our data validate the relative success of an aggressive recruitment policy in a patient population that includes many economically disadvantaged families. For pediatric renal transplant programs with low living-related donor rates, our data should encourage review and possible modification of the donor recruitment process.


Acute myeloid leukemia in the elderly: current therapeutic results and perspectives for clinical research.
More than half of acute myeloid leukemia (AML) diagnoses are currently made in patients older than 60 years. Furthermore, even if the age-specific incidence remains stable in the coming years, the incidence of AML in elderly people is expected to consistently increase, given the progressive ageing of the general population. Consequently, the treatment of the disease in aged individuals represents a daily challenge in clinical hematology. Several studies have shown that, in current practice, a high fraction of patients older than 60 years is negatively selected for inclusion in clinical trials that are based on intensive chemotherapy. Apart from performance status and comorbidity at diagnosis, other non-clinical factors can significantly affect therapeutic choice including the distance from hematologic institution, presence of a carer, physician's and patient's attitude, and the scientific interest of the physician in a given therapeutic programme. In daily practice, a combination of these factors results in relevant selection of patients for clinical trials. Clearly, preselection of patients with AML leads to misleading overly optimistic results in some studies. Treatment of AML in the elderly is difficult and well-controlled trials in this group of patients are uncommon. Frequently, higly selected patients are recruited to relatively small phase II unrandomised trials with complete remission (CR) rates ranging from 25 to 70 %. These figures may turn unrealistic in the current practice. The present article reviews results of most relevant studies addressing therapeutic results in elderly patients with AML. Questions to be addressed will include potential selection biases, results with conventional chemotherapy, the therapeutic potential of autologous and allogeneic stem cell transplantation and a critical review of results achieved with newly developed drugs.


The Role of Spike Protein Mutations in the Infectious Power of SARS-COV-2 Variants: A Molecular Interaction Perspective.
Specific S477N, N501Y, K417N, K417T, E484K mutations in the receptor binding domain (RBD) of the spike protein in the wild type SARS-COV-2 virus have resulted, among others, in the following variants: B.1.160 (20A or EU2, first reported in continental Europe), B1.1.7 (α or 20I501Y.V1, first reported in the United Kingdom), B.1.351 (β or 20H/501Y.V2, first reported in South Africa), B.18.104.22.168 (γ or P.1 or 20J/501Y.V3, first reported in Brazil), and B.18.104.22.168 (ζ, or P.2 or 20B/S484K, also first reported in Brazil). From the analysis of a set of bonding descriptors firmly rooted in the formalism of quantum mechanics, including Natural Bond Orbitals (NBO), Quantum Theory of Atoms In Molecules (QTAIM) and highly correlated energies within the Domain Based Local Pair Natural Orbital Coupled Cluster Method (DLPNO-CCSD(T)), and from a set of computed electronic spectral patterns with environmental effects, we show that the new variants improve their ability to recognize available sites to either hydrogen bond or to form salt bridges with residues in the ACE2 receptor of the host cells. This results in significantly improved initial virus⋅⋅⋅cell molecular recognition and attachment at the microscopic level, which trigger the infectious cycle.


[Parietal manifestations of thoracic actinomycosis. Results in five cases (author's transl)].
The authors review five cases of actinomycosis with thoracic involvement, and emphasize the importance of parietal manifestations and their radiological appearance in the diagnosis of such cases. They refer particulary to the bone locations of the disease and mention rare oesophageal lesions and the development of systemico-pulmonary shunts.


Disrupted cortical network as a vulnerability marker for obsessive-compulsive disorder.
Morphological alterations of brain structure are generally assumed to be involved in the pathophysiology of obsessive–compulsive disorder (OCD). Yet, little is known about the morphological connectivity properties of structural brain networks in OCD or about the heritability of those morphological connectivity properties. To better understand these properties, we conducted a study that defined three different groups: OCD group with 30 subjects, siblings group with 19 subjects, and matched controls group with 30 subjects. A structural brain network was constructed using 68 cortical regions of each subject within their respective group (i.e., one brain network for each group). Both small-worldness and modularity were measured to reflect the morphological connectivity properties of each constructed structural brain network. When compared to the matched controls, the structural brain networks of patients with OCD indeed exhibited atypical small-worldness and modularity. Specifically, small-worldness showed decreased local efficiency, and modularity showed reduced intra-connectivity in Module III (default mode network) and increased interconnectivity between Module I (executive function) and Module II (cognitive control/spatial). Intriguingly, the structured brain networks of the unaffected siblings showed similar small-worldness and modularity as OCD patients. Based on the atypical structural brain networks observed in OCD patients and their unaffected siblings, abnormal small-worldness and modularity may indicate a candidate endophenotype for OCD.


Magnetic resonance imaging of brain death.
Fifteen patients with clinical diagnosis of brain death were examined by magnetic resonance (MR) imaging. Aortography with intraarterial digital subtraction angiography (IADSA) was also performed in nine patients. MR imaging indications of the flow void phenomenon were evaluated in the cavernous portion of internal carotid artery (ICA) and the middle or anterior cerebral artery, and compared with the IADSA findings. The relative intensities of gray and white matters were also measured. MR imaging showed that flow voids were absent in the ICA in all eight patients in whom non-filling was confirmed by IADSA. In one patient, IADSA demonstrated intracranial flow despite the diagnosis of brain death and the flow void pattern was normal. Serial MR imaging showed disappearance or abnormality of flow voids after brain death in six patients and absence before brain death in one. Spotty flow voids became visible in the unilateral ICA of one case after brain death. Partial residual flow voids may be caused by to-and-fro blood movement which was demonstrated by transcranial Doppler sonography. The normal flow void pattern was seen in none of these patients, therefore absence of flow voids indicates cessation of intracranial blood flow. Proton density and T2-weighted MR images showed dissociated intensity changes between white and gray matters, which were thought to be characteristic of brain death. In conclusion, MR imaging can achieve non-invasive diagnosis of the non-filling phenomenon in patients with brain death.


Characterization of rat T helper cell clones specific for Bacteroides gingivalis antigen.
During the past several years, much interest has been directed towards delineating and characterizing different subsets of T helper (Th) cells in order to understand their roles in immune processes. In this study, we report the generation of antigen-specific rat Th cell clones and their characterization in terms of phenotype, function, and lymphokine production. The clones were derived by culturing purified splenic T cells from rats immunized with the pathogen Bacteroides gingivalis with equivalent numbers of irradiated spleen cells from nonimmune rats and B. gingivalis whole-cell antigen. The clones required antigen stimulation but not exogenously added interleukin-2 for growth and were maintained in culture for approximately 6 months. The cloned T cells proliferated in response to the mitogen concanavalin A and to B. gingivalis whole-cell antigen but not to other microbial antigens. Phenotypic characterization of the cloned T cells for cell surface markers demonstrated that these cells were OX19+ W3/25+ OX8- OX22- and therefore probably represented a mature subpopulation of CD4+ Th cells. These cloned T cells were positive for interleukin-2 receptor expression. Culture supernatants from the Th cell clones which were collected at various times after antigen stimulation exhibited low interleukin-2 activity and high gamma interferon activity. This in vitro study provides evidence of a rat Th cell subset that could represent an important population in regulating immune responses to microbial antigens.


Nodular adrenal hyperplasia with elevated adrenocorticotropic hormone levels.
Micronodular adrenal hyperplasia is an uncommon adrenal disorder characterized by failure of urinary corticosteroid excretion to be suppressed by high-dose dexamethasone therapy. Thus, micronodular adrenal hyperplasia demonstrates dexamethasone suppressibility that resembles primary adrenal neoplasia. However, since some cases have been reported to have measurable plasma adrenocorticotropic hormone (ACTH) levels, it is unclear whether this disorder arises primarily in the pituitary-hypothalamic region or in the adrenal gland. Our patient had clinical features of Cushing's syndrome and elevated urinary corticosteroid excretion that did not suppress with even high doses of dexamethasone; however, ACTH levels were elevated and were suppressible with high-dose dexamethasone therapy. At operation, enlarged adrenal glands with multiple micronodules were found. This case is compatible with the hypothesis that hypothalamic-pituitary hyperfunction precedes the development of micronodular adrenal disease in some cases.


Sadness is unique: neural processing of emotions in speech prosody in musicians and non-musicians.
Musical training has been shown to have positive effects on several aspects of speech processing, however, the effects of musical training on the neural processing of speech prosody conveying distinct emotions are yet to be better understood. We used functional magnetic resonance imaging (fMRI) to investigate whether the neural responses to speech prosody conveying happiness, sadness, and fear differ between musicians and non-musicians. Differences in processing of emotional speech prosody between the two groups were only observed when sadness was expressed. Musicians showed increased activation in the middle frontal gyrus, the anterior medial prefrontal cortex, the posterior cingulate cortex and the retrosplenial cortex. Our results suggest an increased sensitivity of emotional processing in musicians with respect to sadness expressed in speech, possibly reflecting empathic processes.


The effect of gonadotropin-releasing hormone analog treatment (leuprolide) on body fat distribution in idiopathic central precocious puberty.
Gonadotropin-releasing hormone analog (GnRHa) therapy is used in idiopathic central precocious puberty (ICPP) worldwide. It has also been shown that during this therapy, body mass index (BMI) increases slightly as a side effect. We investigated the side effects of GnRHa treatment in ICPP on body composition and insulin resistance (IR). Twenty girls (7.55 +/- 1.02 y) with ICPP were treated with GnRHa (leuprolide) for an average of 20.83 +/- 4.8 months. Bioelectrical Impedance Analysis (BIA) was used to measure the body's fat balance. Nine patients out of 20 (45%) had significant gain weight. We showed a significant elevation in trunk fat mass compare to baseline values (p < 0.01). These nine patients had high homeostasis model assessment (HOMA)-IR and low glucose/insulin (G/I) index. This study showed a slight increase in BMI, moderate increase in total body fat, and exaggerated elevation in trunk fat mass and IR in GnRHa-treated ICPP children.


Sexually stimulating signals of canary (Serinus canaria) songs: evidence for a female-specific auditory representation in the HVc nucleus during the breeding season.
During the breeding season under long-day conditions, male canaries sing sexually attractive songs and females respond behaviorally to such songs. This study assessed whether auditory response properties of neurons in nucleus HVc of female and male canaries are tuned to sexually salient song features: special song phrases and canary song segmentation. In sexually receptive female canaries, neurons responded to special song phrases with a decreased spike rate and were sensitive to canary song segmentation. The nonreceptive females showed no clear response to special song phrases. In females on short days, neurons responded to song phrases with an increase in activity. In males on long days, they exhibited phasic responses after the phrase onset, whatever the song phrase and song segmentation. This study demonstrates both a plasticity in relation to females' sexual responsiveness and a sexual dimorphism in the auditory processing performed in the HVc.


A new flap from the dorsum of the first intermetacarpal area: the first dorsal intermetacarpal flap.
Soft-tissue reconstruction of the hand still remains a challenge for plastic and reconstructive surgeons. Several flaps have been described to cover soft-tissue defects of the digits and the hand. In the first web region, there are some communications between the intermediate artery arising from the dorsal branch of the radial artery and the volar arteries of the thumb and the index finger. Depending on these communications, a new distally based flap is raised from the first dorsal intermetacarpal area. This flap has been used to cover various defects of the thumb in four patients and the distal radial side of the palmar area in one patient. Donor sites have been closed primarily except in one patient. There were no complications, and the results show that this flap is useful to cover soft-tissue defects of the thumb and proximal phalanx of the index finger as well as the radial side of the palmar and dorsal surfaces of the hand.


Update on prognostic and predictive biomarkers for pancreatic neuroendocrine tumors.
Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. These tumors are often indolent but they have the potential to cause symptoms through release of hormones and through local or distant spread. Pancreatic neuroendocrine tumors (pNET) represent a subset of NETs and they have a unique pattern of symptoms and disease progression. Due to the heterogeneity of this disease it is important to identify reliable markers to help guide prognosis and predict response to therapy. The recent approval of two new agents in the treatment of advanced pNET has raised additional interest in the significance of molecular markers in this disease. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, several investigators reported on collaborative efforts to develop clinically useful biomarkers for this disease. Choti et al. (Abstract #4126) reported data about the functional characteristics of NETs and pNETs among a multi-institutional cohort finding that a substantial minority of patients have functional symptoms even when the disease is localized. Faggiano et al. (Abstract #1604) looked at a wide spectrum of NETs in several referral centers and reported on predictors of both short term and long term survival in this setting. Yao et al. (Abstract #4014) reported analysis of predictive biomarkers among patients in the RADIANT-2 trial which looked at the role of the mTOR inhibitor, everolimus compared to placebo in NET. Fischer et al. (Abstract #4128) looked at a novel biomarker, placental growth factor (PlGF) and evaluated the role of serum and tissue levels of this protein as a predictive marker. Finally, Khan et al. (Abstract #4123) investigated the role of circulating tumor cells in NET (and pNET) and found that this may have potential as a prognostic marker and an early marker of response to therapy. The authors review and summarize these abstracts in this article.


Tumor-Associated and Systemic Autoimmunity in Pre-Clinical Breast Cancer among Post-Menopausal Women.
Autoantibodies to tumor-associated antigens (anti-TAA) are potential biomarkers for breast cancer, but their relationship systemic autoimmunity as ascertained though antinuclear antibodies (ANA) is unknown and warrants consideration given the common occurrence of autoimmunity and autoimmune diseases among women. The relationship between anti-TAAs and ANA among women who were later diagnosed with breast cancer and others who remained cancer free in the Women's Health Initiative cohort. The study sample included 145 post-menopausal women with baseline ANA data. A total of 37 ANA-positive women who developed breast cancer (i.e., cases; mean time to diagnosis 6.8 years [SE 3.9]) were matched to a random sample of 36 ANA-negative cases by age and time to diagnosis. An age-matched control sample was selected including 35 ANA-positive and 37 ANA-negative women who did not develop breast cancer (i.e., controls; follow-up time ~13 years [SE 3]). Baseline sera were assessed for Immunoglobulin G (IgG) antibodies, measured by custom microarray for 171 breast and other cancer-associated TAA. We used linear regression to estimate cross-sectional associations of ANA with log-transformed anti-TAA among cases and controls. Most anti-TAA did not vary by ANA status. Two anti-TAA were elevated in ANA-positive compared to ANA-negative cases: anti-PGM3 (p = 0.004) and anti-TTN (p = 0.005, especially in cases up to 7 years before diagnosis, p = 0.002). Anti-TAA antibodies were not generally related to ANA, a common marker of systemic autoimmunity. Associations of ANA with particular antigens inducing autoimmunity prior to breast cancer warrant further investigation.


Intracellular calcium signalling patterns reflect the differentiation status of human T cells.
Stimulation of T lymphocytes results in the calcium-dependent activation and repression of a large number of genes. However, the functional response made by different T cell subsets is heterogeneous, as their differentiation results in alterations in their sensitivity to activation and in the secretion of cytokines. Here we have investigated the patterns of calcium responses in CD4 and CD8 T cell subsets to help explain their different responses to activation. CD4(+) CD45RA(+) T cells isolated freshly from human blood gave a sustained calcium signal after stimulation, but this was smaller than elicited in CD4(+) CD45RO(+) cells. On in vitro differentiation of CD4(+) CD45RA(+) cells to CD45RO(+), the level of the cytoplasmic calcium response rose initially, but then declined steadily during further rounds of differentiation. The proportion producing an oscillatory calcium response or not responding was increased and differentiation was accompanied by a shift in the calcium between intracellular pools. CD8(+) T cells gave a smaller calcium response than paired CD4(+) T cells and showed a difference in the numbers of cells giving a transient, rather than sustained, calcium signal. The increase in oscillating cells in the CD4(+) CD45RO(+) population may reflect the heterogeneity of this population, particularly in terms of cytokine production. The changing patterns of calcium responses in T cells as they differentiate may explain variation in the cellular response to activation at different stages in their lifespan and emphasize the importance of the both the quantity and the quality of the calcium signal in determining the outcome of T cell activation.


Gene flow and population structure of a solitary top carnivore in a human-dominated landscape.
While African leopard populations are considered to be continuous as demonstrated by their high genetic variation, the southernmost leopard population exists in the Eastern and Western Cape, South Africa, where anthropogenic activities may be affecting this population's structure. Little is known about the elusive, last free-roaming top predator in the region and this study is the first to report on leopard population structuring using nuclear DNA. By analyzing 14 microsatellite markers from 40 leopard tissue samples, we aimed to understand the populations' structure, genetic distance, and gene flow (Nm). Our results, based on spatially explicit analysis with Bayesian methods, indicate that leopards in the region exist in a fragmented population structure with lower than expected genetic diversity. Three population groups were identified, between which low to moderate levels of gene flow were observed (Nm 0.5 to 3.6). One subpopulation exhibited low genetic differentiation, suggesting a continuous population structure, while the remaining two appear to be less connected, with low emigration and immigration between these populations. Therefore, genetic barriers are present between the subpopulations, and while leopards in the study region may function as a metapopulation, anthropogenic activities threaten to decrease habitat and movement further. Our results indicate that the leopard population may become isolated within a few generations and suggest that management actions should aim to increase habitat connectivity and reduce human-carnivore conflict. Understanding genetic diversity and connectivity of populations has important conservation implications that can highlight management of priority populations to reverse the effects of human-caused extinctions.


Ketamine potentiates oxidative stress and influences behavior and inflammation in response to lipolysaccharide (LPS) exposure in early life.
Immune activation (IA) during the early neonatal period is a risk factor for the development of schizophrenia. Lipopolysaccharide (LPS) injected in neonates lead to behavioral and brain changes that persist to adult life. We investigated oxidative stress, levels of cytokines, and the locomotor activity of IA in a schizophrenia animal model in which neonatal male Wistar rats were administered with an injection of LPS (50μg/kg) on postnatal day 3 and different doses of ketamine (5, 15 and 25mg/kg) for 7days during adulthood. Rats LPS-induced did not have locomotor activity alterations. Locomotor activity was elevated in neonatally saline-injected in the higher dose ketamine-treated animals. Carbonyl protein in the prefrontal cortex (PFC), hippocampus and striatum were increased in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Lipid damage occurred in the PFC, striatum and hippocampus in the LPS- and saline-induced in the ketamine (15 and 25mg/kg) -treated animals. In the hippocampus the superoxide dismutase (SOD) was decreased in the LPS- and saline-induced in the ketamine-treated with the dose of 25mg/kg. In the PFC SOD was reduced in the LPS-induced in the ketamine (25mg/kg)-treated animals. Catalase in the PFC and hippocampus was reduced in the LPS- and saline-induced in the ketamine (25mg/kg)-treated animals. Pro- and anti-inflammatory cytokines were lower in the brains of LPS-induced in the higher dose ketamine-treated rats. IA influences the locomotor activity and cytokine levels induced by ketamine, and it has a negative effect in potentiating the oxidative stress by higher doses of ketamine in the brain.


Mosaic prophages with horizontally acquired genes account for the emergence and diversification of the globally disseminated M1T1 clone of Streptococcus pyogenes.
The recrudescence of severe invasive group A streptococcal (GAS) diseases has been associated with relatively few strains, including the M1T1 subclone that has shown an unprecedented global spread and prevalence and high virulence in susceptible hosts. To understand its unusual epidemiology, we aimed to identify unique genomic features that differentiate it from the fully sequenced M1 SF370 strain. We constructed DNA microarrays from an M1T1 shotgun library and, using differential hybridization, we found that both M1 strains are 95% identical and that the 5% unique M1T1 clone sequences more closely resemble sequences found in the M3 strain, which is also associated with severe disease. Careful analysis of these unique sequences revealed three unique prophages that we named M1T1.X, M1T1.Y, and M1T1.Z. While M1T1.Y is similar to phage 370.3 of the M1-SF370 strain, M1T1.X and M1T1.Z are novel and encode the toxins SpeA2 and Sda1, respectively. The genomes of these prophages are highly mosaic, with different segments being related to distinct streptococcal phages, suggesting that GAS phages continue to exchange genetic material. Bioinformatic and phylogenetic analyses revealed a highly conserved open reading frame (ORF) adjacent to the toxins in 18 of the 21 toxin-carrying GAS prophages. We named this ORF paratox, determined its allelic distribution among different phages, and found linkage disequilibrium between particular paratox alleles and specific toxin genes, suggesting that they may move as a single cassette. Based on the conservation of paratox and other genes flanking the toxins, we propose a recombination-based model for toxin dissemination among prophages. We also provide evidence that a minor population of the M1T1 clonal isolates have exchanged their virulence module on phage M1T1.Y, replacing it with a different module identical to that found on a related M3 phage. Taken together, the data demonstrate that mosaicism of the GAS prophages has contributed to the emergence and diversification of the M1T1 subclone.


Polysaccharides sulfated at the time of gastrulation in embryos of the sea urchin Clypeaster japonicus.
Based on the fact that the development of sea urchin embryos is arrested at the blastula stage in sulfate-free sea water (SFSW), we attempted in the present study to elucidate the nature of sulfated polysaccharides (PSs) which appear at the time of gastrulation in embryos of the sea urchin Clypeaster japonicus. Electrophoretic analysis of PSs prepared from embryos at different developmental stages revealed that three kinds of PSs (3A, 3B, 3C) appear de novo at the gastrula stage, and that these PSs are not found in embryos at the hatching blastula stage, nor are they found in permanent blastula reared in SFSW. These, three PSs were mostly of extracellular matrix origin. Among them, 3C was identified as dermatan sulfate on the basis of its electrophoretic mobility and sensitivity to enzymatic digestion. 3A and 3B remained to be identified. Further, a plausible precursor of 3C, which was sulfated under normal conditions, was detected as 6D in the embryos reared in SFSW. Autoradiographic analysis using [35S]sulfate revealed that these three PSs, accounted for more than 90% of [35S]sulfate incorporated into the acid PS fraction during gastrulation.


Regulation of abscisic acid signaling by the ethylene response pathway in Arabidopsis.
Although abscisic acid (ABA) is involved in a variety of plant growth and developmental processes, few genes that actually regulate the transduction of the ABA signal into a cellular response have been identified. In an attempt to determine negative regulators of ABA signaling, we identified mutants, designated enhanced response to ABA3 (era3), that increased the sensitivity of the seed to ABA. Biochemical and molecular analyses demonstrated that era3 mutants overaccumulate ABA, suggesting that era3 is a negative regulator of ABA synthesis. Subsequent genetic analysis of era3 alleles, however, showed that these are new alleles at the ETHYLENE INSENSITIVE2 locus. Other mutants defective in their response to ethylene also showed altered ABA sensitivity; from these results, we conclude that ethylene appears to be a negative regulator of ABA action during germination. In contrast, the ethylene response pathway positively regulates some aspects of ABA action that involve root growth in the absence of ethylene. We discuss the response of plants to ethylene and ABA in the context of how these two hormones could influence the same growth responses.


The association between chrononutrition behaviors and muscle health among older adults: The Study of Muscle, Mobility and Aging (SOMMA).
Emerging studies highlight chrononutrition's impact on body composition through circadian clock entrainment, but its effect on older adults' muscle health remains largely overlooked. To determine the associations between chrononutrition behaviors and muscle health in older adults. Dietary data from 828 older adults (76±5y) recorded food/beverage amounts and their clock time over the past 24 hours. Studied chrononutrition behaviors included: 1) The clock time of the first and last food/beverage intake; 2) Eating window (the time elapsed between the first and last intake); and 3) Eating frequency (Number of self-identified eating events logged with changed meal occasion and clock time). Muscle mass (D 3 -creatine), leg muscle volume (MRI), grip strength (hand-held dynamometer), and leg power (Keiser) were used as outcomes. We used linear regression to assess the relationships between chrononutrition and muscle health, adjusting for age, sex, race, marital status, education, study site, self-reported health, energy, protein, fiber intake, weight, height, and moderate-to-vigorous physical activity. Average eating window was 11±2 h/d; first and last intake times were at 8:22 and 19:22, respectively. After multivariable adjustment, a longer eating window and a later last intake time were associated with greater muscle mass (β±SE: 0.18±0.09; 0.27±0.11, respectively, P <0.05). The longer eating window was also marginally associated with higher leg power ( P =0.058). An earlier intake time was associated with higher grip strength (-0.38±0.15; P =0.012). Chrononutrition behaviors, including longer eating window, later last intake time, and earlier first intake time were associated with better muscle mass and function in older adults. Chrononutrition behaviors, including longer eating window, later last intake time, and earlier first intake time were associated with better muscle mass and function in older adults.


LAMP3 expression correlated with poor clinical outcome in human ovarian cancer.
Lysosome-associated membrane protein 3 belongs to the lysosome-associated membrane glycoprotein family, which is associated with lymph node, metastasis, poor overall survival, and resistance to chemotherapy and radiotherapy. Epithelial ovarian cancer is one of the most deadly global female gynecologic malignant tumors. Its clinical outcome is poor and most epithelial ovarian cancer patients tend to relapse because of drug resistance. However, lysosome-associated membrane protein 3 expression in epithelial ovarian cancer and its relationship between clinicopathologic factors remain poorly understood. To clarify the prognostic implications of lysosome-associated membrane protein 3 in epithelial ovarian cancer, we analyzed both messenger RNA and protein levels of lysosome-associated membrane protein 3 in ovarian carcinomas. Polymerase chain reaction results showed higher expression of lysosome-associated membrane protein 3 messenger RNA in epithelial ovarian cancer than in noncancerous tissues. Immunohistochemical results showed that high lysosome-associated membrane protein 3 cytoplasmic expression was significantly related to tumor grade ( p = 0.038), lymph node metastasis ( p = 0.049), metastasis ( p < 0.001), level of CA125 ( p = 0.030), and International Federation of Gynecology and Obstetrics (FIGO) ( p < 0.001). High lysosome-associated membrane protein 3 nuclear expression was significantly associated with tumor grade ( p = 0.046), tumor single or double (representative whether the tumor involving one or both ovaries) ( p = 0.016), metastasis ( p < 0.001), and FIGO stage ( p < 0.001). Survival analysis indicated that high lysosome-associated membrane protein 3 cytoplasmic expression (hazard ratio: 4.632, 95% confidence interval: 2.421-8.864; p < 0.001), patients' age (hazard ratio: 1.729, 95% confidence interval: 1.027-2.911; p = 0.039), and FIGO stage (hazard ratio: 2.049, 95% confidence interval: 1.113-3.774; p = 0.021) were significantly correlated with poor survival outcome of epithelial ovarian cancer patients.


[Lactoferrin in human lung tumors].
Immunodiffusion technique was used to study the lactoferrin (LF) distribution in human fetal, normal and tumour tissue extracts. If was found that LF concentration in lung tumour extracts was higher than in normal lung one. Indirect immunoperoxidase method revealed LF in alveolar macrophages of normal and tumour lung tissues, in afflux of these cells around the tumour cells, but never--in the original lung cancer cells. It is suggested that LF is not a lung tumour-associated antigen.


Post-stroke immunosuppression: Exploring potential implications beyond infections.
Stroke is a leading cause of mortality and disability. It occurs when cerebral blood flow is disrupted via vascular occlusion or rupture, causing tissue damage. Research has extensively examined the role of the immune response in stroke pathophysiology, focusing on infiltrated immune cells and inflammatory molecules. However, the stroke's impact on immune physiology remains underexplored. While initially stroke triggers the activation of peripheral inflammation, a subsequent profound immunosuppression occurs in a matter of hours/days. This response, potentially shielding the brain from excessive inflammation, significantly affects stroke patients. Beyond rendering patients more susceptible to infections, immunosuppression generates diverse consequences by disrupting immune system functions that are crucial for organ homeostasis. This review explores the effects of immunosuppression on stroke patients, shedding light on potential issues in immune organs such as the spleen and bone marrow, as well as non-immune organs like the small intestine, liver and heart. By synthesizing existing literature and offering additional insights, this manuscript highlights the multifaceted impact of post-stroke immunosuppression.


Cortical, thalamic, and amygdaloid projections of rat temporal cortex.
The cortical, thalamic, and amygdaloid connections of the rodent temporal cortices were investigated by using the anterograde transport of iontophoretically injected biocytin. Injections into area Te1 labeled axons and terminals in the ventral regions of the dorsal and ventral subnuclei of the medial geniculate complex, area Te3, the rostrodorsal part of area Te2, and the ventrocaudal caudate putamen. No amygdaloid labeling was observed. Thalamic projections from Te2 targeted the lateral posterior nucleus, the dorsal part of the dorsal subnucleus of the medial geniculate complex, and the peripeduncular nucleus. Corticocortical projections mainly terminated in the dorsal perirhinal cortex, but moderately dense projections were observed in medial and lateral peristriate cortex, and only light projections were observed to Te1 and Te3. Projections to these isocortical regions terminated in layers I and VI. Amygdaloid projections targeted the ventromedial subdivision of the lateral nucleus and the adjacent part of the anterior basolateral nucleus. Area Te3 was observed to project to the ventrolateral parts of the dorsal and ventral subnuclei of the medial geniculate complex, the dorsal perirhinal cortex, rostral Te2, and Te1. In the amygdala, labeled fibers and terminals were concentrated in the dorsolateral subdivision of the lateral nucleus. These data confirm that areas Te1 and Te3 are hierarchically organized cortical areas connected with auditory relay nuclei in the thalamus. Area Te2, in contrast, appears to be weakly connected with Te1 and Te3 but is heavily connected with the peristriate cortex and tectorecipient thalamic nuclei. Te2 appears to be a visually related cortical area. The data also indicate that projections from Te2 and Te3 target different subregions of the lateral nucleus and that Te2, but not Te3, projects to the basolateral nucleus.


Molecular evolution of GPCRs: Secretin/secretin receptors.
In mammals, secretin is a 27-amino acid peptide that was first studied in 1902 by Bayliss and Starling from the extracts of the jejunal mucosa for its ability to stimulate pancreatic secretion. To date, secretin has only been identified in tetrapods, with the earliest diverged secretin found in frogs. Despite being the first hormone discovered, secretin's evolutionary origin remains enigmatic, it shows moderate sequence identity in nonmammalian tetrapods but is highly conserved in mammals. Current hypotheses suggest that although secretin has already emerged before the divergence of osteichthyans, it was lost in fish and retained only in land vertebrates. Nevertheless, the cognate receptor of secretin has been identified in both actinopterygian fish (zebrafish) and sarcopterygian fish (lungfish). However, the zebrafish secretin receptor was shown to be nonbioactive. Based on the present information that the earliest diverged bioactive secretin receptor was found in lungfish, and its ability to interact with both vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide potently suggested that secretin receptor was descended from a VPAC-like receptor gene before the Actinopterygii-Sarcopterygii split in the vertebrate lineage. Hence, secretin and secretin receptor have gone through independent evolutionary trajectories despite their concurrent emergence post-2R. A functional secretin-secretin receptor axis has probably emerged in the amphibians. Although the pleiotropic actions of secretin are well documented in the literature, only limited information of its physiological functions in nonmammalian tetrapods have been reported. To decipher the structural and functional divergence of secretin and secretin receptor, functional characterization of the ligand-receptor pair in nonmammals would be the next perspective for investigation.


Unbalanced deoxyribonucleotide synthesis caused by methotrexate.
The effect of methotrexate on the free intracellular pools of thymidylate triphosphate (dTTP) and deoxyadenosine triphosphate (dATP) in normal human phytohaemagglutinin-transformed lymphocytes has been studied. Methotrexate caused a fall in the dTTP pool ranging from 38% to 88% and a rise in the dATP pool ranging from 24% to 185%.A rise in the free intracellular pool of dATP is thought to inhibit both rubonucleotide reduction and polynucleotide ligase, an enzyme concerned in DNA synthesis and repair. The hypothesis is suggested here that folate deficiency per se, as well as a functional folate deficiency induced by methotrexate may cause reduced DNA synthesis, megaloblastic changes, and chromosome abnormalities by producing a rise in the free intracellular pool of dATP as well as by causing a fall in free intracellular dTTP.


The importance of severity of arthrosis for the reliability of bone mineral density measurement in women.
The objective of this study is to investigate the effect of the severity of degenerative changes on measurements of A-P lumbar spines BMD values and to determine the reliability of DEXA measurements associated with severity of the disease on A-P lumbar spines BMD values using DEXA. The measurements using DEXA were taken from L2-L4 spines and femoral neck of total 271 female cases. One hundred and ten of them had mild arthrosis (Group 0), and 69 had severe arthrosis (Group 1). Ninety-two cases without arthrosis were chosen as control group (Group 2). The cases with arthrosic changes were grouped according to their degree of severity of arthrosis. The groups were compared two by two and Tukey multiple comparison test was used for the analysis of the difference of the means of the groups. The mean age of cases was 61.79, 61.84, and 60.47, respectively. The average height was 157.26, 155.93, and 15.92 cm while the average weight was 69.21, 70.78, and 71.45 kg, respectively. The mean body mass index (BMI) was 0.00283, 0.00291, and 0.00293, respectively. L2-L4 A-P spinal BMD values were 0.9870, 0.9848, and 1.0836 g/cm(2) while the femoral neck BMD values were 0.7964, 0.8056, and 0.8223 g/cm(2), respectively. There was no statistical significance between study and control groups in terms of age, weight, height, BMI, and BMD values obtained from femoral neck. However, lumbar region BMD values of the cases with severe arthrosis were statistically significantly high when compared with other two groups. The femoral neck measurement is the prominent alternative method in severe arthrosis while taking measurements from lumbar region is still the most appropriate method in cases with mild arthrosis without having giant osteophytes.


Phyloseq: a bioconductor package for handling and analysis of high-throughput phylogenetic sequence data.
We present a detailed description of a new Bioconductor package, phyloseq, for integrated data and analysis of taxonomically-clustered phylogenetic sequencing data in conjunction with related data types. The phyloseq package integrates abundance data, phylogenetic information and covariates so that exploratory transformations, plots, and confirmatory testing and diagnostic plots can be carried out seamlessly. The package is built following the S4 object-oriented framework of the R language so that once the data have been input the user can easily transform, plot and analyze the data. We present some examples that highlight the methods and the ease with which we can leverage existing packages.


Onset of gluconate-H+ symport in Schizosaccharomyces pombe is regulated by the kinases Wis1 and Pka1, and requires the gti1+ gene product.
In the fission yeast Schizosaccharomyces pombe, glucose represses onset of gluconate-H+ symport and inhibits transiently the activity of the symport protein. Wild-type cells harvested from high glucose medium take up gluconate very slowly and the rate of uptake is increased 150-fold in response to glucose starvation. Here it is shown that an intact cAMP cascade is necessary to prevent premature onset in the presence of high glucose concentrations. Cells which have lost either adenylate cyclase (Cyr1) or cAMP-dependent protein kinase (Pka1) transport gluconate up to 60-fold faster than wild-type cells when harvested from high glucose medium. Moreover, inactivation of the stress-sensing Wis1-Sty1 MAP kinase pathway, by loss of Wis1 MAP kinase kinase, diminishes 10-fold the onset of gluconate uptake in response to starvation. A mutant was identified showing a comparable phenotype. By complementation, the gti1+ (gluconate transport inducer 1) gene has been isolated. Disruption of gti1 reduces starvation-induced onset by a similar factor to that observed in wis1 delta cells. Cells over-expressing gti1+ induce gluconate uptake much faster resulting in a threefold higher uptake rate, although gti1+ does not code for the gluconate transport protein. In contrast to the repression of onset, transient downregulation of the gluconate symporter is independent of Pka1 activity and requires ongoing glucose influx. Addition of glucose to starved cyr1 delta cells reduces uptake 9-fold, whereas starved pka1 delta cells, which are able to synthesise cAMP, respond with a 60-fold decrease in transport.


Two distinct pathways supply anthranilate as a precursor of the Pseudomonas quinolone signal.
Pseudomonas aeruginosa is an opportunistic pathogen that causes serious infections in immunocompromised patients and those with cystic fibrosis (CF). This gram-negative bacterium uses multiple cell-to-cell signals to control numerous cellular functions and virulence. One of these signals is 2-heptyl-3-hydroxy-4-quinolone, which is referred to as the Pseudomonas quinolone signal (PQS). This signal functions as a coinducer for a transcriptional regulator (PqsR) to positively control multiple virulence genes and its own synthesis. PQS production is required for virulence in multiple models of infection, and it has been shown to be produced in the lungs of CF patients infected by P. aeruginosa. One of the precursor compounds from which PQS is synthesized is the metabolite anthranilate. This compound can be derived from the conversion of chorismate to anthranilate by an anthranilate synthase or through the degradation of tryptophan via the anthranilate branch of the kynurenine pathway. In this study, we present data which help to define the kynurenine pathway in P. aeruginosa and show that the kynurenine pathway serves as a critical source of anthranilate for PQS synthesis. We also show that the kyn pathway genes are induced during growth with tryptophan and that they are autoregulated by kynurenine. This study provides solid foundations for the understanding of how P. aeruginosa produces the anthranilate that serves as a precursor to PQS and other 4-quinolones.


The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma.
Ninety-two patients from 12 kindreds with hereditary medullary thyroid carcinoma (MTC) were evaluated. We sought to determine if the stimulated plasma calcitonin (CT) level at the time of diagnosis was of prognostic significance. The patients were divided into four groups according to their preoperative stimulated plasma CT levels (1) 250-1,000 pg/ml (n=25); (2) 1,000-5,000 pg/ml (n=36); (3) 5,000-10,000 pg/ml (n=8); (4) greater than 10,000 pg/ml (n=23). Compared between the four groups were several parameters, including incidence of regional lymph node metastases, incidence of residual MTC post-thyroidectomy (as indicated by increased (greater than 300 pg/ml) plasma CT levels after operation), incidence of distant metastases, and incidence of death. Also compared were the incidences of microscopic or gross MTC in thyroidectomy specimens. The incidence of regional lymph node involvement ranged from a minimum of one (4%) of 25 patients in Group 1 to 13 (57%) of 23 patients in Group 4. Similarly, plasma CT levels were elevated in only one (4%) of 25 patients in Group 1 compared to 14 (61%) of 23 patients in Group 4. There was no evidence of distant metastases or death in the patients in Groups 1, 2, or 3. In the 23 patients in group 4, however, four (17.4%) had distant metastases and two (8.7%) died of disease during the period of observation. Of th 25 patients in Group 1, MTC was evident only by microscopic examination in 14 (56%). Eleven (44%) of the patients in Group 1 had macroscopically evident medullary thyroid carcinoma. This is in contrast with patients in Group 4 where all 23 had grossly evident MTC. These data indicate that the stimulated plasma CT level at the time of diagnosis is an excellent prognostic indicator of the extent of a disease in patients with hereditary MTC. Aggressive screening of kindred members at risk is of critical importance for establishing the diagnosis and instituting therapy at a time when the neoplasm is confined to the thyroid gland.


Healthcare reform stews in Congressional pressure cooker.
The United States Congress responded to Americans' healthcare worries with more than 30 healthcare reform proposals in 1991. Each bill falls into one of three camps: incremental approaches that favor improvements in the current system, employer-based programs, and single-payer programs, which would funnel all funds through a public administrator. Although major reform is unlikely to pass through Congress in the next year, knowing the details of proposals from Congress and other groups helps provide a framework for discussion of healthcare reform.


Identification of a novel human B cell activation antigen involved in B cell growth factor-dependent proliferation.
The B6.4 mAb we present here identifies a novel activation Ag of B cell lineage. The B6.4 mAb was generated by immunizing mice with B cell growth factor (BCGF)-responding BA3 cells, and selected by its capability to block BCGF-induced proliferation of BA3 cells. The inhibitory effect of this antibody on BCGF-dependent proliferation was further confirmed by using normal activated B cells in the presence of exogenous BCGF derived from T cells or B cells. Furthermore, it did not affect IL-2-dependent proliferation of B cells. The expression of the B6.4 Ag, as analyzed by FACS, is restricted to in vitro activated B cells, and remains undetectable on resting B or T cells, PHA-activated T cells, and monocytes. The B6.4 Ag is also expressed on some lymphoblastoid B cell lines and most of the lymphomas and CLL of B cell origin; however, it did not express on pre-B cell ALL and plasma cell leukemias. The B6.4 Ag has a Mr of 35,000 Da, as determined by SDS-PAGE of radiolabeled immunoprecipitates from activated B cells. The B6.4 Ag is detectable on B cells as early as 8 h after activation, and precedes that of the IL-2R or transferrin R. All of these results suggest that the B6.4 Ag is an early activation Ag of B cells and is functionally related to a receptor of BCGF, but not IL-2.


An analysis of surgical shunts for the management of portal hypertension at Aga Khan University Hospital.
The objective of our study was to analyze the outcome of surgical shunts for the management of variceal bleeding associated with portal hypertension. This was a retrospective analysis carried out at The Aga Khan University Hospital, Karachi of medical records from Jan 1991--Dec 2001. The main outcome measures included morbidity and mortality associated with the surgical procedure, and the long term outcome in terms of recurrent bleeding. A total of 30 patients underwent a shunt procedure during the study period. The mean age was 35+/-13.75 years, with 22 (73%) males and 8 (27%) females. The indication for surgery was recurrent bleeding in 23 (77%) patients, and active bleeding refractory to endoscopic therapy in 7 (23%) patients. According to Child-Pugh classification, 19 (63%) patients were classified as Childs' A, 7 (23%) as Childs' B, and 4 (13%) as Childs' C. The surgical procedure included distal splenorenal shunt in 25 (83%), central splenorenal shunt in 3 (10%), and portocaval shunt in 2 (7%) cases. Five patients expired within 30 days of surgical intervention with mortality rate of 16%. Three of these patients were Childs' C, as compared to one each in Childs' A and B, the difference being statistically significant. Similarly, the frequency of encephalopathy and recurrent bleeding was also significantly higher in patients with Childs' class C. Surgical shunts may be considered as a reasonable alternative for long term control of recurrent variceal bleeding in patients with good hepatic reserve.


Optical Coherence Tomography Predictors of SIde Branch REstenosis after unprotected Left Main bifurcation angioplasty using double kissing crush technique (OP-SIBRE LM Study).
Among the two stent strategies, contemporary evidence favors double kissing crush technique (DKC) for complex unprotected distal left main bifurcation (UdLMB) lesions. However one of the major challenges to these lesions is side branch (SB) restenosis. Our aim was to identify optical coherence tomographic (OCT) characteristics that may predict SB restenosis (SBR) after UdLMB angioplasty using DKC technique. This was a single-center, retrospective study that included 60 patients with complex UdLMB disease, who underwent OCT-guided angioplasty using DKC technique. Angiographic follow-up was performed in all patients at 1 year to identify patients with SBR. Patients with SBR group were compared with patients without SBR (NSBR group) for OCT parameters during index procedure. Twelve (20%) patients developed SBR at 1-year follow-up. The SBR group had longer SB lesion (18.8 ± 3.2 vs. 15.3 ± 3.7 mm, p = 0.004) and neo-metallic carinal length (2.1 vs. 0.1 mm, p < 0.001) when compared to the NSBR group. Longer neo-metallic carinal length was associated with the absence of the dumbbell sign, presence of hanging stent struts across the SB ostium on OCT of final MB pullback. On multivariate regression analysis, SB distal reference diameter (DRD) and SB stent expansion were identified as independent predictors of SBR with SB-DRD of ≤2.8 mm (area under curve-0.73, sensitivity-83.3%, and specificity-62.5%) and SB stent expansion of ≤89% (area under curve-0.88, sensitivity-83.3%, and specificity- 81.2%) as the best cut off values to predict SBR. SB DRD and SB stent expansion are the OCT predictors of future SBR after UdLMB angioplasty using DKC technique.


Genetically Related Choriocarcinoma Developing 5 Yr After a Complete Hydatidiform Mole and Simulating a Cornual Ectopic Pregnancy.
Persistent gestational trophoblastic disease can arise from any type of antecedent pregnancy, including molar and tubal pregnancies. While most cases of persistent gestational trophoblastic disease present within the first year following initial diagnosis, recurrence has rarely been reported many years after initial diagnosis. Distinguishing recurrence from a new independent lesion is clinically important. A 25-yr-old woman presented with a mass in the right uterine cornu that was discontiguous with the endometrial cavity and was associated with an elevated serum human chorionic gonadotropin level. She had a history of an invasive complete hydatidiform mole with lung involvement treated with chemotherapy 5 yr prior. Wedge resection of the right cornu was performed due to concern for a cornual ectopic pregnancy. Pathologic evaluation demonstrated a choriocarcinoma. Molecular genotyping confirmed the tumor as recurrent disease genetically related to the prior complete hydatidiform mole. She completed 4 cycles of EMA-CO therapy, and has been disease-free with undetectable serum human chorionic gonadotropin level for 2 yr.


[Bacillus cereus pneumonia after thoracic trauma. Case report and review of the literature].
We report on the case of a pneumonia caused by Bacillus cereus in a patient who sustained severe thoracic trauma, fractures of ribs 3-12, left lung contusion and haematopneumothorax. Bronchoscopic alveolar lavage (BAL) performed on ICU day four helped identifying the underlying cause of pneumonia. Inspite of early diagnosis and antibiotic treatment with clindamycin, cefotaxim and tobramycin, which rapidly eliminated the bacteria from the patient's lungs, the patient eventually died from the severe underlying injuries. However, this case emphasises that early performed BAL and rapid microbiological staining techniques can help diagnose pneumonia in critically ill patients. We also review the literature on pulmonary infections caused by Bacillus cereus.


Arterial Stiffness, Genetic Risk, and Type 2 Diabetes: A Prospective Cohort Study.
We aimed to investigate prospective associations of pulse wave arterial stiffness index (ASI) and pulse pressure (PP) with type 2 diabetes (T2D) and assess the modifying effect of genetics. We included 152,611 participants free of diabetes and cardiovascular disease in the UK Biobank. All participants had ASI and blood pressure measurements collected at baseline visit. In total, 37 single nucleotide polymorphisms were used to calculate the genetic risk score (GRS) of T2D. During a median follow-up of 9.5 years, 3,000 participants developed T2D. Per-SD increase in ASI was associated with a 3% higher T2D risk (95% CI 2-4%). The hazard ratio (HR) (95% CI) of T2D was 1.58 (1.39-1.80) in the highest quintile group compared with the lowest quintile group of ASI. However, the association between PP and T2D was nonlinear. Compared with the lowest quintile group, the risk of T2D in higher quintile groups of PP was 0.91 (0.79-1.04), 0.98 (0.86-1.11), 1.15 (1.01-1.30), and 1.24 (1.10-1.41), respectively. Furthermore, we observed an interaction between ASI and genetic susceptibility to T2D, because the elevated HR of T2D associated with high ASI was more evident among participants with higher GRS of T2D (P interaction = 0.008), whereas the interaction between PP and GRS was nonsignificant (P interaction = 0.55). ASI was associated with an elevated risk of T2D in a dose-response fashion, whereas PP and T2D showed a nonlinear J-shaped association. Additionally, the association between ASI and T2D was partially strengthened by higher genetic susceptibility to T2D.


[Aortic stenosis : new developments in management].
Aortic stenosis (AS) is the most common valve disease in our countries; most often of degenerative origin, its prevalence is constantly increasing due to the aging of the population. Its development is a continuum ranging from aortic sclerosis to severe aortic stenosis, the diagnosis of which is essentially based on transthoracic echocardiography, which will allow classification into subcategories. Even if today no treatment makes it possible to prevent the progression of the disease, the management has clearly evolved with an increasingly important place for new approaches to valve replacement by the percutaneous route, and an indication of management at an increasingly early stage.


Brain white matter fiber tracts involved in post-transjugular intrahepatic portosystemic shunt hepatic myelopathy.
We aimed to detect alterations in diffusion characteristics of brain white matter in hepatic myelopathy (HM) patients. Liver cirrhosis patients with (n=25) and without (n=18) HM after transjugular intrahepatic portosystemic shunt and 26 healthy controls were enrolled in this study. All participants were scanned with diffusion tensor imaging on a 3T Siemens scanner. Tract-based spatial statistics analysis was used to detect abnormalities of intracranial white matter tracts. Correlations between clinical characteristics and diffusion metrics were also calculated. HM patients showed widespread decreased fractional anisotropy values in association fibers, callosal fibers, thalamic fibers, and limbic system fibers (P<0.01, family-wise error-corrected) compared with healthy controls. In addition, HM patients showed lower fractional anisotropy values in the corpus callosum, corona radiata, external capsule, and superior longitudinal fasciculus compared with cirrhosis patients without myelopathy (P<0.01, family-wise error-corrected). Furthermore, limb muscle strength grading was correlated with the diffusion characteristics of the corpus callosum and superior longitudinal fasciculus in HM patients (P<0.05). HM patients suffer from more distinct changes of white matter fiber tracts than cirrhosis patients without myelopathy. In addition, alterations of the corpus callosum and superior longitudinal fasciculus may be associated with the major motor disturbance in HM. Our finding may shed light on the underlying neuropathological mechanism of HM.


A proposal for a comprehensive grading of Parkinson's disease severity combining motor and non-motor assessments: meeting an unmet need.
Non-motor symptoms are present in Parkinson's disease (PD) and a key determinant of quality of life. The Non-motor Symptoms Scale (NMSS) is a validated scale that allows quantifying frequency and severity (burden) of NMS. We report a proposal for using NMSS scores to determine levels of NMS burden (NMSB) and to complete PD patient classification. This was an observational, cross-sectional international study of 935 consecutive patients. Using a distribution of NMSS scores by quartiles, a classification based on levels from 0 (no NMSB at all) to 4 (very severe NMSB) was obtained and its relation with Hoehn and Yahr (HY) staging, motor and health-related quality of life scales was analyzed. Concordance between NMSB levels and grouping based on clinician's global impression of severity, using categorical regression, was determined. Disability and HRQoL predictors were identified by multiple regression models. The distribution of motor and QoL scales scores by HY and NMSB levels was significantly discriminative. The difference in the classification of cases for both methods, HY and NMSB, was significant (gamma = 0.45; ASE = 0.032). Concordance between NMSB and global severity-based levels from categorical regression was 91.8%, (kappaw = 0.97). NMS score was predictor of disability and QoL. Current clinical practice does not address a need for inclusion of non-motor scores in routine assessment of PD in spite of the overwhelming influence of NMS on disability and quality of life. Our data overcome the problems of "pure motor assessment" and we propose a combined approach with addition of NMSB levels to standard motor assessments.


Training family practice residents in HIV care.
Although family physicians are likely to encounter patients at risk for or diagnosed with HIV, they rarely are trained in prevention and treatment techniques. From 1997 to 2000, the University of Minnesota developed and evaluated a longitudinal curriculum to train family practice residents in the prevention and comanagement of HIV disease. Five residency programs participated. The core curriculum was based on 18 teaching modules incorporated into the standard 3-year residency program and covers topics in prevention, diagnosis, and treatment of HIV disease. Residents were encouraged to participate in elective rotations of HIV clinical care, service, and research, as well as attend a Sexual Attitude Reassessment Seminar. Baseline and postcurriculum attitude and knowledge surveys were performed and scores were compared before and after completion of the curriculum, as well as between the participants and a historical control group of residents who graduated in 1997. During the 3 academic years from 1997 to 2000, 214 residents participated in the study. Entering classes did not differ in baseline knowledge. Residents' knowledge about HIV disease, attitudes, confidence, and intention to treat HIV-positive patients improved (p < 0.01). The yearly number of HIV enzyme-linked immunosorbent assay (ELISA) tests performed at the residency sites increased from 1145 to 1665 by the project's end. The HIV Curriculum Project provides a useful model of an interdisciplinary program for training family medicine residents in HIV/AIDS. The evaluation data provide an assessment of the curriculum itself and an important look at family practice residents' knowledge, attitudes, and performance related to HIV over time.


Essential role for STIM1/Orai1-mediated calcium influx in PDGF-induced smooth muscle migration.
We recently demonstrated that thapsigargin-induced passive store depletion activates Ca(2+) entry in vascular smooth muscle cells (VSMC) through stromal interaction molecule 1 (STIM1)/Orai1, independently of transient receptor potential canonical (TRPC) channels. However, under physiological stimulations, despite the ubiquitous depletion of inositol 1,4,5-trisphosphate-sensitive stores, many VSMC PLC-coupled agonists (e.g., vasopressin and endothelin) activate various store-independent Ca(2+) entry channels. Platelet-derived growth factor (PDGF) is an important VSMC promigratory agonist with an established role in vascular disease. Nevertheless, the molecular identity of the Ca(2+) channels activated by PDGF in VSMC remains unknown. Here we show that inhibitors of store-operated Ca(2+) entry (Gd(3+) and 2-aminoethoxydiphenyl borate at concentrations as low as 5 microM) prevent PDGF-mediated Ca(2+) entry in cultured rat aortic VSMC. Protein knockdown of STIM1, Orai1, and PDGF receptor-beta (PDGFRbeta) impaired PDGF-mediated Ca(2+) influx, whereas Orai2, Orai3, TRPC1, TRPC4, and TRPC6 knockdown had no effect. Scratch wound assay showed that knockdown of STIM1, Orai1, or PDGFRbeta inhibited PDGF-mediated VSMC migration, but knockdown of STIM2, Orai2, and Orai3 was without effect. STIM1, Orai1, and PDGFRbeta mRNA levels were upregulated in vivo in VSMC from balloon-injured rat carotid arteries compared with noninjured control vessels. Protein levels of STIM1 and Orai1 were also upregulated in medial and neointimal VSMC from injured carotid arteries compared with noninjured vessels, as assessed by immunofluorescence microscopy. These results establish that STIM1 and Orai1 are important components for PDGF-mediated Ca(2+) entry and migration in VSMC and are upregulated in vivo during vascular injury and provide insights linking PDGF to STIM1/Orai1 during neointima formation.


ATP synthases: cellular nanomotors characterized by LILBID mass spectrometry.
Mass spectrometry of membrane protein complexes is still a methodological challenge due to hydrophobic and hydrophilic parts of the species and the fact that all subunits are bound non-covalently together. The present study with the novel laser induced liquid bead ion desorption mass spectrometry (LILBID-MS) reports on the determination of the subunit composition of the F(1)F(o)-ATP synthase from Bacillus pseudofirmus OF4, that of both bovine heart and, for the first time, of human heart mitochondrial F(1)F(o)-ATP synthases. Under selected buffer conditions the mass of the intact F(1)F(o)-ATP synthase of B. pseudofirmus OF4 could be measured, allowing the analysis of complex subunit stoichiometry. The agreement with theoretical masses derived from sequence databases is very good. A comparison of the ATP synthase subunit composition of 5 different ATPases reveals differences in the complexity of eukaryotic and bacterial ATP synthases. However, whereas the overall construction of eukaryotic enzymes is more complex than the bacterial ones, functionally important subunits are conserved among all ATPases.


Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes.
The worldwide prevalence of type 2 diabetes (T2D) is increasing. Despite normal to higher bone density, patients with T2D paradoxically have elevated fracture risk resulting, in part, from poor bone quality. Advanced glycation endproducts (AGEs) and inflammation as a consequence of enhanced receptor for AGE (RAGE) signaling are hypothesized culprits, although the exact mechanisms underlying skeletal dysfunction in T2D are unclear. Lack of inducible models that permit environmental (in obesity) and temporal (after skeletal maturity) control of T2D onset has hampered progress. Here, we show in C57BL/6 mice that a onetime pharmacological intervention (streptozotocin, STZ) initiated in adulthood combined with high-fat diet-induced (HFD-induced) obesity caused hallmark features of human adult-onset T2D, including prolonged hyperglycemia, insulin resistance, and pancreatic β cell dysfunction, but not complete destruction. In addition, HFD/STZ (i.e., T2D) resulted in several changes in bone quality that closely mirror those observed in humans, including compromised bone microarchitecture, reduced biomechanical strength, impaired bone material properties, altered bone turnover, and elevated levels of the AGE CML in bone and blood. Furthermore, T2D led to the premature accumulation of senescent osteocytes with a unique proinflammatory signature. These findings highlight the RAGE pathway and senescent cells as potential targets to treat diabetic skeletal fragility.


An evaluation of radio frequency exposure from therapeutic diathermy equipment.
To assess the physiotherapist's exposure to radio frequency electromagnetic fields (RF) leaking from short wave diathermy equipment, we conducted on-site measurements of stray electric and magnetic fields (27.12 MHz) close to continuous wave (CW) short wave equipment. The results show that the operator's knees may have the highest exposure level for both electric field (E-field) and magnetic field (H-field) in the normal operating position, i.e., behind the device console. The whole-body E-field exposure normally does not exceed the 1992 IEEE recommended limit during a normal treatment session. On the other hand, the operator's whole-body exposure to H-field was barely below the recommended limit. Our data suggest little chance of immediate harmful effects of RF leakage from the diathermy. Nonetheless, physiotherapists should still be advised to remain at a distance of at least 20 cm from the electrodes and cables to avoid possible overexposure.