Antioxidant enzymes in ciprofibrate-induced oxidative stress.
To understand the mechanism of peroxisome proliferator-induced oxidative stress in non-mutagenic carcinogenesis, the effect of ciprofibrate, a peroxisome proliferator, on the activities and protein amounts of various antioxidant enzymes in different subcellular compartments was examined. Ciprofibrate treatment for short-term (3 weeks) as well as long-term (12 weeks) duration increased the total cellular catalase activity, whereas superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities were decreased significantly. Withdrawal of ciprofibrate from the diet did not normalize these activities. The observed decreases in total cellular SOD and GPX activities following ciprofibrate treatment were due to significant decreases in cytosolic CuZn SOD and GPX, whereas mitochondrial levels of Mn SOD and GPX were relatively unchanged. The peroxisomal CuZn SOD and GPX activities were increased significantly after both short- and long-term treatment, whereas catalase activity was reduced. Western blot analysis of cytoplasm for GPX and CuZn SOD showed a significant decrease in GPX and CuZn SOD proteins. Mitochondrial GPX protein was found to be slightly decreased, whereas Mn SOD protein levels did not show any significant change. The excessive production of H2O2 by oxidases and O2- by the cytochrome P450 enzyme system, along with the observed loss of antioxidant protection by loss of activities of catalase in peroxisomes and GPX and CuZn SOD in cytoplasm, may be the critical factors in peroxisomal proliferator-induced oxidative stress and initiation and promotion of carcinogenesis by this class of non-mutagenic agents. Both enzyme activities, as well as protein amounts of GPX and CuZn SOD, were higher in peroxisomes but lower in cytoplasm in ciprofibrate-treated liver as compared to control liver. The Mn SOD protein was decreased in peroxisomes, whereas mitochondrial Mn SOD was relatively unaffected in ciprofibrate-treated liver as compared to control. These observations suggest that the regulation of expression of peroxisomal CuZn SOD and Mn SOD is different from their counterparts in other cellular compartments.


Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat.
Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer.


Pulse electromagnetic fields effects on serum E2 levels, chondrocyte apoptosis, and matrix metalloproteinase-13 expression in ovariectomized rats.
Observe pulse electromagnetic fields (PEMFs) effects on ovariectomized (OVX) rats, to study the mechanisms of PEMFs therapy for postmenopausal osteoarthritis. Forty-eight female rats were exposed to PEMFs (PEMFs group), administrated E2 and placebo PEMFs (E group), or were treated with placebo PEMFs (OVX and Sham groups). The treatment duration was 30 days after which serum E2 levels, chondrocyte morphology, chondrocyte apoptosis and matrix metalloproteinases-13 expression in knee joint was analyzed. We observed differential chondrocyte formation in each group, and serum E2 content in the PEMFs and E group were significantly higher than the OVX group. The apoptosis index of chondrocytes and the positive index of MMP13 expression in the PEMFs group and E group were significantly lower than the OVX group. PEMFs has a systemic effect on estrogen metabolism in ovariectomized rats, then inhibit chondrocyte apoptosis and downregulate MMP13 expression of knee joint cartilage. It may be the mechanisms by which PEMFs therapy works for on postmenopausal osteoarthritis.


Double excitations within time-dependent density functional theory linear response.
Within the adiabatic approximation, time-dependent density functional theory yields only single excitations. Near states of double excitation character, the exact exchange-correlation kernel has a strong dependence on frequency. We derive the exact frequency-dependent kernel when a double excitation mixes with a single excitation, well separated from the other excitations, in the limit that the electron--electron interaction is weak. Building on this, we construct a nonempirical approximation for the general case, and illustrate our results on a simple model.


Sinus node recovery time and abnormal postpacing phase in the aged patients with sick sinus syndrome.
The sinus node function was evaluated by rapid atrial pacing in 35 aged patients (mean age 78.2 years) including 10 aged controls, 12 cases with various degrees of AV block, 6 with bradycardia-tachycardia syndrome (BTS), and 7 with sinus bradyarrhythmia (SB). AV block was further divided into A-H block (7 cases) and H-V block (5 cases) by His bundle electrogram which was simultaneously recorded with 3 leads of surface electrocardiogram. Sinus node recovery time (SRT) was measured and its maximum value (SRTmax) was selected from SRTs obtained after pacing with various rates and durations in each patient. SRTmax was also expressed as percentage of the control P-P interval (%SRTmax). For patients in whom the study was repeated 3 to 8 months later, %SRTmax was reproducible in 9 of 14 instances. Prolongation of SRT was not always observed as the rate and/or duration of pacing was increased. SRTmax and %SRTmax were 1,363 +/- 188 msec and 147 +/- 19% (mean +/- SD), respectively, for aged controls, 1,597 +/- 442 msec and 156 +/- 31% for patients with AV block, 2,087 +/- 1,315 msec and 203 +/- 132% for those with BTS, and 3,069 +/- 1,287 msec and 247 +/- 115% for those with SB. SRTmax exceeding the range for aged controls was noted in 4 of 7 cases (57%) with A-H block, 2 of 6 (33%) with BTS, and 5 of 7 (71%) with SB; normal SRT was not infrequently observed in patients with sick sinus syndrome, especially in those with BTS. Analysis of 10 consecutive atrial cycles following cessation of pacing revealed that in 8 cases the first P-P interval (SRT) was followed by longer ones in some occasions (secondary suppression). It was observed almost exclusively in patients with sick sinus syndrome. The possibility of this phenomenon to reflect another feature of sinus node abnormality was discussed.


The effectiveness of a training method using self-modeling webcam photos for reducing musculoskeletal risk among office workers using computers.
An intervention study was conducted to examine the effectiveness of an innovative self-modeling photo-training method for reducing musculoskeletal risk among office workers using computers. Sixty workers were randomly assigned to either: 1) a control group; 2) an office training group that received personal, ergonomic training and workstation adjustments or 3) a photo-training group that received both office training and an automatic frequent-feedback system that displayed on the computer screen a photo of the worker's current sitting posture together with the correct posture photo taken earlier during office training. Musculoskeletal risk was evaluated using the Rapid Upper Limb Assessment (RULA) method before, during and after the six weeks intervention. Both training methods provided effective short-term posture improvement; however, sustained improvement was only attained with the photo-training method. Both interventions had a greater effect on older workers and on workers suffering more musculoskeletal pain. The photo-training method had a greater positive effect on women than on men.


Application of filter paper method for collection of blood for MLPA test.
The results of MLPA test using serum and filter paper eluate have been compared in this paper. Testing 64 patient samples at 1:32 dilution, 31 were negative by both serum and eluate, 20 were positive by both, six were positive only by serum and one was positive only eluate. In six other cases eluate gave equivocal results while serum result was clearly positive. Some eluates negative at 1:32 dilution gave weak positive agglutination at 1:16 dilution.


Treatment of splenic marginal zone lymphoma: splenectomy versus rituximab.
Splenic marginal zone lymphoma (SMZL) is an uncommon indolent B-cell lymphoma causing marked splenic enlargement with CD20-rich lymphoma cells infiltrating blood and bone marrow. In the pre-rituximab era, the treatment of choice for patients with symptomatic splenomegaly or threatening cytopenia was splenectomy, since chemotherapy had limited efficacy. Responses to splenectomy occurred in approximately 90% of patients. However, SMZL patients are often elderly and poor surgical risks. Since approval of rituximab, treatment of such patients with the anti-CD20 antibody both alone or in combination with chemotherapy has shown remarkable responses. In retrospective series of rituximab monotherapy totaling 52 patients, including both chemotherapy-naive and -refractory patients, overall responses of 88% to 100% were noted with marked and prompt regression of splenomegaly and improvement of cytopenias. Sustained responses occurred both with and without rituximab maintenance in 60% to 88% of patients at 3 years. Relapsed patients responded to second courses of rituximab monotherapy. Overall survival was comparable to that reported following splenectomy. Rituximab in combination with purine nucleosides may provide further improvement in progression-free survival; however, confirmatory prospective trials are necessary. These results suggest that splenectomy should no longer be considered as initial therapy for SMZL but rather as palliative therapy for patients not responsive to immunotherapy with or without chemotherapy.


Involvement of IL-9 in Th17-associated inflammation and angiogenesis of psoriasis.
It is thought that a Th1/Th17-weighted immune response plays a predominant role in the pathogenesis of psoriasis. Our findings now indicate a link between IL-9, a Th2 and Th9 cytokine, and Th17 pathway in psoriasis. In K5.hTGF-β1 transgenic mice, exhibiting a psoriasis-like phenotype, we found increased IL-9R and IL-9 expression in the skin and intradermal IL-9 injection induced Th17-related inflammation. IL-9 also promoted angiogenesis and VEGF and CD31 overexpression in mice in vivo and increased tube formation of human endothelial cells in vitro. Injecting anti-IL-9 antibody into K5.hTGF-β1 transgenic mice not only diminished inflammation (including skin infiltration by T cells, monocytes/macrophages, and mast cells) and angiogenesis but also delayed the psoriasis-like skin phenotype. Notably, injection of anti-psoriatic acting anti-IL-17 antibody reduced skin IL-9 mRNA and serum IL-9 protein levels in K5.hTGF-β1 transgenic mice and prevented IL-9-induced epidermal hyperplasia and inflammation of the skin of wild type mice. In addition, we observed that IL-9R expression in lesional skin from psoriasis patients was markedly higher than in healthy skin from control subjects. Moreover, IL-9 significantly enhanced IL-17A production by cultured human peripheral blood mononuclear cells or CD4+ T cells, especially in psoriasis patients. Thus, IL-9 may play a role in the development of psoriatic lesions through Th17-associated inflammation and angiogenesis.


Outpatient EEG monitoring in the presurgical evaluation of patients with refractory temporal lobe epilepsy.
Most epilepsy centers obtain ictal EEG recordings to localize the epileptogenic zone during presurgical evaluations. Inpatient monitoring is standard practice but is expensive and can be inconvenient. The authors sought to determine whether outpatient monitoring can be safe and effective as the sole method of recording seizures in the presurgical evaluation of patients with refractory temporal lobe epilepsy. They reviewed the data of seven temporal lobectomy patients whose presurgical monitoring was performed entirely outside the hospital. Mean baseline seizure frequency was at least 9.1 seizures per week. An average of 7.4 seizures was recorded over 9.4 days of monitoring. Only one patient had any antiepileptic drug taper; none suffered any complications. After temporal lobectomy on the side of demonstrated ictal onset, postoperative follow-up averaged 5.5 years. At the most recent follow-up, all patients were either seizure free or had only rare disabling or nocturnal seizures (four patients had outcomes in Engel's class I and three patients in Engel's class II). A comparison group who underwent standard inpatient monitoring was similar in average seizure frequency, monitoring duration, number of seizures recorded, and postoperative outcome, although all but one had antiepileptic drugs tapered during monitoring. The authors conclude that there is a subset of patients for whom solely outpatient presurgical EEG monitoring can be used to help plan successful temporal lobectomy.


Effect of mouse hepatitis virus infection on combination therapy of P388 leukemia with cyclophosphamide and pyrimidinones.
At least three marked differences were noted in the results compared from two parallel experiments using identical protocols with virus-free mice and mouse hepatitis virus (MHV) infected mice inoculated with P388 leukemia. First, the therapeutic effect of cyclophosphamide (CY), a cytotoxic antitumor drug, was apparently augmented in MHV-infected mice. A 162% increase of life span (ILS) was obtained in MHV-infected mice compared to a 100% ILS in uninfected mice. Second, the experimental error in terms of the range of animal survival time was much larger with MHV-infected mice than with uninfected mice. In MHV-infected mice, the therapeutic effect of the combination treatment with CY and pyrimidinone was not statistically different from that of the treatment with CY alone. In uninfected mice, the effects of the combination therapy at all doses of pyrimidinone were statistically more effective than that of CY treatment alone.


Chronic alcohol ingestion alters claudin expression in the alveolar epithelium of rats.
Previously we determined that chronic alcohol ingestion (6 weeks) in rats increases lung epithelial permeability in vivo approximately 5-6-fold and promotes flooding of the alveolar airspaces with proteinaceous fluid in response to stresses such as sepsis. In parallel, alveolar epithelial cells isolated from alcohol-fed rats fail to form tight monolayers in vitro, even when cultured for up to 8 days in the absence of alcohol. However, the molecular mechanisms underlying alcohol-induced permeability are unknown. Claudins are key components of tight junctions that restrict the paracellular movement of water, proteins, and solutes across cellular barriers including the alveolar epithelium. In this study, we examined the expression of multiple members of the claudin protein family in the lungs of alcohol-fed versus control-fed rats (Lieber-DeCarli liquid diet with either 36% of calories as alcohol or an isocaloric substitution with maltin-dextrin for 6 weeks). We determined that chronic alcohol ingestion affected the expression of multiple claudins; most striking were decreases in claudin-1 and claudin-7, and an increase in claudin-5, in the whole lung and in alveolar epithelial monolayers derived from alcohol-fed rats. In parallel, immunocytochemistry of alveolar epithelial monolayers from alcohol-fed rats revealed abnormal intracellular accumulation of claudin-7 protein and relatively decreased localization to cell membranes. Claudin-1 and claudin-7 are relatively specific to alveolar epithelial type I pneumocytes that form the vast majority of the alveolar epithelial barrier in vivo, and increases in claudin-5 have been associated with increased epithelial permeability in other systems. Therefore, these findings suggest that changes in claudin expression in the alveolar epithelium produce a "leakier" phenotype that renders the alcoholic lung susceptible to alveolar flooding during acute inflammatory stresses.


A stochastic version of corticosteriod pharmacogenomic model.
The purpose of this study was to develop a stochastic version of corticosteriod fifth generation pharmacogenomic model. The Gillespie algorithm was used to generate the independent time courses of the receptor messenger RNA (mRNA). Initial parameters for the stochastic simulation were adapted from the study by Jin et al. The result obtained from the proposed stochastic model showed an overall agreement with the deterministic fifth generation model. This study suggested that because the stochastic model takes into account the "noise" nature of gene regulation, it would have potential application in pharmacogenomic modeling.


Estrogen receptor α protects pancreatic β-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress.
Estrogen receptor α (ERα) action plays an important role in pancreatic β-cell function and survival; thus, it is considered a potential therapeutic target for the treatment of type 2 diabetes in women. However, the mechanisms underlying the protective effects of ERα remain unclear. Because ERα regulates mitochondrial metabolism in other cell types, we hypothesized that ERα may act to preserve insulin secretion and promote β-cell survival by regulating mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this hypothesis using pancreatic islet-specific ERα knockout (PERαKO) mice and Min6 β-cells in culture with Esr1 knockdown (KD). We found that Esr1-KD promoted reactive oxygen species production that associated with reduced fission/fusion dynamics and impaired mitophagy. Electron microscopy showed mitochondrial enlargement and a pro-fusion phenotype. Mitochondrial cristae and endoplasmic reticulum were dilated in Esr1-KD compared with ERα replete Min6 β-cells. Increased expression of Oma1 and Chop was paralleled by increased oxygen consumption and apoptosis susceptibility in ERα-KD cells. In contrast, ERα overexpression and ligand activation reduced both Chop and Oma1 expression, likely by ERα binding to consensus estrogen-response element sites in the Oma1 and Chop promoters. Together, our findings suggest that ERα promotes β-cell survival and insulin secretion through maintenance of mitochondrial fission/fusion-mitophagy dynamics and EndoRetic function, in part by Oma1 and Chop repression.


Post-infectious disease syndrome.
Many post-infectious syndromes have been recognized in the last 50 years, some following viral infections and others closely related to bacterial disease. The occurrence of prolonged fatigue following an apparent viral illness of varying severity is also well documented. The lack of a recognizable precipitating cause and the tendency for epidemic fatigue to occur among hospital staff led many to believe that the illness may be psychogenic in origin. However, there is serological evidence that some cases may follow enterovirus infections or occasionally delayed convalescence from infectious mononucleosis. Much interesting work is currently in progress relating fatigue to persisting immunological abnormalities, and the development of molecular immunology makes this a most exciting field of research. This paper reviews the evidence for and against a definitive post-viral fatigue syndrome and examines the results of research carried out in the last 50 years.


Quantifying the critical thickness of electron hybridization in spintronics materials.
In the rapidly growing field of spintronics, simultaneous control of electronic and magnetic properties is essential, and the perspective of building novel phases is directly linked to the control of tuning parameters, for example, thickness and doping. Looking at the relevant effects in interface-driven spintronics, the reduced symmetry at a surface and interface corresponds to a severe modification of the overlap of electron orbitals, that is, to a change of electron hybridization. Here we report a chemically and magnetically sensitive depth-dependent analysis of two paradigmatic systems, namely La1-xSrxMnO3 and (Ga,Mn)As. Supported by cluster calculations, we find a crossover between surface and bulk in the electron hybridization/correlation and we identify a spectroscopic fingerprint of bulk metallic character and ferromagnetism versus depth. The critical thickness and the gradient of hybridization are measured, setting an intrinsic limit of 3 and 10 unit cells from the surface, respectively, for (Ga,Mn)As and La1-xSrxMnO3, for fully restoring bulk properties.


[Left main coronary artery aneurysm detected by myocardial scintigraphy, coronary angiography and multislice computed tomography].
Aneurysm of the left main coronary artery is rare and is found in 0.1% of angiograms. A case of left main coronary aneurysm with no flow-limiting atherosclerotic coronary disease in a 53-year-old male is reported. In the history only a familial hypercholesterolemia was present. After some episodes of angina at rest and positive troponin, exercise myocardial scintigraphy detected a septal and inferior defect only after stress. Coronary angiography reveals an aneurysmal dilation of the left trunk involving the origin of the left anterior descending and left circumflex coronary arteries, also detected at multislice computed tomography. No intracranial or abdominal aneurysm was associated. The patient was treated medically with anticoagulant medication, low doses of beta-blockers and statins, with no adverse events at 2 and 4 months of follow-up.


Association of clinically significant weight loss with number of patient visits and months of attendance at an Australian multidisciplinary weight management clinic.
Despite the obesity epidemic, there are relatively few multidisciplinary obesity services in Australia, and only limited data on the effectiveness of these services. The aim of this study was to evaluate the effectiveness of a university hospital-based weight management clinic-the 'Healthy Weight Clinic' in supporting patients to achieve clinically significant weight loss (≥5% reduction in body weight), weight maintenance, and changes in body composition. A retrospective review was conducted to determine weight and associated health outcomes in patients who attended an initial consultation in the first 2 years of the clinic-between March 2017 and March 2019. Follow up was at least 1 year for all patients. Patients who underwent bariatric surgery were excluded. Of 213 total patients, 172 patients attended more than one follow-up consultation for lifestyle modification. Mean weight change and percentage total weight change at last follow-up was -6.2 kg (SD 7.4) and - 6.0% (SD 6.9), respectively. For every additional clinic follow-up, there was 21.4% increased odds of achieving clinically significant weight loss, and for every additional month of follow-up, there was 10.1% increased odds of achieving clinically significant weight loss. Twenty percent of patients (34/172) maintained ≥5% of initial body weight loss for at least 1 year. Body composition measurements were also favourable, with significant changes in percentage skeletal muscle mass of +0.8% (SD 1.5) and in percentage fat mass by -1.4% (SD 3.2). Regular support in a structured holistic multidisciplinary obesity service enables patients to achieve clinically meaningful weight loss and improved skeletal muscle mass to body fat ratio, and maintain this loss for at least 1 year. Improved weight loss was associated with more patient visits and longer duration of attendance at the clinic.


A randomized clinical trial to examine enhancing cognitive-behavioral group therapy for obsessive-compulsive disorder with motivational interviewing and thought mapping.
Obsessive-compulsive disorder (OCD) is characterized by repeated and persistent attempts to control thoughts and actions with rituals. These rituals are used in order to prevent feared or personally distressing outcomes. Cognitive behavioral group therapy (CBGT) has been reported to be effective for treating OCD patients. However, about one-third (30%) of patients do not benefit from CBGT. Some of these patients do not show significant improvement and continue to use rituals following CBGT, partially because they fail to complete the exposure and ritual prevention (ERP) exercises. Consequently, it is important to motivate patients to fully engage in CBGT treatment and complete the ERP exercises. A randomized behavioral trial examined 12 weeks of manual directed CBGT, with the addition of individual sessions of Motivational Interviewing (MI) and Thought Mapping (TM), and compared treatment outcome to the effectiveness of CBGT group alone. Subjects were randomized (n=93) into a CBGT group or a CBGT group with MI+TM. When the two groups were compared, both groups reduced OCD symptoms. However, symptom reduction and remission were significantly higher in the MI+TM CBGT group. Positive outcomes were also maintained, with additional symptom reduction at the 3-month follow-up for the MI+TM CBGT group. Adding two individual sessions of MI and TM before CBGT successfully reduced OCD symptoms and was more effective than using CBGT group alone.


Enabling Broader Adoption of Biocatalysis in Organic Chemistry.
Biocatalysis is becoming an increasingly impactful method in contemporary synthetic chemistry for target molecule synthesis. The selectivity imparted by enzymes has been leveraged to complete previously intractable chemical transformations and improve synthetic routes toward complex molecules. However, the implementation of biocatalysis in mainstream organic chemistry has been gradual to this point. This is partly due to a set of historical and technological barriers that have prevented chemists from using biocatalysis as a synthetic tool with utility that parallels alternative modes of catalysis. In this Perspective, we discuss these barriers and how they have hindered the adoption of enzyme catalysts into synthetic strategies. We also summarize tools and resources that already enable organic chemists to use biocatalysts. Furthermore, we discuss ways to further lower the barriers for the adoption of biocatalysis by the broader synthetic organic chemistry community through the dissemination of resources, demystifying biocatalytic reactions, and increasing collaboration across the field.


The Impact of Perioperative Hormonal Therapy for Breast Cancer on Transverse Rectus Abdominis Myocutaneous Flap Abdominal Complications.
The pedicled transverse rectus abdominis myocutaneous (TRAM) flap is a reliable reconstructive option in breast cancer patients; however, it carries known risk of donor site hernia formation. Some hormonal therapy drugs have been associated with hernia formation in animal models. Minimal data exist concerning impact of hormonal therapy for breast cancer on abdominal donor site complications after breast reconstruction. Patients who underwent TRAM flap for breast cancer or high-risk status at a single institution by the senior author from 2003 to 2015 were identified. Charts were reviewed. Patient demographics, comorbidities, treatments, and abdominal complications were recorded. Patients were divided into groups based on use of hormonal therapy as well as exposure to specific drugs. Statistical analyses were performed. A total of 358 patients were included. Overall hernia rate was 5.9%. About 231 (64.5%) patients had hormonal therapy, whereas 127 (35.5%) did not. Difference in hernia formation was not statistically significant between the hormonal therapy group (6.9%) and the no hormonal therapy group (3.9%; P = 0.359). Patients exposed to tamoxifen and those exposed to anastrozole had no significant difference in complication rates compared with the no hormonal therapy group, whereas patients exposed to letrozole had increased rate of hernia (13.5%; P = 0.037) and infection (21.6%; P = 0.013) compared with the no hormonal therapy group (3.9% and 7.1%, respectively). Hormonal therapy is a useful adjunct for chemoprevention in breast cancer; however, use of letrozole in patients undergoing reconstruction with pedicled TRAM can lead to increase in certain complication rates.


Chromatography-based methods for determining molar extinction coefficients of cytotoxic payload drugs and drug antibody ratios of antibody drug conjugates.
UV spectrophotometry is widely used to determine the molar extinction coefficients (MECs) of cytotoxic drugs as well as the drug antibody ratios (DARs) of antibody drug conjugates (ADCs). However, the unknown purity of a drug due to interfering impurities can lead to erroneous MECs and DARs. Hence, reliable methods to accurately determine purity and the MECs of drugs with limited quantity is urgently needed in Drug Discovery. Such a method has been developed. It achieves absolute purity and accurate MEC determination by a single automated HPLC analysis that uses less than 5μg of material. Specifically, analytical HPLC separation with online UV detection was used to resolve impurities and measure absorbance from only the compound of interest. Simultaneously, an online chemiluminescence nitrogen detector (CLND) was used to determine the concentration of the analyte. The MECs were then calculated from the absorbance and concentration results. The accuracy of the method was demonstrated using caffeine and a commercial cytotoxic drug, DM1. This approach is particularly suited to analyzing mixtures or samples with low purities. Excellent reproducibility was demonstrated by analyzing a proprietary drug with linker synthesized from different batches with very different levels of purity. In addition, the MECs of drug with linker, along with ADC peak areas measured from size exclusion chromatography (SEC), were used to calculate DARs for 21 in-house ADCs. The DAR results were consistent with those obtained by MS analysis.


Analysis of metastatic involvement in bone using anatomical and functional information from 18F-FDG PET/CT.
Although the overall incidence of bone metastasis is not known, over one-half of the people who die of cancer in the USA every year are thought to have bone involvement. In this study we have developed a method to quantify the metabolic and anatomic changes induced by different types of bone metastases in cancer patients using PET/CT images. Seventy-three cancer patients with no previous history of chemotherapy or radiotherapy who had definite bone metastases documented by PET/CT and other conventional modalities were selected for this study. PET and computed tomography (CT) images were resampled to the same pixel size. Thereafter, the bone structure was segmented using thresholding. The 50% of the maximum standardized uptake value within the bone mask was used to identify bone lesions in each slice. Using the final regions of interest defined at 70% of the maximum, the lesion characteristics including the mean Hounsfield Units were computed from the PET/CT images. The lesions were subjected to visual confirmation by an experienced physician who also categorized them on the basis of the appearances in CT as lytic, sclerotic, mixed, or no-change type. The lesion characteristics were compared using statistical methods. In all, 340 bony lesions in 73 patients with different cancer types were analyzed. The lesions were further categorized into four groups on the basis of their anatomical location. The spine hosts the largest number of lesions. The lumbar bones are the most preferential sites within the spine. Statistical comparison of CT values indicated that the difference between no-change and lytic types was significant. Uptake period did not seem to have a significant impact on no-change and sclerotic types. Quantitatively, maximum standardized uptake value for lytic, no change, mixed, and sclerotic lesions were 7.4, 6.1, 8.2, and 7.2, respectively. A quantitative method provides a convenient way that may serve as a useful tool in monitoring and assessing the response to therapy.


Qualitative Video Analysis of Track-Cycling Team Pursuit in World-Class Athletes.
Track-cycling team pursuit (TP) is a highly technical effort involving 4 athletes completing 4 km from a standing start, often in less than 240 s. Transitions between athletes leading the team are obviously of utmost importance. To perform qualitative video analyses of transitions of world-class athletes in TP competitions. Videos captured at 100 Hz were recorded for 77 races (including 96 different athletes) in 5 international track-cycling competitions (eg, UCI World Cups and World Championships) and analyzed for the 12 best teams in the UCI Track Cycling TP Olympic ranking. During TP, 1013 transitions were evaluated individually to extract quantitative (eg, average lead time, transition number, length, duration, height in the curve) and qualitative (quality of transition start, quality of return at the back of the team, distance between third and returning rider score) variables. Determination of correlation coefficients between extracted variables and end time allowed assessment of relationships between variables and relevance of the video analyses. Overall quality of transitions and end time were significantly correlated (r = .35, P = .002). Similarly, transition distance (r = .26, P = .02) and duration (r = .35, P = .002) were positively correlated with end time. Conversely, no relationship was observed between transition number, average lead time, or height reached in the curve and end time. Video analysis of TP races highlights the importance of quality transitions between riders, with preferably swift and short relays rather than longer lead times for faster race times.


A really quick easy cheap effective rugged and safe (QuEChERS) extraction procedure for the analysis of particle-bound PAHs in ambient air and emission samples.
A quick easy cheap effective rugged and safe (QuEChERS) like extraction procedure is presented for the measurement of polycyclic aromatic hydrocarbons (PAHs) associated to particulate matter from ambient air or combustion process. The procedure is based on a short mechanical agitation (vortex during 90 s) using a small volume of acetonitrile (7 ml) as extraction solvent. Equivalent extraction efficiencies were obtained when comparing the QuEChERS and the traditional pressurized solvent extraction (ASE) procedures for ambient air and emission (wood combustion) filter samples. The developed QuEChERS extraction protocol was validated with the analysis of a standard reference material (NIST SRM 1649a, urban dust). By comparison to other extraction methods including ASE, the simplicity of the QuEChERS protocol allows to minimize experimental errors, to decrease about a factor 5 the cost per extraction and to increase the productivity per working day by a 10-fold factor. This paper constitutes the first report on the applicability of a QuEChERS-like approach for the quantification of PAHs or other organic compounds in atmospheric particulate matter.


Protease-activated indocyanine green nanoprobes for intraoperative NIR fluorescence imaging of primary tumors.
Tumor-targeted fluorescent probes in the near-infrared spectrum can provide invaluable information about the location and extent of primary and metastatic tumors during intraoperative procedures to ensure no residual tumors are left in the patient's body. Even though the first fluorescence-guided surgery was performed more than 50 years ago, it is still not accepted as a standard of care in part due to the lack of efficient and non-toxic targeted probes approved by regulatory agencies around the world. Herein, we report protease-activated cationic gelatin nanoparticles encapsulating indocyanine green (ICG) for the detection of primary breast tumors in murine models with high tumor-to-background ratios. Upon intravenous administration, these nanoprobes remain optically silent due to the energy resonance transfer among the bound ICG molecules. As the nanoprobes extravasate and are exposed to the acidic tumor microenvironment, their positive surface charges increase, facilitating cellular uptake. The internalized nanoprobes are activated upon proteolytic degradation of gelatin to allow high contrast between the tumor and normal tissue. Since both gelatin and ICG are FDA-approved for intravenous administration, this activatable nanoprobe can lead to quick clinical adoption and improve the treatment of patients undergoing image-guided cancer surgery.


Cardiac Magnetic Resonance for the Evaluation of Suspected Cardiac Thrombus: Conventional and Emerging Techniques.
We present the conventional cardiac magnetic resonance (CMR) protocol for evaluating a suspected thrombus and highlight emerging techniques. The appearance of a mass on certain magnetic resonance (MR) sequences can help differentiate a thrombus from competing diagnoses such as a tumor. T1 and T2 signal characteristics of a thrombus are related to the evolution of hemoglobin properties. A thrombus typically does not enhance following contrast administration, which also helps differentiation from a tumor. We also highlight the emerging role of T1 mapping in the evaluation of a thrombus, which can add another level of support in diagnosis. Prior to any CMR exam, patient screening and interviews are critical to ensure safety and to optimize patient comfort. Effective communication during the exam between the technologist and the patient promotes proper breath holding technique and higher quality images. Volumetric post processing and structured reporting are helpful to ensure that the radiologist answers the ordering services' question and communicates these results effectively. Optimal pre-MR safety evaluation, CMR exam execution, and post exam processing and reporting allow for delivery of high quality radiological service in the evaluation of a suspected cardiac thrombus.


Comparison of the anesthetic effects of 2,2,2-tribromoethanol on ICR mice derived from three different sources.
This study was conducted to compare the anesthetic effects of 2,2,2-tribromoethanol (TBE, Avertin®) in ICR mice obtained from three different sources. TBE (2.5%) was intraperitoneally injected at three doses: high-dose group (500 mg/kg), intermediate-dose group (250 mg/kg), and low-dose group (125 mg/kg). Anesthesia time, recovery time, end-tidal peak CO2 (ETCO2), mean arterial blood pressure, heart rate, oxygen saturation (SpO2), body temperature, pH, PCO2, and PO2 of the arterial blood were measured. Stable anesthesia was induced by all doses of TBE and the anesthesia time was maintained exhibited dose dependency. No significant differences in anesthetic duration were found among the three different strains. However, the anesthesia time was longer in female than in male mice, and the duration of anesthesia was significantly longer in female than in male mice in the high-dose group. The recovery time was significantly longer for female than male mice in the intermediate- and high-dose groups. In the ICR strains tested, there were no significant differences in the mean arterial blood pressure, SPO2, arterial blood PCO2, and PO2, which decreased after TBE anesthesia, or in heart rate and ETCO2, which increased after TBE anesthesia. In addition, body temperature, blood biochemical markers, and histopathological changes of the liver, kidney, and lung were not significantly changed by TBE anesthesia. These results suggested that ICR mice from different sources exhibited similar overall responses to a single exposure to TBE anesthesia. In conclusion, TBE is a useful drug that can induce similar anesthetic effects in three different strains of ICR mice.


Virtual Pediatric Emergency Department Telehealth Network Program: A Case Series.
Pediatric patients living in rural, underserved areas have reduced access to medical care. There is a lack of research describing the use of telemedicine (TM) for general pediatric emergency medicine (PEM). In 2013, we established the Child Ready Virtual Pediatric Emergency Department Telehealth Network (CR-VPED), a PEM TM consultation service serving rural hospitals across the state of New Mexico. The aim of this article is to describe our experience for 6 years (2013-2018). We describe the process of establishing the CR-VPED Telehealth Network. We reviewed all the TM consultations completed from June 22, 2013, to September 6, 2018. In our review, we focus on patient demographics, medical complaint, transfer status, type of referring provider, and problems encountered with each TM consultation. We had a total of 58 PEM TM consultations between June 22, 2013, and September 6, 2018. All consultations occurred at 6 of the 12 established sites. Most TM consultations (71%; 41/58) were with Indian Health Service sites. Among all TM consultations, patients ranged in age from 30 days to 17 years (mean, 54 months; median, 32 months). Only 26% (15/58) of the patients with TM consultations were transferred to the tertiary care hospital. There was a heterogeneous mix of chief complaints and diagnoses. Rash was the most common chief complaint (24%; 14/58). There was a mix of referring providers, with family medicine physicians being most common (31%; 18/58). Common technical issues were not properly recording the encounter into the electronic medical record (12%; 7/58) and difficulty logging into the CR-VPED Telehealth Network (9%; 5/58). Previous studies have investigated the use of TM in pediatric acute care, but most studies have focused on critical care or subspecialty care in the office setting. Our experience with CR-VPED has shown that it has been feasible to provide general pediatric emergency care to patients in underserved, rural emergency departments across New Mexico. Patients requiring TM consultation were heterogeneous in age and presentation.


Nanogenerator for Biomedical Applications.
In the past 10 years, the development of nanogenerators (NG) has enabled different systems to operate without external power supply. NG have the ability to harvest the mechanical energies in different forms. Human body motions and activities can also serve as the energy source to drive NG and enable self-powered healthcare system. In this review, a summary of several major actual applications of NG in the biomedical fields is made including the circulatory system, the neural system, cell modulation, microbe disinfection, and biodegradable electronics. Nevertheless, there are still many challenges for NG to be actually adopted in clinical applications, including the miniaturization, duration, encapsulation, and output performance. It is also very important to further combine the NG development more precisely with the medical principles. In future, NG can serve as highly promising complementary or even alternative power suppliers to traditional batteries for the healthcare electronics.


Is it acute omphalitis or necrotizing fasciitis? Report of three fatal cases.
We describe 3 Costa Rican newborns that developed acute omphalitis, complicated with fulminant abdominal wall and genital necrotizing fasciitis. The emergency practitioner should be capable of distinguishing promptly between acute omphalitis and early necrotizing fasciitis. Prompt medical treatment and surgical debridement should be encouraged to decrease the high associated morbidity and mortality rates.


EVIDENCE OF A BIOGEOGRAPHIC BREAK BETWEEN POPULATIONS OF A HIGH DISPERSAL STARFISH: CONGRUENT REGIONS WITHIN THE INDO-WEST PACIFIC DEFINED BY COLOR MORPHS, mtDNA, AND ALLOZYME DATA.
Both mtDNA variation and allozyme data demonstrate that geographic groupings of different color morphs of the starfish Linckia laevigata are congruent with a genetic discontinuity between the Indian and Pacific Oceans. Populations of L. laevigata sampled from Thailand and South Africa, where an orange color morph predominates, were surveyed using seven polymorphic enzyme loci and restriction fragment analysis of a portion of the mtDNA including the control region. Both allozyme and DNA data demonstrated that these populations were significantly genetically differentiated from each other and to a greater degree from 23 populations throughout the West Pacific Ocean, where a blue color morph is predominant. The genetic structure observed in L. laevigata is consistent with traditional ideas of a biogeographic boundary between the Indian and Pacific Oceans except that populations several hundreds kilometers off the coast of north Western Australia (Indian Ocean) were genetically similar to and had the same color morphs as Pacific populations. It is suggested that gene flow may have continued (possibly at a reduced rate) between these offshore reefs in Western Australia and the West Pacific during Pleistocene falls in sea level, but at the same time gene flow was restricted between these Western Australian populations and those in both Thailand and South Africa, possibly by upwellings. The molecular data in this study suggest that vicariant events have played an important role in shaping the broadscale genetic structure of L. laevigata. Additionally, greater genetic structure was observed among Indian Ocean populations than among Pacific Ocean populations, probably because there are fewer reefs and island archipelagos in the Indian Ocean than in the Pacific, and because present-day surface ocean currents do not facilitate long-distance dispersal.


Alterations in the content and composition of glycosaminoglycans in human laryngeal carcinoma.
Glycosaminoglycans in normal and cancerous human laryngeal cartilage were isolated and characterized by means of enzyme susceptibility and high performance liquid chromatography. The known mammalian glycosaminoglycans were identified in all samples but their content and composition varied between normal and malignant samples. Chondroitin/dermatan sulphate was the major glycosaminoglycan in all cases, but its relative proportion was decreased in malignant samples. Its sulphation pattern showed that in normal samples it was sulphated mainly at the C6 position of galactosamine, whereas in malignant samples it was sulphated mainly at C4. Dermatan sulphate, expressed as a result of the different digestion of samples with chondroitinases, was present in very small amounts in normal samples (2.7% of total sulphated glycosaminoglycans) but increased in proportion up to 27.7% in malignant samples. The content of oversulphated chondroitin/dermatan was increased twofold in malignant samples. The content of heparan sulphate was increased almost fivefold in malignant samples as compared to normal ones. The content of hyaluronan was increased in malignant samples 3.5-fold, amounting to up to 11.4% of total glycosaminoglycans. These dramatic changes in the content and composition of glycosaminoglycans seemed to be characteristic of the tumour and independent of its status.


Optimising timing of steroid administration in preterm pre-eclampsia.
Antenatal corticosteroids (ACS) are an established intervention to improve outcomes in preterm birth. ACS are optimally timed if the administration-to-birth interval is greater than 24 h and <7 days. Evidence has emerged suggesting harm associated with administration-to-birth intervals greater than seven days, or with repeated courses of ACS. Pre-eclampsia is a leading cause of iatrogenic preterm birth, as delivery of the fetus and placenta remains the only cure. This study investigated optimal ACS use in women delivering before 35 weeks' gestation in the United Kingdom with a diagnosis of preterm pre-eclampsia. Of 1,632 women with suspected pre-eclampsia, 250 delivered before 35 weeks' gestation with pre-eclampsia. 31 % (78/250) received optimally timed ACS, 49 % (122/250) received ACS more than seven days pre-delivery and 20 % (50/250) did not receive ACS. There were no significant differences in gestational age, mean birthweight, respiratory distress syndrome, neonatal unit admission or neonatal death between groups. There was a higher rate of intrauterine fetal death in the group of women who did not receive ACS (p < 0.05), and a corresponding increase in vaginal delivery and reduction in caesarean section (p < 0.05). Optimal ACS administration is poor in women delivering preterm with pre-eclampsia and the largest group of mistimed ACS administration were those given more than 7 days prior to birth. Clinicians should defer ACS until a decision for delivery has been made, at which point ACS should be prioritised. Judicious use of ACS may improve outcomes.


Critical care in the near future: patient-centered, beyond space and time boundaries.
Modern Critical Care aims at improving patient-centered outcomes, not limited to survival. Recently, along with traditional research evaluating single drugs or procedures, more elusive elements have been evaluated, like organizational and teamwork aspects, delivery of critical care before Intensive Care Unit (ICU) admission and after discharge. The aim of this review is to offer an up-to-date, comprehensive, and maybe "visionary" big picture of Critical Care in the near future beyond its traditional boundaries. In particular, we wish to suggest key elements that will allow a leap forward in terms of quality of care. Patient-centeredness will be the main issue, taking the patient's wishes into account more than in the past. This means improving communication with patients and their relatives, and pursuing a holistic approach: we should pay more attention to natural light, noise reduction, music, prevention of sleep fragmentation, soft colors for walls, privacy, psychological support. An open visiting policy should be the standard. End-of-Life practices should become centered on patient wishes and dignity. Rapid response teams will bring timely critical care services to patients outside ICUs, preventing avoidable adverse events and unplanned ICU admission. In ICU, standardized protocols, checklists, daily goals sheets, advanced information technology and multidisciplinary rounds will improve quality of care and safety. Multicenter studies will be made easier and research should become part of daily practice in most ICU. Finally, the post ICU syndrome should be prevented and treated by a well-designed longitudinal care model taking care of patients from the ICU to the outpatient setting.


Primary Aminothiourea-Catalyzed Enantioselective Synthesis of Rauhut-Currier Adducts of 3-Arylcyclohexenone with a Tethered Enone on the Aryl Moiety at the Ortho-Position.
An enantioselective synthesis of Rauhut-Currier (RC) adducts from 3-aryl cyclohexenone with a tethered enone moiety at the ortho-position on the aryl group is accomplished. This method provides a wide range of valuable synthetic building blocks having a unique [6-5-6] all-carbon-fused tricyclic skeleton. A primary amine-containing thiourea, a bifunctional organocatalyst, was found to be an efficient catalyst for this transformation. The primary amine counterpart of the catalyst possibly activates the aliphatic enone via dienamine formation (HOMO activation), whereas the thiourea counterpart activates the tethered enone (LUMO activation). Considering the difficulty in achieving an RC reaction of β,β-disubstituted (alkyl and aryl) enones, this method would be significantly rewarding.


Concentration of cations in different parts of male reproductive system and their influence on in vitro sperm motility in lizard, Mabuya carinata Schneider.
Concentrations of mono- and divalent cations in the testis, three different regions of the epididymis and the vas deferens of lizard, M. carinata were determined. The concentrations of Na+, K+ and Ca2+ increased gradually from testis to vas deferens. However, no significant variation in the levels of Mg2+ was observed between testis and anterior epididymis, and between posterior epididymis and vas deferens. Further, in an in vitro sperm motility study, wherein different concentrations of the cations were tested, the maximum forward progressive motility of posterior epididymal spermatozoa was observed following treatment with 140 mMNaCl, 25 mM KCl, and 50 mM CaCl2 whereas, treatment with magnesium brought about a decrease in sperm motility. The results indicate that Na+, K+, and Ca2+ have stimulatory effect at an optimum dose, whereas Mg2+ has an inhibitory effect even at very low concentration, on sperm motility in the lizard M carinata.


Snapshot PCR surveillance for SARS-CoV-2 in hospital staff in England.
Significant nosocomial transmission of SARS-CoV-2 has been demonstrated. Understanding the prevalence of SARS-CoV-2 carriage amongst HCWs at work is necessary to inform the development of HCW screening programmes to control nosocomial spread. Cross-sectional 'snapshot' survey from April-May 2020; HCWs recruited from six UK hospitals. Participants self-completed a health questionnaire and underwent a combined viral nose and throat swab, tested by Polymerase Chain Reaction (PCR) for SARS-CoV-2 with viral culture on majority of positive samples. Point prevalence of SARS-CoV-2 carriage across the sites was 2.0% (23/1152 participants), median cycle threshold value 35.70 (IQR:32.42-37.57). 17 were previously symptomatic, two currently symptomatic (isolated anosmia and sore throat); the remainder declared no prior or current symptoms. Symptoms in the past month were associated with threefold increased odds of testing positive (aOR 3.46, 95%CI 1.38-8.67; p = 0.008). SARS-CoV-2 virus was isolated from only one (5%) of nineteen cultured samples. A large proportion (39%) of participants reported symptoms in the past month. The point-prevalence is similar to previous estimates for HCWs in April 2020, though a magnitude higher than in the general population. Based upon interpretation of symptom history and testing results including viral culture, the majority of those testing positive were unlikely to be infectious at time of sampling. Development of screening programmes must balance the potential to identify additional cases based upon likely prevalence, expanding the symptoms list to encourage HCW testing, with resource implications and risks of excluding those unlikely to be infectious with positive tests. Public Health England.


Genome-Wide Identification and Homoeologous Expression Analysis of PP2C Genes in Wheat (Triticum aestivum L.).
Plant protein phosphatase 2Cs (PP2Cs) play crucial roles in phytohormone signaling, developmental processes, and both biotic and abiotic stress responses. However, little research has been conducted on the PP2C gene family in hexaploid wheat (Triticum aestivum L.), which is an important cereal crop. In this study, a genome-wide investigation of TaPP2C gene family was performed. A total of 257 homoeologs of 95 TaPP2C genes were identified, of which 80% of genes had all the three homoeologs across A, B, and D subgenomes. Domain analysis indicated that all the TaPP2C homoeologs harbored the type 2C phosphatase domains. Based on the phylogenetic analysis, TaPP2Cs were divided into 13 groups (A-M) and 4 single branches, which corresponded to the results of gene structure and protein motif analyses. Results of chromosomal location and synteny relationship analysis of TaPP2C homoeologs revealed that known chromosome translocation events and pericentromeric inversions were responsible for the formation of TaPP2C gene family. Expression patterns of TaPP2C homoeologs in various tissues and under diverse stress conditions were analyzed using publicly available RNA-seq data. The results suggested that TaPP2C genes regulate wheat developmental processes and stress responses. Homoeologous expression patterns of TaPP2C triad homoeologs from A, B, and D subgenomes, revealed expression bias within triads under the normal condition, and variability in expression under different stress treatments. Quantitative real-time PCR (qRT-PCR) analysis of eight TaPP2C genes in group A revealed that they were all up-regulated after abscisic acid treatment. Some genes in group A also responded to other phytohormones such as methyl jasmonate and gibberellin. Yeast two-hybrid assays showed that group A TaPP2Cs also interacted with TaSnRK2.1 and TaSnRK2.2 from subclass II, besides with subclass III TaSnRK2s. TaPP2C135 in group A was transformed into Arabidopsis and germination assay revealed that ectopic expression of TaPP2C135 in Arabidopsis enhanced its tolerance to ABA. Overall, these results enhance our understanding of the function of TaPP2Cs in wheat, and provide novel insights into the roles of group A TaPP2Cs. This information will be useful for in-depth functional analysis of TaPP2Cs in future studies and for wheat breeding.


BRCA1 and BRCA2 Gene Mutations and Lung Cancer Sisk: A Meta-Analysis.
Background and objective: BRCA1 and BRCA2 are associated with many cancer types in addition to hereditary breast and ovarian cancers. However, their relation to lung cancer remains to be explored. Materials and Methods: Observation studies were systematically reviewed to explore the association of BRCA1 or BRCA2 with lung cancer. PubMed, MEDLINE [EBSCOhost], and relevant articles published up to 7 January 2020 were searched. Odd ratio (OR), standardized morbidity rate (SMR), and cancer-specific standardized incidence ratios (SIRs) were pooled together as relative risk (RR) estimates (95% confidence interval [CI], 0.66-1.40). Results: Thirteen studies were included for analysis. Results showed that the RR of BRCA2 is 0.76 (95% CI, 0.48-1.19), the overall RR is 0.96 (95% CI, 0.66-1.40), and that of BRCA1 is 0.66 (95% CI, 0.41-1.05), indicating that it was not associated with lung cancer. Conclusion: With the limitation of the retrospective study design and severe heterogeneity, these results inform clinicians and relevant families that BRCA1 and BRCA2 mutation carriers have no increased risk of lung cancer.


Functional imaging for early prediction of response to chemoradiotherapy: 3'-deoxy-3'-18F-fluorothymidine positron emission tomography--a clinical application model of esophageal cancer.
Pathologic complete response after neoadjuvant chemoradiation therapy is associated with increased survival in esophageal cancer. Early detection of response or nonresponse to neoadjuvant chemoradiation might allow individualization of treatment strategies and avoidance of unnecessary treatment. Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) permits detection of changes in tumor proliferation before any change in tumor size occurs, and FDG-PET findings have been correlated with outcomes in esophageal cancer. However, FDG-PET may fail to distinguish between residual tumor and inflammation and between complete response and partial response with substantial residual tumor burden. PET with the nucleoside analogue 3'-deoxy-3'-18F-fluorothymidine (FLT) has been found to be more accurate than FDG-PET in visualizing early changes in tumor proliferation. In a recent study in experimental models of esophageal cancer, FLT-PET was more accurate than FDG-PET in detecting early changes in proliferation following docetaxel and radiation therapy in human SEG-1 cells and mouse SEG-1 xenografts, including having a much stronger correlation with histologic findings. Clinical studies are needed to determine if FLT-PET can distinguish among degrees of response to neoadjuvant chemoradiation in patients with esophageal cancer.


Comparison between self-reported smoking habits and daily ad-libitum smoking topography in a group of Korean smokers.
Tobacco smoking is associated with a high global mortality rate since it is known to cause cancers and lung and heart diseases. To control and reduce annual mortality attributed to smoking, it is essential to design applicable smoke cessation programs based on realistic tobacco exposure risk assessment. In this regard, understanding the smoking habits of the smoker is crucial. Using self-report smoking habit surveys is a common approach in measuring basic variables of smoking habits. However, smoking topography measurement devices have recently become available for investigating smoking habit variables accurately. In this study, we conducted a self-report survey to investigate a group of Korean smokers' smoking habit variables such as the number of smoked cigarettes per day, puff counts, and total smoking time. The survey also included items from the Fagerström Test for Nicotine Dependence (FTND). The results were compared with the corresponding variables from machine-determined data to investigate their correlation and reliability. Results indicate that Korean smokers have a reliable understanding of the average number of cigarettes they smoke daily (ρ = 0.517, Cronbach's α = 0.754) and the time to first cigarette (TTFC) after waking up (ρ = -0.587, Cronbach's α = 0.623), as fundamental items of the FTND score. Nevertheless, these smokers significantly under-reported the puff number and total smoking time, which can cause significant underestimation in the tobacco exposure risk assessment. Consequently, we suggest the application of self-report surveys that are based on the amount of daily smoked cigarettes (e.g. FTND) for clinical or risk assessment purposes. Using smoking topography measurement devices is recommended overusing self-report surveys in measuring smoking habit variables such as puff count and smoking time more accurately.


Survey on transition from inpatient to outpatient for patients on insulin: what really goes on at home?
To identify the diabetes-specific, posthospital discharge issues that may arise for patients sent home on insulin therapy. We designed and conducted a telephone survey covering predischarge issues such as survival skill education and insulin discharge instructions, postdischarge logistical problems such as obtaining diabetes medications and supplies, and overall glucose control. The questionnaire was administered by telephone 1 week after discharge from the hospital to adult patients sent home on long-acting insulin. We attempted to contact 61 patients who were eligible for the study. Eleven patients were unable to be reached by telephone despite multiple attempts. Forty-seven of 50 patients contacted agreed to be interviewed. Nearly 100% of patients received appropriate "survival skills" training, including instruction regarding self-monitoring of blood glucose, insulin administration, and treatment of hypoglycemia. Once discharged, 10 patients (21%) had difficulty obtaining diabetes medications and supplies. Thirty-seven patients (79%) felt that their blood glucose control was "good" in the week after they left the hospital compared with author perception of 25 patients having good glucose control (53%) on the basis of pre-defined criteria. Although patients received instruction on insulin dosing and when and who to call for problems and questions, specific guidelines on how to manage insulin in the setting of changing glucocorticoid dosages were not communicated to patients. On the basis of our findings, we anticipate implementing improvements in diabetes-specific discharge prescriptions, new guidelines on when patients should call for assistance, and specific orders on how to adjust insulin for changes in glucocorticoid dosages.


Synthesis of medium-ring lactams and macrocyclic peptide mimetics via conjugate addition/ring expansion cascade reactions.
A novel conjugate addition/ring expansion (CARE) cascade reaction sequence is reported that enables medium-sized ring and macrocyclic bis-lactams to be prepared from primary amines and cyclic imides. The reactions are simple to perform, generally high yielding, and very broad in scope, especially with respect to the primary amine component. CARE reactions can also be performed iteratively, enabling β-peptoid-based macrocyclic peptide mimetics to be 'grown' via well controlled, sequential 4-atom ring expansion reactions, with the incorporation of varied functionalised amines during each iteration.


Bioequivalence of two oral formulations of glyburide (glibenclamide).
Glyburide (glibenclamide) is a sulfonylurea derivative that is very widely used in the treatment of type II diabetes mellitus. Currently, there are several pharmaceutical formulations available in Mexico containing this drug, however, very limited information about their bioavailabilities is known. The purpose of this study was to compare the bioavailability of two formulations of glyburide used in Mexico, Daonil and Gen-Glybe. Twenty-four Mexican healthy volunteers participated in this study that was carried out following the recommendations of the Declaration of Helsinki. Subjects received a dose of 10 mg of glyburide (two tablets of 5 mg) under fasting conditions in two separate sessions using a randomized crossover design with a one week washout period. Plasma samples were obtained at selected times over 24 hours and stored frozen until analyzed. Pharmacokinetic parameters were obtained and values (mean +/- S.E.M.) were as follows: Cmax 273.32 +/- 25.84 versus 294.83 +/- 27.12 ng/ml; tmax 3.03 +/- 0.23 versus 2.87 +/- 0.24 h; and AUC24h 1396.66 +/- 130.18 versus 1557.99 +/- 140.24 ng x h/ml, for Daonil and Gen-Glybe tablets, respectively. Pharmacokinetic parameters were compared using analysis of variance for a cross-over design and ratios of AUC24h and Cmax and 90% confidence intervals were obtained. As confidence intervals did not exceed the limits of acceptance (80--125%) for Cmax and AUC24h, it is concluded that the formulations tested are bioequivalent.


Difluoromethylene phosphabetaine as an equivalent of difluoromethyl carbanion.
A method for nucleophilic difluoromethylation of reactive Michael acceptors, aldehydes, and azomethines is described. The reaction is performed using the readily available and air-stable reagent difluoromethylene phosphabetaine. The process involves interaction of an electrophilic substrate with in situ generated difluorinated phosphonium ylide followed by hydrolysis of the carbon-phosphorus bond under mild conditions.


Longitudinal Heschl's gyrus growth during childhood and adolescence in typical development and autism.
Heightened auditory sensitivity and atypical auditory processing are common in autism. Functional studies suggest abnormal neural response and hemispheric activation to auditory stimuli, yet the neurodevelopment underlying atypical auditory function in autism is unknown. In this study, we model longitudinal volumetric growth of Heschl's gyrus gray matter and white matter during childhood and adolescence in 40 individuals with autism and 17 typically developing participants. Up to three time points of magnetic resonance imaging data, collected on average every 2.5 years, were examined from individuals 3-12 years of age at the time of their first scan. Consistent with previous cross-sectional studies, no group differences were found in Heschl's gyrus gray matter volume or asymmetry. However, reduced longitudinal gray matter volumetric growth was found in the right Heschl's gyrus in autism. Reduced longitudinal white matter growth in the left hemisphere was found in the right-handed autism participants. Atypical Heschl's gyrus white matter volumetric growth was found bilaterally in the autism individuals with a history of delayed onset of spoken language. Heightened auditory sensitivity, obtained from the Sensory Profile, was associated with reduced volumetric gray matter growth in the right hemisphere. Our longitudinal analyses revealed dynamic gray and white matter changes in Heschl's gyrus throughout childhood and adolescence in both typical development and autism.


Plasma concentrations of homocysteine and other aminothiol compounds are related to food intake in healthy human subjects.
We investigated total, free and protein-bound plasma homocysteine, cysteine and cysteinylglycine in 13 subjects aged 24-29 y after a breakfast at 0900 h containing 15-18 g of protein and a dinner at 1500 h containing approximately 50 g of protein. Twelve subjects had normal fasting homocysteine (mean +/- SD, 7.6 +/- 1.1 mumol/L) and methionine concentrations (22.7 +/- 3.5 mumol/L) and were included in the statistical analyses. Breakfast caused a small but significant increase in plasma methionine (22.2 +/- 20.6%) and a brief, nonsignificant increase followed by a significant decline in free homocysteine. However, changes in total and bound homocysteine were small. After dinner, there was a marked increase in plasma methionine by 16.7 +/- 8.9 mumol/L (87.9 +/- 49%), which was associated with a rapid and marked increase in free homocysteine (33.7 +/- 19.6%, 4 h after dinner) and a moderate and slow increase in total (13.5 +/- 7.5%, 8 h) and protein-bound (12.6 +/- 9.4%, 8 h) homocysteine. After both meals, cysteine and cysteinylglycine concentrations seemed related to changes in homocysteine, because there were parallel fluctuations in the free:bound ratios of all three thiols. Dietary changes in plasma homocysteine will probably not affect the evaluation of vitamin deficiency states associated with moderate to severe hyperhomocysteinemia but may be of concern in the risk assessment of cardiovascular disease in patients with mild hyperhomocysteinemia. Synchronous fluctuations in the free:bound ratio of the plasma aminothiol compounds indicate that biological effects of homocysteine may be difficult to separate from effects due to associated changes in other aminothiol compounds.


Regulation of human prostate-specific G-protein coupled receptor, PSGR, by two distinct promoters and growth factors.
PSGR is a newly identified human prostate tissue-specific gene belonging to the G-protein coupled receptor (GPCR) family. Overexpression of PSGR is associated with human prostate intraepithelial neoplasia (PIN) and prostate tumors, suggesting PSGR may play an important role in early prostate cancer development and progression. To understand the regulation of tissue-specific expression of human PSGR and its upregulation mechanism in prostate cancers, we characterized the promoter region of PSGR and analyzed the control mechanism for PSGR expression in human prostate tissues/cells. In this report, we demonstrate that two distinct promoters control the transcriptional regulation of PSGR in human prostate cells. The first promoter region includes exon 1 and a TATA box at -31 site. The minimal DNA sequence with promoter activity is about 123 bp upstream of exon 1. Exon 1 contains tissue specific regulatory activity for the first promoter of PSGR gene. The second promoter is located in the upstream region of exon 2, which is a TATA-less and non-GC-rich promoter. Primer extension and RNA protection assays (RPA) revealed that the transcription driven by the second promoter is initiated at the junction of intron and exon 2 within a cluster of nucleotides located about 250 bp upstream from the junction. Both promoters show prostate cell-specific characteristics in our luciferase assays in transfected cells. Furthermore, we investigated the regulation of the promoter activities of the PSGR gene by different growth factors and cytokines, and demonstrated that interleukin-6 (IL-6) activates the promoter activities of PSGR in human prostate cancer cells. These data suggest that two functional promoters regulate the transcriptional expression of PSGR in human prostate tissues and PSGR is a new target for IL-6 transcriptional regulation.


Dyschromatosis universalis hereditaria: report of a case.
The case of a 43-old-year woman who had a generalized asymptomatic pigmentary disorder with onset at about age 20 is presented. Tracing back her family history, we found that her father and six of her siblings had also suffered a similar skin pigmentary defect with onset at the same approximate age. In depigmented lesions, three distinct histopathological features were observed: (1) decreased epidermal melanin content and lower density of melanocytes in the upper dermis; and (3) ultrastructural vacuolar degeneration in the focal melanocytes and in the keratinocytes immediately nearby. No deposit of amyloid was observed in the biopsied skin specimens. In hyperpigmented lesions, the histopathological features included: (1) increased melanin content and high density of melanocytes; (2) few melanophages in the papillary dermis of focal areas, but no vacuolar degeneration of the epidermal cells; and (3) an increased number of melanosomes in the basal and suprabasal keratinocytes. Direct immunofluorescence examination revealed no deposit of immunoglobulins in either the hyperpigmented or depigmented lesions. By indirect immunofluorescence examination, the serum of the patient was found to contain antinuclear antibodies (ANA, IgG, class, homogeneous pattern); however, the maximal positive dilution titer of sera against cultured human cells was much higher in melanocytes (1:500 dilution) than in keratinocytes (1:50 dilution) or fibroblasts (1:10 dilution). The pathogenesis of dyschormatosis universalis hereditaria remains unclear; however, hereditary genetic defects may play an important role in alternating regular melanogenesis, which results in a pigmentary anomaly.


Vitamin D levels among adult psychiatric inpatients and the association with psychosis.
The association between low vitamin D levels and mental illness has been described in earlier research. The aim of our study was to examine the association between vitamin D levels with psychotic symptoms among hospitalized patients. A total of 1,456 patient records from an academic psychiatric hospital were examined. Vitamin D levels were classified as normal (>30 ng/mL); insufficient (20 to 30 ng/mL); and deficient (<20 ng/mL). We then analyzed the association among vitamin D groups and symptoms of psychosis. The average vitamin D level in our sample was 23.59 ng/mL, with 76.2% of patients presenting with vitamin D levels <30 ng/mL. There was a significant association between vitamin D levels <20 ng/mL and symptoms of psychosis (P < .05). African American patients had lower mean vitamin D levels than White patients (15.6 ± 0.2 ng/mL vs 25.8 ± 0.4 ng/mL, P < .001). There was no sex difference in vitamin D levels (females: 23.3 ± 11.5 ng/mL; males: 23.9 ± 11.0 ng/mL). Patients with vitamin D levels <30 ng/mL were 1.5 times more likely to have symptoms of psychosis. Patients who were African American, Hispanic, Asian, or biracial had lower vitamin D levels than patients who were White. Multivariate analysis found that after adjusting for age, sex, and race, the association between vitamin D and psychosis was not statistically significant. Possible explanations could include the known tendency to overdiagnose psychosis among individuals who are African American, referral bias, subgroup effect, or an epiphenomenon.


Newly discovered Staphylococcus aureus serine hydrolase probe and drug targets.
There is an urgent need for new diagnosis and treatment options for the bacterial pathogen Staphylococcus aureus. This review will summarize data on ten recently discovered biofilm-associated serine hydrolases called fluorophosphonate-binding hydrolases (FphA-J). Based on the summarized findings, many of these proteins represent intriguing new targets for probe and drug development.


DOES COSMOPOLITANISM RESULT FROM OVERCONSERVATIVE SYSTEMATICS? A CASE STUDY USING THE MARINE SPONGE CHONDRILLA NUCULA.
The sponge species Chondrilla nucula has a simple morphology and a very wide geographical distribution. To verify whether the latter might be an artifact of the former, samples of this species were collected across 10,000 km of its range, in the Mediterranean, the Caribbean, and the southwestern atlantic. The classical (spicule morphology) and molecular (allozymes) systematic approaches were compared, to try to define the geographic limits between populations and detect possible cryptic species. We found five distinct genetic forms within C. nucula that sometimes showed morphological homogeneity and other times plasticity. The difference in size of spicules could not be related to the clear-cut genetic differences, suggesting that the use of spicule sizes for sponge systematics should be reappraised. The population of one of the genetic forms along 3000 km of the Brazilian coast was highly structured (FST = 0.21; Ne m = 0.96). Our results reject the null hypothesis of cosmopolitanism of C. nucula and indicate that the putative worldwide distribution of some marine sponges, and possibly many other benthic invertebrates, may be the result of overly conservative systematics. Cryptic species appear to be particularly prevalent when genera are well defined but species are characterized by only a few morphological characters.


Dose-escalating ruxolitinib for refractory hemophagocytic lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder characterized by excessive secretion of cytokines. Even with the recommended HLH-94/2004 regimen, over 30% of patients remain refractory to frontline therapy or relapse after an initial response, leading to poor clinical outcomes. Ruxolitinib, a JAK1/2 inhibitor targets key cytokines in HLH, has shown promising therapeutic effects. However, there has been little attention given to patients who do not respond to ruxolitinib and whether an escalating dose can provide a resolution. This study analyzed eight HLH patients who received dose-escalating ruxolitinib who had previously failed to respond to the general dose. The efficacy and safety were mainly analyzed. Overall, four out of eight (50%) patients achieved better remission after dose escalation. Two patients who only showed improvement with the general dose achieved complete remission (CR) after dose escalation, and the other two patients also achieved CR after dose escalation when they did not respond to the general dose. The median time to achieve the best overall response was 18.5 days (IQR 13.25-23.75 days). There was no correlation of treatment outcome with blood count, liver function, LDH, cytokines, ferritin levels, NK cell activity, or the time to initiation of ruxolitinib and maximum dosage. The etiology of HLH (p=0.029) and level of sCD25 (p=0.021) correlated with treatment response to dose-escalating ruxolitinib. The area of sCD25 under the ROC curve was 0.8125 (95% CI 0.5921 to 1.033, p=0.035) when using 10,000 pg/ml as the cut-off value for predicting therapeutic effects. After a median follow-up of 159 days, two patients died, and the estimated 2-month overall survival rate was 75%. Adverse effects possibly related to the dose-escalating of ruxolitinib included two cases of extremity pain and one of aminotransferase increased. No grade 3 or higher adverse events were reported. This is the first comprehensive study on the use of dose-escalating ruxolitinib in HLH. Ruxolitinib at an escalated dose represent a viable and relatively safe solution for managing refractory HLH. The levels of sCD25 (with a cut-off of 10000pg/ml) can serve as an indicator for early consideration of chemotherapy during treatment.


An integrative model for neural dynamics of feature selection in visual object processing: An explorative study.
Objects and features represent fundamental selection units of visual attention. The associated mechanisms, however, had been mostly explored in isolation. Not least for this reason, apparently contradictory theories persist about feature selection in visual object processing. Our previous study demonstrated the time-dependent nature of this process. In the present explorative study, we used electroencephalographic recordings to examine feature-specific selection during the time course of object processing. For this, we analyzed the feature-specific selection negativities (SNs), i.e., the SNs when human subjects attended to or ignored one (color or shape) relative to attending to all (color and shape) constituent features of an object (a square). We found that the feature-specific SN amplitude of the task-relevant feature was significantly decreased in a time bin from 500 to 850 ms after trial onset in comparison to an earlier (100-450 ms) and a later time bin (900-1250 ms). Whereas, the feature-specific SN amplitude of the task-irrelevant feature was firstly positive, indicating no specific selection of this feature, and secondly, it marginally increased from the first to the second time bin. This leads to the proposed integrative model, which indicates that sustained feature-specific prioritization only emerges over time, this process consisting of three phases: after initial selection of the relevant feature and inhibition of the irrelevant feature (first time bin), further inhibition of the irrelevant feature is accompanied by co-inhibition of the relevant feature, causing prioritization to decline (second time bin), before the relevant feature eventually regains priority by being facilitated again (third time bin).


The I of the storm-relations between self and conscious emotion experience: comment on Lambie and Marcel (2002).
J. A. Lambie and A. J. Marcel (2002) outlined a framework for understanding varieties of conscious emotion experience. In their analysis, the self plays an important role in conscious emotion experience. In this critique, however, the authors propose that Lambie and Marcel's presentation of the self needs further specification if it is to account for varieties of conflicted emotional experience, particularly those characteristic of dissociative states. The authors propose that a more elaborated self-construct is necessary to account for these phenomena involving either the "splitting off of significant self-related concerns or the existence of multiple self-constructs. These arguments are illustrated by clinical and subclinical case examples.


A role for endogenous glucocorticoids in wound repair.
Exogenous glucocorticoids are known to inhibit wound repair, but the roles and mechanisms of action of endogenous glucocorticoids during the healing process are as yet unknown. Therefore, we wounded mice expressing a DNA-binding-defective mutant version of the glucocorticoid receptor (GR(dim) mice) and also analysed fibroblasts from these animals in vitro. We found a remarkably enlarged granulation tissue with a high fibroblast density in GR(dim) mice. This difference is likely to result from an increased migratory and proliferative capacity of GR(dim) fibroblasts and from elevated expression levels of soluble factors involved in granulation tissue formation in wounds of GR(dim) mice. In spite of the larger granulation tissue seen in early wounds, late wounds appeared normal, most likely due to an enhanced ability of GR(dim) fibroblasts to contract collagen. These results demonstrate an as yet unidentified role of endogenous glucocorticoids in the regulation of wound repair.


Payment reform a primer for taking on risk.
To reduce unnecessary care and improve patient outcomes through bundled payments or population health management, healthcare organizations must define both the population for which they are assuming risk and the services that they will provide. Organizations also must be able to manage variations in cost and quality and demonstrate both the economic and clinical value they provide to the populations they serve. To effectively coordinate care across a patient population, providers--including physicians, hospitals, and postacute care facilities--must be willing to collaborate on efforts to reengineer care delivery.


Lessons From Pediatric MDS: Approaches to Germline Predisposition to Hematologic Malignancies.
Pediatric myelodysplastic syndromes (MDS) often raise concern for an underlying germline predisposition to hematologic malignancies, referred to as germline predisposition herein. With the availability of genetic testing, it is now clear that syndromic features may be lacking in patients with germline predisposition. Many genetic lesions underlying germline predisposition may also be mutated somatically in de novo MDS and leukemias, making it critical to distinguish their germline origin. The verification of a suspected germline predisposition informs therapeutic considerations, guides monitoring pre- and post-treatment, and allows for family counseling. Presentation of MDS due to germline predisposition is not limited to children and spans a wide age range. In fact, the risk of MDS may increase with age in many germline predisposition conditions and can present in adults who lack classical stigmata in their childhood. Furthermore, germline predisposition associated with DDX41 mutations presents with older adult-onset MDS. Although a higher proportion of pediatric patients with MDS will have a germline predisposition, the greater number of MDS diagnoses in adult patients may result in a larger overall number of those with an underlying germline predisposition. In this review, we present a framework for the evaluation of germline predisposition to MDS across all ages. We discuss characteristics of personal and family history, clinical exam and laboratory findings, and integration of genetic sequencing results to assist in the diagnostic evaluation. We address the implications of a diagnosis of germline predisposition for the individual, for their care after MDS therapy, and for family members. Studies on MDS with germline predisposition have provided unique insights into the pathogenesis of hematologic malignancies and mechanisms of somatic genetic rescue vs. disease progression. Increasing recognition in adult patients will inform medical management and may provide potential opportunities for the prevention or interception of malignancy.


Measurement, analysis and prediction of topical UV filter bioavailability.
The aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2-ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Fick's second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products.


Navigation in implantology.
The primary objective of implant insertion is optimal prosthetic implant positioning while simultaneously protecting sensitive anatomical structures. In this context, navigated implants show significantly better results than freehand-inserted implants. Computer-assisted navigation, in combination with three-dimensional (3D) imaging by cone beam computed tomography (CBCT), is an ideal way to achieve higher predictability for successful implant therapy. Basically, one can distinguish between static navigation using templates, and direct dynamic navigation using optical transmission systems. Both options demonstrate comparably good results as far as the precision of implant positioning is concerned. Today, the gold standard is digital manufacturing of the template. Direct navigation is the more attractive option, provided acquisition costs can be reduced by simplifying the system. This article presents patient cases that demonstrate different variants of navigated implantology.


Perceptual learning, aging, and improved visual performance in early stages of visual processing.
In the present study, we examined whether perceptual learning methods can be used to improve performance of older individuals. Subjects performed a texture discrimination task in the peripheral visual field and a letter discrimination task in central vision. The SOA threshold was derived by presenting a mask following the stimuli. Older subjects (age greater than 65 years) were either trained for 2 days using near threshold stimuli (experimental group) or were trained with the task with supra-threshold stimuli (older control group). The experimental group showed significant improvement in the task as a result of training whereas the older control group showed no significant improvement. The improved performance post-training equaled that of a younger control group and was maintained for at least 3 months. The results of two additional experiments indicate that the improved performance was not due to changes in divided attention, that the effect of perceptual learning was location specific, and that the pattern of learning was similar to that of younger subjects. These results indicate that perceptual learning with near threshold training can be used to improve visual performance among older individuals, that the improvements are not the result of practice with the visual task, and that the improvements do not transfer to non-trained locations.


Recurrences from malignant parotid salivary gland tumors.
The clinical course of 130 patients treated for malignant parotid tumors at the three institutions have been reviewed. Fifty-six of these 130 patients developed recurrences following their primary treatment by a surgical procedure. There were a total of 109 recurrences among these 56 patients. The average number of recurrences was two per patient. The average survival from first recurrence was 3.7 years, with the median survival 2 years. The range of survival was 0.5 to 17 years. Once recurrence developed, treatment was by surgery, radiation therapy, chemotherapy, or a combination. Of 56 patients with recurrence, 33 are dead and 9 patients are alive with disease. Fourteen patients are alive and well with no evidence of disease. These NED patients had an average number of 1.6 recurrences and a median survival to date of only 3 years. Our study indicates that for the majority of patients who develop recurrence, survival is relatively short and treatment is usually ineffective in three of four patients. The authors conclude that after a surgical procedure for malignant salivary gland tumors, a trial of wide field postoperative radiation therapy to high dose should be considered as part of the initial treatment.


MRI findings in Shwachman diamond syndrome.
Shwachman Diamond Syndrome (SDS) is a rare congenital disorder characterized by pancreatic insufficiency, bone marrow dysfunction, and skeletal changes. Because of the heterogeneous clinical presentation and the limits of laboratory tests that assess pancreatic insufficiency, the diagnosis of SDS can be challenging. Pancreatic lipomatosis, a typical feature of this syndrome, is also difficult to assess by direct tissue sampling. In these circumstances, magnetic resonance imaging (MRI) provides a readily available, noninvasive tool to evaluate the pancreatic fat content. We report a case of a 12-month-old male in which abdominal MRI was used to confirm the clinical diagnosis of SDS.


From Early Micro-Temporal Interaction Patterns to Child Cortisol Levels: Toward the Role of Interactive Reparation and Infant Attachment in a Longitudinal Study.
Parental mental disorders increase the risk for insecure attachment in children. However, the quality of caregiver-infant interaction plays a key role in the development of infant attachment. Dyadic interaction is frequently investigated via global scales which are too rough to uncover micro-temporal mechanisms. Prior research found that the latency to reparation of uncoordinated dyadic states is associated with infant behavioral and neuroendocrine regulation. We investigated the hypothesis that this interactive mechanism is critical in predicting secure vs. insecure attachment quality in infancy. We also assessed the predictive quality of infant attachment regarding neuroendocrine reactivity later in childhood. A subsample of N = 58 dyads (n = 22 mothers with anxiety disorders, n = 36 controls) from a larger study were analyzed. At 3-8 months postpartum, maternal anxiety disorders were diagnosed via a structured clinical interview as well as dyadic interaction during the Face-to-Face-Still-Face (FFSF) was observed and coded on a micro-temporal scale. Infant attachment quality was assessed with the strange situation paradigm at 12-24 months of age. In an overlapping subsample of N = 39 (n = 13 mothers with anxiety disorder; n = 26 controls), we assessed child cortisol reactivity at 5 to 6 years of age. Generalized linear modeling revealed that longer latencies to interactive reparation during the reunion episode of the FFSF as well as maternal diagnosis at 3-8 months of age predict insecure attachment in children aged 12-24 months. Cox regressions demonstrated that dyads with infants who developed insecure attachment at 12-24 months of age were 48% less likely to achieve an interactive reparation at 3-8 months of age. Mixed models revealed that compared to securely attached children, children who had developed an insecure attachment at 12-24 months of age had an increased cortisol reactivity at 5 to 6 years of age during free play. The results confirm the hypothesis that the development of attachment is affected by experienced micro-temporal interactive patterns besides diagnostic categories. They also showed that infants of mothers with postpartum anxiety disorders have a more than fivefold increased risk of developing an insecure attachment than the infants of the control group. Moreover, results imply that these patterns may influence neurohormonal regulation even in preschool aged children.


Stimulation of myoglobin-dependent lipid peroxidation by adriamycin.
The objective of this investigation was to determine whether myoglobin can serve as a physiological source of iron in the catalysis of Adriamycin-stimulated lipid peroxidation. In vitro peroxidation of arachidonic acid was stimulated 2-fold by 50 microM Adriamycin, the extent of lipid peroxidation being dependent on the duration of incubation and the concentrations of both Adriamycin and myoglobin. Differential inhibition studies suggest that hydroxyl radicals are involved in this reaction; however, superoxide and hydrogen peroxide were not implicated. The results demonstrate a potentially important stimulation by Adriamycin of myoglobin-dependent membrane-lipid peroxidation. In light of the abundance of myoglobin and the deficiency of oxygen radical detoxifying enzymes in the heart, this interaction may be a significant determinant of the cardioselective toxicity of Adriamycin.


Retooling Leishmania metabolism: from sand fly gut to human macrophage.
To survive extremely different environments, intracellular parasites require highly adaptable physiological and metabolic systems. Leishmania donovani extracellular promastigotes reside in a glucose-rich, slightly alkaline environment in the sand fly vector alimentary tract. On entry into human macrophage phagolysosomes, promastigotes differentiate into intracellular amastigotes. These cope with an acidic milieu, where glucose is scarce while amino acids are abundant. Here, we use an axenic differentiation model and a novel high-coverage, comparative proteomic methodology to analyze in detail protein expression changes throughout the differentiation process. The analysis identified and quantified 21% of the parasite proteome across 7 time points during differentiation. The data reveal a delayed increase in gluconeogenesis enzymes, coinciding with a decrease in glycolytic capacity. At the same time, beta-oxidation, amino acid catabolism, tricarboxylic acid cycle, mitochondrial respiration chain, and oxidative phosphorylation capacities are all up-regulated. The results indicate that the differentiating parasite shifts from glucose to fatty acids and amino acids as its main energy source. Furthermore, glycerol and amino acids are used as precursors for sugar synthesis, compensating for lack of exogenous sugars. These changes occur while promastigotes undergo morphological transformation. Our findings provide new insight into changes occurring in single-cell organisms during a developmental process.


Multidrug-resistant Iberian epidemic clone of methicillin-resistant Staphylococcus aureus endemic in a hospital in northern Portugal.
Forty-two methicillin-resistant Staphylococcus aureus (MRSA) isolates collected during 1992-1995 at a hospital in the north of Portugal were characterized by a variety of genomic fingerprints. Hybridization of ClaI and SmaI restriction digests with the mecA- and Tn554-specific DNA probes was used to identify polymorphs and determine their localization in chromosomal DNA preparations, and pulsed-field gel electrophoretic analysis of SmaI digests was used to determine chromosomal backgrounds. A major clone (and its variants) carrying the mecA polymorph I, Tn554 type E in the PFGE background of pattern A, accounted for 85% of all MRSA tested in 1992-1993 and 66% in 1994-1995. This clone is closely related to the epidemic Iberian clone that was associated with outbreaks in Spain during 1989-1993 and was endemic in 1992-1993 in two hospitals in Lisbon (Portugal).