Bio-Inspired Untethered Robot-Sensor Platform for Minimally Invasive Biomedical Sensing.
Conventional catheter- or probe-based in vivo biomedical sensing is uncomfortable, inconvenient, and sometimes infeasible for long-term monitoring. Existing implantable sensors often require an invasive procedure for sensor placement. Untethered soft robots with the capability to deliver the sensor to the desired monitoring point hold great promise for minimally invasive biomedical sensing. Inspired by the locomotion modes of snakes, we present here a soft kirigami robot for sensor deployment and real-time wireless sensing. The locomotion mechanism of the soft robot is achieved by kirigami patterns that offer asymmetric tribological properties that mimic the skin of the snake. The robot exhibits good deployability, excellent load capacity (up to 150 times its own weight), high-speed locomotion (0.25 body length per step), and wide environmental adaptability with multimodal movements (obstacle crossing, locomotion in wet and dry conditions, climbing, and inverted crawling). When integrated with passive sensors, the versatile soft robot can locomote inside the human body, deliver the passive sensor to the desired location, and hold the sensor in place for real-time monitoring in a minimally invasive manner. The proof-of-concept prototype demonstrates that the platform can perform real-time impedance monitoring for the diagnosis of gastroesophageal reflux disease.


Making the most of routine data in palliative care research--a case study analysis of linked hospital and mortality data on cancer and heart failure patients in Scotland and Oxford.
The research base of palliative care is growing rapidly, but despite methodological advances, some of the practical challenges of working with people at the end of life will persist. This means that analysis of routine data is arguably more important in studying palliative care than it is in other aspects of health services research. End-of-life researchers have been using the high-quality linked data from cancer registries for many years. This paper explores the value of a less well-known resource for palliative care research: linked mortality and hospital activity data. Two case studies are presented using information from Scotland (population 5.1 million) and the former Oxford region of England (population 2.5 million). The advantages and limitations of linked hospital and mortality data for research and service planning in palliative care are drawn out through analyses investigating hospital bed utilisation by people with cancer and heart failure and the influence of social deprivation on the use of hospital services in the last year of life. The use of such data deserves a higher profile.


The effects of x-rays and beta rays (tritium) on the growth of Rickettsia mooseri and Rickettsia akari in embrvonate eggs.
The growth of Rickettsia mooseri was accelerated and quantitatively increased in embryonate eggs containing tritium oxide at levels of 180, 90, and 45 mc./egg during the growth period. The eggs of a group containing 22.5 mc./egg showed only a slight increase in the rate of growth of organisms; the infections in the eggs of a group given 11.2 mc./egg did not differ significantly from those of the control group. On the other hand, growth of R. akari was inhibited in embryonate eggs containing tritium oxide at levels of 180, 90, and 45 mc./egg, and partially inhibited in groups containing 22.5 and 11.2 mc./egg. The patterns of growth of R. mooseri and of R. akari exposed to tritium oxide for 6 hours prior to inoculation into embryonate eggs did not differ significantly from that of the control group. Single and divided doses of x-rays to the host resulted in partial inhibition of the growth of R. akari.


Occurrence and fate of linear and branched alkylbenzenesulfonates and their metabolites in surface waters in the Philippines.
Laguna de Bay in the Philippines is one of the largest freshwater lakes in Asia and is considered a primary source of drinking water, but also receives daily discharges of effluent from both domestic and industrial activities. Branched alkylbenzenesulfonates (ABS), which were banned in Europe and withdrawn from the market in the U.S. since the mid-1960s, but not in Southeast Asia, and linear alkylbenzenesulfonates (LAS) are anionic surfactants used in detergent formulations and are therefore main components of effluent discharges. The presence of both LAS and ABS in several water streams in the catchment area of Laguna de Bay was determined using liquid chromatography-mass spectrometry (LC-MS). The concentration levels of LAS (1.2-73 and 2.2-102 microg l(-1)) and ABS (1.1-75 and 1-66 microg l(-1)) in some tributaries of Laguna de Bay and its outlet (Pasig River) to Manila Bay were assessed in December 1999 and March 2000, respectively. The LAS/ABS ratio was calculated as an indication of the extent of the distribution and fate of these surfactants in the surface water. The nearer the location to the metropolitan area of Manila, the higher the levels of LAS and ABS detected in the waters. Moreover, the extent of biodegradation was investigated by monitoring their alkyl homologue distribution and the presence of sulfophenylcarboxylate (SPC) metabolites. Similarly, differences in the levels of SPC and the homologues were apparent at the different sampling points. Presumably, even the quite recalcitrant ABS form SPCs under the conditions present in Southeast Asia. Since wastewater treatment facilities are not well established in developing countries like the Philippines, the call for the use of environmentally friendly chemicals is of even higher significance.


The relation of passive smoking to lung cancer.
To evaluate the role of passive smoking in the development of lung cancer among nonsmokers, data were pooled from three large incident case-control interview studies. Ninety-nine lung cancer cases and 736 controls never used any form of tobacco. Overall the adjusted odds ratio for lung cancer among nonsmokers ever living with a smoker was 0.8 (95% confidence interval, 0.5-1.3) rising to 1.2 among those exposed for 40 or more years. Persons living with a spouse who smoked cigarettes were at increased risk (adjusted odds ratio, 1.5; 95% confidence interval, 0.8-2.8). When adjusted for age and gender, there was a significant trend in risk with increasing amounts smoked per week by the spouse (P = 0.05) and with cumulative pack-years of exposure (P = 0.03). This effect was limited to females, especially older women whose husbands were heavy smokers. The elevated risk associated with spouse smoking was restricted to squamous and small cell carcinomas (odds ratio, 2.9; 95% confidence interval, 0.9-9.3), which provides additional evidence linking passive smoking to lung cancer.


Signet-ring cell carcinoma co-existing with adenocarcinoma of the ampulla of vater. A case report.
We report a case of signet-ring cell carcinoma admixed with adenocarcinoma of the ampulla of Vater. Signet-ring cell carcinoma of the ampulla of Vater is rarely encountered in clinical practice. A 78-year-old man was admitted to our hospital with jaundice. Computed tomography demonstrated dilatation of the biliary tract and an enhanced mass lesion measuring 1.5 cm in the pancreatic head. Endoscopic examination showed a reddish swollen papilla of Vater, and the pathological findings on a biopsy from the papilla suggested signet-ring cell carcinoma. A pancreaticoduodenectomy was performed with a diagnosis of carcinoma of the ampulla of Vater. Postoperative pathological examination showed that the tumor was composed of signet-ring cell carcinoma and tubular adenocarcinoma. The signet-ring cell carcinoma had infiltrated to the duodenal wall and pancreatic parenchyma. Both the signet-ring cell carcinoma and the adenocarcinoma were positive on immunohistochemical staining with 45M1. Several cases of signet-ring cell carcinoma of the ampulla of Vater have previously been reported. In our case, the histological origin of both signet-ring cell and adenocarcinoma was hypothesized to have been pancreaticobiliary epithelial cells.


Human vestibular nerve morphology and labyrinthectomy.
Surgical labyrinthectomy leads to extensive and degenerative changes in the membranous labyrinth and is often followed by fibrosis and ossification of the vestibule and neuroma formation. After labyrinthectomy the distal processes of the vestibular nerve degenerate, but the nerve trunk within the internal auditory canal, including Scarpa's ganglion, does not show an obvious loss of neurons. Electron microscopic examination of the cells of Scarpa's ganglion revealed many changes similar to those of chromatolysis, indicating increased cell metabolism and probable regenerative changes. Many nerve fibers appeared to be in the process of regeneration. Some ganglion cells were fibrotic and showed ultrastructural features similar to those of cells that had undergone atrophy but survived in a sublethal state.


γ-Tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2.
Chemotherapy-induced oral mucositis is a common adverse event in patients with oral squamous cell carcinoma, and is initiated through a variety of mechanisms, including the generation of reactive oxygen species (ROS). In this study, we examined the preventive effect of γ-tocotrienol on the 5-FU-induced ROS production in human oral keratinocytes (RT7). We treated RT7 cells with 5-FU and γ-tocotrienol at concentrations of 10 µg/ml and 10 nM, respectively. When cells were treated with 5-FU alone, significant growth inhibition was observed as compared to untreated cells. This inhibition was, in part, due to the ROS gene-rated by 5-FU treatment, because N-acetyl cysteine (NAC), a ROS scavenger, significantly ameliorated the growth of RT7 cells. γ-tocotrienol showed no cytotoxic effect on the growth of RT7 cells. Simultaneous treatment of cells with these agents resulted in the significant recovery of cell growth, owing to the suppression of ROS generation by γ-tocotrienol. Whereas 5-FU stimulated the expression of NF-E2-related factor 2 (Nrf2) protein in the nucleus up to 12 h after treatment of RT7 cells, γ-tocotrienol had no obvious effect on the expression of nuclear Nrf2 protein. Of note, the combined treatment with both agents stabilized the 5-FU-induced nuclear Nrf2 protein expression until 24 h after treatment. In addition, expression of Nrf2-dependent antioxidant genes, such as heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1), was significantly augmented by treatment of cells with both agents. These findings suggest that γ-tocotrienol could prevent 5-FU-induced ROS generation by stabilizing Nrf2 activation, thereby leading to ROS detoxification and cell survival in human oral keratinocytes.


The aberrant asynchronous replication - characterizing lymphocytes of cancer patients - is erased following stem cell transplantation.
Aberrations of allelic replication timing are epigenetic markers observed in peripheral blood cells of cancer patients. The aberrant markers are non-cancer-type-specific and are accompanied by increased levels of sporadic aneuploidy. The study aimed at following the epigenetic markers and aneuploidy levels in cells of patients with haematological malignancies from diagnosis to full remission, as achieved by allogeneic stem cell transplantation (alloSCT). TP53 (a tumor suppressor gene assigned to chromosome 17), AML1 (a gene assigned to chromosome 21 and involved in the leukaemia-abundant 8;21 translocation) and the pericentomeric satellite sequence of chromosome 17 (CEN17) were used for replication timing assessments. Aneuploidy was monitored by enumerating the copy numbers of chromosomes 17 and 21. Replication timing and aneuploidy were detected cytogenetically using fluorescence in situ hybridization (FISH) technology applied to phytohemagglutinin (PHA)-stimulated lymphocytes. We show that aberrant epigenetic markers are detected in patients with hematological malignancies from the time of diagnosis through to when they are scheduled to undergo alloSCT. These aberrations are unaffected by the clinical status of the disease and are displayed both during accelerated stages as well as in remission. Yet, these markers are eradicated completely following stem cell transplantation. In contrast, the increased levels of aneuploidy (irreversible genetic alterations) displayed in blood lymphocytes at various stages of disease are not eliminated following transplantation. However, they do not elevate and remain unchanged (stable state). A demethylating anti-cancer drug, 5-azacytidine, applied in vitro to lymphocytes of patients prior to transplantation mimics the effect of transplantation: the epigenetic aberrations disappear while aneuploidy stays unchanged. The reversible nature of the replication aberrations may serve as potential epigenetic blood markers for evaluating the success of transplant or other treatments and for long-term follow up of the patients who have overcome a hematological malignancy.


Differential, dominant activation and inhibition of Notch signalling and APP cleavage by truncations of PSEN1 in human disease.
PRESENILIN1 (PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including production of the Amyloidβ (Aβ) peptide from the AMYLOID BETA A4 PRECURSOR PROTEIN (APP). We previously reported that interference with splicing of transcripts of the zebrafish orthologue of PSEN1 creates dominant negative effects on Notch signalling. Here, we extend this work to show that various truncations of human PSEN1 (or zebrafish Psen1) protein have starkly differential effects on Notch signalling and cleavage of zebrafish Appa (a paralogue of human APP). Different truncations can suppress or stimulate Notch signalling but not Appa cleavage and vice versa. The G183V mutation possibly causing Pick disease causes production of aberrant transcripts truncating the open reading frame after exon 5 sequence. We show that the truncated protein potentially translated from these transcripts avidly incorporates into very stable Psen1-dependent higher molecular weight complexes and suppresses cleavage of Appa but not Notch signalling. In contrast, the truncated protein potentially produced by the P242LfsX11 acne inversa mutation has no effect on Appa cleavage but, unexpectedly, enhances Notch signalling. Our results suggest novel hypotheses for the pathological mechanisms underlying these diseases and illustrate the importance of investigating the function of dominant mutations at physiologically relevant expression levels and in the normally heterozygous state in which they cause human disease rather than in isolation from healthy alleles.


Influence of socioeconomic factors on hospital readmissions for heart failure and acute myocardial infarction in patients 65 years and older: evidence from a systematic review.
Cardiovascular diseases are the leading cause of death and disability worldwide. Among these diseases, heart failure (HF) and acute myocardial infarction (AMI) are the most common causes of hospitalization. Therefore, readmission for HF and AMI is receiving increasing attention. Several socioeconomic factors could affect readmissions in this target group, and thus, a systematic review was conducted to identify the effect of socioeconomic factors on the risk for readmission in people aged 65 years and older with HF or AMI. The search was carried out by querying an electronic database and hand searching. Studies with an association between the risk for readmission and at least one socioeconomic factor in patients aged 65 years or older who are affected by HF or AMI were included. A quality assessment was conducted independently by two reviewers. The agreement was quantified by Cohen's Kappa statistic. The outcomes of studies were categorized in the short-term and the long-term, according to the follow-up period of readmission. A positive association was reported if an increase in the risk for readmission among disadvantaged patients was found. A cumulative effect of socioeconomic factors was computed by considering the association for each study and the number of available studies. A total of eleven articles were included in the review. They were mainly published in the United States. All the articles analyzed patients who were hospitalized for HF, and four of them also analyzed patients with AMI. Seven studies (63.6%) were found for the short-term outcome, and four studies (36.4%) were found for the long-term outcome. For the short-term outcome, race/ethnicity and marital status showed a positive cumulative effect on the risk for readmission. Regarding the educational level of a patient, no effect was found. Among the socioeconomic factors, mainly race/ethnicity and marital status affect the risk for readmission in elderly people with HF or AMI. Multidisciplinary hospital-based quality initiatives, disease management, and care transition programs are a priority for health care systems to achieve better coordination.


Homocysteine and atherosclerotic disease: the epidemiologic evidence.
Homocysteine is a sulphur-containing amino acid formed during metabolism by one of two pathways by remethylation and transsulfuration. Altered homocysteine metabolism may be implicated as a factor in atherosclerosis, cerebrovascular disease or peripheral vascular disease. It is postulated that homocysteine may damage endothelial cells or acts as a direct causal factor in the thromboembolic process. Several studies have reported that there are a number of factors that may influence levels of homocysteine in humans. Serum homocysteine levels may be associated with low levels of folate, vitamin B6 and vitamin B12. These studies showed that serum homocysteine levels were higher in men and older adults, and some showed that there was a direct relationship between homocysteine and cigarette smoking, diabetes, obesity, and hypertension. Subjects who consume larger amounts of coffee were also noted to have higher serum homocysteine levels. Several cross-sectional, case-control, and cohort studies have linked homocysteinaemia with cardiovascular disease morbidity and mortality. In the Framingham Heart Study, the cohort study in Tromso, Norway, and the Atherosclerosis Risk in Communities (ARIC) Study, homocysteine levels were found to be higher in adults with asymptomatic or symptomatic coronary artery disease. In the British Regional Heart Study, homocysteine levels were found to be significantly higher in patients with stroke. Thus, there are suggestions that vitamin therapy and alteration of lifestyle habits such as cigarette smoking may lower homocysteine levels. There may be less coronary heart disease morbidity and mortality with lower homocysteine levels.


A new form of neurite outgrowth sustained by the exocytosis of enlargeosomes expressed under the control of REST.
In neurons and neurosecretory (nerve) cells, neurite outgrowth requires surface enlargement sustained by exocytosis of specific but poorly characterized vesicles. A canonical, relatively slow form of outgrowth is known to require the v-SNARE Ti-VAMP. Recently, we have identified a new, rapid form, triggered by activation of Rac1 and sustained by the exocytosis of enlargeosomes (v-SNARE: VAMP4). By parallel study of various pheochromocytoma PC12 cell clones exhibiting either a single or both forms of outgrowth, we show that expression of enlargeosomes, their exocytosis at growth cones and their form of neurite outgrowth are positively governed by the RE-1 silencing transcription factor (REST), a repressor of many nerve cell-specific genes. Using a high REST/enlargeosome-rich PC12 clone transfected with TrkA, we found (i) that nerve growth factor (NGF) can increase the expression of both REST and the enlargeosome maker, Ahnak; and (ii) that outgrowth triggered by NGF, independent from the form triggered by Rac1 and supported mostly by exocytic, Ti-VAMP-positive organelles distinct from enlargeosomes, occurs at slow or fast rates depending on the strength of the TrkA signaling. These results confirm the duality of the outgrowth forms sustained by the two types of exocytic vesicles, reveal their distinct properties and identify new aspects of the REST impact in nerve cell specificity/function.


The Expanding Therapeutic Armamentarium for Inflammatory Bowel Disease: How to Choose the Right Drug[s] for Our Patients?
The therapeutic landscape for inflammatory bowel disease [IBD] is rapidly evolving. Two new biologic drugs, vedolizumab and ustekinumab, have recently entered the marketplace, the first biosimilars have been introduced, and several other agents are at an advanced stage of clinical development. In parallel, therapeutic goals have shifted from symptom control towards mucosal healing and prevention of bowel damage. In the coming years, gastroenterologists will be faced with unprecedented choices when selecting the best treatment for their patients with IBD. In this article, we review existing data on the mechanisms of action, efficacy, and safety of recently approved and late-stage pipeline therapies, and use this information to speculate on the positioning of these drugs, alone or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.


The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.
Parkinson's disease (PD) is a common neurodegenerative disease that is mainly in middle-aged people and elderly people, and the pathogenesis of PD is complex and diverse. The ubiquitin-proteasome system (UPS) is a master regulator of neural development and the maintenance of brain structure and function. Dysfunction of components and substrates of this UPS has been linked to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Moreover, UPS can regulate α-synuclein misfolding and aggregation, mitophagy, neuroinflammation and oxidative stress to affect the development of PD. In the present study, we review the role of several related E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) on the pathogenesis of PD such as Parkin, CHIP, USP8, etc. On this basis, we summarize the connections and differences of different E3 ubiquitin ligases in the pathogenesis, and elaborate on the regulatory progress of different DUBs on the pathogenesis of PD. Therefore, we can better understand their relationships and provide feasible and valuable therapeutic clues for UPS-related PD treatment research.


A Case of Iatrogenic Chordal Rupture after Transcatheter Aortic Valve Implantation Procedure Requiring a Second Valve.
Transcatheter aortic valve implantation (TAVI) has emerged as a therapeutic option for high-risk aortic stenosis. Malposition of the prosthesis and severe residual aortic regurgitation are known complications of the procedure, which might require a second valve implantation. Although the implantation of a second valve seems to be an effective method, very few data are available describing this technique. Herein is reported a case of iatrogenic chordal rupture in a TAVI procedure which required a second valve implantation due to dislodgment of the first prosthesis.


Testing a multigene signature of prostate cancer death in the Swedish Watchful Waiting Cohort.
Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Orebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions.


Protean appearances of immunodeficiencies: syndromes and inborn errors involving other systems which express associated primary immunodeficiency.
Developmental defects interrupting the normal evolution of immunocytes can explain many of the congenital immunodeficiency syndromes. Observations accumulated during the last decade have, however, shown that this is not the only cause, and that many diseases have signs of immunodeficiency as an accompanying feature. Severe combined immunodeficiency (SCID) is a good example of the multiple etiology of similar clinical features--they are phenocopies of a well-delineated hereditary disease. A number of recently described syndromes are reviewed, albeit an incomplete list. Metabolic disorders due to inactivity of enzymes may present characteristic ID. Some of them are explained by lack or increased need of co-enzymes (like biotin or zinc). In other syndromes, better understanding of the pathogenesis might pin down the primary failure to one single point, as shown in the hyper IgE syndrome. Other fundamental disturbances are located in the chromosome itself, eg decreased repair capacity, deletion, translocation. An attempt is made to propose a general classification accommodating all etiologic factors known to date which lead to immunodeficiency. It is obvious that within this framework the same clinical syndrome may be repeated.


Twelve-Months Follow-Up Postmarket Study of a Hydrophobic Intraocular Lens Using a Preloaded Automated Injector in an Indian Population.
To assess real-world clinical outcomes and safety of the Clareon® intraocular lens (IOL) and AutonoMe® automated preloaded delivery system in an Indian population. This was a prospective, single-arm, multicenter, 12-month clinical study in patients aged ≥20 years with unilateral or bilateral cataracts. Surgery was performed by phacoemulsification followed by implantation of the Clareon monofocal IOL (CNA0T0). Monocular best-corrected distance visual acuity (BCDVA) and uncorrected distance visual acuity (UCDVA) were assessed at 1 week and 1, 6, and 12 months after implantation. Posterior capsular opacification (PCO), surface haze, and glistenings were evaluated at all visits. Surgeons' satisfaction with automated injector system was also evaluated using a questionnaire. Safety was assessed by monitoring adverse events (AEs). A total of 151 eyes received the CNA0T0 IOL. Mean ± SD monocular BCDVA improved from 0.53±0.44 logMAR preoperatively to 0.00±0.08 logMAR at week 1 and -0.03±0.08 logMAR at 12 months after implantation. At 12 months, 137/137 (100%) of eyes achieved BCDVA of 0.3 logMAR or better. Mean ± SD monocular UCDVA was 0.78±0.40 logMAR preoperatively, 0.11±0.15 logMAR at week 1, and 0.08±0.13 logMAR at 12 months after implantation. At 12 months, 132/137 (96%) eyes achieved UCDVA of 0.3 logMAR or better. Serious intraoperative AEs were posterior capsule rupture (n=1) and ciliary zonular dehiscence (n=1). Surgeons reported that the automated preloaded device was more intuitive compared with other push- or screw-style preloaded injector systems. None of the eyes in this study presented surface haze; all were graded as 0 glistenings at all visits. No clinically significant PCO or neodymium-doped yttrium aluminum garnet (Nd:YAG) capsulotomies were reported. The hydrophobic IOL preloaded in an automated injector system provided good visual and refractive outcomes, as well as no surface haze and grade 0 glistenings. None of the patients required Nd:YAG capsulotomy.


Antimicrobial activity of ofloxacin and other agents against mycobacterial isolates from postoperative sternotomy wounds.
In 1987 and 1988, 16 patients in a cardiothoracic hospital developed median sternotomy wound infections from Mycobacterium fortuitum or Mycobacterium chelonei (M fortuitum, 14 patients; M chelonei, two patients). For M fortuitum isolates, the minimum inhibitory concentration (MIC) (by agar dilution) of ofloxacin was 0.32 to 1.25 mg/L; of amikacin, 0.5 to 1 mg/L; of sulfadiazine, 16 to 256 mg/L; of imipenem, less than or equal to 2 to 4 mg/L; of cefoxitin, 4 to 16 mg/L; of ampicillin, 64 to greater than 256 mg/L; of cephapirin, 64 to 128 mg/L; of cefoperazone, greater than 256 mg/L; and of ceftazidime, greater than 256 mg/L. Addition of sulbactam to ampicillin and cefoperazone resulted in at least a four- to eight-fold reduction of their respective MICs. For M chelonei isolates, the MIC of ofloxacin was greater than 20 mg/L; of amikacin, 8 mg/L; of sulfadiazine, 64 mg/L; of imipenem, 8 mg/L; of cefoxitin, 16 mg/L; of ampicillin, 128 mg/L; of cephapirin, 128 mg/L; of cefoperazone, greater than 256 mg/L; and of ceftazidime, greater than 256 mg/L. Addition of sulbactam resulted in much smaller reductions of the MICs of ampicillin and cefoperazone. Synergism was noticed between ofloxacin and amikacin against M chelonei but not against M fortuitum. The results indicate that ofloxacin alone is as effective as the combination of ofloxacin and amikacin in treating M fortuitum, but not M chelonei, infection.


KCNQ1 channels sense small changes in cell volume.
Many important physiological processes involve changes in cell volume, e.g. the transport of salt and water in epithelial cells and the contraction of cardiomyocytes. In this study, we show that voltage-gated KCNQ1 channels, which are strongly expressed in epithelial cells or cardiomyocytes, and KCNQ4 channels, expressed in hair cells and the auditory tract, are tightly regulated by small cell volume changes when co-expressed with aquaporin 1 water-channels (AQP1) in Xenopus oocytes. The KCNQ1 and KCNQ4 current amplitudes precisely reflect the volume of the oocytes. By contrast, the related KCNQ2 and KCNQ3 channels, which are prominently expressed in neurons, are insensitive to cell volume changes. The sensitivity of the KCNQ1 and KCNQ4 channels to cell volume changes is independent of the presence of the auxiliary KCNE1-3 subunits, although modulated by KCNE1 in the case of KCNQ1. Incubation of the oocytes in cytochalasin D and experiments with truncated KCNQ1 channels suggest that KCNQ1 channels sense cell volume changes through interactions between the cytoskeleton and the N-terminus of the channel protein. From our results we propose that KCNQ1 and KCNQ4 channels play an important role in cell volume control, e.g. during transepithelial transport of salt and water.


Self-protections in the narcissistic transference.
This is a study of two patients who had what might be considered classical examples of narcissistic transferences. They were both severely disturbed persons and one could decompensate into a disruptive psychosis. Consequently it is not surprising that their transference projections would be consonant with their primitive orientations. They projected hateful and hating parts of the self onto the analyst. But within all this hatred was a part of the self that had the potential to achieve good things for the patient. I believe the latter is a special feature of narcissistic transferences that has revieved very little emphasis and a feature that may cause us to view such patients and their projections somewhat more optimistically in terms of their potential for growth and treatability.


Ion Pairing Controls Physical Properties of Ionic Liquid-Solvent Mixtures.
The dissolution of room temperature ionic liquids (RTILs) in organic solvents has been shown to enhance ion dynamics. We previously used molecular dynamics (MD) simulations to study the ionic liquid ([BMIM+][Tf2N-]) in 22 unique solvents over a wide range of concentrations. By screening over a large parameter space, we reached several conclusions: (1) ion diffusivity increases monotonically as a function of increasing ionic liquid composition, (2) pure solvent diffusivity strongly correlates with ion diffusivity, and (3) conductivity predicted by the Nernst-Einstein (NE) equation has a maximum at intermediate compositions of ionic liquid. Building off this work, we now utilize the same parameter space to study the structure of ([BMIM+][Tf2N-]) solvated in organic solvents. We explore ion correlations through a number of structural and thermodynamic properties, including liquid densities, pair correlation functions, ion pairing and ion caging lifetimes, and free energy calculations. Through these analyses, we find that some solvents are much more effective at screening ion-ion interactions than others and that these differences impact the ion dynamics in these mixtures. In general, the strong pairing of ionic liquids negatively impacts transport properties, but some solvents can robustly screen these interactions, resulting in greatly enhanced ion dynamics. These results uncover trends connecting ionic liquid structure to transport, which can help in the design of new electrolytes for energy storage devices, such as electrical double layer capacitors and batteries.


Comparison of expressed sequence tags from male and female sexual organs of Marchantia polymorpha.
A total of 935 expressed sequence tags (ESTs) from male immature sexual organ were determined, of which 600 ESTs were assembled into 110 non-redundant groups, resulting in 445 unique EST sequences. Of these, 244 sequences shared significant similarities to known nucleotide or amino acid sequences in other organisms. The remaining 201 unique sequences showed no significant matches and thus are likely to be novel transcripts. ESTs from male and female immature sexual organs of a liverwort, Marchantia polymorpha, were compared to characterize gene expression patterns during sex differentiation. Ninety-nine male ESTs turned out to be common genes found also in the female library. Interestingly, one of the ESTs found only in male shows a significant similarity to the transformer-2 gene involved in sex determination in Drosophila. In female, several unique lectin ESTs were found that are not present in the male library.


Changes in the clinical phenotypes of multiple sclerosis during the past 50 years in Japan.
In order to clarify whether or not marked changes in the social environment during the past 50 years in Japan may have altered the clinical phenotypes of multiple sclerosis (MS), we retrospectively analyzed 143 consecutive patients with clinically definite MS who developed the disease between 1950 and 1997. Fifty-two patients were classified as Asian type MS showing a selective involvement of the optic nerves and the spinal cord, while 91 patients were considered to have Western type MS which demonstrated the involvement of multiple sites in the central nervous system including the cerebrum, cerebellum and brainstem. The ratio of Asian type versus Western type MS was 1:0.5 in the patients born in the 1920s and 1:1.27, 1:1.64 and 1:1.7 in those born in the 1930s, 1940s and 1950s, respectively, and thereafter it increased to 1:4.67 in those born in the 1960s and 1:4 in those born after the 1970s. As a result, the proportion of Asian type MS significantly decreased in the patients born after 1960 as compared with those born from 1930 to 1959 (P=0.0121). In the Asian type MS, the age of onset was significantly higher in the patients who developed the disease from 1985 to 1997 (42.4+/-13.5 years) than in those who developed the disease from 1950 to 1984 (32.3+/-12.4 years) (P=0.0149), while in the Western type MS no such change in the age of onset was observed. These findings suggest that the frequency of Asian type MS has apparently decreased in younger Japanese born after 1960 when Japan's rapid economic growth had just started, and environmental factors are therefore considered to contribute to determine the clinical phenotypes of MS in Asians.


Simulation-Based System Analysis: Testing Preparedness for Extracorporeal Membrane Oxygenation Cannulation in Pediatric COVID-19 Patients.
Coronavirus Disease-2019 presents risk to both patients and medical teams. Staff-intensive, complex procedures such as extracorporeal membrane oxygenation (ECMO) or extracorporeal cardiopulmonary resuscitation (eCPR) may increase chances of exposure and spread. This investigation aimed to rapidly deploy an in situ Simulation-based Clinical Systems Testing (SbCST) framework to identify Latent Safety Threats (LSTs) related to ECMO/eCPR initiation during a pandemic. The adapted SbCST framework tested systems related to ECMO/eCPR initiation in the Neonatal and Pediatric Intensive Care Units. Systems were evaluated in six domains (Resources, Processes/Systems, Facilities, Clinical Performance, Infection Control, and Communication). We conducted three high-fidelity simulations with members from the Neonatal Intensive Care Unit General Surgery, Pediatric Intensive Care Unit Cardiovascular Surgery (CV), and Pediatric Intensive Care Unit General Surgery teams. Content experts evaluated systems issues during simulation, and LSTs were identified during debriefing. Data were analyzed for frequency of LSTs and trends in process gaps. Sixty-six LSTs were identified across three scenarios. Resource issues comprised the largest category (26%), followed by Process/System issues (24%), Infection Control issues (24%), Communication issues (17%), and Facility and Clinical Performance issues (5% each). LSTs informed new team strategies such as the use of a "door/PPE monitor" and "inside/outside" team configuration. The adapted SbCST framework identified multiple LSTs related to ECMO/eCPR cannulation and infection control guidelines in the setting of Coronavirus Disease-2019. Through SbCSTs, we developed guidelines to conserve PPE and develop optimal workflows to reduce patient/staff exposure in a high-risk procedure. This project may guide other hospitals to adapt SbCSTs strategies to test/adjust rapidly changing guidelines.


Cardioprotective Effects of Malvidin Against Isoproterenol-Induced Myocardial Infarction in Rats: A Mechanistic Study.
BACKGROUND Malvidin (alvidin-3-glucoside) is a polyphenol that belongs to the class of natural anthocyanin, which is abundantly found in red wines, colored fruits, and the skin of red grapes. Therefore, the current investigation was intended to evaluate the effect of malvidin against myocardial infarction induced by isoproterenol in the rats. MATERIAL AND METHODS The cardioprotective effects was assessed by determining the effect of malvidin on the activities of endogenous antioxidants - catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH) - and on the levels of lipid peroxidation and serum marker enzymes. The serum levels of IL-6 and TNF-α were also determined using an enzyme-linked immunosorbent assay (ELISA) kit. RESULTS The present study demonstrated a significant cardioprotective effect of malvidin by restoring the defensive activities of endogenous antioxidants - catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH) - and by reducing the levels of lipid peroxidation and serum marker enzymes lactate dehydrogenase (LD) and creatine kinase (CK). Malvidin significantly ameliorated the histopathological changes and impaired mitochondria in the cardiac necrosis stimulated with isoproterenol. Additionally, the results also demonstrated that nuclear translocation of Nrf-2 and subsequent HO-1 expression might be associated with nuclear factor kappa B (NF-κB) pathway activation. CONCLUSIONS Our findings suggest that malvidin exerts cardioprotective effects that might be due to possible strong antioxidant and anti-inflammatory activities. Therefore, this study provides the basis for the development of malvidin as a safe and effective treatment of myocardial infarction.


Marine macroinvertebrate ecosystem services under changing conditions of seagrasses and mangroves.
This study aimed to investigate the impact of changing environmental conditions on MMI ES in seagrasses and mangroves. We used data from satellite and biodiversity platforms combined with field data to explore the links between ecosystem pressures (habitat conversion, overexploitation, climate change), conditions (environmental quality, ecosystem attributes), and MMI ES (provisioning, regulation, cultural). Both seagrass and mangrove extents increased significantly since 2016. While sea surface temperature showed no significant annual variation, sea surface partial pressure CO2, height above sea level and pH presented significant changes. Among the environmental quality variables only silicate, PO4 and phytoplankton showed significant annual varying trends. The MMI food provisioning increased significantly, indicating overexploitation that needs urgent attention. MMI regulation and cultural ES did not show significant trends overtime. Our results show that MMI ES are affected by multiple factors and their interactions can be complex and non-linear. We identified key research gaps and suggested future directions for research. We also provided relevant data that can support future ES assessments.


Effect of statin treatment on short term mortality after pneumonia episode: cohort study.
To determine whether statins protect against all cause mortality after a diagnosis of pneumonia. Cohort study using propensity score based method to control for differences between people prescribed and not prescribed statins. United Kingdom Health Improvement Network database, which contains electronic primary care medical records of more than six million patients. Every patient starting a statin between 1995 and 2006 (129,288) matched with up to five non-statin users (n = 600,241); 9073 patients had a recorded diagnosis of pneumonia, of whom 1398 were using a statin. All cause mortality within six months of diagnosis of pneumonia. Among users and non-users of statins with comparable propensity scores, 95/942 users and 686/3615 non-users died on the day that pneumonia was diagnosed. In the following six month period, 109/847 statin users died compared with 578/2927 non-users, giving an adjusted hazard ratio of 0.67 (0.49 to 0.91). If these observed benefits translated into clinical practice, 15 patients would need to be treated with a statin for six months after pneumonia to prevent one death. Compared with people who were not taking statins, the risk of dying in the six month period after pneumonia was substantially lower among people who were already established on long term statin treatment when the pneumonia occurred. Whether some or all of this protective effect would be obtained if statin treatment begins when a patient first develops pneumonia is not known. However, given that statins are cheap, safe, and well tolerated, a clinical trial in which people with pneumonia are randomised to a short period of statin treatment is warranted.


Coexistence of a colon carcinoma with two distinct renal cell carcinomas: a case report.
We present the case of a patient with two tumors in his left kidney and a synchronous colon cancer. While coexisting tumors have been previously described in the same kidney or the kidney and other organs, or the colon and other organs, to the best of our knowledge no such concurrency of three primary tumors has been reported in the literature to date. A 72-year-old man of Greek nationality presenting with pain in the right hypochondrium underwent a series of examinations that revealed gallstones, a tumor in the hepatic flexure of the colon and an additional tumor in the upper pole of the left kidney. He was subjected to a right hemicolectomy, left nephrectomy and cholecystectomy, and his postoperative course was uneventful. Histopathology examinations showed a mucinous colon adenocarcinoma, plus two tumors in the left kidney, a papillary renal cell carcinoma and a chromophobe renal cell carcinoma. This case underlines the need to routinely scan patients pre-operatively in order to exclude coexisting tumors, especially asymptomatic renal tumors in patients with colorectal cancer, and additionally to screen concurrent tumors genetically in order to detect putative common genetic alterations.


A Pooled Genome-Wide Association Study of Asperger Syndrome.
Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.


Dry habitats were crucibles of domestication in the evolution of agriculture in ants.
The evolution of ant agriculture, as practised by the fungus-farming 'attine' ants, is thought to have arisen in the wet rainforests of South America about 55-65 Ma. Most subsequent attine agricultural evolution, including the domestication event that produced the ancestor of higher attine cultivars, is likewise hypothesized to have occurred in South American rainforests. The 'out-of-the-rainforest' hypothesis, while generally accepted, has never been tested in a phylogenetic context. It also presents a problem for explaining how fungal domestication might have occurred, given that isolation from free-living populations is required. Here, we use phylogenomic data from ultra-conserved element (UCE) loci to reconstruct the evolutionary history of fungus-farming ants, reduce topological uncertainty, and identify the closest non-fungus-growing ant relative. Using the phylogeny we infer the history of attine agricultural systems, habitat preference and biogeography. Our results show that the out-of-the-rainforest hypothesis is correct with regard to the origin of attine ant agriculture; however, contrary to expectation, we find that the transition from lower to higher agriculture is very likely to have occurred in a seasonally dry habitat, inhospitable to the growth of free-living populations of attine fungal cultivars. We suggest that dry habitats favoured the isolation of attine cultivars over the evolutionary time spans necessary for domestication to occur.


Ece1 and Tbx1 define distinct pathways to aortic arch morphogenesis.
Pharyngeal arch artery (PAA) remodeling defects account for several cases of congenital heart disease. Mutations in the Endothelin-1 genetic pathway or Tbx1, a candidate gene for DiGeorge syndrome, cause similar aortic arch defects. Previous research suggests that Tbx1 may trigger diffusible signals from the pharyngeal arches to support the growth of the PAAs that contribute to the mature aortic arch. The demonstration of genetic interaction between Tbx1 and Fgf8 pointed to FGF signaling as a possible candidate. Because Fgf8 interacts with Endothelin-1 signaling and because Endothelin-1 signaling interacts with neural crest-derived cells in the pharyngeal apparatus, we hypothesized that Tbx1 and Endothelin-1 signaling may contribute to the same pathway required for aortic arch morphogenesis. Therefore, we have analyzed mice mutated for the endothelin converting enzyme (Ece1) or Tbx1 genes and compound mutants. Results show that the two genes have different roles in the remodeling of the PAAs and do not interact. We propose that Tbx1 is required for the formation and early growth and remodeling of the PAAs, whereas Ece1 is necessary for regression of the cranial arch arteries and growth of the most caudal arch arteries. The latter function is likely related to the known role of the Endothelin-1 pathway in neural crest function.


Cancer chemoprevention by dietary chlorophylls: a 12,000-animal dose-dose matrix biomarker and tumor study.
Recent pilot studies found natural chlorophyll (Chl) to inhibit carcinogen uptake and tumorigenesis in rodent and fish models, and to alter uptake and biodistribution of trace (14)C-aflatoxin B1 in human volunteers. The present study extends these promising findings, using a dose-dose matrix design to examine Chl-mediated effects on dibenzo(def,p)chrysene (DBC)-induced DNA adduct formation, tumor incidence, tumor multiplicity, and changes in gene regulation in the trout. The dose-dose matrix design employed an initial 12,360 rainbow trout, which were treated with 0-4000ppm dietary Chl along with 0-225ppm DBC for up to 4weeks. Dietary DBC was found to induce dose-responsive changes in gene expression that were abolished by Chl co-treatment, whereas Chl alone had no effect on the same genes. Chl co-treatment provided a dose-responsive reduction in total DBC-DNA adducts without altering relative adduct intensities along the chromatographic profile. In animals receiving DBC alone, liver tumor incidence (as logit) and tumor multiplicity were linear in DBC dose (as log) up to their maximum-effect dose, and declined thereafter. Chl co-treatment substantially inhibited incidence and multiplicity at DBC doses up to their maximum-effect dose. These results show that Chl concentrations encountered in Chl-rich green vegetables can provide substantial cancer chemoprotection, and suggest that they do so by reducing carcinogen bioavailability. However, at DBC doses above the optima, Chl co-treatments failed to inhibit tumor incidence and significantly enhanced multiplicity. This finding questions the human relevance of chemoprevention studies carried out at high carcinogen doses that are not proven to lie within a linear, or at least monotonic, endpoint dose-response range.


Negative regulation of lymphocyte activation by the adaptor protein LAX.
The membrane-associated adaptor protein LAX is a linker for activation of T cells (LAT)-like molecule that is expressed in lymphoid tissues. Upon stimulation of T or B cells, it is phosphorylated and interacts with Grb2 and the p85 subunit of PI3K. LAX, however, is not capable of replacing LAT in the TCR signaling pathway. In this study we report that upon T or B cell activation, the LAX protein was up-regulated dramatically. Although disruption of the LAX gene by homologous recombination had no major impact on lymphocyte development, it caused a significant reduction in CD23 expression on mature B cells. Interestingly, naive LAX(-/-) mice had spontaneous germinal center formation. Compared with normal T and B cells, LAX(-/-) T and B cells were hyperresponsive and had enhanced calcium flux, protein tyrosine phosphorylation, MAPK and Akt activation, and cell survival upon engagement of the T or B AgRs. Our data demonstrate that LAX functions as a negative regulator in lymphocyte signaling.


[Perforated juxta-papillary duodenal diverticula: two cases].
Perforation of juxta-ampullary duodenal diverticula, occurring spontaneously or after abdominal trauma, is a severe condition. Diagnosis is difficult to establish and is based on tomodensitometry, which is the most reliable diagnostic tool. Treatment consists in diverticulectomy that can be associated with drainage of the duodenum or anastomosis between digestive and biliary tract. We report two cases of perforated juxta-ampullary duodenal diverticula. Perforation was spontaneous in one case and complicated a blunt abdominal trauma in the other case.


Associations Between Psychosocial Measures and Digital Media Use Among Transgender Youth: Cross-sectional Study.
Transgender, nonbinary, and gender-diverse (TNG) youth encounter barriers to psychosocial wellness and also describe exploring identities and communities on the web. Studies of cisgender youth connect increased digital technology use with lower well-being, parent relationships, and body image scores as well as increased loneliness and fear of missing out (FOMO). However, little is known about the psychosocial factors associated with digital technology use among TNG compared with cisgender youth. This study aims to examine the associations between psychosocial measures and digital technology use and its importance for cisgender and TNG youth. We surveyed a nationally representative sample of adolescents (aged 13-18 years) about psychosocial wellness and digital technology use. Psychosocial measures included assessment of well-being, parental relationships, body image, loneliness, and FOMO. Digital media use assessments included the short Problematic and Risky Internet Use Screening Scale-3 and the Adolescent Digital Technology Interactions and Importance (ADTI) scale and subscales. We compared psychosocial measures between gender identity groups. We also compared stratified correlations for psychosocial measures (well-being, parent relationships, body image, loneliness, and FOMO) with ADTI and Problematic and Risky Internet Use Screening Scale-3 scores between gender identity groups. All comparisons were adjusted for age, race, and ethnicity. Among 4575 adolescents, 53 (1.16%) self-identified as TNG youth. TNG youth had lower scores for well-being (23.76 vs 26.47; P<.001), parent relationships (19.29 vs 23.32; P<.001), and body image (13.50 vs 17.12; P<.001), and higher scores for loneliness (9.28 vs 6.55; P<.001) and FOMO (27.93 vs 23.89; P=.004), compared with cisgender peers. In a pattern different from that of their cisgender peers, better well-being scores and body image for TNG youth predicted higher problematic internet use (PIU) scores (correlation coefficients of 0.32 vs -0.07; P=.004 and 0.26 vs -0.21; P=.002, respectively). FOMO was a stronger positive predictor of higher ADTI total and subscale scores for cisgender youth compared with TNG youth. Overall, this study supports previously demonstrated disparities in the psychosocial wellness of TNG youth and adds that these disparities include loneliness and FOMO. This study shows prediction of PIU by both higher well-being and better body image, indicating that PIU may not be unilaterally driven by problematic factors among TNG youth. We suggest that this may be because of the specific digital media functions that TNG youth engage with as a disenfranchised population.


Code-based Diagnostic Algorithms for Idiopathic Pulmonary Fibrosis. Case Validation and Improvement.
Population-based studies of idiopathic pulmonary fibrosis (IPF) in the United States have been limited by reliance on diagnostic code-based algorithms that lack clinical validation. To validate a well-accepted International Classification of Diseases, Ninth Revision, code-based algorithm for IPF using patient-level information and to develop a modified algorithm for IPF with enhanced predictive value. The traditional IPF algorithm was used to identify potential cases of IPF in the Kaiser Permanente Northern California adult population from 2000 to 2014. Incidence and prevalence were determined overall and by age, sex, and race/ethnicity. A validation subset of cases (n = 150) underwent expert medical record and chest computed tomography review. A modified IPF algorithm was then derived and validated to optimize positive predictive value. From 2000 to 2014, the traditional IPF algorithm identified 2,608 cases among 5,389,627 at-risk adults in the Kaiser Permanente Northern California population. Annual incidence was 6.8/100,000 person-years (95% confidence interval [CI], 6.1-7.7) and was higher in patients with older age, male sex, and white race. The positive predictive value of the IPF algorithm was only 42.2% (95% CI, 30.6 to 54.6%); sensitivity was 55.6% (95% CI, 21.2 to 86.3%). The corrected incidence was estimated at 5.6/100,000 person-years (95% CI, 2.6-10.3). A modified IPF algorithm had improved positive predictive value but reduced sensitivity compared with the traditional algorithm. A well-accepted International Classification of Diseases, Ninth Revision, code-based IPF algorithm performs poorly, falsely classifying many non-IPF cases as IPF and missing a substantial proportion of IPF cases. A modification of the IPF algorithm may be useful for future population-based studies of IPF.


The Parkinson's Disease-Associated Protein DJ-1 Protects Dictyostelium Cells from AMPK-Dependent Outcomes of Oxidative Stress.
Mitochondrial dysfunction has been implicated in the pathology of Parkinson's disease (PD). In Dictyostelium discoideum, strains with mitochondrial dysfunction present consistent, AMPK-dependent phenotypes. This provides an opportunity to investigate if the loss of function of specific PD-associated genes produces cellular pathology by causing mitochondrial dysfunction with AMPK-mediated consequences. DJ-1 is a PD-associated, cytosolic protein with a conserved oxidizable cysteine residue that is important for the protein's ability to protect cells from the pathological consequences of oxidative stress. Dictyostelium DJ-1 (encoded by the gene deeJ) is located in the cytosol from where it indirectly inhibits mitochondrial respiration and also exerts a positive, nonmitochondrial role in endocytosis (particularly phagocytosis). Its loss in unstressed cells impairs endocytosis and causes correspondingly slower growth, while also stimulating mitochondrial respiration. We report here that oxidative stress in Dictyostelium cells inhibits mitochondrial respiration and impairs phagocytosis in an AMPK-dependent manner. This adds to the separate impairment of phagocytosis caused by DJ-1 knockdown. Oxidative stress also combines with DJ-1 loss in an AMPK-dependent manner to impair or exacerbate defects in phototaxis, morphogenesis and growth. It thereby phenocopies mitochondrial dysfunction. These results support a model in which the oxidized but not the reduced form of DJ-1 inhibits AMPK in the cytosol, thereby protecting cells from the adverse consequences of oxidative stress, mitochondrial dysfunction and the resulting AMPK hyperactivity.


Clinical characterization and mutation spectrum in Caribbean Hispanic families with Lynch syndrome.
Lynch syndrome (LS) is an inherited form of colorectal cancer (CRC) caused by germline mutations in the mismatch repair (MMR) genes. It accounts for approximately 5% of all CRCs. The prevalence of LS among US Hispanics is unknown. The objective of this study was to describe the germline mutations of LS in Caribbean Hispanics from Puerto Rico and Dominican Republic. A total of 89 subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. A total of 35 individuals with deficient MMR system were identified: 22 had MMR mutations and 13 had tumors with absent MMR protein expression. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7%) mutations, followed by MLH1 (25.0%). One mutation was identified in MSH6 (8.3%). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutation-positive individuals were found to be more likely to have a prominent family history of CRC and tumors located at the proximal colon. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC and LS associated cancers. Furthermore, insurance coverage for genetic testing was found to be limited in the study population with 65.1% of the individuals recruited were denied coverage. This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients.


An artificial model for studying fluid dynamics in the obstructed and stented ureter.
Fluid dynamics in the obstructed and stented ureter represents a non-trivial subject of investigation since, after stent placement, the urine can flow either through the stent lumen or in the extra-luminal space located between the stent wall and the ureteric inner wall. Fluid dynamic investigations can help understanding the phenomena behind stent failure (e.g. stent occlusions due to bacterial colonization and encrustations), which may cause kidney damage due to the associated high pressures generated in the renal pelvis. In this work a microfluidic-based transparent device (ureter model, UM) has been developed to simulate the fluid dynamic environment in a stented ureter. UM geometry has been designed from measurements on pig ureters. Pressure in the renal pelvis compartment has been measured against three variables: fluid viscosity (μ), volumetric flow rate (Q) and level of obstruction (OB%). The measurements allowed a quantification of the critical combination of μ, Q and OB% values which may lead to critical pressure levels in the kidney. Moreover, an example showing the possibility of applying particle image velocimetry (PIV) technology to the developed microfluidic device is provided.


Grafted Polymer Coatings Enhance Fouling Inhibition by an Antimicrobial Peptide on Reverse Osmosis Membranes.
Bacterial biofilms that are formed on surfaces are highly detrimental to many areas of industry and medicine. Seawater desalination by reverse osmosis (RO) suffers from biofilm growth on the membranes (biofouling), which limits its widespread use because biofouling decreases water permeance and necessitates module cleaning and replacement, leading to increased economic and environmental costs. Antimicrobial peptides (AMPs) bound covalently to RO membranes inhibit biofilm growth and might delay membrane biofouling. Here we examined how various hydrophilic membrane coatings composed of zwitterionic, neutral, positively charged, and poly(ethylene glycol) (PEG)-grafted polymers affected the biocidal activity and the biofilm inhibition of a covalently bonded AMP on RO membranes. AMP magainin-2 was linked by the copper-catalyzed azide-alkyne cycloaddition reaction to a series of RO membranes that were grafted with different methacrylate polymers. Surface characterization by infrared spectroscopy, X-ray photoelectron spectroscopy, and water drop contact angle gave evidence of successful RO modifications, and zeta potential analysis reflected the increase in surface charge due to the linked, positively charged peptide. All AMP-modified membranes inhibited Pseudomonas aeruginosa growth compared to unmodified membranes, and the grafted methacrylic polymers did not significantly interfere with the peptide activity. On the other hand, membranes coated with zwitterionic and other acrylate polymers including AMP attachment inhibited biofilm growth more than either the AMP or the polymer coating alone. This enhancement led to ∼20% less biofilm biovolume on the membrane surfaces. The combination of antimicrobial coatings with polymer coatings known to resist fouling might aid future designs of surface coatings susceptible to biofilm growth.


Carnitinuria in rickets due to vitamin D deficiency.
In this study, we measured the serum-urine total carnitine levels and PTH levels before and after treatment in 18 patients with nutritional rickets. The urine and blood samples were taken on the first (pretreatment) and the 15th day of the study (post-treatment). The total carnitine levels of serum and urine samples, serum PTH and serum-urine creatinine concentrations were determined. We found that the levels of carnitine excreted in the urine on the first (pre-treatment) and on the 15th day (post-treatment) were higher than the reference levels. Decrease in carnitine excretion on the 15th day seemed to be correlated with decrease in aminoaciduria at that time. The study showed a significant correlation between urinary carnitine excretion and serum PTH levels. In our study we did not find any significant difference between the serum total carnitine levels on the first (pre-treatment) and the 15th day (post-treatment), and both values were lower than the reference values for the same age group. We observed that the total serum carnitine levels did not change on the 15th day of the post-treatment period in spite of a decrease in urinary carnitine excretion. The results of the present study indicated that carnitine metabolism is disturbed in nutritional rickets. Further evaluation of rickets cases and new studies will probably lead to a better understanding of carnitine metabolism in nutritional rickets.


Facile dynamic one-step modular assembly based on boronic acid-diol for construction of a micellar drug delivery system.
Nano-assembled amphiphilic micelles with characteristics including facile control, a simplified construction procedure, convenient and efficient drug loading, and a controlled release at pathological sites are in high demand. This study reports a facile and dynamic one-step modular assembly strategy based on boronic acid-diol for constructing focus-responsive micellar drug delivery systems. In this manner, a dopamine modified hydrophilic building block, phenylboronic acid modified hydrophobic building block and drug molecules (Dox) spontaneously one-step assembled into drug encapsulated distinct core/shell micelles (Dox/PBAE-M) in mild physiological media. After a simple adjustment of weight ratios between these three building blocks, Dox/PBAE-M, with the highest Dox-loading capacity (22.4%) and optimal physical dimensions, was generated. Furthermore, the desirable pH-dependent disassembly of Dox/PBAE-M was independently verified by morphological changes alongside in vitro release of Dox in different simulated environments. The experimental results here demonstrated that Dox/PBAE-M kept structural integrity in normal physiological environments, while accomplishing a selective nano-disassembly and Dox release within acid endo/lysosomes. As a result, Dox/PBAE-M exhibited the highest cytotoxicity and apoptosis induction among all of the tested groups on the 4T1 breast cancer xenograft model. This newly proposed assembly strategy gave new insight into easy fabrication and disassembly of multi-functional micellar drug delivery systems.


The genome sequence of the rice blast fungus Magnaporthe grisea.
Magnaporthe grisea is the most destructive pathogen of rice worldwide and the principal model organism for elucidating the molecular basis of fungal disease of plants. Here, we report the draft sequence of the M. grisea genome. Analysis of the gene set provides an insight into the adaptations required by a fungus to cause disease. The genome encodes a large and diverse set of secreted proteins, including those defined by unusual carbohydrate-binding domains. This fungus also possesses an expanded family of G-protein-coupled receptors, several new virulence-associated genes and large suites of enzymes involved in secondary metabolism. Consistent with a role in fungal pathogenesis, the expression of several of these genes is upregulated during the early stages of infection-related development. The M. grisea genome has been subject to invasion and proliferation of active transposable elements, reflecting the clonal nature of this fungus imposed by widespread rice cultivation.


Topical Fluoxetine as a Novel Therapeutic That Improves Wound Healing in Diabetic Mice.
Diabetic foot ulcers represent a significant source of morbidity in the U.S., with rapidly escalating costs to the health care system. Multiple pathophysiological disturbances converge to result in delayed epithelialization and persistent inflammation. Serotonin (5-hydroxytryptamine [5-HT]) and the selective serotonin reuptake inhibitor fluoxetine (FLX) have both been shown to have immunomodulatory effects. Here we extend their utility as a therapeutic alternative for nonhealing diabetic wounds by demonstrating their ability to interact with multiple pathways involved in wound healing. We show that topically applied FLX improves cutaneous wound healing in vivo. Mechanistically, we demonstrate that FLX not only increases keratinocyte migration but also shifts the local immune milieu toward a less inflammatory phenotype in vivo without altering behavior. By targeting the serotonin pathway in wound healing, we demonstrate the potential of repurposing FLX as a safe topical for the challenging clinical problem of diabetic wounds.


Pyrethroid insecticides in municipal wastewater.
Pyrethroids are widely used insecticides, but minimal information has been published on their presence in municipal wastewater in the United States. Pyrethroids in wastewater from the Sacramento, California, USA, area consisted of permethrin, bifenthrin, cypermethrin, and cyhalothrin, with a combined concentration of 200 ng/L to 500 ng/L. Sampling within the wastewater collection system leading to the treatment plant suggested pyrethroids did not originate primarily from urban runoff, but could be from any of several drain disposal practices. Wastewater from residential areas was similar in pyrethroid composition and concentration to that from the larger metropolitan area as a whole. Secondary treatment removed approximately 90% of pyrethroids, but those remaining exceeded concentrations acutely toxic to sensitive species. Toxicity to the amphipod, Hyalella azteca, was consistently evident in the final effluent. The large river into which this particular plant discharged provided sufficient dilution such that pyrethroids were undetected in the river, and there was only slight toxicity of unknown cause in 1 river sample, but effects in receiving waters elsewhere will be site-specific.


Kinetics of bone marrow eosinophilopoiesis and associated cytokines after allergen inhalation.
Allergen inhalation is associated with increased eosinophil/basophil progenitors in bone marrow 24 hours after allergen inhalation. This study examined the kinetics of eosinophilopoiesis in dual (n = 14), compared with isolated early, responders (n = 12). Dual responders, in contrast to isolated early responders, develop significant sputum and blood eosinophilia and prolonged airway hyperresponsiveness. Bone marrow aspirates were taken before and 5, 12, 24, and 48 hours after allergen inhalation. In dual responders, increases in interleukin (IL)-3-responsive progenitors were detected as early as 5 hours after allergen inhalation, and IL-5-responsive progenitors were detected at 12 and 24 hours. No changes were detected in isolated early responders. Bone marrow IL-5 protein levels increased at 12 and 24 hours in dual responders only and these increases correlated with increases in IL-5-responsive progenitors. In addition, bone marrow IFN-gamma levels increased in dual responders at 48 hours. These data demonstrate that, in dual responders, there is allergen-induced activation of an eosinophilopoietic process that is rapid and sustained, and a relationship between increased bone marrow IL-5 levels and increased eosinophil production. We propose that after allergen inhalation, time-dependent changes in cytokine levels in the bone marrow control differentiation of eosinophil/basophil progenitors.


Integrated Phloem Sap mRNA and Protein Expression Analysis Reveals Phytoplasma-infection Responses in Mulberry.
To gain insight into the response of mulberry to phytoplasma-infection, the expression profiles of mRNAs and proteins in mulberry phloem sap were examined. A total of 955 unigenes and 136 proteins were found to be differentially expressed between the healthy and infected phloem sap. These differentially expressed mRNAs and proteins are involved in signaling, hormone metabolism, stress responses, etc. Interestingly, we found that both the mRNA and protein levels of the major latex protein-like 329 (MuMLPL329) gene were increased in the infected phloem saps. Expression of the MuMLPL329 gene was induced by pathogen inoculation and was responsive to jasmonic acid. Ectopic expression of MuMLPL329 in Arabidopsis enhances transgenic plant resistance to Botrytis cinerea, Pseudomonas syringae pv tomato DC3000 (Pst. DC3000) and phytoplasma. Further analysis revealed that MuMLPL329 can enhance the expression of some defense genes and might be involved in altering flavonoid content resulting in increased resistance of plants to pathogen infection. Finally, the roles of the differentially expressed mRNAs and proteins and the potential molecular mechanisms of their changes were discussed. It was likely that the phytoplasma-responsive mRNAs and proteins in the phloem saps were involved in multiple pathways of mulberry responses to phytoplasma-infection, and their changes may be partially responsible for some symptoms in the phytoplasma infected plants.


S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen receptors.
The defining characteristic of a tumor cell is its ability to escape the constraints imposed by neighboring cells, invade the surrounding tissue and metastasize to distant sites. This invasive property of tumor cells is dependent on activation of proteinases at the cell surface. The serine proteinase plasmin is one of the key proteinases that participate in the pericellular proteolysis associated with the invasive program of tumor cells. The assembly of plasminogen and tissue plasminogen activator at the endothelial cell surface or on the fibrin clot provides a focal point for plasmin generation and therefore plays an important role in maintaining blood fluidity and promoting fibrinolysis. S100A10, a member of the S100 family of Ca2+-binding proteins, is a dimeric protein composed of two 11 kDa subunits. Typically, S100A10 is found in most cells bound to its annexin A2 ligand as the heterotetrameric (S100A10)2(annexin A2)2 complex, AIIt. In addition to an intracellular distribution, S100A10 is present on the extracellular surface of many cells. The carboxyl-terminal lysines of S100A10 bind tPA and plasminogen resulting in the stimulation of tPA-dependent plasmin production. Carboxypeptidases cleave the carboxyl-terminal lysines of S100A10, resulting in a loss of binding and activity. Plasmin binds to S100A10 at a distinct site and the formation of the S100A10-plasmin complex stimulates plasmin autoproteolysis thereby providing a highly localized transient pulse of plasmin activity at the cell surface. The binding of tPA and plasmin to S100A10 also protects against inhibition by physiological inhibitors, PAI-1 and alpha2-antiplasmin, respectively. S100A10 also colocalizes plasminogen with the uPA-uPAR complex thereby localizing and stimulating uPA-dependent plasmin formation to the surface of cancer cells. The loss of S100A10 from the extracellular surface of cancer cells results in a significant loss in plasmin generation. In addition, S100A10 knock-down cells demonstrate a dramatic loss in extracellular matrix degradation and invasiveness as well as reduced metastasis. Annexin A2 plays an important role in plasminogen regulation by controlling the levels of extracellular S100A10 and by acting as a plasmin reductase. The mechanism by which annexin A2 regulates the extracellular levels of S100A10 is unknown. This review highlights the important part that S100A10 plays in plasmin regulation and the role this protein plays in cancer cell invasiveness and metastasis.


[Thoracoscopic clipping of thoracic duct in a woman with persisting chylothorax].
A 78-year-old female had chest pain, radiating to the back, caused by a thoracic aneurysm of the aorta. A vascular prosthesis was sutured into place through a left-sided thoracotomy. Six days after the operation she developed chylothorax on the right side. Following 14 days of conservative management, chyle leakage persisted at a rate of 1500 ml per 24 hours. By thoracoscopy the thoracic duct was dissected and clipped, which stopped the chyle leakage. The patient recovered moderately well. Conservative measures, such as adjusted nutrition, are successful in 50% of patients. Clipping of the thoracic duct by thoracoscopy is a definitive and minimally invasive procedure to treat persistent chyle leakage.


Inhibition of NADPH oxidase by apocynin promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress in rats.
Preventive and/or therapeutic interventions for ischemic heart disease have gained considerable attention worldwide. We investigated the mechanism(s) underlying cardioprotection of apocynin (APO) and whether it attenuates isoproterenol (ISO)-induced myocardial damage in vivo. Thirty-two male Wistar Albino rats were randomised into four groups (n = 8 for each group): Group I (Control); Group II (ISO), ISO was given intraperitoneally (ip) (150 mg/kg/d) daily for 2 consecutive days; Group III (APO + ISO), APO was applied ip 20 mg/kg 30 min before the first ISO administration and continued for the next 2 d after the second ISO administration; Group IV (ISO + APO), after the ISO treatment on days 1 and 2, 20 mg/kg APO was given ip on days 3 and 4. Cardioprotective effects of APO were evaluated by biochemical values, histopathological observations and the antiapoptotic relative proteins. Mean blood pressure, heart rate, and electrocardiography (ECG) were also monitored. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), caspase-3 and connexin 43 levels were determined. Major ECG changes were observed in the ISO-treated rats. MDA, TOS, OSI and creatine kinase levels decreased and SOD, CAT, GSH and TAC levels increased, indicating that APO reduced cardiac injury and oxidative stress compared with controls. APO also decreased the number of cardiomyocytes with pyknotic nuclei, inflammatory cell infiltration, intracytoplasmic vacuolisation and myofibrils. APO provides preventive and therapeutic effects on ISO-induced myocardial injury in rats by inhibiting reactive oxygen species production, blocking inflammation and enhancing antioxidant status.


Proliferation of ineffective erythropoiesis with nuclear abnormalities and megaloblastoid appearance in preleukaemia.
Erythropoiesis of two patients in the early stage of acute leukaemia and two patients with refractory anaemia and hypercellular bone marrow (preleukaemia?) was studied with the cytophotometric-autoradiographic method. Megaloblastoid erythroblasts show a decreased proliferative activity in comparison to the morphologically normal cells and are in the maturation stage of E4 (early polychromatic normoblasts) mainly in the G1-phase; they are therefore largely comparable to the megaloblastoid erythroblasts in erythroleukaemia. Erythroblasts in preleukaemia with nuclear abnormalities are found in a high percentage in the G2-phase or are unlabelled with a DNA content of between diploid and tetraploid value. They show a similar proliferative behaviour to the megaloblasts in pernicious anaemia. Early polychromatic erythroblasts arrested in G2-phase can differentiate without mitosis into tetraploid mature erythroblasts (E5). They can divide elsewhere endomitotically, produce binucleated E5 or take up the DNA synthesis and become polyploid. E4 with nuclear abnormalities do not proliferate and are mainly found in the premitotic phase.


Honey: A realistic antimicrobial for disorders of the skin.
Resistance of pathogenic microorganisms to antibiotics is a serious global health concern. In this review, research investigating the antimicrobial properties of honeys from around the world against skin relevant microbes is evaluated. A plethora of in vitro studies have revealed that honeys from all over the world have potent microbicidal activity against dermatologically important microbes. Moreover, in vitro studies have shown that honey can reduce microbial pathogenicity as well as reverse antimicrobial resistance. Studies investigating the antimicrobial properties of honey in vivo have been more controversial. It is evident that innovative research is required to exploit the antimicrobial properties of honey for clinical use and to determine the efficacy of honey in the treatment of a range of skin disorders with a microbiological etiology.


Dickkopf-3 acts as a modulator of B cell fate and function.
The mechanisms responsible for the generation of a mature B1 and B2 cell compartment are still poorly understood. In this study, we demonstrated that absence of Dickkopf-3 (DKK3) led to changes in the composition of the B cell compartment, which were due to an altered development and maintenance program of B cells. Development of B2 cells was impaired at the pre- and immature B cell stage, resulting in decreased numbers of follicular B cells in adult DKK3-deficient mice. Furthermore, DKK3 limited B1 cell self-maintenance in the periphery, by decreasing the survival and proliferation behavior of B1 cells. DKK3 may act via the BCR signaling pathway, as Ca(2+) influx upon BCR stimulation was increased and SiglecG, a molecule shown to inhibit Calcium signaling, was downregulated in the absence of DKK3. DKK3-deficient mice exhibited altered Ab responses and an increased secretion of the cytokine IL-10. Additionally, DKK3 limited autoimmunity in a model of systemic lupus erythematosus. In summary, we identified DKK3 as a novel modulator interfering with B cell fate as well as the maintenance program of B cells, leading to changes in B cell immune responses.


Oseltamivir-warfarin interaction in hypoplastic left heart syndrome: case report and review.
An 8-year-old boy with hypoplastic left heart syndrome with a previous history of thrombosis within the inferior vena cava receiving stable warfarin dosing for anticoagulation was diagnosed with influenza B. He was subsequently placed on oseltamivir therapy according to the Centers for Disease Control and Prevention clinical practice guidelines. During the hospitalization, his international normalized ratio steadily increased to supratherapeutic levels and returned to baseline after discontinuation of oseltamivir therapy. This case represents a drug-drug interaction that has not been previously reported in children or adolescents. An extensive review of the pharmacokinetic and pharmacodynamic literature did not uncover a definitive etiology for this interaction. However, several undefined aspects in each drug's disposition pathway need further elucidation. Until this interaction is understood, caution is warranted, and close monitoring of the international normalized ratio should be performed in all patients prescribed oseltamivir concomitantly with warfarin.


Fatty acid changes in liver and plasma lipid fractions after safflower oil was fed to rats deficient in essential fatty acids.
1. Fatty acid patterns of liver and plasma triglycerides, phospholipids and cholesteryl esters were determined at intervals during 24hr. after essential fatty acid-deficient rats were given one feeding of linoleate (as safflower oil). 2. Liver triglyceride, phospholipid and cholesteryl ester fatty acid compositions did not change up to 7hr. after feeding. Between 7 and 10hr., linoleic acid began to increase in all fractions, but arachidonic acid did not begin to rise in the phospholipid until 14-19hr. after feeding. 3. Oleic acid and eicosatrienoic acid in liver phospholipid began to decline at about the time that linoleic acid increased, i.e. about 9hr. before arachidonic acid began to increase. 4. Changes in linoleic acid, arachidonic acid and eicosatrienoic acid in phosphatidylcholine resembled those of the total phospholipid. Phosphatidylethanolamine had a higher percentage content of arachidonic acid before the linoleate was given than did phosphatidylcholine, and after the linoleate was given the fatty acid composition of this fraction was little changed. 5. The behaviour of the plasma lipid fatty acids was similar to that of the liver lipids, with changes in linoleic acid, eicosatrienoic acid and arachidonic acid appearing at the same times as they occurred in the liver. 6. The results indicated that linoleic acid was preferentially incorporated into the liver phospholipid at the expense of eicosatrienoic acid and oleic acid. The decline in these fatty acids apparently resulted from their competition with linoleic acid for available sites in the phospholipids rather than from any direct replacement by arachidonic acid.


Associations between physical activity and fat mass in adolescents: the Stockholm Weight Development Study.
Obesity is multifactorial. However, the accumulation of fat mass (FM) is proposed to be due to a positive energy balance, which may be caused by reduced physical activity (PA). The objectives of the study were to describe the independent associations between PA and FM in adolescents and to describe the intergenerational association of FM between mothers and their offspring. We conducted a cross-sectional study in 445 (190 M, 255 F) 17-y-old adolescents and their mothers. PA was assessed with a self-reported questionnaire and validated by comparison with accelerometric data in a subsample of the cohort. Body composition was measured by using air-displacement plethysmography. Males were significantly more active than were females (P<0.01). PA was significantly and inversely associated with FM (beta=-3.63, P=0.005) and percentage FM (beta=-3.117, P=0.017) in males but not in females (beta=-0.576, P=0.54; beta=-0.532, P=0.59, respectively) after adjustment for birth weight and maternal FM and education level. However, FM and percentage FM in females were significantly associated with maternal FM (beta=0.159, P<0.0001; beta=0.145, P=0.002, respectively) and education level (beta=-1.048, P<0.005; beta=-1.085, P=0.006, respectively). No such associations were observed in males. PA was independently associated with FM in males but not in females. The data also showed an intergenerational association of FM between mothers and their daughters but not between mothers and their sons.


Important role of physicians in addressing psychological aspects of interstitial cystitis/bladder pain syndrome (IC/BPS): a qualitative analysis.
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood source of chronic pain causing significant morbidity, with variable treatment success. Despite the need to understand patient perspectives in chronic pain, there is a paucity of qualitative data for IC/BPS. We aimed to acquire information regarding patient experience with IC/BPS symptoms and with their medical care to elicit suggestions to improve patient satisfaction with that care. Fifteen women with IC/PBS participated in a total of four focus groups. Sessions were recorded and transcribed and information deidentified. Focus groups were conducted until thematic saturation was reached. All transcripts were coded and analyzed by a minimum of three independent physician reviewers. Investigators identified emergent themes and concepts using grounded-theory methodology. Participant's mean age was 52.6 years, with an average IC/BPS duration of 6.3 years. Thematic saturation was reached after four focus groups. We identified three emergent patient experience concepts: IC/PBS is debilitating, the disease course is unpredictable and unrelenting, and patients experience significant isolation. Importantly, suicidal ideation was expressed in each group. Patients voiced strong preference for physicians who provided education regarding the condition, an array of treatment options, organized treatment plans, and optimism and hope regarding treatment outcomes. Our study presents novel findings of the importance of patient-physician interaction in IC/BPS and reinforces the tremendous disability and burden of this disease, which frequently manifests in suicidal ideation. Patients preferred organized treatment plans with diverse choices and providers who offered hope in dealing with their condition.


Secretion of newly taken up ascorbic acid by adrenomedullary chromaffin cells originates from a compartment different from the catecholamine storage vesicle.
Chromaffin cells in primary culture take up [14C]ascorbic acid from the incubation medium. Cells, stimulated immediately after a short labeling period with [14C]ascorbate, secrete ascorbic acid concomitantly with catecholamines (CA) through a nicotinic receptor-mediated Ca2+-dependent process. A proportional release of CA and [14C]ascorbic acid was observed through a large range of secretion rates obtained by varying the concentration of nicotine or by changing the concentrations of Ca2+ and Na+ in the external medium. However, under the same conditions of stimulation, different cell preparations secrete 2-10 times more CA than [14C]ascorbate (as percentage of cell content). Furthermore, a different time course of secretion was observed for CA and [14C]ascorbate for each of several secretagogues. In addition, Ba2+ is a much more potent stimulus for CA secretion than for secretion of [14C]ascorbate, and Ca2+ channel blockers are more potent in inhibiting CA secretion than [14C]ascorbate secretion. These data suggested the possibility that newly taken up ascorbate was being secreted from a compartment altogether distinct from the chromaffin vesicle. This hypothesis was confirmed by subcellular distribution studies, where only a minor fraction of newly taken up [14C]ascorbate was found in the vesicular fraction (P2) from homogenates of chromaffin cells prepared after a short incubation with [14C]ascorbate. However, the subcellular distribution of [14C]ascorbate follows that of endogenous ascorbate when a short pulse with the label is chased by a prolonged equilibration period in the absence of ascorbate, indicating that a transfer has occurred from the extravesicular compartment(s) to the CA storage organelle. Endogenous ascorbate, which is found both inside and outside the chromaffin vesicle, was also found to be secreted from chromaffin cells, indicating that ascorbic acid could be released simultaneously from two different subcellular compartments.


Distinctive diffusive properties of swimming planktonic copepods in different environmental conditions.
Suspensions of small planktonic copepods represent a special category in the realm of active matter, as their size falls within the range of colloids, while their motion is so complex that it cannot be rationalized according to basic models of self-propelled particles. Indeed, the wide range of individual variability and swimming patterns resemble the behaviour of much larger animals. By analysing hundreds of three-dimensional trajectories of the planktonic copepod Clausocalanus furcatus, we investigate the possibility of detecting how the motion of this species is affected by different external conditions, such as the presence of food and the effect of gravity. While this goal is hardly achievable by direct inspection of single organism trajectories, we show that this is possible by focussing on simple average metrics commonly used to characterize colloidal suspensions, such as the mean square displacement and the dynamic correlation functions. We find that the presence of food leads to the onset of a clear localization that separates a short-time ballistic from a long-time diffusive regime. Such a benchmark reflects the tendency of C. furcatus to remain temporally feeding in a limited space and disappears when food is absent. Localization is clearly evident in the horizontal plane, but is negligible in the vertical direction, due to the effect of gravity. Our results suggest that simple average descriptors may provide concise and useful information on the swimming properties of planktonic copepods, even though single organism behaviour is strongly heterogeneous.


Organization and sequences of genes for the subunits of ATP synthase in the thermophilic cyanobacterium Synechococcus 6716.
The sequences of the genes for the nine subunits of ATP synthase in the thermophilic cyanobacterium Synechococcus 6716 have been determined. The genes were identified by comparison of the encoded proteins with sequences of ATP synthase subunits in other species, and confirmed for subunits alpha, beta, delta and epsilon, by determining their N-terminal sequences. They are arranged at three separate loci. Six of them are in one cluster in the order a: c: b': b: delta: alpha, and those for the beta and epsilon subunits form a second and separate cluster. The gene for the gamma-subunit is at a third site. As in other bacteria, the gene for subunit a is immediately preceded by a gene coding for a small hydrophobic protein of unknown function, known as uncI in Escherichia coli. The gene orders in Synechococcus 6716 are related to the orders of ATP synthase genes in the plastid genomes of higher plants, and particularly of a red alga and a diatom. The sequences of the subunits are similar to those of chloroplast ATP synthase, the alpha, beta and c subunits being particularly well conserved. Differences in the primary structures of the Synechococcus 6716 and chloroplast gamma subunits probably underlie different mechanisms of activation of ATP synthase. The nucleotide sequences that are presented also contain 12 other open reading frames. One of them encodes a protein sequence related to the E. coli DNA repair enzyme, photolyase, and another codes for a protein that contains internal repeats related to sequences in the myosin heavy chain.


Blockade of endogenous angiotensin-(1-7) in the hypothalamic paraventricular nucleus reduces renal sympathetic tone.
In this study, we tested the hypothesis that angiotensin-(1-7) [Ang-(1-7)] acting in the neurons of paraventricular hypothalamic nucleus (PVN) contributes to the maintenance of sympathetic activity and blood pressure. For this purpose, the effects of microinjection of the A-779, the receptor Mas antagonist, into the PVN on mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were evaluated. In rats anesthetized with urethane (1.2 to 1.4 g/kg IP), bilateral microinjections of A-779 (0.1 nmol) into the PVN resulted in a selective and significant decrease in RSNA (-26+/-6% versus -2+/-3% vehicle; saline 0.9%). The magnitude of the decrease in RSNA produced by A-779 was comparable to that observed after microinjection of muscimol (1 nmol; -26+/-4%), a powerful neuronal inhibitor. A higher dose of A-779 (1 nmol) caused a reduction in RSNA (-21+/-4%) that was comparable in magnitude to the reduction observed with the lower dose. When compared with vehicle solution, no significant changes in MAP or HR were observed with both doses of A-779 tested. A decrease in RSNA was also observed after microinjections into the PVN of the angiotensin II type 2 (AT2) receptor antagonist PD123319 (1 nmol; -18+/-4%). Microinjections of the AT1 antagonist losartan but not CV 11974 reduced MAP without changing RSNA. These results suggest that Ang-(1-7) Mas receptors and AT2 receptors in the PVN neurons play a role in mediating the tonic maintenance of RSNA.


Reducing Time to First on Scene: An Ambulance-Community First Responder Scheme.
The importance of early access to prehospital care has been demonstrated in many medical emergencies. This work aims to describe the potential time benefit of implementing a student Community First Responder scheme to support ambulance services in an inner-city setting in the United Kingdom. Twenty final and penultimate year medical students in the UK were trained in the "First Person on Scene" Business and Technology Education Council (BTEC) qualification. Over 12 months, they attended 89 emergency calls in an inner-city setting as Community First Responders (CFRs), alongside the West Midlands Ambulance Service, UK. At the end of this period, a qualitative survey investigated the perceived educational value of the scheme. The mean CFR response time across all calls was an average of 3 minutes and 8 seconds less than ambulance crew response times. The largest difference was to calls relating to falls (12 min). The difference varied throughout the day, peaking between 16:00 and 18:00. All questionnaire respondents stated that they felt more prepared in assessing and treating acutely unwell patients. In this paper, the authors present a symbiotic solution which has both reduced time to first on scene and provided training and experience in medical emergencies for senior medical students.