A qualitative study into the experience of living with acalculia after stroke and other forms of acquired brain injury.
Acalculia, an acquired disability following a brain injury, involves difficulty processing numerical information and/or calculations. Acalculia is not routinely screened for, and as a result there is a lack of understanding about the nature and prevalence and the impact of the condition. This qualitative study was initiated by stroke survivors with a strong interest in acalculia. Sixteen stroke/brain injury survivors with acalculia and seven carers were interviewed using semi-structured online interviews. Participants ranged in age, gender, time post-onset, country of residence and numeracy level prior to brain injury. Data were analysed using thematic analysis. Three main themes were identified: Awareness and Diagnosis; Emotional and Practical Impact (independence); Support, Coping Strategies and Self-training. Participants and carers repeatedly referred to the lack of awareness and treatment for acalculia and the impact acalculia has had on their lives and independence. Practical impacts included managing money, making appointments, using timetables, organizing social activities and employment, and managing medication. Our results highlight the urgent need to develop suitable assessments and interventions for acalculia and the scope for this to be Patient, Carer and Public involvement (PCPI)-led. The data also reveal useful strategies and suggestions regarding effective timing, targets and approaches for intervention.


Midlife iron status is inversely associated with subsequent cognitive performance, particularly in perimenopausal women.
The link between iron status and cognition has been established in infants and children, yet evidence in adults is scant and heterogeneous. We examined sex- and menopause-specific cross-time associations of iron status with cognition in the French Supplémentation en Vitamines et Minéraux Antioxydants Study cohort (1539 men, 1431 pre-/perimenopausal women, 962 postmenopausal women). Serum ferritin and hemoglobin data were obtained in 1995. Cognition was assessed after a mean of 13 y through 6 validated instruments, including the RI-48 cued recall test, phonemic and semantic fluency tasks, forward and backward digit span tasks, and a trail-making test. The standardized individual test scores were summed to form a composite cognitive performance measure. Associations between ferritin and hemoglobin and subsequent cognitive performance were examined through multivariable linear regression. Among men, no significant associations were observed. In postmenopausal women, an inverse association was found between ferritin and phonemic fluency (adjusted β: -0.11; 95% CI: -0.21, -0.01). Significant inverse associations between ferritin and both the composite cognitive measure (adjusted β: -0.09; 95% CI: -0.17, -0.00) and the forward digit span scores (adjusted β: -0.13; 95% CI: -0.22, -0.03) were observed only among premenopausal women aged ≥ 46 y at baseline. No significant findings with hemoglobin emerged. This study supports an inverse association between midlife iron status and subsequent cognitive performance that is sex- and menopause-dependent. Given the urgent need for prevention research on age-related disorders, future investigations of iron status and cognition are warranted. The study is registered at www.clinicaltrials.gov as NCT00272428.


Efficient 3-d object representations for industrial vision systems.
The representation of 3-D objects is an important step in solving many problems in scene analysis. One of the most successful techniques is that based on the surfaces of objects. We describe several methods for obtaining such surface representations from various types of intrinsic images. In particular, previous work is reviewed and an algorithm based on region growing is investigated in terms of its efficiency in segmenting a set of points in 3-D space into planar faces. Information on the neighborhood structure of the points in the form of a spatial proximity graph is used to direct the segmentation. Applications to industrial objects are demonstrated.


Structural insights into three phosphates with distinct polyanionic configurations.
Three mixed-metal phosphates, namely, centrosymmetric LiSrP3O9 and LiCsP2O6 as well as noncentrosymmetric K2SrP4O12 have been synthesized by the high temperature solution method. These structures were characterized by single-crystal X-ray diffraction and their P-O units are shown to feature distinct polyanionic configurations from [PO3]∞ chains in LiSrP3O9 to [P4O12]4- rings in LiCsP2O6 and K2SrP4O12. Besides, K2SrP4O12 shows a moderate second harmonic generation response about 0.6 times that of KH2PO4 and can be applied as a potential nonlinear optical material for the ultraviolet spectral region. Thermal behaviour analyses indicate that the compounds LiSrP3O9 and K2SrP4O12 remain stable up to 659 and 698 °C, respectively. In addition, the crystal structures, thermal stabilities and infrared spectra of the title compounds have been examined.


Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury.
Healthy vascular endothelium is coated by the glycocalyx, important in multiple endothelial functions, but destroyed by ischaemia-reperfusion. The impact of volatile anaesthetics on this fragile structure has not been investigated. We evaluated the effect of cardiac pre- and post-conditioning with sevoflurane on integrity of the endothelial glycocalyx in conjunction with coronary vascular function. Isolated guinea pig hearts perfused with Krebs-Henseleit buffer underwent 20 min stopped-flow ischaemia (37 degrees C), either without or with 1 MAC sevoflurane. This was applied for 15 min before, for 20 min after, or both before and after ischaemia. Transudate was collected for assessing coronary net fluid extravasation and histamine release by mast cells. Coronary release of syndecan-1 and heparan sulphate was measured. In additional experiments with and without continuous sevoflurane, cathepsin B and tryptase beta-like protease activity were measured in effluent. Hearts were perfusion-fixed to visualize the endothelial glycocalyx. Ischaemia led to a significant (P<0.05) increase by 70% in transudate formation during reperfusion only in hearts without sevoflurane. This was accompanied by significant (P<0.05) increases in heparan sulphate (four-fold) and syndecan release (6.5-fold), with electron microscopy revealing massive degradation of glycocalyx. After ischaemia, histamine was released into transudate, and cathepsin B activity increased in effluent (P<0.05). Sevoflurane application attenuated all these changes, except for histamine release. Sevoflurane protects the endothelial glycocalyx from ischaemia-reperfusion-induced degradation, with both preconditioning and rapid post-conditioning being successful. The mechanism seems to involve attenuation of lysosomal cathepsin B release and to be independent from tissue mast cell degranulation.


BIRC5 is a novel target of peroxisome proliferator‑activated receptor γ in brain microvascular endothelium cells during cerebral ischemia.
Cerebral ischemia is a leading cause of ischemic stroke, which may lead to severe disability and mortality worldwide. There are some key factors concerned in cardioprotection, such as peroxisome proliferator‑activated receptor γ (PPARγ), a ligand binding transcription factor involved in various biological functions including atherosclerosis, vascular dysfunction and hypertension, and baculoviral IAP repeat‑containing 5 (BIRC5), which may protect human brain endothelial cells from ischemia‑induced apoptosis. To determine the potential roles of PPARγ in brain microvascular endothelial (bEnd.3) cells during cerebral ischemia and the relationship between PPARγ and BIRC5, a cerebral ischemia model was established with bEnd.3 cells cells by oxygen‑glucose deprivation (OGD) treatment. OGD treatment reduced proliferation and enhanced apoptosis of bEnd.3 cells in a time‑dependent manner. PPARγ expression levels were decreased in bEnd.3 cells following OGD treatment. Upregulation of PPARγ expression protected bEnd.3 cells from ischemia injury and also upregulated BIRC5 expression. PPARγ‑specific binding sites in the BIRC5 promoter were predicted bioinformatically and verified by luciferase reporter experiments. Results from electrophoretic mobility shift/supershift and chromatin immunoprecipitation assays suggested that BIRC5 may be a novel target of PPARγ transcriptional regulation during ischemic injury. The present results indicated that PPARγ may serve a protective role on bEnd.3 cells and that BIRC5 may be a downstream target of PPARγ regulation during cerebral ischemia.


Pre-Infusion Checklist For Rituximab In Pemphigus Vulgaris Patients: Clinical Audit.
To evaluate whether or not the pre-infusion checklist for rituximab was followed in patients of pemphigus vulgaris. The audit, intervention and re-audit was conducted at the Dermatology Department, Medical Teaching Institution-Lady Reading Hospital, Peshawar, Pakistan, and comprised in-patients of pemphigus vulgaris, confirmed by skin biopsy and immunofluorescence, who received rituximab between January 1 to March 31, 2022. The randomly picked cases were reviewed to check if the standard guidelines for rituximab prior to infusion had been followed. After completion of the first audit cycle, the medical team was give awareness about the latest pre infusion rituximab guidelines, and they were also provided with a checklist and consent form to implement the change. Re-audit was performed from May to July, 2022, using the same method to see if improvements had been made. Data was analysed using SPSS 23. Of the 20 cases evaluated against 16 parameters, the first audit showed 7(43.5%) parameters to have been met across all cases. Re-audit comprised another set of 20 cases, and showed that 15(93.75%) parameters had been applied across the board Pneumococcal and influenza vaccine was the only element 1(6.25%) not touching universal application. Re-audit showed major improvement in compliance with the standard guidelines.


The histologic fate of autologous collagen injected into the canine vocal fold.
Collagen is a functionally essential component of the five-layered structure of the vocal fold. Soluble bovine collagen has previously been shown to be an effective injectable bioimplant for vocal fold defects, paralysis, and, especially, scarred larynges. Although bovine collagen appears to be well tolerated, the concern for possible adverse immunologic responses has deterred approval from the Food and Drug Administration for its clinical use in the larynx. Currently we are investigating the use of injectable autologous collagen for vocal fold augmentation. The purpose of this study is to examine the histologic fate of autologous collagen injected into the canine vocal fold at multiple intervals after injection. An ellipse of skin measuring 3 x 6 cm was harvested from each of three dogs and processed into a naturally cross-linked injectable solution of collagen (Autologen). This autologous collagen was injected into one vocal fold and a control injection of buffer solution was injected contralaterally. The injections were well tolerated and no dog appeared to suffer any immediate or delayed ill effects. The dog larynges were harvested 1, 3, and 6 months after collagen injection and examined grossly and histologically. Injected autologous collagen material persisted in these experimental animals and appeared to be well tolerated. Based on this preliminary study, we anticipate autologous collagen to be at least as suitable as bovine chemically cross-linked collagen as an injectable bioimplant for vocal fold augmentation. It may also have the advantage of added safety and stability.


Association of torpedo maculopathy and keratoconus in a young patient: A multimodal imaging study.
To report and document a case of torpedo maculopathy found in a patient affected by keratoconus.Case report: An healthy 16-year-old male patient, affected by keratoconus in both eyes, was referred to the cornea service of our hospital for a follow-up visit.During the dilated fundus examination of the left eye, an oval, well-demarcated, hypopigmented lesion was observed in the juxtafoveal temporal region, pointing towards the center of the macula. Multimodal imaging of the lesion was performed, and the diagnosis of Torpedo Maculopathy was established based on the clinical picture. This is the first case of torpedo maculopathy described in a patient affected by keratoconus. This association may be merely fortuitous or the result of developmental abnormalities affecting both corneal and retinal structures.


Telehealth Serious Illness Care Program for Older Adults with Hematologic Malignancies: A single-arm pilot study.
Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) feel shocked and bewildered when diagnosed. Serious illness conversations (SICs) may increase disease understanding and preparations for the future. However, SICs often happen late, due in part clinician-perceived patient discomfort. Telehealth may promote patient comfort by allowing SICs to take place at home. This study assesses the feasibility and usability of a telehealth-delivered Serious Illness Care Program (SICP) for older adults with AML and MDS. We conducted a single-arm pilot including 20 older adults with AML and MDS. Feasibility was measured using retention rate: >80% considered feasible. Usability was measured using telehealth usability questionnaire (TUQ, range 1-7): >5 considered usable. We collected other outcomes including acceptability and disease understanding and conducted post-visit qualitative interviews to elicit feedback. Hypothesis testing was performed at α=0.10 due to the pilot nature and small sample size. Retention rate was 95% (19/20); mean TUQ scores were 5.9 (SD 0.9) and 5.9 (SD 1.1) for patients and caregivers, respectively. We found the SICP to be acceptable. The majority of patients found the SICP to be very or extremely worthwhile (88.2%, 15/17) and it increased closeness with their clinician (75.0%, 12/16). After their visit, patient estimates of curability and overall life expectancy aligned more closely with those of their clinicians. In qualitative interviews, most patients said they would recommend this program to others (89.5%, 17/19). This study demonstrated that delivery of the telehealth SICP to older patients with AML and MDS is feasible, usable, and acceptable. This trial is registered at www.clinicaltrials.gov as NCT04745676.


The relationships between sediment findings and culture results and the presence of proteinuria in canine urine samples.
To assess relationships between urine sediment and microbial culture findings and the presence of proteinuria in canine urine samples, and to assess the change in the percentage of proteinuric samples and urine protein-to-creatinine ratio when urine abnormalities resolve. Canine urine samples collected via cystocentesis and submitted for culture and contemporaneous urinalysis (including urine protein-to-creatinine ratio) were retrospectively identified. Dogs receiving corticosteroids were excluded. Associations between haematuria (red blood cells>5/high-power field), pyuria (white blood cells>5/high-power field), presence of microorganisms on microscopy, active sediment, and positive culture and proteinuria (urine protein-to-creatinine ratio>0.5) were investigated. Patient characteristics were considered possible confounders. In dogs with repeat urinalysis, the associations between active sediment and positive culture resolution on proteinuria and urine protein-to-creatinine ratio were assessed. One hundred and ninety-two of 491 samples were proteinuric (39.1%). Age was positively associated with proteinuria. In the multivariable analysis corrected for age, active sediment was the only variable significantly associated with proteinuria (adjusted odds ratio: 2.12; 95% confidence interval: 1.44 to 3.11); however, only 49.8% of samples with active sediment were proteinuric. Neither resolution of active sediment nor positive culture were associated with reduced proportions of proteinuric samples (from 57.9% to 42.1% and from 40.0% to 25.0%, respectively) or significant reductions in urine protein-to-creatinine ratio (median change: -0.16 and -0.14, respectively). Attributing proteinuria to urinalysis abnormalities or a positive urine culture in canine cystocentesis samples is not supported by our findings, and could result in alternative causes of proteinuria (e.g. renal proteinuria) being overlooked.


Effects of 5-HT1 and 5-HT 2 Receptor Agonists on Electromagnetic Field-Induced Analgesia in Rats.
Much evidence demonstrates the antinociceptive effect of magnetic fields (MFs). However, the analgesic action mechanism of the electromagnetic field (EMF) is not exactly understood. The aim of the present study was to investigate the effects of 5-HT1 and 5-HT2 receptor agonists (serotonin HCl and 2,5-dimethoxy-4-iodoamphetamine [DOI] hydrochloride) on EMF-induced analgesia. In total, 66 adult male Wistar albino rats with an average body mass of 225 ± 13 g were used in this study. The animals were subjected to repeated exposures of alternating 50 Hz and 5 mT EMF for 2 h a day for 15 days. Prior to analgesia tests, serotonin HCl (5-HT1 agonist) 4 mg/kg, WAY 100635 (5-HT1 antagonist) 0.04 mg/kg, DOI hydrochloride (5-HT2 receptor agonist) 4 mg/kg, and SB 204741 (5-HT2 antagonist) 0.5 mg/kg doses were injected into rats. For statistical analysis of the data, analysis of variance was used and multiple comparisons were determined by Tukey's test. Administration of serotonin HCl MF (5 mT)-exposed rats produced a significant increase in percent maximal possible effect (% MPE) as compared with EMF group (P < 0.05). On the contrary, injection of WAY 100635 to MF-exposed rats produced a significant decrease in analgesic activity (P < 0.05). Similarly, the administration of DOI hydrochloride significantly increased % MPE values as compared with the EMF group while SB 204741 reduced it (P < 0.05). In conclusion, our results suggested that serotonin 5-HT1 and 5-HT2 receptors play an important role in EMF-induced analgesia; however, further research studies are necessary to understand the mechanism. Bioelectromagnetics. 2019;40:319-330. © 2019 Bioelectromagnetics Society.


[Radiation-induced cranial tumors: clinical series and literature review].
Radiation induced tumors are well-known but rare complications of radiotherapy. Meningiomas are the most common radiation-induced (RI) cranial tumors, followed by gliomas and sarcomas, while other tumors as haemangioblastomas remain extremely exceptional. We present 7 patients with RI brain tumors diagnosed and treated at our institution between 1990 and 2006. Retrospective review of their clinical charts is supplied. All patients were irradiated during childhood as a treatment for another disease, and fulfilled the criteria of RI neoplasia. Four patients developed meningiomas and three developed other tumors (one glioblastoma, one softtissue sarcoma and one hemangioblastoma). In all cases a complete surgical removal was achieved. Preoperative assessment based on MRI supplied the correct diagnosis in six patients. The most important risks factors described in the literature for developing RI tumors are the age at which radiotherapy was administered and the dose of radiation applied. Differential diagnosis of RI tumors includes any tumor appearing after radiotheraphy, especially recurrences of the primary disease, as RI neoplasias are a rare complication. Even in cases with complete surgical resection, prognosis of this clinical entity is basically related to the histology of the RI tumor.


Anti-mesothelin antibodies and circulating mesothelin relate to the clinical state in ovarian cancer patients.
Most human ovarian carcinomas express mesothelin, which is shed as a diagnostically useful biomarker. We applied an ELISA to measure antibodies to native mesothelin in serum from a series of patients with divergent clinical outcomes. The level of anti-mesothelin antibodies determined as OD(450 nm) and referred to as absorption units (AU) for 1:20 diluted serum was higher in patients who remained disease-free after therapy [no evidence of disease (NED); n = 14] than in patients whose disease recurred [clinical evidence of disease (CED); n = 21; P < 0.01]. Applying AU > or = 0.5 at a serum dilution of 1:20 as cutoff, 10 of 14 (71%) ovarian carcinoma patients with NED and 9 of 21 (43%) patients with CED had antibodies to mesothelin compared with 6 of 23 (26%) healthy women (P < 0.008) and 5 of 24 (21%) women with other benign gynecologic diseases (P < 0.003), whereas 7 of 9 (78%) of women with pelvic inflammatory disease were positive. Three of the 14 (21%) NED patients had circulating mesothelin detected as an AU > or = 0.2 at a serum dilution of 1:40 (P < 0.005) compared with 15 of 21 (71%) CED patients, and 9 of 14 (64%) NED patients (P < 0.0002) were positive for antibodies and negative for antigen compared with 1 of 21 (5%) CED patients. Although our data indicate that an antibody response to mesothelin is an important correlate of ovarian carcinoma, prospective studies are needed to show whether the measurement of such antibodies (alone or together with antigen) aids the diagnosis and monitoring of patients.


Impact of conventional anesthesia on auditory brainstem responses in mice.
Anesthesia is known to affect the auditory brainstem response (ABR) in animals often used in hearing research. This study describes the differences in ABRs between awake and anesthetized FVB/N mice. Intracranial electrodes connected to a head fixation pedestal were used for click-evoked ABR recordings. This pedestal served to immobilize mice, either awake or under anesthesia, in a 'free' sound field. The presence of myogenic noise in the awake condition obviously increases recording time. However it is demonstrated that recording times can be significantly reduced by increasing the stimulus repetition rate from 23 up to 80 impulses per second. This causes only a small but significant increase in absolute peak latencies in the awake condition, but has no significant effect on the overall ABR-waveform, nor on the ABR-threshold, nor on the ABR interpeak latencies, nor on the absolute peak latencies in the anesthetized condition. Anesthesia with ketamine/xylazine caused a significant prolongation of ABR-peak latencies and interpeak latencies as well as a significant upward shift (8.0+/-1.8 dB) of ABR-thresholds as compared to the awake condition. Under anesthesia the measurement accuracy of peak latencies, interpeak latencies and thresholds decreases. In conclusion, the awake condition is preferable for more accurate measurements of ABR characteristics, in spite of the myogenic noise concomitant with this condition.


Sutureless pars plana vitrectomy through self-sealing sclerotomies.
A new technique of creating self-sealing pars plana sclerotomies is described. In a series of 50 consecutive vitrectomies, no complication was encountered related to this new technique. All of the 47 primary vitrectomy procedures performed had self-sealing sclerotomies that did not require suturing at the end of surgery. This type of wound construction allows for sutureless closure of sclerotomies with better control of intraoperative ocular pressure.


An unusual cause of abdominal distension: intraperitoneal bladder perforation secondary to intermittent self-catheterisation.
We report a strikingly unusual case of traumatic intraperitoneal perforation of an augmented bladder from clean intermittent self-catheterisation (CISC), which presented a unique diagnostic challenge. This case describes a 48-year-old T1 level paraplegic, who had undergone clamshell ileocystoplasty for detrusor overactivity, presenting with abdominal distension, vomiting and diarrhoea. Initial investigations were suggestive of disseminated peritoneal malignancy with ascitic fluid collections, but the ascitic fluid was found to be intraperitoneal urine from a perforation of the urinary bladder. This was associated with an inflammatory response in the surrounding structures causing an appearance of colonic thickening and omental disease. Although the diagnostic process was complex due to this patient's medical history, the treatment plan initiated was non-operative, with insertion of an indwelling urinary catheter and radiologically guided drainage of pelvic and abdominal collections. Overdistension perforations of augmented urinary bladders have been reported, but few have described perforation from CISC.


Some characteristics of the outer membrane material released by growing enterotoxigenic Escherichia coli.
The high-molecular-weight material released into the medium by Escherichia coli AP1, an enterotoxigenic strain of porcine origin, has been isolated and resolved into two clearly distinct fractions, based on sucrose density gradient and differential centrifugation, chemical analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and freeze-fracture electron microscopy. These two fractions, referred to as "medium vesicles" and "medium lipopolysaccharides", were compared with the cellular outer and cytoplasmic membranes, the periplasmic fraction, and the cytoplasmic fraction. The medium vesicles closely resembled outer membrane and accounted for 3 to 5% of the total cellular outer membrane. They contained most of the heat-labile enterotoxin (LT) activity released into the medium by E. coli AP1. The medium lipopolysaccharide consisted mostly of lipopolysaccharide and a small amount of outer membrane and contained relatively little LT activity. Based on experiments with E. coli K-12 strains, in which about 5% of the newly synthesized outer membrane is lost from areas of outer membrane synthesis, it is proposed that enterotoxigenic E. coli strains release LT as part of such newly synthesized outer membrane fragments and that released outer membrane fragments may function as physiologically significant LT carriers.


Yeast Tripartite Biosensors Sensitive to Protein Stability and Aggregation Propensity.
In contrast to the myriad approaches available to study protein misfolding and aggregation in vitro, relatively few tools are available for the study of these processes in the cellular context. This is in part due to the complexity of the cellular environment which, for instance, interferes with many spectroscopic approaches. Here, we describe a tripartite fusion approach that can be used to assess in vivo protein stability and solubility in the cytosol of Saccharomyces cerevisiae. Our biosensors contain tripartite fusions in which a protein of interest is inserted into antibiotic resistance markers. These fusions act to directly link the aggregation susceptibility and stability of the inserted protein to antibiotic resistance. We demonstrate a linear relationship between the thermodynamic stabilities of variants of the model folding protein immunity protein 7 (Im7) fused into the resistance markers and their antibiotic resistance readouts. We also use this system to investigate the in vivo properties of the yeast prion proteins Sup35 and Rnq1 and proteins whose aggregation is associated with some of the most prevalent neurodegenerative misfolding disorders, including peptide amyloid beta 1-42 (Aβ42), which is involved in Alzheimer's disease, and protein α-synuclein, which is linked to Parkinson's disease.


Medical costs associated with type 2 diabetes complications and comorbidities.
To estimate the direct medical costs associated with type 2 diabetes, its complications, and its comorbidities among U.S. managed care patients. Data were from patient surveys, chart reviews, and health insurance claims for 7109 people with type 2 diabetes from 8 health plans participating in the Translating Research Into Action for Diabetes (TRIAD) study between 1999 and 2002. A generalized linear regression model was developed to estimate the association of patients' demographic characteristics, tobacco use status, treatments, related complications, and comorbidities with medical costs. The mean annualized direct medical cost was $2465 for a white man with type 2 diabetes who had been diagnosed fewer than 15 years earlier, was treated with oral medication or diet alone, and had no complications or comorbidities. We found annualized medical costs to be 10% to 50% higher for women and for patients whose diabetes had been diagnosed 15 or more years earlier, who used tobacco, who were being treated with insulin, or who had several other complications. Coronary heart disease, congestive heart failure, hemiplegia, and amputation were each associated with 70% to 150% higher costs. Costs were approximately 300% higher for end-stage renal disease treated with dialysis and approximately 500% higher for end-stage renal disease with kidney transplantation. Most medical costs incurred by patients with type 2 diabetes are related to complications and comorbidities. Our cost estimates can help when determining the most cost-effective interventions to prevent complications and comorbidities.


A chromosome-level genome for the nudibranch gastropod Berghia stephanieae helps parse clade-specific gene expression in novel and conserved phenotypes.
How novel phenotypes originate from conserved genes, processes, and tissues remains a major question in biology. Research that sets out to answer this question often focuses on the conserved genes and processes involved, an approach that explicitly excludes the impact of genetic elements that may be classified as clade-specific, even though many of these genes are known to be important for many novel, or clade-restricted, phenotypes. This is especially true for understudied phyla such as mollusks, where limited genomic and functional biology resources for members of this phylum has long hindered assessments of genetic homology and function. To address this gap, we constructed a chromosome-level genome for the gastropod Berghia stephanieae (Valdés, 2005) to investigate the expression of clade-specific genes across both novel and conserved tissue types in this species. The final assembled and filtered Berghia genome is comparable to other high quality mollusk genomes in terms of size (1.05 Gb) and number of predicted genes (24,960 genes), and is highly contiguous. The proportion of upregulated, clade-specific genes varied across tissues, but with no clear trend between the proportion of clade-specific genes and the novelty of the tissue. However, more complex tissue like the brain had the highest total number of upregulated, clade-specific genes, though the ratio of upregulated clade-specific genes to the total number of upregulated genes was low. Our results, when combined with previous research on the impact of novel genes on phenotypic evolution, highlight the fact that the complexity of the novel tissue or behavior, the type of novelty, and the developmental timing of evolutionary modifications will all influence how novel and conserved genes interact to generate diversity.


Organ-specific changes in norepinephrine turnover against various stress conditions in thermoneutral mice.
The effects of three stressors of different categories, namely cold exposure, immobilization, and lipopolysaccharide (LPS) treatment, on sympathetic nerve activity were examined by assessing its biochemical index norepinephrine (NE) turnover in peripheral organs of C57BL/6 mice. NE turnover was assessed by measuring the decrease in the organ NE concentration 3 h after inhibition of catecholamine biosynthesis with alpha-methyl-p-tyrosine. NE turnover in brown adipose tissue (BAT) in the room temperature (23 degrees C) control group was as high as that in the cold exposure (4 degrees C) group. Similarly, the mRNA level of the thermogenic marker uncoupling protein 1 (UCP1) in the room temperature control group was as high as that in the cold exposure group. As sympathetic stimulation upregulates the UCP1 mRNA level, we thought that sympathetic nerve tonus in BAT was already accelerated at room temperature. To exclude factors affecting basal sympathetic nerve activity, mice housed at thermoneutral temperature (30 degrees C) were used as controls for the subsequent experiments. In this condition, cold exposure accelerated NE turnover in the BAT, as well as heart and pancreas. The corticosterone level showed a higher trend in the cold exposure group in comparison to the control group. Immobilization accelerated NE turnover in the spleen, pancreas, and white adipose tissue and elevated the corticosterone level. LPS (3 mg/kg, i.p.) did not affect NE turnover in all peripheral organs but elevated the corticosterone level. In summary, the sympathetic nervous and adrenocortical responses to three stressors differed greatly. In particular, sympathetic responses showed clear organ-specific acceleration patterns. This important feature may improve our understanding of the multiplicity of biological responses.


Norepinephrine overflow and renin pattern of the individual kidney in patients with unilateral renal artery stenosis.
This study was performed to determine divided renal efferent sympathetic nerve activity from kidneys in seven patients with renin-positive, unilateral renal artery stenosis before and 30 minutes after an acute intravenous dose of 1.25 mg enalaprilat. Renal norepinephrine release was calculated from split renal plasma flow, venoarterial plasma concentration gradients across the kidney, and the fractional extraction of tritiated norepinephrine. All patients had unilateral renin secretion, the affected kidney increasing its plasma renin activity gradient 1.7-fold, whereas no statistically significant change was noted on the contralateral side in response to enalaprilat. Total norepinephrine release to plasma and norepinephrine plasma clearance (assessed by isotope dilution) were similar before and after administration of enalaprilat (approximately 400 ng/min and 1.0 l/min), despite a 26% fall in mean arterial pressure (from 125 mm Hg, p less than 0.01). Heart rate remained unchanged. After enalaprilat, norepinephrine venoarterial difference increased in the renin-secreting kidney (from 264 to 396, SED = 57 pg/ml, p less than 0.05), whereas it increased only slightly in the contralateral kidney (from 149 to 256, SED = 72 pg/ml, NS). Tritiated norepinephrine extraction fell approximately 25% (p less than 0.01) in both kidneys. Thus, renal norepinephrine spillover increased from 49 to 62, SED = 9 ng/min (NS) and from 81 to 129, SED = 17 ng/min (p less than 0.05) from the affected and the contralateral kidney, respectively. Hence, in this relatively small study in patients with renovascular hypertension, no evidence for increased renal nerve activity could be observed in the affected kidney, despite its marked renin production.(ABSTRACT TRUNCATED AT 250 WORDS)


Recovery and normalization of triple coincidences in PET.
Triple coincidences in positron emission tomography (PET) are events in which three γ-rays are detected simultaneously. These events, though potentially useful for enhancing the sensitivity of PET scanners, are discarded or processed without special consideration in current systems, because there is not a clear criterion for assigning them to a unique line-of-response (LOR). Methods proposed for recovering such events usually rely on the use of highly specialized detection systems, hampering general adoption, and/or are based on Compton-scatter kinematics and, consequently, are limited in accuracy by the energy resolution of standard PET detectors. In this work, the authors propose a simple and general solution for recovering triple coincidences, which does not require specialized detectors or additional energy resolution requirements. To recover triple coincidences, the authors' method distributes such events among their possible LORs using the relative proportions of double coincidences in these LORs. The authors show analytically that this assignment scheme represents the maximum-likelihood solution for the triple-coincidence distribution problem. The PET component of a preclinical PET/CT scanner was adapted to enable the acquisition and processing of triple coincidences. Since the efficiencies for detecting double and triple events were found to be different throughout the scanner field-of-view, a normalization procedure specific for triple coincidences was also developed. The effect of including triple coincidences using their method was compared against the cases of equally weighting the triples among their possible LORs and discarding all the triple events. The authors used as figures of merit for this comparison sensitivity, noise-equivalent count (NEC) rates and image quality calculated as described in the NEMA NU-4 protocol for the assessment of preclinical PET scanners. The addition of triple-coincidence events with the authors' method increased peak NEC rates of the scanner by 26.6% and 32% for mouse- and rat-sized objects, respectively. This increase in NEC-rate performance was also reflected in the image-quality metrics. Images reconstructed using double and triple coincidences recovered using their method had better signal-to-noise ratio than those obtained using only double coincidences, while preserving spatial resolution and contrast. Distribution of triple coincidences using an equal-weighting scheme increased apparent system sensitivity but degraded image quality. The performance boost provided by the inclusion of triple coincidences using their method allowed to reduce the acquisition time of standard imaging procedures by up to ∼25%. Recovering triple coincidences with the proposed method can effectively increase the sensitivity of current clinical and preclinical PET systems without compromising other parameters like spatial resolution or contrast.


Inferior canine hindlimb ischemia and reperfusion impairs femoral artery endothelium-dependent wall relaxation.
This experimental investigation was carried out to study the endothelium-dependent ischemia-reperfusion injury upon the release of nitric oxide (NO) in the canine femoral artery. The tested experimental model was the inferior canine hindlimb ischemia induced by infrarenal abdominal aortic clamping followed by reperfusion. The research protocol was standardized in four experimental groups (n=6): (1) Control group; (2) Ischemia (120 minutes) group; (3) Ischemia (90 minutes) and reperfusion (60 minutes) group; and (4) Ischemia (120 minutes) and reperfusion (90 minutes) group. The femoral artery vascular reactivity was studied in vitro with the aid of an eight "organ chambers'' setup, where segments from 4 to 5 mm, with and without endothelium, were suspended and connected to force transducers. The fundamental data of this study were as follows: (1) Ischemia caused by 120 minutes of infrarenal aortic clamping did not cause femoral artery endothelium dysfunction. (2) Ischemia caused by 90 minutes of clamping followed by 60 minutes of reperfusion also did not cause endothelium dysfunction, with an observed tendency to signal transduction impairment (studied by the sodium fluoride dose response curves). (3) Ischemia caused by 120 minutes of clamping followed by 90 minutes of reperfusion caused endothelium dysfunction, observed by the femoral artery impaired capacity of the endothelium-dependent NO release evoked by acetylcholine, adenosine diphosphate, and sodium fluoride. The present pharmacologic in vitro observations are concordant with the evidence that the NO-release impairment, caused by inferior canine hindlimb ischemia followed by reperfusion, is a consequence of endothelium cell membrane receptors, and G-proteins signal transduction dysfunction.


Pregnancy and Antiphospholipid Syndrome.
Antiphospholipid syndrome (APS) is classified as the association of thrombotic events and/or obstetric morbidity in patients persistently positive for antiphospholipid antibodies (aPL). APS is also the most frequently acquired risk factor for a treatable cause of recurrent pregnancy loss and increases the risk of conditions associated with ischemic placental dysfunction, such as stillbirth, intrauterine death, preeclampsia, premature birth, and fetal growth restriction. The use of low-dose aspirin and heparin has improved the pregnancy outcome in obstetric APS and approximately 70% of pregnant women with APS will deliver a viable live infant. However, current management does not prevent all maternal, fetal, and neonatal complications of APS and the current treatment fails in 20 to 30% of APS pregnancies, raising the need to explore other treatments to improve obstetrical outcome. Two clinical studies of retrospective design have suggested that the immunomodulator hydroxychloroquine (HCQ) may play a role in the prevention of pregnancy complications in women with aPL and APS. The randomized controlled multicenter trial of hydroxychloroquine versus placebo during pregnancy in women with antiphospholipid antibodies (HYPATIA) of HCQ versus placebo will provide scientific evidence on the use of HCQ in pregnant women with aPL.


Restricting movements of lower face leaves recognition of emotional vocalizations intact but introduces a valence positivity bias.
Blocking facial mimicry can disrupt recognition of emotion stimuli. Many previous studies have focused on facial expressions, and it remains unclear whether this generalises to other types of emotional expressions. Furthermore, by emphasizing categorical recognition judgments, previous studies neglected the role of mimicry in other processing stages, including dimensional (valence and arousal) evaluations. In the study presented herein, we addressed both issues by asking participants to listen to brief non-verbal vocalizations of four emotion categories (anger, disgust, fear, happiness) and neutral sounds under two conditions. One of the conditions included blocking facial mimicry by creating constant tension on the lower face muscles, in the other condition facial muscles remained relaxed. After each stimulus presentation, participants evaluated sounds' category, valence, and arousal. Although the blocking manipulation did not influence emotion recognition, it led to higher valence ratings in a non-category-specific manner, including neutral sounds. Our findings suggest that somatosensory and motor feedback play a role in the evaluation of affect vocalizations, perhaps introducing a directional bias. This distinction between stimulus recognition, stimulus categorization, and stimulus evaluation is important for understanding what cognitive and emotional processing stages involve somatosensory and motor processes.


I kappaB alpha physically interacts with a cytoskeleton-associated protein through its signal response domain.
The I kappaB alpha protein is a key molecular target involved in the control of NF-kappaB/Rel transcription factors during viral infection or inflammatory reactions. This NF-kappaB-inhibitory factor is regulated by posttranslational phosphorylation and ubiquitination of its amino-terminal signal response domain that targets I kappaB alpha for rapid proteolysis by the 26S proteasome. In an attempt to identify regulators of the I kappaB alpha inhibitory activity, we undertook a yeast two-hybrid genetic screen, using the amino-terminal end of I kappaB alpha as bait, and identified 12 independent interacting clones. Sequence analysis identified some of these cDNA clones as Dlc-1, a sequence encoding a small, 9-kDa human homolog of the outer-arm dynein light-chain protein. In the two-hybrid assay, Dlc-1 also interacted with full-length I kappaB alpha protein but not with N-terminal-deletion-containing versions of I kappaB alpha. I kappaB alpha interacted in vitro with a glutathione S-transferase-Dlc-1 fusion protein, and RelA(p65) did not displace this association, demonstrating that p65 and Dlc-1 contact different protein motifs of I kappaB alpha. Importantly, in HeLa and 293 cells, endogenous and transfected I kappaB alpha coimmunoprecipitated with Myc-tagged or endogenous Dlc-1. Indirect immunofluorescence analyzed by confocal microscopy indicated that Dlc-1 and I kappaB alpha colocalized with both nuclear and cytoplasmic distribution. Furthermore, Dlc-1 and I kappaB alpha were found to associate with the microtubule organizing center, a perinuclear region from which microtubules radiate. Likewise, I kappaB alpha colocalized with alpha-tubulin filaments. Taken together, these results highlight an intriguing interaction between the I kappaB alpha protein and the human homolog of a member of the dynein family of motor proteins and provide a potential link between cytoskeleton dynamics and gene regulation.


Presenting Symptoms of Pituitary Apoplexy.
The classical term "pituitary apoplexy" (PA) describes a clinical syndrome usually characterized by abrupt onset of headache accompanied by neurologic and/or endocrinologic deterioration due to sudden expansion of a mass within the sella turcica as a result of hemorrhage or infarction within a pituitary tumor and adjacent pituitary gland. PA is a medical emergency and a difficult diagnosis to establish. Thus this article reviews the presenting symptoms of PA patients to help clinicians recognize or at least suspect this critical condition early on. PA commonly occurs in the setting of a preexisting adenoma, and several patients are unaware of its existence prior to the onset of apoplexy symptoms, which are mainly of a neurologic, ophthalmologic, and endocrinologic nature. Neurologic symptoms include sudden-onset severe headache and other symptoms of subarachnoid hemorrhage, symptoms from compression of the cavernous sinus contents, nausea/vomiting, impaired consciousness, and symptoms of meningeal irritation. Ophthalmologic symptoms include visual field defects, visual loss, diplopia, and ophthalmoplegia. Endocrinologic disturbances include pituitary adenoma symptoms, cortisol deficiency, panhypopituitarism, diabetes insipidus, and syndrome of inappropriate secretion of antidiuretic hormone. Magnetic resonance imaging is the imaging method of choice to aid the PA diagnosis. Its differential diagnoses include cerebrovascular accidents, infectious diseases, and other causes of endocrinologic imbalance. Transsphenoidal surgery is the treatment of choice, especially if there are associated visual abnormalities and ophthalmoplegia. Clinicians should be aware of the presenting symptoms because early diagnosis may reduce the morbidity and mortality of this neurosurgical emergency.


Evolutionary Diversification of Host-Targeted Bartonella Effectors Proteins Derived from a Conserved FicTA Toxin-Antitoxin Module.
Proteins containing a FIC domain catalyze AMPylation and other post-translational modifications (PTMs). In bacteria, they are typically part of FicTA toxin-antitoxin modules that control conserved biochemical processes such as topoisomerase activity, but they have also repeatedly diversified into host-targeted virulence factors. Among these, Bartonella effector proteins (Beps) comprise a particularly diverse ensemble of FIC domains that subvert various host cellular functions. However, no comprehensive comparative analysis has been performed to infer molecular mechanisms underlying the biochemical and functional diversification of FIC domains in the vast Bep family. Here, we used X-ray crystallography, structural modelling, and phylogenetic analyses to unravel the expansion and diversification of Bep repertoires that evolved in parallel in three Bartonella lineages from a single ancestral FicTA toxin-antitoxin module. Our analysis is based on 99 non-redundant Bep sequences and nine crystal structures. Inferred from the conservation of the FIC signature motif that comprises the catalytic histidine and residues involved in substrate binding, about half of them represent AMP transferases. A quarter of Beps show a glutamate in a strategic position in the putative substrate binding pocket that would interfere with triphosphate-nucleotide binding but may allow binding of an AMPylated target for deAMPylation or another substrate to catalyze a distinct PTM. The β-hairpin flap that registers the modifiable target segment to the active site exhibits remarkable structural variability. The corresponding sequences form few well-defined groups that may recognize distinct target proteins. The binding of Beps to promiscuous FicA antitoxins is well conserved, indicating a role of the antitoxin to inhibit enzymatic activity or to serve as a chaperone for the FIC domain before translocation of the Bep into host cells. Taken together, our analysis indicates a remarkable functional plasticity of Beps that is mostly brought about by structural changes in the substrate pocket and the target dock. These findings may guide future structure-function analyses of the highly versatile FIC domains.


[Comparative studys on ages-related changes in collagen structures of Achilles and tail tendons in rats].
The rate and degree of age changes in collagen structures of the Achilles and tail tendons were studied in 0.5, 1, 3, 12 and 24 month old rats. The hydration degree and imino acid content were determined in the tendon collagen fibres. The proline/hydroxyproline ratio and collagen content in tendons were calculated. The wide-angle X-ray studies in the air-dried samples obtained from collagen fibres were conducted for estimating orientation and texture degree of collagen fibres. By all the studied parameters the formation and development of collagen structures in the Achilles tendons are more rapid and intensive than in the tail ones.


"Schizotaxia": clinical implications and new directions for research.
We sought to show that (1) schizotaxia (Meehl's term for the predisposition to schizophrenia) is a clinically consequential condition, and (2) distinguishing it from schizotypal personality disorder may be useful from both clinical and scientific perspectives. We review the features of schizotaxia that may be relevant in clinical settings and discuss their implications for the diagnosis, psychosocial functioning, family intervention and treatment of people in schizophrenia families. Our review indicates that prior work finds some of the nonpsychotic and nonschizotypal relatives of schizophrenia patients to have a psychiatric syndrome characterized by negative symptoms, neuropsychological impairment, and psychosocial dysfunction. Following Meehl, we call this constellation of clinical and neurobiological features schizotaxia. The studies we review suggest it may be worthwhile to consider schizotaxia as a separate diagnostic class. Doing so would alert clinicians to a neurobehavioral syndrome not adequately covered by current diagnostic criteria and would motivate researchers to develop diagnostic and therapeutic approaches aimed at helping schizotaxic individuals and, perhaps, preventing the onset of schizophrenia.


Lipoprotein lipase enables triacylglycerol hydrolysis by perfused newborn rat liver.
Fasted 1-day-old rat liver has high heparin-releasable (endothelial) lipoprotein lipase (LPL) activity, and its hepatocytes synthesize LPL protein. To test the physiological role of this LPL, we perfused the isolated organ with a 0.8 mM triacylglycerol (TAG) (Intralipid + glycerol tri[3H]oleate) 6.3% serum medium. Samples of the recirculated perfusate were taken at different times to determine 3H in TAG, free fatty acid (FFA), and water-soluble (WS) fractions. In the medium [3H]TAG disappeared and [3H]FFA and [3H]WS fractions appeared linearly with time. This TAG hydrolysis was 1) absent when medium was recirculated without liver, 2) not affected by chloroquine addition, 3) inhibited by anti-LPL immunoglobulins, 4) absent when serum was omitted from the medium, and 5) restituted when apolipoprotein CII was added to the medium without serum. Therefore, lysosomal lipase is not involved in this TAG hydrolysis, the features of which are characteristic of LPL, not of the so-called "hepatic endothelial lipase." Thus LPL activity enables the neonatal rat liver to hydrolyze and take up circulating TAG, i.e., has the same function as extrahepatic LPL.


Adult lead poisoning.
Although the incidence of occupational and adult lead poisoning has declined, the problem still exists. It often goes unrecognized for long periods because of a low index of suspicion compounded by incomplete surveillance of risk populations. Abdominal pain, fatigue and arthralgia are the most frequent symptoms. Anemia, basophilic stippling of red blood cells and hyperuricemia are the most common clues. Diagnosis is based on blood lead levels. Chelation by calcium disodium edetate, followed by oral penicillamine, is the standard treatment.


Ventricular pneumocephalus and septic meningoencephalitis secondary to dorsal rhinotomy and nasal polypectomy in a dog.
A 4-year-old sexually intact female French Bulldog was evaluated because of lethargy, anorexia, and chronic rhinitis-sinusitis. The dog had nasal discharge of 18 months' duration; dorsal rhinotomies were performed 3 months and 2 weeks prior to referral. On initial evaluation, intraventricular pneumocephalus and sinusitis were diagnosed; CSF analysis revealed high total protein concentration and mononuclear pleocytosis. The dog's condition improved with treatment. Two weeks after discharge, it was treated by a local veterinarian because of upper airway obstruction; 3 days later, the dog was referred because of seizures. Computed tomography revealed a large fluid-filled, left lateral ventricle and a soft tissue mass protruding through a cribriform plate defect. The mass was histologically consistent with brain tissue. Findings of clinicopathologic analyses were unremarkable. Results of cytologic examination of a CSF sample were indicative of septic, suppurative inflammation, and bacteriologic culture of CSF yielded Escherichia coli. Amputation of the herniated olfactory bulb and antimicrobial treatment resolved the septic meningoencephalitis, but neurologic deficits recurred 6 weeks later. Definitive correction of the cribriform plate defect with bone and fascial grafts was attempted. Postoperative rotation of the bone graft resulted in cerebral laceration and hemorrhage, and the dog was euthanized. Findings suggest that following dorsal rhinotomy and nasal polypectomy surgery, the dog developed herniation of the left olfactory bulb, intra-ventricular pneumocephalus, and septic meningo-encephalitis because of a cribriform plate defect. Care must be taken to prevent rotation of bone grafts used in cribriform defect repair.


Occurrence and Sources of Radium in Groundwater Associated with Oil Fields in the Southern San Joaquin Valley, California.
Geochemical data from 40 water wells were used to examine the occurrence and sources of radium (Ra) in groundwater associated with three oil fields in California (Fruitvale, Lost Hills, South Belridge). 226Ra+228Ra activities (range = 0.010-0.51 Bq/L) exceeded the 0.185 Bq/L drinking-water standard in 18% of the wells (not drinking-water wells). Radium activities were correlated with TDS concentrations (p < 0.001, ρ = 0.90, range = 145-15,900 mg/L), Mn + Fe concentrations (p < 0.001, ρ = 0.82, range = <0.005-18.5 mg/L), and pH (p < 0.001, ρ = -0.67, range = 6.2-9.2), indicating Ra in groundwater was influenced by salinity, redox, and pH. Ra-rich groundwater was mixed with up to 45% oil-field water at some locations, primarily infiltrating through unlined disposal ponds, based on Cl, Li, noble-gas, and other data. Yet 228Ra/226Ra ratios in pond-impacted groundwater (median = 3.1) differed from those in oil-field water (median = 0.51). PHREEQC mixing calculations and spatial geochemical variations suggest that the Ra in the oil-field water was removed by coprecipitation with secondary barite and adsorption on Mn-Fe precipitates in the near-pond environment. The saline, organic-rich oil-field water subsequently mobilized Ra from downgradient aquifer sediments via Ra-desorption and Mn/Fe-reduction processes. This study demonstrates that infiltration of oil-field water may leach Ra into groundwater by changing salinity and redox conditions in the subsurface rather than by mixing with a high-Ra source.


Lineage-specific regulation of allergic airway inflammation by the lipid phosphatase Src homology 2 domain-containing inositol 5-phosphatase (SHIP-1).
Inpp5d (Src homology 2 domain-containing inositol-5-phosphatase [Ship1])-deficient mice experience spontaneous airway inflammation and have enhanced sensitivity to allergen-induced airway inflammation. We hypothesized that lineage-specific deletion of Ship1 expression in cells known to be crucial for adaptive TH2 responses would uncover distinct roles that could either positively or negatively regulate susceptibility to allergic airway inflammation (AAI). Ship1 expression was deleted in B cells, T cells, or dendritic cells (DCs), and the resulting Ship1(ΔB cell), Ship1(ΔT cell), Ship1(ΔDC), or Ship1(F/F) (wild-type) control mice were evaluated in a model of house dust mite (HDM)-induced AAI. Unlike germline panhematopoietic Ship1 deletion, deletion of Ship1 selectively in either the B-cell, T-cell, or DC lineages did not result in spontaneous airway inflammation. Strikingly, although loss of Ship1 in the B-cell lineage did not affect HDM-induced AAI, loss of Ship1 in either of the T-cell or DC lineages protected mice from AAI by skewing the typical TH2 immune response toward a TH1 response. Although panhematopoietic deletion of Ship1 leads to spontaneous lung inflammation, selective deletion of Ship1 in T cells or DCs impairs the formation of an adaptive TH2 response and protects animals from HDM-induced AAI.


The possible pain experienced during execution by different methods.
The physiology and pathology of different methods of capital punishment are described. Information about this physiology and pathology can be derived from observations on the condemned persons, postmortem examinations, physiological studies on animals undergoing similar procedures, and the literature on emergency medicine. It is difficult to know how much pain the person being executed feels or for how long, because many of the signs of pain are obscured by the procedure or by physical restraints, but one can identify those steps which are likely to be painful. The general view has been that most of the methods used are virtually painless, and lead to rapid dignified death. Evidence is presented which shows that, with the possible exception of intravenous injection, this view is almost certainly wrong.


Georhizobium profundi gen. nov., sp. nov., a piezotolerant bacterium isolated from a deep-sea sediment sample of the New Britain Trench.
A novel alphaproteobacterium, strain WS11T, was isolated from a deep-sea sediment sample collected from the New Britain Trench. The full-length 16S rRNA gene of strain WS11T had the highest sequence similarity of 97.6 % to Rhizobium subbaraonis JC85T, followed by Mycoplana ramosa DSM 7292T (96.9 %) and Rhizobium azooxidifex Po 20/26T (96.8 %). Phylogenetic analysis of concatenated 16S rRNA, atpD and recA gene sequences showed that strain WS11T was deeply separated from the species within the family Rhizobiaceae. Phylogenomic analysis based on the whole-genome protein sequences showed that strain WS11T formed an independent monophyletic branch in the family Rhizobiaceae, paralleled with the species in the families Brucellaceae and Phyllobacteriaceae within the order Rhizobiales. Cells were Gram-stain-negative, oxidase- and catalase-positive, and aerobic short rods (1.5-2.4×0.9-1.0 µm). Growth was observed at salinities ranging from 0 to 5% (optimum, 1 %), from pH 6.5 to 9 (optimum, pH 7) and at temperatures between 20 and 30 °C (optimum, 28 °C). Strain WS11T was piezotolerant, growing optimally at 0.1 MPa (range 0.1-70 MPa). The main fatty acid was summed feature 8 (C18 : 1 ω7c/C18 : 1 ω 6c). The sole respiratory quinone was ubiquinone-10 (Q-10). The predominant polar lipids were phosphatidylcholine, two unidentified aminophospholipids and an unidentified phospholipid. The genome size was about 4.36 Mbp and the G+C content was 62.3 mol%. The combined genotypic and phenotypic data show that strain WS11T represents a novel species of a novel genus in the family Rhizobiaceae, for which the name Georhizobium profundi gen. nov., sp. nov. is proposed (type strain WS11T=MCCC 1K03498T=KCTC 62439T).


Branching morphology of the rat hepatic portal vein tree: a micro-CT study.
In contrast to the lung and the myocardium, the liver is a relatively homogeneous organ with fewer anatomic constraints on vascular branching. Hence, we hypothesize that the hepatic vasculature could more closely follow optimization of branching geometry than is the case in other organs. The geometrical and fractal properties of the rat hepatic portal vein tree were investigated, with the aid of three-dimensional micro-computed tomography data. Frequency distributions of vessel radii were obtained at three different voxel resolutions and fitted to a theoretical model of dichotomous branching. The model predicted an average junction exponent of 3.09. Hemodynamic model calculations showed that with generation, relative shear stress decreases. Branching angles were found to oscillate between those predicted by two optimality principles of minimum power loss and volume, and of minimum shear stress and surface. The liver shows a variation in branching morphology similar to that of other organs. Therefore, we conclude that anatomic constraints do not have a major perturbing impact.


Shohat type-spondyloepimetaphyseal dysplasia: Further phenotypic delineation.
Spondyloepimetaphyseal dysplasia-Shohat type (SEMDSH) is an ultra-rare type of skeletal dysplasia. Only nine patients from six families have been reported and genetically confirmed to have biallelic pathogenic variants in the DDRGK1 gene. We present a patient with typical clinical features of the disorder, including disproportionate short-limbed short stature, short neck, short chest with pectus carinatum, exaggerated lumbar lordosis and marked genu vara. Our patient further showed microcephaly, unilateral choanal atresia and antenatal fractures, features that were not reported before in association with this disorder. Radiological changes over time were presented, including delayed epiphyseal ossification, broad metaphysis with marked irregularities that progressed with age, fibular overgrowth, and characteristic spine changes with early platyspondyly and squaring of vertebral bodies at a later age. Exome sequencing revealed a homozygous pathogenic donor splice site variant in the DDRGK1 gene (NM_023935.3:c.408+1G > A). This mutation was also previously identified in patients from Iraqi descent. Our study expands the phenotypic spectrum of SEMDSH, emphasizes the radiological changes with age in SEMDSH patients, and recommends prolonged follow-up for these cases better to delineate the phenotype and surveillance for possible complications.


[Non-heart-beating-donor transplant: the first experience in Italy].
A promising way to increase the number of kidneys for transplantation is to expand the donor pool by including non-heart-beating donors (NHBDs). The centers involved in NHBD transplantation programs have reported a 16-40% increase in kidney transplants. A key issue with NHBD is the significantly higher rate of delayed graft function (DGF) and primary non-function (PNF) compared with that associated with heart-beating donor (HBD) transplants. However, although transplants from NHBD are associated with a greater incidence of early adverse events, long-term graft survival appears to be similar to that observed after transplants from HBDs. In addition, the use of extracorporeal membrane oxygenation and mechanical perfusion, the careful selection of recipients and donors, and an adequate therapeutic strategy may at least partially reduce the risk of PNF and DGF and improve transplant outcome.


Dry cow therapy with a non-antibiotic intramammary teat seal - a review.
: Dry cow antibiotic therapy is used to eliminate existing intramammary infections and to prevent new infections in the dry period. It is implemented as part of a total management system known as the 'Five-Point Plan' for mastitis control. Recent public concerns over the widespread prophylactic use of antibiotics, coupled with an increasing interest in organic farming, have lead to a re-evaluation of the treatment of cows at drying-off. As a result, attention has focussed on the use of novel alternatives to antibiotic therapy at the end of lactation. One such therapy involves the application of a non-antibiotic bismuth-based intramammary teat seal designed for use in cows with low cell counts at the end of lactation. Like the keratin plug that forms naturally in teats of cows that have been dried-off, teat seal forms a physical barrier to invading pathogens. To date, a number of independent studies have shown that teat seal is as effective as traditional dry cow antibiotic products in preventing the occurrence of new infection during the dry period in cows with somatic cell counts of ≤200,000 cells ml-1 at drying-off. This paper reviews the efficacy of teat seal in preventing dry period mastitis in both conventional and organic dairying systems.


Effectiveness of pulmonary artery catheters in aortic surgery: a randomized trial.
To evaluate the routine use of pulmonary artery catheters (PAC) in patients who undergo aortic surgery. One hundred twenty patients were randomized to placement of PACs for perioperative monitoring and hemodynamic optimization (tune up) in the intensive care unit on the night before aortic operation, or to intravenous hydration in the ward and perioperative monitoring without PACs. Before randomization, all patients underwent routine adenosine thallium-201 scintigraphy. To meet predetermined endpoints, 30 PAC patients (50%) received nitrates, inotropic agents, or both. PAC patients received more fluid in the preoperative period (p < 0.001) and in the first 24 hours after operation (p = 0.002) than control subjects. Eleven PAC patients (18%) and three control subjects (5%) had adverse intraoperative events (p = 0.02). There were 20 adverse postoperative events in 15 PAC patients (25%; nine cardiac, seven pulmonary, four acute tubular necrosis), which was not different compared with 11 postoperative events in 10 control subjects (17%; five cardiac, five pulmonary, one acute tubular necrosis). There were also no differences in duration of mechanical ventilation, intensive care unit stay, or hospital stay between groups. Postoperative cardiac complications were more common among patients who had a history of congestive heart failure (p = 0.02; odds ratio, 3.75; confidence interval, 1.3 to 11) or reperfusion defects on adenosine thallium scintigraphy (p = 0.01; odds ratio, 3.4; confidence interval, 1.2 to 9.4), regardless of group. Routine use of PACs for perioperative monitoring with the above protocol during aortic surgery is not beneficial and may be associated with a higher rate of intraoperative complications. Preoperative tune up does not prevent postoperative cardiac, renal, and other complications. Variables such as cardiac risk factors and adenosine thallium scintigraphy may be more important predictors of cardiac events in patients who undergo aortic operations.


The Donor-Linking Practices of Australian Fertility Clinics.
While Australia is a world leader in providing statutory donor-linking services - the practice whereby individuals connected through donor conception seek access to information about each other - there has been only limited exploration of how fertility clinics respond when approached with donor-linking requests. This article reports on 19 qualitative interviews conducted with Australian fertility clinic staff that explored how clinics manage requests to share identifying and non-identifying information about parties involved in donor conception. Our findings indicate that fertility clinics have experienced an increase in donor-linking requests in recent years, but that they are typically dealt with on an ad hoc basis. Two approaches to donor linking were identified: (1) an "active" approach where clinics supported donor linking and were willing to engage in outreach to see if the other party was open to information exchange; and (2) a "passive" approach whereby clinics were reluctant to facilitate linking and were unwilling to outreach to other parties. The variety of responses to donor-linking requests highlight the ways in which donor-conceived adults, parents and donors can have dramatically different access to information, depending on the clinic that provided treatment.


[EHF-puncture in combined rehabilitation of children with vertebrobasilar insufficiency syndrome in spinal deformities].
The results were compared of different programs of rehabilitation in 45 patients aged 5 to 18 years with spinal deformities and vertebrobasilar failure. Control patients received only basic therapy, the study group received also EHF-puncture. The efficacy of rehabilitation was confirmed by electropuncture diagnosis and rheoencephalogram. The patients with high tonicity of small vessels demonstrated a significantly improved regional circulation. This favours differential use of EHF puncture in the complex of rehabilitative measures.


Communicating the promise, risks, and ethics of large-scale, open space microbiome and metagenome research.
The public commonly associates microorganisms with pathogens. This suspicion of microorganisms is understandable, as historically microorganisms have killed more humans than any other agent while remaining largely unknown until the late seventeenth century with the works of van Leeuwenhoek and Kircher. Despite our improved understanding regarding microorganisms, the general public are apt to think of diseases rather than of the majority of harmless or beneficial species that inhabit our bodies and the built and natural environment. As long as microbiome research was confined to labs, the public's exposure to microbiology was limited. The recent launch of global microbiome surveys, such as the Earth Microbiome Project and MetaSUB (Metagenomics and Metadesign of Subways and Urban Biomes) project, has raised ethical, financial, feasibility, and sustainability concerns as to the public's level of understanding and potential reaction to the findings, which, done improperly, risk negative implications for ongoing and future investigations, but done correctly, can facilitate a new vision of "smart cities." To facilitate improved future research, we describe here the major concerns that our discussions with ethics committees, community leaders, and government officials have raised, and we expound on how to address them. We further discuss ethical considerations of microbiome surveys and provide practical recommendations for public engagement.


The high reactivity of peroxiredoxin 2 with H(2)O(2) is not reflected in its reaction with other oxidants and thiol reagents.
Peroxiredoxin 2 is a member of the mammalian peroxiredoxin family of thiol proteins that is important in antioxidant defense and redox signaling. We have examined its reactivity with various biological oxidants, in order to assess its ability to act as a direct physiological target for these species. Human erythrocyte peroxiredoxin 2 was oxidized stoichiometrically to its disulfide-bonded homodimer by hydrogen peroxide, as monitored electrophoretically under nonreducing conditions. The protein was highly susceptible to oxidation by adventitious peroxide, which could be prevented by treating buffers with low concentrations of catalase. However, this did not protect peroxiredoxin 2 against oxidation by added H(2)O(2). Experiments measuring inhibition of dimerization indicated that at pH 7.4 catalase and peroxiredoxin 2 react with hydrogen peroxide at comparable rates. A rate constant of 1.3 x 10(7) M(-1) s(-1) for the peroxiredoxin reaction was obtained from competition kinetic studies with horseradish peroxidase. This is 100-fold faster than is generally assumed. It is sufficiently high for peroxiredoxin to be a favored cellular target for hydrogen peroxide, even in competition with catalase or glutathione peroxidase. Reactions of t-butyl and cumene hydroperoxides with peroxiredoxin were also fast, but amino acid chloramines reacted much more slowly. This contrasts with other thiol compounds that react many times faster with chloramines than with hydrogen peroxide. The alkylating agent iodoacetamide also reacted extremely slowly with peroxiredoxin 2. These results demonstrate that peroxiredoxin 2 has a tertiary structure that facilitates reaction of the active site thiol with hydrogen peroxide while restricting its reactivity with other thiol reagents.


Fluctuation of a cancer-associated lactate dehydrogenase during S phase of the cell cycle in HeLa cells.
An unusual isozyme of lactate dehydrogenase, originally detected in Kirsten sarcoma virus-infected cells and later shown to be induced in normal mammalian cells by anaerobic shock, has also been reported at elevated levels in several human carcinomas. This enzyme is subject to inhibition by guanosine triphosphate and by the dinucleosides 5',5"'-diadenosine tetraphosphate and 5',5"'-diguanosine tetraphosphate (4). Fluctuation of the activity of this enzyme in soluble extracts of synchronized HeLa cells suggests the enzyme may be linked to DNA synthesis. The lactate dehydrogenase K activity increased in early S phase and then decreased to nearly undetectable levels during the period of most active DNA synthesis. This was observed in cells synchronized by thymidine excess or by aphidicolin, an inhibitor of DNA polymerase alpha.


Manipulating the epigenome for the treatment of urological malignancies.
Urological malignancies (cancers of the prostate, bladder, kidney and testes) account for 15% of all human cancers and more than 500,000 deaths worldwide each year. This group of malignancies is spread across multiple generations, affecting the young (testicular) through middle and old-age (kidney, prostate and bladder). Like most human cancers, urological cancers are characterized by widespread epigenetic insult, causing changes in DNA hypermethylation and histone modifications leading to silencing of tumor suppressor genes and genomic instability. The inherent stability yet dynamic plasticity of the epigenome lends itself well to therapeutic manipulation. Epigenetic changes are amongst the earliest lesions to occur during carcinogenesis and are essentially reversible (unlike mutations). For this reason, much attention has been placed over the past two decades on deriving pharmacological compounds that can specifically target and reverse such epi-mutations, either halting cancer on its developmental trajectory or reverting fully formed cancers to a more clinically manageable state. This review discusses DNA methyltransferase and histone deacetylase inhibitors that have been extensively studied in preclinical models and clinical trials for advanced and metastatic urological cancers.


Protein foods from animal sources, incident cardiovascular disease and all-cause mortality: a substitution analysis.
Protein-rich foods are major parts of the human diet and are highly heterogeneous in nutrient composition and health effects. Designing healthy diets for disease prevention requires careful consideration of substituting unhealthier protein foods with healthier protein foods. This was a pooled analysis of six prospective cohort studies of 29 682 US participants. Data were collected in 1985-2016. Adjusted hazard ratios (HRs) and 30-year absolute risk differences (ARDs) were calculated for the associations between simultaneous substitution of one or more animal protein foods with other animal or plant protein foods at various amounts, and incident cardiovascular disease (CVD) and all-cause mortality. Substituting eggs, processed meat, unprocessed red meat or poultry with nuts, whole grains, legumes or fish was associated with lower risks of incident CVD and all-cause mortality. According to different substitution amounts (varying from one serving per week to one serving per day) and different numbers of protein foods being simultaneously substituted (varying from one to four), estimates ranged between 1%: HR, 0.99 [95% confidence interval (CI), 0.98-1.00], and 54%: HR, 0.46 (0.35-0.60), lower risks on the relative scale and between 0.3%: ARD, -0.29% (-0.48% to -0.05%), and 14.0%: ARD, -13.96% (-17.29% to -9.96%) lower risks on the absolute scale. Nuts, whole grains, legumes and fish appeared to be healthier protein sources than eggs, processed meat, unprocessed red meat and poultry for preventing incident CVD and premature death. The magnitude of lower risk for incident CVD and all-cause mortality was driven by amount and number of animal protein foods substituted.


Proteomic searches comparing two (R)-lacosamide affinity baits: An electrophilic arylisothiocyanate and a photoactivated arylazide group.
We have advanced a novel strategy to search for lacosamide ((R)-1) targets in the brain proteome where protein binding is expected to be modest. Our approach used lacosamide agents containing affinity bait (AB) and chemical reporter (CR) units. The affinity bait moiety is designed to irreversibly react with the target, and the CR group permits protein detection and capture. In this study, we report the preparation and evaluation of (R)-N-(4-azido)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-3) and show that this compound exhibits potent anticonvulsant activities in the MES seizure model in rodents. We compared the utility of (R)-3 with its isostere, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-2), in proteomic studies designed to identify potential (R)-1 targets. We showed that despite the two-fold improved anticonvulsant activity of (R)-3 compared with (R)-2, (R)-2 was superior in revealing potential binding targets in the mouse brain soluble proteome. The difference in these agents utility has been attributed to the reactivity of the affinity baits (i.e., (R)-2: aryl isothiocyanate moiety; (R)-3: photoactivated aryl azide intermediates) in the irreversible protein modification step, and we conclude that this factor is a critical determinant of successful target detection where ligand (drug) binding is modest. The utility of (R)-2 and (R)-3 in in situ proteome studies is explored.


[Prevention of binge drinking in adolescents: do family doctors have a role to play?].
Binge drinking has nearly become the norm for young people and is thus worrying. Although alcohol use in males attracts more media attention, females are also frequently affected. A variety of preventive measures can be proposed: at the individual level by parents, peers and family doctors; at the school and community level, particularly to postpone age of first use and first episode of drunkenness; at the structural level through a policy restricting access to alcohol for young people and increasing its price. Family doctors can play an important role in identifying at risk users and individualising preventive messages to which these young people are exposed in other contexts.


Leber's optic neuropathy. New observations.
Leber's disease is a hereditary optic neuropathy characterized by a triad of ocular fundus changes, including circumpapillary telangiectatic microangiopathy, pseudoedema of the nerve fiber layer around the disc, and absence of peripapillary staining on fluorescein angiography. We report two families in which the first afflicted member had insufficient fundus changes to enable a diagnosis of Leber's disease. However, the presence of telangiectatic microangiopathy in either a symptomatic or asymptomatic family member established the diagnosis of Leber's optic nerve disease under these circumstances. These observations suggest that circumpapillary telangiectatic microangiopathy is a genetic marker and may not always be a pathogenetic predeterminant of Leber's optic neuropathy. In view of our findings, we propose the term "typical Leber's disease" for patients demonstrating the characteristic fundus triad and the term "atypical Leber's disease" for patients who lack diagnostic fundus changes but who have a family member with classic telangiectatic microangiopathy.


Risk of rabies exposure among travellers.
In recent years, requests for rabies immunoglobulin have increased at Amsterdam's Academic Medical Center's travel clinic. Travellers who received rabies pre-exposure prophylaxis (PrEP) before travel departure have immunological memory that can quickly be activated by timely booster vaccinations after possible exposure to rabies. PrEP alleviates the need for costly and scarcely available rabies immunoglobulin in case of exposure. This study describes which travellers are at risk of rabies exposure and would benefit from PrEP. The secondary aim was to specify which factors influence decision-making on taking PrEP. We reviewed electronic patient files of travellers attending our clinic for rabies post-exposure prophylaxis between January 2009 and February 2014. Demographic and travel characteristics were compared with a sample of patients who were seen for pre-travel advice at our clinic. To assess which factors had influenced the decision to take PrEP, a questionnaire survey was conducted. A total of 161 travellers experienced animal-associated injury. Compared with travellers from the pre-travel database, more people travelled to Southeast Asia (49.5% vs. 30.9%, p = 0.035) for comparable time periods (median 21 vs. 21 days, p = 0.083). Transcutaneous injuries (type III) were common (73.9%), most often inflicted by dogs (45%). Only ten travellers (6.2%) had received PrEP. Barriers for PrEP were high costs and a short time interval between consultation and travel departure. Travellers t o Southeast Asia should particularly be informed about rabies and the possibility of PrEP. Long-term travel was not associated with a higher risk of rabies exposure.


Long-term use of low-dose aspirin for cancer prevention: A 10-year population cohort study in Hong Kong.
Aspirin, commonly used for prevention of cardiovascular and cerebrovascular diseases, has been found to possess protective effects against cancer development in the Western populations. Such effects among Asian populations remain uncertain. The objective of this study is to investigate the use of aspirin on prevention of different cancers among Chinese users. This population-based study utilized database from the Hong Kong Hospital Authority; adults with aspirin prescription for at least 6 months between 2000 and 2004 were included and followed up until 2013. Aspirin users were age-sex matched with non-aspirin users at a 1:2 ratio. Incidences of cancer were the primary outcome measured by relative risk (RR). A total of 204,170 aspirin users and 408,339 non-aspirin users were included, with the mean age 67.5 years, 7.7 years average duration of aspirin prescription and 80 mg as the median dose of aspirin. Cancer incidences were found in 26,929 (13.2%) aspirin users and 70,755 (17.3%) non-aspirin users. Compared with patients who had not been prescribed aspirin, aspirin usage led to significant reduction of cancers in liver (RR: 0.49), stomach (RR: 0.42), colorectum (RR: 0.71), lung (RR: 0.65), pancreas (RR: 0.54), oesophagus (RR: 0.59) and leukaemia (RR: 0.67). There was no demonstrable reduction of kidney cancer, bladder cancer, prostate cancer and multiple myeloma in association with the usage of aspirin. Risk of breast cancer was shown to marginally increase (RR: 1.14) with aspirin usage. This study demonstrated that the long-term use of low-dose aspirin is associated with the reduction in risk of various cancers but not for breast cancer. Further investigation is needed before promoting aspirin as a primary chemoprotective agent.


Long-Term Engraftment and Fetal Globin Induction upon BCL11A Gene Editing in Bone-Marrow-Derived CD34+ Hematopoietic Stem and Progenitor Cells.
To develop an effective and sustainable cell therapy for sickle cell disease (SCD), we investigated the feasibility of targeted disruption of the BCL11A gene, either within exon 2 or at the GATAA motif in the intronic erythroid-specific enhancer, using zinc finger nucleases in human bone marrow (BM) CD34+ hematopoietic stem and progenitor cells (HSPCs). Both targeting strategies upregulated fetal globin expression in erythroid cells to levels predicted to inhibit hemoglobin S polymerization. However, complete inactivation of BCL11A resulting from bi-allelic frameshift mutations in BCL11A exon 2 adversely affected erythroid enucleation. In contrast, bi-allelic disruption of the GATAA motif in the erythroid enhancer of BCL11A did not negatively impact enucleation. Furthermore, BCL11A exon 2-edited BM-CD34+ cells demonstrated a significantly reduced engraftment potential in immunodeficient mice. Such an adverse effect on HSPC function was not observed upon BCL11A erythroid-enhancer GATAA motif editing, because enhancer-edited CD34+ cells achieved robust long-term engraftment and gave rise to erythroid cells with elevated levels of fetal globin expression when chimeric BM was cultured ex vivo. Altogether, our results support further clinical development of the BCL11A erythroid-specific enhancer editing in BM-CD34+ HSPCs as an autologous stem cell therapy in SCD patients.


Neck-to-shoulder pain as an unusual presentation of pulmonary embolism in a patient with cervical spinal cord injury: A case report.
Information on referred pain can be helpful for diagnosing diseases of the visceral organs. Here, the authors report a patient with cervical spinal cord injury (SCI) who had referred pain at the right side from the neck to shoulder, as a presentation of pulmonary embolism (PE). A 55-year-old man with complete tetraplegia, due to cervical SCI after C5 and C6 vertebral body fracture, complained of right neck-to-shoulder pain (numerical scale rating: 6). Despite pain medication (meloxicam 15 mg, gabapentin 400 mg, and propacetamol HCl 1 g), the pain was not reduced. Along with right neck-to-shoulder pain, he presented mild fever (37.8°C) and mildly elevated respiratory rate (20 breaths/min). D-dimer level was also mildly elevated to 6.09 mg/mL (normal value: < 0.5 mg/mL). Computed tomography pulmonary angiography revealed PE in the right lower lobe pulmonary artery. For managing PE, rivaroxaban was administered for three days. After the administration of rivaroxaban, the patient's pain completely disappeared. This study shows that pain at the neck-to-shoulder area can occur following unexpected causes such as PE. Not limited to PE, the evaluation of diseases in the thoracic or abdominal organs is recommended if patients with cervical SCI present refractory pain in the dermatomes innervated by high cervical nerve roots.


The quantum measurement problem.
Despite the spectacular success of quantum mechanics (QM) over the last 80 years in explaining phenomena observed at the atomic and subatomic level, the conceptual status of the theory is still a topic of lively controversy. Most of the discussion centers around two famous paradoxes (or, as some would have it, pseudoparadoxes) associated, respectively, with the names of Einstein, Podolsky, and Rosen (EPR) and with Schrodinger's cat. In this Viewpoint, I will concentrate on the paradox of Schrodinger's cat or, as it is often known (to my mind somewhat misleadingly), the quantum measurement paradox.


Mixed-linker MOFs with CAU-10 structure: synthesis and gas sorption characteristics.
The metal–organic framework compound [Al(OH)(BDC-Br)] (1) (BDC-Br2− = 5-bromo-1,3-benzenedicarboxylate) denoted CAU-10-Br was synthesised under solvothermal reaction conditions. Its structure was successfully refined by Rietveld methods. The framework is based on the connection of infinite helical chains of cis-corner-sharing AlO6-polyhedra via BDC-Br2− ions. Thus non-intersecting parallel channels are formed, each periodically varying in diameter between 1.1 and 6.6 Å. Nevertheless 1 adsorbs CO2 at 298 K, while it is non-porous towards H2 and N2 at 77 K. Employing high-throughput (HT) methods we identified synthesis conditions that lead to the formation of mixed-linker MOFs with CAU-10 topology. Starting with a molar ratio H2BDC:H2BDC-Br = 3:1 we established a synthesis procedure for the partially bromo-functionalised mixed-linker-MOF [Al(OH)(BDC)0.8(BDC-Br)0.2] (2) denoted as CAU-10-H/Br. Starting with a molar ratio H2BDC-NH2:H2BDC-NO2 = 1:1 the partially NO2- and NH2-functionalised mixed-linker MOF [Al(OH)(BDC-NO2)0.55(BDC-NH2)0.23(BDC-NHCHO)0.22] (3) denoted as CAU-10-NO2/NH2 was synthesised, in which the NH2-groups were found to be partially formylated. The partial bromo-functionalisation in CAU-10-H/Br (2) leads to a lower sorption capacity in comparison with the parent structure CAU-10-H, while the pore accessibility is comparable. The incorporation of NO2-, NH2- and NHCHO-groups in CAU-10-NO2/NH2 (3) does not only affect the accessibility of the pores for N2, but results also in an increased capacity for H2 and CO2 in comparison with the parent structure CAU-10-NO2. The reproducibility of the synthesis procedures was tested regarding the composition of the MOFs and the resulting gas sorption properties. In 2 a molar fraction of (BDC)2− = 80 ± 2% is found, while in 3 a molar fraction of (BDC-NO2)2− = 55 ± 2% is observed. Starting from the molar ratio H2BDC:H2BDC-CH3 = 1:1 mixed linker MOFs denoted as CAU-10-H/CH3 (4) were also obtained. In contrast to 2 and 3 the molar ratios of BDC2−/BDC-CH32− and especially the sorption properties differ substantially for every batch. The compounds were further characterised by X-ray powder diffraction, thermogravimetric/elemental analysis, NMR/Vis/IR-spectroscopy, and gas sorption measurements.


Emerging opportunities for site-specific molecular and cellular interventions in autoimmune hepatitis.
Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block autoantigen expression, a dimeric recombinant human fusion protein of cytotoxic T lymphocyte antigen-4, monoclonal antibodies against tumor necrosis factor-alpha, recombinant interleukin 10, tolerization techniques for disease-triggering autoantigens, T regulatory cell transfer, vaccination against antigen-specific cytotoxic CD8+ T cells, and gene silencing methods using small inhibitory RNAs are feasible interventions to explore. Treatments directed at dampening immunocyte activation with soluble cytotoxic T lymphocyte antigen-4, inhibiting immunocyte differentiation with recombinant interleukin 10, and improving immunosuppressive activity with regulatory T cell modulation have the most immediate promise. Progress in the development of an animal model of autoimmune hepatitis and experiences in other immune-mediated diseases justify the evaluation of site-specific molecular and cellular interventions in this disease.


Immunometabolism of Phagocytes and Relationships to Cardiac Repair.
Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.


Early intervention with immunomodulatory agents in the treatment of multiple sclerosis.
Multiple sclerosis (MS) is a lifelong neurologic disease leading to moderate or severe disability in the majority of affected patients. Studies of the natural history of MS suggest that 90% of patients with relapsing-remitting MS eventually develop secondary progressive (SP) disease. Magnetic resonance imaging (MRI) studies have consistently shown a high frequency of new T2 lesions and new gadolinium enhancing lesions even in the absence of clinical relapse. Lesion burden on T2 MRI increases by 5% to 10% per year and both axonal transection and cerebral atrophy are present at the earliest stages of RR MS. A wealth of evidence suggests that MS is a disease process that is continuously active, and that irreversible damage occurs early in the disease. Despite knowledge of the natural history and the availability of treatments that reduce relapse rates, decrease the accumulation of disability, and decrease surrogate measures of disease activity, only 60% of eligible patients have been treated with immunomodulating agents. This paper reviews the available evidence suggesting that immunomodulatory therapy modifies the natural history of MS and presents an argument for early intervention in the treatment of MS.


Age-related changes in Arc transcription and DNA methylation within the hippocampus.
The transcription of genes that support memory processes are likely to be impacted by the normal aging process. Because Arc is necessary for memory consolidation and enduring synaptic plasticity, we examined Arc transcription within the aged hippocampus. Here, we report that Arc transcription is reduced within the aged hippocampus compared to the adult hippocampus during both "off line" periods of rest, and following spatial behavior. This reduction is observed within ensembles of CA1 "place cells", which make less mRNA per cell, and in the dentate gyrus (DG) where fewer granule cells are activated by behavior. In addition, we present data suggesting that aberrant changes in methylation of the Arc gene may be responsible for age-related decreases in Arc transcription within CA1 and the DG. Given that Arc is necessary for normal memory function, these subregion-specific epigenetic and transcriptional changes may result in less efficient memory storage and retrieval during aging.


Physiotherapy group treatment for patients with fibromyalgia--an embodied learning process.
To study how patients with fibromyalgia (FM) experienced physiotherapy group treatment comprising pool exercise and education. Nineteen patients with FM were interviewed and the transcribed interviews were analysed using a phenomenological life-world approach. The participants' mean age was 45 years and their mean symptom duration was 10 years. Physiotherapy group treatment was experienced as an embodied learning process, comprising the themes: positive experience of body, sharing experiences of living with FM and creating new patterns of acting. The positive experience of body comprised the following categories: experiencing relaxation, experiencing physical capacity, acknowledging limitations and changing the pattern of activity. Sharing experiences comprised the following categories: not being alone and sharing joy. Three patterns of participation were identified: reciprocity, distancing and remaining outside. Creating new patterns comprised the following categories; calming down, creating a new relationship to self, creating a new relationship to social roles and creating new patterns for managing pain. The study indicates that physiotherapy group treatment was experienced as an embodied learning process. Positive experiences of body were intertwined with a new relationship to self and objects in the world. Interactions between the co-participants promoted the process of creating new patterns of thinking and acting in the social world.


Functional plasticity of the swim bladder as an acoustic organ for communication in a vocal fish.
Teleost fishes have evolved a number of sound-producing mechanisms, including vibrations of the swim bladder. In addition to sound production, the swim bladder also aids in sound reception. While the production and reception of sound by the swim bladder has been described separately in fishes, the extent to which it operates for both in a single species is unknown. Here, using morphological, electrophysiological and modelling approaches, we show that the swim bladder of male plainfin midshipman fish (Porichthys notatus) exhibits reproductive state-dependent changes in morphology and function for sound production and reception. Non-reproductive males possess rostral 'horn-like' swim bladder extensions that enhance low-frequency (less than 800 Hz) sound pressure sensitivity by decreasing the distance between the swim bladder and inner ear, thus enabling pressure-induced swim bladder vibrations to be transduced to the inner ear. By contrast, reproductive males display enlarged swim bladder sonic muscles that enable the production of advertisement calls but also alter swim bladder morphology and increase the swim bladder to inner ear distance, effectively reducing sound pressure sensitivity. Taken together, we show that the swim bladder exhibits a seasonal functional plasticity that allows it to effectively mediate both the production and reception of sound in a vocal teleost fish.