Involvement of the zebrafish trrap gene in craniofacial development.
Trrap (transformation/transcription domain-associated protein) is a component shared by several histone acetyltransferase (HAT) complexes and participates in transcriptional regulation and DNA repair; however, the developmental functions of Trrap in vertebrates are not fully understood. Recently, it has been reported that human patients with genetic mutations in the TRRAP gene show various symptoms, including facial dysmorphisms, microcephaly and global developmental delay. To investigate the physiological functions of Trrap, we established trrap gene-knockout zebrafish and examined loss-of-function phenotypes in the mutants. The trrap zebrafish mutants exhibited smaller eyes and heads than the wild-type zebrafish. The size of the ventral pharyngeal arches was reduced and the mineralization of teeth was impaired in the trrap mutants. Whole-mount in situ hybridization analysis revealed that dlx3 expression was narrowly restricted in the developing ventral pharyngeal arches, while dlx2b expression was diminished in the trrap mutants. These results suggest that trrap zebrafish mutants are useful model organisms for a human disorder associated with genetic mutations in the human TRRAP gene.


Reconstitution of membrane transport powered by a novel dimeric kinesin motor of the Unc104/KIF1A family purified from Dictyostelium.
Motor-powered movement along microtubule tracks is important for membrane organization and trafficking. However, the molecular basis for membrane transport is poorly understood, in part because of the difficulty in reconstituting this process from purified components. Using video microscopic observation of organelle transport in vitro as an assay, we have purified two polypeptides (245 and 170 kD) from Dictyostelium extracts that independently reconstitute plus-end-directed membrane movement at in vivo velocities. Both polypeptides were found to be kinesin motors, and the 245-kD protein (DdUnc104) is a close relative of Caenorhabditis elegans Unc104 and mouse KIF1A, neuron-specific motors that deliver synaptic vesicle precursors to nerve terminals. A knockout of the DdUnc104 gene produces a pronounced defect in organelle transport in vivo and in the reconstituted assay. Interestingly, DdUnc104 functions as a dimeric motor, in contrast to other members of this kinesin subfamily, which are monomeric.


Medicare fees and the volume of physicians' services.
This paper estimates the relationship between Medicare fees and quantities provided by physicians for eight specific services. It uses data for 13,707 physicians who responded to surveys in 2000/2001 and/or 2004/2005 and were linked to all Medicare claims for their Medicare patients. Results show that Medicare fees are positively related to quantity provided for all eight services, and are significantly different from zero and elastic for five of them. The findings are consistent with the general economic proposition that supply curves for medical services are positively sloped, and provide no evidence of volume-offset behavior for the services examined. These results also imply that Medicare could influence volume growth for specific services by varying their fee changes, and that uniform fee changes will have differential effects on service volume because of variation in underlying supply elasticities.


HIV-associated benign lymphoepithelial cysts of the parotid glands confirmed by HIV-1 p24 antigen immunostaining.
Approximately 1%-10% of patients with HIV infection have been reported to have salivary gland enlargement. Parotid swelling in patients with HIV is often associated with salivary gland disease, including benign lymphoepithelial cysts (BLECs). The presence of BLEC can serve as an indicator of HIV infection, and the diagnosis of HIV-associated BLEC is usually based on clinical course, HIV confirmatory blood testing, such as western blot or viral detection, and imaging studies, but not on biopsies or immunostaining. To exclude other diseases such as tuberculosis and malignant lymphoma and to further improve the diagnostic accuracy of BLEC, the detection of the HIV-1 p24 antigen by immunohistochemistry is a useful diagnostic method. We report a case of a 65-year-old Japanese man with swelling of the parotid glands and HIV-associated BLEC confirmed via HIV-1 p24 immunohistochemical staining.


Room temperature aqueous synthesis of UiO-66 derivatives via postsynthetic exchange.
Herein, we report the room temperature aqueous synthesis of the Zr(iv)-based metal-organic framework UiO-66 and a series of functionalized derivatives through postsynthetic exchange from a perfluorinated UiO-66-F4 precursor. All synthesized MOFs in this study were thoroughly characterized to verify formation of the desired MOF, porosity, crystallinity, and exchanged ligand content. This report represents a green, aqueous, room temperature synthesis of a highly valued series of Zr(iv)-based MOFs.


Understanding the Impact of Stroke on Brain Motor Function: A Hierarchical Bayesian Approach.
Stroke is a disturbance in blood supply to the brain resulting in the loss of brain functions, particularly motor function. A study was conducted by the UCI Neurorehabilitation Lab to investigate the impact of stroke on motor-related brain regions. Functional MRI (fMRI) data were collected from stroke patients and healthy controls while the subjects performed a simple motor task. In addition to affecting local neuronal activation strength, stroke might also alter communications (i.e., connectivity) between brain regions. We develop a hierarchical Bayesian modeling approach for the analysis of multi-subject fMRI data that allows us to explore brain changes due to stroke. Our approach simultaneously estimates activation and condition-specific connectivity at the group level, and provides estimates for region/subject-specific hemodynamic response functions. Moreover, our model uses spike and slab priors to allow for direct posterior inference on the connectivity network. Our results indicate that motor-control regions show greater activation in the unaffected hemisphere and the midline surface in stroke patients than those same regions in healthy controls during the simple motor task. We also note increased connectivity within secondary motor regions in stroke subjects. These findings provide insight into altered neural correlates of movement in subjects who suffered a stroke.


Post-Encephalitic Parkinsonism and Sleep Disorder Responsive to Immunological Treatment: A Case Report.
We describe a 70-year-old man who, after a viral encephalitis associated with pneumonia, progressively developed a parkinsonism associated with lethargy. Encephalitis manifested with persistent hiccups, seizures and impairment of consciousness. After 2 weeks, the initial neurologic symptoms subsided and the patient progressively developed movement disorders (rigidity and bradykinesia, resistant to L-DOPA), lethargy and behavioral hypersomnia. Magnetic resonance imaging showed thalamic and hippocampal signal abnormalities, immunohistochemistry on a mouse brain substrate revealed serum autoantibodies binding to the brainstem neuropil. Polysomnographic monitoring was consistent with a very severe disruption of sleep: the sleep-wake cycle was fragmented, and the NREM-REM ultradian cycle was irregular. Intravenous immune globulin therapy resulted in the complete reversal of the movement and the sleep disorders. Our observation confirms that parkinsonism and sleep disorders may be consequences of encephalitis, that an immune-mediated pathogenesis is likely, and, consequently, that immunotherapy can be beneficial in these patients. The polysomnographic monitoring suggests that lethargia, rather than a mere hypersomnia, is the result of a combination between sleep disruption and altered motor control.


Control of rhGH Release Profile from PEG-PAF Thermogel.
Poly(ethylene glycol)-poly(l-alanine-co-l-phenyl alanine) diblock copolymers (PEG-PAF) of 2000-990 Da (P2K) and 5000-2530 Da (P5K) with the different molecular weights of PEGs, but having a similar molecular weight ratio of hydrophobic block to hydrophilic block were synthesized to compare their solution behavior and corresponding protein drug release profiles from their in situ formed thermogels. The PEG-PAF aqueous solutions underwent heat-induced sol-to-gel transition in a concentration range of 18.0-24.0 wt % and 8.0-12.0 wt % for P2K and P5K, respectively. P5K formed bigger micelles than P2K, of a broad distribution, whereas the PAF blocks of P5K developed richer in α-helix than those of P2K in the core of the micelles. As the temperature increased, the micelles underwent dehydration of the PEG, which led to the aggregation of micelles, while the secondary structure of PAF was slightly affected during the sol-to-gel transition. The P5K exhibited higher tendency to aggregate and formed a tighter gel than P2K. Upon injection into the subcutaneous layer of rats, both polymer aqueous solutions formed a biocompatible gel with typical mild inflammatory tissue responses. Recombinant human growth hormone (rhGH) maintained its stability without forming any aggregates in both sol (4 °C) and gel (37 °C) states of the PEG-PAFs. Even though P2K and P5K have a similar molecular weight ratio of hydrophobic block to hydrophilic block, the P5K system exhibited a reduced initial burst release, improved bioavailability, and prolonged therapeutic duration of the rhGH, compared to the P2K system. The current research suggests that a drug release profile is a complex function of self-assembling carriers and incorporated drugs, and thus, a promising protein delivery system could be designed by adjusting the molecular parameters of a thermogel.


The effects of hypercapnia on DTI quantification in anesthetized rat brain.
Diffusion Tensor Imaging (DTI) offers a valuable in vivo tool to characterize water diffusion behavior in biological tissues, particularly brain tissues. The accuracy of DTI derived parameters can directly affect the interpretation of underlying microstructures, physiology or pathologies. It is anticipated that measurement of apparent diffusion coefficient (ADC) using DTI could be influenced and complicated by the presence of water molecules in brain vasculature. However, little is known about to what degree does blood signal from vasculature affect the diffusion quantitation. In this study, we examined the effects of hypercapnia on DTI quantification in rat brains using inhalation of 5% carbon dioxide (CO2). It was found that statistically significant changes occurred in parametric DTI maps in response to cerebrovascular challenges, indicating that vascular factors could interfere with in vivo DTI characterization of neural tissues. Consequently, hemodynamic alterations can potentially affect the DTI quantitation and detection of tissue microstructures and pathological alterations. Therefore, cautions must be taken when interpreting DTI parameters in vivo.


CYP3A genetic variation and taxane-induced peripheral neuropathy: a systematic review, meta-analysis, and candidate gene study.
Background: Taxane-induced peripheral neuropathy (TIPN) is an important cause of premature treatment cessation and dose-limitation in cancer therapy. It also reduces quality of life and survivorship in affected patients. Genetic polymorphisms in the CYP3A family have been investigated but the findings have been inconsistent and contradictory. Methods: A systematic review identified 12 pharmacogenetic studies investigating genetic variation in CYP3A4*22 and CYP3A5*3 and TIPN. In our candidate gene study, 288 eligible participants (211 taxane participants receiving docetaxel or paclitaxel, and 77 control participants receiving oxaliplatin) were successfully genotyped for CYP3A4*22 and CYP3A5*3. Genotyping data was transformed into a combined CYP3A metaboliser phenotype: Poor metabolisers, intermediate metabolisers and extensive metabolisers. Individual genotypes and combined CYP3A metaboliser phenotypes were assessed in relation to neurotoxicity, including by meta-analysis where possible. Results: In the systematic review, no significant association was found between CYP3A5*3 and TIPN in seven studies, with one study reporting a protective association. For CYP3A4*22, one study has reported an association with TIPN, while four other studies failed to show an association. Evaluation of our patient cohort showed that paclitaxel was found to be more neurotoxic than docetaxel (p < 0.001). Diabetes was also significantly associated with the development of TIPN. The candidate gene analysis showed no significant association between either SNP (CYP3A5*3 and CYP3A4*22) and the development of TIPN overall, or severe TIPN. Meta-analysis showed no association between these two variants and TIPN. Transformed into combined CYP3A metaboliser phenotypes, 30 taxane recipients were poor metabolisers, 159 were intermediate metabolisers, and 22 were extensive metabolisers. No significant association was observed between metaboliser status and case-control status. Summary: We have shown that the risk of peripheral neuropathy during taxane chemotherapy is greater in patients who have diabetes. CYP3A genotype or phenotype was not identified as a risk factor in either the candidate gene analysis or the systematic review/meta-analysis, although we cannot exclude the possibility of a minor contribution, which would require a larger sample size.


IGF-I induced phosphorylation of S6K1 and 4E-BP1 in heart is impaired by acute alcohol intoxication.
The purpose of the present study was to determine whether acute alcohol (EtOH) intoxication impairs the signal transduction pathway used to coordinate insulin-like growth factor (IGF)-I stimulation of myocardial protein synthesis. Rats were injected intraperitoneally with EtOH or saline. After 2.5 h, IGF-I or saline was injected intravenously and the heart was excised at 2 min or 20 min. Additional rats were pretreated with RU486 or tumor necrosis factor (TNF) binding protein (BP) to assess the importance of elevations in glucocorticoids or TNF, respectively, as endogenous modulators of IGF-I signal transduction. EtOH did not alter the total amount or tyrosine phosphorylation of the IGF-I receptor, IRS-1 or PKB under basal or IGF-stimulated conditions. However, EtOH attenuated the ability of IGF-I to phosphorylate ribosomal S6 kinase (S6K)-1 on residues T389 ( approximately 62%) and T421/S424 ( approximately 40%), and also reduced ribosomal protein S6 phosphorylation. Under basal conditions, EtOH altered the distribution of eukaryotic initiation factor (eIF) 4E, as evidenced by a decreased amount of the active eIF4E.eIF4G complex (53%), an increased amount of inactive eIF4E.4E-BP1 complex ( approximately 3-fold), and decreased phosphorylation of 4E-BP1 (56%). EtOH also impaired the ability of IGF-I to reverse the above-mentioned changes in the eIF4E system. Pretreatment of rats with RU486 or TNFBP was unable to attenuate the EtOH-induced changes in either eIF4E distribution or the phosphorylation state of 4E-BP1, S6K1 or S6. These data indicate that acute EtOH intoxication alters selected aspects of translational control in the heart under basal conditions. Furthermore, despite appropriate stimulation of IGF-I receptor, IRS-1 and PKB, EtOH impairs IGF-I signaling via S6K1 and 4E-BP1 pathways, and this defect is regulated in a glucocorticoid- and TNF-independent manner. This IGF-I resistance may represent a participating mechanism by which alcohol limits protein synthesis in heart.


Sustainable farming of the mealworm Tenebrio molitor for the production of food and feed.
The farming of edible insects is an alternative strategy for the production of protein-rich food and feed with a low ecological footprint. The industrial production of insect-derived protein is more cost-effective and energy-efficient than livestock farming or aquaculture. The mealworm Tenebrio molitor is economically among the most important species used for the large-scale conversion of plant biomass into protein. Here, we review the mass rearing of this species and its conversion into food and feed, focusing on challenges such as the contamination of food/feed products with bacteria from the insect gut and the risk of rapidly spreading pathogens and parasites. We propose solutions to prevent the outbreak of infections among farmed insects without reliance on antibiotics. Transgenerational immune priming and probiotic bacteria may provide alternative strategies for sustainable insect farming.


A statistical model for analyzing the rotational error of single isocenter for multiple targets technique.
To develop a statistical model that incorporates the treatment uncertainty from the rotational error of the single isocenter for multiple targets technique, and calculates the extra PTV (planning target volume) margin required to compensate for this error. The random vector for modeling the setup (S) error in the three-dimensional (3D) patient coordinate system was assumed to follow a 3D normal distribution with a zero mean, and standard deviations of σx , σy , σz . It was further assumed that the rotation of clinical target volume (CTV) about the isocenter happens randomly and follows a three-dimensional (3D) independent normal distribution with a zero mean and a uniform standard deviation of σδ . This rotation leads to a rotational random error (R), which also has a 3D independent normal distribution with a zero mean and a uniform standard deviation of σR equal to the product of σδπ180 and dI⇔T, the distance between the isocenter and CTV. Both (S and R) random vectors were summed, normalized, and transformed to the spherical coordinates to derive the Chi distribution with three degrees of freedom for the radial coordinate of S+R. PTV margin was determined using the critical value of this distribution for a 0.05 significance level so that 95% of the time the treatment target would be covered by the prescription dose. The additional PTV margin required to compensate for the rotational error was calculated as a function of σR and dI⇔T. The effect of the rotational error is more pronounced for treatments that require high accuracy/precision like stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT). With a uniform 2-mm PTV margin (or σx = σy = σz = 0.715 mm), a σR = 0.328 mm will decrease the CTV coverage probability from 95.0% to 90.9%, or an additional 0.2-mm PTV margin is needed to prevent this loss of coverage. If we choose 0.2 mm as the threshold, any σR > 0.328 mm will lead to an extra PTV margin that cannot be ignored, and the maximal σδ that can be ignored is 0.45° (or 0.0079rad ) for dI⇔T = 50 mm or 0.23° (or 0.004rad ) for dI⇔T = 100 mm. The rotational error cannot be ignored for high-accuracy/-precision treatments like SRS/SBRT, particularly when the distance between the isocenter and target is large.


Performance of Sustainable Insulated Wall Panels with Geopolymer Concrete.
The increase in the population creates an increased demand for construction activities with eco-friendly, sustainable, and high-performance materials. Insulated concrete form (ICF) is an emerging technology that satisfies the sustainability demands of the construction sector. ICF is a composite material (a combination of expanded polystyrene (EPS) and geopolymer concrete (GPC)) that enhances the performance of concrete (such as thermal insulation and mechanical properties). To investigate the axial strength performance, five different types of prototypes were created and tested. Type I (without reinforcement): (a) hollow EPS without concrete, (b) alternative cells of EPS filled with concrete, (c) and all the cells of EPS filled with concrete; and Type II (with reinforcement): (d) alternative cells of EPS filled with concrete; (e) and all the cells of EPS filled with concrete. Amongst all the five prototypes, two grades of GPC were employed. M15 and M20 grades are used to examine the effectiveness in terms of cost. For comparing the test results, a reference masonry unit was constructed with conventional clay bricks. The main aim of the investigation is to examine the physical and mechanical performance of sandwich-type ICFs. The presence of polystyrene in ICF changes the failure pattern from brittle to ductile. The result from the study reveals that the Type II prototype, i.e., the specimen with all the cells of EPS filled with concrete and reinforcement, possesses a maximum load-carrying capacity greater than the reference masonry unit. Therefore, the proposed ICF is recommended to replace the conventional load-bearing system and non-load-bearing walls.


Reasons for repeated medical visits among patients with chronic back pain.
This study identifies the key motivations of patients repeatedly seeking medical care for chronic back problems. We conducted one-on-one, in-depth interviews with patients to discuss their experiences with low back pain and its care. To validate our interpretation of the qualitative data, participants were mailed questionnaires listing the themes identified in the interviews and asked to rate the importance to them of each of the themes. Managed health care plans in Atlanta, Dallas, and Seattle. Fifty-four patients (37% male, 63% female) who were 25 to 65 years of age and had three or more medically attended episodes of low back pain during the 3 years preceding the study. In describing their motivations for seeking medical care for back pain, nearly all participants cited difficulty in performing normal activities and the desire to discover the cause of the pain. Other motivations for seeking medical care for back pain included increased pain and the desire for a diagnostic test or a new treatment. Many of the verbalized reasons for repeated medical visits among patients with chronic back pain are probably best understood as seeking validation of their suffering. Patients with chronic back pain report many unmet needs and expectations. Overall satisfaction might be improved if clinicians elicit patients' views of underlying causes and their expectations from office visits.


Needs of Families with Children with Cerebral Palsy in Latvia and Factors Affecting These Needs.
In order to provide targeted support to families who are raising children with developmental disorders, it is important to study the family needs and to understand circumstances that may affect them. The aim of this study was to identify the needs of the families with preschool children with cerebral palsy, and study how these needs relate to factors associated with families, children and rehabilitation services. Descriptive analysis showed that families living in Latvia most often need information, social and financial support and coordination of services, and they also need financial support to cover the costs of child care and treatment. The results of the data analysis support the hypothesis that factors characterising families, children with cerebral palsy and rehabilitation services affect the needs of the families with preschool children with cerebral palsy living in Latvia, and the unique impact of these factors depends on the type of needs. Regression analysis revealed that the most important factors affecting the needs of families were related with the socio-economic situation, as well as the support of peers and professionals. The availability and regularity of rehabilitation services, limitations to the child's functions and health impairments were factors that affected family needs to a lesser extent.


Quality of life in patients with treated and clinically stable Wilson's disease.
Health-related quality of life (HRQoL) in Wilson's disease (WD) has not been extensively studied. Therefore, the purpose of this cross-sectional study was to identify clinical and demographic factors influencing HRQoL in 60 treated, clinically stable patients with WD using a generic questionnaire, the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36). The level of disability and grading of WD multisystemic manifestations were assessed by the Global Assessment Scale for WD (GAS for WD). The Mini Mental State Examination (MMSE) and the 21-item Hamilton Depression Rating Scale (HDRS) scoring were also applied by the same trained interviewers. Lower scores on the SF-36 domains were found in patients with neurological compared with those with a predominantly hepatic form of WD. The HRQoL of patients with WD and psychiatric symptoms was also lower than that of those without them. Finally, significant inverse correlations were obtained between the various SF-36 domains and all the following: period of latency from the first symptoms/signs appearance and treatment initiation, MMSE and HDRS scores, and different domains of the GAS for WD.


Acetyl-L-carnitine-mediated neuroprotection during hypoxia is attributed to ERK1/2-Nrf2-regulated mitochondrial biosynthesis.
Neuronal damage in hypoxia and several neurodegenerative disorders is invariably associated with oxidative damage and mitochondrial dysfunction. Administration of acetyl-L-carnitine (ALCAR) on the other hand attenuates neuronal damage, prevents apoptosis, and improves energy status in hypoxic stress through less understood mechanisms. Becasue mitochondrial biogenesis could be a possible mechanism for ALCAR-induced improvement in bioenergetics in neurons, the present study aimed at exploring signaling pathways of ALCAR-induced neuroprotection in hypoxia and possible occurrence of mitochondrial biogenesis. To create global hypoxia, adult Sprague-Dawley rats were exposed to a simulated altitude of 7,620 m at standard temperature and humidity conditions. We here demonstrate that administration of ALCAR to hypoxic rats for a period of 2 weeks effectively protected hippocampal neurons from mitochondrial dysfunction, excitotoxicity, and neurodegeneration. ALCAR administration resulted in peroxisome proliferator-activated receptor γ coactivator-1α and nuclear respiratory factor-1-induced mitochondrial biogenesis, the expression of which was regulated by an extracellular-related kinase-nuclear factor erythroid 2-related factor 2 (ERK-Nrf2)-mediated mechanism. Most notably, calcium buffering into nonfunctional mitochondria ameliorated excitotoxicity and improved bioenergetic status of the hippocampal neurons. Together, the data reveal the immense therapeutic potential of ALCAR for the treatment of ischemia, stroke, and other neurodegenerative disorders associated with hypoxic stress and excitotoxicity.


Acquired tonsillar herniation and syringomyelia after pleural effusion aspiration: case report.
We present a case of brachial plexus avulsion and reconstructive surgery with cerebrospinal fluid leak between the cervical subarachnoid space and the pleural cavity responsible for tonsillar herniation and syringomyelia. A 17-year-old man presented with headaches when he was positioned upright, simultaneously with a persistent right pleural effusion for about 4 months after reconstructive surgery for a right brachial plexus avulsion. In addition, the headaches had worsened considerably after two aspirations of the pleural effusion. Magnetic resonance imaging (MRI) demonstrated signs of chronic intracranial hypotension and tonsillar herniation with a presyrinx cavity from vertebral level C1 to C7. None of those abnormalities were seen on the MRI scan obtained a few days after the initial trauma 7 months previously. Plexus brachial MRI confirmed the presence of a cerebrospinal fluid leak between the avulsed root of C8 and the pulmonary apex. The leak was treated by surgical closure of the dural tear of the C8 root. Postoperatively, the patient's headaches immediately resolved, and MRI 4 months later showed resolution of cerebellar tonsil herniation and regression of the syrinx. Resolution of acquired tonsillar herniation and syringomyelia can be achieved by closure of the dural tear responsible of the cerebrospinal fluid leak.


[The role of the extent of hydration of reversed micelles of surfactant s in the regulation of the peroxidase activity of ferritin and immunocomplexes of cortisol-peroxidase conjugates].
The effect of the degree of hydration (W0) of reversed micelles of Aerosol OT (AOT) and its mixture with Triton X-45 in heptane on the peroxidase activity of horse spleen ferritin in the oxidation of various substrates by hydrogen peroxide and organic hydroperoxides and on the activity of solubilized or immobilized immunocomplexes of horseradish peroxidase-cortisol conjugates (HP-COR) was studied. The peroxidase activity versus W0 plot has maxima at W0 8-14 and 19-22, which cannot be attributed to dissociation of immunocomplexes into its components or of ferritin into its subunits. The possibility of the stabilization of the conformers of oligomeric proteins by reversed micelles and the effect of the self-association of micelles on the peroxidase activity of the HP-COR immunocomplexes and ferritin were discussed. A procedure for the isolation of the iron-containing cluster from the ferritin molecule without reduction of the Fe3+ ions was suggested.


Utility of a Systematic Approach to Teaching Photographic Nasal Analysis to Otolaryngology Residents.
Photographic nasal analysis constitutes a critical step along the path toward accurate diagnosis and precise surgical planning in rhinoplasty. The learned process by which one assesses photographs, analyzes relevant anatomical landmarks, and generates a global view of the nasal aesthetic is less widely described. To discern the common pitfalls in performing photographic nasal analysis and to quantify the utility of a systematic approach model in teaching photographic nasal analysis to otolaryngology residents. This prospective observational study included 20 participants from a university-based otolaryngology residency program. The control and intervention groups underwent baseline graded assessment of 3 patients. The intervention group received instruction on a systematic approach model for nasal analysis, and both groups underwent postintervention testing at 10 weeks. Data were collected from October 1, 2015, through June 1, 2016. A 10-minute, 11-slide presentation provided instruction on a systematic approach to nasal analysis to the intervention group. Graded photographic nasal analysis using a binary 18-point system. The 20 otolaryngology residents (15 men and 5 women; age range, 24-34 years) were adept at mentioning dorsal deviation and dorsal profile with focused descriptions of tip angle and contour. Areas commonly omitted by residents included verification of the Frankfort plane, position of the lower lateral crura, radix position, and ratio of the ala to tip lobule. The intervention group demonstrated immediate improvement after instruction on the teaching model, with the mean (SD) postintervention test score doubling compared with their baseline performance (7.5 [2.7] vs 10.3 [2.5]; P < .001). At 10 weeks after the intervention, the mean comparative improvement in overall graded nasal analysis was 17% (95% CI, 10%-23%; P < .001). Otolaryngology residents demonstrated proficiency at incorporating nasal deviation, tip angle, and dorsal profile contour into their nasal analysis. They often omitted verification of the Frankfort plane, position of lower lateral crura, radix depth, and ala-to-tip lobule ratio. Findings with this novel 10-minute teaching model should be validated at other teaching institutions, and the instruction model should be further enhanced to teach more sophisticated analysis to residents as they proceed through training. NA.


Single-institutional study on role of ureteroscopy and retrograde intrarenal surgery in treatment of pediatric renal calculi.
Ureteroscopy (URS) is accepted as a primary modality to treat ureteral calculi in children and extracorporeal shock wave lithotripsy and percutaneous nephrolithotomy continue to be the primary option for renal stones. We report our experience with the use of URS in managing pediatric upper tract calculi and evaluate the results in relation to stone location, size, and the use of URS as a primary or secondary treatment modality. A retrospective chart review was performed for all children who underwent URS for renal stones from 1999 to 2004. Success was defined as complete radiologic clearance. A total of 19 patients (mean age 6.9 years) with 23 calculi underwent URS and were followed up for a mean of 23 months. The stones were located in the renal pelvis in 8 patients, and the polar regions in 4 and 7 patients had partial staghorn calculi with >1 caliceal extension. The primary and secondary success rate for patients with renal calculi was 80% (5 of 8) and 66% (2 of 3) for pelvic stones and 100% (4 of 4) for polar stones. Only 1 of the partial staghorn calculi was completely cleared with URS. Complications included distal ureteral perforation in 1 and urinoma in 1. URS achieves reasonable results with minimal complications in pediatric patients with renal pelvic calculi. Polar stones required multiple sessions for complete clearance, and staghorn calculi were not amenable to URS. Additional studies are necessary to define the role of URS as an option in the surgical treatment of children with renal calculi.


Exception from informed consent for biomedical research in emergency settings: A study from Jordan.
Research conduction in emergency settings is of paramount importance to promote knowledge and experiences related to treating acutely ill patients. However, the complexity of situations creates a considerable ethical challenge facing researchers who basically deal with emergent cases. This study aimed to determine attitudes of healthcare providers (HCPs) towards exception from informed consent (EFIC) and enrollment willingness in emergency research in Jordan. A quantitative research with face-to-face questionnaire was conducted by an interviewer during 6-month period in 2019. Survey measures included items related to EFIC policy and overall willingness of HCPs to participate or support their family members' participation in emergency research. A total of 151 HCPs in the emergency departments (EDs) in Jordan was recruited. Positive attitude toward emergency research dominated among participants; about 21.9% of participants reported previous experience in the conduction of emergency research and 12.3% had related publications. Regarding EFIC policy, there was a general consensus of disagreement to most of the examined items. There was a trend for little support of EFIC policy when questioned about the enrollment of family members or public in emergency research, however, the application of EFIC was accepted for self-enrollment of respondents in emergency research. No significant differences (P = 0.37), among participants from different disciplines, were reported regarding the attitudes towards EFIC items or willingness to enroll in emergency research. Generally, HCPs reported an overall positive support to emergency research despite a consensus of disagreement related to EFIC terms. Therefore, it is recommended to pursue future studies to compare well-informed subjects; recruited from well-developed institutions in regard to emergency research potentials; with the present basic attitudinal surveillance in order to dissipate the effect of such confounder and to get better insight of the actual attitudes related to emergency research and EFIC. In addition, efficient multidisciplinary communication channels between researchers and policy makers can lather the way to collaborative research with simultaneous innovative delivery of quality emergency care.


Evolutionary conservation of the polyproline II conformation surrounding intrinsically disordered phosphorylation sites.
Intrinsically disordered (ID) proteins function in the absence of a unique stable structure and appear to challenge the classic structure-function paradigm. The extent to which ID proteins take advantage of subtle conformational biases to perform functions, and whether signals for such mechanism can be identified in proteome-wide studies is not well understood. Of particular interest is the polyproline II (PII) conformation, suggested to be highly populated in unfolded proteins. We experimentally determine a complete calorimetric propensity scale for the PII conformation. Projection of the scale into representative eukaryotic proteomes reveals significant PII bias in regions coding for ID proteins. Importantly, enrichment of PII in ID proteins, or protein segments, is also captured by other PII scales, indicating that this enrichment is robustly encoded and universally detectable regardless of the method of PII propensity determination. Gene ontology (GO) terms obtained using our PII scale and other scales demonstrate a consensus for molecular functions performed by high PII proteins across the proteome. Perhaps the most striking result of the GO analysis is conserved enrichment (P < 10(-8) ) of phosphorylation sites in high PII regions found by all PII scales. Subsequent conformational analysis reveals a phosphorylation-dependent modulation of PII, suggestive of a conserved "tunability" within these regions. In summary, the application of an experimentally determined polyproline II (PII) propensity scale to proteome-wide sequence analysis and gene ontology reveals an enrichment of PII bias near disordered phosphorylation sites that is conserved throughout eukaryotes.


A model lightning safety policy for athletics.
The purpose of this paper is to present a model policy on lightning safety for athletic trainers. Among college athletic programs in the United States there is a serious lack of written policy on lightning safety. Available evidence shows that most National Collegiate Athletic Association (NCAA) Division I institutions, even though they are located in high lightning activity areas of the country, do not have formal, written lightning safety policies. The policy presented herein, which is at the forefront of such policies, is the lightning safety policy written as part of a policies and procedures manual for the division of sports medicine at a public NCAA Division I university. This is a policy based on practicality that utilizes the "flash-to- bang" method for determining the distance of lightning activity from the observer. The policy begins with the importance of prevention, including the daily monitoring of weather reports. The policy defines a "safe shelter" and specifies the chain of command for determining who removes a team or individuals from an athletic site in the event of dangerous lightning activity.


Contamination of Retail Meat Samples with Multidrug-Resistant Organisms in Relation to Organic and Conventional Production and Processing: A Cross-Sectional Analysis of Data from the United States National Antimicrobial Resistance Monitoring System, 2012-2017.
During food animal production, animals are exposed to, colonized by, and sometimes infected with bacteria that may contaminate animal products with susceptible and multidrug-resistant organisms (MDRO). The United States' Organic Foods Production Act resulted in decreased antibiotic use in some animal production operations. Some studies have reported that decreased antibiotic use is associated with reduced MDRO on meat. The aim of this study was to investigate associations of meat production and processing methods with MDRO and overall bacterial contamination of retail meats. Bacterial contamination data from 2012 to 2017 for chicken breast, ground beef, ground turkey, and pork chops were downloaded from the National Antimicrobial Resistance Monitoring System. Poisson regression models with robust variance were used to estimate associations with MDRO contamination and any contamination (adjusted for year and meat type) overall, and according to bacteria genus (Salmonella, Campylobacter, Enterococcus, Escherichia coli) and meat type. A total of 39,349 retail meat samples were linked to 216 conventional, 123 split (conventional and organic), and three organic processing facilities. MDRO contamination was similar in conventionally produced meats processed at split vs. conventional facilities but was significantly lower in organically produced meats processed at split facilities [adjusted prevalance ratio (aPR)=0.43; 95% CI: 0.30, 0.63]. Meat processed by split vs. conventional processors had higher or similar MDRO contamination for all tested bacterial genera except Campylobacter (aPR=0.29; 95% CI: 0.13, 0.64). The prevalence of any contamination was lower in samples processed at split vs. conventional facilities for aggregated samples (aPR=0.70; 95% CI: 0.68, 0.73) and all meat types and bacterial genera. Organically produced and processed retail meat samples had a significantly lower prevalence of MDRO than conventionally produced and processed samples had, whereas meat from split processors had a lower prevalence of any contamination than samples from conventional processors had. Additional studies are needed to confirm findings and clarify specific production and processing practices that might explain them. https://doi.org/10.1289/EHP7327.


Replication of hepatitis B in HBsAg-positive siblings.
Persistent hepatitis B virus (HBV) replication is important for progression of chronic liver diseases. To understand whether there is a trend of HBV replication in siblings or not, 1850 relatives of patients with hepatocellular carcinoma (HCC) were examined prospectively for liver function test, viral markers and HBV DNA. The prevalence of HBsAg in the parents', siblings', children's and grandchildren's generations were 43.4%, 57.2%, 35.5% and 32.1%, respectively. The prevalence of hepatitis B e antigen (HBeAg) in sibling's generation (mean age 44.4 years) was 19%, which is higher than that of asymptomatic HBsAg carriers. For siblings in the children's generation, the prevalence of HBeAg in hepatitis B surface antigen (HBsAg) carriers declined from 40% in the eldest siblings to 19% in the youngest siblings. In 75 families clustered with three or more HBsAg carrier siblings, the mean age for seven families of which all siblings remained HBeAg + was younger, whereas the mean age for 35 families of which all siblings had cleared HBeAg was older. For the remaining 33 families, in only 10 families had the older siblings cleared the HBeAg earlier than the younger siblings. Twenty families showed that younger siblings cleared the HBeAg earlier than the older or middle siblings. We concluded that HBV replication in HCC relatives cannot be explained by familial tendency alone. A significant number of younger siblings appeared to have a shorter HBV replication phase than their older siblings. The possible role of this in maternal-fetal transmission is discussed.


Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation.
The Swedish double mutation (KM670/671NL) of amyloid precursor protein (APPsw) is associated with early-onset familial Alzheimer's disease (FAD) and results in from three- to sixfold increased beta-amyloid production. The goal of the present study was to elucidate the effects of APPsw on mechanisms of apoptotic cell death. Therefore, PC12 cells were stably transfected with human APPsw. Here we report that the vulnerability of APPsw-bearing PC12 cells to undergo apoptotic cell death was significantly enhanced after exposure to hydrogen peroxide compared to human wild-type APP-bearing cells, empty vector-transfected cells, and parent untransfected cells. In addition, we have analyzed the potential influence of several mechanisms that can interfere with the execution of the apoptotic cell death program: the inhibition of cell death by the use of caspase inhibitors and the reduction of oxidative stress by the use of (+/-)-alpha-tocopherol (vitamin E). Interestingly, oxidative stress-induced cell death was significantly attenuated in APPsw PC12 cells by pretreatment with caspase-3 inhibitors but not with caspase-1 inhibitors. In parallel, caspase-3 activity was markedly elevated in APPsw PC12 after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (+/-)-alpha-tocopherol. The protective potency of (+/-)-alpha-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.


Early full weight bearing is safe in open-wedge high tibial osteotomy.
In open-wedge, valgus osteotomy of the upper tibia, there are concerns regarding the initial stability and ability to retain the correction. Rehabilitation protocols vary depending on the osteotomy technique and the fixation method. Angle-stable implants offer superior initial stability. Early full weight bearing appears to be possible using these implants. In this prospective cohort study, we measured migration in open-wedge osteotomy in patients following an early full weight bearing protocol and compared the results to those from a historical cohort of open-wedge osteotomy patients who followed a standard protocol (full weight bearing after 6 weeks) using radiostereometry. 14 open-wedge osteotomies fixated with the angle-stable Tomofix implant were performed; patients were allowed full weight bearing as soon as pain and wound healing permitted. Radiostereometry was used to measure motion across the osteotomy at regular intervals. Improvement in pain and functional outcome were assessed postoperatively. The results were compared to those from a group of 23 patients who had undergone the same operation but had used a standard rehabilitation protocol. There were no adverse effects because of the early full weight bearing protocol. There were no differences in motion at the osteotomy between groups as measured by radiostereometry. In both groups, pain and function improved substantially without any differences between groups. Patients in the early weight bearing group achieved the same result but in a shorter time. Tomofix-plate-fixated open-wedge high tibial osteotomy allows early full weight bearing without loss of correction.


[Expressions of transient receptor potential A1 and related inflammatory factors in the rat model of prostatic inflammation].
To explore the molecular mechanism of pain associated with chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) in the rat model of prostatic inflammation. Thirty-six male SD rats were equally randomized to an experimental and a control group, the former injected with 50 μl of 3% λ-carrageenan into the ventral prostate to make the model of non-bacterial prostatic inflammation, while the latter with the same volume of sterile saline solution. At 1, 2 and 4 weeks after modeling, the prostate, L6-S1 dorsal root ganglion (DRG) and spinal cord were harvested for examination of the expressions of the nerve growth factor (NGF), transient receptor potential ankyrin 1 (TRPA1), and calcitonin-gene-related peptide (CGRP) by immunohistochemistry and Western blot. The expressions of NGF, TRPA1 and CGRP in the prostatic tissue were all significantly increased in the experimental group as compared with the control (P <0.05), with a gradual decrease with the prolonging of time (P <0.05). In the L6-S1 DRG and spinal cord, the expressions of NGF, TRPA1 and CGRP exhibited no significant differences between the experimental and control groups at 1 week after modeling (P >0.05) and kept at high levels in the experimental group at 2 and 4 weeks, though not significantly different from those at 1 week (P >0.05). Statistically significant differences were observed in the expressions of the three proteins in the experimental rats among different time points (P <0.05), but not between the two groups at any time point (P >0.05). The molecular mechanism of CP/CPPS can be evaluated in the rat model of prostatic inflammation established by injecting λ-carrageenan into the prostate. TRPA1 may play an important role in connecting the upstream and down-stream pathways of CP/CPPS-associated pain.


Interpreting clinical and laboratory tests: importance and implications of context.
Clinical and laboratory tests in clinical medicine include a range of measurements that may be categorized as "normal range" tests, positive or negative tests, or contextual tests. Normal range test results are quantitative and are compared to a reference interval or range provided by the laboratory. Positive or negative tests are also quantitative tests and characteristically have a cutoff value that specifies the result. Contextual tests require a context, a physiological condition, to correctly interpret the result. A closer examination of reference intervals suggests that these also are contextual. The fact that there is a range of apparently normal values indicates the presence of cultural, biological, physiological and behavioral diversity in the population sampled to determine normality. As such, the reference interval describes the population from which it was determined and may have utility in this regard.


Antibiotic and other lock treatments for tunnelled central venous catheter-related infections in children with cancer.
The risk of developing a tunnelled central venous catheter (CVC)-related infection ranges between 0.1 and 2.3 per 1000 catheter days for children with cancer. These infections are difficult to treat with systemic antibiotics (salvage rate 24% - 66%) due to biofilm formation in the CVC. Lock treatments can achieve 100 - 1000 times higher concentrations locally without exposure to high systemic concentrations. Our objective was to investigate the efficacy of antibiotic and other lock treatments in the treatment of CVC-related infections in children with cancer compared to a control intervention. We also assessed adverse events of lock treatments. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, issue 3, 2011), MEDLINE/PubMed (1945 to August 2011) and EMBASE/Ovid (1980 to August 2011). In addition we searched reference lists from relevant articles and the conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2006 to 2010), American Society of Clinical Oncology (ASCO) (from 2006 to 2010), the Multinational Association of Supportive Care in Cancer (MASCC) (from 2006 to 2011), the American Society of Hematology (ASH) (from 2006 to 2010) and the International Society of Thrombosis and Haematology (ISTH) (from 2006 to 2011). We scanned the ISRCTN Register and the National Institute of Health Register for ongoing trials (www.controlled-trials.com) (August 2011). Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing an antibiotic lock or other lock treatment (with or without concomitant systemic antibiotics) with a control intervention (other lock treatment with or without concomitant systemic antibiotics or systemic antibiotics alone) for the treatment of CVC-related infections in children with cancer. For the description of adverse events, cohort studies were also eligible for inclusion. Two authors independently selected studies, extracted data and performed 'Risk of bias' assessments of included studies. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Two RCTs evaluated urokinase lock treatment with concomitant systemic antibiotics (n = 56) versus systemic antibiotics alone (n = 48), and one CCT evaluated ethanol lock treatment with concomitant systemic antibiotics (n = 15) versus systemic antibiotics alone (n = 13). No RCTs or CCTs evaluating antibiotic lock treatments were identified. All studies had methodological limitations and clinical heterogeneity between studies was present. We found no evidence of significant difference between ethanol or urokinase lock treatments with concomitant systemic antibiotics and systemic antibiotics alone regarding the number of participants cured, the number of recurrent CVC-related infections, the number of days until the first negative blood culture, the number of CVCs prematurely removed, ICU admission and sepsis. Not all studies were included in all analyses. No adverse events occurred in the five publications of cohort studies (one cohort was included in two publications) assessing this outcome; CVC malfunctioning occurred in three out of five publications of cohort studies assessing this outcome. No significant effect of urokinase or ethanol lock in addition to systemic antibiotics was found. However, this could be due to low power or a too-short follow-up. The cohort studies identified no adverse events; some cohort studies reported CVC malfunctioning. No RCTs or CCTs were published on antibiotic lock treatment alone. More well-designed RCTs are needed to further explore the effect of antibiotic or other lock treatments in the treatment of CVC-related infections in children with cancer.


Prevention and control of type 2 diabetes by Mediterranean diet: a systematic review.
We conducted a systematic review of the available studies that assessed the effect of a Mediterranean diet in type 2 diabetes. We searched publications up to 30 November 2009. Seventeen studies were included. Two large prospective studies report a substantially lower risk (83% and 35%, respectively) of type 2 diabetes in healthy people or in post-infarct patients with the highest adherence to a Mediterranean diet. Five randomized controlled trials have evaluated the effects of a Mediterranean diet, as compared with other commonly used diets, on indices of glycaemic control in subjects with type 2 diabetes. Improvement of fasting glucose and HbA1c levels was greater with a Mediterranean diet and ranged from 7 to 40mg/dl for fasting glucose, and from 0.1 to 0.6% for HbA1c. No trial reported worsening of glycaemic control with a Mediterranean diet. Two controlled trials in a secondary prevention setting demonstrated that post-infarct patients, including diabetic patients, had cardiovascular benefits from a Mediterranean diet. The evidence so far accumulated suggests that adopting a Mediterranean diet may help prevent type 2 diabetes, and also improve glycaemic control and cardiovascular risk in persons with established diabetes.


Imipenem in the treatment of febrile neutropenic children.
Infection of neutropenic children treated with malignancies is even now the major cause of early morbidity and mortality. Febrile neutropenic attacks without complications are successfully treated with wide-spectrum anti-pseudomonal cephalosporins or carbapenems. To determine the efficacy and safety of imipenem in the treatment of febrile neutropenia in children with cancer. Twenty-four patients who had a febrile neutropenic (FN) episodes followed by initiation of empirical imipenem therapy were included in the study. Of the patients, 10 (41.7%) had solid tumors, while 14 (58.3%) were diagnosed to have acute leukemia. Among all, 5 (20.8 %) and 15 (62.5 %) of the infections were identified microbiologically and clinically, respectively. Fever of unknown origin was observed in 4 (16.7 %) patients. The mean duration of neutropenia was 6.3 -/+ 1.4 (4-8) days in patients with solid tumors, and 9.3 -/+ 7.4 (3-25) days in the group with leukemia. Average time of stay in hospital was 9.0 -/+ 4.1 (4-20) days for patients with solid tumors, and 14.4 -/+ 10.6 (4-33) days for patients with leukemia. FN duration was observed to be significantly longer in patients with an ANC of less than 200/mm3, and in children who were not in remission for the underlying malignant disease. In addition, average time of stay in hospital was observed to be significantly longer in patients who were not in remission for the underlying malign disease. All of the patients were discharged. The success rate of empirical therapy started with imipenem was found be 95.8 %. Imipenem is effective and safe in the treatment of FN in pediatric cancer patients.


[Health care usage by Moroccans and Turks compared to the indigenous Dutch population: no higher consumption of health care and lower medication costs].
Examination of whether health care consumption of Moroccan or Turkish insured under the Dutch national health system varies from that of the indigenous Dutch population. Retrospective, transverse. Research was performed on the database of an insurance company concerning medication, referrals to a specialist, admissions to the hospital and use of physiotherapy. Data of 22,603 Moroccan and 15,190 Turkish persons from the records for 1999 were compared with a random sample of 17,976 other persons in the database and differences were tested after correction for differences in age and sex. Foreigners received 50% less physiotherapy, while hospital admissions did not differ from the control group. The number of referrals to a specialist and the number of prescriptions for Moroccans appeared to be higher, but the number of consumers appeared to be equal to the control group. Turks on the contrary showed an equal number of referrals, but fewer prescriptions. The differences concerned mostly long-term physiotherapy and also referrals to specialists in internal medicine and gynaecology. Differences in prescriptions were found for certain medication groups. Costs for medication for foreigners were lower per insured person. Foreigners did not have a higher consumption of health services than indigenous persons, whilst medication costs were lower.


Soliton creation during a Bose-Einstein condensation.
We use the stochastic Gross-Pitaevskii equation to study dynamics of Bose-Einstein condensation. We show that cooling into a Bose-Einstein condensate (BEC) can create solitons with density given by the cooling rate and by the critical exponents of the transition. Thus, counting solitons left in its wake should allow one to determine the critical exponents z and nu for a BEC phase transition. The same information can be extracted from two-point correlation functions.


Signposts in the assembly of chylomicrons.
Intestinal cells synthesize and secrete chylomicrons in the postprandial state. Synthesis of these particles is defective in abetalipoproteinemia and chylomicron retention disease. Chylomicrons are very large, heterogeneous, lipid-rich particles ranging in diameters from 75 to 450 nm and function to transport dietary fat and fat-soluble vitamins to blood. The size heterogeneity of the secreted particles depends on the rate of fat absorption, type and amount of fat absorbed. The fatty acid composition of triglycerides present in chylomicrons reflects the composition of dietary fat, whereas the fatty acid composition of chylomicron phospholipids does not. The differences in the fatty acid compositions are also observed when lipids are labeled with glycerol. Thus, the differences are not due to differential incorporation of dietary fatty acids into different lipids but are mainly due to different pools of lipids used for chylomicron assembly. It has been suggested that preformed phospholipids and nascent triglycerides are preferentially used for intestinal lipoprotein assembly. Biosynthesis of chylomicrons requires apoB48. ApoB48 is translated from apoB mRNA that is post-transcriptionally edited in the intestinal cells to incorporate a stop codon. Nascent apoB48 may be cotranslationally lipidated and this process is critically dependent on the presence of microsomal triglyceride transfer protein. Two different models have been proposed for the assembly of chylomicrons. In the independent model, intestinal cells are hypothesized to synthesize VLDL and chylomicron by two independent pathways. The chylomicron assembly pathway is hypothesized to be sensitive to a surfactant, Pluronic L81, but that of VLDL assembly is not. In the sequential assembly model, synthesis of all lipoproteins is hypothesized to begin with the assembly of apoB-containing primordial lipoprotein particles. The primordial particles are suggested to fuse with triglyceride-rich lipid droplets that are synthesized independently of apoB. This process results in the core expansion of primordial particles and the synthesis of nascent lipoproteins. Differences in the size of secreted lipoproteins may be due to differences in the size of triglyceride-rich lipid droplets. Pluronic L81 is hypothesized to inhibit the formation of large triglyceride-rich droplets that serve as precursors for chylomicron assembly. In this review, we have discussed some signposts that might be unique to different steps in the assembly of chylomicrons. First, it is proposed that the association of preformed phospholipids with nascent apoB in the endoplasmic reticulum may serve as a signpost for the very early steps in the assembly of chylomicrons. Second, association of large amounts of newly synthesized triglycerides compared to preformed triglycerides may serve as a signpost for the assembly of larger lipoproteins. Third, the incorporation of retinyl esters may serve as markers for the final stages of chylomicron assembly. These signposts may be helpful in the identification and characterization of various intermediates in the assembly of chylomicrons. The knowledge about the molecular assembly of chylomicrons may lead to better therapeutic agents for controlling various hyperlipidemias, obesity, and atherosclerosis.


Role of adrenergic receptors in mediating estradiol-17 beta-stimulated increases in uterine blood flow of cows.
This study was conducted to investigate the association between estradiol-17 beta (E2 beta) and periarterial alpha and beta-adrenergic receptors in altering blood flow to the bovine uterus. Three nonpregnant Hereford cows were ovariectomized, and an electromagnetic blood flow transducer was placed around the middle uterine artery supplying one uterine horn. A catheter was then placed into a branch of the same artery for infusion of drugs or vehicle. Beginning 3 wk after surgery, uterine blood flow (UBF) of each cow was recorded for 5 min at 20-min intervals throughout a 160-min period three times weekly for 6 wk. Vehicle (.9% NaCl), phentolamine (PHEN, 1 or 10 micrograms) or propranolol (PROP, 1 or 10 micrograms) was infused for 5 min beginning 20 min after the initial UBF measurements, while vehicle or E2 beta (1 microgram) was infused for 5 min beginning at 40 min. Within a week, the first and third 160-min periods contained the same treatment (vehicle or E2 beta), and the second period consisted of vehicle or E2 beta plus PHEN or PROP, allowing for direct comparison of periods 1 and 3 with period 2. Twenty minutes after infusion of E2 beta, UBF was elevated (26.8 +/- 5.4 ml/min; P less than .05) over baseline, reaching a maximal increase at 40 min before starting to decline by 120 min. Uterine blood flow increased (39.2 +/- 7.6 ml/min; P less than .01) during the 5-min infusion of PHEN, and thereafter the magnitude and pattern were similar to those resulting from E2 beta treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Preparation of benzylpenicilloyl-polylysine: a preliminary study.
The manufacturing of PrePen (benzylpenicilloyl-polylysine) was suspended from September 2000 through November 2001 because of Food and Drug Administration intervention. PrePen is penicilloyl bound to polylysine and is considered to be the major determinant of penicillin metabolism; it is used as a skin-testing reagent to detect immunoglobulin E antibodies in people with a history of penicillin allergy. Because of the uncertainty of whether PrePen would be made available in the future, we attempted to make benzylpenicilloyl-polylysine in our laboratory using a modification of a previously described method. Subsequently, we compared our preparation with PrePen by enzyme-linked immunosorbent assay and skin testing. Using a patient previously documented to have a positive reaction to PrePen by history and intradermal skin testing, a puncture test to PrePen as well as dilutions of benzylpenicilloyl-polylysine was negative. Positive intradermal tests were performed on PrePen and benzylpenicilloyl-polylysine at 5 mg/mL. The enzyme-linked immunosorbent assay was performed to compare the antigenicity of PrePen and benzylpenicilloyl-polylysine and revealed similar binding to both. Subsequently, cutaneous testing on 10 additional penicillin-allergic people was performed, with corroborative results. Our benzylpenicilloyl-polylysine production methodology could prove useful to those who do not have access to PrePen or another similar reagent.


[Methods of determining lipid peroxidation products in the serum using a thiobarbituric acid test].
Main principles for carrying out of the thiobarbituric acid (TBA)-test of blood serum were characterized. These principles involved incubation of the sample at pH 1.3-1.6, extraction of the reaction products with butanol and spectrofluorimetric or spectrophotometric estimation. Content of TBA-active products in blood serum of healthy donors constituted 3.86 +/- 0.66 nmol malonic dialdehyde per ml of blood serum as shown in fluorimetric estimation by means of the procedure developed.


"Health is the Ability to Manage Yourself Without Help": How Older African American Men Define Health and Successful Aging.
Few studies have explored how older African American men understand the relationship between health and successful aging. The goal of this study was to examine how older African American men's conceptions and definitions of health and notions of successful aging are interrelated. Using data from 22 semistructured individual interviews with African American men ages 55-76, we examine how cultural and normative ideals about health map onto the core components of Rowe and Kahn's (1997) definition of successful aging. We also explore how these notions influence factors that have implications for health. Consistent with prior research, we found that older African American men operationalized notions of health in ways that mapped onto three elements of successful aging: (a) the absence of disease and disability, (b) the ability to maintain physical and cognitive functioning, and (c) meaningful social engagement in life. A fourth theme, what men actually do, emerged to highlight how regular health practices were key components of how men define health. These findings highlight key elements of how older African American men conceptualize health in ways that are interrelated with yet expand notions of successful aging in ways that are critical for health promotion research and interventions.


Dioxygen reduction by cobalt(II) octaethylporphyrin at liquid|liquid interfaces.
Oxygen reduction catalyzed by cobalt(II) (2,3,7,8,12,13,17,18-octaethylporphyrin) [Co(OEP)] at soft interfaces is studied by voltammetry and biphasic reactions. When Co(OEP) is present in a solution of 1,2-dichloroethane in contact with an aqueous acidic solution, oxygen is reduced if the interface is positively polarized (water phase versus organic phase). This reduction reaction is facilitated when an additional electron donor, here ferrocene, is present in excess in the organic phase.


The pigeon heart 5'-nucleotidase responsible for ischaemia-induced adenosine formation.
1. A 5'-nucleotidase with a strong preference for AMP over IMP was characterized in homogenates and subcellular fractions of pigeon heart by using concentrations of ATP, ADP and AMP which mimicked those present in the ischaemic tissue. 2. The AMP-5'-nucleotidase had a neutral pH optimum and an apparent Km in the range 4.6-5.2 mM. It was stimulated by ATP plus ADP, and was inhibited by other nucleoside monophosphates, Pi and p-nitrophenyl phosphate, but not by ribose 5-phosphate or beta-glycerophosphate. The enzyme was not inhibited by [alpha beta-methylene] ADP or by 5'-deoxy-5'-isobutylthioadenosine, an inhibitor of the previously purified IMP-preferring cytosolic 5'-nucleotidase. 3. Subcellular-fractionation studies indicated that the enzyme has access to cytosolic AMP, although it may be associated by weak ionic interactions with an organelle present in the low-speed particulate fraction. 4. A 5'-nucleotidase was detected under similar conditions in homogenates of rat heart. 5. The activity of the pigeon heart AMP-5'-nucleotidase was sufficient to account for previously measured rates of ischaemia-induced adenosine formation. The similar activity in rat heart could, however, account for only part of ischaemia-induced adenosine formation in this tissue.


Tissue injury regulates serotonin 1D receptor expression: implications for the control of migraine and inflammatory pain.
The anti-migraine action of "triptan" drugs involves the activation of serotonin subtype 1D (5-HT1D) receptors expressed on "pain-responsive" trigeminal primary afferents. In the central terminals of these nociceptors, the receptor is concentrated on peptidergic dense core vesicles (DCVs) and is notably absent from the plasma membrane. Based on this arrangement, we hypothesized that in the resting state the receptor is not available for binding by a triptan, but that noxious stimulation of these afferents could trigger vesicular release of DCVs, thus externalizing the receptor. Here we report that within 5 min of an acute mechanical stimulus to the hindpaw of the rat, there is a significant increase of 5-HT1D-immunoreactivity (IR) in the ipsilateral dorsal horn of the spinal cord. We suggest that these rapid immunohistochemical changes reflect redistribution of sequestered receptor to the plasma membrane, where it is more readily detected. We also observed divergent changes in 5-HT1D-IR in inflammatory and nerve-injury models of persistent pain, occurring at least in part through the regulation of 5-HT1D-receptor gene expression. Finally, we found that 5-HT1D-IR is unchanged in the spinal cord dorsal horn of mice with a deletion of the gene encoding the neuropeptide substance P. This result differs from that reported for the partial differential-opioid receptor, which is also sorted to DCVs, but is greatly reduced in preprotachykinin mutant mice. We suggest that a "pain"-triggered regulation of 5-HT1D-receptor expression underlies the effectiveness of triptans for the treatment of migraine. Moreover, the widespread expression of 5-HT1D receptor in somatic nociceptive afferents suggests that triptans could, in certain circumstances, treat pain in nontrigeminal regions of the body.


A novel strategy for avian species identification by cytochrome b gene.
We report a DNA-based test that can be applied to any avian species so that the amplicon can be used in species identification. The need for the test arose from the requirement to enforce the Wildlife Conservation Act in Taiwan where over 150 avian species are protected. It is difficult to enforce the law if no gross morphology is present and hence there is a requirement to develop a DNA test. This study uses a novel strategy for avian species identification by the cytochrome b gene where a series of primer pairs producing amplicons of decreasing size was designed. The test is designed to produce the largest possible amplicon based upon the quality of the DNA in the sample. A total of 331 avian samples were tested representing 40 species. Sequencing of the amplicons revealed limited intraspecies variation and that no DNA sequence was shared by samples from two different avian species. The closest genetic distance among the 40 species was 0.059 which was between Lonchura punctulata and Estrilda melpoda based upon data from the smallest amplicon. A DNA databank including 138 sequence types from 331 samples tested, representing 40 different species, was constructed in this study. A blind test was used to determine the value for this system for forensic applications that successfully identified the species.


Anti-Neu5Gc and anti-non-Neu5Gc antibodies in healthy humans.
Our group previously investigated the levels of anti-Gal and anti-nonGal IgM and IgG in a cohort of 75 healthy humans of various backgrounds, and found some significant differences related to factors such as age, gender, ABO blood group, diet, vaccination history, and geographic location during childhood. We have now expanded our cohort (n = 84) to investigate the levels of anti-Neu5Gc and anti-nonGal/nonNeu5Gc antibodies in healthy humans. Anti-nonGal and anti-nonGal/nonNeu5Gc human IgM and IgG binding to pRBCs and pAECs from GTKO/CD46 and GTKO/CD46/Neu5GcKO pigs were measured by flow cytometry. Anti-Gal and anti-Neu5Gc IgM and IgG levels were measured by ELISA. In summary, (i) the great majority (almost 100%) of humans had anti-Neu5Gc IgM and IgG antibodies that bound to pAECs and approximately 50% had anti-Neu5Gc antibodies that bound to pRBCs, (ii) there was significantly less human antibody binding to pig cells that did not express either Gal or Neu5Gc compared with those that did not express Gal alone, (iii) the levels of both IgM and IgG binding to GTKO/CD46/Neu5GcKO pRBCs and pAECs were low, (iv) the level of anti-Neu5Gc IgG was higher in men than women, (v) the level did not change with age or diet, and there was some variability associated with (vi) previous vaccination history and (vii) the geographic region in which the individual spent his or her childhood. Our study confirms that human antibody binding to RBCs and AECs from GTKO/CD46/Neu5GcKO pigs is greatly reduced compared to binding to GTKO/CD46 cells. However, all humans appear to have a low level of antibody that binds to pAECs that is not directed to either Gal or Neu5Gc. Our findings require consideration in planning clinical trials of xenotransplantation.


Establishment of a human urachal adenocarcinoma cell line (KO-BT-1) and its chemosensitivity.
A new human urachal adenocarcinoma cell line (KO-BT-1) was established and characterized. It consisted of cuboidal, spindle, and polymorphic giant cells and continued to grow for more than 27 months without contact inhibition. Doubling time was about 15.5 h at the 70th passage. In nude mice the cells produced tumors, the histologies of which were similar to the original patient-derived tumor. Moreover, serum carcinoembryonic antigen level was elevated in the patient and the histological section of tumor formed in nude mice was stained with an antibody to carcinoembryonic antigen by peroxidase-antiperoxidase method. Electron microscopically, the cells covered with microvilli had cell-junction complexes. The chromosome number was aneuploid with a modal number of 60. At clinically achievable concentrations, doxorubicin, cis-platinum, mitomycin C, and 40487S which was an in vitro-active type of cyclophosphamide did not reduce colony formation to 30% or less of the control value; likewise in this patient chemotherapy had not been effective. In addition, among human recombinant tumor necrosis factor, alpha-interferon, and recombinant beta- and gamma-interferon, recombinant IFN-beta was most effective against this tumor. These results indicated that KO-BT-1 cells showed the similar chemosensitivity and properties to those of the original tumor, and might be useful in basic studies for the diagnosis, treatment, and etiology of urachal tumors.


Intercalated clay catalysts.
Recent advances in the intercalation of metal complex cations in smectite clay minerals are leading to the development of new classes of selective heterogeneous catalysts. The selectivity of both metal-catalyzed and proton-catalyzed chemical conversions in clay intercalates can often be regulated by controlling surface chemical equilibria, interlamellar swelling, or reactant pair proximity in the interlayer regions. Also, the intercalation of polynuclear hydroxy metal cations and metal cluster cations in smectites affords new pillared clay catalysts with pore sizes that can be made larger than those of conventional zeolite catalysts.


Performance-based assessment of falls risk in older veterans with executive dysfunction.
Falling is a serious hazard for older veterans that may lead to severe injury, loss of independence, and death. While the American Geriatrics Society (AGS) provides guidelines to screen individuals at risk for falls, the guidelines may be less successful with specific subgroups of patients. In a veteran sample, we examined whether the Timed Up and Go (TUG) test, including a modified version, the TUG-Cognition, effectively detected potential fallers whose risk was associated with cognitive deficits. Specifically, we sought to determine whether TUG tasks and AGS criteria were differentially associated with executive dysfunction, whether the TUG tasks identified potential fallers outside of those recognized by AGS criteria, and whether these tasks distinguished groups of fallers. Participants included 120 mostly male patients referred to the Memory Assessment Clinic because of cognitive impairment. TUG-Cognition scores were strongly associated with executive dysfunction and differed systematically between fallers grouped by number of falls. These findings suggest that the TUG-Cognition shows promise in identifying fallers whose risk is related to or compounded by cognitive impairment. Future research should study the predictive validity of these measures by following patients prospectively.


GPNMB enhances bone regeneration by promoting angiogenesis and osteogenesis: potential role for tissue engineering bone.
Bone regeneration is a coordinated process involving the connection between blood vessels and bone cells. Glycoprotein non-metastatic melanoma protein B (GPNMB) is known to be vital in bone formation. However, the effect of GPNMB on bone regeneration and the underlying molecular mechanism are still undefined. Fibroblast growth factor receptor (FGFR)-mediating signaling is pivotal in bone formation and angiogenesis. Therefore, we assessed GPNMB function as a communicating molecule between osteoblasts and angiogenesis, and the possible correlation with FGFR-1 signaling. Recombinant GPNMB dose-dependently increased the differentiation of human bone marrow stromal cells (hBMSCs) into osteoblasts, as well as the mRNA levels of osteoblasts marker alkaline phosphatase (ALP) and osteocalcin (OCN). Furthermore, these increases depended on the activation of FGFR-1 signaling, as pretreatment with FGFR-1 siRNA or its inhibitor SU5402 dramatically dampened GPNMB-induced osteogenesis. Additionally, GPNMB triggered dose-dependently the proliferation and migration of human umbilical vein endothelial cells (hUVECs), FGFR-1 phosphorylation, as well as capillary tube and vessels formation in vitro and in vivo. Blocking FGFR-1 signaling dampened GPNMB-induced angiogenic activity. Following construction of a rodent cranial defect model, scaffolds delivering GPNMB resulted in an evident increase in blood vessels and new bone formation; however, combined delivery of GPNMB and SU5402 abated these increase in defect sites. Taken together, these results suggest that GPNMB stimulates bone regeneration by inducing osteogenesis and angiogenesis via regulating FGFR-1 signaling. Consequently, our findings will clarify a new explanation about how GPNMB induces bone repair, and provide a potential target for bone regeneration therapeutics and bone engineering.


Functional stoichiometry and local enrichment of calmodulin interacting with Ca2+ channels.
Calmodulin (CaM) interactions with Ca2+ channels mediate both Ca2+ regulation of channels and local Ca2+ triggering of transcription factors implicated in neuronal memory. Crucial to these functions are the number of CaM molecules (CaMs) regulating each channel, and the number of CaMs privy to the local Ca2+ signal from each channel. To resolve these parameters, we fused L-type Ca2+ channels to single CaM molecules. These chimeric molecules revealed that a single CaM directs L-type channel regulation. Similar fusion molecules were used to estimate the local CaM concentration near Ca2+ channels. This estimate indicates marked enrichment of local CaM, as if a "school" of nearby CaMs were poised to enhance the transduction of local Ca2+ entry into diverse signaling pathways.


[SURGICAL COMPLICATIONS IN ACUTE POISONING AND PROTEIN--ENERGY DYSFUNCTION].
The article presents a review of acute surgical pathology and the frequency of its occurrence, complicating alcohol poisoning, cauterizing liquids, narcotic and psychotropic drugs and acute emerging metabolic (protein-energy). The development of surgical complications in poisoning was observed in patients in severe and very severe condition and is accompanied by a sharp increase in mortality (75%) and severe energy dysfunction. The most diverse and difficult flowing surgical complications were encountered in alcohol poisoning and cauterizing liquids.


The GpIA7 effector from the potato cyst nematode Globodera pallida targets potato EBP1 and interferes with the plant cell cycle.
The potato cyst nematode Globodera pallida acquires all of its nutrients from an elaborate feeding site that it establishes in a host plant root. Normal development of the root cells is re-programmed in a process coordinated by secreted nematode effector proteins. The biological function of the G. pallida GpIA7 effector was investigated in this study. GpIA7 is specifically expressed in the subventral pharyngeal glands of pre-parasitic stage nematodes. Ectopic expression of GpIA7 in potato plants affected plant growth and development, suggesting a potential role for this effector in feeding site establishment. Potato plants overexpressing GpIA7 were shorter, with reduced tuber weight and delayed flowering. We provide evidence that GpIA7 associates with the plant growth regulator StEBP1 (ErbB-3 epidermal growth factor receptor-binding protein 1). GpIA7 modulates the regulatory function of StEBP1, altering the expression level of downstream target genes, including ribonucleotide reductase 2, cyclin D3;1, and retinoblastoma related 1, which are down-regulated in plants overexpressing GpIA7. We provide an insight into the molecular mechanism used by the nematode to manipulate the host cell cycle and demonstrate that this may rely, at least in part, on hindering the function of host EBP1.


Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation.
The heme oxygenase-1 (HO-1) enzyme system remains an attractive therapeutic target for the treatment of inflammatory conditions. HO-1, a cellular stress protein, serves a vital metabolic function as the rate-limiting step in the degradation of heme to generate carbon monoxide (CO), iron, and biliverdin-IXα (BV), the latter which is converted to bilirubin-IXα (BR). HO-1 may function as a pleiotropic regulator of inflammatory signaling programs through the generation of its biologically active end products, namely CO, BV and BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of proinflammatory or anti-inflammatory cytokines and mediators. HO-1 and CO may also have immunomodulatory effects with respect to regulating the functions of antigen-presenting cells, dendritic cells, and regulatory T cells. Therapeutic strategies to modulate HO-1 in disease include the application of natural-inducing compounds and gene therapy approaches for the targeted genetic overexpression or knockdown of HO-1. Several compounds have been used therapeutically to inhibit HO activity, including competitive inhibitors of the metalloporphyrin series or noncompetitive isoform-selective derivatives of imidazole-dioxolanes. The end products of HO activity, CO, BV and BR may be used therapeutically as pharmacologic treatments. CO may be applied by inhalation or through the use of CO-releasing molecules. This review will discuss HO-1 as a therapeutic target in diseases involving inflammation, including lung and vascular injury, sepsis, ischemia-reperfusion injury, and transplant rejection.


Health care reform: public views of problems and solutions.
Public opinion surveys have found growing discontent with the health care system. In response, major reform legislation has been introduced in Washington and in many statehouses as well. Nonetheless, very few, if any, state-level public opinion surveys examining health care have been conducted in the South. During November of 1991, a statewide survey of 1,250 Alabamians was conducted to collect information on a wide range of health care issues. The survey is perhaps the largest and most complete survey on health care issues ever conducted in a southern state. Major findings of the survey are as follows: (1) Two-thirds of Alabamians believe the health care system needs fundamental change or needs to be completely rebuilt; however, there is little consensus on the shape of this new health care system. (2) Over 50 percent of Alabamians believe that rising health care costs are the most important issue facing the country. Yet, only about one-third support managed-care mechanisms as a means of controlling personal health care costs. (3) Four of ten Alabamians believe access to care is a critical health care issue. Nonetheless, only 16 percent are willing to pay more than $100 in additional annual taxes to guarantee health care for everyone. This survey yields a set of conflicting conclusions. Policy makers and elected officials should be aware of these issues as they attempt to forge health care reform legislation.


[Russian society and patients with rheumatic diseases].
The morbidity, primary morbidity, temporary incapacity for work and disablement due to rheumatoid diseases registered among Russia's population in the recent 3 years are described on the basis of an analysis of Russian statistics. Issues related with mortality, caused by rheumatic diseases, the related expenses and influence on patients' life quality are under discussion. A conclusion is made on a high social-and-medical importance of the above category of diseases as viewed from the standpoint of society (state), patient and his or her family.


Crisis service utilization following completion of a suicide safety plan for Veterans with and without affective and nonaffective psychosis.
Psychosis is associated with increased suicide risk. Safety planning is a suicide prevention practice that is associated with decreased suicidal behavior and psychiatric hospitalizations. A common feature of safety planning is listing of crisis line numbers. The primary purpose of this study was to compare Veterans with and without psychosis who completed a safety plan in terms of their next year crisis service use, including Veterans Crisis Line (VCL) calls, and suicidal behavior. Data were drawn from the VA San Diego's electronic medical record system for (N = 1602) safety plans from 2018 to 2021. Clinical records of crisis services and suicide attempt/death were recorded for one year after the safety plan. Following completion of a safety plan, Veterans with psychosis were more likely to have a next year psychiatric hospitalization (OR = 4.1), emergency department visit (OR = 2.3), and psychiatric emergency clinic visit (OR = 2.2) than those without psychosis. In contrast, there were no group differences in likelihood of calling the VCL. Veterans with psychosis who recently completed a safety plan do not show elevated rates of VCL use that are commensurate with increases in crisis service use. Interventions for this high-risk group may focus on understanding the motivation and ability to call the VCL as ways to enhance safety planning.


Individual exploration and selective social learning: balancing exploration-exploitation trade-offs in collective foraging.
Search requires balancing exploring for more options and exploiting the ones previously found. Individuals foraging in a group face another trade-off: whether to engage in social learning to exploit the solutions found by others or to solitarily search for unexplored solutions. Social learning can better exploit learned information and decrease the costs of finding new resources, but excessive social learning can lead to over-exploitation and too little exploration for new solutions. We study how these two trade-offs interact to influence search efficiency in a model of collective foraging under conditions of varying resource abundance, resource density and group size. We modelled individual search strategies as Lévy walks, where a power-law exponent (μ) controlled the trade-off between exploitative and explorative movements in individual search. We modulated the trade-off between individual search and social learning using a selectivity parameter that determined how agents responded to social cues in terms of distance and likely opportunity costs. Our results show that social learning is favoured in rich and clustered environments, but also that the benefits of exploiting social information are maximized by engaging in high levels of individual exploration. We show that selective use of social information can modulate the disadvantages of excessive social learning, especially in larger groups and when individual exploration is limited. Finally, we found that the optimal combination of individual exploration and social learning gave rise to trajectories with μ ≈ 2 and provide support for the general optimality of such patterns in search. Our work sheds light on the interplay between individual search and social learning, and has broader implications for collective search and problem-solving.


Effect of A Reduction in glomerular filtration rate after NEphrectomy on arterial STiffness and central hemodynamics: rationale and design of the EARNEST study.
There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group. The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure. This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease. These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program (NCT01769924).


An Assessment of Possible Neuropathology and Clinical Relationships in 46 Sporadic Amyotrophic Lateral Sclerosis Patient Autopsies.
Recent studies have suggested overlapping pathological features among motor neuron, cognitive and neurodegenerative diseases. Secondary analysis of 46 amyotrophic lateral sclerosis (ALS) patient autopsies was performed to independently assess pathological feature prevalence (e.g. percent of patients with any positive finding), degree of severity (e.g. mild, moderate, severe), and 2,200+ potential clinical/neuropathological correlations. The possible impact of gender, onset age, onset type (limb vs. bulbar), riluzole treatment, and severe TDP-43 pathology was assessed within patient subgroups. Assessed features (prevalence, severity) include: lateral corticospinal tract degeneration (89%, moderate); Purkinje cell loss (85%, mild); localized neuronal loss (83%, mild to moderate); TDP-43 inclusions (80%, moderate); Betz cell loss (76%, mild); neurofibrillary tangles (78%, severe); anterior corticospinal tract degeneration (72%, moderate); spinal ventral root atrophy (65%, moderate); atherosclerosis (35%, mild); β-amyloid (35%, mild); tauopathy/tau inclusions (17%, mild); ventricular dilation (13%, mild); Lewy body formation (11%, mild); microinfarcts (7%, mild); and α-synuclein (4%, mild). Twenty-two percent of patients met criteria for Alzheimer's disease (AD) and 26% for frontotemporal lobar degeneration. Substantial differences were identified in the AD group and in the different onset age groups. Our findings support the hypothesis that ALS and its variants could comprise a larger neuropathological continuum.


Bicarbonate transport in cortical and outer medullary collecting tubules.
The collecting ducts are thought to represent a low-capacity high-gradient acidification system. However, the inaccessibility of the various regions of the collecting duct system has prevented direct segmental analysis of its contribution to distal acidification. The present in vitro microperfusion studies compare bicarbonate transport (in pmol . mm-1 . min-1) in rabbit cortical (CCT) and outer medullary collecting tubules (MCT) perfused and bathed with symmetrical Ringer bicarbonate solution at pH 7.4. Cortical segments from normal animals exhibited no net bicarbonate transport (-2.15 +/- 1.93) whereas MCT from normal animals reabsorbed bicarbonate at a rate of 11.3 +/- 1.4. Both bicarbonate reabsorption and the lumen-positive voltage (+9.4 +/- 1.1 mV) in MCT were totally inhibited by 10(-4) M acetazolamide. CCT from NH4Cl-treated rabbits demonstrated significant bicarbonate reabsorption (1.8 +/- 0.7) when perfused at slow rates. CCT harvested from animals given a NaHCO3 load for 48 h prior to death secreted bicarbonate (-6.2 +/- 2.5). These studies confirm earlier observations of the ability of the CCT to reabsorb or secrete bicarbonate. In addition, they demonstrate significant axial heterogeneity in acidification in the collecting duct system and identify the outer medullary collecting tubule from inner stripe of outer medulla as a segment of major capacity.


CRISPR-mediated accelerated domestication of African rice landraces.
African Oryza glaberrima and Oryza sativa landraces are considered valuable resources for breeding traits due to their adaptation to local environmental and soil conditions. They often possess superior resistance to endemic pests and tolerance to drought and nutrient deficiencies when compared to the "imported" high production Asian rice varieties. In contrast, "domestication traits" such as seed shattering, lodging, and seed yield are not well established in these African landraces. Therefore, the use of these African varieties for high production agriculture is limited by unpredictable yield and grain quality. We are addressing this shortcoming by developing protocols for genetically transforming African landraces to allow the use of CRISPR-Cas mediated breeding approaches. Here we use as proof of concept the cultivated African landrace Kabre to target selected known "domestication loci" and improve the agronomic potential of Kabre rice. Stable genetic transformation with CRISPR-Cas9-based vectors generated single and simultaneous multiple gene knockouts. Plants with reduced stature to diminish lodging were generated by disrupting the HTD1 gene. Furthermore, three loci shown to control seed size and/or yield (GS3, GW2 and GN1A) were targeted using a multiplex CRISPR-Cas9 construct. This resulted in mutants with significantly improved seed yield. Our study provides an example of how new breeding technologies can accelerate the development of highly productive African landrace rice varieties, an important advancement considering that Africa is a hotspot for worldwide population growth and therefore prone to food shortage.


Synthesis of osteonectin by human retinal pigment epithelial cells is modulated by cell density.
To determine whether human retinal pigment epithelial (HRPE) cells are able to synthesize the antiadhesive protein osteonectin, also known as secreted protein, acidic and rich in cysteine (SPARC). Additionally, because locally produced SPARC may modulate cellular behavior during tissue repair, to ascertain whether HRPE SPARC production and HRPE proliferation, migration, and/or differentiation are associated, in a simple HRPE wound-healing model. Immunohistochemical and Western blot analyses of SPARC protein expression by low- and high-density cultured HRPE cells were undertaken. Total RNA extracted from cultures was studied by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis. Western and Northern blot analyses were evaluated by densitometry. Experiments were repeated with HRPE cells cultured in the presence of 1, 10, or 100 microM of the differentiating agents butyric acid (BA) and retinoic acid (RA). HRPE cell cultures exhibited SPARC immunoreactivity. Western blot analysis of cell lysates and conditioned media showed a 43-kDa protein. RT-PCR and Northern blot analysis confirmed the presence of SPARC mRNA (with transcripts at 2.2 and 3.0 kb). Protein and mRNA transcript band densitometry revealed a higher proportion of SPARC protein and mRNA in high-density HRPE cell culture than in low-density culture. Neither BA nor RA (at the concentrations assessed) had a significant effect on SPARC production by HRPE cells in high- or low-density culture. HRPE can synthesize SPARC. Although the findings do not support an invariable association between SPARC production by HRPE and HRPE proliferation, migration, or differentiation, they demonstrate that synthesis of SPARC by HRPE is modulated by cell density.