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This article discusses a study on sclerosing melanocytic tumors with MAP2K1 in-frame deletions and copy number gains in 15q. The study examines the histomorphologic, immunophenotypic, and cytogenetic features of these tumors. The authors found that these tumors can be recognized by the presence of SPARK-like architecture and a desmoplastic Spitz nevus-like appearance. They also observed chromosomal copy number changes, with a gain in chromosome 15 being a common finding. The article suggests that these tumors may represent a distinctive pathway of nevogenesis and further research is needed to understand their biologic potential. [Extracted from the article]

Grid convergence of plasma drift turbulence simulations in the Large Plasma Device is studied. When first order upwind advection schemes are used, numerical finite difference diffusion errors cause turbulence statistics, especially saturation levels to vary when grid spacing is changed. The significance and magnitude of the variation is explored, and it is found that use of very fine meshes or higher order advection schemes combined with artificial diffusion and viscosity can lead to grid convergence, while maintaining experimentally consistent saturation levels. It is also found that the details of dissipation range dynamics, such as the level of diffusion, have a significant impact on driven range dynamics due to the lack of a large inertial range in the simulations (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

OBJECTIVES: To examine, in community-dwelling elderly persons with disabilities, the association between oral health-related quality of life (OHRQOL) as measured using the 14-item Oral Health Impact Profile (OHIP-14) and specific oral health, health, and disability status variables; life satisfaction; living alone; and low income. DESIGN: Observational cross-sectional. SETTING: A Medicare demonstration conducted in 19 counties in three states. PARTICIPANTS: Six hundred forty-one disabled, cognitively intact, community-dwelling individuals aged 65 and older. MEASUREMENTS: The subjects' OHRQOL was assessed using the OHIP-14, which was scored using three different methods. Data on oral health, health and functional status, life satisfaction, prior health services use, and sociodemographics were collected using interviewer-administered questionnaires. RESULTS: The participants' mean age was 79.1, and they were dependent in an average of 1.8 activities of daily living (ADLs); 43.1% were edentulous, 77.4% wore a denture, 40.4% felt that they were currently in need of dental treatment, and 64.7% had not had a dental examination in the previous 6 months. Seven of the 16 variables of interest had significant bivariate relationships using three OHIP scoring methods. Logistic regression analysis found that poor OHRQOL was significantly associated with perceived need for dental treatment (odds ratio (OR)=2.61), poor self-rated health (OR=2.29), poor (OR=2.00) and fair (OR=1.73) mental health, fewer than 17 teeth (OR=1.74), and relatively poor cognitive functioning (OR=1.52). CONCLUSION: OHRQOL is associated with some (perceived need for dental treatment, poor self-rated health, worse mental health, fewer teeth, and relatively poor cognitive status) but not all (e.g., ADL and instrumental ADL dependence) measures of oral health, health, and disability status and not with life satisfaction, living alone, or low income. [ABSTRACT FROM AUTHOR]

Tixocortol pivalate is a steroid reportedly without significant adrenal-pituitary axis suppression when administered via the gastrointestinal tract. To determine whether this steroid would suppress the gastrointestinal manifestations of systemic mastocytosis, we performed an open clinical trial for safety and efficacy with tixocortal pivalate in four patients for periods of 8-15 weeks. All patients showed a decrease in the symptoms of abdominal pain and frequency of stools. Laboratory parameters of malabsorption improved in parallel with symptom relief. Histopathologic abnormalities of the small bowel improved in one patient. There was no significant suppression of the pituitaryadrenal axis. Two patients developed fluid retention while on tixocortol pivalate, which was attributed to a mineralocorticoid effect. One patient had a fall in AM cortisol. In summary, this study strongly suggests that tixocortol pivalate, when administered orally, has gastrointestinal anti-inflammatory activity comparable lo conventional steroids, but may not be entirely without adrenal-suppressive effect and may lead to fluid retention in some patients. Further studies are warranted to assess the value of tixocortol pivalate in the therapy of inflammatory diseases of the upper gastrointestinal tract. [ABSTRACT FROM AUTHOR]

We have evaluated the capacity of cultured human respiratory epithelial cells (HTE) lo produce granulocyte-macrophage colony-stimulating factor (GM-CSF) and have examined the ability of proinflammatory stimuli and of glucocorticoids to modulate the production of GM-CSF by these cells. Conditioned medium (CM) was obtained after 24-hr culture of HTE in the presence or absence of serum (5%) and was assayed for GM-CSF activity using the M-07e cell line, which proliferates in response to GM-CSF and interleukin-3 (IL-3). HTE produced 1.1 ± 0.7 and 2.1 ± 1.5 ng GM-CSF/106 cells in the presence or absence of serum, respectively (n = 4). The identity of this activity as GM-CSF was established by neutralization with specific antibody to GM-CSF, while antibody to IL-3 was without effect. Dexamethasone (10-6 M) inhibited basal GM-CSF release to below the limit of detection of the assay (0.12 ng GM-CSF/ml conditioned media). GM-CSF release was significantly enhanced by 10-6 M histamine (1.6 ± 0.7 versus 2.13 ± 0.8 ng GM-CSF/10-6 cells: n = 9 ) and 5 ng/ml interleukin-1 (IL-1) (0.6 ± 0.2 versus 3.2 ± 0.5 ng GM-CSF/106 cells; n = 3). Stimulation of GM-CSF release by IL-1 was dose-dependent. A significant increase in GM-CSF activity was observed with 0.1 ng/ml, while maximal stimulation occurred at 5 ng/ml IL-1. In kinetic studies, GM-CSF activity was first detected in CM from cells incubated in the absence of stimulus at 8 hr of incubation, and continued to increase up to 24 hr. IL-1-stimulated GM-CSF activity was detected in CM as early as 4 hr and continued to increase significantly up to 24 hr. Thus, human tracheal epithelial cells release GM-CSF and this release is regulated by inflammatory mediators and glucocorticoids. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 37-year-old man suffering from diverticulitis. The man was presented with dyspnoea, anorexia, and high grade fever. The patient developed weakness of the right lower limb, with considerable loss of power in the knee and ankle. Computed tomography (CT) of the brain showed multiple ring-enhancing lesions in the right fronto-parietal region; magnetic resonance imaging of the spine revealed partially septated lesion.

Aim: This exploratory study aimed to examine differences in rates of self and clinician-reports of trauma in youth at clinical high risk for psychosis (CHR) and whether rates of reporting differed by ethnicity., Methods: Self-reported history of trauma was collected at intake amongst youth at CHR enrolled in Coordinated Specialty Care (CSC) services (N = 52). A structured chart review was conducted for the same sample to identify clinician-reported history of trauma throughout treatment in CSC., Results: For all patients, frequency of self-reported trauma at intake to CSC (56%) was lower compared to clinician-reports of trauma throughout treatment (85%). Hispanic patients self-reported trauma at intake (35%) less frequently than non-Hispanics (69%) (p = .02). No differences were found in clinician reported exposure to trauma by ethnicity throughout treatment., Conclusion: Whilst further research is needed, these findings suggest the need for formalised, repeated, and culturally appropriate assessments of trauma within CSC., (© 2023 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

The skill sets of genetic counselors are strongly utilized in industry, as evidenced by 20% of genetic counselors reporting employment within industry in 2016. In addition, industry genetic counselors are expanding their roles, taking on new responsibilities, and creating new opportunities. These advances have impacted the profession as a whole including, but not limited to, genetic counseling training curricula, a shift back to genetic counseling directly to patients, and a growing influence of genetic counselors on industry test offerings. Industry genetic counselors and training programs are working together to address the challenges and opportunities presented by workforce changes and novel interpretations of how genetic counselors' core competencies can be utilized. Counseling of patients by industry genetic counselors has become more commonplace and addresses a need for alternate service delivery models. Industry genetic counselors often provide significant contributions to test development, education, marketing, and interpretation. Beyond these broad examples, individual industry genetic counselors have created unique niches for themselves, using their genetic counseling training combined with unique opportunities offered through industry, as illustrated by genetic counselors' various roles and responsibilities highlighted here., (© 2018 Wiley Periodicals, Inc.)

Neurodevelopmental disorders (NDD) are common, with 1-3% of general population being affected, but the etiology is unknown in most individuals. Clinical whole-exome sequencing (WES) has proven to be a powerful tool for the identification of pathogenic variants leading to Mendelian disorders, among which NDD represent a significant percentage. Performing WES with a trio-approach has proven to be extremely effective in identifying de novo pathogenic variants as a common cause of NDD. Here we report six unrelated individuals with a common phenotype consisting of NDD with severe speech delay, hypotonia, and facial dysmorphism. These patients underwent WES with a trio approach and de novo heterozygous predicted pathogenic novel variants in the KAT6A gene were identified. The KAT6A gene encodes a histone acetyltransfrease protein and it has long been known for its structural involvement in acute myeloid leukemia; however, it has not previously been associated with any congenital disorder. In animal models the KAT6A ortholog is involved in transcriptional regulation during development. Given the similar findings in animal models and our patient's phenotypes, we hypothesize that KAT6A could play a role in development of the brain, face, and heart in humans. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

We review the organizational principles of the cortical vasculature and the underlying patterns of blood flow under normal conditions and in response to occlusion of single vessels. The cortex is sourced by a two-dimensional network of pial arterioles that feeds a three-dimensional network of subsurface microvessels in close proximity to neurons and glia. Blood flow within the surface and subsurface networks is largely insensitive to occlusion of a single vessel within either network. However, the penetrating arterioles that connect the pial network to the subsurface network are bottlenecks to flow; occlusion of even a single penetrating arteriole results in the death of a 500 μm diameter cylinder of cortical tissue despite the potential for collateral flow through microvessels. This pattern of flow is consistent with that calculated from a full reconstruction of the angioarchitecture. Conceptually, collateral flow is insufficient to compensate for the occlusion of a penetrating arteriole because penetrating venules act as shunts of blood that flows through collaterals. Future directions that stem from the analysis of the angioarchitecture concern cellular-level issues, in particular the regulation of blood flow within the subsurface microvascular network, and system-level issues, in particular the role of penetrating arteriole occlusions in human cognitive impairment., (© 2015 John Wiley & Sons Ltd.)

Objectives/hypothesis: By phage display, we have developed a novel peptide (NP41) that binds selectively to nerves following systemic administration. We evaluated the pattern of facial nerve labeling with fluorescently-labeled NP41 (F-NP41). We also tested whether F-NP41 highlights facial nerves well enough to identify nerve stumps accurately several weeks after nerve transection., Study Design: Forty-seven wild-type mice were studied prospectively. One surgeon performed the nerve transection, reanastomosis, and monitoring of functional recovery., Methods: Fluorescent labeling: F-NP41 was administered intravenously (20 mice). Nerve labeling was studied with fluorescence microscopy. Transection and reanastomosis: the right facial nerve was transected (25 mice). Three weeks after transection, F-NP41 was administered intravenously and fluorescence microscopy was used to identify the nerve stumps and reanastomosis in one group. Nerve identification and reanastomosis was performed with white light in another group without F-NP41. The control group underwent sham surgery. Time to nerve identification was recorded. Functional recovery was monitored for at least 8 weeks., Results: We found excellent labeling of intact and transected facial nerves following F-NP41 administration. Several weeks following nerve transection, F-NP41 provided accurate identification of the proximal and distal nerve stumps. Following reanastomosis, time to recovery and level of functional recovery was similar in the absence and presence of F-NP41., Conclusions: We show improved visualization of facial nerves with a novel systemically applied fluorescently labeled probe. Use of F-NP41 resulted in accurate identification of facial nerve stumps several weeks following transection. Functional recovery was similar with and without the use of F-NP41., (Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.)

We report a new disorder with diverse neurological problems resulting from abnormal brainstem function. Consistent features of this disorder, which we propose should be called the Atabascan brainstem dysgenesis syndrome, include horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Other features seen in some patients include swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies. All affected children described are of Athabascan Indian heritage, with eight children from the Navajo tribe and two patients who are of Apache background. The disorder can be distinguished from the Moebius syndrome by the pattern of central nervous system findings, especially the sensorineural deafness, horizontal gaze palsy, and central hypoventilation. Recognition of children with some features of Athabascan brainstem dysgenesis syndrome should prompt investigation for other related abnormalities. Published 2003 Wiley-Liss, Inc.

1. The pharmacokinetic and pharmacodynamic properties of a novel 2-indolealkanoic acid derivative (MK-0591), a potent inhibitor of leukotriene biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days were administered. 2. After the single-dose administration following overnight fasting, Cmax and AUC of MK-0591 in plasma increased in a dose-dependent manner, while elimination half-life remained constant (11.2-13.2 h) irrespective of dose. Food intake decreased Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple-dose administration before meals, there were no significant differences in the pharmacokinetic parameters between the first and last days, indicating a lack of significant accumulation of MK-0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the study. 3. Ionophore-stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single-dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore-stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK-0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)

The present investigation evaluated the serum transferrin receptor concentration in subjects with nontransfusional iron overload who were identified in two separate studies on the basis of a serum ferritin level above 400 micrograms/L. Subjects with preclinical hereditary hemochromatosis were evaluated in the first study and those with the African form of iron overload in the second. In the first study, hereditary hemochromatosis was identified in 14 white men on the basis of a persistent elevation in transferrin saturation above 55%. The serum receptor concentration was elevated above the upper cut-off of 8.5 mg/L in two of the subjects, but the mean receptor of 6.1 +/- 1.4 mg/L (mean +/- 2 SE) did not differ significantly from the normal mean for this assay of 5.6 +/- 0.3 mg/L. In the same study, 60 control subjects with secondary iron overload were identified on the basis of a serum ferritin persistently above 400 micrograms/L, with a normal serum C-reactive protein concentration but with a transferrin saturation < 55%. Three of these subjects had an elevated serum receptor concentration but the mean value of 5.5 +/- 0.4 mg/L did not differ from normals nor from subjects with hemochromatosis. In the second study, 49 black Africans with iron overload were divided into those with or without an elevated transferrin saturation. The mean serum receptor concentration of 5.0 +/- 0.8 mg/L and 4.5 +/- 0.4 mg/L, respectively, did not differ statistically. It was concluded that there is no evidence of generalized dysregulation of the transferrin receptor in hemochromatosis or African siderosis.

Therapeutic uses of calcium antagonists have expanded to include not only ischemic heart disease but arrhythmias, systemic hypertension, congestive heart failure, and various pulmonary and gastrointestinal diseases. Many patients receiving a calcium antagonist concomitantly receive digoxin. Although the potential interaction between these agents has frequently been investigated, literature reports are confusing and inconsistent. We summarized the pharmacodynamics, pharmacokinetics, and mechanisms of interaction to help clinicians evaluate the potential calcium antagonist-digoxin interaction.

A study was done to evaluate the effect of ferrous and ferric chelators on the interaction between transferrin-iron and cultured human blood monocytes. This interaction has been previously shown to involve a specific receptor and vesicle protonation. Transferrin-iron uptake was significantly inhibited by the hydrophobic ferrous chelator 2,2' bipyridine, and the inhibition was shown not to be a consequence of the mobilisation of intracellular iron by the chelator. Chase experiments and prolonged incubation studies suggested that the chelator prevented the iron released from transferrin from negotiating the unit membrane. The iron and transferrin then appeared to be returned independently to the incubation medium. In contrast, a hydrophilic ferrin chelator, desferrioxamine, had only a very modest effect on the interaction. These findings are compatible with the hypothesis that transferrin-iron is reduced to the ferrous state during its uptake by the culture human blood monocyte.

Certain metabolic pathways of iron were studied in macrophages (cultured human monocytes) obtained from normal and hemochromatotic subjects. The relative abilities of the hydrophobic ferrous chelator 2,2' bipyridine and the hydrophilic ferric chelators desferrioxamine (DFO) and diethylenetriaminepenta-acetic acid (DTPA) to release iron from normal and hemochromatotic macrophages which had previously been loaded with diferric transferrin were tested but there were no differences between the two groups. The relative affinity of the macrophages for diferric transferrin was next studied. Although the hemochromatic macrophages had a somewhat lower affinity for diferric transferrin iron than normal macrophages (Kd 4.7 x 10(-8) M vs. 3.0 x 10(-8)M) the difference did not reach statistical significance (t = 2.01013; P less than 0.07). In a further experiment there was no evidence that apotransferrin was directly involved in the release of iron from hemochromatotic macrophages. A clue to the nature of postendocytotic trans-membrane transport of iron was provided by the finding that it was inhibited by the hydrophobic ferrous chelator 2,2' bipyridine. However, the degree of inhibition was similar in both normal and hemochromatotic macrophages. In summary, none of the metabolic processes examined in the present study was abnormal in cultured human blood monocytes from hemochromatotic subjects.