Pharmacological therapy of vascular malformations of the gastrointestinal tract.

Vascular malformation (AVM) in the gastrointestinal tract is an uncommon, but not rare, cause of bleeding and iron deficiency anemia, especially in an aging population. While endoscopic coagulative therapy is the method of choice for controlling bleeding, a substantial number of cases require additional therapy. Adjunctive or even primary phamacotherapy may be indicated in recurrent bleeding. However, there is little evidence-based proof of efficacy for any agent. The bulk of support is derived from anecdotal reports or case series. The present review compares the outcome of AVM after no intervention, coagulative therapy or focus on pharmacological agents. Most of the literature encompasses two common AVMs, angiodysplasia and hereditary hemorrhagic telangiectasia. Similarly, the bulk of information evaluates two therapies, hormones (estrogen and progesterone) and the somatostatin analogue octreotide. Of these, the former is the only therapy evaluated in randomized trials, and the results are conflicting without clear guidelines. The latter therapy has been reported only as case reports and case series without prospective trials. In addition, other anecdotally used medications are discussed.     

Expression of keratin K2e in cutaneous and oral lesions: association with keratinocyte activation,proliferation, and keratinization

The cytoskeleton in keratinocytes is a complex of highly homologous structural proteins derived from two families of type I and type II polypeptides. Keratin K2e is a type II polypeptide that is expressed in epidermis late in differentiation. Here we report the influence of keratinocyte activation, proliferation, and keratinization on K2e expression in samples of cutaneous and oral lesions. The normal expression of K2e in the upper spinous and granular layers of interfollicular epidermis is increased in keloid scars but showed distinct down-regulation in psoriasis and hypertrophic scars where keratinocytes are known to undergo activation. Unlike normal and psoriatic skin, K2e expression in hypertrophic and keloid scars began in the deepest suprabasal layer. In cutaneous basal and squamous cell carcinomas, K2e was absent in most tumor islands but the overlying epidermis showed strong expression. No significant K2e expression in nonkeratinized or keratinized oral epithelia, including buccal mucosa, lateral border of tongue and gingiva was detected. In oral lichen planus K2e expression was undetectable, but in benign keratoses of lingual mucosa induction of K2e along with K1 and K10 was observed. In mild-to-moderate oral dysplasia with orthokeratinization, K2e was highly expressed compared with parakeratinized areas but in severe dysplasia as well as in oral squamous cell carcinoma, K2e expression was undetectable. Taken together, the data suggest that K2e expression in skin is sensitive to keratinocyte activation but its up-regulation in oral lesions is a reflection of the degree of orthokeratinization.     

Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells

Radiation exposure is an occupational hazard for military personnel, some health care professionals, airport security screeners, and medical patients, with some individuals at risk for acute, high-dose exposures. Therefore, the biological effects of radiation, especially the potential for chromosome damage, are major occupational and health concerns. However, the biophysical mechanisms of chromosome instability subsequent to radiation-induced DNA damage are poorly understood. It is clear that interphase chromosomes occupy discrete structural and functional subnuclear domains, termed chromosome territories (CT), which may be organized into ‘neighborhoods’ comprising groups of specific CTs. We directly evaluated the relationship between chromosome positioning, neighborhood composition, and translocation partner choice in primary lymphocytes, using a cell-based system in which we could induce multiple, concentrated DNA breaks via high-dose irradiation. We critically evaluated mis-rejoining profiles and tested whether breaks occurring nearby were more likely to fuse than breaks occurring at a distance. We show that CT neighborhoods comprise heterologous chromosomes, within which inter-CT distances directly relate to translocation partner choice. These findings demonstrate that interphase chromosome arrangement is a principal factor in genomic instability outcomes in primary lymphocytes, providing a structural context for understanding the biological effects of radiation exposure, and the molecular etiology of tumor-specific translocation patterns.     

Optimizing Efforts to Promote Mental Health on College and University Campuses: Recommendations to Facilitate Usage of Services,Resources, and Supports

The Journal of Behavioral Health Services & Research - Mental health has long been a challenge on college and university campuses. Though it has historically taken a back seat to physical...     

Public discourse and policy change: Absence of harm from increased oversight and transparency in OPO performance

The Centers for Medicare and Medicaid Services announced changes to the Final Rule for organ procurement organizations (OPOs) in November 2020, after a 23-month period of public debate. One concern among transplant stakeholders was that public focus on OPO underperformance would harm deceased donation. Using CDC-WONDER data, we studied whether donation performance dropped during the era of public debate about OPO reform (December 2018–February 2020). Overall OPO performance as measured relative to cause, age, and location-consistent deaths rose by 12.3% in 2019, compared to a median annual change of 2.5% 2009–2019. Organ recoveries exceeded seasonally adjusted forecasts by 4.2% in the first half of 2019, by 8.1% following the Executive Order issuing a mandate for OPO metric reform, and by 14.1% between the Notice of Public Rule Making and the onset of COVID-19-related systemic disruptions. We describe changes in donor phenotype in the period of increased performance; improvement was greatest for older and donation after cardiac death (DCD) donors, and among decedents who did not have a drug-related mechanism of death. In summary, performance during an era of intense public debate and proposed regulatory changes yielded 692 additional donors over expectations, and no detriment to organ donation was observed.     

Progressive amplification and overexpression of the eukaryotic initiation factor 4E gene in different zones of head and neck cancers.

PURPOSE: Eukaryotic initiation factor 4E (eIF4E) binds to mRNA as the initial rate-limiting step in protein synthesis. Amplification and overexpression of the eIF4E gene has been associated with malignant transformation. The objectives of this study were to 1) quantify the eIF4E gene in head and neck squamous cell carcinoma (HNSCC) specimens, 2) quantify eIF4E protein elevation and examine its association with eIF4E gene amplification, and 3) determine whether there is progression in eIF4E gene amplification and protein overexpression in the tumor-free resection margin, the transition zone, and the tumor core of HNSCC specimens. MATERIALS AND METHODS: Eighteen HNSCC specimens were divided into three zones: 1) tumor core; 2) transition zone; and 3) "tumor-free" margin. Competitive polymerase chain reaction was performed to determine eIF4E gene copy number. eIF4E protein expression was quantified using Western blot analysis. RESULTS: All 18 HNSCC specimens tested had significant eIF4E gene amplification (4.3+/-1.2; P < .05). In contrast, none of the 10 benign specimens from noncancer patients had any eIF4E gene amplification (1.1+/-0.5). In the 12 HNSCC specimens examined for the three zones, the tumor core and transition zone showed eIF4E gene amplification (5.2+/-1.1 and 3.5+/-0.9, respectively) compared with the "tumor-free" margin (2.1+/-1.1; P < .05). The tumor core and transition zone showed significant efF4E protein elevation (15.5+/-9.3, 4.4+/-4.6, respectively) compared with the "tumor-free" margin (0.9+/-0.5, P < .05). CONCLUSIONS: The eIF4E gene is amplified and overexpressed in HNSCC. Amplification and elevation of eIF4E were highest in the tumor core, intermediate in the transition zone, and lowest in the tumor-free margin. There appears to be progression of eIF4E gene amplification and overexpression from the "tumor-free" margin to the tumor core.     

Mononuclear cell proliferation and hyperplasia during Wallerian degeneration in the visual system of the goldfish in the presence or absence of regenerating optic axons

Patterns of proliferation and changes in non-neuronal cell number in the visual system of the goldfish have been quantitatively examined during optic axon regeneration after an optic nerve crush (ONC). In addition, in order to examine the effect of the regenerating axons on cellular responses in the visual pathways, we did a similar analysis of animals with the right eye removed (ER). Finally, we used double labeling protocols to demonstrate that the proliferating cells that we were counting were mostly phagocytic cells of the mononuclear lineage. In animals with an ONC, we observed an early burst of proliferation that peaked between 7 and 14 days after surgery in all parts of the visual system. In the optic tract, there was also a secondary rise that peaked at 21 days. Levels of proliferation returned to normal by 32 days postoperative in the tract and tectum, while they remained somewhat elevated in the optic nerve for at least 93 days. The total number of non-neuronal cells in the visual paths also rose to peak values between 7 and 14 days after ONC surgery. In the optic tract and tectum, the values fell rapidly after this time, while in the optic nerve, there was a secondary peak at 32 days after which values remained elevated for the duration of the experiment. As compared to animals with an ONC, enucleation resulted in elevated proliferation and hyperplasia at early postoperative intervals. However, because these differences occurred when axons had not yet regenerated into the affected structures, these data do not provide strong evidence for a direct effect of regenerating optic axons on the early cellular responses during Wallerian degeneration in the goldfish. In addition, in the tectum, there was an early increment in cell number that was not associated with elevated levels of proliferation. We believe that this increment represents immigration of resident microglia from other regions of the brain.     

Development of acute lymphoblastic leukemia following treatment for acute myeloid leukemia in children with Down syndrome: A case report and retrospective review of Children's Oncology Group acute myeloid leukemia trials

Children with Down syndrome have a 150‐fold increased risk of developing acute myeloid leukemia (AML) and 20‐fold increased risk of developing acute lymphoblastic leukemia (ALL). Although the risk of developing AML and ALL is significantly increased in children with Down syndrome, the development of both malignancies in the same patient is very rare. We describe a patient with Down syndrome who developed ALL 6 years after being diagnosed with AML. We performed a literature review and Children's Oncology Group query and discovered eight published cases and five cases of ALL following AML in pediatric patients with Down syndrome, as well as six cases of ALL following AML in non‐Down syndrome patients. There was a similar cumulative incidence of ALL after treatment for AML in the Down syndrome and non‐Down syndrome populations. Overall survival in patients with Down syndrome who developed ALL after treatment for AML was comparable to overall survival for patients with Down syndrome with de novo ALL with an average follow‐up of 7 years after ALL diagnosis. Clinical data collected were used to discuss whether this phenomenon represents a secondary leukemia, second primary cancer, or mixed‐lineage leukemia.