Phenocopy behavioral variant frontotemporal dementia: A case study.

Objective: Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative condition characterized by progressive changes in behavior, cognition, and day-to-day functioning. Progression of the disease usually leads to death 3-5 years after diagnosis. However, there are reports of individuals who are initially diagnosed with bvFTD but fail to progress. These individuals are thought to have what is becoming known as phenocopy bvFTD (phFTD). Methods: This manuscript reviews a single case study of a 68-year-old male Veteran who was diagnosed with bvFTD in 2010, which has not progressed over time. Results: Review of serial neuropsychological evaluations was broadly normal with mild evidence of executive dysfunction with minimal reliable change in his performances from 2015, 2017, and 2022 evaluations. He also has not developed neuroimaging evidence of FTD. Conclusions: This case illustrates the importance of monitoring individuals over time and incorporating neuroimaging data into the diagnosis. We believe this Veteran's presentation is most consistent with what has been described as phFTD.

The Impact of Mental Illness Disclosure in Applying for Residency.

OBJECTIVE: Medical students have higher rates of depression than age-matched peers. Given the societal stigma against mental illness, students with depression often seek guidance on disclosing this in residency applications. This study aimed to answer whether disclosing a mental illness during the residency application process affects an applicant's success in the National Resident Matching Program. The authors hypothesized candidates disclosing mental illness would receive fewer interviews and would be ranked lower than those disclosing physical illness. METHODS: The authors randomized program directors from residencies accredited by the Accreditation Council for Graduate Medical Education (ACGME) to receive one of two surveys. Both surveys included similar demographic information and three applicant vignettes, varying only in presence and type of illness disclosed (major depression or diabetes mellitus). The authors analyzed data using the Generalized Estimating Equation method for ordinal logistic regression. RESULTS: Out of 3838 ACGME residency programs, 596 responded (16.9%). A total of 380 (10.7%) program directors (survey 1, n = 204, 5.3%; survey 2, n = 176, 4.6%) completed the survey. Applicants who disclosed a history of depression had higher odds of being in a lower category of receiving an invitation (OR = 3.60, p < .001 for a "perfect" applicant, OR = 2.39, p < .001 for a "good" applicant with leave of absence) and a lower category for match ranking (OR = 1.94, p = .01 for a perfect applicant, OR = 2.30, p < .001 for a good applicant with leave of absence) compared with the candidate who disclosed a history of diabetes. However, strong applicants who disclosed depression still fared better in the application process than an average applicant without disclosed illness (OR = 0.13, p < .001 for invite and OR = 0.04, p < .001 for rank). CONCLUSION: Disclosing depression during the residency application process puts an applicant at a notable, however not insurmountable, disadvantage compared with applicants who do not disclose mental illness.

Primary Care Medical Practices: Are Community Health Care Providers Ready for Disasters?

OBJECTIVE: This study seeks to determine the capacity of community primary care practices to meet the needs of patients during public health emergencies and to identify the barriers and resources necessary to participate in a coordinated response with public safety agencies. METHODS: The self-administered web-based survey was distributed in January 2014 via e-mail to primary care providers in Pennsylvania using the listservs of several professional societies. RESULTS: A total of 179 primary care providers participated in the survey. In total, 38% had practice continuity of operations plan in place and 26% reported that they had a plan for patient surge in the outpatient setting. Thirty percent reported that they were registered on the state Health Alert Network and 41% said they were able to communicate with patients during disasters. Only 8% of providers reported that they believed that their patients with special health care needs were prepared for a disaster, although over two-thirds of responding practices felt they could assist these patients with disaster preparedness. Providers indicated that more information regarding government agency plans and community resources, patient education materials, and more time to devote to counseling during patient encounters would improve their ability to prepare their patients with special health care needs for disasters. Providers also reported that they would benefit from partnerships to help the practice during emergencies and communications technology to reach large numbers of patients quickly. CONCLUSIONS: Community-based primary care practices can be useful partners during public health emergencies. Efforts to promote continuity of operations planning, improved coordination with government and community partners, as well as preparedness for patients with special health care needs, would augment their capabilities and contribute to community resilience. (Disaster Med Public Health Preparedness. 2019;13:128-132).

Retrospective evaluation of acute liver failure in dogs (1995-2012): 49 cases.

OBJECTIVE: To characterize the clinical presentation and outcome of dogs with acute liver failure (ALF). DESIGN: Retrospective case series from January 1995 to December 2012. SETTING: University teaching hospital. ANIMALS: Forty-nine dogs were diagnosed with ALF defined as the acute onset of clinical signs accompanied by serum hyperbilirubinemia and coagulopathy (prothrombin time >1.5 times the upper limit of the reference interval) with or without signs of hepatic encephalopathy. METHODS: Medical records were retrospectively analyzed for clinical presentation, history, physical examination findings, clinicopathologic data, diagnostic imaging findings, hepatic histopathology, treatment, and outcome. MAIN RESULTS: Presenting signs included anorexia (28/49, 57%), vomiting (25/49, 51%), neurologic abnormalities (17/49, 35%), and polydipsia/polyuria (10/49, 20%). Neurologic impairment compatible with hepatic encephalopathy occurred at some point during hospitalization in 28/49 (57%) of dogs. Common clinicopathologic abnormalities on presentation other than hyperbilirubinemia and increased serum liver enzyme activity included thrombocytopenia (25/49, 51%), hypoalbuminemia (23/49, 46%), leukocytosis (17/49, 34%), anemia (14/49, 29%), hypokalemia (13/49, 27%), and hypoglycemia (10/49, 20%). The causes of ALF included neoplasia (13/49, 27%), presumptive leptosporosis (4/49, 8%), and ischemia (1/49, 2%). The remaining cases were idiopathic although 15 of these dogs had exposure to possible hepatotoxins. Common lesions in the 35/49 (71%) dogs that had hepatic histopathology were necrosis (19/39, 48%), lipidosis (16/39, 41%), vacuolar change (7/49, 14%), and inflammation (4/49, 8%). Complications included ascites (20/49, 41%), bleeding tendencies (14/49, 29%), pancreatitis (12/49, 24%), and acute tubular necrosis (11/49, 22%). Seven (14%) dogs survived to discharge. Survivors had higher alanine aminotransferase activity, and were more likely to maintain normal albumin concentrations and not develop clinical bleeding or ascites during hospitalization. CONCLUSIONS: Canine ALF is associated with multiple etiologies and a high mortality rate. Strategies to increase survival are urgently required.

Comparison between clinical, ultrasound, CT, MRI, and pathology findings in dogs presented for suspected thyroid carcinoma.

This study compares clinical, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and pathology findings in 16 prospectively, and seven retrospectively recruited dogs presented for suspected thyroid carcinoma. Of these, 17 were confirmed thyroid carcinoma, while six were initially misdiagnosed. These included four carotid body tumors, one para-esophageal abscess, and one undifferentiated squamous cell carcinoma. Thyroid carcinomas occurred in older dogs without evidence of sex predilection, and were more often unilateral. All were large, heterogeneous, moderately to strongly vascularized, and most commonly contained areas of dystrophic mineralization and/or fluid accumulations. On MRI, thyroid carcinomas appeared hyperintense compared to surrounding musculature in all imaging sequences used, while on CT they had a lower attenuation value than normal thyroid gland tissue. Histologically confirmed tumor capsule disruption with invasion of the surrounding structures was most commonly detected with MRI. Palpation was not an accurate predictor of locally invasive vs. well-encapsulated masses. Computed tomography had the highest specificity (100%) and MRI had the highest sensitivity (93%) in diagnosing thyroid carcinoma, while ultrasound had considerably lower results. We conclude that ultrasound is adequate for use as a screening tool for dogs with suspected thyroid carcinoma, but recommend either CT or MRI for preoperative diagnosis and staging.

Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1.

The human genomic instability syndrome ataxia telangiectasia (A-T), caused by mutations in the gene encoding the DNA damage checkpoint kinase ATM, is characterized by multisystem defects including neurodegeneration, immunodeficiency and increased cancer predisposition. ATM is central to a pathway that responds to double-strand DNA breaks, whereas the related kinase ATR leads a parallel signaling cascade that is activated by replication stress. To dissect the physiological relationship between the ATM and ATR pathways, we generated mice defective for both. Because complete ATR pathway inactivation causes embryonic lethality, we weakened the ATR mechanism to different degrees by impairing HUS1, a member of the 911 complex that is required for efficient ATR signaling. Notably, simultaneous ATM and HUS1 defects caused synthetic lethality. Atm/Hus1 double-mutant embryos showed widespread apoptosis and died mid-gestationally. Despite the underlying DNA damage checkpoint defects, increased DNA damage signaling was observed, as evidenced by H2AX phosphorylation and p53 accumulation. A less severe Hus1 defect together with Atm loss resulted in partial embryonic lethality, with the surviving double-mutant mice showing synergistic increases in genomic instability and specific developmental defects, including dwarfism, craniofacial abnormalities and brachymesophalangy, phenotypes that are observed in several human genomic instability disorders. In addition to identifying tissue-specific consequences of checkpoint dysfunction, these data highlight a robust, cooperative configuration for the mammalian DNA damage response network and further suggest HUS1 and related genes in the ATR pathway as candidate modifiers of disease severity in A-T patients.

Bilateral intraocular malignant neuroectodermal tumors in a telescope goldfish (Carassius auratus).

Abstract A 5-year-old male telescope goldfish (Carassius auratus) developed buphthalmia of the left eye. An enucleation was performed and a diagnosis of a neuroectodermal tumor was made on histological examination. Although the fish initially recovered, it was killed 49 days postsurgery due to a severe decline in its condition. On histological evaluation of postmortem tissue samples, it was determined that the fish also had a neuroectodermal tumor of the right eye with local invasion of the brain. On immunohistochemistry, the neoplastic cells were positive for S-100. To the authors' knowledge, this is the first published case of naturally occurring bilateral intraocular neuroectodermal tumors in a fish.

Multiphoton microscopy as a diagnostic imaging modality for lung cancer.

Lung cancer is the leading killer among all cancers for both men and women in the US, and is associated with one of the lowest 5-year survival rates. Current diagnostic techniques, such as histopathological assessment of tissue obtained by computed tomography guided biopsies, have limited accuracy, especially for small lesions. Early diagnosis of lung cancer can be improved by introducing a real-time, optical guidance method based on the in vivo application of multiphoton microscopy (MPM). In particular, we hypothesize that MPM imaging of living lung tissue based on two-photon excited intrinsic fluorescence and second harmonic generation can provide sufficient morphologic and spectroscopic information to distinguish between normal and diseased lung tissue. Here, we used an experimental approach based on MPM with multichannel fluorescence detection for initial discovery that MPM spectral imaging could differentiate between normal and neoplastic lung in ex vivo samples from a murine model of lung cancer. Current results indicate that MPM imaging can directly distinguish normal and neoplastic lung tissues based on their distinct morphologies and fluorescence emission properties in non-processed lung tissue. Moreover, we found initial indication that MPM imaging differentiates between normal alveolar tissue, inflammatory foci, and lung neoplasms. Our long-term goal is to apply results from ex vivo lung specimens to aid in the development of multiphoton endoscopy for in vivo imaging of lung abnormalities in various animal models, and ultimately for the diagnosis of human lung cancer.

Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin.

Runx1/AML1 is a transcription factor implicated in tissue stem cell regulation and belongs to the small Runx family of cancer genes. In the hair follicle (HF), Runx1 epithelial deletion in morphogenesis impairs normal adult hair homeostasis (cycle) and blocks adult hair follicle stem cells (HFSCs) in quiescence. Here, we show that these effects are overcome later in adulthood. By deleting Runx1 after the end of morphogenesis, we demonstrate its direct role in promoting anagen onset and HFSC proliferation. Runx1 deletion resulted in cyclin-dependent kinase inhibitor Cdkn1a (p21) upregulation. Interfering with Runx1 function in cultured HFSCs impaired their proliferation and normal G(0)/G1 and G(1)/S cell cycle progression. The proliferation defect could be rescued by Runx1 readdition or by p21 deletion. Chemically induced skin tumorigenesis in mice turned on broad Runx1 expression in regions of the skin epithelium, papillomas, and squamous cell carcinomas. In addition, it revealed reduced rates of tumor formation in the absence of Runx1 that were accompanied by decreased epithelial levels of phospho-Stat3. Runx1 protein expression was similar in normal human and mouse hair cycles. We propose that Runx1 may act as a skin oncogene by directly promoting proliferation of the epithelial cells.

Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration.

In response to DNA damage, checkpoint proteins halt cell cycle progression and promote repair or apoptosis, thereby preventing mutation accumulation and suppressing tumor development. The DNA damage checkpoint protein Hus1 associates with Rad9 and Rad1 to form the 9-1-1 complex, which localizes to DNA lesions and promotes DNA damage signaling and repair. Because complete inactivation of mouse Hus1 results in embryonic lethality, we developed a system for regulated Hus1 inactivation in the mammary gland to examine roles for Hus1 in tissue homeostasis and tumor suppression. Hus1 inactivation in the mammary epithelium resulted in genome damage that induced apoptosis and led to depletion of Hus1-null cells from the mammary gland. Conditional Hus1 knockout females retained grossly normal mammary gland morphology, suggesting compensation by cells that failed to undergo Cre-mediated Hus1 deletion. p53-deficiency delayed the clearance of Hus1-null cells from conditional Hus1 knockout mice and caused the accumulation of damaged, dying cells in the mammary gland. Notably, compensatory responses were impaired following combined Hus1 and p53 loss, resulting in aberrant mammary gland morphology and lactation defects. Overall, these results establish a requirement for Hus1 in the survival and proliferation of mammary epithelium and identify a role for p53 in mammary gland tissue regeneration and homeostasis.

Genome maintenance defects in cultured cells and mice following partial inactivation of the essential cell cycle checkpoint gene Hus1.

Cell cycle checkpoints are evolutionarily conserved signaling pathways that uphold genomic integrity. Complete inactivation of the mouse checkpoint gene Hus1 results in chromosomal instability, genotoxin hypersensitivity, and embryonic lethality. To determine the functional consequences of partial Hus1 impairment, we generated an allelic series in which Hus1 expression was incrementally reduced by combining a hypomorphic Hus1 allele, Hus1(neo), with either wild-type or null (Hus1(Delta1)) alleles. Primary Hus1(neo/Delta1) embryonic fibroblasts exhibited spontaneous chromosomal abnormalities and underwent premature senescence, while higher Hus1 expression in Hus1(neo/neo) cells allowed for normal proliferation. Antioxidant treatment almost fully suppressed premature senescence in Hus1(neo/Delta1) cultures, suggesting a critical role for Hus1 in oxidative stress responses. Treatment of Hus1(neo/neo) and Hus1(neo/Delta1) cells with the DNA adducting agent benzo(a)pyrene dihydrodriol epoxide resulted in a loss of cell viability that was associated with S-phase DNA damage checkpoint failure. Likewise, the DNA polymerase inhibitor aphidicolin triggered increased cell death, chromosomal aberrations, and H2AX phosphorylation, a marker for double-stranded DNA breaks, in Hus1(neo/neo) and Hus1(neo/Delta1) cultures compared to controls. Despite these pronounced genome maintenance defects in cultured Hus1(neo/Delta1) and Hus1(neo/neo) cells, mice of the same genotypes were born at expected frequencies and appeared grossly normal. A significant increase in micronucleus formation was observed in peripheral blood cells from Hus1(neo/Delta1) mice, but reduced Hus1 expression did not cause an elevated predisposition to spontaneous tumor development or accelerate tumorigenesis in p53-deficient mice. These results identify differential effects of altered Hus1 gene dosage on genome maintenance during in vitro culture, genotoxic stress responses, embryonic development, and adult homeostasis.

Histopathologic features of canine uremic gastropathy: a retrospective study.

Uremic gastritis is a term commonly used to describe the gastrointestinal signs and histopathologic changes associated with renal failure in the dog. This retrospective study reviews the clinical, serum biochemical, and postmortem histopathologic data from 28 dogs with renal failure to determine the prevalence of gastric histopathology, characterize the gastric histopathology, and identify associations between gastric histopathology and serum concentrations of blood urea nitrogen (BUN), creatinine (Cr), calcium-phosphorus product (Ca x Phos), and hematocrit. Affected and control dogs with available renal and gastric tissue, serum biochemistry data, and urinalysis data were identified over a 10-year period (1992-2002) in the pathology department postmortem examination database at the Cornell University College of Veterinary Medicine. The serum biochemistry data and histopathologic findings were scored as normal, mild, moderate, and severe. All affected dogs had derangements of BUN, Cr, or Ca x Phos with gastric histopathology in 22 of 28 dogs (79%). Dogs with renal failure had a higher prevalence of gastric histopathologic changes compared with the control group. Associated histopathologic changes in the stomach were edema (P = .008), mineralization (P = .03), and vasculopathy (P = .03). Only 1 dog had evidence of gastric ulceration. Gastric necrosis was an uncommon finding (4/28, 14%). Gastric histopathology appears to be common in dogs with renal failure and is associated with increasing severity in the serum biochemistry data. Unlike humans with renal failure, in whom gastric ulceration predominates, gastric necrosis and ulceration appear to be uncommon in dogs with renal failure.

Sarcomatoid renal cell carcinoma in a binturong (Arctictis binturong).

An adult, female binturong (Arctictis binturong) was examined due to lethargy, inappetence, and an abdominal mass. Diagnostic investigations, including radiographs, abdominal ultrasound, clinical laboratory findings, and a fine-needle aspirate of the mass, were suggestive of a sarcoma with metastasis. Necropsy and histopathologic findings confirmed a widely disseminated sarcomatoid variant of a renal cell carcinoma, likely originating in the left kidney, with metastasis to the right kidney, spleen, pancreas, liver, mesenteric lymph nodes, and lungs. This is the first report of this neoplasm in a binturong and only the second report in the veterinary literature. Sarcomatoid renal cell carcinoma is a rare histologic variant of renal cell carcinoma that is aggressive, commonly metastatic, and associated with a very poor prognosis in humans. Accurate antemortem diagnosis of this tumor may be complicated by its biphasic morphology, which may resemble carcinoma or sarcoma (or both), often necessitating the use of immunohistochemical techniques.