Acute changes in whole body corticosterone in response to perceived predation risk: A mechanism for anti-predator behavior in anurans?

Anuran larvae exhibit behavioral and morphological plasticity in response to perceived predation risk, although response type and magnitude varies through ontogeny. Increased baseline corticosterone is related to morphological response to predation risk, whereas the mechanism behind behavioral plasticity remains enigmatic. Since tadpoles alter behavioral responses to risk immediately upon exposure to predator cues, we characterized changes in whole body corticosterone at an acute (<1h post-exposure) timescale. Tadpoles (Lithobates sylvaticus) at Gosner stage (GS) 25 (free-swimming, feeding larvae) increased corticosterone levels to a peak at 10-20min post-exposure to predator cues, paralleling the acute stress response observed among other taxa. Tadpoles reared for 3weeks (mean GS29) with predation risk (caged, fed Aeshnid dragonfly nymph) had lower corticosterone levels at 10-20min post-exposure to dragonfly cues than predator-naïve controls, suggesting habituation, although the magnitude of increase was markedly diminished when compared to younger tadpoles (GS25). These experiments represent the first assessment of tadpole hormonal responses to predation risk at the acute timescale. Further research is required to establish causality between hormonal responses and behavioral changes, and to examine how and why responsiveness changes over ontogeny and with chronic exposure to risk.

CARM1 automethylation is controlled at the level of alternative splicing.

Co-activator-associated arginine methyltransferase 1 (CARM1) is subjected to multiple post-translational modifications. Our previous finding that automethylation of CARM1 is essential for regulation of transcription and pre-mRNA splicing prompted us to investigate how automethylation is regulated. Here, we report that automethylation is regulated by alternative splicing of CARM1 mRNA to remove exon 15, containing the automethylation site. Specifically, we find that two major alternative transcripts encoding full-length CARM1 (CARM1FL) and CARM1 with exon 15 deleted (CARM1ΔE15) exist in cells, and each transcript produces the expected protein. Further biochemical characterizations of the automethylation-defective mutant and CARM1ΔE15 reveal overlapping yet different properties. Interestingly, other arginine methylation substrates also have missing exons encompassing the site(s) of methylation, suggesting that protein arginine methylation level may, in general, be controlled by the alternative splicing mechanism. Finally, we observed differential distribution of CARM1FL and CARM1ΔE15 in epithelial and stromal cells in normal mouse mammary gland. Thus, alternative splicing not only serves as the determinant for CARM1 automethylation but also generates cell type-specific isoforms that might regulate normal ERα biology in the mammary gland.

Effects of opioids on reproduction in Japanese medaka, Oryzias latipes.

To study the effects of exposure of fish to opioid drugs, we exposed Japanese medaka (Oryzias latipes) over a full life cycle to codeine spiked into river water at nominal concentrations of 100, 1,000 and 25,000 ng/L and to fentanyl spiked into river water at nominal concentrations of 5, 25 and 1,000 ng/L. The measured concentrations during medaka exposures were consistent with the nominal concentrations. Treatments with codeine at all test concentrations reduced the number of eggs produced by female medaka, as well as the number of mature oocytes observed histologically in the ovaries. Exposures to codeine also resulted in altered concentrations of hormones within the hypothalamic-pituitary-gonadal axis, including reduced levels of 17ß-estradiol in female medaka. Fentanyl did not affect reproduction or the levels of hormones in medaka at the concentrations tested. Monitoring of surface waters in southern Ontario, Canada downstream of wastewater treatment plants showed that the test concentrations of fentanyl and codeine were environmentally relevant. The results of this work contribute to the literature on the impacts of opioids and other drugs of abuse released into surface waters.

Musculoskeletal manifestations in liver transplantation recipients.

BACKGROUND: The prevalence and type of musculoskeletal problems among liver transplant recipients have not been well characterized in the current literature. OBJECTIVE: We conducted a retrospective analysis of both outpatients and inpatients (total 234) who underwent liver transplantation or had rheumatologic consultation during 2002-2004, to document the cause for their rheumatologic symptoms. We hypothesized that infection, crystal diseases, and corticosteroid complications would be more common in this cohort of immunosuppressed patients as compared with de novo connective tissue disease. RESULTS: Among the outpatients, we found that arthralgia presumably secondary to tacrolimus/sirolimus; osteoarthritis, peripheral neuropathy, and myalgia were the most common diagnoses. The only autoimmune disease documented was Hepatitis C Virus-associated cryoglobulinemic vasculitis. Hyperuricemia was also prevalent in this patient population. Infection and gout were seen frequently among the inpatients. CONCLUSIONS: It is important for physicians to be cognizant of the variety and prevalence of musculoskeletal disorders in the liver transplantation patient population.

Effect of imidacloprid on the survival of Xenopus tadpoles challenged with wild type frog virus 3.

The sensitivity of amphibians to Ranavirus may be increased by exposure to other environmental stressors, including chemical contaminants. Neonicotinoid insecticides comprise 27% of the global insecticide market and have been detected in wetlands and other aquatic habitats. The present study focused on the effects of exposure of pre-metamorphic Xenopus laevis to the neonicotinoid, imidacloprid (IMI) on sensitivity to frog virus 3 (FV3) infection. It was hypothesized that exposure of tadpoles to IMI at sublethal concentrations of 1 and 500µgL-1 would increase FV3 related mortalities relative to tadpole mortalities in a control treatment with only the virus. However, contrary to the predicted outcome, IMI reduced the rates of mortality following viral challenge, although the total mortalities by the 25th day after infection did not differ among the treatments. These results should not be interpreted as an indication that neonicotinoid insecticides are beneficial to aquatic ecosystems, since these insecticides cause toxic responses at low concentrations to other non-target aquatic organisms.

Immune Myopathy With Perimysial Pathology Associated With Interstitial Lung Disease and Anti-EJ Antibodies.

OBJECTIVES: We report a case of immune myopathy with perimysial pathology associated with anti-glycyl-transfer RNA synthetase (anti-EJ) antibody and an excellent treatment response. METHODS: Chart review. RESULTS: A 36-year-old woman presented with 3 months of fatigue, weight loss, progressive weakness in a scapuloperoneal distribution, and dysphagia. Nerve conduction studies, electromyography, and ultrasound suggested an irritable myopathy. She had marked elevations of creatine kinase and positive anti-glycyl-transfer RNA synthetase (anti-EJ) antibodies. A left biceps muscle biopsy revealed inflammation of the perimysium and surrounding perimysial blood vessels with focal fragmentation of the perimysium. Further evaluation revealed interstitial lung disease. Treatment with prednisone and mycophenolate mofetil led to marked clinical improvement of her symptoms. CONCLUSIONS: Our case adds to the growing spectrum of inflammatory myopathies and highlights the importance of performing a comprehensive, multisystem workup.

Temporal factors alter effects of social housing conditions on responses to chemotherapy and hormone levels in a Shionogi mammary tumor model.

OBJECTIVE: To identify possible hormonal factors involved in the differential responses to chemotherapy observed in our tumor model, we investigated if the timing among tumor cell injection, rehousing, and chemotherapy administration differentially affects levels of corticosterone (CORT), growth hormone (GH), and testosterone and tumor and host responses to chemotherapy. METHODS: Mice were reared either individually (I) or in groups (G). At 2 to 4 months, mice were injected with tumor cells and retained in their original housing conditions or rehoused into different experimental groups (GG, IG, II, GI) either immediately (experiment 1) or 14 days later (experiment 2); chemotherapy was administered when tumors weighed approximately 0.8 g. RESULTS: In experiment 1, IG and GG mice had better responses to chemotherapy than GI mice. Chemotherapy increased CORT levels in II mice and decreased GH levels in GI mice compared with those of their drug vehicle-treated counterparts. Under the temporal conditions of experiment 2, IG and GG mice lost the advantage seen in experiment 1 in terms of tumor and host responses to chemotherapy. Before chemotherapy administration, CORT levels in IG mice and GH levels in GI mice were higher than those in mice in all other housing conditions. At 1 day after chemotherapy, CORT levels were higher for chemotherapy-treated than for drug vehicle-treated IG mice, and at 5 days post chemotherapy, GH levels were higher in GI than in IG mice. CONCLUSIONS: Temporal relationships among tumor cell injection, rehousing, and chemotherapy administration critically influence responses to chemotherapy; these effects may be mediated, in part, by alterations in hormone levels.

The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice.

There is evidence that standard-dose chemotherapy may impact cognitive function in cancer patients. The present study evaluated the effects of a combination of two anti-cancer drugs, methotrexate (37.5 mg/kg) and 5-fluorouracil (5FU, 75 mg/kg) on cognitive function in a mouse model. Drug-induced deficits were observed in adult BALB/C mice on tests of spatial memory, non-matching-to-sample (NMTS) learning and in a delayed-NMTS test of non-spatial memory. There were no group differences on tests of cued memory or discrimination learning. Performance-related variables were ruled out as possible explanations of the observed impairments. The impaired performance of the drug group, which was consistent with cognitive deficits observed in human cancer patients treated with similar types of chemotherapy, was attributed to functional changes in specific brain regions, including the frontal lobes and hippocampus.

Rituximab Not Effective for Hearing Loss in Cogan's Syndrome.

Importance. Rituximab was not effective in ameliorating the hearing loss in a patient with atypical Cogan's syndrome. Observations. We report the case of a patient who developed acute bilateral uveitis and sensorineural hearing loss. A diagnosis of atypical Cogan's syndrome was made. The patient's hearing loss did not improve despite high dose steroids and azathioprine. Rituximab was administered given a recent report of its efficacy in a patient with refractory disease; however, our patient's hearing loss did not improve. Conclusion. Hearing loss in Cogan's syndrome is difficult to treat. Though rituximab was ineffective in our case, earlier administration in the disease course could be effective for future patients.

Fellow use of medical jargon correlates inversely with patient and observer perceptions of professionalism: results of a rheumatology OSCE (ROSCE) using challenging patient scenarios.

The NYC Rheumatology Objective Structured Clinical Examination (NYC-ROSCE) is held annually to assess fellow competencies. We recently redesigned our OSCE to better assess subspecialty trainee communication skills and professionalism by developing scenarios in which the patients encountered were psychosocially or medically complex. The objective of this study is to identify which types of verbal and non-verbal skills are most important in the perception of professionalism in the patient-physician interaction. The 2012-2013 NYC-ROSCEs included a total of 53 fellows: 55 MD evaluators from 7 NYC rheumatology training programs (Hospital for Special Surgery-Weill Cornell (HSS), SUNY/Downstate, NYU, Einstein, Columbia, Mount Sinai, and North Shore/Long Island Jewish (NSLIJ)), and 55 professional actors/standardized patients participated in 5 stations. Quantitative fellow performance assessments were made on the following: maintaining composure; partnering with the patient; honesty; professionalism; empathy; and accountability. Free-text comments were solicited regarding specific strengths and weaknesses. A total of 53/53 eligible (100 %) fellows were evaluated. MD evaluators rated fellows lower for professionalism than did the standardized patients (6.8 ± 0.6 vs. 7.4 ± 0.8, p = 0.05), suggesting that physicians and patients view professionalism somewhat differently. Fellow self-evaluations for professionalism (6.6 ± 1.2) were concordant with those of the MD evaluators. Ratings of empathy by fellows themselves (6.6 ± 1.0), MD evaluators (6.6 ± 0.7), and standardized patients (6.6 ± 1.1) agreed closely. Jargon use, frequently cited by evaluators, showed a moderate association with lower professionalism ratings by both MD evaluators and patients. Psychosocially challenging patient encounters in the NYC-ROSCE permitted critical assessment of the patient-centered traits contributing to impressions of professionalism and indicate that limiting medical jargon is an important component of the competency of professionalism.

Acute Myopericarditis Likely Secondary to Disseminated Gonococcal Infection.

Disseminated gonococcal infection (DGI) is a rare complication of primary infection with Neisseria gonorrhoeae. Cardiac involvement in this condition is rare, and is usually limited to endocarditis. However, there are a number of older reports suggestive of direct myocardial involvement. We report a case of a 38-year-old male with HIV who presented with chest pain, pharyngitis, tenosynovitis, and purpuric skin lesions. Transthoracic echocardiogram showed acute biventricular dysfunction. Skin biopsy showed diplococci consistent with disseminated gonococcal infection, and treatment with ceftriaxone improved his symptoms and ejection fraction. Though gonococcal infection was never proven with culture or nucleic acid amplification testing, the clinical picture and histologic findings were highly suggestive of DGI. Clinicians should consider disseminated gonococcal infection when a patient presents with acute myocarditis, especially if there are concurrent skin and joint lesions.

Mycobacterium kansasii causing chronic monoarticular synovitis in a patient with HIV/AIDS.

Mycobacterium kansasii is a nontuberculous mycobacterium that primarily causes pulmonary disease in AIDS patients, however it has also been known, rarely, to result in skeletal infection. When skeletal infection occurs, the time from onset of symptoms to diagnosis is up to 5 years in previously reported cases. We describe a 48-year-old woman with HIV/AIDS who presented with chronic, isolated left knee pain and swelling of over two decades which had recently worsened. Radiographs and magnetic resonance imaging demonstrated marked subarticular erosions, synovial thickening, and bone marrow edema, which had progressed compared with prior imaging done seven years earlier. Synovial biopsy grew Mycobacterium kansasii. Following the presentation of our case, clinical and imaging findings, including the differential diagnosis, of monoarticular arthritis caused by Mycobacterium kansasii are reviewed and discussed.

Do estrogens always increase breast cancer risk?

The etiology of breast cancer is closely linked to the female hormone estrogen, with high life-time exposure being suggested to increase breast cancer risk [Nature 303 (1983) 767]. However, there appears to be a disparity between studies attempting to establish an association between high estrogen levels and breast cancer risk. This disparity becomes smaller by taking into consideration a timing factor, and we propose that estrogens can increase, decrease, or have no effect on breast cancer risk, depending on the timing of estrogen exposure. We further propose that the timing of estrogenic exposures may play at least as important a role in affecting breast cancer risk as life-time exposure.

Inflammatory arthritis in the elderly.

The three most common inflammatory arthritic conditions affecting the elderly are reviewed, along with current information about the various treatments.

Inflammatory arthropathy: a review of rheumatoid arthritis in older patients.

Rheumatoid arthritis (RA) is the most common inflammatory synovitis in older adults. The primary care physician may see its presentatiion as the late stage of a long-term disorder, or alternatively as an elderly-onset disease. These two presentations of RA may differ significantly with respect to mode of onset, prevalence of associated systemic symptoms (eg, fatigue, weight loss, depression), criteria for diagnosis (eg, rheumatoid factor or rheumatoid nodules), progression of diseases and functional outcomes. Because RA is responsive to treatmentt, and new treatments are available, diagnosis of this disorder is imperative. Differential diagnostic possibilities and therapies are reviewed, with particular emphasis on the cause and effect of comorbid disease such as infection, osteoporosis, and cardiovascular disease.

Rheumatologists on the road: a subspecialist's role in caring for the homebound.

OBJECTIVE: By 2030, the number of permanently homebound individuals in the US will increase by 50% to reach 2 million. However, no medicine subspecialty consult services exist for this rising subset of the population. This pilot program establishes a rheumatology consult service for the Mount Sinai Visiting Doctors, the largest primary care academic home visit program in the nation serving more than 1,000 patients in New York City. Our service addresses the unmet need for homebound patients with rheumatic diseases, and secondarily provides an educational opportunity for trainees in community-based rheumatology. METHODS: Using an electronic medical record, home-based primary care physicians sent consult requests to the Rheumatology Division. Initial assessments were made using the Routine Assessment of Patient Index Data 3 (RAPID3) questionnaire. RESULTS: Over 12 months, 57 home visits were made: 31 new consults and 26 followup visits. Reasons for referral included medical management of a known connective tissue disease, question of inflammatory arthritis, and procedures. The demographics for new consults were as follows: 94% women, 45% Hispanic, and 80% between ages 60 and 101 years. Thirty-nine percent of patients had rheumatoid arthritis. Treatment interventions included addition of a disease-modifying antirheumatic drug in 11 patients, 11 procedures, nonpharmacologic management in 8 patients, and a change in the dose of the existing medication in 5 patients. At the initial evaluation, the average RAPID3 scores for patients reflected high severity of disease. CONCLUSION: The number of consults and the severity of disease seen highlight the importance of a rheumatologist's role in the community, especially because the number of homebound patients will dramatically increase in the future.

Neonatal experiences differentially influence mammary gland morphology, estrogen receptor {α} protein levels, and carcinogenesis in BALB/c mice.

Prevention of breast cancer can be achieved with a better understanding of the factors contributing to normal breast development. Because the breast develops postnatally, alterations in the development and lifetime activity of the neuroendocrine system may set up an environment that increases cancer risk. The present study examined how two neonatal experiences over the first 3 weeks of life influence normal and malignant mammary gland development in female BALB/c mice. Following puberty, both brief (15 minutes) and prolonged (4 hours) daily maternal separations of newborn mice accelerated mammary gland development relative to nonseparated mice. Despite similar mammary gland morphologies between mice exposed to these two neonatal separation experiences, only mice exposed to prolonged maternal separation bouts showed a higher incidence and faster onset of mammary tumorigenesis following adulthood carcinogen [7,12-dimethylbenz(a)anthracene] administration. Molecular analysis of estrogen receptor α (ERα) and p53, two proteins that have been implicated in breast cancer, revealed that for mice exposed to prolonged neonatal maternal separation bouts, mammary gland ERα protein levels were upregulated in a transcription-independent manner. On the other hand, p53 expression in mammary glands of adult mice was not differentially influenced by neonatal experiences. Our findings show that chronic, moderate psychosocial stress during the neonatal period increases the expression of ERα protein and promotes mammary tumorigenesis in adulthood.

Opportunistic infections mimicking gastrointestinal vasculitis in systemic lupus erythematosus.

Patients with systemic lupus erythematosus who are on chronic immunosuppressive therapy are at risk for developing infectious complications. We present 2 cases of immunosuppressed patients with systemic lupus erythematosus who presented with abdominal complaints without other systemic lupus symptoms. These patients were initially thought to have gastrointestinal vasculitis based on preliminary pathologic reports; however, further workup and careful review of the pathologic specimens confirmed an opportunistic infection as the etiology in each case. It is critical that physicians maintain a high index of suspicion for infection when treating immunocompromised patients with systemic lupus erythematosus with abdominal complaints to avoid delay in appropriate treatment.

Refractory pulmonary hypertension in a lupus patient with occult pulmonary vasculitis.

Primary pulmonary hypertension is a disease that has become increasingly recognized in lupus patients. Pathologic findings from lupus patients usually do not differ from those who have idiopathic pulmonary hypertension. In recent years, intravenous vasodilator therapy has improved morbidity and mortality in patients with primary pulmonary hypertension. In this case report, we describe a young woman with severe pulmonary hypertension refractory to aggressive parenteral vasodilator treatment. Steroid treatment was initiated after a tentative diagnosis of lupus was made on the basis of the presence of Raynaud's phenomenon, proteinuria, pericarditis with tamponade, and a positive anti-Ro antibody. Despite treatment with vasodilators and steroids, the patient's condition rapidly deteriorated and she died. Unexpectedly, active pulmonary arteritis was demonstrated at autopsy. This case suggests that immunosuppressive therapy should be considered in lupus patients with severe pulmonary hypertension who are refractory to aggressive vasodilator therapy and high-dose parenteral steroids.