Protein Malnutrition and the Febrile Response in the Fischer Rat

We assessed the effect of protein deprivation on the ability of peritoneal macrophages from Fischer rats to produce interieukin‐1 (IL‐1) after in vitro stimulation. Pyrogenic activity of supernatants was measured by an in vivo febrile response assay. Control rats were given a 23% casein diet and protein‐malnourished rats were given an 8% casein diet for 4 weeks. IL‐1‐containing supernatants prepared from peritoneal macrophages were injected into assay rats, whose temperatures were measured for 6 hours (δT6). Rats injected with IL‐1‐containing supernatants derived from peritoneal macrophage cultures of protein‐deprived rats had significantly less fever (δT6 = 0.20 ± 0.09°) than rats injected with IL‐1 containing supernatants derived from peritoneal macrophage cultures of control rats (δT6 = 0.56 ± 0.09°), P < .01. Protein malnutrition leads to diminished pyrogenicity of macrophage culture supernatants and may be at least partly responsible for the decreased febrile response seen in the malnourished animals.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142038/1/jlb0036.pd

Fever of Unknown Origin in the Elderly: Lymphoma Presenting as Vertebral Compression Fractures

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111209/1/j.1532-5415.1994.tb06080.x.pd

Susceptibility of Yeast-Like Fungi to a New Antifungal Agent, LY 121019

LY 121019, a new antifungal antibiotic agent, was tested for activity against 200 clinical isolates of Candida and other yeast-like fungi. LY 121019 had its greatest inhibitory effect on C. albicans , and C. tropicalis. C. glabrata and most other Candida species were not as sensitive. Cryptococcus and other yeast-like fungi, with the exception of a few strains, were not susceptible to LY 121019. Zusammenfassung :  LY 121019, ein neues Antimyzetikum, wurde auf seine AktivitÄt gegen 200 klinische Isolate von Candida und anderen, hefeÄhnlichen Pilzen untersucht. LY 121019 hat seine grÖßte Hemmwirkung gegen C. albicans und C. tropicalis. C. glabrata und die meisten anderen Candida -Arten waren nicht so empfindlich. Cryptococcus und andere, hefeÄhnliche Pilze waren, mit Ausnahme weniger StÄmme, nicht fÜr LY 121019 empfindlich.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73892/1/j.1439-0507.1988.tb04426.x.pd

Monokine Secretion in Aging and Protein Malnutrition

Aged and protein‐malnourished hosta have diminished febrile responses and increased morbidity and mortality from infection that could be due to deficiencies in the production of certain monokines. In this study, the ability of peritoneal macrophages from aged and protein‐malnourished rats to produce IL‐1 and TNF was explored. Aged rats fed a standard diet produced less IL‐1 and TNF, as measured by the thymocyte proliferation and L929 cytotoxicity assays, than young and middle‐aged rats. Monokine production was not diminished by protein malnutrition in any age group. No synergistic decline in IL‐1 or TNF production was seen with increasing age in malnourished rats. Diminished IL‐1 and TNF production may partially explain the severity of infection seen in the elderly patient, but not the malnourished host. The role of other cytokines such as IL‐6 and cytokine inhibitors in aging and malnutrition should be explored.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141681/1/jlb0510.pd

Opportunistic Infections in Patients with Temporal Arteritis Treated with Corticosteroids

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111238/1/j.1532-5415.1997.tb00949.x.pd

Introduction of a Waterless Alcohol-based Hand Rub in a Long-term Care Facility

OBJECTIVE: To examine the impact of introduction of an alcohol-based hand rub on hand hygiene knowledge and compliance and hand colonization of healthcare workers (HCWs) in a long-term-care facility (LTCF). METHODS: Two floors of an LTCF participated. Ward A used the hand rub as an adjunct to soap and water; ward B was the control. HCWs\u27 hands were cultured using the bag-broth technique for Staphylococcus aureus, gram-negative bacilli (GNB), Candida, and vancomycin-resistant enterococci (VRE). HCWs completed a questionnaire at baseline and after an educational intervention and introduction of rub. RESULTS: Hand hygiene practices, knowledge, and opinions did not change after the educational or rub intervention. Ward A HCWs thought that the rub was faster (P = .002) and less drying (P = .04) than soap. Hand hygiene frequency did not differ at baseline between the two floors, but increased on ward A by the end of the study (P = .04). HCWs were colonized frequently with GNB (66%), Candida (41%), S. aureus (20%), and VRE (9%). Although colonization did not change from baseline on either ward, the rub was more effective in clearing GNB P =.03) and S. aureus (P = .003). Nosocomial infection rates did not change. CONCLUSION: The alcohol-based hand rub was a faster, more convenient, less drying method of hand hygiene for HCWs in an LTCF, and it improved compliance. Although microbial colonization did not change, the rub was more efficacious in removing pathogens already present on the hands of HCWs

Hepatosplenic candidiasis: Successful treatment with fluconazole

To determine if fluconazole is effective treatment for hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine treatment. Six patients (ages 3 to 44) with acute leukemia and hepatosplenic candidiasis who did not respond to prior antifungal therapy were treated with fluconazole. All six patients had fever and three had nausea and vomiting, computed tomographic (CT) scan showed lucencies in the liver in six, lucencies in the spleen in five, and lucencies in the kidneys in three. Prior therapy with 1.6 to 4 g of amphotericin B in the five adults and 526 mg of amphotericin B in the child (with the addition of flucytosine in four) failed to improve clinical symptoms or lucencies in the liver, spleen, and kidneys seen on CT scan. Fluconazole was given at a dose of 200 to 400 mg daily (70 to 100 mg in the child) for 2 to 14 months. All patients had resolution of fever and other symptoms in 2 to 8 weeks. Improvement of the lesions noted on CT scan was seen in 4 to 8 weeks in all patients. Total resolution of lesions noted on CT scan occurred by 4 weeks in two patients, but took 4 to 5 months for three patients and 13 months for one patient. Three patients had relapse of their acute leukemia and two died, presumably cured of their candidiasis. Two patients underwent successful bone marrow transplantation without relapse of their candidiasis. Fluconazole appears to be useful in the treatment of hepatosplenic candidiasis that has not resolved with amphotericin B and flucytosine therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29188/1/0000241.pd

Human and Non-Human Primate Intestinal FcRn Expression and Immunoglobulin G Transcytosis

PURPOSE: To evaluate transcytosis of immunoglobulin G (IgG) by the neonatal Fc receptor (FcRn) in adult primate intestine to determine whether this is a means for oral delivery of monoclonal antibodies (mAbs). METHODS: Relative regional expression of FcRn and localization in human intestinal mucosa by RT-PCR, ELISA & immunohistochemistry. Transcytosis of full-length mAbs (sandwich ELISA-based detection) across human intestinal segments mounted in Ussing-type chambers, human intestinal (caco-2) cell monolayers grown in transwells, and serum levels after regional intestinal delivery in isoflurane-anesthetized cynomolgus monkeys. RESULTS: In human intestine, there was an increasing proximal-distal gradient of mucosal FcRn mRNA and protein expression. In cynomolgus, serum mAb levels were greater after ileum-proximal colon infusion than after administration to stomach or proximal small intestine (1–5 mg/kg). Serum levels of wild-type mAb dosed into ileum/proximal colon (2 mg/kg) were 124 ± 104 ng/ml (n = 3) compared to 48 ± 48 ng/ml (n = 2) after a non-FcRn binding variant. In vitro, mAb transcytosis in polarized caco-2 cell monolayers and was not enhanced by increased apical cell surface IgG binding to FcRn. An unexpected finding in primate small intestine, was intense FcRn expression in enteroendocrine cells (chromagranin A, GLP-1 and GLP-2 containing). CONCLUSIONS: In adult primates, FcRn is expressed more highly in distal intestinal epithelial cells. However, mAb delivery to that region results in low serum levels, in part because apical surface FcRn binding does not influence mAb transcytosis. High FcRn expression in enteroendocrine cells could provide a novel means to target mAbs for metabolic diseases after systemic administration

Epidemiology of oral candidiasis in HIV-infected patients: Colonization, infection, treatment, and emergence of fluconazole resistance

: To study the epidemiology of oral candidiasis and the effect of treatment of thrush in human immunodeficiency virus (HIV)-infected patients.: We conducted a prospective observational study of 92 patients over 1 year, including a nonblinded, randomized treatment trial of thrush with clotrimazole troches or oral fluconazole. Oral sites were cultured monthly and when thrush occurred. Candida albicans strains were typed by contour-clamped homogeneous electric field (CHEF) electrophoresis. Changes in strains were evaluated over time and in regard to their associations with particular sites, episodes of thrush, relapse after treatment, and colonization of sexual partners. Susceptibility to fluconazole was tested and CHEF analysis was done on these strains to determine the epidemiology of fluconazole resistance.: Yeasts colonized 84% of patients. C albicans accounted for 81% of all isolates and was separated into 34 distinct strains. Most patients had persistent carriage of 1 or 2 dominant strains of C albicans. Three couples shared strains. Nineteen different C albicans strains caused 82 episodes of thrush in 45 patients. CD4 Torulopsis glabrata and Saccharomyces cerevisiae increased after treatment with either drug, but these organisms were never a sole cause of thrush. In a subset of 35 patients followed for over 3 months in whom fluconazole susceptiblities were performed, minimum inhibitory concentrations (MICs) to fluconazole increased only in those on fluconazole prophylaxis. Clinical failure of fluconazole was associated with an MIC &gt;= 64 [mu]g/mL in 3 patients, and with an MIC of 8 [mu]g/mL in 1 patient. In 2 of these 4 patients, the prior colonizing strain developed fluconazole resistance. In the other 2, new resistant strains were acquired.: Many different strains of C albicans colonize and cause thrush in patients infected with HIV. Patients are usually persistently colonized with a single strain, and recurrences following treatment are usually due to the same strain. Transmission of strains may occur between couples. Fluconazole and clotrimazole are equally effective in treating thrush, but mycologic cure occurs more often with fluconazole.Fluconazole resistance in C albicans occurs most often in patients who have low CD4 counts and are taking fluconazole prophylactically for recurrent thrush. Fluconazole resistance may occur through acquisition of a new resistant strain or by development of resistance in a previously susceptible strain.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31920/1/0000873.pd

Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation

Neurons that produce gonadotropin-releasing hormone (GnRH) are the final common pathway by which the brain regulates reproduction. GnRH neurons are regulated by an afferent network of kisspeptin-producing neurons. Kisspeptin binds to its cognate receptor on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion—thus gating down-stream events supporting reproduction. We have developed kisspeptin antagonists to facilitate the direct determination of the role of kisspeptin neurons in the neuroendocrine regulation of reproduction. In vitro and in vivo studies of analogues of kisspeptin-10 with amino substitutions have identified several potent and specific antagonists. A selected antagonist was shown to inhibit the firing of GnRH neurons in the brain of the mouse and to reduce pulsatile GnRH secretion in female pubertal monkeys; the later supporting a key role of kisspeptin in puberty onset. This analogue also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the post-castration rise in LH in sheep, rats and mice, suggesting that kisspeptin neurons mediate the negative feedback effect of sex steroids on gonadotropin secretion in mammals. The development of kisspeptin antagonists provides a valuable tool for investigating the physiological and pathophysiological roles of kisspeptin in the regulation of reproduction and could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer