Circadian Rhythmicity as a Predictor of Quality of Life in Allogeneic Hematopoietic Cell Transplant Patients

Context

Quality of life (QoL) is increasingly recognized as an important outcome of cancer treatment. Previous studies have examined clinical predictors of QoL, but with the increasing prevalence of wearable sensors that monitor sleep and activity patterns, further investigation into whether these behaviors are predictive of post-treatment QoL is now feasible. Among patients receiving aggressive cancer treatment such as hematopoietic cell transplantation (HCT), analysis of circadian rhythms (24-hour patterns of sleep and activity) via wearable sensors is limited.

The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

Cathepsin S is a lysosomal cysteine protease that has been shown to play a key role in MHC class II antigen presentation. Consequently, it has been extensively evaluated as a therapeutic target in autoimmune diseases, such as rheumatoid arthritis and psoriasis. Additionally, clinical and mechanistic evidence is emerging, revealing its inappropriate expression and secretion in a wide range of disease states including atherosclerosis and tumourigenesis. This review covers the known role and consequences of cathepsin S activity in these pathological disorders, highlighting various studies that have demonstrated its utility as a therapeutic target. This review also examines challenges that exist towards the development of agents that specifically target this protease and discusses the studies to date that have applied cathepsin S inhibitors in disease models.     

Lakota Elders’ Views on Traditional Versus Commercial/Addictive Tobacco Use; Oral History Depicting a Fundamental Distinction

This qualitative study is intended to elucidate Lakota elders’ views on traditional tobacco and commercial/addictive tobacco use, capturing the oral history that depict the cultural protocol regarding traditional tobacco, called Cansasa. Commercial tobacco use has significantly impacted the Northern Plains Indians. National surveillance systems report that tobacco use is more prevalent among American Indian/Alaska Natives than any other population, and is notably higher than the national average. Lung cancer among Native Americans is highest in the Northern Plains and Alaska, where smoking prevalence is also the highest, and smoking is responsible for nearly 90 % of all lung cancer cases. Yet, the use of traditional tobacco is largely ignored by surveillance and seems to have a distinct, positive role. Using a community-based participatory research approach, semi-structured interviews, and qualitative analysis tools, the research team, including 2 Lakota tribe elders, Lakota speaking tribal college students, and university faculty, sought to discern tribal elders’ distinctions between traditional and the addictive commercial tobacco. The team interviewed thirty Lakota elders, transcribed the interviews and field notes, and analyzed them using immersion/crystallization organizing framework. The research design engaged the Lakota tribal community in all stages, from planning to publication. Analysis revealed a clear distinction between traditional and commercial tobacco: tribal elders conveyed strong positive messages connected to traditional tobacco use (i.e., spirituality, respect, health and wellness, humility, and thoughtfulness) versus strong negative messages linked to addictive tobacco (i.e., crime, loss of control and self-esteem, lack of respect to self and others, sickness and death). These messages, along with stories in the Lakota language that were told and recorded during the interviews, can guide new ways to address addictive tobacco prevention in this community, to enhance cultural pride, and to serve as a cross-generation bridge regarding tobacco use.     

B19 parvovirus replicates in circulating cells of acutely infected patients

B19 parvovirus is the etiologic agent of fifth disease and transient aplastic crisis. In natural infections, B19 antigen and DNA have been detected in sera early in the course of aplastic crisis and only rarely in fifth disease. We have found B19 DNA in circulating cells of infected patients by DNA dot blot with a virus-specific probe: in four of four sickle cell patients with aplastic crisis, in one asymptomatic sibling, and in one normal adult with fifth disease. Only two of the sera showed B19 DNA. High-molecular weight intermediate forms were detected by Southern analysis of DNA extracted from cells, thus indicating active replication of virus in cells rather than passive adsorption to their surface membranes. Separation of cells into high- and low-density fractions resulted in a concentration of the virus DNA in the granulocytic fraction.     

Epidemiologic investigation of an outbreak of cutaneous leishmaniasis in a defined geographic focus of transmission.

An outbreak of cutaneous leishmaniasis occurred in a unit of 608 Puerto Rican national guardsmen conducting jungle warfare training in the Panama Canal Area in July 1984. An epidemiologic investigation of reported nonhealing, ulcerating skin lesions was conducted among 540 (89%) unit members in November and December 1984. Fifteen (88%) of 17 individuals with chronic, ulcerating skin lesions were confirmed as cases of cutaneous leishmaniasis by culture or histopathology. Twelve cases yielded positive Leishmania cultures, identified as L. braziliensis panamensis by cellulose acetate electrophoresis. Evaluation of different diagnostic techniques revealed that direct examination of tissues by Giemsa-stained histological examination was the most sensitive test (87% sensitivity), with an indirect immunofluorescent antibody test being rather insensitive (67%). All but one of the confirmed cases operated in small units that trained and slept overnight at a mortar firing site for a period of three days, yielding a site-specific attack rate of 22% (14 of 64). This contrasted with a much lower attack rate of 0.2% (1 of 476), experienced by unit members who trained at other locations during the same time frame (P less than 0.001). The median incubation period calculated from day of arrival at the mortar firing site was 17 days (range 2-78) for the 15 confirmed cases. Available personal protection methods, such as the use of insect repellents, were not appropriately implemented by unit personnel and thus, were not found to effectively protect against Leishmania infection. This is the largest reported outbreak of cutaneous leishmaniasis in military personnel associated with a single geographic focus of infection and contrasts with the usual sporadic disease experience in Panama.     

Ghrelin increases food intake in obese as well as lean subjects

OBJECTIVE: To investigate whether effects on food intake are seen in obese subjects receiving exogenous administration of ghrelin. DESIGN: Randomised, double-blind, placebo-controlled study of intravenous ghrelin at doses 1 pmol/kg/min and 5 pmol/kg/min. SUBJECTS: In all, 12 healthy lean subjects (mean body mass index (BMI) 20.5+/-0.17 kg/m(2)) and 12 healthy overweight and obese subjects (mean BMI 31.9+/-1.02 kg/m(2)). MEASUREMENTS: Food intake, appetite and palatability of food, ghrelin and other obesity-related hormones, growth hormone. RESULTS: Low-dose infusion of ghrelin increased ad libitum energy intake at a buffet meal in the obese group only (mean increase 36.6+/-9.4%, P<0.01.) High-dose ghrelin infusion increased energy intake in both groups (mean increase 20.1+/-10.6% in the lean and 70.1+/-15.5% in the obese, P<0.01 in both cases.) Ghrelin infusion increased palatability of food in the obese group. CONCLUSION: Ghrelin increases food intake in obese as well as lean subjects. Obese people are sensitive to the appetite-stimulating effects of ghrelin and inhibition of circulating ghrelin may be a useful therapeutic target in the treatment of obesity.     

A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.     

Eosinophil autofluorescence and its use in isolation and analysis of human eosinophils using flow microfluorometry

Unstained human eosinophils exhibit unusually bright autofluorescence, which allows them to be distinguished from other leukocytes using fluorescence microscopy. Eosinophil fluorescence is associated with the cytoplasmic granules of the cells. Eosinophil granule extracts, containing an as-yet-undefined eosinophil fluorescence factor, exhibited excitation maxima at 370 nm and 450 nm, with maximum emission at 520 nm. Eosinophils adhering to opsonized parasites in vitro deposit fluorescent material onto the parasite surface. Eosinophil fluorescence was of sufficient intensity to allow the preparation of viable, highly enriched (greater than or equal to 98%), eosinophil suspensions from peripheral blood of normal and eosinophilic donors using a fluorescence- activated cell sorter. Quantitative studies of eosinophil autofluorescence were performed using flow microfluorometry. Fluorescence intensity of blood eosinophils from normal volunteers and eosinophilic patients varied inversely with the log of the donor's absolute eosinophil count regardless of clinical diagnosis.     

Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition

Pediatric acute myelogenous leukemia (AML) has a poor prognosis, and novel therapies are needed. The FLT3 tyrosine kinase represents a promising target in pediatric AML. FLT3 is constitutively activated either by an internal tandem duplication (ITD) or by a point mutation (PM) in 17% to 24% of pediatric AML cases. Autocrine stimulation of wild-type (WT) FLT3 by coexpressed FLT3 ligand (FL) occurs in many other cases. FLT3/ITD mutations confer a particularly poor prognosis in pediatric AML patients. Inhibitors of FLT3 are being tested in adult AML patients, with promising preliminary results. In this study, cytotoxicity and apoptosis assays were performed on 44 diagnostic pediatric AML blast samples (14 FLT3/WT, 15 FLT3/ITD, 15 FLT3/PM) using CEP-701, a potent and selective FLT3 inhibitor. Pronounced cytotoxicity and induction of apoptosis were observed in a higher percentage of FLT3/ITD samples (93%) than FLT3/PM (27%) or FLT3/WT (29%). The cytotoxicity was greatest in samples with a high FLT3/ITD mutant-to-wild-type allelic ratio. The addition of FL enhanced the survival and augmented the sensitivity to FLT3 inhibition for the CEP-701-responsive subset of FLT3/WT and FLT3/PM samples. Clinical testing of FLT3 inhibitors as molecularly targeted agents for the improvement of outcome of pediatric AML patients is warranted.     

Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations

Successful allogeneic hematopoietic stem cell transplantation (HSCT) requires reconstitution of normal T-cell immunity. Recipient thymic activity, biologic features of the allograft, and preparative regimens all contribute to immune reconstitution. We evaluated circulating T-cell phenotypes and T-cell receptor rearrangement excision circles (TRECs) in 331 blood samples from 158 patients who had undergone allogeneic HSCTs. All patients had received myeloablative conditioning regimens and were full donor chimeras in remission. Younger patients exhibited more rapid recovery and higher TRECs (P =.02). Recipients of T-cell-depleted allografts initially had lower TRECs than unmodified allograft recipients (P <.01), but the difference abated beyond 9 months. TREC level disparities did not achieve significance among adults with respect to type of allograft. Measurable, albeit low, TREC values correlated strongly with severe opportunistic infections (P <.01). This finding was most notable during the first 6 months after transplantation, when patients are at greatest risk but before cytofluorography can detect circulating CD45RA(+) T cells. Low TRECs also correlated strongly with extensive chronic graft-versus-host disease (P <.01). Recipients of all ages of either unmodified or T-cell-depleted allografts therefore actively generate new T cells. This generation is most notable among adult recipients of T-cell-depleted allografts, most of whom had also received antithymocyte globulin for rejection prophylaxis. Low TREC values are significantly associated with morbidity and mortality after transplantation. T-cell neogenesis, appropriate to age but delayed in adult recipients of T-cell-depleted allografts, justifies interventions to hasten this process and to stimulate desirable cellular immune responses.