Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

Interleukin-2 augmentation of interleukin-1 and prostaglandin E2 production.

Some of the major side effects of interleukin-2 (IL-2) therapy in the treatment of malignancies may be related to increased interleukin-1 (IL-1) and/or prostaglandin E2 (PGE2) production. We examined the effect of recombinant (rIL-2) on the in vitro production of IL-1 beta and PGE2 by unstimulated and LPS-activated human blood mononuclear cells (PBMC). We also compared the effect of rIL-2 on IL-1 beta production by adherent and nonadherent blood mononuclear cell populations. Cultures of PBMC (5 x 10(6)/ml) were incubated for 24 hr in media only (control, 1,000 U/ml rIL-2, 2 micrograms/ml LPS, or both LPS and rIL-2. Supernatants obtained from these cultures were analyzed for levels of IL-1 beta and PGE2 by radioimmunoassays. The addition of rIL-2 caused an increase in IL-1 beta production in 13 of 13 control PBMC cultures and in 11 of 13 LPS-stimulated cultures, which were significant increases as determined by paired t tests. When PBMC were fractionated into plastic adherent and nonadherent populations, the rIL-2 induced increases in IL-1 beta production were more consistent in control (six of seven cases) and LPS (seven of seven cases) cultures of plastic nonadherent cells than in control (three of seven cases) and LPS (four of seven cases) cultures of plastic adherent cells. Recombinant IL-2 did not increase PGE2 production in control PBMC cultures (none of four cases), but did so in LPS-stimulated PBMC cultures (three of four cases]. These results suggest that rIL-2 may increase IL-1 production in vivo and thus possibly account for some of the side effects of this therapy.

T helper/inducer (CD4+) cells prestimulated with PPD induce monocytes to produce interleukin-1 beta.

We obtained peripheral blood mononuclear cells (PBMC) from four healthy, tuberculin purified protein derivative (PPD) reactive donors and cultured these cells in media containing PPD (low dose = 200 ng/ml or high dose = 1 micrograms/ml). Five days after the addition of PPD, T cells were isolated, washed, and added to autologous adherent cell cultures at a 1:1 ratio. Adherent cells were then cultured for 24 h in media only (baseline), media plus lipopolysaccharide (LPS, 2 micrograms/ml; positive control), or media containing the prestimulated T cells. After 24 h, supernatants were harvested and interleukin 1 beta (IL-beta) levels were assayed by radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). The results show that T cells prestimulated with low dose PPD (200 micrograms/ml) did not induce IL-1 production by adherent cells (mean increase over baseline 0.2 +/- 1.3 standard deviation [SD] ng/ml, P = 0.61). However, T cells prestimulated with high dose PPD (1 microgram/ml) did induce adherent cells to secrete IL-1 beta (mean increase over baseline 1.7 +/- 0.62 [SD] ng/ml, P = 0.01), but this induction was abolished when cell-to-cell contact was prevented by use of double well chambers (mean increase over baseline 0.1 +/- 0.36 [SD] ng/ml, P = 0.69). Prestimulated T helper (CD4+) cells were able to induce monocytes to secrete IL-1 beta but prestimulated CD8+ T cells were not. These data suggest that when T helper (CD4+) cells are sufficiently activated they acquire the ability to induce monocytes to secrete IL-1 beta. Cell-to-cell contact between monocytes and T cells is required. This function of activated T cells may be important in the normal cellular immune response.

Golden Syrian hamsters: a new experimental model for adrenal compensatory hypertrophy.

We report that adrenal compensatory hypertrophy occurs in the golden syrian hamster, an animal secreting cortisol as the primary adrenal glucocorticoid. This response is seen at 3, 6, 10, and 21 days after unilateral adrenalectomy. The response is present in hypophysectomized hamsters and when endogenous ACTH secretion is suppressed by administration of dexamethasone by im injection or by dexamethasone and ACTH using the Alzet osmotic pump. Administration of either aldosterone alone or in combination with dexamethasone and ACTH by Alzet pump completely blocks adrenal compensatory hypertrophy after unilateral adrenalectomy.

Value of Mycobacterium tuberculosis fingerprinting as a tool in a rural state surveillance program.

OBJECTIVE: This study demonstrates the value of Mycobacterium tuberculosis fingerprinting used in conjunction with traditional epidemiologic methods to identify smoldering outbreaks of tuberculosis in endemic areas where background rates of tuberculosis are high. METHODS: IS6110 DNA fingerprinting was performed on isolates of M tuberculosis from verified cases of tuberculosis in Alabama from 1994 to 1998. A statewide database groups isolates into "clusters" and tracks them cumulatively over time. A large cluster was identified and was secondarily investigated using traditional epidemiologic methods. RESULTS: Twenty-five isolates were found to be identical by fingerprinting analysis. Patients were living within 10 counties across the state, and 12 cases were localized to a single county. This represented an ongoing, statewide tuberculosis outbreak previously unrecognized by local and state health officials. Secondary investigation of the cases revealed the primary sites of transmission to be a correctional facility and two homeless shelters. CONCLUSIONS: Population surveillance using M tuberculosis fingerprinting was successfully utilized to detect a significant and smoldering tuberculosis outbreak. Measures are currently in place to identify and prevent further transmission in the involved locations.

Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients.

BACKGROUND: Despite the use of directly observed therapy (DOT) by tuberculosis control programs, patient treatment failure, relapse, and acquired drug resistance remain problematic in a small number. We investigated serum drug levels in non-HIV-infected tuberculosis patients who were receiving DOT by the health department and did not respond to treatment as expected. METHODS: The indications for checking levels were as follows: (1) slow clinical response or failure to convert the sputum culture within 12 weeks; (2) treatment failure, early disease relapse < 13 months since being declared cured; (3) relapse, late disease reactivation > or = 13 months since being declared cured; and (4) acquired drug resistance while receiving DOT. Baseline characteristics of control subjects who responded to therapy as expected were compared. Venous blood for analysis was obtained at 2 h after directly observed ingestion and measured by high-performance liquid chromatography. RESULTS: Twenty-four patients receiving daily or twice-weekly standard therapy with isoniazid (INH, 300 or 900 mg) and rifampin (RMP, 600 mg) were identified; 22 had drug levels evaluated at 2 h. For INH, 15 of 22 patients (68%) had levels less than the reported target range. For RMP, 14 of 22 patients (64%) had low levels. Among the 14 patients receiving INH, 900 mg, and RMP, 600 mg, 4 (29%) had very low levels of both. Use of a combination INH/RMP tablet was associated with lower INH levels (p=0.04); however, RMP levels were higher (p<0.02). Alcohol use was associated with significantly higher RMP (p<0.01) serum concentrations. CONCLUSIONS: Important questions remain concerning the utility and timing of serum drug measurements. However, if a patient is not responding to therapy as expected and one is assured that the Mycobacterium tuberculosis organism is susceptible to the drugs given and that the patient is taking the medication as prescribed, drug level monitoring should be considered.

Childhood tuberculosis in Alabama: epidemiology of disease and indicators of program effectiveness, 1983 to 1993.

An 11-year review of childhood tuberculosis in Alabama was made in order to define indicators of program effectiveness in interrupting community transmission. Minority (nonwhite) children, 96% of whom were black, had the highest risk of disease (odds ratio, 5.5; 95% confidence interval, 3.9, 7.7). Of 171 cases, 71% (n = 122) occurred in blacks and 2% (n = 3) occurred in Asian-Pacific islanders. Age 0 to 4 years (107 of 171) compared with age 5 to 14 years (64 of 171) was an additional risk factor for the development of tuberculosis (odds ratio, 3.4; 95% confidence interval 2.5, 4.7)), whereas gender was not. Males accounted for 49% of cases (83 of 171). During the period 1983 to 1993 there was no trend of increasing or decreasing numbers among child cases (trend test P = 0.94) despite significant changes by year. The purified protein derivative test had a 9% (8 of 89) false negative rate and was significantly more likely to be negative in children younger than 1 year (4 of 12 vs. 4 of 77; P = 0.01). During the 2-year interval 1992 to 1993, 19% of cases were thought to be preventable. We believe that the PPD skin test is useful and an improved contact investigation is essential to preventing childhood tuberculosis. Miniepidemics of transmission of tuberculosis from adults to a large group of children partially explain the observed disease pattern.

Restriction fragment length polymorphism screening of Mycobacterium tuberculosis isolates: population surveillance for targeting disease transmission in a community.

SETTING: Alabama State Tuberculosis Control Program, USA. OBJECTIVE: To combine molecular screening data with routine information to assess transmission of Mycobacterium tuberculosis and improve control efforts. DESIGN: Since January 1994, samples from tuberculosis cases statewide have been systematically analyzed by IS6110 restriction fragment length polymorphism (RFLP). All cases during 1994-1995 with a predominate RFLP pattern were evaluated and risk factors assessed. pTBN12 was used to evaluate a large cluster in the Birmingham-Jefferson County (BJC) area. RESULTS: Statewide, a common two-band pattern was found, named JH2 (99/566, 17.5%). The most important risk associated with this pattern was homelessness (odds ratio, 8.9; P < 0.001). In the BJC area, the homeless accounted for 29% (51/175) of new cases diagnosed during the study period. For the BJC homeless, there were 13 unique RFLP patterns, and JH2 was predominant (29/33, 88%) among three clusters. Secondary analysis of the homeless JH2 cluster revealed a large group that included 19 of 24 (79%) isolates analyzed. Compared with the BJC non homeless (n = 124), the homeless were younger (P < 0.001), of male gender (P < 0.001), black race (P = 0.002), and were heavy alcohol (P < 0.001) and non-injection drug (P = 0.001) users. CONCLUSIONS: By screening tuberculosis cases statewide, a common two-band RFLP pattern was identified. Its predominance is explained by an ongoing tuberculosis epidemic among Birmingham's homeless population, highlighting RFLP as a tool for population surveillance. The pattern differences observed by pTBN12 typing clearly demonstrate that the isolates might be related but are not clonal.

Spot sputum screening: evaluation of an intervention in two homeless shelters.

SETTING: Two homeless shelters in Birmingham, Alabama. OBJECTIVE: To interrupt tuberculosis transmission and evaluate the utility of spot sputum screening. DESIGN: Two shelters participated in the study between May 1996 and February 1997. A spot sputum specimen was collected on a given evening from each overnight client. Information was obtained regarding symptoms and tuberculin skin test (TST) status. There were four screenings during two rounds, with TST in round one only. RESULTS: Of 127 persons involved in the study, 120 (95%) provided specimens, and four tuberculosis cases were identified (4/127, 3.1%). Symptoms were infrequently reported. RFLP analysis (IS6110) confirmed a two-band cluster in three of the four cases; another matching two-band strain was found in a drug rehabilitation client staying in one shelter. Secondary RFLP typing (pTBN12) confirmed the homeless cluster. Costs were $1311 per case identified. Among 92 clients with a prior TST, 40% reported a positive result (37/92). Of 21 PPD tests read, 11 were > or =10 mm (52%). CONCLUSION: Spot sputum screening is effective in identifying unsuspected tuberculosis cases in shelters. It has acceptable costs, is logistically simple and efficient. Symptom screening was not useful in this general homeless population. RFLP analysis showed cloning of the two-band strain. Given the evidence for ongoing transmission, sputum screening should be considered in shelter settings.

Immunology of tuberculosis.

TB is a chronic, necrotizing infection caused by M. tuberculosis. The clinical manifestations of disease are the result of a balance between the host response and bacterial virulence. Cellular immunity is responsible for effective control of infection, but cytokines released during the process of cellular immunity may also cause harm to the host. Humoral immunity plays little part in protection against TB. Individuals with defective cellular immunity are much more susceptible to disease from M. tuberculosis and are more likely to have a disseminated form of TB.

Corticosteroid therapy in asthma.

Corticosteroids are useful in the treatment of both allergic and idiosyncratic asthma. Although the mechanisms of corticosteroid action in asthma are poorly understood, several possible sites of action have been proposed. Corticosteroids alter the cellular and vascular inflammatory response to bronchial injury, affect catecholamine action on airways, and alter the production of eicosanoids, all of which aid in the resolution of bronchospasm in asthmatic patients. Corticosteroids should only be used for the treatment of asthma after therapeutic levels of methylxanthines and beta agonists have been achieved. Although the optimal doses of corticosteroids in asthma have not been defined, guidelines exist to aid in therapy. In the treatment of status asthmaticus, the intravenous route of administration is preferable. Short courses of corticosteroids may be useful in the treatment of chronic asthma. When long-term corticosteroid therapy is the only option for control of bronchospasm, alternate-day and/or aerosolized corticosteroids are preferable to daily corticosteroids and are associated with fewer side effects. Corticosteroids are useful in the pregnant asthmatic patient when bronchospasm cannot be controlled with bronchodilators. The major risk to the fetus in pregnant asthmatics is hypoxia from uncontrolled bronchospasm, and not from therapy. However, the lowest possible dose of systemic corticosteroids needed to control symptoms, with or without the use of aerosolized corticosteroids, is recommended. All asthmatics who have needed systemic or aerosolized corticosteroids within 6 months prior to surgery should receive preoperative and post-operative corticosteroid therapy. For patients not usually on systemic corticosteroids, conversion to oral prednisone, with a rapid taper is recommended. Side effects from short-term corticosteroid therapy are minimal, with hyperglycemia and psychosis being the major concerns. Long-term steroid therapy has significant side effects, however, and use should be minimized. Suppression of the HPA axis is one of the most potentially dangerous side effects of corticosteroids, and therefore any patient who has been treated with corticosteroids for longer than 4 weeks should be evaluated for possible adrenal suppression.

Cushing's syndrome. Screening methods in hospitalized patients.

We studied 18 patients with Cushing's syndrome and 25 patients in which Cushing's syndrome was excluded on follow-up to evaluate screening tests for Cushing's syndrome in hospitalized patients. Plasma cortisol values (at 8 AM) were found least helpful yielding 29% false-positive and 60% false-negative values. Diurnal variation of cortisol was present in 30% of patients with Cushing's syndrome and absent in 18% of patients without Cushing's syndrome. When corrected for total urinary creatinine, 24-hour urinary 17-hydroxycorticosteroids were specific (all patients without Cushing's syndrome had normal values) but not very sensitive (two of 12 patients with Cushing's syndrome had normal values). Similarly, 24-hour 17-ketosteroids were of little help with 17% false-positive and 35% false-negative values. Twenty-four-hour urinary free cortisol was both a sensitive and specific screening test for Cushing's syndrome (no false-positive and no false-negative results). We conclude that urinary free cortisol is the most efficient screening method for Cushing's syndrome in hospitalized patients.

Aldosterone blocks adrenal compensatory hypertrophy in the rat.

We report that adrenal compensatory hypertrophy occurs in intact and hypophysectomized anesthetized rats as well as in rats in which endogenous ACTH is suppressed by administration of dexamethasone or of dexamethasone plus low-dose ACTH. However, adrenal compensatory hypertrophy is blocked in intact and hypophysectomized animals when aldosterone alone or the combination of aldosterone, dexamethasone, and ACTH is administered using Alzet pumps. These data support previous reports that questioned the validity of the hypothesis that adrenal compensatory hypertrophy is controlled by the glucocorticoid-ACTH negative feedback system. These results require modification of current hypotheses concerning the mechanism of adrenal compensatory hypertrophy to allow for a central nervous system or other effect of aldosterone.

Corticosteroids in asthma.

The use of corticosteroids in the treatment of asthma has significantly decreased the morbidity and mortality from this disease. However, corticosteroids have devastating side effects when given frequently or for prolonged periods. High doses of systemic corticosteroid preparations should be used only during bouts of acute bronchospasm, whereas the lowest possible dose needed to control symptoms is recommended for the treatment of chronic asthma. Aerosolized steroids offer an alternative to systemic preparations and have less associated morbidity. Various corticosteroid preparations have various potencies and durations of action that need to be considered. Patients with coexisting liver disease require preparations that do not need hepatic hydroxylation, whereas patients with congestive heart failure require preparations that minimize salt retention. When asthma and pregnancy coexist, it is vital that symptoms of bronchospasm are controlled to protect the fetus. During stressful situations, such as surgery, it is important to consider the possibility of hypothalamic-pituitary-adrenal axis suppression if the asthmatic patient has been previously treated with corticosteroids.

Drug-resistant tuberculosis in adults: implications for the health care worker.

In recent years, several outbreaks of drug-resistant tuberculosis have occurred in U.S. hospitals. In response to this recognized risk of tuberculosis exposure in health care facilities, the Centers for Disease Control and the Occupational Safety and Health Administration have issued guidelines or policy procedures for minimizing risks of tuberculosis transmission within these facilities. Some of the recommendations outlined in these governmental documents have been controversial. In this review the guidelines/policies and the debate surrounding them are discussed as they affect the health care worker who cares for adult patients with tuberculosis.

Analysis of the monocyte Fc receptors and antibody-mediated cellular interactions required for the induction of T cell proliferation by anti-T3 antibodies.

The induction of human T cell proliferation by antibodies that cross-link T3 antigens is dependent on functional interactions of anti-T3 antibodies with monocyte Fc receptors. In this report, we used a panel of anti-T3 antibodies of differing heavy chain isotype and a variety of other monoclonal antibodies to analyze several features of the antibody-mediated interactions between T cells and monocytes that are required for mitogenesis. Whereas three IgG2a anti-T3 antibodies were mitogenic for cells from all individuals, IgM and IgG2b anti-T3 antibodies did not induce T cell proliferation in any donor and could block the proliferative responses induced by other mitogenic anti-T3 antibodies. Dose-response analyses with four IgG1 anti-T3 antibodies demonstrated donor heterogeneity as reported by other investigators. However, in contrast to these previous reports, high concentrations of IgG1 anti-T3 antibodies were found to be mitogenic for all donors, indicating that this heterogeneity is based on relative rather than absolute defects in low responder monocytes. Cell mixing experiments in which monocytes from two different low responder donors were co-cultured with T cells and IgG1 anti-T3 antibodies did not identify any complementary defects, suggesting that the low responder phenotype results from a relatively restricted polymorphism. To assess the nature of the signals required for inducing T cell proliferation, nonmitogenic anti-T3 antibodies were co-cultured with other pan-T cell antibodies having the IgG2a isotype. The combination of signals from T3 antigen cross-linkage and those independently generated by other IgG2a antibodies bound to monocyte Fc receptors did not induce T cell proliferation. Hence, it appears that the T3 antigen or closely associated structures must be clustered at the monocyte membrane for mitogenesis. Finally, in competitive inhibition experiments, the isotype specificity of monocyte Fc receptors involved in the induction of T cell proliferation was examined. Two distinct Fc receptor sites, one that binds murine IgG2a and IgG3 antibodies and a second that binds murine IgG1 antibodies, were identified. Murine IgM or IgG2b did not appear to bind either of these receptor sites. Taken together, these data indicate that human monocytes have two distinct Fc receptor sites, which must specifically and directly interact with T cell-bound anti-T3 antibodies for mitogenesis.