Lawrence A. Cone

Recombinant Human Erythropoietin in the Treatment of Anemia Associated with Human Immunodeficiency Virus (HIV) Infection and Zidovudine Therapy: Overview of Four Clinical Trials

OBJECTIVE To assess the effect of recombinant human erythropoietin (r-HuEPO) on anemia in patients with the acquired immunodeficiency syndrome (AIDS) who are receiving zidovudine therapy. DESIGN Combined analysis of four 12-week, randomized, double-blind, controlled clinical trials. SETTING Multiple centers in the United States. PATIENTS Two hundred and ninety-seven anemic (hematocrit < 30%) patients with AIDS who were receiving zidovudine therapy. Of the 297 patients, 255 were evaluable for efficacy, but all patients were included in analysis of safety. INTERVENTION Patients were randomly assigned to receive either r-HuEPO (100 to 200 U/kg body weight) or placebo, intravenously or subcutaneously, three times per week for up to 12 weeks. MEASUREMENTS Changes in mean hematocrit, transfusion requirement, and quality of life. RESULTS Sixty-nine percent of patients had endogenous serum erythropoietin levels less than or equal to 500 IU/L, and 31% had erythropoietin levels greater than 500 IU/L. In patients with low erythropoietin levels (< or equal to 500 IU/l), r-HuEPO therapy decreased the mean number of units of blood transfused per patient when compared with placebo (3.2 units and 5.3 units, respectively; P = 0.003) and increased the mean hematocrit from the baseline level (4.6 percentage points and 0.5 percentage points, respectively; P <0.001). Overall quality of life improved in patients on r-HuEPO therapy (P = 0.13). Patients with erythropoietin levels greater than 500 IU/L showed no benefit from r-HuEPO in any outcome variable. Placebo and r-HuEPO recipients did not differ in the incidence of adverse effects or opportunistic infections. CONCLUSION Therapy with r-HuEPO can increase the mean hematocrit and decrease the mean transfusion requirement in anemic patients with AIDS who are receiving zidovudine and have endogenous low erythropoietin levels (< or equal to 500 IU/L). Such therapy is of no apparent benefit in patients whose endogenous erythropoietin levels are higher than 500 IU/L.

Association of CCR5 Δ32 deletion with early death in multiple sclerosis

Purpose: The interaction between chemokines and their receptors is extremely important in controlling T cell migration into sites of CNS inflammation. Because trafficking of inflammatory T cells into the central nervous system (CNS) is a key player in the pathogenesis of multiple sclerosis (MS), we investigated the possible association of CCR5 Δ32 deletion in this disorder.Methods: DNA isolated from postmortem brain tissue samples of 132 patients with MS and from blood tissue samples of 163 gender and ethnicity-matched healthy controls was used to screen for the CCR5 Δ32 deletion allele.Results: An increased frequency of 32-bp deletion allele was found to be associated with early death (P = 0.00005) and with a progressive reduction in the years of survival (onset to death). The death hazard ratio of CCR5 with deletion versus no deletion was 2.12, suggesting that MS patients with the 32-bp deletion have twice the mortality rate of patients with the normal genotype. This effect was more significant in females (hazard ratio 3.58).Conclusion: A strong association of the CCR5 Δ32 deletion with early death could serve as a prognostic marker for MS.

A multigene test for the risk of sporadic breast carcinoma

Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol‐0‐methyltransferase gene (COMT), the dopamine D2 receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR).

RANTES: a genetic risk marker for multiple sclerosis

Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a beta-chemokine and has been detected in brain lesions of multiple sclerosis (MS) patients. Considering its potential role in MS, we screened two functional polymorphisms in the proximal promoter region of the RANTES in MS patients versus controls. Methods: We examined 140 postmortem brain samples from subjects with a primary diagnosis of MS, and peripheral blood samples from 216 control subjects. The RANTES-28C/G and -403G/A promoter polymorphisms were examined. All subjects were non-Hispanic Caucasians. Results: MS cases differed from controls showing a significant association with the 403G/A polymorphism (odds ratio, 2.359, [1.465-3.799]; P-0.0001), but not the -28C/G (P-NS) polymorphism. There was a significant association of the -28G allele with both early onset (P-0.031) and longer survival (P-0.006). Conclusion: There is a significant but complex association of the RANTES gene with MS.

Pyomyositis of the Anterior Tibial Compartment

Five oncology patients developed bacterial pyomyositis involving the anterior tibial compartment and resulting in compartment syndrome with ischemia and abnormalities of neuromuscular function. All patients were neutropenic and thrombocytopenic, and four were receiving or had recently received cancer chemotherapy. Three infections were due to gram-negative bacilli and two to Staphylococcus aureus. Appropriate antimicrobial therapy and surgical drainage in four patients resulted in the resolution of these infections with good residual muscle function. To our knowledge, primary pyomyositis has never previously been known to cause compartment syndrome.

Malignant melanoma of the rectal ampulla: report of a case and review of the literature.

SummaryDocumentation of the seventeenth case of melanoma of the rectum is presented. The world literature is reviewed. The effectiveness of immunotherapy with BCG or BCG in combination with CCNU and DTIC remains to be established.

Reversible ALS-like disorder in HIV infection An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy

To the Editor: Two recent articles by Moulignier et al.1 and MacGowen et al.2 present clinical and laboratory evidence of a probable increased incidence of ALS in patients infected by human immunodeficiency viruses (HIV)-1 and HIV-2. Several possible mechanisms were suggested including direct neuronal damage, disease due to cytokine production and autoimmunity. The fact that symptoms and signs of ALS improved with antiretroviral therapy implied that the effect was specifically on HIV-induced disease. However, Kaposi’s sarcoma (KS), which now appears almost certainly to be due to human herpesvirus-8 (HHV-8), also often disappears with antiretroviral therapy. It is of more than passing interest that up to 35% of homosexual men with the acquired immunodeficiency syndrome demonstrate antibodies to HHV-8,3 whereas they are present in less than 4% of US blood donors.3 We have recently had an opportunity to study HHV-8 antibody levels in five non-HIV+ patients with ALS. Two of the five patients were women, one was black, and all five had associated medical disorders including monoclonal gammopathy, lymphoma of the lung, scleroderma, osteoarthritis, and hyperlipidemia. Their ages ranged from 70 to 81 years. Three ultimately died from aspiration pneumonia. Antibody titers as measured by indirect immunofluorescence using the BCP-1 cell line4 were positive in all patients and ranged from 1:20 to 1:60. HHV-8 in blood by PCR was identified in only one patient. The presence of HHV-8 antibody in all of our patients in this small study would suggest that this may also be the case in patients with …

Purpura fulminans due to Streptococcus pneumoniae sepsis following gastric bypass.

An older female underwent bariatric surgery which was followed by a significant weight loss and diarrhea, from which C. difficile was isolated just before her hospitalization. Less than 48 hours after admission, she became febrile, developed deep venous thrombosis of the leg and a pulmonary embolus. Blood cultures grew out Streptococcus pneumoniae and the patient developed purpura fulminans. There was convincing laboratory evidence for disseminated intravascular coagulation and a marked depletion of proteins C and S as well as antithrombin. Treatment with ceftriaxone and drotrecogin alfa together with parenteral nutrition led to disappearance of the pathogen and ultimate normalization of the anticoagulant factors. We believe that malabsorption of vitamin K dependent proteins C, S and antithrombin due to bariatric surgery predisposed the patient to purpura fulminans and disseminated intravascular coagulation.

Molecular interactions of leptin and prostate cancer.

BACKGROUNDEpidemiological studies have found obesity to be a risk factor for prostate cancer. Our prior independent studies in women have reported a strong relationship between variants of OB (leptin) gene, body mass index, and age at menarche and sporadic breast cancer. The current study investigates an association between genetic variants of the human obesity gene, serum leptin levels, and body mass index in subjects with prostate carcinoma and in age- and gender-matched normal subjects. METHODSBlood samples from 69 patients with prostate cancer and 137 age-matched control subjects were collected. Serum leptin level was investigated by radioimmunoassay, and body mass index was calculated. Allele sizes were determined via standard polymerase chain reaction. Statistical analysis was performed using SPSS10.0 computer software. RESULTSThere was a strong association with significantly elevated serum leptin levels, high body mass index, and higher frequency of LEPR longer alleles in patients with prostate cancer than in control subjects. By contrast, a modest but not significant increase in the frequency of LEP short alleles was found in patients with prostate cancer as compared with control subjects. Analysis within groups 1 (low leptin level and low body mass index) and 2 (other) showed a significant association only in group 2, with high frequency of OB gene variants (LEPR long alleles and LEP short alleles) in patients with prostate cancer but not in control subjects. CONCLUSIONSThese results represent the first report of a significant association between specific leptin gene alleles, serum leptin levels, and body mass index in subjects with prostate cancer. Consistent with prior reports, we also report a significantly elevated serum leptin level in patients with prostate cancer, suggesting a strong link with obesity as an increased risk factor.

Herpes Zoster and the Acquired Immunodeficiency Syndrome

Excerpt To the editor: Gottlieb (1) recently tabulated some infectious complications of the acquired immunodeficiency syndrome, including limited cutaneous herpes zoster. In the same issue, Rogers ...