Locus assignment of two alpha-globin structural mutants from the Caribbean basin: alpha Fort de France (alpha 45 Arg) and alpha Spanish Town (alpha 27 Val)

Two alpha-globin structural mutants were mapped to their encoding loci by in vitro translation of hybrid-selected alpha 1- and alpha 2-globin mRNA. The more highly expressed mutant, alpha Spanish Town (alpha 27Val), is encoded at the alpha 2 locus and the less expressed mutant, alpha Fort de France (alpha 45Arg), is encoded at the alpha 1 locus. These results further define the distribution of alpha-globin structural mutations within the alpha-globin gene cluster and substantiate the dominant role of the alpha 2-globin locus in alpha- globin expression.     

Immune predispositions for cytomegalovirus retinitis in AIDS. The HNRC Group.

CMV retinitis develops in approximately 28-35% of all AIDS patients at later stages of disease, often leading to blindness. To determine whether the subset of AIDS patients who developed CMV retinitis (CMV-R) were immunologically predisposed, T cell proliferation responses to CMV were examined prospectively in an HIV infected, HLA typed, longitudinal study population. Individuals who developed CMV-R had significantly lower T cell proliferation responses to CMV, both early and late in disease, compared to CD4 matched controls who have not developed CMV-R. Since HLA proteins influence T-cell recognition, phenotypes of 21 CMV-R patients were examined to determine whether certain HLA alleles were associated with low immune response and predisposed AIDS patients to CMV-R. HLA DR7 and B44 were at increased (nearly twice the expected) frequency in those with CMV-R. The combined association of either B44, 51 or DR7 with CMV-R was highly significant (P = .008, relative risk of CMV-R = 15) with correction for multiple comparisons. Low immune responses were twice as frequent in those with (61%) compared to those without (30%) predisposing alleles. Thus, AIDS patients with immunogenetically related hyporesponsiveness to CMV antigens may be at increased risk of retinitis.     

Skin Test Reactivity and Cellular Immune Responses to Mycobacterium avium Sensitin in AIDS Patients at Risk for Disseminated M. avium Infection

Skin tests and lymphocyte proliferation assays (LPA) were performed with Mycobacterium avium sensitin on patients with AIDS. Among 139 subjects, 13% had positive skin test results and 32% had positive LPA results. The LPA may be a more sensitive indicator of prior M. avium infection in this population.     

Transfusion-transmissible viral infections among US military recipients of whole blood and platelets during Operation Enduring Freedom and Operation Iraqi Freedom

BACKGROUND: Current US military clinical practice guidelines permit emergency transfusions of non–Food and Drug Administration (FDA)‐compliant freshly collected blood products in theaters of war. This investigation aimed to characterize the risks of transfusion‐transmitted infections (TTIs) associated with battlefield transfusions of non–FDA‐compliant blood products. STUDY DESIGN AND METHODS: US Service members who received emergency transfusion products in Iraq and Afghanistan (March 1, 2002‐September 30, 2007) were tested for hepatitis C virus (HCV), human immunodeficiency virus (HIV), and hepatitis B virus (HBV) infections using reposed pre‐ and posttransfusion sera. Selected regions of viral genomes from epidemiologically linked infected recipients and their donors were sequenced and compared. RESULTS: Of 761 US Service members who received emergency transfusion products, 475 were tested for HCV, 472 for HIV, and 469 for HBV. One transfusion‐transmitted HCV infection (incidence rate of 2.1/1000 persons) was identified. The pretransfusion numbers (prevalence per 1000 persons) were HCV—four (8/1000), HIV—zero (0/1000), chronic HBV—two (4 /1000), and naturally immune (antibody to HBV core antigen)—nine (19/1000). CONCLUSION: One HCV TTI was determined to be associated with emergency blood product use. The pretransfusion HCV and HBV prevalence in transfusion recipients, themselves members of the potential donor population, indicates better characterization of the deployed force's actual donor population, and further investigations of the TTI prevalence in these donors are needed. These data will inform countermeasure development and clinical decision making.     

The Role of Cohort Studies in Drug Development: Clinical Evidence of Antiviral Activity of Serotonin Reuptake Inhibitors and HMG-CoA Reductase Inhibitors in the Central Nervous System

Background Effective antiretroviral therapy (ART) has reduced the incidence of HIV-associated neurocognitive impairment (HNCI) but its prevalence remains high. Clinical trials have yet to identify a consistently effective treatment for HNCI, other than ART, but in vitro data support that some drugs approved by the Food and Drug Administration (FDA) for other indications might benefit individuals with HNCI. Some of these drugs, such as serotonin reuptake inhibitors (SRIs) and HMG-CoA reductase inhibitors (statins), may do so by reducing HIV replication in the CNS and are already widely used by HIV-infected individuals. Methods Six-hundred fifty-eight HIV-infected participants of the CHARTER cohort had a baseline assessment, which included comprehensive neuropsychological (NP) testing and HIV RNA measurements in plasma and cerebrospinal fluid (CSF). Four-hundred sixty-seven (71%) subjects used ART, 195 (30%) used SRIs, and 63 (10%) used statins. Results SRI users were less likely to have HIV RNA levels in CSF above 50 copies (c)/mL (29 vs. 37% in non-SRI users, OR 0.69, p = 0.05). This association was most evident for three of the seven SRIs (citalopram, sertraline, and trazodone, or “antiviral” SRIs, combined 25 vs. 38% in non-SRI users, OR 0.56, p = 0.01) and was strongest in those not taking concomitant ART (61 vs. 83%, OR 0.31, p = 0.01). “Antiviral” SRI users also performed better on NP tests (median global deficit score 0.37 vs. 0.47, p = 0.04). Statin users were also less likely to have HIV RNA levels in CSF above 50 c/mL (16 vs. 37%, p < 0.001) but, in contrast to SRIs, the association was strongest in those taking ART (2 vs. 18%, p < 0.001). Statin use was not associated with better NP performance. Multivariate analyses indicated that the use of “antiviral” SRIs—but not statins—was associated with undetectable HIV RNA levels in CSF and better NP performance. Conclusions SRIs may reduce HIV replication in CSF and improve NP performance. This was particularly true for three SRIs—supporting differences in antiviral efficacy between drugs—in individuals who were not taking ART. In contrast, statins were not associated with lower HIV replication in CSF in multivariate analyses and were not associated with better NP performance. These analyses support the value of large observational cohort studies in identifying FDA-approved drugs that may be worth further investigation.     

Penicillinase-producing Neisseria gonorrhoeae in Great Britain, 1977-81: alarming increase in incidence and recent development of endemic transmission

Since penicillinase-producing Neisseria gonorrhoeae appeared five years ago in West Africa and South-east Asia reported cases have doubled annually in Great Britain, primarily as a result of increasing importation. Importation of penicillinase-producing Neisseria gonorrhoeae has increased exponentially because dramatic expansion of these strains in their regions of origin has led to increasing infection of male air travellers. From 1977 to 1980 infections acquired in Great Britain played only a minor part in the exponential increase. During 1981 the number of indigenous cases increased much more rapidly than imported cases, indicating that these strains have become truly endemic in Great Britain. Currently, identification of patients at high risk and initial treatment with penicillinase-resistant antibiotics offers the best hope of containing the strains. The emergence and rapid spread of penicillinase-producing Neisseria gonorrhoeae shows the international consequences of the abuse of antibiotics.     

Haemodynamic Studies During the Management of Severe Tetanus

Detailed invasive haemodynamic studies were performed in 27of 32 patients with severe tetanus. Nineteen had severe uncomplicatedtetanus and eight had associated major complications, chieflyinfection and pulmonary complications. The results were comparedwith those obtained from 15 healthy male volunteers who servedas controls. There were two deaths in 32 patients (mortality6.25 per cent). Severe tetanus without major complications wascharacterized by a high output hyperkinetic circulatory statewith tachycardia (heart rate 131 (19.2) beats/minute), increasedstroke volume index (43.1 (10.7) ml/m²), increased cardiac index(5.48 (0.94)1/min/m²) and a normal left ventricular stroke workindex (60.5 (15.9) g/m/m²). Volume loading demonstrated a significanthaemodynamic response and increased vascular capacitance. Evenso the maximum percent rise from baseline values of these indicesafter volume load was significantly higher in controls (p <0.001). Autonomic cardiovascular disturbances affected bothsympathetic and parasympathetic activity. Hypertension and tachycardiaalternating with hypotension and bradycardia were related tosudden fluctuations in systemic vascular resistance. Our studiessuggested some degree of myocardial dysfunction in patientswith severe uncomplicated tetanus. The haemodynamics of severetetanus were masked and altered by complicating infection, pneumonia,and atelectasis.