Stanley C. Deresinski

N-acetylcysteine replenishes glutathione in HIV infection.

Glutathione (GSH) deficiency is common in HIV‐infected individuals and is associated with impaired T cell function and impaired survival. N‐acetylcysteine (NAC) is used to replenish GSH that has been depleted by acetaminophen overdose. Studies here test oral administration of NAC for safe and effective GSH replenishment in HIV infection.

Reemerging Leptospirosis, California

Leptospirosis is a reemerging infectious disease in California. Leptospirosis is the most widespread zoonosis throughout the world, though it is infrequently diagnosed in the continental United States. From 1982 to 2001, most reported California cases occurred in previously healthy young adult white men after recreational exposures to contaminated freshwater. We report five recent cases of human leptospirosis acquired in California, including the first documented common-source outbreak of human leptospirosis acquired in this state, and describe the subsequent environmental investigation. Salient features in the California cases include high fever with uniform renal impairment and mild hepatitis. Because leptospirosis can progress rapidly if untreated, this reemerging infection deserves consideration in febrile patients with a history of recreational freshwater exposure, even in states with a low reported incidence of infection.

Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate (tenofovir DF) is a bioavailable prodrug of tenofovir, a potent nucleotide analogue reverse-transcriptase inhibitor with activity against human immunodeficiency virus (HIV) and hepatitis B virus. It is administered as a single 300-mg tablet once daily. It was approved for the treatment of HIV infection on the basis of data from clinical trials demonstrating activity in treatment-experienced patients, and it was subsequently shown to be effective when used as a component of initial therapy. Tenofovir DF is active against some nucleoside-resistant strains of HIV. However, cross-resistance is associated with multiple thymidine analogue mutations that include 41L or 210W. The signature mutation is the K65R mutation, which causes variable loss in susceptibility to tenofovir DF, didanosine, and abacavir. Tenofovir DF has been well tolerated in clinical trials with durations of follow-up up to 96 weeks. It is associated with more-favorable lipid profiles than stavudine and has not been associated with the mitochondrial toxicity attributed to other nucleoside analogues.

Miconazole in coccidioidomycosis: II. Therapeutic and pharmacologic studies in man

Fourteen patients with chronic coccidioidomycosis, many of whom had complicating concurrent diseases and/or had failed to respond to amphotericin therapy, were treated with intravenous miconazole, a synthetic imidazole drug previously shown to be effective in experimental murine coccidioidomycosis. Up to 3.6 g/day was given for up to three months. 7inimal inhibitory concentrations of mycelial and endospore phases of all clinical isolates of C. immitis were less than 2.0 mug/ml. Peak concentrations in the blood of up to 7.5 mug/ml (by assay against C. immitis in vitro) were achieved. Doses above 9 mg/kg or 350 mg/m2 were more efficacious in producing blood levels over 1 mug/ml. Serum protein binding, determined by several methods, was approximately 90 per cent. The disappearance of bioactive drug from blood after infusion has a rapid initial phase (t1/2 approximately 30 minutes) and a final plateau (t1/2 approximately 20 hours). Eight patients had objective evidence of response, three had slight or equivocal responses, two could not be evaluated, and one was a treatment failure. Side effects were generally uncommon, minor and transient except for phlebitis. Infusion into central venous catheters appears to circumvent this problem. Miconazole is a potentially useful drug in the treatment of coccidioidomycosis.

Coccidioidomycosis In Compromised Hosts: Experience at Stanford University Hospital

To determine the frequency and clinical characteristics of infection with Coccidioides immitis in immunosuppressed patients at Stanford University Hospital, clinical records of 14 years were examined. Thirteen cases met the diagnostic criteria. Half had Hodgkins disease. In six the infection was disseminated; five of the six died early in the course of their infectious illness, frequently without diagnosis. Conclusions include: 1. The occurrence of coccidioidomycosis in immunosuppressed patients seen at institutions in or adjacent to the endemic area is not as rare as the literature suggests. 2. Dissemination is frequently explosive and the radiographic appearance of pulmonary involvement may appear late. Widespread pulmonary dissemination may occur within 24 hours after a negative x-ray. 3. Although the skin test loses its diagnostic value, the serology remains valid. Thus immunosuppressed patients with febrile illnesses (with or without radiographically evident pulmonary involvement) who have a history of travel to an endemic area should have serological examinations. 4. Lymphocytopenia correlates with risk of dissemination of coccidioidomycosis. 5. The administration of immunsuppressive chemotherapy correlates with such risk while radiotherapy and the malignant or non-malignant nature of the disease do not.

Visceral bacillary epithelioid angiomatosis: Possible manifestations of disseminated cat scratch disease in the immunocompromised host: A report of two cases

Opportunistic infection with the causative agent of cat scratch disease may be responsible for an unusual vascular proliferative lesion, referred to as bacillary epithelioid angiomatosis, previously described only in human immunodeficiency virus (HIV)-infected patients. We present a case of an HIV-infected patient with bacillary epithelioid angiomatosis involving the liver and bone marrow causing progressive hepatic failure. We also report a case of a cardiac transplant recipient with hepatic and splenic bacillary epithelioid angiomatosis manifesting as a fever of unknown origin, a previously unreported event in a non-HIV-infected patient. These cases represent the first documentation of bacillary epithelioid angiomatosis with visualization of cat scratch-like organisms involving internal organs.

Frontostriatal fiber bundle compromise in HIV infection without dementia

Background:Quantitative fiber tracking derived from diffusion tensor imaging (DTI) was used to determine whether white matter association, projection, or commissural tracts are affected in nondemented individuals with HIV infection and to identify the regional distribution of sparing and impairment of fiber systems. Methods:DTI measured fractional anisotropy and diffusivity, quantified separately for longitudinal (λL) diffusivity (index of axonal injury) and transverse (λT) diffusivity (index of myelin injury), in 11 association and projection white matter tracts and six commissural tracts in 29 men and 13 women with HIV infection and 88 healthy, age-matched controls (42 men and 46 women). Results:The total group of HIV-infected individuals had higher diffusivity (principally longitudinal) than controls in the posterior sectors of the corpus callosum, internal and external capsules, and superior cingulate bundles. High longitudinal diffusivity, indicative of axonal compromise, was especially prominent in posterior callosal sectors, fornix, and superior cingulate bundle in HIV with AIDS. Unmedicated patients had notably high transverse diffusivity, indicative of myelin compromise, in the occipital forceps, inferior cingulate bundle, and superior longitudinal fasciculus. Pontocerebellar projection fibers were resistant to HIV effects as were commissural fibers coursing through premotor and sensorimotor callosal sectors. Conclusion:This quantitative survey of brain fiber tract integrity indicates that even nondemented HIV patients can have neuroradiological evidence for damage to association and commissural tracts. These abnormalities were vulnerable to exacerbation with AIDS and possibly mitigated by HAART.

Contribution of alcoholism to brain dysmorphology in HIV infection: effects on the ventricles and corpus callosum.

Nonrigid registration and atlas-based parcellation methods were used to compare the volume of the ventricular system and the cross-sectional area of the midsagittal corpus callosum on brain MRIs from 272 subjects in four groups: patients with HIV infection, with and without alcoholism comorbidity, alcoholics, and controls. Prior to testing group differences in regional brain metrics, each measure was corrected by regression analysis for significant correlations with supratentorial cranial volume and age, observed in 121 normal control men and women, whose age spanned six decades. Disregarding HIV disease severity, we observed a graded pattern of modest enlargement of the total ventricular system (0.28 SD for uncomplicated HIV, 0.65 SD for HIV comorbid with alcoholism, and 0.72 SD for the alcoholism group). The pattern of callosal thinning showed a similar but small ( approximately 0.5 SD) graded effect. A different pattern emerged, however, when HIV severity in the context of alcoholism comorbidity was factored into the analysis. Substantially greater volume abnormalities were present in individuals with a history of an AIDS-defining event or low CD4+ T cell counts (<or=200 mm(3)) irrespective of alcoholism comorbidity, and the effect of HIV severity was disproportionately exacerbated by alcoholism comorbidity, with 1 SD size deficit in the genu of corpus callosum and nearly 2 SD greater volume of the frontal and body regions of the ventricles for the AIDS + alcohol comorbid group. The differences in brain volumes between the AIDS groups with vs. without alcoholism could not be attributed to differences in HIV disease severity, defined by CD4+ count, viral load, or Karnofsky score. The substantial effect of the alcoholism-AIDS interaction on ventricular and callosal dysmorphology, in the context of the modest changes observed in non-AIDS, nonalcohol abusing HIV-infected individuals, highlight the need to consider alcohol use disorders as a major risk factor for neuropathology among HIV-infected persons.

Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study.

Advances in treatment have transformed human immunodeficiency virus (HIV) infection from an inexorable march to severe morbidity and premature death to a manageable chronic condition, often marked by good health. Thus, infected individuals are living long enough that there is a potential for interaction with normal senescence effects on various organ systems, including the brain. To examine this interaction, the brains of 51 individuals with HIV infection and 65 uninfected controls were studied using 351 magnetic resonance imaging and a battery of neuropsychological tests collected 2 or more times over follow-up periods ranging from 6 months to 8 years. Brain tissue regions of interest showed expected age-related decrease in volume; cerebrospinal fluid-filled spaces showed increase in volume for both groups. Although HIV-infected individuals were in good general health, and free of clinically-detectable dementia, several brain regions supporting higher-order cognition and integration of functions showed acceleration of the normal aging trajectory, including neocortex, which extended from the frontal and temporal poles to the parietal lobe, and the thalamus. Beyond an anticipated increase in lateral ventricle and Sylvian fissure volumes and decrease in tissue volumes (specifically, the frontal and sensorimotor neocortices, thalamus, and hippocampus) with longer duration of illness, most regions also showed accelerated disease progression. This accelerated loss of cortical tissue may represent a risk factor for premature cognitive and motor compromise if not dementia. On a more promising note, HIV-infected patients with increasing CD4 counts exhibited slower expansion of Sylvian fissure volume and slower declines of frontal and temporoparietal cortices, insula, and hippocampus tissue volumes. Thus, attenuated shrinkage of these brain regions, likely with adequate pharmacologic treatment and control of further infection, has the potential of abating decline in associated higher-order functions, notably, explicit memory, executive functions, self-regulation, and visuospatial abilities.

Regional Brain Structural Dysmorphology in Human Immunodeficiency Virus Infection: Effects of Acquired Immune Deficiency Syndrome, Alcoholism, and Age

BACKGROUND Human immunodeficiency virus (HIV) infection and alcoholism each carries liability for disruption of brain structure and function integrity. Despite considerable prevalence of HIV-alcoholism comorbidity, few studies examined the potentially heightened burden of disease comorbidity. METHODS Participants were 342 men and women: 110 alcoholics, 59 with HIV infection, 65 with HIV infection and alcoholism, and 108 healthy control subjects. This design enabled examination of independent and combined effects of HIV infection and alcoholism along with other factors (acquired immune deficiency syndrome [AIDS]-defining events, hepatitis C infection, age) on regional brain volumes derived from T1-weighted magnetic resonance images. RESULTS Brain volumes, expressed as Z scores corrected for intracranial volume and age, were measured in 20 tissue and 5 ventricular and sulcal regions. The most profound and consistent volume deficits occurred with alcohol use disorders, notable in the cortical mantle, insular and anterior cingulate cortices, thalamus, corpus callosum, and frontal sulci. The HIV-only group had smaller thalamic and larger frontal sulcal volumes than control subjects. HIV disease-related factors associated with greater volume abnormalities included CD4 cell count nadir, clinical staging, history of AIDS-defining events, infection age, and current age. Longer sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities in both alcohol groups. CONCLUSIONS Having HIV infection with alcoholism and AIDS had an especially poor outcome on brain structures. That longer periods of sobriety and less lifetime alcohol consumption were predictive of attenuated brain volume abnormalities encourages the inclusion of alcohol recovery efforts in HIV/AIDS therapeutic settings.