Background-Human herpesvirus-6 (HHV-6), a ubiquitous β-herpesvirus, is the causative agent of roseola infantum and has been associated with a number of neurologic disorders including seizures, encephalitis/meningitis, and multiple sclerosis. Although the role of HHV-6 in human CNS disease remains to be fully defined, a number of studies have suggested that the CNS can be a site for persistent HHV-6 infection.

BackgroundHuman herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)–positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters.Methods and FindingsHHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive—the first demonstration of an ex vivo HHV-6–infected astrocyte culture isolated from HHV-6–positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression.ConclusionsOverall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.

One-half of bone-marrow transplant (BMT) and stem-cell transplant recipients have reactivation of latent human herpesvirus (HHV)-6 2-4 weeks after transplant. Although the detection of viral DNA, RNA, and antigen in brain material confirmed active HHV-6 variant B infection, peak viral loads in cerebrospinal fluid (CSF) and serum occurred 2-4 weeks before death and decreased to low levels before or at autopsy. All autopsy samples consistently demonstrated HHV-6 active infection in the hippocampus. Astrocytic cells positive for viral antigen provided support for an HHV-6-specific tropism for hippocampal astrocytes. HHV-6 DNA in CSF and serum may not reflect the level of active viral infection in the brain after BMT.

Though first described as a lymphotropic virus, human herpesvirus 6 (HHV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra-and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra-and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HHV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes.

Ondansetron (OND) is a new 5-HT3 receptor antagonist that give complete protection from emesis/nausea in approximately 50% of cisplatin (CDDP)-treated patients. To evaluate if dexamethasone (DEX) added to OND increases antiemetic efficacy, we carried out a double-blind randomized crossover study to compare the antiemetic activity of OND with OND plus DEX. One hundred two chemotherapy-naive patients (44 women and 58 men) scheduled to receive CDDP chemotherapy at doses greater than or equal to 50 mg/m2 entered the study. Eighty-nine patients completed both cycles with the following results: complete protection from emesis/nausea was obtained in 57/59 patients (64.0%/66.3%) with OND and in 81/79 (91.0%/88.8%) with OND plus DEX (P = .0005/P = .0021). At the end of the study, 53% of the patients expressed a treatment preference, and of these, 74% chose OND plus DEX compared with 26% who preferred OND alone, a statistically significant difference (P less than .003). Side effects were very mild and not significantly different between the two treatments. We conclude that OND plus DEX is more efficacious than OND in protecting patients from CDDP-induced emesis and nausea.

Delayed emesis has been arbitrarily defined as vomiting and/or nausea beginning, or persisting for, more than 24 h after chemotherapy administration. Acute emesis is the most important prognostic factor for delayed emesis. Owing to the relatively high incidence and severity all patients treated with cisplatin > or = 50 mg/m(2) should receive antiemetic prophylaxis. In these patients a combination of dexamethasone plus metoclopramide or a 5-HT3 antagonist is the most efficacious regimen. All patients submitted to moderately emetogenic chemotherapy, such as cyclophosphamide, carboplatin, doxorubicin and epirubicin, should also receive antiemetic prophylaxis with oral dexamethasone to prevent delayed emesis.

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Background: Patients receiving home parenteral nutrition (HPN) because of intestinal failure are at high risk of developing osteoporosis. Objective: We studied the effect of the bisphosphonate clodronate on bone mineral density (BMD) and markers of bone turnover in HPN patients. Design: A 12-mo, double-blind, randomized, placebo-controlled trial was conducted to study the effect of 1500 mg clodronate, given intravenously every 3 mo for 1 y, in 20 HPN patients with a bone mass T score of the hip or lumbar spine of less than Ϫ1. The main outcome measure was the difference in the mean percentage change in the BMD of the lumbar spine measured by dual-energy X-ray absorptiometry. Secondary outcome measures included changes in the BMD of the hip, forearm, and total body and biochemical markers of bone turnover, ie, serum osteocalcin, urinary pyridinoline, and urinary deoxypyridinoline. Results: The mean (ϮSEM) BMD of the lumbar spine increased by 0.8 Ϯ 2.0% in the clodronate group and decreased by 1.6 Ϯ 2.0% in the placebo group (P ϭ 0.43). At all secondary skeletal sites (ie, hip, total body, and distal forearm), we observed no changes or small increases in the BMD of the clodronate group. In the clodronate group, biochemical markers of bone resorption decreased significantly (P Ͻ 0.05). Conclusions: Clodronate significantly inhibits bone resorption as assessed by changes in biochemical markers of bone turnover. Although the mean BMD increased in the clodronate group, cyclic clodronate therapy failed to increase spinal BMD significantly at 12 mo. (Am J Clin Nutr 76:482-488, 2002)