The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response.

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Treatment of acute stroke with hyperbaric oxygen: time window for efficacy.

We conducted a retrospective statistical analysis of the Heyman, Saltzman, Whalen 1966 study of 22 stroke patients treated with hyperbaric oxygen (HBO2)--13 of them one to five hours post-stroke. We examined patients who received HBO2 treatment within seven hours post-stroke. An exploratory logistic regression analysis examining the influence of time post-stroke, time in chamber and dose of HBO2, range 2.02 atmospheres absolute (ATA) to 3.04 ATA, was conducted. Only time post-stroke was a significant influence for recovery, with each passing hour decreasing the chance of at least partial transient recovery by 62% - odds ratio: 0.38 (95% CI: 0.15 -0.95), p = 0.039. In the one- to five-hour group of 13 patients, nine (41% of 22) had recovery or recovery with relapse. This represented 69% (+/- 25% SE) of this time frame. Only two of the nine had permanent recovery. Past six hours poststroke, only one patient (11% +/- 21% SE) had partial recovery with relapse. The other eight past six hours had no recovery at all. The first three hours post-stroke HBO2 administration has the most promise for efficacy and improvement of rtPA therapy. HBO2 may also prove to be a useful challenge pre-rtPA administration to assess the risk-benefit ratio for giving rtPA.

Antiemetic efficacy of granisetron plus dexamethasone in bone marrow transplant patients receiving chemotherapy and total body irradiation.

Few trials exist regarding the antiemetic efficacy of granisetron in bone marrow transplant (BMT) recipients conditioned with high-dose chemotherapy and total body irradiation (TBI). In this single-center, open-label, prospective, trial, the antiemetic efficacy and safety of granisetron plus dexamethasone were evaluated in 26 patients conditioned with cyclophosphamide-containing regimens (the majority receiving 60 mg/kg per day on 2 consecutive days), and TBI (12 Gy divided over 4 days). Daily intravenous doses of granisetron 1 mg plus dexamethasone 10 mg were given 30 min prior to chemotherapy or radiation, and continued for 24 h after the last conditioning treatment for a median of 6 days (range 3-9). Emetic control was defined by the number of emetic episodes occurring within a 24 h period, or the requirement for rescue medication for nausea or vomiting. A total of 25 patients completed 186 evaluable treatment days. Response (emetic control by treatment days) was complete in 50% of patients, major in 48%, minor in 2%, and there were no failures. Adverse effects were minor, with diarrhea (15%), headache (14%), and constipation (11%) reported most often. Based on these results, the antiemetic regimen of granisetron plus dexamethasone appears effective and well tolerated during BMT conditioning with high-dose cyclophosphamide and TBI.

The correlation between neuropsychological and neuroanatomic changes over time in asymptomatic and symptomatic HIV-1-infected individuals.

To determine the relationship between neuroanatomic and neuropsychological changes in both asymptomatic and symptomatic HIV-1-infected individuals, we conducted a longitudinal study of 47 HIV-infected individuals, 15 of whom were asymptomatic and 32 of whom had either AIDS-related complex or AIDS. To measure neuroanatomic change over a 30-month period, we conducted quantitative MRI measures of bicaudate/brain ratio (BCR) and bifrontal/ brain ratio. A comparison of change over time between BCR and neuropsychological performance showed a correlation between increase in atrophy and worsening in certain cognitive functions. The correlation held for both asymptomatic and symptomatic groups, with more pronounced changes in the symptomatic group.

Vitamin B12 deficiency and nervous system disease in HIV infection.

BACKGROUND: Vitamin B12 deficiency may result in a number of neurological and neuropsychiatric disorders. Patients with human immunodeficiency virus type 1 (HIV-1) infection may have a high rate of vitamin B12 deficiency and nervous system disease. Vitamin B12 deficiency may contribute to neurological disease in HIV-1-infected individuals. OBJECTIVE: To evaluate the possible contribution of vitamin B12 deficiency to neurological disease in HIV-1-infected individuals. MAIN OUTCOME MEASURES: Comparison of serum vitamin B12 levels with neurological, neuropsychological, and mood state abnormalities in 153 HIV-1-positive subjects and 57 high-risk seronegative controls. A subgroup of 67 subjects underwent additional extensive clinical neurophysiological, cerebrospinal fluid, and magnetic resonance imaging evaluations. RESULTS: No statistically significant relationships were noted between vitamin B12 levels and abnormalities on any of the measures examined. CONCLUSIONS: This study does not indicate an important role for vitamin B12 deficiency in the neurological disease of HIV-1 infection.

Neuropsychologic functioning of human immunodeficiency virus-infected children with hemophilia.

Efforts to detect subtle but objective neuropsychologic deficits could clarify the early involvement of the central nervous system and the progression of human immunodeficiency virus (HIV) infection in older children and young adolescents. Baseline examinations of 63 children and adolescents with hemophilia were conducted by examiners unaware of HIV status or staging or of our study's major hypotheses. They measured six domains of neuropsychologic functioning (motor, language, memory, attention, visual processing, and problem solving), and no differences between groups of similar age, race, and socioeconomic status defined by HIV seropositivity (n = 25) and HIV seronegativity (n = 38) were revealed. A high incidence of subtle neuropsychologic deficits relative to (1) age norms and (2) individual cognitive potential was found on measures of motor performance, attention, and speeded visual processing within both infected and uninfected groups. On the basis of these baseline data, it seems premature to attribute early, subtle neuropsychologic deficits in seropositive children with hemophilia to the central nervous system effects of HIV infection.

Cerebrospinal fluid analysis in human immunodeficiency virus infection.

Cerebrospinal fluid (CSF) analytes were evaluated in 59 human immunodeficiency virus (HIV+) individuals to assess neurological involvement. Glucose, total protein, cell counts, p24 antigen, CSF: serum albumin/IgG ratios, and oligoclonal bands were measured. Eighty percent of samples showed abnormalities in one or more analyte. In some patients samples, these abnormalities could mimic those of secondary opportunistic infection when none was present. The presence of oligoclonal banding in CSF (31 percent) and disturbances in CSF: serum albumin/IgG ratio (30 percent) were related to decreases in serum CD4+ lymphocytes. Disturbances in CSF: Serum albumin/IgG ratio were also related to severity of non-neurological HIV disease staging. Cerebrospinal fluid oligoclonal bands were distinct from that found in serum in the same subjects. Since immune complexes between immunoglobulins and enzymes are observed in these same patients, these oligoclonal bands may result in artifactually elevated enzyme results secondary to decreased clearance leading to erroneous clinical decisions. There was no significant relationship between any abnormalities and the presence of neurologic disease as established by a wide variety of other studies. It is important to recognize the limits of CSF interpretation in this patient group.

Peripheral neuropathy in a cohort of human immunodeficiency virus-infected patients. Incidence and relationship to other nervous system dysfunction.

A cohort of 94 patients infected with human immunodeficiency virus was evaluated clinically and electrophysiologically for the presence of peripheral neuropathy, and the results were compared with evaluations of central nervous system function. Thirty-two (34%) had some degree of peripheral neuropathy; 18 (19%) (six [12%] of the 49 asymptomatic patients, five [45%] of the 11 patients with acquired immunodeficiency syndrome [AIDS], and seven [21%] of the 34 patients with AIDS-related complex) had neuropathy on clinical examination; and 21 (23%) (eight [16%] asymptomatic, four [36%] AIDS, and nine [26%] AIDS-related complex) had neuropathy on electrophysiologic evaluation. There was a significant correlation between the presence of neuropathy and evidence of central nervous system dysfunction.

Pegademase bovine: replacement therapy for severe combined immunodeficiency disease.

Severe combined immunodeficiency (SCID) represents a syndrome characterized by abnormal function of cellular and humoral immunity. Of the various types of SCID, approximately one-fourth are associated with adenosine deaminase (ADA) deficiency. Treatment consists of bone marrow transplantation, red blood cell transfusions, enzyme replacement, and, more recently, gene therapy. Pegademase bovine is the sole agent available for enzyme replacement therapy of SCID associated with ADA deficiency. The drug is administered intramuscularly to infants from birth and to children of any age at time of diagnosis. At present, few adverse effects or drug interactions have been documented. Although it is expensive (approximately $60,000 annually), pegademase bovine offers an alternative to standard means of therapy.