SNP screening of central MHC-identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi's sarcoma.

The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi's sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and human herpes virus-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls. We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a fourfold increase of risk (odds ratio (OR)=4.09; 95% confidence interval (CI)=1.90-8.80; P=0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI=2.54-43.6; P=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120-kb-long haplotype (OR=1.52; 95% CI=1.01-2.28; P=0.047) formed by rs7029 A>G (GPANK1 3' untranslated region), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 read through) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.

Wake-up Strokes Are Similar to Known-Onset Morning Strokes in Severity and Outcome.

BACKGROUND: Stroke symptoms noticed upon waking, wake-up stroke, account for up to a quarter of all acute ischemic strokes. Patients with wake-up stroke, however, are often excluded from thrombolytic therapy. METHODS: Using our prospectively collected stroke registry, wake-up stroke and known-onset morning strokes were identified. Wakeup stroke was defined as a patient who was asleep >3 hours and first noted stroke symptoms upon awakening between 0100 and 1100. Known-onset morning stroke was defined as a patient who had symptom onset while awake during the same time interval. We compared wake-up stoke to known-onset morning stroke with respect to patient demographics, stroke severity, etiology and outcomes. RESULTS: One-quarter of patients with acute ischemic strokes (391/1415) had documented time between 0100 and 1100 of symptom onset: 141 (36%) wake-up strokes and 250 (64%) known-onset morning strokes. No difference in baseline characteristics, stroke severity, stroke etiology, neurologic deterioration, discharge disposition or functional outcome was detected. Known-onset morning stroke patients were significantly more likely to get thrombolytic therapy and have higher risk of in-hospital mortality. Wake-up stroke patients tended to be older, have higher diastolic blood pressure and have longer length of hospital stay. DISCUSSION: While patients with wake-up stroke were similar to patients with known-onset morning stroke in many respects, patients with known onset morning stroke were significantly more likely to get treated with thrombolytic therapy and have higher in-hospital mortality.

Confirmation of allele HLA-A*3116 found in a family of a leukaemia patient with Caucasian and Caribbean origin.

We confirm allele HLA-A*3116 that we found in the family of a leukaemia patient of mixed Caucasian and Caribbean origin by sequence based typing. This allele is closest related to HLA-A*310102 with one nucleotide replacement at position 221 (C>T) leading to an amino acid substitution at position 50 of the mature protein from proline to leucine. As the amino acid at position 50 in the alpha 1 domain is part of the peptide-binding region, this change could be relevant for the functionality in peptide presentation.

Randomized phase III study of granulocyte transfusions in neutropenic patients.

Despite antibiotics, antifungals and haematopoietic growth factors, infections remain a major threat to neutropenic patients. To determine the role of granulocyte transfusions (GTs) in anti-infective therapy during neutropenia, GT administration was randomized in 74 adults with haematological or malignant diseases, febrile neutropenia and pulmonary or soft-tissue infiltrates after conventional or high-dose chemotherapy, a majority of them after allo-SCT (n=39). Neutrophil reconstitution was equal in the treatment and control arm. GT toxicity was minimal. The probability of 28-day survival after randomization was >80% in both groups, and no effect of GT on survival until day 100 could be detected in patients with fungal (n=55), bacterial or unknown infection (n=17) and various levels of neutropenia (ANC <500 vs >500 x 10(6)/l). These findings can be attributed primarily to procedural obstacles, such as long delay from randomization to first GT, low cell content and slow sequence of GT, difficulties in randomizing a safe and potentially life-saving treatment in severely endangered individuals, and a large proportion of rapidly recovering patients in both arms. The requirement of another trial in a more specific patient population with daily transfusions of sufficient numbers of granulocytes to support or refute the empirically acknowledged benefits of GT is discussed.

Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial.

BACKGROUND: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. OBJECTIVE: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. DESIGN: An open randomized, controlled, multicenter trial, powered for equivalence. SETTING: 60 oncology centers in 10 countries. PATIENTS: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. INTERVENTION: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. MEASUREMENTS: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. RESULTS: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. CONCLUSIONS: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

Comparison of toxicity and outcome in patients with acute myeloid leukemia treated with high-dose cytosine arabinoside consolidation after induction with a regimen containing idarubicin or daunorubicin.

The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one (n = 6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses, and another (n = 10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (< 500 neutrophils/microl) following HDara-C/DNR was 31.2 +/- 16 days (mean +/- SEM) in the IDA group compared with 18.7 +/- 5 days in the DNR group (p < .001 Mann-Whitney U-test). The duration 'of thrombocytopenia (platelets < 25000/microl) was 34.8 +/- 20 days in the IDA group vs. 18.5 +/- 6 days in the DNR group (p < .005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 +/- 24 vs. 6.9 +/- 5.2 days). A greater incidence, length (11 +/- 8 vs. 1.2 +/- 2 days), and severity of diarrhea were observed in the IDA-pretreated group. Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group 6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was 87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be proven in larger trials.

[Pulmonary complications of induction therapy in acute myeloid leukemia in adults. Findings in chest x-rays and computer tomography]. / Pulmonale Komplikationen der Induktionstherapie bei akuter myeloischer Leukämie des Erwachsenen. Befunde in Thoraxübersichtsaufnahme und Computertomographie.

UNLABELLED: To exclude pulmonary complications, 359 chest radiographs and 50 computed tomographs of the lung were performed in 95 patients suffering from acute myeloid leukemia. The radiological findings were registered, described and correlated with clinical findings in the present study on 2395 days of observation. RESULTS: In summary, 52 patients showed alterations of the lung. Pulmonary hyperhydration was seen in 21 cases, bacterial pneumonia was found in 18 cases, invasive pulmonary aspergillosis was documented in 14 cases, and 5 cases of severe haemorrhage were seen. An unexplained pulmonary edema in 13 patients with interstitial and alveolar infiltrates is considered to be a complication of treatment with cytosine- arabinoside. CONCLUSION: The results demonstrate that chest X- ray and computed tomography have a high impact in detection and treatment of pulmonary complications following intensive chemotherapy. We may expect the development of diffuse opacity following administration of cytosine-arabinoside in medium-sized doses.

Progressive formation of neuritic plaques and neurofibrillary tangles is exponentially related to age and neuronal size. A morphometric study of three geographically distinct series of aging people.

Neuronal size and the incidence of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were morphometrically and quantitatively studied in the entorhinal cortex of 300 autopsied individuals without dementia in three geographically distinct series (Brazil, Germany and Japan), and an additional series including 30 clinically diagnosed Alzheimer's disease patients. The mean ages at onset of NPs and NFTs were similar between the three normal series, and the incidence of NPs and NFTs increased exponentially with age, but at different rates. A correlation was found between larger neuronal size and higher incidence of NPs and NFTs. Neuronal size distribution largely seemed to account for the differences between the series. While the onset of neurodegeneration may be tightly programmed, i.e., in a species-specific manner, our data support the idea that the incidence of NPs and NFTs and the progression from NPs to NFTs may vary remarkably, depending on neuronal size.

Stroke rehabilitation: a family-team education program.

A stroke causes considerable anxiety and practical difficulties to the family of the patient. Additional confusion results because the difference between the acute care and the prolonged rehabilitation is poorly understood. For these reasons, a family-team conference was established at the Massachusetts Rehabilitation Hospital. Its purpose was to relieve anxiety and explain the scientific and professional aspects of the team approach to rehabilitation. The family-team program consisted of role descriptions presented by the representatives from the various disciplines involved in the rehabilitation process and a discussion of individual family-patient problems. Results of a three-year study were used to evaluate the sucess of the conference. Records of family attendance were compared with the number of persons contacted. Questionnaires completed by family members at the conference showed that the anxiety level of individual families had decreased. A better understanding of the team approach was indicated in more than 75% of those participating. More than 70% of the families felt more comfortable in visits to their relatives and in approaching team members with future questions. The family-team program is a practical instrument for expanding stroke rehabilitation and for including the needs and participation of the family.