Genetics of schizophrenia in the South African Xhosa.

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

Intralesional granulocyte-monocyte colony-stimulating factor followed by subcutaneous interleukin-2 in metastatic melanoma: a pilot study in elderly patients.

AIM AND BACKGROUND: Recent data in the literature indicate that antigen-presenting cells (APC) are inactive in tumour tissue because of local immunosuppression. Tumour-infiltrating lymphocyte (TIL) signal activation transducing mechanisms are also seriously impaired. Administration of granulocyte macrophage-colony stimulating factor (GM-CSF) may lead to APC recovery and interleukin (IL)-2 may restore local TIL activation. Moreover, IL-2 increases the systemic lymphocyte population, an event that seems to correlate with a better prognosis. STUDY DESIGN: The present phase I-II study was carried out to examine whether intralesional injection of GM-CSF followed by subcutaneous IL-2 would induce a clinical response in advanced, pretreated elderly melanoma patients. METHODS: Sixteen patients over 60 years of age received intralesional GM-CSF (150 ng per lesion on day 1), generally divided between the two largest cutaneous lesions, followed by perilesional subcutaneous IL-2 (3,000,000 IU) for 5 days (days 3-7 inclusive) every 3 weeks. RESULTS: Four clinical responses [two partial (PR) and two minimal (MR)] (25%), which also involved lesions that had not been directly treated, and nine cases of stable disease were observed. The response duration for PR and MR was 9, 4, 4 and 2.5 + months, respectively. Stable disease (56%) recorded in the nine patients was short-term (3-6 months). Three patients rapidly progressed after two, two and one therapy cycles, respectively. The patient who reached the best PR had a fairly high absolute lymphocyte count (1600-2400/mm3). The second one, who reached complete remission after subsequent locoregional chemotherapy and hyperthermia, however, had a low absolute lymphocyte count that had doubled by the end of treatment. Blood lymphocyte values in the other patients were too varied to allow any correlation with clinical response. Therapy was well tolerated and only mild fever was observed, with the exception of one patient who had grade 3 fever, with muscle pain and arthralgia. CONCLUSIONS: Considering the very low toxicity observed, this treatment might be indicated in elderly patients for whom systemic therapy is no longer a viable option. Improved scheduling and timing could result from further studies.

Detection of germline BRCA1 mutations by Multiple-Dye Cleavase Fragment Length Polymorphism (MD-CFLP) method.

We describe the Multiple-Dye Cleavase Fragment Length Polymorphism (MD-CFLP) method set up for a sensitive and preliminary rapid screening of BRCA1 mutations. We analysed exons 11 and 16, which are known to cover slightly more than 70% of the whole coding region of the gene, subdivided into 4 amplicons and labelled with different fluorescent dUTPs. MD-CFLP was first utilised on a panel of 30 DNA samples in which the presence of single-base substitutions or small deletions/insertions had been previously identified by direct sequencing as gold standard, in order to define the optimal conditions in terms of PCR amplification and temperature of digestion. In a second step, we blindly analysed 21 DNA samples by MD-CFLP to verify its reliability. The sensitivity and specificity of MD-CFLP were both 100% in the first study, and 80% and 94%, respectively, in the blind sample assay. Our results demonstrate the capability of the MD-CFLP method to detect DNA sequence alterations in fragments of more than 1 kb. We conclude that CFLP is a powerful tool in mutational analysis, offering reliable results in a shorter time and at a lower cost than conventional methods, and its potential can be enhanced when internal fluorescent labelling and laser detection are used.

Resection with curative intent after endoscopic treatment of airway obstruction.

BACKGROUND: Endoscopic treatment of malignant central airway obstructions usually is done for palliation. The exact role of such a procedure as preparatory to operation remains controversial. METHODS: From 1987 through 1996, 24 patients at our institution underwent tracheobronchial pulmonary resection after preliminary endoscopic treatment. During the same period, 304 patients underwent 449 operative rigid bronchoscopies for airway obstructions, most involving the use of a neodymium:yttrium-aluminum-garnet laser. The indications for operation were squamous cell carcinoma in 14 patients, bronchial gland tumors in 8 patients, and papillary thyroid cancer infiltrating the trachea in 2 patients. The total resection rate was 9.5% (5% for squamous cell carcinoma, 75% for low-grade malignant bronchial tumors, and 75% for papillary thyroid cancer). The median period between operative rigid bronchoscopy and operation was 18 days. RESULTS: No complications were observed after endoscopic treatment. There were two perioperative deaths (adult respiratory distress syndrome after carinal resection and pulmonary embolism after pneumonectomy) and one major complication (poor postoperative pulmonary function after pneumonectomy). No anastomotic complications were observed in the tracheobronchoplastic procedures. Follow-up was possible in every patient but 1: 6 patients died at a median of 30.5 months after operation (range, 3 to 46 months), 2 patients are alive with disease, and the rest are alive without evidence of disease at a median of 21 months (range, 2 to 61 months). CONCLUSIONS: Most patients who require endoscopic therapy for malignant airway obstructions are not candidates for operative resection. Preliminary endoscopic relief of obstruction can increase operability and improve surgical results in a highly selected group of patients.

Evaluation of the minimum instream flow of the tiber river basin.

This paper discusses various methods for calculating the minimum instream flows for the protection of aquatic life for the purpose of illustrating its increasing complexity. These procedures are the Montana method (Tennant, 1976); the wetted perimeter method (Collings, 1974; Cochnauer, 1976) and the IFIM method (Instream Flow Incremental Methodology; Bovee, 1982). An analysis is then made of some regionalisation criteria based on these methods, from which useful suggestions can be drawn for the development of a procedure to be applied to basins. A method is thus proposed for calculating the recommended flows for protecting the aquatic environment based on simple hydrological variables, such as Q7 10, which can be estimated for a basin on the basis of area A and a Base Flow Index (BFI) which summarises its hydrogeological characteristics. This approach can be used when the field data necessary for more complex methods is not available. These require the defining of the environmental suitability of a watercourse for certain designated reference fish species, according to the flow and the morphology of the channel. The positive results of this approach were verified by Leonard (1990) and this methodology was applied to the Tiber river basin.