Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders

Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the "immunocannabinoid" system. This system can be an important signaling pathway for immune modulation. To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation. The CB2 cDNA 188-189 GG/GG polymorphism predicts the substitution of glutamine at amino acid position 63 by arginine. T lymphocytes from CB2 188-189 GG/GG homozygotes had approximately twofold reduction of endocannabinoid-induced inhibition of proliferation compared with cells from CB2 188-189 AA/AA homozygotes. In GG/GG subjects, the reduced endocannabinoid inhibitory response was highly significant for N-arachidonylglycine and nearly significant for 2-arachidonylglycerol, and a specific CB2 receptor antagonist partially blocked these effects. Also, patients with autoimmune diseases had an increased prevalence of the homozygous GG/GG genotype. Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188-189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity. The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses while avoiding CB1 receptor-mediated cannabinoid adverse effects.     

Fowl plague virus adapted to human epithelial tumor cells and human myeloblasts in vitro

Summary A strain of avian influenza A virus, originally isolated from an epidemic among turkeys, was adapted to human cells by serial passages. Four passage levels of the virus were compared with respect to their growth potential in human cell monolayers and their plaque morphology in chick embryo fibroblasts and in HeLa cells. The original virus, never passed in human cells before, was already able to replicate in human cells. Serial passages in human epithelial cells increased this ability. Further serial passages in human myeloblasts resulted in the selection of an apparently stable mutant which grew well in human malignant epithelial cells and even better in diploid human fibroblasts.     

Heterogeneous malignant non Hodgkin's lymphomas as a causative disorder in lethal midline granuloma

Summary The present report describes the results of a combined morphological, enzyme- and immunohistochemical analysis of nine cases of malignant non Hodgkin's lymphomas (NHL) clinically presenting as lethal midline granuloma. In a previous report written before antibodies directed against B and T lymphocytes were available, a histiocytic origin of such neoplasms had been suggested. A panel of antibodies reactive with most B cells (L26, MB1, KiB3) and a majority of T cells (MT1, UCHL1) was applied on paraffin sections of formalin fixed tissues as well as antibodies directed against leukocyte common antigen (LCA), myeloid/histiocyte antigen (MAC 387), lysozyme, alpha-1-antitrypsin, alpha-1-antichymotrypsin, S-100 protein, prekeratin and immunoglobulin light chains. Enzyme histochemistry included tests for non-specific acid esterase, acid phosphatase, betaglucuronidase and chloroacetate esterase. As a result, five T, two B and two unclassified (malignant histiocytosis probable) NHL were identified, indicating distinct heterogeneity of NHL as causative disorders in lethal midline granuloma.     

RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database.

PURPOSE: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). PATIENTS AND METHODS: Eligibility criteria were age > or = 18 years, Karnofsky performance score > or = 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. RESULTS: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P =.0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P =.006). There was a 54% reduction in the risk of death for RSR13 patients (P =.0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. CONCLUSION: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.     

Vascular compression of the airway: Indications for and results of surgical management

Vascular compression of the airway is a significant cause of respiratory compromise in children. While the indications for surgical repair are sometimes life threatening, they can also be subtle. This retrospective study examines 45 surgical cases of tracheobronchial compromise secondary to vascular compression at a large children's hospital between July 1983 and February 1996. A total of 34 were diagnosed with innominate artery compression, ten with a double aortic arch and one with an anomalous right subclavian artery. The 45 patients, 25 male and 20 female, ranged in age from 12 days to 11 years at surgery (average 13 months). A total of 21 (47%) presented with proven or suspected episodes of cyanosis or apnea. All 45 patients had evidence of vascular compression during microlaryngoscopy and bronchoscopy. The diagnosis was confirmed by magnetic resonance imaging (MRI) in 23/45 (51%), barium swallow in 22/45 (49%) and aortogram in 3/45 (7%). There was one death. One patient had a tracheotomy before surgery and continues to require it after surgery. Complete resolution of symptoms was achieved in 39/45 (87%) with five requiring more than one operation before their symptoms resolved completely. A total of four patients experienced a recurrence of symptoms within a variable length of time after surgery. Surgical indications and treatment alternatives will be discussed.     

A follow-up study of infants ≤ 2000 g birthweight treated in central Queensland

This follow-up study was undertaken in an effort to ascertain the morbidity in the survivors of infants ≤2000 g birthweight cared for in the two Rockhampton intensive care nurseries.

Methodology:

The records of all infants ≤2000 g delivered in or transferred to Rockhampton during the 11 year period 1979 through 1989 inclusive were extracted. Efforts were made to contact and examine all of these children. Those found to be disabled were assessed as being mildly, moderately or severely affected.

Results:

Of the 482 infants of birthweight ≤2000 g treated in the period under review, 393 survived to be discharged from hospital. Eight were known to have died subsequently. Of the remaining 385 children, 288 (74.8%) were able to be contacted and their health status determined. A total of 36 infants were found to have significant disabilities. Twenty-four were mildly affected, five moderately and seven severely affected. Severe disability in infants of ≤1000 g was 16% (3/19).

Conclusions:

The incidence of disability was established in 74.8% of the surviving population, It was not dissimilar to the incidence of disability in similar birthweight groups in some Australian tertiary centres for the years under study. It is emphasized that the follow-up was incomplete and recognized that the survival rates and incidence of disability in survivors has improved in tertiary centres since the time frame of this study.