Alagille syndrome and optic pit

Background Optic disc anomalies are frequently associated with Alagille syndrome. We report here the first case of a patient with Alagille syndrome combined with optic pit and serous macular detachment. Methods A male patient with Alagille syndrome was referred from the pediatric hepatology department for investigation of visual loss in the right eye. Anterior segment examination showed evidence of posterior embryotoxon, confirmed by gonioscopic evaluation. Dilated fundus examination revealed serous macular detachment and optic pit. Results OCT 3 scans confirmed the clinical findings. Conclusions Optic pit is uncommon and should prompt a search for genetic disorders or development abnormalities. The association between the two syndromes in this patient might be due to failure of correct neuroectodermal development, for which a common genetic pathway is likely.     

Rapp-Hodgkin Syndrome with Pili Canaliculi

Abstract: A 20-year-old woman and her 12-year-old brother had hypohidrotic ectodermal dysplasia, cleft lip and palate, midfacial hypoplasia with narrow nose from the nasal bridge to the tip, narrow dysplastic nails, and conical teeth and hypodontia, and hypospadias and hypoplastic uvula in the boy. The woman had major underdevelopment of intellectual capacity. The most important hair anomalies in both siblings were sparse eyebrows, pili torti, and pili canaliculi. Some of the pili canaliculi had two canals (pili bicanaliculi), and the cross section for scanning electron microscopy had a quadrangular aspect. This is the seventh family reported with Rapp-Hodgkin ectodermal dysplasia.     

Transglutaminase in cell proliferation and transformation

Transglutaminase (TGase) activity was reduced in intact mitogen-stimulated human peripheral blood lymphocytes (PBL) when compared to intact resting PBL. Moreover, a treatment of the same quiescent immunocompetent cells with purified liver TGase and Ca²⁺ completely suppressed the mitogen-induced blast transformation. A decrease in TGase activity in neoplastically transformed seminal vesicle epithelial cells with respect to their normal parent counterpart was also observed. Our data support the notion of a possible implication of TGase in cell proliferation and transformation.     

Therapeutic criteria in hydrocephalic children

The xanthine, hypoxanthine, and total oxypurine levels were determined in the CSF of 28 hydrocephalic patients (age from newborn to 2 years) and 8 healthy controls using HPLC. The Evans' index, the mean weekly increase in cranial circumference, and the intracranial pressure were also measured. Of the hydrocephalic patients 13 were self-compensated and the other 15 had a shunt implanted during the course of the study. The mean xanthine, hypoxanthine, and total oxypurine levels in the normal children were 5.20, 5.94, and 11.29 mol/l, respectively. In the self-compensated hydrocephalics these levels were 5.17, 5.71, and 10.79 mol/l, respectively. In the noncompensated hydrocephalics, they were 9.90, 9.91, and 19.82 mol/l. The differences between the latter group and the first two are statistically significant (P<0.001). The mean Evans' index and the mean weakly increase in cranial circumference in the self-compensated hydrocephalics were 0.35 and 0.25 cm, respectively. In the noncompensated hydrocephalics, they were 0.55 and 0.95 cm. The differences between the two groups are statistically significant (P<0.001). Two weeks after implantation of shunts in the noncompensated cases, the mean xanthine, hypoxanthine, and total oxypurine levels fell to 4.22, 4.57, and 8.80 mol/l, respectively. These changes are statistically significant (P<0.001). We think that the two criteria (clinical and biochemical) are equally useful for the prediction of self-compensation in hydrocephalic children and that the oxypurine values after shunt implantation can be used to monitor progress in noncompensated cases.     

Effect of dipyridamole on fluorodeoxyuridine cytotoxicity in vitro and in cancer patients

Summary Dipyridamole (DP) has previously been studied both in vitro and in vivo in combination with various antimetabolites, including methotrexate and 5-fluorouracil (5FU). We evaluated in vitro and clinically the effects of adding DP to fluorodeoxyuridine (FUDR) in colorectal cancer. Using a human colony-forming assay, we observed that 0.05 M DP increased the cytotoxicity of FUDR by a median of 33.5-fold vs 1.5-fold for 5FU against human colon-cancer cell lines. The mechanism of the DP-enhanced antitumor activity of FUDR is not completely understood but appears to be related to a profound inhibition by DP of thymidine accumulation in and FUDR efflux from colon-cancer cell lines. On the basis of these in vitro results, 28 patients with metastatic colon cancer were entered in a clinical trial of monthly courses of 0.1 mg/kg FUDR daily for 14 days and 75 mg oral DP 5 times daily for 14 days starting on the 3rd day of continuous i.v. FUDR infusion. The pharmacokinetics of DP was studied in three patients; the results showed that 98% of total serum DP was protein-bound and that free DP levels were significantly lower than the concentrations necessary for the expected in vitro DP/FUDR modulation. Treatment was well tolerated, with only 12 patients developing mild to moderate toxicity. Of 27 evaluable patients, 4 achieved a partial response that lasted 2, 3, 5, and 6+ months. This relatively low response rate (15%), which is similar to that achieved with FUDR alone, may be explained by the low steady-state plasma concentrations of free DP achieved in our patients. Other means of DP administration, such as i.v., i.a., and i.p. injection, may be required to achieve free DP concentrations necessary for successful biochemical modulation of FUDR in patients.Supported in part by grants CA17094, CA23074, and CA39629 from the National Institutes of Health, Bethesda, Md 20205, and a grant from the Arizona Chronic Disease Commission. HSG is a recipient of an American Cancer Society Career Development Award     

The potential role of lonidamine (LND) in the treatment of malignant glioma

Summary Up-to-date unsatisfactory results obtained in multimodality treatments of malignant glioma have prompted the research of new therapeutic modalities with unconventional modes of action. Lonidamine (LND) is a drug which reduces aerobic glycolytic activity in both human and experimental tumors. This effect mainly depends on the inhibition of mitochondrially-bound hexokinase (HK) which is present in large amounts in malignant cells. A Phase II study was conducted on patients with recurrent glioma; 12 patients were admitted to the study. Clinical side effects were moderate, necessitating a reduction of the dosage in only 1 case. The objective results were evaluated according to the indications of Levin. 2 responders and 3 cases of stable disease were observed out of 10 evaluable patients. The potential value of this new drug is discussed.     

Neutralization assay using a modified vaccinia virus Ankara vector expressing the green fluorescent protein is a high-throughput method to monitor the humoral immune response against vaccinia virus

Vaccination against smallpox is again considered in order to face a possible bioterrorist threat, but the nature and the level of the immune response needed to protect a person from smallpox after vaccination are not totally understood. Therefore, simple, rapid, and accurate assays to evaluate the immune response to vaccinia virus need to be developed. Neutralization assays are usually considered good predictors of vaccine efficacy and more informative with regard to protection than binding assays. Currently, the presence of neutralizing antibodies to vaccinia virus is measured using a plaque reduction neutralization test, but this method is time-consuming and labor-intensive and has a subjective readout. Here, we describe an innovative neutralization assay based on a modified vaccinia virus Ankara (MVA) vector expressing the green fluorescent protein (MVA-gfp). This MVA-gfp neutralization assay is rapid and sensitive and has a high-throughput potential. Thus, it is suitable to monitor the immune response and eventually the efficacy of a large campaign of vaccination against smallpox and to study the vector-specific immune response in clinical trials that use genetically engineered vaccinia viruses. Most importantly, application of the highly attenuated MVA eliminates the safety concern in using the replication-competent vaccinia virus in the standard clinical laboratory.