T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years

In 1990, a clinical trial was started using retroviral-mediated transfer of the adenosine deaminase (ADA) gene into the T cells of two children with severe combined immunodeficiency (ADA- SCID). The number of blood T cells normalized as did many cellular and humoral immune responses. Gene treatment ended after 2 years, but integrated vector and ADA gene expression in T cells persisted. Although many components remain to be perfected, it is concluded here that gene therapy can be a safe and effective addition to treatment for some patients with this severe immunodeficiency disease.     

Functional characterisation of P2 purinoceptors in PC12 cells by measurement of radiolabelled calcium influx

The aim of this study was to determine whether 45Ca2+ influx could be used as a quantitative measure of channel activation for functional characterisation of P2X purinoceptors in cell lines. In undifferentiated PC12 cells, grown in suspension, ATP (EC50 = 45 microM), ATP gamma S (EC50 = 50 microM) and 2-meSATP (EC50 = 81 microM) but not alpha beta meATP (1 mM) stimulated 45Ca2+ influx 2-5 fold. This effect did not appear to be due to activation of P2U or P2Y purinoceptors since 1 mM UTP, ADP or ADP beta S did not produce any significant effect. Similarly, the effects of ATP were not apparently mediated through activation of P2Z purinoceptors since dibenzylATP behaved as a weak (EC50 = 191 microM) partial agonist (Maximal effect 29.5% of ATP maximum) and there was no detectable ATP-stimulated ethidium bromide uptake in the PC12 cells. ATP-stimulated 45Ca2+ influx was not affected by nifedipine suggesting that it was not secondary to activation of L-type calcium channels and rather reflected influx through a P2X purinoceptor present in these cells. The ATP-stimulated 45Ca2+ influx could be reduced by monovalent cations, presumably as a result of direct competition for influx through the cation channel, with the following rank order of potency:- guanidinium (EC50 = 16 mM) > sodium > Tris > choline > N-methyl-D-glucamine = sucrose). A number of P2 purinoceptor antagonists inhibited ATP-stimulated 45Ca2+ influx. Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (3-300 microM), pyridoxal 5-phosphate (3-300 microM) and d-tubocurarine (30-300 microM) produced an insurmountable antagonism of responses to ATP, with no marked change in agonist EC50. Suramin (100-300 microM) and cibacron blue (30-300 microM) produced a surmountable antagonism while DIDS (4,4'-diisothiocyanatostilbene-2,2'disulfonic acid) only antagonised responses to ATP at concentrations in excess of 300 microM. The general properties of the P2X purinoceptor population identified in these cells were consistent with them being P2X2 purinoceptors. These findings suggest that ATP-stimulated 45Ca2+ influx may be used as a reliable and quantitative functional assay for characterisation of P2X purinoceptor subtypes in cell lines.     

Protection by endoscopy against death from colorectal cancer. A case-control study among veterans

BACKGROUND: Although several clinical and epidemiologic studies suggest that timely diagnostic procedures of the large bowel may reduce mortality from colorectal cancer, the evidence for this relationship is primarily circumstantial. METHODS: A case-control study was conducted among hospitalized US military veterans to investigate whether diagnostic procedures of the large bowel were performed in the period preceding the diagnosis of colorectal cancer less frequently in patients dying of colorectal cancer than in control patients. Data files of a total of 4411 veterans dying of colorectal cancer between 1988 and 1992 were extracted from the records of the US Department of Veterans Affairs, Washington, DC. Data of four living control patients and four dead control patients without colorectal cancer were matched by age, sex, and race to each case patient. The case and the two control populations were compared by conditional logistic regression, calculating odds ratios, and their 95% confidence interval. RESULTS: Diagnostic procedures of the large bowel reduced mortality from colorectal cancer, the odds ratio being 0.41 (range, 0.33 to 0.50) for the comparison with living control patients. The protective effects of proctosigmoidoscopy, colonoscopy, and polypectomy lasted for 5 years. The procedures were protective against death from cancer of the colon, as well as cancer of the rectum. The most protective influence was associated with removal of tissue through biopsy, fulguration, and polypectomy. Similar influences were found comparing case patients with dead control patients. CONCLUSION: Removal of tissue represents the most effective means to reduce mortality from cancers of the large bowel. It retains its efficacy over a time period of 5 years.     

Metastasizing auricular basal cell carcinoma

Basal cell carcinoma represents the most common skin cancer and involves the head and neck area in 80% to 85% of all patients treated. Despite their frequent occurrence, metastatic spread from these tumors is rare. This paper presents a case of a patient who had a metastasizing basal cell carcinoma. Despite control of primary disease by radical surgery and adjunctive irradiation, bony metastasis was found within nine months of therapy. Palliative therapy was given, but the patient died five months later. The pathophysiology of the metastasizing basal cell carcinomas is described, and a rationale for therapy presented.     

Prolongation of responses in decentralization supersensitivity

In chronically decentralized nictitating membranes of cats the responses to norepinephrine and to acetylcholine were markedly prolonged. The increased duration was not directly related to the increased amplitude of the contractions. It is likely to be due to a change of the muscle itself.     

Sensory nerve conduction velocity: technical requirements and normal values for branches of the radial and ulnar nerves of the dog

Conduction velocities of compound action potentials of sensory axons of alteral superficial radial (LSR) and dorsal ulnar nerves (DUN) of the dog were determined by averaging potentials evoked and recorded through subcutaneous needle electrodes. Suitable locations for electrodes were identified and specificities of sites for LSR and DUN were verified by recording before and after cutting the nerves. Stimulus rates of 4/second to 20/second did not markedly affect conduction velocities. Increasing stimulus intensity in steps from threshold to 8 X threshold recruited more axons into the compound action potentials but resulted in interference from movement and muscle potentials at 4 X or 8 X threshold. Mean conduction velocities at 2 X threshold were: LSR = 61.7 +/- 0.76 SEM; DUN = 68.1 +/- 2.71 SEM.