Eledoisin and lacrimal secretion in the rabbit

Eledoisin has been tried as a possible treatment for dry eye based on the hypothesis that it pharmacologically stimulates tear secretion when topically applied to the eye. To determine if topically applied eledoisin pharmacologically stimulates orbital lacrimal secretion, the orbital lacrimal gland excretory duct of normal rabbits was cannulated, and eledoisin was applied topically with and without prior administration of proparacaine. To determine if topically applied eledoisin stimulated accessory lacrimal gland secretion, isotonic buffer with and without eledoisin was tested in a rabbit model with only accessory lacrimal tissue remaining after the administration of proparacaine. Topically applied eledoisin did not pharmacologically stimulate lacrimal secretion but rather increased lacrimal gland secretion only in non-anesthetized eyes through a sensory reflex mechanism that is blocked by proparacaine.     

Phase I evaluation of diaziquone in childhood cancer

Summary We conducted a phase I clinical study of aziridinylbenzoquinone (Diaziquone, AZQ) given as a 4 hour infusion weekly × 4. Forty-five children with recurrent acute leukemia and 33 children with various advanced solid tumors participated. Severe myelosuppression was the dose limiting toxic effect, occurring in all patients at the upper dose levels. Gastrointestinal and hepatic toxicities were infrequent and not severe. No allergic reactions occurred. Objective tumor regression was noted in 3 of 25 patients with a CNS tumor and in 6 of 45 patients with acute leukemia. For phase II trials the recommended dosage of Diaziquone given by this schedule is 18 mg/M²×4 for patients with a solid tumor, and is 30 mg/M²/week × 4 for children with acute leukemia.     

Biochemical consequences of 5-fluorouracil gastrointestinal toxicity in rats; effect of high-dose uridine

Selective protection of the normal host tissues from the toxic effects of anticancer agents would allow the use of higher, probably more effective, doses of the drugs. It has been demonstrated that delayed high-dose uridine administration after 5-fluorouracil decreases the extent of myelosuppression and causes faster regeneration of the bone marrow. We studied the biochemical consequences of the gastrointestinal toxicity caused by 5-fluorouracil and the potential of high-dose uridine treatment to influence these adverse effects. 5-Fluorouracil caused dose-related decreases in the biochemical parameters (thymidine kinase, sucrase, maltase, alkaline phosphatase) selected as early markers of the impaired metabolic activity of the intestinal mucosa. The nadir of the biochemical changes was reached between 24 h and 72 h after 5-fluorouracil treatment, and complete regeneration of the mucosa took 6–7 days. Delayed high-dose uridine administration failed to mitigate the severity of the gastrointestinal damage that ensued after 5-fluorouracil treatment, but caused significantly earlier regeneration of the mucosa.     

Omeprazole: A Comprehensive Review

Omeprazole is a member of a new class of substituted benzimidazoles. These agents inhibit the proton pump in the gastric parietal cell, blocking the final step in the gastric acid secretory pathway. Omeprazole has been investigated for the treatment of gastric ulcer, duodenal ulcer, gastroesophageal reflux, and various hypersecretory states. The prolonged inhibition of gastric acid secretion allows for once-daily dosing in patients with peptic ulcer disease and gastroesophageal reflux, and once- or twice-daily dosing in patients with Zollinger-Ellison syndrome. Compared with currently available therapies, omeprazole is well tolerated and demonstrates a more rapid ulcer healing rate. It is superior to conventional therapies in the treatment of Zollinger-Ellison syndrome. Side effects are infrequent when the drug is used for the short-term management of ulcers.     

Role of intracortical mechanisms in the late part of the silent period to transcranial stimulation of the human motor cortex

Transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) of the human motor cortex produce a silent period (SP) following motor evoked potentials (MEPs). The early part of the SP can be explained by decreased alpha motor neuron excitability, whereas the late part is presumably due to suprasegmental mechanisms. In order to determine the level of the suprasegmental contribution to the generation of SPs, we recorded excitatory and inhibitory responses to TMS, TES, and percutaneous electrical brainstem stimulation (PBS) in the voluntarily activated first dorsal interosseous muscle of the hand. Stimulus intensities were set so that PBS and TES induced MEPs with areas equal to or larger than those of MEPs obtained with TMS. This procedure revealed that SPs were 49% and 83% shorter with TES and PBS, respectively, than with TMS. As TMS is more effective than TES or PBS in activating cortical interneurons, these findings support the idea that a significant component of the SP arises from intracortical mechanisms.     

Large granular lymphocyte expansions in patients with Felty's syndrome: analysis using anti-T cell receptor V beta-specific monoclonal antibodies.

Felty's syndrome (FS), the association of rheumatoid arthritis (RA) and idiopathic neutropenia, remains an unexplained phenomenon. HLA-DR4 is found in over 90% of cases. Patients with FS may have a T cell lymphocytosis of CD3+CD8+CD57+ large granular lymphocytes (LGL syndrome). In this study of 47 patients with FS, 19% had clear evidence for LGL expansions, while in total 42% had variable evidence for the LGL syndrome using currently available techniques. Of these T cell expansions, 76% were clonal, as demonstrated by Southern blotting and analysis with T cell receptor (TCR) beta chain constant region probes. This technique may fail to detect clonal populations in some patients. Cytofluorographic analysis using antibodies specific for TCR V beta chains identified patients with clonal LGL expansions with results comparable to those obtained with Southern blotting. No evidence for shared V beta usage among expansions from different patients was seen. The role of LGL in RA and FS is currently unclear, but this technique offers a practical and accessible means of identifying patients with LGL expansions, as a starting point for further investigation.     

Dorsal fracture of the hamate: distinctive radiographic appearance

Six patients who injured their wrists had radiographs documenting a dorsal, 5- to 10-mm oblong fragment of bone immediately proximal to the base of the fourth and/or fifth metacarpal bones. The fragment was seen on the pronation oblique and/or lateral projections, but not on the posteroanterior projection. The radiographic appearance of the fragment was remarkably similar in all cases. In the one patient in which it was performed, pluridirectional tomography demonstrated that the fragment originated from the dorsal surface of the hamate. Five of the six patients also had associated posterior dislocation of the fourth and/or fifth metacarpals. We conclude that this fragment represents a coronal fracture through the body of the hamate resulting from posterior dislocation or subluxation of the fourth and/or fifth metacarpal.     

Stimulus-secretion coupling of arginine-induced insulin release. Resistance of arginine- and ornithine-stimulated glucagon and insulin release to D,L-alpha-difluoromethylornithine

In the isolated perfused rat pancreas, D,L-difluoromethylornithine, tested at a concentration of 3 mmol/L, failed to affect the release of glucagon and insulin caused, over 15 min stimulation, by either L-arginine or L-ornithine (2.0, 5.0 or 10.0 mmol/L) in the presence of either 3.3 or 5.6 mmol/L D-glucose. The inhibition of ornithine decarboxylase also failed to affect the release of glucagon provoked by either L-leucine (2 or 3 mmol/L) or L-glutamine (2 mmol/L) and the secretion of insulin stimulated by a rise in glucose concentration from 5.6 to 10.6 mmol/L. These data are interpreted to suggest that the rapid generation of polyamines from either L-arginine or L-ornithine does not play any significant role in the immediate glucagonotropic and insulinotropic action of these cationic amino acids.     

The binding of blood-borne estrogens in normal vegetarian and omnivorous women and the risk of breast cancer

Serial blood samples were taken at two-hour intervals over a 24-hour period from 25 premenopausal vegetarians (12 vegans and 13 ovolactovegetarians) and from 21 omnivorous controls. All members of the former group had been on a vegetarian diet for a minimum of three years. The mean proportion of estradiol unbound to blood proteins was similar in both vegetarians (1.26%) and meat eaters (1.16%). However, the amount bound to albumin was significantly raised in vegetarians (50.1% vs. 43.1%, p less than 0.009), whereas that bound to sex hormone-binding globulin (SHBG) was correspondingly lower (48.7% vs. 55.8%, p = 0.01). Mean levels of SHBG were similar in vegetarians (59.9 nmole/l) and omnivores (62.0 nmole/l), as was the total amount of free fatty acid (0.42 mmole/l for both). Within the vegetarian group, no differences were detected between vegans and ovolactovegetarians.