Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid

We report the results of an expanded trial of 5-fluorouracil (FUra) combined with high-dose folinic acid for treatment of patients with advanced colorectal or gastric adenocarcinoma. In each treatment course, the patients received both FUra (340-400 mg/m2/day by iv infusion over 15 minutes) and folinic acid (200 mg/m2/day by iv bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete response (CR) and partial response (PR) rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to FUra attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates above 10(-5) M were achieved after a rapid single iv injection of 200 mg/m2 of folinic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

The glycine receptor: pharmacological studies and mathematical modeling of the allosteric interaction between the glycine- and strychnine-binding sites

The displacement by glycine of 3H-strychnine binding to rat spinal cord membranes cannot be explained by a simple competitive interaction. Indeed, protein-modifying reagents can completely abolish the inhibition of 3H-strychnine binding by glycine and other agonists, whereas the interaction of strychnine itself and other related compounds with the binding site is unimpaired. Moreover, glycine cannot inhibit completely saturable 3H-strychnine binding, the extent of its maximum inhibitory effect depending on the ionic composition of the medium. Hill coefficients less than 1 (whose magnitude also depends on the assay medium) were obtained from glycine displacement curves. These properties are consistent with a mathematical model of two different, but mutually interacting, binding sites for strychnine and glycine on the glycine receptor. The effect of ions and protein-modifying reagents might be explained in this model as modifications of the mechanisms that mediate the allosteric interaction, and/or the affinity of glycine for the receptor. The agonists beta-alanine and taurine and the new antagonists, THAZ, iso-THAZ, and 4,5-TAZA, also seem to interact with a site different from the strychnine-binding site, probably the glycine-binding site.     

Minocycline Hydrochloride Hyperpigmentation Complicating Treatment of Pyoderma Gangrenosum

Minocycline-associated hyperpigmentation is an uncommon side effect We report the case of a patient with pyoderma gangrenosum successfully treated with oral minocycline but complicated by marked hyperpigmentation in his pyoderma gangrenosum and acne scars. One of the clinical forms of minocycline hyperpigmentation includes dark-blue or black macules in depressed acne scars or other sites of skin inflammation; this pattern seems to be independent of the total cumulative dose and the skin process.     

An Absent Ophthalmic Artery or Carotid Siphon Signal on Transcranial Doppler Confirms the Presence of Severe Ipsilateral Internal Carotid Artery Disease

Transcranial Doppler ultrasound provides a useful adjunct to extracranial ultrasound in the diagnosis of carotid bifurcation disease. Previous studies have shown that collateral flow patterns and diminished flow velocities in the ipsilateral middle cerebral artery correlate with hemodynamically significant carotid disease. In a series of 7,054 carotid duplex and transcranial Doppler examinations, 12.5% (95% confidence interval [CI]: 8.7, 16.4) of 287 ophthalmic arteries ipsilateral to an apparent carotid occlusion had no detectable flow signal, compared with 0.5% (95% Cl: 0.3, 0.7) of 6,767 ophthalmic arteries ipsilateral to a nonoccluded carotid artery (p < 0.001 ). Carotid siphon signals were not detectable in 24.4% (95% Cl: 19.4, 29.4) of arteries ipsilateral to the carotid occlusion, versus 1.0% (95% Cl: 0.8, 1.3) ipsilateral to nonoccluded carotid arteries (p < 0.001 ). A significant number of absent ophthalmic artery and carotid siphon signals (5.7 and 8.7%, respectively) were also found in patients with 80 to 99% extracranial carotid stenosis. A subset of 216 studies with angiographic correlation confirmed the high association of these transcranial Doppler findings with severe stenosis or occlusion of the internal carotid artery. Primary ophthalmological disease or siphon occlusion did not explain these findings. An absent ophthalmic artery or carotid siphon signal on transcranial Doppler examination is believed to represent a failure to detect slow flow distal to severe carotid bifurcation lesions. As a sign of ipsilateral carotid occlusion, the sensitivities of absent ophthalmic artery and carotid siphon signals are quite low (12.5 and 24.4%, respectively). The high specificities of 99.5 and 99.0%, however, make these findings useful in confirming the diagnosis of presumptive carotid occlusion by carotid duplex ultrasound.     

Results of a randomized study of early stage Hodgkin's disease using ABVD,EBVD, or MBVD

From January 1986 to December 1989, 157 previously untreated patients, with Hodgkin's disease stage I or II without bulky disease, were enrolled in a clinical comparative study. The objectives of the study were to compare the efficacy and safety of using epirubicine or mitoxantrone instead of adriamycin in the combination chemotherapy regimen ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine). The complete response rate was better in the patients treated with the ABVD or EBVD regimens compared to the MBVD arm. Also, differences in overall survival and relapse-free survival were better in the patients who received ABVD or EBVD compared to the MBVD regimen. Hematological, gastrointestinal and cardiac toxicity were similar in the three groups. Dose intensity, delays and complications were also similar in the three groups. The mitoxantrone-containing regimen was found to have less efficacy in comparison to the other regimens tested in the present study in patients with favorable stage I or II Hodgkin's disease. © 1995 Wi1ey-Liss Inc.     

Impaired hair follicle morphogenesis and cycling with abnormal epidermal differentiation in nackt mice,a cathepsin L-deficient mutation

We previously described an autosomal-recessive mutation named nackt (nkt) exhibiting partial alopecia associated with CD4(+) T-cell deficiency. Also, we recently reported that nkt (now Ctsl(nkt)) comprises a deletion in the cathepsin L (Ctsl) gene. Another recent study reported that Ctsl knockout mice have CD4(+) T-cell deficiency and periodic shedding of hair, which recapitulate the nkt mutation and the old furless (fs) mutation. The current study focuses on the dermatological aspects of the nkt mutation. Careful histological analysis of skin development of homozygous nkt mice revealed a delayed hair follicle morphogenesis and late onset of the first catagen stage. The skin of Ctsl(nkt)/Ctsl(nkt) mice showed mild epidermal hyperplasia and hyperkeratosis, severe hyperplasia of the sebaceous glands, and structural alterations of hair follicles. Epidermal differentiation seems to be affected in nkt skin, with overexpression of involucrin and profilaggrin/filaggrin along with focal areas of keratin 6 expression in the interfollicular epidermis. Severe epidermal hyperplasia, acanthosis, orthokeratosis, and hyperkeratosis were only observed in mice maintained in nonpathogen-free environments. The analysis of Rag2-/- Ctsl(nkt)/Ctsl(nkt) double-mutant mice indicates that the skin defect remains under the absence of T and B cells. This animal model provides in vivo evidence that cysteine protease cathepsin L plays a critical role in hair follicle morphogenesis and cycling, as well as epidermal differentiation.     

Morphologic Study of the Participation of the Complement System in Hyperacute Rejection of Renal Xenotransplants

The role of polymorphonuclear leukocyte (PMN) and platelet infiltration in the hyperacute rejection of renal xenotransplants was studied. In a first group, a dog kidney was grafted to rabbit recipients with intact immune adherence and chemotaxis. A second group included recipients depleted of PMN's with nitrogen mustard, and in a third group, immune adherence and chemotaxis were modified by depleting the third component of complement by means of cobra venom factor. Serial kidney biopsies were studied with light and electron microscopic technics. A semiquantitative evaluation of PMN and platelet glomerular infiltration indicated that a reduction in the number of PMN's or platelets is associated with an increased survival time of the transplanted kidney.     

Orbital meningioma with a granular cell component in a dog, with extracranial metastasis

A meningioma with a significant component of granular cells is described in the left ocular orbit of a 5-year-old male Golden retriever dog that presented with exophthalmos. The neoplastic mass surrounded the optic nerve. Microscopically, the tumour was characterized by nests of large, round to polygonal cells, variable in size, with eccentric nuclei and abundant eosinophilic cytoplasm, containing PAS-positive granules. In focal areas, cells were smaller and occasionally formed whorl-like structures. Immunohistochemical analysis revealed that neoplastic cells reacted positively for vimentin and, with less intensity, for neuron specific enolase and S-100, whereas they were negative for glial fibrillary acidic protein and cytokeratins. Metastatic growths, formed by similar cells, were seen in the lung and heart.     

Comparison of synaptic plasma membrane and synaptic vesicle polypeptides by two-dimensional polyacrylamide gel electrophoresis.

Extracts of chick brain synaptic plasma membranes, synaptic vesicles, and mixtures of membranes and vesicles were examined by electrophoresis on two-dimensional polyacrylamide gels by a modification of the O'Farrell technique. Synaptic plasma membranes had twenty-one major polypeptides; synaptic vesicles had seventeen. Thirteen major polypeptides were common to both fractions. The similarities between the synaptic vesicle and synaptic plasma membrane patterns are unlikely to be due to contamination of one fraction by the other or to contamination of both fractions by microsomes, synaptoplasm or mitochondria. Our findings are consistent with mixing of membrane proteins occurring during exocytosis but it remains to be shown that these synaptic subfractions are not contaminated by a type of membrane for which markers are not yet available.     

An operational evaluation of the Community Oral Rehydration Units in Peru

Since 1984, in Latin America donor agencies and national governments have extensively supported the implementation of the Community Oral Rehydration Units (CORUs) in an attempt to increase the access to oral rehydration therapy and improve the case management of diarrhoea at the community level. This study surveyed 40 CORUs in two regions of Peru to assess their operation, the number of patients with diarrhoea attended, and the knowledge of volunteers in charge. The results show that CORUs were mainly implemented close to existing health centres; the median of case load was 2.0 patients in the preceding month; and the volunteers' knowledge of case management was principally deficient in the diagnosis of hydration status, dietary management and in preventive measures. This lack of knowledge was replicated by professionals at the supervising health centres. Despite the fact that CORUs have been functioning for around four years, they exhibit numerous deficiencies which prevent them from fulfilling their objectives. A global review of the whole CORU strategy is called for.