Histamine H2-receptor antagonists stimulate proliferation but not migration of human gastric mucosal cellsin vitro

Gastric mucosal cell migration and proliferation are crucial events in the repair of gastric mucosal erosions. This study was designed to test the hypothesis that the H₂ blockers roxatidine and ranitidine might stimulate migration and proliferation of gastric mucous cells derived from a human well-differentiated gastric adenocarcinoma cell line (MKN 28 cells)in vitro, in conditions independent of systemic factors and of acid inhibition. Confluent monolayers of MKN 28 cells were wounded with a razor blade and were then incubated with roxatidine or ranitidine. The number of cells migrating to the damaged area was determined 24 hr later. Cell proliferation was assessed by means of [³H]thymidine uptake and cell counts after incubation with roxatidine or ranitidine. Neither H₂ antagonist significantly stimulated cell migration. On the other hand, cell proliferation was dose-dependently and significantly enhanced by incubation with roxatidine and ranitidine. Exogenous administration of TGF- significantly stimulated MKN 28 cell division. However, incubation with roxatidine or ranitidine did not increase the steady-state mRNA expression of TGF- or EGFR as assessed by northern blot analysis. Based on thesein vitro findings, we postulate that the ulcer healing effect of these H₂ antagonistsin vivo might be due in part to stimulation of gastric mucosal cell proliferation.Data from this paper have been presented in part at the 1995 meeting of the American Gastroenterological Association and published in abstract form in Gastroenterology 108:A72, 1995.     

Characterization of a family with moderate hypercholesterolemia and binding defective low density lipoprotein

Familial defective apolipoprotein B-100 (FDB) is a genetic disorder presenting with hypercholesterolemia and abnormal low density lipoprotein (LDL) that binds poorly to LDL receptors. This disease appears to be caused by a mutation in the apo B gene. In the present study thirteen members of a family with moderate hypercholesterolemia (250–350 mg/dl) were investigated. Biochemical studies on cultured skin fibroblasts ruled out classical familial hypercholesterolemia (receptor deficiency). LDL from nine affected members displayed, in an in vitro cell binding assay, a reduced affinity (2.5 fold) for the receptor, and had normal electrophoretic mobility, size and chemical composition. Lp(a) levels in family members were comparable to those present in normolipidemics and lower than those observed in primary hypercholesterolemia. The disorder is transmitted over three generations as an autosomal codominant trait and all the affected members are heterozygotes and hypercholesterolemic.Corresponding author.     

Comparison of fibrin glue, bioresorbable tubing and sutures in peripheral nerve repair

Regeneration of severed rat tibial nerves was functionally and morphologically compared with repair following the use of 3 anastomosis techniques: collagen guide tubes, fibrin glue and conventional microsurgical sutures. In addition, one tibial nerve was crushed in some rats. At ten weekly intervals, functional recovery, assessed by sciatic nerve stimulated evoked contraction of the flexor digitorum muscle, was quicker and more complete following nerve crush than following the anastomosis techniques which were not different from each other. Ten weeks following the surgery, the retrograde transport morphological technique indicated that the anastomosis techniques were not different from each other. The number of labeled tibial motoneurons (tube and suture groups) was significantly less than the crush group, but the glue group was intermediate. Thus, although having less extensive recovery following crush, the quicker and easier techniques of nerve repair, i.e., collagen tubes or fibrin glue, produced comparable anatomical and functional recovery as the more time-consuming, technically demanding microsurgical repair with fine sutures.     

Heterogeneity of toxicant response: sources of human variability.

While risk assessment models attempt to predict human risk to toxicant exposure, in many cases these models cannot account for the wide variety of human responses. This review addresses several primary sources of heterogeneity that may affect individual responses to drug or toxicant exposure. Consideration was given to genetic polymorphisms, age-related factors during development and senescence, gender differences associated with hormonal function, and preexisting diseases influenced by toxicant exposure. These selected examples demonstrate the need for additional steps in risk assessment that are needed to more accurately predict human responses to toxicants and drugs.     

Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation.

Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r=0.58) but not with cdk5 (r=0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.     

Aminopenicillin allergy

Eight two children with histories of maculopapular or urticarial rashes during aminopenicillin treatment underwent skin tests, patch tests, radioallergosorbent assays and, in some cases, oral challenges. Hypersensitivity was diagnosed in eight (9.8%): immediate in four with urticarial reactions and delayed (that is cell mediated) in four with maculopapular rashes. In 49 children (38 with maculopapular eruptions, 11 with urticarial/angiooedematous reactions), negative allergologic findings were confirmed using oral challenges with the suspected drug. Maculopapular rashes may reflect delayed hypersensitivity to aminopenicillins, which can be diagnosed on the basis of late intradermal reactions and/or patch test positivity. The allergen panel must include the suspected aminopenicillin itself, as many cases are side chain specific. Most patients with urticarial reactions (more typical of immediate hypersensitivity) will also react to penicilloyl polylysine and minor determinant mixture. The time elapsed between the reaction and testing must be considered if negative results emerge, because IgE mediated sensitivity (unlike cell mediated forms) declines in the absence of antigen exposure.     

Maximum tolerable doses of intravenous zidovudine in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer patients

Background: Experimental studies have demonstrated that 5-fluorouracil(5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity.Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZTis 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU +l-leucovorin (LV), and that this combination has promising antitumor activity.The purpose of this study was therefore to evaluate the antitumor activity ofweekly bolus 5-FU + LV + AZT, administered at its MTD, and to determinewhether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells.Patients and methods: Twenty-nine chemotherapy-naïve metastaticcolorectalcancer patients with measurable disease entered the study to evaluate theactivity of a weekly 5-FU 500 mg/m² i.v. bolus + LV 250mg/m² i.v. two-hour infusion + AZT 8000mg/m² i.v. two-hour infusion. In 10 different patients, whoduring three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNAstrand breaks in blood nuclear cells were determined by a fluorescent analysisof DNA unwinding.Results: Treatment was generally well tolerated and WHO grades III–IVtoxicities, consisting mostly of diarrhea (17%), were uncommon. Onepatient died of severe diarrhea with consequent hypokalemia and cardiacarrhythmia. All patients were considered evaluable for response, and 3(10%) complete and 10 (35%) partial responses were observed, foran objective response rate of 45% (95% confidence limit interval26%–64%). Both 5-FU + LV and AZT decreased the percentageof double stranded DNA in nuclear blood cells. The greatest effect wasobserved with 5-FU + LV + AZT, which reduced the percentage of double strandedDNA to 50% and 36% after 24 and 48 hours, respectively, and thisinteraction between 5-FU + LV and AZT was found to be cumulative.Conclusions: These studies demonstrate that the present dose and scheduleof AZT in combination with 5-FU + LV has significant activity in metastaticcolorectal cancer and that the combination of 5-FU + LV with AZT increases theamount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrantsfurther study in colorectal cancer.     

A registry-based study of follow-up failures in the screening experience of cervical cancer patients

Amadori A, Gentilini P, Bucchi L, Innocenti MP, Falcini F, Martini F, Fabbri M, Liverani M, Danesi S, Piantini B, Milandri C, Saragoni L, Amadori D. A registry-based study of follow-up failures in the screening experience of cervical cancer patients. Int J Gynecol Cancer 1998; 8 : 251–256.
Although all components of cervical screening are at risk of error, most studies of the previous screening experience of cervical cancer patients addressed only the false negative cytology results. Other reports showed the importance of screening failures not attributable to the Pap smear. We studied the relative frequency of all types of error observed in the screening history of 115 cervical cancer cases (median age, 60; range, 23–89) registered with the population-based Romagna Cancer Registry in Forlì (northern Italy) between 1986 and 1993. For each case, a search was made for all cytology, colposcopy, biopsy, and treatment reports issued prior to diagnosis. Eighty-one (70.4%) patients had never had a Pap smear. Eight (7.0%) were diagnosed at their first test. Twenty-six patients (22.6%) had had at least one previous smear. Among these, 10 were screened during the five years prior to diagnosis: three patients had false negative cytology results, one patient did not comply with the recommendation for an early repeat smear, two patients with positive cytology results underwent colposcopy with considerable delay (7 and 9 months), one patient had a negative colposcopy (without biopsy), and three patients had biopsies histologically reported as negative. An overview of the registry-based studies of screening histories reported so far from Italy (total number of cases 262) demonstrated that patients with serious shortcomings in follow-up after smear test, colposcopy, biopsy, clinical assessment, and treatment accounted for a substantial proportion of screening failures.     

Spontaneous Splenic Rupture in a Patient with Acute Lymphoblastic Leukemia of Burkitt Type

We describe a case of spontaneous splenic rupture occurred in a patient with acute lymphoblastic leukemia of Burkitt type before starting cytotoxic chemotherapy. Left hypochondrial pain radiating to the homolateral shoulder was the only clinical symptom. Emergency computed tomography showed splenic laceration and hemoperitoneum. The patient underwent immediate laparotomy with splenectomy and experienced an uneventful postoperative recovery. Eight days after surgery, chemotherapy could be administered and complete remission was achieved. Although spontaneous rupture of the spleen is rare in leukemia and related disorders, this diagnosis should be taken in account also when clinical symptoms are mild. Following immediate operative management, patients may completely recover and receive cytotoxic chemotherapy with substantial possibilities of achieving complete remission.