Cryoglobulinemia and chronic liver diseases]

Taxotere, a promising anticancer agent, is metabolized almost exclusively in liver and excreted from bile in all species. To determine which cytochrome P450 is involved in taxotere biotransformation, 11 cDNA-expressed human cytochrome P450s were examined for their activity in the metabolism of taxotere and its derivatives. Of all P450s, cytochrome P450 3A4 and 3A5 were the most active for the oxidation of taxotere to the primary metabolite RPR104952 and for subsequent oxidation of RPR104952 to RPR111059 and RPR111026. RP70617, an epimer of taxotere was also metabolized by both P450 3A enzymes to form metabolite XII. The activity of 3A4/5 enzymes for these substrates was 4-50-fold greater than the other P450s examined. The Kms of 3A4 and 3A5 for taxotere were 0.91 and 9.28 microM, and Vmax for the formation of RPR104952 were 1.17 and 1.36 m(-1), respectively. The contribution of the 3A enzyme complex to the metabolism of taxotere in human livers from 21 individuals was assessed with the inhibitory monoclonal antibody and ranged from 64-93%. The primary oxidative metabolism of taxotere by human liver microsomes was well correlated with 3A4-dependent reactions for testosterone 6beta-hydroxylation (r2 = 0.84), taxol aromatic hydroxylation (r2 = 0.67) and aflatoxin B1 3alpha-hydroxylation (r2 = 0.63); whereas a poor correlation was found for reactions specifically catalysed by other P450s (all r2 < or =O.17). The extent of taxotere metabolism also closely correlated with levels of 3A4 enzyme in human livers quantified with immunoblot monoclonal antibody (r2 = 0.61). These results demonstrate that the P450 3A4 and 3A5 enzymes are major determinants in taxotere oxidation and suggest that care must be taken when administering this drug with other drugs that are also substrates for these enzymes.     

Historical origin and evolution of the agents of infectious diseases

Data on the establishment and further evolution of the causative agents of human infectious diseases were systematized. Saprophytes proved to be the initial stage of this evolution for all the parasitic species. It was demonstrated by concrete examples that evolution of parasitism was the result of an interaction of many factors (the mechanism of transmission of the causative agents, the immunity formation in the population, hereditary resistance, etc.) and not only the sequence of a unilateral action of the transmission mechanism. The author considers that some properties of the causative agents of the infecticus diseases of man (spore formation, the capacity to reproduction on the objects of the external environment) were not newly acquired in the process of the parasitic species formation, but atavistic signs which persisted from saprophytic ancestors. The dialectics of progressive and regressive processes in the acqisition of the parasitic properties by saprophytes is considered.     

The chronopharmacotherapy of diseases]

Peroperative cholangiography (POC) performed as a routine during cholecystectomy for cholelithiasis was evaluated in 102 patients. POC was normal 93 patients. Nine patients had abnormal POCs: 5 were true positive--CBD stones (4) and sphincteric fibrosis (1): 4 were false positive--air bubbles (2) and sphincteric spasm (2). Preoperative indication of CBD stones were present in 12 patients-5 of these had abnormal POC (4 true positive and 1 false positive). CBD exploration was avoided in 7 patients with normal POC. Ninety patients did not have any preoperative indication of CBD stones-4 of these had abnormal POC (1 true positive and 3 false positive). None of the patients with a normal POC had any clinical evidence of residual stones on follow up for one year. POC did not help in any case to delineate biliary ductal anatomy. Routine POC during cholecystectomy should be abandoned and should be performed selectively in patients suspected to have CBD stones only to avoid a negative CBD exploration.     

Nosocomial infections implying viruses and unconventional transmissible agents]

Nosocomial infections due to viruses are frequent, especially in pediatrics. They are usually benign, sometimes inapparent or associated with each other. However, they can be more serious in compromised people and become life threatening. In all cases, the hands of medical staff are the main route of viral transmission and this must be strictly prevented. Transmission by infected instruments remains an unresolved question. It happens most often with unconventional agents resistant to common procedures of disinfection and is presently the main concern of hospital wards.     

Pharmacologic management of periodontal diseases using systemically administered agents

Since the establishment of bacteria-laden plaque as a causative agent in gingivitis, the search for specific bacteria that induce different types of periodontitis has generated extensive research. In contrast to many other microbial-induced disorders, the specific periodontal pathogen(s) has not been identified to date. Therefore, the search for an effective systemic agent to prevent the loss of attachment through the selective reduction of known periodontal pathogens has remained elusive. It is not surprising then that antibiotics are not used solely to manage periodontal diseases but rather as an adjunct to the mechanical débridement of root surfaces in select periodontal diseases. Further, the sole use of antibiotics in patients with adult periodontitis (or those who exhibit signs of inflammation but are periodontally stable) has shown little benefit and only increases the chance of microbial resistance to antibiotics. Despite these limitations, considerable progress in antibiotic therapy has delivered regimens that enhance the effectiveness of conventional therapy. In contrast to traditional antimicrobial therapy, new treatment modalities have begun to focus on modulating the responses of host cells to bacteria rather than modulating only the bacteria. Current drugs used to regulate host cells inhibit the cyclooxygenase pathway, reduce the activity of metalloproteinases, or inactivate bone resorptive cells (see Table 1). Although these drugs offer great potential to modulate a variety of mammalian cells, a notable and consequential limitation of these agents is a lack of specificity. Inflammation, bone metabolism, and connective tissue metabolism are two-edged swords; all are necessary for the homeostasis of the tissue, but some or all may also be involved in the pathologic destruction of that same tissue. Hence, drugs that inhibit destruction of the connective tissue in one site of the periodontium also interfere with wound healing at another. As a result of these limitations, the efficacy, safety, and cost-effectiveness of the long-term use of these agents is unknown. Preliminary results of treatment with these drugs are promising, and future generations of host-modulating drugs will provide clinicians with additional agents to help improve the success rate of periodontal treatment for patients. Antibiotics remain an important adjunctive therapy in the treatment of periodontal diseases, and the use of host modulating drugs as supplemental agents in the management of periodontal diseases continues to grow. As more knowledge is gained about the causes of periodontal diseases, new drugs that are potent, effective, site specific, and safe can be delivered at optimal times by simply having the patient take a few tablets. Considering the dramatic progress in the past decade in understanding the cause and pharmacologic management of periodontal diseases, the twenty-first century holds great promise for the development of magic bullets.     

Radioisotope diagnosis in lung diseases]

Following immunization against sheep erythrozytes, it is possible to induce a double-peaked antibody response curve in the serum of experimental animals (rats) by using vincristine sulfate (Vi). Immunosuppression is enhanced in thymectomised and sensitised animals during rechallenge following Vi/Cy, as compared to animals treated with cyclophosphamide (Cy) alone, and an attentuated anamnestic reaction is subsequently observed. Survival time of allogeneic skin grafts in colony bred and inbred rat strains could not be prolonged by using Vi/Cy, as compared to animals treated with Cy alone.     

Radiation diagnosis of spleen diseases]

The paper discusses the present-day radiation diagnosis of renal bulky formations: tumors and cysts. Based on the study of a great body of clinical data on 708 patients, the authors showed the potentialities of routine X-ray and currently available radiation techniques in the diagnosis of benign and malignant tumors and cysts of the kidney. Based on the data available in the literature and their own findings, the authors concluded that at the earliest stages of their preclinical development, tumors can be today diagnosed by a complete package of up-to-date diagnostic tools. Ultrasonic and computerized tomographies are of the highest informative value in diagnosing tumors and cystic formations. However, in some cases, a diagnosis is made via a routine excretory urography, angiography and needle biopsy. Excretory urography is of limited value for the diagnosis of renal bulky formations and it is used as an auxiliary mainly when a pathological process takes place in the renal hilus area. Angiography retains its significance as a supplementary technique. In the vast majority of cases, an accurate nosological diagnosis can be made on the basis of evaluation of the pattern of blood supply (the presence of abnormal vessels and their topographic features). The paper details the semiotics of a wide range of renal bulky processes by applying all currently available techniques of radiation diagnosis.     

Inflammatory bowel diseases in children]

From an incidence cohort diagnosed during 1962-1987 we identified all patients with onset of IBD before the age of 15 in order to describe the course and to compare course and prognosis with adult onset IBD. The mean incidence of IBD among children below 15 years was 2.2/10(5), 2.0 for ulcerative colitis (UC), and 0.2 for Crohns disease (CD). At diagnosis, UC children had more extensive disease compared to adults (p < 0.05). Abdominal pains were also more frequent. The cumulative colectomy probability was 6% after one year and 29% after 20 years, not different from adults. Regarding disease activity, it was found that 60-70% of UC patients were in remission in the first 10 years of disease, for CD about 50% were in remission. One UC patient developed carcinoma of the sigmoid colon. Time between onset and development of carcinoma was 12 years. For CD no differences in clinical appearance at diagnosis and course between children and adults were found. No deaths occurred among CD patients. Three CD patients were found to have severe growth retardation already at diagnosis. In conclusion, the incidence of IBD is low in childhood. At diagnosis children with UC have more widespread disease than adults. Children with CD do not differ in clinical presentation, course or prognosis compared to adult onset CD. However, growth retardation is a problem among CD patients.     

Manipulation of genes causing diseases]

This study investigated the severity of retinopathy of prematurity (ROP) and its relationship to childhood development. The subjects were 21 children with a birthweight of 2500 g or less who were tested for flash visual evoked potential (FVEP) at conceptual ages ranging from 1 to 3 years. We also examined 73 children with a birthweight of 1500 g or less, using the Developmental Quotient (DQ) test, at 2 1/2 years of age. Twenty-five of this group were given an Intelligence Quotient (IQ) test at 6 to 7 years of age. The P100 latency of FVEP in the severe ROP group was significantly longer than that of the mild ROP group (P < 0.05). The main DQ in the severe ROP group was 99.1 +/- 17.9, significantly lower than the 108.7 +/- 15.5 of the mild ROP group (P < 0.05). No significant IQ differences were found between the two groups. The proportion of children with verbal-performance IQ discrepancies was, however, significantly greater in the severe ROP group than in the mild ROP group (P < 0.05). Since infants with severe ROP are more likely to suffer developmental disorders, long-term follow-up is absolutely necessary and must be done in cooperation with pediatricians.