Novel antidiabetic and hypolipidemic agents. 5. Hydroxyl versus benzyloxy containing chroman derivatives.

Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.     

Risk factors in dental implant failure

The goal of this study was to assess risk factors for dental implant failure. Eighty-three implants were placed in thirty patients who were followed for three years using digital subtraction radiography. The following putative risk factors for implant failure were employed in the model: age, sex, implant length, implant position, implant surface coating, smoking habit, and presence of infection. Implant failure was defined as progressive bone loss compromising the implant. We found that the presence of infection (P < 0.001) and absence of HA coating (P < 0.001) were the primary factors associated with early implant failure.     

Risk factors for retinopathy in diabetes mellitus in Kelantan, Malaysia

Few attempts have been made to determine the risk factors for diabetic retinopathy which is a major cause of visual impairment and blindness. One hundred and forty patients of diabetes mellitus were studied to determine the prevalence and types of retinopathy, and its relation to various risk factors. Nearly half (48.6%) of the patients suffered from retinopathy. The significant associated risk factors were long duration of diabetes, proteinuria and elevated serum creatinine level. However, there was no significant association between the prevalence of retinopathy and high levels of serum cholesterol, C-peptide levels, associated hypertension, and glycaemic control of diabetes mellitus. An effective screening programme for detection of retinopathy in the patients of diabetes as a regular practice is encouraged.     

Mechanism of activation of an N-ras oncogene of SW-1271 human lung carcinoma cells.

An N-ras-related transforming gene was detected in the human lung carcinoma cell line SW-1271 and molecularly cloned. The lesion responsible for its acquisition of transforming activity was localized to a single nucleotide transition from A to G in codon 61 of the predicted protein. This lesion in the second exon results in the substitution of arginine for glutamine at this position. These findings, together with previous studies, indicate that the activation of ras oncogenes in human tumors is most commonly due to point mutations at one of two major "hot spots" in the ras coding sequence.     

Effect of chronic tobacco-betel-lime "quid" chewing on human salivary secretions

Salivary flow rates by mechanical stimulation with forced spitting method and by chemical stimulation with 10% citric acid were determined in 25 healthy adult subjects with a history of chronic tobacco-betel-lime "quid" chewing and in 25 healthy control adults with no history of chewing. The chewers secreted more saliva as compared to nonchewers on chemical, but not on mechanical stimulation. The salivary amylase, potassium, and sodium levels were lower in chewers, but the reductions of the first two components only were significant. These reductions were thought to be due to increased salivary flow with its dilutional effect. There was no difference between the two groups with respect to salivary pH. The salivary flow rates by either method had significant positive correlation with the duration of chewing, but not with the amount of tobacco chewed. Salivary potassium was inversely correlated with the amount of tobacco chewed. It was concluded that chronic tobacco-betel-lime quid chewing induces excessive secretion of more watery saliva leading to a concomitant decrease in enzyme and electrolyte content. One or more of the following factors were considered to be operating in causing increased salivary flow in chewers effect of nicotine or tobacco on other constituents of the quid, chronic salivary gland hyperplasia, or chronic hypertrophy of the muscles of mastication.     

Histogenesis of pseudo-ductular changes induced in the pancreas of guinea pigs treated with N-methyl-N-nitrosourea

Tumors of the exocrine pancreas of the inbred strain 13 guinea pigs, induced by N-methyl-N-nitrosourea, reveal duct-like glandular differentiation and marked desmoplastic reaction of the stroma, characteristic of adenocarcinoma of human pancreas. During the course of induction of these tumors in the guinea pigs by N-methyl-N-nitrosourea, atypical pseudo-ductular proliferations were encountered in the pancreas which appeared to be precursor lesions for pancreatic carcinoma. The histogenesis of these pseudo-ductular lesions was studied by light and electron microscopy. The earliest changes consisted of dilatation of acinar lumina with decrease of apical cytoplasm and increased mitotic activity of the acinar cells. The actively proliferating, well-formed pseudo-ductules were lined by cuboidal or flattened epithelium containing a prominent nucleus and scant cytoplasm with few or no discernible zymogen granules by light microscopy. By electron microscopy, the cells lining the pseudo-ductules displayed features of immature or embryonic pancreatic acinar cells characterized by prominent nucleoli, marked decrease in rough endoplasmic reticulum with increase of free ribosomes, atypical zymogen granules and abundant microfilaments and microtubules. In two guinea pigs, transition from pseudo-ductular changes to adenocarcinoma was clearly evident. On the basis of these findings, it is proposed that the pseudo-ductular lesions of the guinea pig pancreas, and possibly those occuring in other species, are derived from acinar cells as a consequence of carcinogen induced cell proliferation leading to immature or dedifferentiated phenotypes. This hypothesis can, in part, be confirmed by immunocytochemical localization of pancreatic acinar cell specific secretory proteins and lectins in these pseudo-ductules.     

Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans

In this critical review, I would like to provide a brief outline of the morphology, biochemical composition, distribution, and functions of peroxisomes. The induction of peroxisome proliferation and peroxisome-associated enzymes in the rodent liver by two classes of chemicals (hypolipidemic drugs and the industrial plasticizers) will be considered. The role of peroxisomes in lipid metabolism will be discussed. Carcinogenicity studies in rats and mice with these peroxisome proliferators will be evaluated critically. Careful consideration will be given to the hypothesis that "potent hepatic peroxisome proliferators as a class are carcinogenic." The possible mechanism(s) by which peroxisome proliferators induce liver tumors will be outlined. Particular attention will be paid to the possible role of peroxisome proliferation-mediated radical toxicity and generation of endogenous initiators of carcinogenesis.     

Effect of retinoids on the induction of colon cancer in F344 rats by N-methyl-N-nitrosourea or by 1,2-dimethyihydrazine

The possible modifying effect of synthetic and natural retinoidson the incidence of colon cancer in rats induced by 2 intrarectaldoses of 2.5 mg of N-methyl-N-nitrosourea (MNU) given once aweek for 2 successive weeks or a single 150 mg/kg body weightdose of 1,2-dime-thylhydrazine (DMH), s.c. was investigated.Emphasis was on the effect of the development of early tumorsas visualized by endoscopy. With the retinoids N-ethyl-retinamide,N-2-hydroxyethylretinamide, N-(4-hydro- xyphenyl)-all-trans-retinamide(RAHA), and retinyl acetate (RA) administered orally after thecarcinogens, significant differences in early developing tumorswere not found. At histopathological examination of the tumorsthe RAHA + DMH group had significantly fewer adenomas per animal.The percentage of adenoma bearing rats was significantly lowerin groups receiving RAHA + DMH or RA + DMH. However, food consumptionwas lower in rats consuming either RAHA or RA. Retinyl palmitate(RP) and RAHA was administered intrarectally to MNU-inducedrats either before or after the carcinogen. When administeredbefore MNU, RP caused a significant increase in the percentageof tumor bearing animals and the average number of tumors peranimal as visualized endos copically. At histopathological examination,all retinoid groups except RAHA given after the carcinogen,produced significantly more adenomas per animal and a significantlygreater adenoma incidence than did the control groups. Thus,in two systems, the oral administration of retinoids did notclearly inhibit the early or later stages of colon tumor development.Inirarectal infusion of two retinoids had no effect on colonicmor phology but at histopathological examination of later stagetumors there was an enhanced adenoma response.