Biomedical subjects
Publications and source records attributed to P Pinto.
We have discovered that introduction of appropriate amino acid derivatives at P'2 position improved the binding potency of P3-capped alpha-ketoamide inhibitors of HCV NS3 serine protease. X-ray crystal structure of one of the inhibitors (43) bound to the protease revealed the importance of the P'2 moiety.
OBJECTIVE: To analyze risk factors for type 2 diabetes among women attending menopause clinics in Italy for counselling about the menopause. SUBJECTS: Women attending a network of first-level outpatient menopause clinics in Italy for general counselling about menopause or treatment of menopausal symptoms. METHODS: Cross-sectional study with no exclusion criteria. Type 2 diabetes was defined according to National Diabetes Data Groups Indications and the fasting blood glucose at an oral glucose tolerance test within the previous year. RESULTS: Out of the 44 694 considered in this analysis, 808 had a diagnosis of diabetes type 2 (1.8%). In comparison with women aged < 50 years, the multivariate odds ratios (OR) of type 2 diabetes were 1.31 (95% confidence interval (CI), 0.99-1.74) for women aged 50-52 years, 1.66 (95% CI, 1.27-2.17) at 53-56 years and 2.84 (95% CI, 2.20-3.67) in women aged > or = 57 years. Type 2 diabetes was less frequently reported in more educated women (OR high school/university vs. primary school = 0.44 (95% CI, 0.36-0.55)). Being overweight was associated with an increased risk of type 2 diabetes. In comparison with women reporting a low level of physical activity, the multivariate OR of type 2 diabetes was 0.67 (95% CI, 0.54-0.84) for women reporting regular physical activity. In comparison with premenopausal women, the multivariate OR of type 2 diabetes was 1.38 (95% CI, 1.03-1.84) in women with natural menopause. This finding was present also after allowing for the potential confounding effect of age. The multivariate OR of diabetes for users of hormonal replacement therapy was 0.58 (95% CI, 0.46-0.73). CONCLUSIONS: This large cross-sectional study suggests that postmenopausal women are at higher risk of type 2 diabetes after allowance for the effect of age. Other main determinants of risk of type 2 diabetes in women around menopause were low socioeconomic status and being overweight. Diabetes was found less frequently in those taking hormone replacement therapy.
Most estrogen actions are mediated by two estrogen receptor subtypes (ERalpha and ERbeta). While a single ERbeta appears to be present in higher vertebrates, two forms of ERbeta encoded by different genes have recently been isolated in some teleost fish species. We investigated whether this also applies to the hermaphrodite sparid sea bream (Sparus auratus) and cloned a second ERbeta (sbERbeta2) in this species. We have also compared the tissue distribution of the three receptors as yet identified in sea bream, designated sbERalpha, sbERbeta1, and sbERbeta2.
BACKGROUND: Two sizes of endoscopic gastrointestinal anastomosis (Endo-GIA) staples are currently available for vascular control. The purpose of this study was to compare the Endo-GIA 30-2.0 mm with the Endo-GIA 30-2.5 mm vascular staple. METHODS: The renal blood vessels, aorta, and vena cava were divided laparoscopically using the Endo-GIA 30-2.0 and 30-2.5 mm in four pigs, respectively. The arterial and venous segments were harvested en bloc for ex vivo burst pressure studies. RESULTS: Both 2.0-mm and 2.5-mm staples achieved vessel sealing at supraphysiologic mean burst pressures (> or =310 mmHg). There were no statistical differences between mean burst pressures of vessels stapled by 2.0-mm compared to 2.5-mm staples. Both staples sealed arteries up to 17 mm and veins up to 22 mm in diameter. CONCLUSION: Endo-GIA 30-2.0 mm and 30-2.5 mm vascular staples are equivalent in sealing vessels at supraphysiologic mean burst pressures.
UNLABELLED: We evaluated a technique for implantation of right kidneys with short renal veins without the need for venous reconstruction. METHOD: The technique of iliac vein transposition was performed in six recipients who received right kidneys with short renal veins. Two cases were living related donors, two were living unrelated, one was an autotransplant, and one was a cadaver kidney recipient. The common and external iliac veins and arteries of the recipient were thoroughly mobilized, allowing for the lateral transposition of the external iliac vein with respect to the external iliac artery. The renal vessels were subsequently implanted in an end to side fashion onto the corresponding transposed external iliac vessels. After implantation, the iliac vein remained lateral with respect to the iliac artery. CONCLUSIONS: The technique described allows for the implantation of right kidneys without the need for venous reconstruction. Such an approach is especially useful in cases of grafts with short veins.
PURPOSE: To report a new technique for radiofrequency (RF) ablation of a solid renal mass. PATIENT AND METHODS: An 83-year-old man with a history of chronic renal insufficiency was found to have solid mass in the right kidney. Retroperitoneoscopic localization of the renal mass was accomplished using intraoperative ultrasonography. The lesion was treated with a 14-gauge RITA Starburst XL probe (Rita Medical Systems, Inc., Mountain View, CA). RESULTS: The total treatment time included two cycles of 5.5 minutes. There were no intraoperative complications. Tissue desiccation was noted during treatment. A CT scan 48 hours after ablation showed a decrease in the density of the lesion suggestive of coagulation necrosis. The postoperative hospital course was uneventful. CONCLUSION: The retroperitoneal laparoscopic technique is a feasible approach to performing RF ablation of a solid renal mass. It facilitates direct insertion of the RF probe, allows viewing and avoidance of adjacent structures such as bowel, and permits better staging by enabling biopsy of perirenal fatty tissue.
The tongue is a rare site of localization of cystic echinococcosis. We report a 3-year-old patient with cystic echinococcosis of the tongue demonstrated by histopathology. The cyst of the tongue was surgically removed. The tongue lesion led us to find additional liver and lung cystic lesions that were successfully treated with albendazole therapy.
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We describe the immunophenotypic and gross DNA defects in 55 patients with myeloma and 50 patients with monoclonal gammopathy and review the literature on this subject (MedLine, 1994-2000). Our data confirmed previous reports indicating that in myeloma nearly all marrow plasma cells are abnormal (98.7 +/- 8.1%). In monoclonal gammopathy the fraction of abnormal plasma cells was 35.0 +/- 32.8%. In both myeloma and monoclonal gammopathy, the most frequent aberrant phenotypic features consisted of absence of expression of CD19, strong expression of CD56, and decreased intensity of expression of CD38; aberrant expression of CD10, CD20, CD22, or CD28 was observed in less than one-third of myeloma cases. The vast majority of cases had two or more phenotypic aberrations. In the DNA studies, 7% of myeloma cases were biclonal and 93% of cases were monoclonal. In those studies with only one plasma cell mitotic cycle, 37% had normal DNA content and 63% were aneuploid (hyperploid, 61%; hypoploid, 2%). The mean percentages of plasma cells in S- and G2M phases were 4.9 +/- 8.5 and 4.4 +/- 6.9%, respectively. Thirty-eight percent of cases had more than 3% of plasma cells in S phase. In monoclonal gammopathy, the DNA index of abnormal plasma cells ranged from 0.89 to 1.30 and the percentage of diploid (31%) and aneuploid (69%) cases was not different from the results found in myeloma. The differences in percentage of abnormal plasma cells in S- (7.4 +/- 8.6%) and G2M-phases (2.4 +/- 1.7%) in patients with monoclonal gammopathy were not statistically significant.
We report a case of minor salivary gland sialolithiasis presenting as acute, painful swelling of the upper lip. Conventional, unguided, incision and drainage removed three of the sialoliths. Diagnostic ultrasound identified two further sialoliths which were successfully removed with real-time, ultrasound-guided, needle localization. This technique of sialolith retrieval has not been previously reported.
Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.
We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.
We have studied the development of the adrenal gland in the rat comprising the ages ranging from 0 to 90 days after birth. The weight of the animals and that of the adrenal glands demonstrated a linear growth with time until 75 days, both in males and females. The area of the zona glomerulosa (ZG) increased in size from birth until approximately 40 days of age. After that, growth had a much smaller slope (females, r=0.84, P < 0.001; males, r=0.81, P < 0.001). Aldosterone secretion had a marked increase until 20 days of age and thereafter demonstrated a tendency for a decrease (females, r=-0.19, P < 0.02: males r=-0.26, P < 0.001). Plasma renin activity followed a trend parallel to that of aldosterone. The steroid precursor 18-OH-deoxycorticosterone (18-OH-DOC) demonstrated a different course as it increased progressively with age especially in the females (females, r=0.57, P < 0.001; males, r=0.40, P <0.001). The expression of the enzyme 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) was also studied by immunohistochemistry and it was shown to be very low at birth and starting to increase by 10 days of age. After 30/40 days of age the amount of this enzyme existing in the ZG was comparable with that of the outer zona fasciculata (ZF). We conclude that the development of the ZG in the rat has particularities that make it different from that of the rest of the cortex.
We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.
Among the different classes of human epidermal lipids, Ceramides are definitely one of the most important and studied class judging from the significant amount of scientific information accumulated over the years, specially after being established its crucial role in skin physiology and pathophysiology. However, a clear demonstration of its usefulness resulting from the regular use of these substances included in topical formulations, either in a therapeutical or in a cosmetological perspective have not been entirely achieved. Many difficulties are normally present, from its origin to formulation and protocol design, and to the experimental demonstration of the relative efficacy of these compounds. In the present paper, the authors developed a systematic approach to the problem, using "human-identical" ceramides included into negatively charged liposomes, which were topically applied in a normalised panel of human healthy volunteers. Biological analysis were conducted with non-invasive methodologies by means of bioengineered reference methods (Epidermal capacitance, Evaporimetry; Light Transmission Profilometry; and High Resolution Ultrasonography). The experimental methodologies included the study of acute effects as well as the study of the effects resulting from continuous repeated application of formulations, basically expressed in terms of epidermal water content and skin surface profile. Additionally, an eventual protective "barrier" reinforcement resulting from ceramide application was also assessed by means of a SLS (5% solution) challenge-test. This systematic although preliminary approach indicated that these compounds do have a considerable impact on human skin physiology, justifying further research to clarify their potential use in human cutaneous health.
Ferritin is a protein of 24 subunits which assemble into a shell with 432 point symmetry. It can be denatured reversibly in acidic guanidine hydrochloride, with the formation of poorly populated renaturation intermediates. In order to increase the accumulation of intermediates and to study the mechanism of ferritin renaturation, we analysed variants of the human ferritin H-chain altered at the N-terminus (delta(1-13)), near the 4-fold axis (Leu-169 --> Arg), the 3-fold axis (Asp-131 --> Ile + Glu-134 --> Phe) or the 2-fold axis (Ile-85 --> Cys). We also carried out specific chemical modifications of Cys-130 (near the 3-fold axis) and Cys-85 (near the 2-fold axis). Renaturation of the modified ferritins yielded assembly intermediates that differed in size and physical properties. Alterations of residues around the 2-, 4- and 3-fold axes produced subunit monomers, dimers and higher oligomers respectively. All these intermediates could be induced to assemble into ferritin 24-mers by concentrating them or by co-renaturing them with wild-type H-ferritin. The results support the hypothesis that the symmetric subunit dimers are the building blocks of ferritin assembly, and are consistent with a reassembly pathway involving the coalescence of dimers, probably around the 4-fold axis, followed by stepwise addition of dimers until the 24-mer cage is completed. In addition they show that assembly interactions are responsible for the large hysteresis of folding and unfolding plots. The implications of the studies for in vivo heteropolymer formation in vertebrates, which have two types of ferritin chain (H and L), are discussed.
Aldehyde oxidase and xanthine dehydrogenase are a group of ubiquitous hydroxylases, containing a molybdenum cofactor (MoCo) and two iron-sulfur groups. Plant aldehyde oxidase and xanthine dehydrogenase activities are involved in nitrogen metabolism and hormone biosynthesis, and their corresponding genes have not yet been isolated. Here we describe a new gene from tomato, which shows the characteristics of a MoCo containing hydroxylase. It shares sequence homology with xanthine dehydrogenases and aldehyde oxidases from various organisms, and similarly contains binding sites for two iron-sulfur centers and a molybdenum-binding region. However, it does not contain the xanthine dehydrogenase conserved sequences thought to be involved in NAD binding and in substrate specificity, and is likely to encode an aldehyde oxidase-type activity. This gene was designated tomato aldehyde oxidase 1 (TAO1). TAO1 belongs to a multigene family, whose members are shown to map to clusters on chromosomes 1 and 11. MoCo hydroxylase activity is shown to be recognized by antibodies raised against recombinant TAO1 polypeptides. Immunoblots reveal that TAO1 cross-reacting material is ubiquitously expressed in various organisms, and in plants it is mostly abundant in fruits and rapidly dividing tissues.
Activation of the stress system induces physiologic alterations as well as behavioural ones that ultimately improve the adaptability of the organism to adverse conditions. In our previous study on the morpho-functional evolution of the adrenal cortex, from birth to adulthood, the question of what could be the contribution of immobilization stress to the observed hormonal levels was brought up. Male adult rats were submitted to immobilization of variable duration. The antibody IZAb was used to allow a correct differentiation between the zona glomerulosa (ZG) and the inner zones of the cortex (IZ). A significant increase of the ACTH levels, especially at 5 and 30 min was observed. Corticosterone (B), surprisingly, revealed 2 peaks of secretion: one at 30 sec and another at 30 min. The area of the cortex, determined by an image analyser, only showed a slight decrease at 30 sec. The proportions of the cortical area occupied by ZG and IZ were unaltered. We concluded that a corticosterone peak at 30 sec precedes the elevation of ACTH induced by stress. Only the second peak, in view of its parallel course to ACTH, can be attributed to an effect of this pituitary hormone.