A Novel Conjugate of Bis[((4-bromophenyl)amino)quinazoline], a EGFR-TK Ligand, with a Fluorescent Ru(II)-Bipyridine Complex Exhibits Specific Subcellular Localization in Mitochondria.

The epidermal growth factor receptor (EGFR) is a key target in anticancer research, whose aberrant function in malignancies has been linked to severe irregularities in critical cellular processes, including cell cycle progression, proliferation, differentiation, and survival. EGFR mutant variants, either transmembrane or translocated to the mitochondria and/or the nucleus, often exhibit resistance to EGFR inhibitors. The ability to noninvasively image and quantify EGFR provides novel approaches in the detection, monitoring, and treatment of EGFR-related malignancies. The current study aimed to deliver a new theranostic agent that combines fluorescence imaging properties with EGFR inhibition. This was achieved via conjugation of an in-house-developed ((4-bromophenyl)amino)quinazoline inhibitor of mutant EGFR-TK, selected from a focused aminoquinazoline library, with a [Ru(bipyridine)3]2+ fluorophore. A triethyleneglycol-derived diamino linker featuring (+)-ionizable sites was employed to link the two functional moieties, affording two unprecedented Ru conjugates with 1:1 and 2:1 stoichiometry of aminoquinazoline to the Ru complex (mono-quinazoline-Ru-conjugate and bis-quinazoline-Ru-conjugate, respectively). The bis-quinazoline-Ru-conjugate, which retains an essential inhibitory activity, was found by fluorescence imaging to be effectively uptaken by Uppsala 87 malignant glioma (grade IV malignant glioma) cells. The fluorescence imaging study and a time-resolved fluorescence resonance energy transfer study indicated a specific subcellular distribution of the conjugate that coincides with that of a mitochondria-targeted dye, suggesting mitochondrial localization of the conjugate and potential association with mitochondria-translocated forms of EGFR. Mitochondrial localization was further documented by the specific concentration of the bis-quinazoline-Ru-conjugate in a mitochondrial isolation assay.

Óleos essenciais e vegetais no controle in vitro de Colletotrichum gloeosporioides / Essential and vegetal oils in the in vitro control of Colletotrichum gloeosporioides

RESUMO O objetivo deste trabalho foi avaliar a atividade antifúngica de óleos essenciais e vegetais no controle in vitro de Colletotrichum gloeosporioides, agente causal da antracnose em pós-colheita de frutíferas. Treze óleos essenciais foram utilizados em concentrações de 0,00%, 0,40%, 0,80%, 1,70%, 3,20%, 6,25%, 12,50%, 25,00%, 50,00% e 100,00%, e uma linhagem padrão de Colletotrichum gloeosporioides. Foram avaliadas a concentração inibitória mínima e a concentração mínima fungicida a fim de caracterizar o potencial de cada um dos óleos essenciais avaliados. Verificou-se que os óleos utilizados apresentaram atividade fungicida em diferentes concentrações, as quais variaram de 0,80% (melaleuca), 3,20%, (eucalipto), 6,25% (limão, capim limão, cravo da índia, canela e nim), 12,5% (hortelã e citronela), 25% (copaíba), 50% (coco e gengibre) e 100% (manjericão). O óleo de nim apresentou maior redução da carga microbiana em função do tempo de exposição, sendo necessários 30 minutos para anulação da contagem microbiana. O efeito antifúngico dos óleos essenciais, para controle de Colletotrichum gloeosporioides, depende da planta e da concentração empregada.

ABSTRACT This study aimed to evaluate the antifungal effect of essential and vegetal oils in the in vitro control of Colletotrichum gloeosporioides, a causal agent of anthracnose in fruit postharvest. Thirteen essential oils were used at concentrations of 0.00%, 0.40%, 0.80%, 1.70%, 3.20%, 6.25%, 12.50%, 25.00%, 50.00%, and 100.00%, and also a standard strain of Colletotrichum gloeosporioides, The minimum inhibitory concentration and minimum fungicidal concentration were assessed to characterize the potential of each of the essential oils tested. We found that used oils showed fungicidal activity at different concentrations, which varied in 0.80% (Melaleuca alternifólia), 3.20%, (Eucalyptus globulus), 6.25% (Citrus limonium, Cymbopogon citratus, Syzygium aromaticum, Cinnamomum zeylanicum, and Azadirachta indica), 12.5% (Mentha piperita and Cymbopogon winterianus), 25% (Copaifera langsdorfii), 50% (Cocos nucifera and Zingiber officinale), and 100% (Ocimum basilicum). The Azadirachta indica oil showed greater reduction of microbial load because of the exposure time, and took 30 minutes for annulment of microbial count. The antifungal effect of essential oils to control Colletotrichum gloeosporioides depends on the plant and quantity of concentration.

Role of constitutive behavior and tumor-host mechanical interactions in the state of stress and growth of solid tumors.

Mechanical forces play a crucial role in tumor patho-physiology. Compression of cancer cells inhibits their proliferation rate, induces apoptosis and enhances their invasive and metastatic potential. Additionally, compression of intratumor blood vessels reduces the supply of oxygen, nutrients and drugs, affecting tumor progression and treatment. Despite the great importance of the mechanical microenvironment to the pathology of cancer, there are limited studies for the constitutive modeling and the mechanical properties of tumors and on how these parameters affect tumor growth. Also, the contribution of the host tissue to the growth and state of stress of the tumor remains unclear. To this end, we performed unconfined compression experiments in two tumor types and found that the experimental stress-strain response is better fitted to an exponential constitutive equation compared to the widely used neo-Hookean and Blatz-Ko models. Subsequently, we incorporated the constitutive equations along with the corresponding values of the mechanical properties - calculated by the fit - to a biomechanical model of tumor growth. Interestingly, we found that the evolution of stress and the growth rate of the tumor are independent from the selection of the constitutive equation, but depend strongly on the mechanical interactions with the surrounding host tissue. Particularly, model predictions - in agreement with experimental studies - suggest that the stiffness of solid tumors should exceed a critical value compared with that of the surrounding tissue in order to be able to displace the tissue and grow in size. With the use of the model, we estimated this critical value to be on the order of 1.5. Our results suggest that the direct effect of solid stress on tumor growth involves not only the inhibitory effect of stress on cancer cell proliferation and the induction of apoptosis, but also the resistance of the surrounding tissue to tumor expansion.

Fabrication, characterization, and evaluation in drug release properties of magnetoactive poly(ethylene oxide)-poly(L-lactide) electrospun membranes.

The fabrication of electrospun magnetoactive fibrous nanocomposite membranes based on the water-soluble and biocompatible poly(ethylene oxide) (PEO), the biocompatible and biodegradable poly(L-lactide) (PLLA) and preformed oleic acid-coated magnetite nanoparticles (OA.Fe3O4) is reported. Visualization of the membranes by electron microscopy techniques reveals the presence of continuous fibers of approximately 2 µm in diameter, with the magnetic nanoparticles being evenly distributed within the fibers, retaining at the same time their nanosized diameters (≈ 5 nm). Thermal gravimetric analysis measurements suggest that the magnetic nanoparticles embedded within the polymer fibers affect favorably the thermal stability of the membranes. Moreover, assessment of their magnetic characteristics by vibrating sample magnetometry discloses tunable superparamagnetic behavior at ambient temperature. For the first time, the biocompatibility and biodegradability of PEO/PLLA and the tunable magnetic activity of the OA.Fe3O4 are combined in the same drug delivery system, with N-acetyl-p-aminophenol (acetaminophen) as a proof-of-concept pharmaceutical. Furthermore, their heating ability under alternating current (AC) magnetic field conditions is evaluated using frequency of 110 kHz and corresponding magnetic field strength of 25 mT (19.9 kA/m). Consequently, these magnetoactive fibrous nanocomposites exhibit promising characteristics for future exploitation in magnetothermally triggered drug delivery.

An unusual Michael-induced skeletal rearrangement of a bicyclo[3.3.1]nonane framework of phloroglucinols to a novel bioactive bicyclo[3.3.0]octane.

A novel skeletal rearrangement of bicyclo[3.3.1]nonane-2,4,9-trione (16) to an unprecedented highly functionalized bicyclo[3.3.0]octane system (17), induced by an intramolecular Michael addition, is presented. This novel framework was found to be similarly active to hyperforin (1), against PC-3 cell lines. A mechanistic study was examined in detail, proposing a number of cascade transformations. Also, reactivity of the Δ(7,10)-double bond was examined under several conditions to explain the above results.

Tensile mechanical properties and hydraulic permeabilities of electrospun cellulose acetate fiber meshes.

The mechanical properties and hydraulic permeabilities of biomaterial scaffolds play a crucial role in their efficacy as tissue engineering platforms, separation processors, and drug delivery vehicles. In this study, electrospun cellulose acetate fiber meshes of random orientations were created using four different concentrations, 10.0, 12.5, 15.0, and 17.5 wt % in acetone or ethyl acetate. The tensile mechanical properties and the hydraulic permeabilities of these meshes were measured, and a multiscale model was employed to predict their mechanical behavior. Experimentally, the elastic modulus ranged from 3.5 to 12.4 MPa depending on the polymer concentration and the solvent. Model predictions agreed well with the experimental measurements when a fitted single-fiber modulus of 123.3 MPa was used. The model also predicted that changes in fiber alignment may result in a 3.6-fold increase in the elastic modulus for moderately aligned meshes and a 8.5-fold increase for highly align meshes. Hydraulic permeabilities ranged from 1.4 x 10(-12) to 8.9 x 10(-12) m(2) depending on polymer concentration but not the choice of solvent. In conclusion, polymer concentration, fiber alignment, and solvent have significant impact on the mechanical and fluid transport properties of electrospun cellulose acetate fiber meshes.

Physical activity and gain in abdominal adiposity and body weight: prospective cohort study in 288,498 men and women.

BACKGROUND: The protective effect of physical activity (PA) on abdominal adiposity is unclear. OBJECTIVE: We examined whether PA independently predicted gains in body weight and abdominal adiposity. DESIGN: In a prospective cohort study [the EPIC (European Prospective Investigation into Cancer and Nutrition)], we followed 84,511 men and 203,987 women for 5.1 y. PA was assessed by a validated questionnaire, and individuals were categorized into 4 groups (inactive, moderately inactive, moderately active, and active). Body weight and waist circumference were measured at baseline and self-reported at follow-up. We used multilevel mixed-effects linear regression models and stratified our analyses by sex with adjustments for age, smoking status, alcohol consumption, educational level, total energy intake, duration of follow-up, baseline body weight, change in body weight, and waist circumference (when applicable). RESULTS: PA significantly predicted a lower waist circumference (in cm) in men (ß = -0.045; 95% CI: -0.057, -0.034) and in women (ß = -0.035; 95% CI: -0.056, -0.015) independent of baseline body weight, baseline waist circumference, and other confounding factors. The magnitude of associations was materially unchanged after adjustment for change in body weight. PA was not significantly associated with annual weight gain (in kg) in men (ß = -0.008; 95% CI: -0.02, 0.003) and women (ß = -0.01; 95% CI: -0.02, 0.0006). The odds of becoming obese were reduced by 7% (P < 0.001) and 10% (P < 0.001) for a one-category difference in baseline PA in men and women, respectively. CONCLUSION: Our results suggest that a higher level of PA reduces abdominal adiposity independent of baseline and changes in body weight and is thus a useful strategy for preventing chronic diseases and premature deaths.

Natural and synthetic antioxidants: an updated overview.

Abstract The current understanding of the complex role of ROS in the organism and pathological sequelae of oxidative stress points to the necessity of comprehensive studies of antioxidant reactivities and interactions with cellular constituents. Studies of antioxidants performed within the COST B-35 action has concerned the search for new natural antioxidants, synthesis of new antioxidant compounds and evaluation and elucidation of mechanisms of action of both natural and synthetic antioxidants. Representative studies presented in the review concern antioxidant properties of various kinds of tea, the search for new antioxidants of herbal origin, modification of tocopherols and their use in combination with selenium and properties of two promising groups of synthetic antioxidants: derivatives of stobadine and derivatives of 1,4-dihydropyridine.

Avaliação in vitro da atividade antifúngica de extratos de plantas e óleo de eucalipto sobre Trichophyton mentagrophytes / In vitro evaluation of the antifungal activity of plant extracts and eucalyptus oil on Trichophyton mentagrophytes

O presente estudo teve como objetivo determinar a ação antifúngica de extratos de plantas medicinais e óleo de eucalipto frente ao dermatófito Trichophyton mentagropytes, visando a utilização da fitoterapia no controle. As plantas utilizadas na obtenção dos extratos foram arruda (Ruta graveolens), citronela (Cymbopogon nardus), cravo de defunto (Tagetes minuta), eucalipto (Eucalyptus spp), graviola (Annona muricata), fruta do conde (Annona spp), manga (Mangifera indica), romã (Punica granatum), flores e folhas de primavera (Bougainvillea spectabilis). Verificou-se que uso de 0,5 por cento óleo de eucalipto no combate ao T. mentagropytes foi eficaz, já os extratos de citronela (4 por cento) eucalipto (5 por cento) e romã (8 por cento) atuaram como fungistáticos e os restantes não devem ser usados contra este dermatófito porque não causaram nenhum efeito.

The aim of this study was to assess the antifungal action of medicinal plant extracts and eucalyptus oil against the dermatophyte Trichophyton mentagrophytes in order to employ phytotherapy for its control. The plants used for extract production were common rue (Ruta graveolens), citronella (Cymbopogon nardus), wild marigold (Tagetes minuta), eucalyptus (Eucalyptus spp), sweetsop (Annona muricata), custard apple (Annona spp), mango (Mangifera indica), pomegranate (Punica granatum), besides flowers and leaves of bougainvillea (Bougainvillea spectabilis). The use of 0.5 percent eucalyptus oil was effective in controlling Trichophyton mentagrophytes; however, citronella (4 percent), eucalyptus (5 percent) and pomegranate (8 percent) extracts acted as fungistatic, and the remaining extracts should not be used against this dermatophyte since they did not have any effect.

Synthesis and study of the cancer cell growth inhibitory properties of alpha-, gamma-tocopheryl and gamma-tocotrienyl 2-phenylselenyl succinates.

Vitamin E succinate selenium-conjugated molecules were synthesized and their apoptogenic properties were evaluated. 4-Methyl-2-phenylselenyl succinate (4) was prepared by the reaction of sodium benzeneselenolate with 2-bromosuccinic anhydrite in methanol solution. The methyl ester was converted to the acid (5) by hydrolysis with aqueous hydrochloric acid. Reaction of the 2-phenylselenyl succinic anhydrite (6) with alpha-tocopherol (1a), gamma-tocopherol (1c), and gamma-tocotrienol (2c) in acidic conditions gave the respective esters. The free radical scavenging properties of alpha-tocopheryl-2-phenylselenyl succinate (7), gamma-tocopheryl-2-phenylselenyl succinate (8), and gamma-tocotrienyl-2-phenylselenyl succinate (9) were evaluated in comparison with those of alpha-tocopheryl succinate (10), gamma-tocopheryl succinate (11), and gamma-tocotrienyl succinate (12), respectively, and the free tocopherols and gamma-tocotrienol. Compounds 7-9 induced a statistically significant decrease in prostate cancer cell viability compared to 10-12, respectively, or 5, exhibiting features of apoptotic cell death and associated with caspase-3 activation. These data show that structural modifications of vitamin E components by 5 enhance their apoptogenic properties in cancer cells.

Lesiones inadvertidas en el trauma penetrante abdominal / Unnoticed lesions in abdominal trauma

Antecedentes: Los traumatismos en general y los abdominales en particular están aumentando en todas las sociedades. Las lesiones inadvertidas son una realidad con independencia de la sistemática que se utiliza, tanto en el estudio como en el tratamiento. Objetivos: Analizar la frecuencia y las causas de las lesiones no percibidas tanto en el pre como en el intraoperatorio. Lugar de aplicación: Servicio de Cirugía General, Complejo Hospitalario. Diseño: Estudio retrospectivo. Material y métodos: En una serie de 600 pacientes heridos de bala en abdomen tratados entre diciembre de 1984 y diciembre del 2000 se hallaron 16 lesiones inadvertidas. Las formas clínicas de presentación fueron: hemorragia y shock hipovolémico en cinco casos, peritonitis en cuatro casos, sepsis cuatro casos, salida de orina por los drenajes 2 casos y disartria con tendencia al coma un caso. Resultados: De su análisis se desprende que los errores fueron cometidos tanto en la evaluación preoperatoria (4 casos con un paciente fallecido), como en la exploración intraoperatoria (12 casos con dos fallecidos). En 15 casos inadvertidas aun dentro del área corporal en la cual se produjo la injuria. En un caso la lesión se halló fuera del área corporal de mayor foco de atención. Conclusiones: En nuestra serie las lesiones no percibidas se observaron en el 2,5 por ciento. La frecuencia de aparición en la literatura mundial consultada se halla entre un 3 y un 12 por ciento. En las mismas relatan alta morbimortalidad, la cual en la presente serie fue del 18,7 por ciento. A nuestro entender hay ciertas regiones del abdomen particularmente proclives a presentar este tipo de lesiones (AU)

Lesiones inadvertidas en el trauma penetrante abdominal / Unnoticed lesions in abdominal trauma

Antecedentes: Los traumatismos en general y los abdominales en particular están aumentando en todas las sociedades. Las lesiones inadvertidas son una realidad con independencia de la sistemática que se utiliza, tanto en el estudio como en el tratamiento. Objetivos: Analizar la frecuencia y las causas de las lesiones no percibidas tanto en el pre como en el intraoperatorio. Lugar de aplicación: Servicio de Cirugía General, Complejo Hospitalario. Diseño: Estudio retrospectivo. Material y métodos: En una serie de 600 pacientes heridos de bala en abdomen tratados entre diciembre de 1984 y diciembre del 2000 se hallaron 16 lesiones inadvertidas. Las formas clínicas de presentación fueron: hemorragia y shock hipovolémico en cinco casos, peritonitis en cuatro casos, sepsis cuatro casos, salida de orina por los drenajes 2 casos y disartria con tendencia al coma un caso. Resultados: De su análisis se desprende que los errores fueron cometidos tanto en la evaluación preoperatoria (4 casos con un paciente fallecido), como en la exploración intraoperatoria (12 casos con dos fallecidos). En 15 casos inadvertidas aun dentro del área corporal en la cual se produjo la injuria. En un caso la lesión se halló fuera del área corporal de mayor foco de atención. Conclusiones: En nuestra serie las lesiones no percibidas se observaron en el 2,5 por ciento. La frecuencia de aparición en la literatura mundial consultada se halla entre un 3 y un 12 por ciento. En las mismas relatan alta morbimortalidad, la cual en la presente serie fue del 18,7 por ciento. A nuestro entender hay ciertas regiones del abdomen particularmente proclives a presentar este tipo de lesiones

Advanced glycation end product levels in eye lenses, aorta, and tail tendon in transplanted diabetic inbred Lewis rats.

BACKGROUND: Pancreatic islet transplantation in diabetes, by restoring euglycemia, should in time correct the abnormal accumulation of advanced glycation end products (AGEs) over target tissues, thus delaying the development of late diabetic complications. METHODS: Homologous islet transplantation was performed in inbred Lewis rats 15 days (TA), 4 months (TB), and 8 months (TC) after streptozotocin diabetes. Group TA was studied for 12 months and groups TB and TC were studied for 4 months after transplantation. Normal (N) and diabetic (D) rats formed the control groups. Metabolic control in the transplant (T) groups was evaluated by oral glucose tolerance test. Blood glucose, glycated hemoglobin, and body weight were determined in all groups. AGE levels were determined by spectrofluorometry in eye lens proteins and by ELISA in aortic and tail tendon collagen. RESULTS: T groups showed normal oral glucose tolerance tests and metabolic parameters. The latter were altered in all D groups (P<0.005 to P<0.0001 versus N and T groups). AGEs were increased in the D groups (P<0.05 to P<0.001) versus the N groups. AGEs in the TA and TB groups were not different from those of the N groups but were significantly reduced (P<0.05 to P<0.001) when compared with those of the D groups. In the TC group, eye lens AGEs were significantly elevated (P<0.001) or significantly reduced (P<0.01) when compared with those of the N or D groups, respectively. Aortic collagen AGEs were elevated (P<0.01) by comparison with those of the N groups and not statistically different from those of the D groups. Tail tendon collagen AGE levels lay between those of the N and D groups, without reaching a statistical significance. CONCLUSIONS: These results indicate that primary and early secondary (groups TA and TB) but not late secondary (group TC) islet transplantations are capable of blocking or reducing an abnormal accumulation of AGEs, thus confirming the importance of preventive transplantation therapies.

Effect of islet transplantation on neuroelectrophysiological abnormalities in diabetic inbred Lewis rats: comparison of primary versus secondary prevention.

BACKGROUND: Neuroelectrophysiological abnormalities in diabetes indicate nervous function failure. Restoration of euglycemia by islet transplantation may prevent or reverse these abnormalities. METHODS: Pancreatic islets were transplanted in inbred Lewis rats after 15 days (Ta12, primary prevention) or 8 months (Tb12, secondary prevention) from streptozotocin-induced diabetes. Transplanted and control (normal and diabetic) rats were followed for a total period of 12 months. Metabolic parameters, somato-sensory, brain-stem auditory, and visual evoked potentials were determined at the beginning and at the end of the study and before transplantation for secondary prevention. RESULTS: The metabolic parameters in transplanted animals were similar to those of normal animals. Ta12 and normal group somato-sensory conduction velocities did not vary and were always significantly higher than those of diabetic animals. By contrast, Tb12 group conduction velocities showed only a partial improvement, values lying between those of diabetic and normal rats. Brain-stem auditory (waves I, II, and III) latencies in Ta12 group were similar to those of normal rats and significantly lower than those of diabetic animals (wave I: P<0.01; waves II and III: P<0.05). Tb12 group wave I and II latency values remained altered (P<0.005 and P<0.01 versus normal values respectively). Visual evoked potentials-P1 wave latencies in transplanted rats were always higher than those of normal and diabetic animals. CONCLUSIONS: After primary prevention, central and peripheral neurological alterations were abolished. After secondary prevention, transplantation beneficial effects were partial, occurring mainly at peripheral level. These results highlight the importance of early transplantation to prevent hyperglycemia-dependent neuroelectrophysiological alterations.

Reduction of advanced glycation end-product (AGE) levels in nervous tissue proteins of diabetic Lewis rats following islet transplants is related to different durations of poor metabolic control.

Advanced glycation end-products (AGEs) are irreversible compounds which, by abnormally accumulating over proteins as a consequence of diabetic hyperglycaemia, can damage tissues and thus contribute to the pathogenesis of diabetic complications. This study was performed to evaluate whether restoration of euglycaemia by islet transplantation modifies AGE accumulation in central and peripheral nervous tissue proteins and, as a comparison, in proteins from a non-nervous tissue. Two groups of streptozotocin diabetic inbred Lewis rats with 4 (T1) or 8 (T2) months disease duration were grafted into the liver via the portal vein with 1200-1500 islets freshly isolated from normal Lewis rats. Transplanted rats, age-matched control and diabetic rats studied in parallel, were followed for a further 4-month period. At study conclusion, glycaemia, glycated haemoglobin and body weight were measured in all animals, and an oral glucose tolerance test (OGTT) performed in transplanted rats. AGE levels in cerebral cortex, spinal cord, sciatic nerve proteins and tail tendon collagen were measured by enzyme-linked immunosorbent assay (ELISA). Transplanted animal OGTTs were within normal limits, as were glycaemia and glycated haemoglobin. Diabetic animal AGEs were significantly higher than those of control animals. Protein AGE values were reduced in many transplanted animals compared to diabetic animals, reaching statistical significance in spinal cord (P < 0.05), sciatic nerve (P < 0.02) and tail tendon collagen (P < 0.05) of T1 animals. Thus, return to euglycaemia following islet transplantation after 4 months of diabetes with poor metabolic control reduces AGE accumulation rate in the protein fractions of the mixed and purely peripheral nervous tissues (spinal cord and sciatic nerve, respectively). However, after a double duration of bad metabolic control, a statistically significant AGE reduction has not been achieved in any of the tissues, suggesting the importance of an early therapeutic intervention to prevent the possibly pathological accumulation of AGEs in nervous and other proteins.

Diabetic microangiopathy: lupus anticoagulant dependent thrombotic tendency in type 1 (insulin-dependent) diabetes mellitus.

Type 1 (insulin-dependent) diabetes mellitus is associated with long-term vascular complications. In addition to metabolic factors, immunological and haemostatic mechanisms may be involved. Lupus anticoagulant (LA), an immunoglobulin which interferes with endothelial cell function, is frequently associated with a high risk of thromboembolic events. LA has been described in several diseases but never in diabetes mellitus. The aim of this study was to evaluate if endothelial dysfunction and unmodulated haemostasis are amplified by the presence of LA in Type 1 diabetic patients. Plasma samples collected from clinically and biochemically well-characterized Type 1 diabetic patients were examined for LA, fibrinogen, prothrombin (PT), PTT, prothrombin degradation products (F1 + 2) and activated protein C (APC). The results revealed significantly decreased APC and increased F1 + 2 plasma concentrations in LA-positive but not in LA-negative patients; 60% of LA-positive and only 18% of LA-negative patients had microangiopathy (not significant). No thrombotic episodes in large vessels were found in LA-positive patients. These findings suggest that LA could be considered an additional factor in the onset and/or progression of diabetic complications, acting as a link between the immunological and haemostatic systems in the pathogenesis of diabetic microangiopathy.

Hypertension and non-insulin-dependent diabetes. A comparison between an angiotensin-converting enzyme inhibitor and a calcium antagonist.

The effects of the angiotensin-converting enzyme lisinopril were compared with those of the calcium antagonist nifedipine in 162 non-insulin-dependent diabetic hypertensive patients for a 24-week period. In 83 and 79 patients, respectively, lisinopril and slow-release nifedipine produced similar reductions in blood pressure (systolic/diastolic: -16/-13 mmHg supine and -14/-11 mmHg standing after lisinopril; -15/-12 mmHg supine and -14/-11 mmHg standing nifedipine). Fasting and post-prandial plasma glucose, glycosylated haemoglobin and plasma lipids appeared to be unaffected by either agent. Also, 28% of the patients on lisinopril and 30% of those on nifedipine presented microalbuminuria. Both drugs induced a reduction in the albumin excretion rate (AER). The geometric mean x:tolerance factor of the reduction in AER among the 23 microalbuminuric patients on lisinopril (-10.0 x:1.3 micrograms/min) was greater, though not significantly so, than that observed in the 26 on nifedipine (-0.9 x 1.2 micrograms/min). Moreover, lisinopril appeared to be better tolerated than nifedipine in our study population. Microalbuminuria is an important risk factor for cardiovascular mortality in non-insulin-dependent diabetic patients as well as in the general population. To what extent a reduction in the AER could ameliorate diabetic patients is, at present, unknown. Finally, both lisinopril and nifedipine showed a similar antihypertensive effect in these patients which was not associated with significant differences in plasma glucose, insulin or lipid concentrations. The clinical consequences of the insignificant differences in AER remain unclear.

Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study).

Nicotinamide has been recently introduced, in addition to intensive insulin therapy for patients with recent-onset insulin-dependent diabetes mellitus (IDDM) to protect beta cells from end-stage destruction. However, available data are conflicting. A double blind trial in 56 newly-diagnosed IDDM patients receiving nicotinamide for 12 months at a dose of 25 mg/kg body weight or placebo was designed in order to determine whether this treatment could improve the integrated parameters of metabolic control (insulin dose, glycated haemoglobin and C-peptide secretion) in the year after diagnosis. In addition to nicotinamide or placebo, patients received three to four insulin injections daily to optimize blood glucose levels. Patients treated with nicotinamide or placebo received similar doses of insulin during follow-up and 1 year after diagnosis with comparable glycated haemoglobin levels 6.7 +/- 1.8% nicotinamide vs 7.1 +/- 0.6% placebo). Basal and glucagon stimulated C-peptide secretion detectable at diagnosis were similarly preserved in the course of 12 months follow-up both in nicotinamide and placebo treated patients. No adverse effects were observed in patients receiving nicotinamide. When age at diagnosis was taken into account, nicotinamide treated older patients ( > 15 years of age) showed significantly higher stimulated C-peptide secretion than placebo treated patients (p < 0.02). These results suggest that nicotinamide can preserve and improve stimulated beta-cell function only in patients diagnosed after puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of advanced glycation end-products (AGE) in late diabetic complications.

To evaluate accumulation of advanced glycation end-products (AGE) in diabetes and its possible correlation with late diabetic complications, AGE levels were measured by spectrofluorimetry in eye lens and sciatic nerve proteins and isolated tail tendon collagen of rats with experimental diabetes of 3- and 6-month duration. The values obtained were compared to those from age-matched control rats and correlated with cataract presence and somatosensory evoked potential (SEP) alterations. Diabetic animals had increased AGE levels in all tissues at both times; cataract developed in 29% of diabetic rats at 3 months and in 57% at 6 months; SEP conduction velocity was reduced in diabetic animals both at 3 (54.5 +/- 1.8 S.E.M. m/s vs. 73.9 +/- 1.0, P < 0.0001) and 6 months (59.5 +/- 1.4 vs. 71.5 +/- 1.6, P < 0.0001) from diabetes induction. No eye lens AGE level differences were observed when cataract presence was considered. Interestingly, in diabetic rats, increased sciatic nerve AGE levels were associated with reduced SEP. These data show that: (1) AGE levels are increased as early as 3 months from development of hyperglycemia; (2) other factors, in addition to an enhanced rate of fluorescent AGE formation, might play important roles in the pathogenesis of diabetic cataract; (3) increased peripheral nerve AGE levels are associated with SEP alterations.