Global design of analog cells using statistical optimization techniques

We present a methodology for automated sizing of analog cells using statistical optimization in a simulation based approach. This methodology enables us to design complex analog cells from scratch within reasonable CPU time. Three different specification types are covered: strong constraints on the electrical performance of the cells, weak constraints on this performance, and design objectives. A mathematical cost function is proposed and a bunch of heuristics is given to increase accuracy and reduce CPU time to minimize the cost function. A technique is also presented to yield designs with reduced variability in the performance parameters, under random variations of the transistor technological parameters. Several CMOS analog cells with complexity levels up to 48 transistors are designed for illustration. Measurements from fabricated prototypes demonstrate the suitability of the proposed methodology

Systemic lupus erythematosus in northwestern Spain: a 20-year epidemiologic study

To further investigate the epidemiology of systemic lupus erythematosus (SLE) in southern Europe, we assessed the incidence, prevalence, clinical spectrum of the disease, flares, and survival of patients diagnosed with SLE in the Lugo region of northwestern Spain. Between January 1987 and December 2006, 150 Lugo residents were diagnosed as having SLE according to the 1982 American College of Rheumatology criteria for the classification of SLE. Women outnumbered men (127 [84.7%] vs. 23 [15.3%]). The mean age at the time of disease diagnosis was 46.1 ± 19.6 years. The mean follow-up from the time of disease diagnosis was 7.8 ± 4.5 years. The age- and sex-adjusted annual incidence rate over the 20-year study period was 3.6 (95% confidence interval [CI], 3.0-4.2) per 100,000 population aged 15 years and older. The overall annual incidence rate over the 20-year study period in women (5.9/100,000 population aged ≥15 yr; 95% CI, 4.9-7.0) was higher than in men (1.1/100,000 population aged ≥15 yr; 95% CI, 0.7-1.7) (p < 0.001). By December 31, 2006, the overall age-adjusted SLE prevalence in the Lugo region for patients who fulfilled at least 4 of 1982 American College of Rheumatology criteria was 17.5 per 100,000 population aged 15 years and older (95% CI, 12.6-24.1). Prevalence in women (29.2/100,000 population aged ≥15 yr; 95% CI, 20.0-40.7) was higher than in men (5.8/100,000 population aged ≥15 yr; 95% CI, 2.0-12.0). The most frequent clinical manifestation was arthritis. As reported in population-based studies on SLE patients of European descent, renal disease was observed in only 27.3% of the patients. The rate of flares was 0.084/year. A younger age and the presence of nephritis at the time of disease diagnosis were associated with the development of flares during the follow-up of Lugo patients. Compared with the general population the probability of survival in patients with SLE was significantly reduced (p = 0.04). In conclusion, the present study establishes a baseline estimate of the incidence and clinical spectrum of SLE in northwestern Spain. According to our results, the incidence of SLE in northwestern Spain is slightly higher than that reported in most European regions. Patients with SLE from northwestern Spain have a later average age onset and a lower frequency of nephritis than in the African-American population. However, our data show a reduced probability of survival in Spanish patients with SLE

Audiovestibular manifestations in patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin affecting up to 1% of the population. Little is known about audiovestibular impairment in patients with AS, especially the presence of cochleovestibular dysfunction in these patients. To investigate audiovestibular manifestations in AS, we studied a series of 50 consecutive patients who fulfilled the modified New York diagnostic criteria for AS and 44 matched controls. Individuals with history of cardiovascular disease, cerebrovascular complications, peripheral artery disease, renal insufficiency, syphilis, Meniere and other vestibular syndromes, infections involving the inner ear, barotrauma, or in treatment with ototoxic drugs were excluded. Most patients with AS were men (80%). The mean age at the time of study was 52.5 years, and mean age at the onset of symptoms was 34.4 years. Twenty-nine (58%) patients showed abnormal hearing loss in the audiogram compared to only 8 (18%) controls (p < 0.001). Values of audiometric tests (pure-tone average and speech reception threshold) yielded significant differences between patients and controls (p < 0.001). It is noteworthy that the audiogram shape disclosed a predominant pattern of high-frequency sensorineural hearing loss in AS patients (50%) compared to controls (18%) (p = 0.002). Also, AS patients exhibited abnormal vestibular tests more commonly than controls. AS patients had an increased frequency of head-shaking nystagmus (20%) compared to controls (0%) (p < 0.001). Moreover, patients (26%) showed a significantly increased frequency of abnormal caloric test compared to controls (0%) (p < 0.001). Finally, a significantly increased frequency of abnormal clinical test of sensory integration and balance with a predominant vestibular loss pattern was observed in patients (36%) compared to controls (5%) (p < 0.001). In conclusion, the current study demonstrates strong evidence for inner ear compromise in patients with AS

Preliminary evaluation of the presence of organochlorine pesticides in fish of Vicente Guerrero dam (Tamaulipas, Mexico)

Organochlorine pesticides (OCPs) are classified as persistent organic pollutants. The presence of OCPs in the environment is of global concern as they are persistent, ubiquitous and highly toxic. The purpose of this study was to evaluate the presence of organochlorine pesticides (aldrin, endrin, chlordane, mirex, heptachlor, DDT, DDE and DDD) in the muscle of four fish species from Vicente Guerrero Dam in Tamaulipas (Mexico): catfish (Ictalurus punctatus), carp (Ciprynus carpio), largemouth bass (Micropterus salmoides) and tilapia (Oreochromis niloticus). Solid phase extraction and gas chromatography with electron capture detector was used to detect the pesticides. The highest concentration found was for DDE in largemouth bass, carp and catfish (239.90, 165.98 and 212.31 ng/g, respectively) and for chlordane in catfish and largemouth bass (44.66 and 64.22 ng/g). There is a risk of carcinogenic effects if carp and largemouth bass are regularly consumed by the population in the region as the concentration of p-p′-DDE is higher than the recommendations of the US Environmental Protection AgencyLos pesticidas organoclorados (OCPs por sus siglas en inglés) están clasificados como contaminantes orgánicos persistentes. La presencia de OCPs en el ambiente es de interés mundial debido a que son persistentes, ubicuos y altamente tóxicos. El objetivo de este trabajo fue evaluar la presencia de pesticidas organoclorados (aldrín, endrín, clordano, mirex, heptacloro, DDT, DDE, DDD) en el músculo de 4 especies de pescado de la Presa Vicente Guerrero del estado de Tamaulipas (México): bagre (Ictalurus punctatus); carpa (Ciprynus carpio), lobina (Micropterus salmoides) y tilapia (Oreochromis niloticus). Para la determinación de los pesticidas se usó extracción en fase sólida y cromatografía de gases con detector de captura de electrones. La mayor concentración encontrada fue para el DDE en lobina, carpa y bagre (239,90, 165,98 y 212,31 ng/g, respectivamente) y para el clordano en bagre y lobina (44,66 y 64,22 ng/g). Existe riesgo de cáncer por el consumo de carpa y lobina en forma regular por parte de la población que habita en la región debido a que los altos niveles de p-p′-DDE encontrados superan las recomendaciones de la Agencia de Protección del Medio Ambiente de Estados UnidosA SEMARNAT-CONACYT por el financiamiento al proyecto SEMARNAT–2002–C01–0462S

Anti-TNF-alpha-adalimumab therapy is associated with persistent improvement of endothelial function without progression of carotid intima-media wall thickness in patients with rheumatoid arthritis refractory to conventional therapy

To determine whether treatment with the anti-TNF-alpha blocker adalimumab yields persistent improvement of endothelial function and prevents from morphological progression of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) refractory to conventional therapy, a series of 34 consecutive RA patients, attending hospital outpatient clinics and who were switched from disease modifying antirheumatic drug therapy to anti-TNF-alpha-adalimumab treatment because of severe disease, were assessed by ultrasonography techniques before the onset of adalimumab therapy (at day 0) and then at day 14 and at month 12. Values of flow-mediated endothelium-dependent vasodilatation at day 14 and at month 12 were significantly higher (mean ± standard deviation (SD): 6.1 ± 3.9%; median: 5.7% at day 14, and mean ± SD: 7.4 ± 2.8%; median: 6.9% at month 12) than those obtained at day 0 (mean: 4.5 ± 4.0%; median: 3.6%; P = 0.03 and P < 0.001, resp.). Endothelium-independent vasodilatation results did not significantly change compared with those obtained at day 0. No significant differences were observed when carotid artery intima-media wall thickness values obtained at month 12 (mean ± SD: 0.69 ± 0.21 mm) were compared with those found at day 0 (0.65 ± 0.16 mm) (P = 0.3). In conclusion, anti-TNF-alpha-adalimumab therapy has beneficial effects on the development of the subclinical atherosclerosis disease in RA

GNIP1 E3 ubiquitin ligase is a novel player in regulating glycogen metabolism in skeletal muscle.

Background: Glycogenin-interacting protein 1 (GNIP1) is a tripartite motif (TRIM) protein with E3 ubiquitin ligase activity that interacts with glycogenin. These data suggest that GNIP1 could play a major role in the control of glycogen metabolism. However, direct evidence based on functional analysis remains to be obtained. Objectives: The aim of this study was 1) to define the expression pattern of glycogenin-interacting protein/ Tripartite motif containing protein 7 (GNIP/TRIM7) isoforms in humans, 2) to test their ubiquitin E3 ligase activity, and 3) to analyze the functional effects of GNIP1 on muscle glucose/glycogen metabolism both in human cultured cells and in vivo in mice. Results: We show that GNIP1 was the most abundant GNIP/TRIM7 isoform in human skeletal muscle, whereas in cardiac muscle only TRIM7 was expressed. GNIP1 and TRIM7 had autoubiquitination activity in vitro and were localized in the Golgi apparatus and cytosol respectively in LHCN-M2 myoblasts. GNIP1 overexpression increased glucose uptake in LHCN-M2 myotubes. Overexpression of GNIP1 in mouse muscle in vivo increased glycogen content, glycogen synthase (GS) activity and phospho-GSK-3α/β (Ser21/9) and phospho-Akt (Ser473) content, whereas decreased GS phosphorylation in Ser640. These modifications led to decreased blood glucose levels, lactate levels and body weight, without changing whole-body insulin or glucose tolerance in mouse. Conclusion: GNIP1 is an ubiquitin ligase with a markedly glycogenic effect in skeletal muscle

Influence of Protein Carbonylation on Human Adipose Tissue Dysfunction in Obesity and Insulin Resistance

Background: Obesity is characterized by adipose tissue dysregulation and predisposes individuals to insulin resistance and type 2 diabetes. At the molecular level, adipocyte dysfunction has been linked to obesity-triggered oxidative stress and protein carbonylation, considering protein carbonylation as a link between oxidative stress and metabolic dysfunction. The identification of specific carbonylated proteins in adipose tissue could provide novel biomarkers of oxidative damage related to metabolic status (i.e prediabetes). Thus, we aimed at characterizing the subcutaneous and omental human adipose tissue carbonylome in obesity-associated insulin resistance. Methods: 2D-PAGE was used to identify carbonylated proteins, and clinical correlations studies and molecular biology approaches including intracellular trafficking, reactive oxygen species assay, and iron content were performed using in vitro models of insulin resistance. Results: The carbonylome of human adipose tissue included common (serotransferrin, vimentin, actin, and annexin A2) and depot-specific (carbonic anhydrase and α-crystallin B in the subcutaneous depot; and α-1-antitrypsin and tubulin in the omental depot) differences that point out the complexity of oxidative stress at the metabolic level, highlighting changes in carbonylated transferrin expression. Posterior studies using in vitro prediabetic model evidence alteration in transferrin receptor translocation, linked to the prediabetic environment. Finally, ligand-receptor molecular docking studies showed a reduced affinity for carbonylated transferrin binding to its receptor compared to wild-type transferrin, emphasizing the role of transferrin carbonylation in the link between oxidative stress and metabolic dysfunction. Conclusions: The adipose tissue carbonylome contributes to understanding the molecular mechanism driving adipocyte dysfunction and identifies possible adipose tissue carbonylated targets in obesity-associated insulin resistance

Comportamiento hidroclimático de coníferas en el Cerro Potosí, Nuevo León, México

El Cerro Potosí (CPO) se caracteriza por un gradiente altitudinal de 2 200 a 3 719 m y por ser hábitat de diversas coníferas. Los objetivos de este estudio fueron: 1) generar una red dendrocronológica de Pinus culminicola, Pinus hartwegii, Pseudotsuga menziesii y Pinus greggii; 2) desarrollar una reconstrucción de lluvia estacional; y 3) determinar la influencia de fenómenos atmosféricos de circulación general sobre la variabilidad interanual y multianual de la precipitación en CPO. Para lograr esos objetivos, con métodos dendrocronológicos se generaron cuatro cronologías climáticamente sensitivas; la más extensa (1420-2010) fue de Pinus hartwegii, y las más corta (1850-2010), de Pinus greggii. La asociación entre series dendrocronológicas mostró una respuesta climática común y mediante componentes principales. Se integró una serie representativa de los diversos estratos de elevación, que cubre el período 1700-2010. La reconstrucción de lluvia estacional enero-septiembre detectó que los años más secos fueron 1785 y 1801, y los más húmedos, 1791, 1832 y 1911, con una influencia significativa (r= 0.53, p<0.01) del Niño Oscilación del Sur (ENSO), a través del índice de lluvia tropical (TRI). La influencia de huracanes detectada en las series de madera tardía constituye una alternativa para analizar, históricamente, la influencia de estos fenómenos atmosféricos en el crecimiento de las especies y en la producción de servicios hidrológicos para la región