Serum creatinine is an inadequate screening test for renal failure in ischemic stroke patients

Objective – Serum creatinine (SCr) level is the most commonly used screening test for renal function, but its concentration is affected by factors other than glomerular filtration rate (GFR). We hypothesized that SCr would underestimate the degree of renal failure in ischemic stroke patients. Material and methods – We conducted a prospective study of 273 patients admitted to our institution for ischemic stroke within a year. GFR was calculated using the Cockcroft–Gault formula (CG). Patients were grouped according to the SCr with stages of renal failure according to CG values. Results – Of the 273 patients studied, 231 had normal SCr. Of this group 46.8% (108), 24.7% (57) and 4 (1.7%) had mild, moderate and severe renal failure according to GFR estimation. Among patients with normal SCr, abnormal CG values were identified in 86.2% (150) ≥ 65 years old, 33.3% (19) <65 years old, 69% (89) in men and 78.4% (80) in women. An SCr greater than 1.7 mg/dl had only a sensitivity of 14.7%. Conclusions – This study documents the substantial prevalence of significantly abnormal renal function among patients with normal‐range SCr. Routine estimation of GFR be preferred to SCr as a screening method for the early detection of renal impairment in stroke patients.     

Factores de riesgo de mortalidad de los pacientes quirúrgicos en un hospital terciario: estudio del registro de pacientes en el periodo 2004-2006

Objective

To determine mortality risk factors in surgical patients.

Material and method

A cross-sectional study was carried out on all surgical patients who died while in hospital, over a period of three years (2004-2006). Pre, intra and postoperative variables were analysed. Comparisons were made between patients operated on as emergencies and elective surgery patients. Multivariate analysis was performed on the pre, intra and postoperative variables, using χ² of Pearson correlation with a confidence interval of 95%.

Results

Surgery was performed on a total of 38 815 patients, of which 6 326 were emergency procedures and 32 489 as elective. There were 479 deaths registered: 36 occurred in the operating theatre and 443 died after the operation. Arterial hypertension, diabetes mellitus and cancer were significant causes of death. Intraoperative complications were associated with mortality during the surgical procedure. Emergency surgery was an independent risk factor (mortality, 5.5% vs. 0.4% for elective surgery). Sepsis, cardiac and respiratory related deaths were the main risk factors for postoperative death.

Conclusions

Prevention and adequate treatment of perioperative risk factors should significantly reduce morbidity and mortality rates, mainly in those patient operated as emergencies.     

Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue

OBJECTIVE—Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown.RESEARCH DESIGN AND METHODS—For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1–based cell migration assays.RESULTS—Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Gα. Moreover, in type 2 diabetes, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels.CONCLUSIONS—Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes.Immune response and metabolic regulation are highly integrated, and the proper function of each is dependent on the other (1). Chronic inflammation is frequently associated with central obesity and associated disturbances (2). In patients with obesity and type 2 diabetes, altered serum concentrations of inflammatory markers, including high-sensitivity C-reactive protein, tumor necrosis factor-α (TNF-α), fibrinogen, interleukin (IL)-10, adiponectin, and IL-6, have been frequently reported (2–5). However, the link between inflammation and central obesity is not fully understood.Progranulin is a secreted protein with important functions in several processes, including immune response and embryonic development (6). Progranulin, also known as granulin, acrogranin, proepithelin, and PC cell–derived growth factor, is a 593–amino acid glycoprotein, the mRNA of which is expressed in many epithelial cells both in vitro and in vivo. The widespread occurrence of progranulin mRNA in cells from the hematopoietic system and in epithelia implies important functions in these tissues. Autosomal dominant mutations in the progranulin gene cause frontotemporal dementia (7,8), whereas overexpression of progranulin promotes the invasive progression of a range of tumors, including those of the breast and the brain (9). It has been shown that overexpression of progranulin renders breast cancer cells resistant to tamoxifen (10), suggesting that autocrine regulation of progranulin by cancer cells is critically involved in breast cancer tumorigenesis (11). It was also found that in murine transcutaneous puncture wounds, progranulin mRNA is expressed in the inflammatory infiltrate and is highly induced in dermal fibroblasts and endothelia after injury (12). When applied to a cutaneous wound, progranulin increased the accumulation of neutrophils, macrophages, blood vessels, and fibroblasts in the wound (13), suggesting that progranulin could function as a chemotactic protein for myeloid-origin cell types and an angiogenic factor. A recent study showed that progranulin is an inducible protein in response to hypoxia or acidosis (14). Taken together, progranulin is an important molecule in inflammatory response and could therefore be involved in chronic subclinical inflammation associated with human obesity and type 2 diabetes. However, the role of circulating progranulin in human central obesity and its associated comorbidities is unknown. We therefore developed an enzyme-linked immunosorbent assay (ELISA) for the measurement of human progranulin serum concentrations. To this end, a human progranulin-specific polyclonal antibody (PAb) was generated, which was then used to create a sandwich ELISA. Using this new progranulin ELISA, we sought to determine circulating progranulin in individuals with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance. In addition, we assessed progranulin serum concentration before and after an intensive 4-week physical training program to test whether progranulin levels are regulated in response to training-associated improvements in body weight and insulin sensitivity. Adipose tissue has gained recognition as an important contributor to chronic systemic inflammation (15–17). Especially omental macrophage infiltration correlates with measures of central obesity and associated disturbances (17,18). Different adipokines, including monocyte chemoattractant protein-1 (MCP-1), have been shown to recruit monocytes into adipose tissue (19). We therefore tested the hypothesis that progranulin could facilitate monocyte recruitment into adipose tissue and that circulating progranulin reflects macrophage infiltration into omental adipose tissue.     

Long-term tolerability and efficacy of lamotrigine in infants 1 to 24 months old

This open-label study was designed to evaluate the long-term tolerability and efficacy of lamotrigine in 1- to 24-month-old infants with partial seizures. The study enrolled both lamotrigine-na?ve patients and patients who had been previously exposed to lamotrigine in a randomized, double-blind, placebo-controlled study. Patients (n = 204) received lamotrigine according to a dosing schedule that depended on prior experience with lamotrigine and concurrent antiepileptic drug therapy for up to 48 weeks or their second birthday, whichever occurred last. Total duration of lamotrigine exposure (which included exposure during the placebo-controlled study in lamotrigine-experienced patients) was >/=24 weeks in 92% of patients, >/=48 weeks in 70% of patients, and >/=72 weeks in 20% of patients. A total of 20 (10%) patients (8 lamotrigine-na?ve patients and 12 lamotrigine-experienced patients) transitioned to lamotrigine monotherapy. The most common adverse events were pyrexia (45% of patients), upper-respiratory tract infection (28%), and ear infection (22%). The only adverse event considered reasonably attributable to study medication in >2% of patients was irritability (n = 10; 5% of patients). No cases of serious rash were reported. The median percent reduction from baseline in partial seizure frequency in the sample as a whole was 74%. Seizure frequency was reduced by >/=50% from pre-lamotrigine baseline in 62% of patients in the sample as a whole, 60% of the lamotrigine-na?ve subgroup, and 63% of the lamotrigine-experienced subgroup. In the sample as a whole, 13% of patients were seizure free during the Treatment Phase. Investigators considered clinical status at the last clinic visit to be improved (mildly, moderately, or markedly) relative to prelamotrigine clinical status in 76% of patients (150/197) and to be unchanged in 19% (37/197). In this study-the first large prospective investigation of the long-term tolerability and efficacy of an antiepileptic drug in a patient population 2 years and younger-lamotrigine administered for up to approximately 72 weeks was well tolerated and associated with good seizure control.     

Long-term consequences of soman poisoning in mice: part 2. Emotional behavior

The organophosphorus compound soman produces long-lasting epileptic seizure activity which is associated to brain damage, more particularly in the hippocampus and the amygdala. The companion paper (see part 1 in the same journal issue) describes the neuropathology in the amygdala of soman-poisoned mice. The present paper examines the long-term effects of soman poisoning on emotional reactivity in mice, 30 or 90 days after intoxication using behavioral tasks involving amygdala function. The emotional behavior was estimated in animal tests of unconditioned fear (light/dark boxes, elevated plus-maze) and conditioned fear (auditory and contextual response). In the light/dark boxes and elevated plus-maze, mice intoxicated with soman (110 microg/kg, 1.2 LD(50)) showed an anxiety-like behavior profile at post-poisoning days 30 and 90. In conditioned fear, results showed that both auditory and contextual conditioned responses are increased on post-soman day 30 but no longer on post-soman day 90, evidencing behavioral recovery overtime. This latter behavioral result is in accordance with the delayed neuronal regeneration patterns described in the companion paper (part 1).     

Prevention of murine lupus disease in (NZBxNZW)F1 mice by sirolimus treatment

Sirolimus is a new immunosuppressive drug used to avoid allograft rejection. The immunosuppressive effect of sirolimus is due to inhibition of the mammalian target of rapamycin, necessary for the proliferation and clonal expansion of activated T-cells. Because T-cells play a central role in the pathogenesis of autoimmune disease developed in (NZBxNZW)F1 mice, we evaluated the therapeutic use of sirolimus in such mice. (NZBxNZW)F1 female mice received 1mg/kg/day of sirolimus from 12 to 37 weeks of age. The development of autoimmune disease was evaluated by measuring the serum levels of auto-antibodies (autoAbs) and their immunoglobulin isotypes, prevalence of glomerulonephritis and mortality rates. Sirolimus directly inhibited production of autoAbs, glomerular deposits of immunoglobulins and development of proteinuria; also the survival of these mice was prolonged. Our results demonstrate the beneficial effects of sirolimus in preventing the development of lupus disease in (NZBxNZW)F1 female mice.     

Mitochondrial-nuclear Cross-talk in the Aging and Failing Heart

Hypothesis Damage to heart mitochondrial structure and function occur with aging, and in heart failure (HF). However, the extent of mitochondrial dysfunction, the expression of mitochondrial and nuclear genes, and their cross-talk is not known. Observations Several observations have suggested that somatic mutations in mitochondrial DNA (mtDNA), induced by reactive oxygen species (ROS), appear to be the primary cause of energy decline, and that the generation of ROS is mainly the product of the mitochondrial respiratory chain. The free radical theory of aging, that could also be applied to HF, and in particular the targeting of mtDNA is supported by a plurality of observations from both animal and clinical studies showing decreased mitochondrial function, increased ROS levels and mtDNA mutations in the aging heart. Discussion Aging and HF with their increased ROS-induced defects in mtDNA, including base modifications and frequency of mtDNA deletions, might be expected to cause increased errors or mutations in mtDNA-encoded enzyme subunits, resulting in impaired oxidative phosphorylation and defective electron transport chain (ETC) activity which in turn creates more ROS. These events in both the aging and failing heart involve substantial nuclear–mitochondrial interaction, which is further illustrated in the progression of myocardial apoptosis. In this review the cross-talk between the nucleus and the mitochondrial organelle will be examined based on a number of animal and clinical studies, including our own.