Adiponectin in renal disease: relationship to phenotype and genetic variation in the gene encoding adiponectin

BACKGROUND: The prevalence of cardiovascular disease (CVD) and inflammation is high in patients with end-stage renal disease (ESRD). Adiponectin is an adipocytokine that may have significant anti-inflammatory and anti-atherosclerotic effects. Low adiponectin levels have previously been found in patients with high risk for CVD. METHODS: In a cohort of 204 (62% males) ESRD patients aged 52 +/- 1 years the following parameters were studied: presence of CVD, body composition, plasma adiponectin (N= 107), cholesterol, triglycerides, HDL-cholesterol, serum leptin, high-sensitivity C-reactive protein (hs-CRP), urinary albumin excretion (UAE), and single-nucleotide polymorphisms (SNPs) in the apM1 gene at positions -11391, -11377, 45, and 276. Thirty-six age- (52 +/- 2 years) and gender-matched (64% males) healthy subjects served as control subjects. RESULTS: Markedly (P < 0.0001) elevated median plasma adiponectin levels were observed in ESRD patients (22.2 microg/mL), especially type 1 diabetic patients (36.8 microg/mL), compared to control subjects (12.2 microg/mL). Log plasma adiponectin correlated to visceral fat mass (R=-0.29; P < 0.01) and Log hs-CRP (R=-0.26; P < 0.01). In a stepwise (forward followed by backward) multiple regression model only type-1 diabetes (P < 0.001) and visceral fat mass (P < 0.05) were independently associated with plasma adiponectin levels. The adiponectin gene -11377 C/C genotype was associated with a lower prevalence of CVD (25 vs. 42%) compared to the G/C genotype. CONCLUSION: The present cross-sectional study demonstrates that, whereas genetic variations seem to have a minor impact on circulating adiponectin levels, lower visceral fat mass and type 1 diabetes mellitus are associated with elevated plasma adiponectin levels in ESRD patients. Furthermore, low levels of adiponectin are associated with inflammation in ESRD.     

Activation of microglial cells and complement following traumatic injury in rat entorhinal-hippocampal slice cultures

The complement cascade has been suggested to be involved in development of secondary brain damage following traumatic brain injury (TBI). Previous studies have shown that reactive microglia are involved in activation of the complement cascade following various injuries to the nervous system. Macrophages seem to have a significant role in this process, but it is still unclear whether these cells, as well as the complement components, are derived from reactive microglia or if these biological events only can occur as a result from the influx of plasma and monocytes via a disrupted blood-brain barrier (BBB). The aim of this study was to investigate the response of microglial cells and the complement system in the absence of plasma/blood components following a standardized crush injury in an entorhinal-hippocampal slice culture. There was a clear increase in complement component C1q and C5b-9-IR (Membrane Attack Complex, MAC) in the area near the crush injury. MAC-IR appeared as numerous dots in clusters which co-localized with anti-NeuN labelled neurons in the injury border zone. Complement C1q-IR co-localized with reactive microglia, co-labelled with OX42 antisera. These findings show activation of the complement cascade near the injury zone and in particular, formation of MAC at the surface of neurons in this area. There was a distinct activation of microglial cells (OX42-IR) near the site of injury, as well as an increase in ED-1 expressing macrophages. In the absence of blood and plasma components it is likely that ED-1-labelled cells represent reactive microglia transformed into macrophages. In addition, Neurons (Neun-IR) near the injury were found to co-localize with clusterin-IR indicating upregulation of a defense system to the endogenous complement attack. The present study provides evidence that microglia and complement is activated in the injury border zone of the tissue slice in a similar fashion as in vivo following TBI, despite the absence of plasma/blood products and cells. These findings support the hypothesis that reactive microglia have a key role in complement activation following TBI by local synthesis of complement with a potential impact on development of secondary neuronal insults.     

Absence of association between organic solvent exposure and risk of chronic renal failure: a nationwide population-based case-control study

Exposure to organic solvents has been suggested to cause or exacerbate renal disease, but methodologic concerns regarding previous studies preclude firm conclusions. We examined the role of organic solvents in a population-based case-control study of early-stage chronic renal failure (CRF). All native Swedish residents aged 18 to 74 yr, living in Sweden between May 1996 and May 1998, formed the source population. Incident cases of CRF in a pre-uremic stage (n = 926) and control subjects (n = 998), randomly selected from the study base, underwent personal interviews that included a detailed occupational history. Expert rating by a certified occupational hygienist was used to assess organic solvent exposure intensity and duration. Relative risks were estimated by odds ratios (OR) in logistic regression models, with adjustment for potentially important covariates. The overall risk for CRF among subjects ever exposed to organic solvents was virtually identical to that among never-exposed (OR, 1.01; 95% confidence interval [CI], 0.81 to 1.25). No dose-response relationships were observed for lifetime cumulative solvent exposure, average dose, or exposure frequency or duration. The absence of association pertained to all subgroups of CRF: glomerulonephritis (OR, 0.96; 95% CI, 0.68 to 1.34), diabetic nephropathy (OR, 1.02; 95% CI, 0.74 to 1.41), renal vascular disease (OR, 1.16; 95% CI, 0.76 to 1.75), and other renal CRF (OR, 0.92; 95% CI, 0.66 to 1.27). The results from a nationwide, population-based study do not support the hypothesis of an adverse effect of organic solvents on CRF development, in general. Detrimental effects from subclasses of solvents or on specific renal diseases cannot be ruled out.     

Eustachian tube function and tympanic membrane findings after chronic secretory otitis media

OBJECTIVE: The etiology of secretory otitis media (SOM) is multifactorial. The main factors discussed are infection and tubal dysfunction. This study aimed to detect poor tubal function and tympanic membrane pathology in young adults after extremely long-standing SOM. METHODS: Thirty-four patients, 16-25 years old, with previous chronic SOM persisting at least 6 years (mean 11.2 years, range 6.2-18.6 years), were retrospectively examined at a mean of 18 years after their first myringotomy or tube insertion and comparison was made with 15 controls. The medical records were scrutinized, otomicroscopic examination was performed and the Eustachian tube function was studied in a mini pressure chamber. RESULTS: The mean age at SOM onset was 2.4 years (range 0.5-8.4 years) and the mean period from the last myringotomy or when the last tube had disappeared to follow-up was 6.7 years (range 1.3-12.8 years). Tympanic membrane pathology was found in 76% of the ears of SOM patients and in none (0%) of controls (P<0.001). The youngest patients had more atrophy than the older patients (P<0.05) and more myringosclerosis was observed in patients with shorter interval between SOM ending and examination. The patients were found to have significantly poorer active tubal function; i.e. higher inability to equilibrate negative or negative and positive middle ear pressure, compared with controls (P<0.001). The majority of the patients (74%) still experienced some kind of discomfort in their ears at the time of examination. CONCLUSIONS: Still in adulthood patients with chronic SOM during childhood exhibit dysfunction of the tube and tympanic membrane pathology to a high extent.     

The value of risk‐free cigarettes – do smokers underestimate the risk?

The health risk of smoking is valued using the contingent valuation method, applied to a Swedish sample of smokers. The respondents were asked to put a value on newly developed cigarettes with no associated health risks. The average additional willingness to pay for the new cigarettes is estimated to be between 10 and 41 SEK per pack, where the variation is due to statistical method, discounting, and whether the open-ended or closed-ended question format is used. Using medical data on life shortening effects of smoking, the results indicate rather low values put on a lost life-year, compared to most existing estimates based on other methods. This may indicate that smokers do underestimate the health risk of smoking. There is also initial optimism-bias regarding people's own ability to quit smoking at will. However, there are remaining methodological questions and we found little or no sensitivity to scope.     

A missense mutation in GUCY2D acts as a genetic modifier in RPE65-related Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous severe retinal dystrophy presenting in infancy. To explain the phenotypical variability observed in two affected siblings of a consanguineous pedigree diagnosed with LCA and establish a genotype-phenotype correlation, we screened GUCY2D, RPE65, CRX, AIPL1, and RPGRIP1 for mutations. The more severely affected sibling carried a heterozygous missense mutation in the GUCY2D gene (Ile539Val), which did not segregate with the disease phenotype. Subsequently, a homozygous nonsense mutation (Glu102STOP) in the RPE65 gene was identified in both affected siblings, thus identifying the causative gene. This data provides evidence for the presence of genetic modulation in LCA. It appears that the heterozygous GUCY2D mutation further disrupts the already compromised photoreceptor function resulting in more severe retinal dysfunction in the older sibling. We suggest that the unusual phenotypic variability in these two siblings with LCA is caused by the modifying effect of a heterozygous GUCY2D mutation observed against the disease background of a homozygous RPE65 mutation.     

Fecundity and twinning rates as measures of fertility before diagnosis of germ-cell testicular cancer

Previous studies have suggested an association between subfertility and testicular cancer by using fecundity and semen characteristics to measure fertility. The occurrence of twinning in offspring may be used to investigate male reproductive health, because dizygotic twinning is reduced by male subfertility. We therefore assessed number of children and offspring twinning rates among 4592 Swedish patients with testicular cancer and 12 254 control subjects. Before diagnosis, case patients had a decreased number of children (for testicular cancer, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.62 to 0.81; at least three children compared with no children), with a lower frequency of dizygotic twinning (for unlike-sex twins, OR for the father having testicular cancer = 0.49, 95% CI = 0.22 to 1.08). The ratio of unlike-sex to same-sex twins was 0.22 among children of case patients and 0.66 among children of control subjects (adjusted P =.03, two-sided Wald test). We also found an increased occurrence of twinning after diagnosis, probably attributable to treatment for iatrogenic subfertility. Our study strongly supports evidence of an association between subfertility and the subsequent risk for testicular cancer.