Increased production of proinflammatory cytokines in adipose tissue of patients with end-stage renal disease

ObjectiveThe number of patients with end-stage renal disease (ESRD) is rising and these patients are at higher risk of cardiovascular disease. We studied the role of hormonal production of adipose tissue in the development of chronic inflammation in patients with ESRD before kidney transplantation.MethodsFifteen women with ESRD and 17 healthy women (control) underwent single blood drawing and visceral and subcutaneous adipose tissue sampling during surgery (kidney transplantation in the ESRD group or cholecystectomy in the control group). Serum concentrations of C-reactive protein, interleukin-6, tumor necrosis factor-α, leptin, adiponectin, resistin, monocyte chemoattractant protein-1 were measured. Messenger RNA expression of the same hormones, adiponectin receptors 1 and 2 and immunocompetent cell marker CD68 in subcutaneous and visceral samples were measured using real-time polymerase chain reaction. Adipose tissue was examined immunohistochemically for CD68-positive cells.ResultsSerum concentrations of C-reactive protein, adiponectin, resistin, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 were significantly higher in the ESRD versus control group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-α and CD68 were significantly increased in the ESRD versus control group. Adiponectin receptor-1 and monocyte chemoattractant protein-1 mRNA expressions were significantly higher in visceral but not in subcutaneous adipose tissue of the ESRD group. Messenger RNA expressions of resistin, leptin, adiponectin, interleukin-6, and adiponectin receptor-2 in both fat depots did not significantly differ between groups. Increased infiltration of subcutaneous and visceral adipose tissue with CD68-positive immunocompetent cells was found in the ESRD group by histologic examination.ConclusionSubcutaneous and visceral adipose tissues in ESRD express higher amounts of proinflammatory cytokines and may play a role in the development of systemic inflammation.     

Solution space reduction in the peripheral nerve source localization problem using forward field similarities

Improving our ability to localize bioelectric sources within a peripheral nerve would help us to monitor the control signals flowing to and from any limb or organ. This technology would provide a useful neuroscience tool, and could perhaps be incorporated into a neuroprosthesis interface. We propose to use measurements from a multi-contact nerve cuff to solve an inverse problem of bioelectric source localization within the peripheral nerve. Before the inverse problem can be addressed, the forward problem is solved using finite element modeling. A fine mesh improves the accuracy of the forward problem solution, but increases the number of variables to be solved for in the inverse problem. To alleviate this problem, variables corresponding to mesh elements that are not distinguishable by the measurement setup are grouped together, thus reducing the dimension of the inverse problem without impacting on the forward problem accuracy. A quantitative criterion for element distinguishability is derived using the columns of the leadfield matrix and information about the uncertainty in the measurements. Our results indicate that the number of variables in the inverse problem can be reduced by more than half using the proposed method, without having a detrimental impact on the quality of the localization.     

Lifespan alterations of basal dendritic trees of pyramidal neurons in the human prefrontal cortex: a layer-specific pattern

The postnatal development and lifespan alterations in basal dendrites of large layer IIIC and layer V pyramidal neurons were quantitatively studied. Both classes of neurons were characterized by rapid dendritic growth during the first postnatal months. At birth, layer V pyramidal neurons had larger and more complex dendritic trees than those of layer IIIC; however, at 1 postnatal month both classes of neurons displayed a similar extent of dendritic outgrowth. In addition, after a more than year-long "dormant" period of only fine dendritic rearrangement, layer IIIC pyramidal neurons displayed a second period of dendritic growth, starting at the end of the second year and continuing in the third year. During that period, the dendritic tree of layer IIIC pyramidal neurons became more extensive than that of layer V pyramidal neurons. Thus, layer IIIC pyramidal neurons appear to show a biphasic pattern of postnatal dendritic development. Furthermore, the childhood period was characterized by transient increase in size of pyramidal cell somata, which was more pronounced for neurons in layer IIIC. These structural changes occurred during both the period of rapid cognitive development in preschool children and the period of protracted cognitive maturation during the childhood, puberty, and adolescence.     

Nonprocedural bleeding after left atrial appendage closure versus direct oral anticoagulants: A subanalysis of the randomized PRAGUE-17 trial

Introduction

Observational studies have shown low bleeding rates in patients with atrial fibrillation (AF) treated by left atrial appendage closure (LAAC); however, data from randomized studies are lacking. This study compared bleeding events among patients with AF treated by LAAC and nonvitamin K anticoagulants (NOAC).

Methods

The Prague-17 trial was a prospective, multicenter, randomized trial that compared LAAC to NOAC in high-risk AF patients. The primary endpoint was a composite of a cardioembolic event, cardiovascular death, and major and clinically relevant nonmajor bleeding (CRNMB) defined according to the International Society on Thrombosis and Hemostasis (ISTH).

Results

The trial enrolled 402 patients (201 per arm), and the median follow-up was 3.5 (IQR 2.6–4.2) years. Bleeding occurred in 24 patients (29 events) and 32 patients (40 events) in the LAAC and NOAC groups, respectively. Six of the LAAC bleeding events were procedure/device-related. In the primary intention-to-treat analysis, LAAC was associated with similar rates of ISTH major or CRNMB (sHR 0.75, 95% CI 0.44–1.27, p = 0.28), but with a reduction in nonprocedural major or CRNMB (sHR 0.55, 95% CI 0.31–0.97, p = 0.039). This reduction for nonprocedural bleeding with LAAC was mainly driven by a reduced rate of CRNMB (sHR for major bleeding 0.69, 95% CI 0.34–1.39, p = .30; sHR for CRNMB 0.43, 95% CI 0.18–1.03, p = 0.059). History of bleeding was a predictor of bleeding during follow-up. Gastrointestinal bleeding was the most common bleeding site in both groups.

Conclusion

During the 4-year follow-up, LAAC was associated with less nonprocedural bleeding. The reduction is mainly driven by a decrease in CRNMB.     

Teaching effects of dermatological consultations on nondermatologists in the field of internal medicine. A study of 1290 inpatients

BACKGROUND: Scarce data exist concerning dermatological consultations within departments of internal medicine. To date, no survey has been carried out in Switzerland to elucidate this issue. The aim of this study was to analyze the spectrum of skin diseases internists are confronted with and to study their diagnostic accuracy in cutaneous diseases. In addition, we wanted to evaluate the motivation for dermatologists to cooperate closely with internists. PATIENTS AND METHODS: The study included patients with dermatological problems treated at the Department of Internal Medicine at the Kantonsspital Aarau, Switzerland. All patients had been referred to the Department of Dermatology for examination between 1999 and 2001. Patient data were analyzed demographically, by referral modus, diagnoses and therapy. To evaluate the knowledge of internists and dermatologists in cutaneous medicine, 15 clinical slides of common dermatoses with a patient history were shown and asked for diagnostic suggestions to 32 internists of the Kantonsspital Aarau and to 13 dermatologists of the University Hospital Basel, Switzerland. RESULTS: 1290 patients were referred to the Department of Dermatology. 1737 dermatological diagnoses were made including 348 different dermatoses. Eczema was the single most common diagnosis (12.6%), followed by actinic and bowenoid precancerosis (6.2%), drug eruption (4.2%), verrucae (4%) and mycosis (3.8%). The top ten diagnoses accounted for 41.7% of all skin-related diagnoses. Infection-related dermatoses were most common (20.5%) followed by different types of eczema (12.6%), malignant cutaneous tumors and malignant visceral conditions (11.2%). Local therapy was prescribed in 64.2% and systemic therapy in 22.6% of the patients. 15.9% did not receive specific therapy because the consultation request was only a diagnostic one. 146 skin biopsies were performed (11.3%). Systemic diseases with cutaneous manifestations accounted for 15.7%. In general, these conditions were not commonly seen by dermatologists in daily practice. The internists recognized 51.1% of the cutaneous manifestations during examination and 49% when presented with slides. CONCLUSIONS: Internists are confronted with a different spectrum of cutaneous diseases compared with dermatologists. Due to the broad spectrum of skin diseases, it is a challenging task for internists to recognize dermatoses. Our study elucidates that patients, internists and dermatologists may profit from a close cooperation.     

Biodistribution and elimination characteristics of two 111In-labeled CCK-2/gastrin receptor-specific peptides in rats

BACKGROUND: Due to their high CCK-2/gastrin receptor selectivity, high affinity, and rapid background clearance, radiolabeled minigastrins (MG) are emerging as promising new tools in the diagnosis and therapy of CCK-2/gastrin receptor-positive tumors. In this study, the pharmacokinetic profile, particularly the excretion mode, of two 111In-labeled minigastrins was compared in rats. The first tracer, 111In-MG-0 is based on (D)Glu1-MG, while the second, 111In-MG-11, is its des-(Glu)5-derivative, expected to be less retained in renal tissue. MATERIALS AND METHODS: The fate of 111In-MG-0 and 111In-MG-11 in the body of rats was investigated during biodistribution and bioelimination experiments, while the respective elimination parameters were determined in perfused rat liver and kidney models. RESULTS: During biodistribution both compounds were rapidly cleared from the blood and most non-target organs whereas activity levels in the bowel and stomach declined slowly. The overall contribution of hepatobiliary excretion of 111In-MG-0 and 111In-MG-11 was relatively small. In the perfused rat liver their elimination into the bile was negligible. In contrast, renal excretion was the major excretion pathway for both analogs, mainly via glomerular filtration. However, kidney levels were substantially higher and retention was more prolonged in the case of 111In-MG-0 as compared to 111In-MG-11. CONCLUSION: The presence of the (Glu)5-chain in 111Ln-MG-0 appears to be implicated in the prolonged radioactivity retention in the kidney of rats.     

Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure.

BACKGROUND: Nephrogenic systemic fibrosis is a debilitating disease occurring exclusively in patients with renal failure. The aetiology of nephrogenic systemic fibrosis is unclear, but recent reports suggest that exposure to gadolinium for enhancement of magnetic resonance imaging may play a role. In the present study, we assessed the association of exposure to gadolinium with the development of nephrogenic systemic fibrosis in patients with various stages of chronic kidney disease. METHODS: We analysed the exposure to gadolinium and development of nephrogenic systemic fibrosis in 849 patients on renal replacement therapy over 5 years. We also performed inquiry of development of the nephrogenic systemic fibrosis in 592 patients exposed to gadolinium and estimated to be in stages 3 and 4 of chronic kidney disease. RESULTS: In 849 patients undergoing chronic dialysis from 2001 through 2006 time period, four of the 261 who had received gadolinium (1.5%) and none of the 588 not exposed to gadolinium developed clinically apparent disease. The odds ratio for developing nephrogenic systemic fibrosis was 6.671 [95% confidence interval (CI) 1.537-53.97] in patients with a single gadolinium exposure compared to patients without gadolinium exposure. This ratio increased to 44.5 (95% CI 2.362-2913) in patients with multiple gadolinium exposures compared to patients not receiving gadolinium. None of the 592 patients estimated to be in stage 3 or 4 of chronic kidney disease developed nephrogenic systemic fibrosis after exposure to gadolinium. CONCLUSION: Gadolinium exposure is associated with nephrogenic systemic fibrosis in patients on chronic renal replacement therapy at a low rate. This association appears to increase with repeated exposure to gadolinium. Since nephrogenic systemic fibrosis may be clinically occult, its prevalence may be higher than reported. Despite this association, it is unclear if gadolinium is the sole or most important factor in the pathogenesis of the disease.     

Fluridil, a Rationally Designed Topical Agent for Androgenetic Alopecia: First Clinical Experience

BACKGROUND: Fluridil, a novel topical antiandrogen, suppresses the human androgen receptor. While highly hydrophobic and hydrolytically degradable, it is systemically nonresorbable. In animals, fluridil demonstrated high local and general tolerance. OBJECTIVE: To evaluate the safety and efficacy of a topical anti- androgen, fluridil, in male androgenetic alopecia. METHODS: In 20 men, for 21 days, occlusive forearm patches with 2, 4, and 6% fluridil, isopropanol, and/or vaseline were applied. In 43 men with androgenetic alopecia (AGA), Norwood grade II-Va, 2% fluridil was evaluated in a double-blind, placebo-controlled study after 3 months clinically by phototrichograms, hematology, and blood chemistry including analysis for fluridil, and at 9 months by phototrichograms. RESULTS: Neither fluridil nor isopropanol showed sensitization/irritation potential, unlike vaseline. In all AGA subjects, baseline anagen/telogen counts were equal. After 3 months, the average anagen percentage did not change in placebo subjects, but increased in fluridil subjects from 76% to 85%, and at 9 months to 87%. In former placebo subjects, fluridil increased the anagen percentage after 6 months from 76% to 85%. Sexual functions, libido, hematology, and blood chemistry values were normal throughout, except that at 3 months, in the spring, serum testosterone increased within the normal range equally in placebo and fluridil groups. No fluridil or its decomposition product, BP-34, was detectable in the serum at 0, 3, or 90 days. CONCLUSION: Topical fluridil is nonirritating, nonsensitizing, nonresorbable, devoid of systemic activity, and anagen promoting after daily use in most AGA males.