Cortisol elevations comparable to those that occur during hypoglycemia do not cause hypoglycemia-associated autonomic failure

The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic-sympathetic neural and adrenomedullary response and the resulting neurogenic [autonomic] symptom responses) and thus causes a vicious cycle of recurrent hypoglycemia. To assess the suggestion that it is the cortisol response to antecedent hypoglycemia that mediates HAAF, we tested the hypothesis that plasma cortisol elevations during euglycemia that are comparable to those that occur during hypoglycemia reduce sympathoadrenal and neurogenic symptom responses to subsequent hypoglycemia. To do this, 12 healthy subjects were studied with hyperinsulinemic-stepped hypoglycemic clamps the day after saline or cortisol (1.3 +/- 0.2 micro g. kg(-1) x min(-1)) infusions from 0930 to 1200 and from 1330 to 1600. Compared with saline, antecedent cortisol elevations did not reduce the sympathoadrenal (e.g., final plasma epinephrine levels of 674 +/- 84 vs. 606 +/- 80 pg/ml and final plasma norepinephrine levels of 332 +/- 26 vs. 304 +/- 26 pg/ml) or neurogenic symptom (e.g., final scores of 9.3 +/- 1.1 vs. 13.2 +/- 1.3) responses to subsequent hypoglycemia. Thus, these data do not support the suggestion that cortisol mediates HAAF.     

Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome—a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie

First line immunosuppressive treatment in steroid-resistant nephrotic syndrome in children is still open to discussion. We conducted a controlled multicentre randomized open label trial to test the efficacy and safety of cyclosporin A (CSA) versus cyclophosphamide pulses (CPH) in the initial therapy of children with newly diagnosed primary steroid-resistant nephrotic syndrome and histologically proven minimal change disease, focal segmental glomerulosclerosis or mesangial hypercellularity. Patients in the CSA group (n = 15) were initially treated with 150 mg/m(2) CSA orally to achieve trough levels of 120-180 ng/ml, while patients in the CPH group (n = 17) received CPH pulses (500 mg/m(2) per month intravenous). All patients were on alternate prednisone therapy. Patients with proteinuria >40 mg/m(2) per hour at 12 weeks of therapy were allocated to a non-responder protocol with high-dose CSA therapy or methylprednisolone pulses. At week 12, nine of the 15 (60%) CSA patients showed at least partial remission, evidences by a reduction of proteinuria <40 mg/h per m(2). In contrast, three of the 17 (17%) CPH patients responded (p < 0.05, intention-to-treat). Given these results, the study was stopped, in accordance with the protocol. After 24 weeks, complete remission was reached by two of the 15 (13%) CSA and one of the 17 (5%) CPH patients (p = n.s.). Partial remission was achieved by seven of the 15 (46%) CSA and two of the 15 (11%) CPH patients (p <0.05). Five patients in the CSA group and 14 patients in the CPH group were withdrawn from the study, most of them during the non-responder protocol. The number of adverse events was comparable between both groups. We conclude that CSA is more effective than CPH in inducing at least partial remission in steroid-resistant nephrotic syndrome in children.     

Quality of life in women with stress urinary incontinence

The objective of this study was to identify clinical and demographic factors associated with incontinence-related quality of life (QoL) in 655 women with stress urinary incontinence who elected surgical treatment. The following factors were examined for their association with QoL as measured with the Incontinence Impact Questionnaire (IIQ): number of incontinence (UI) episodes/day; self-reported type of UI symptoms (stress and urge); sexual function as measured by the Prolapse/Urinary Incontinence Sexual Questionnaire; symptom bother as measured by the Urogenital Distress Inventory; as well as other clinical and sociodemographic factors. A stepwise least-squares regression analysis was used to identify factors significantly associated with QoL. Lower QoL was related to the greater frequency of stress UI symptoms, increasing severity, greater symptom bother, prior UI surgery or treatment, and sexual dysfunction (if sexually active). Health and sociodemographic factors associated with lower incontinence-related QoL included current tobacco use, younger age, lower socioeconomic status, and Hispanic ethnicity. Supported by cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases, with additional support from the National Institute of Child Health and Human Development and the Office of Research on Women’s Health, National Institutes of Health.     

Positive predictive value of maximal posterior joint-line tenderness in diagnosing meniscal pathology: a pilot study

OBJECTIVE: The purpose of this prospective study was to determine the positive predictive value (PPV) of the point of maximal posterior joint line tenderness (JLT), as a clinical sign, to diagnose underlying meniscal tears. METHODS: We conducted a prospective study of patients requiring arthroscopic surgery, who consecutively presented to the University of Calgary's Sport Medicine Centre. The femurotibial joint line was palpated for the point of maximal tenderness. We recorded the data on the arthroscopy report. A second examiner (orthopedic sport medicine surgical fellow or sport medicine physician) performed the same protocol. An arthroscopist documented the site of pathology as detected by arthroscopy. RESULTS: We found a PPV of 60.0% and a negative predictive value of 62.5%, suggesting that maximal posterior JLT may be predictive of meniscal pathology. The sensitivity and specificity were 84.6% and 31.2%, respectively (p = 0.155), with Fisher's exact test. The kappa score assessed interobserver reliability and was good at 0.48. Patients with maximal posterior JLT but no meniscal pathology did have other confounding pathology and patients with no maximal posterior JLT who had meniscal pathology usually had confounding knee pathology. CONCLUSIONS: We found a PPV of 60.0% of maximal posterior JLT and meniscal pathology located at the same anatomical site on arthroscopic examination.     

Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis

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B-cell concentration in the apheretic product predicts acute graft-versus-host disease and treatment-related mortality of allogeneic peripheral blood stem cell transplantation

BACKGROUND: The influence of the graft composition on the clinical outcome after allogeneic peripheral blood stem cell (PBSC) transplantation is not well established. METHODS: The cellular composition of the apheretic products obtained from 63 human leukocyte antigen-identical siblings was prospectively correlated with the outcome of patients with hematological malignancies undergoing an allogeneic PBSC transplant after myeloablative conditioning. The concentration of nuclear, mononuclear, CD34+, T-cell subsets, B cells, and natural killer cells in the graft has been analyzed. RESULTS: In univariate analysis, acute graft-versus-host disease (GVHD) correlated with the disease (P=0.002), with the phase of disease at transplant (P=0.01), and with the number of CD20+ cells infused (P=0.05). In multivariate analysis, a dose of CD20+ cells in the graft higher than the median dose remained the only factor negatively affecting the incidence of acute GVHD (P=0.01; 95% confidence interval [CI]: 0.12-0.78). In univariate analysis, treatment-related mortality (TRM) correlated with the disease (P=0.04) and was negatively affected by a dose of infused B cells greater than the median value (28% versus 50%; P=0.02). In multivariate analysis, TRM was close to statistical correlation with the dose of CD20+ cells (P=0.06; 95% CI: 0.02-1.05). No other clinical parameter was influenced by the composition of the graft. CONCLUSIONS: Our results suggest that the concentration of B cells in the apheretic product may predict the incidence of acute GVHD and TRM in patients undergoing an allogeneic PBSC transplantation and open the way to the new preventive and therapeutic strategies for the management of GVHD.     

Nitric oxide boosts TLR‐4 mediated lipocalin 2 expression in chondrocytes

Lipocalin 2 (LCN2) has recently emerged as a novel adipokine involved in different processes including arthritis and chondrocyte inflammatory response. However, little is known about its activity on chondrocyte homeostasis and its regulation by nitric oxide (NO) Hence, we performed a set of experiments aimed to achieve a better understanding of this relationship. Cell vitality was tested in the ATDC5 cell line by the MTT colorimetric assay. Protein expression and gene expression was evaluated by Western blot and real time RT‐PCR, respectively. NO production (determined as nitrite accumulation) was assayed by the Griess reaction. First, we demonstrated that LCN2 decreased murine chondrocytes vitality. Next, LCN2 co‐stimulation with LPS enhanced NOS2 protein expression by murine chondrocytes. In addition, inhibition of LPS‐induced nitric oxide production by aminoguanidine, a selective NOS2 inhibitor, significantly reduced LPS‐mediated LCN2 expression. In contrast, treatment of murine chondrocytes with sodium nitroprussiate (SNP), a classic NO donor, scarcely induced LCN2 expression. Intriguingly, SNP addition to LPS‐challenged chondrocytes, treated with aminoguanidine, provoked a strong induction of LCN2 expression. Finally, murine ATDC5 cells, co‐cultured with LPS pre‐challenged macrophages, had higher LCN2 expression in comparison with murine chondrocytes co‐cultured with non pre‐challenged macrophages. In this work we have described for the first time that NO is able to exert a control on LCN2 expression, suggesting the existence of a feedback loop regulating its expression. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1046–1052, 2013     

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

The early events that occur rapidly after injury trigger signal cascades that are essential for proper wound closure of corneal epithelial cells. We hypothesize that injury releases ATP, which stimulates purinergic receptors and elicits the phosphorylation of epidermal growth factor receptor (EGFR) tyrosine residues and subsequent cell migration by a MMP and HB-EGF dependent pathway. We demonstrated that the inhibition of purinergic receptors with the antagonist, Reactive Blue 2, abrogated the phosphorylation of EGFR and ERK. Pre-incubation of cells with the EGFR kinase inhibitor, AG1478, and subsequent stimulation by injury or ATP resulted in a decrease in phosphorylation of EGFR and migration. Furthermore, downregulation of EGFR by siRNA, inhibited the EGF-induced intracellular Ca(2+) wave. However, the response to injury and ATP was retained indicating the presence of two signaling pathways. Inhibition with either CRM197 or TIMP-3 decreased injury and nucleotide-induced phosphorylation of both EGFR and ERK. Incubation in the presence of a functional blocking antibody to HB-EGF also resulted in a decrease in the phosphorylation of EGFR. In addition, cell migration was inhibited by CRM197 and rescued when cells were incubated with HB-EGF. We showed that injury-induced phosphorylation of specific tyrosine residues and found that a similar pattern of phosphorylation was induced by trinucleotides. These studies indicate that injury-induced purinergic receptor activation leads to phosphorylation of EGFR, ERK and migration.     

Comparison of two wound dressings after laser skin resurfacing.

BACKGROUND: It has been reported that the final outcome of laser resurfacing still depends to a large degree on the efficiency of the post laser resurfacing wound care in promoting wound healing and preventing early and late complications. OBJECTIVE: The objective of this study was to evaluate and compare a new hydrocolloid dressing, H2460, with Flexzan(TM) for healing of an acute wound after laser skin resurfacing (LSR). METHODS: Ten volunteers received LSR of the peri-orbital area with an erbium:YAG laser. Identical parameters were used on both sides: 2 J, 5 mm spot, 8 Hz, 300 micros pulse, two passes on the upper eyelids, four passes on the lower eyelids and six passes on the crow's feet area. Soon after the LSR, one side was covered with Flexzan dressing and the other side was covered with a new hydrocolloid dressing -- H2460. The side of the dressing was randomized by alternating both dressings. All volunteers were evaluated and digitally photographed every day for a week and at 1 month after LSR. The degree of erythema, swelling, bleeding, oozing, crusting, pigmentary changes, scarring, discomfort, itching, burning, ease of application of dressings, initial adhesion, overall adhesion, leakage of fluid, maceration of surrounding skin, ease of removal and adhesive residue upon removal were documented. RESULTS: In all volunteer and investigator's evaluations, the new dressing, H2460, achieved far better results than Flexzan in each category. After a 1-week follow-up all volunteers and the investigator evaluated the H2460 side as: healed better, simple to use, and caused less discomfort in 10 out of 10 volunteers. The blinded observer's assessment showed that the Flexzan side healed better in one volunteer. CONCLUSION: The new dressing, H2460, is a better and suitable alternative to Flexzan as a post LSR dressing.     

Comparison of the open technique with a new wound dressing,H2460, in the healing of an acute wound after laser skin resurfacing

Background: Applying various dressings or leaving the treated area open are two techniques in use after laser skin resurfacing (LSR). Objective: This study was conducted to compare healing of an acute wound using a new hydrocolloid dressing, H2460, with the open technique. Methods: Immediately after LSR, one side was covered with the new hydrocolloid dressing H2460 and the other side was left open. Participants were instructed to clean the open side four times a day and replace the H2460 dressing if it was dislodged. Results: In the volunteers' and investigator's evaluations, the new dressing H2460 generally outperformed the ‘open’ technique. At the 1‐month follow‐up, eight of 10 volunteers reported that the H2460 side resulted in better healing; two of 10 volunteers felt there was no difference between the two sides for final outcome and none believed that the open side had better healing. Overall, the H2460 side healed better in the majority of participants as graded by the blinded observer (60%) and participant themselves (80%). Conclusion: The new hydrocolloid dressing H2460 is a better and suitable alternative to the open technique to manage an acute wound after LSR.