Shiga Toxin Promotes Podocyte Injury in Experimental Hemolytic Uremic Syndrome via Activation of the Alternative Pathway of Complement

Shiga toxin (Stx)–producing Escherichia coli is the offending agent of postdiarrhea-associated hemolytic uremic syndrome (HUS), a disorder of glomerular ischemic damage and widespread microvascular thrombosis. We previously documented that Stx induces glomerular complement activation, generating C3a responsible for microvascular thrombosis in experimental HUS. Here, we show that the presence of C3 deposits on podocytes is associated with podocyte damage and loss in HUS mice generated by the coinjection of Stx2 and LPS. Because podocyte adhesion to the glomerular basement membrane is mediated by integrins, the relevance of integrin-linked kinase (ILK) signals in podocyte dysfunction was evaluated. Podocyte expression of ILK increased after the injection of Stx2/LPS and preceded the upregulation of Snail and downregulation of nephrin and α-actinin-4. Factor B deficiency or pretreatment with an inhibitory antibody to factor B protected mice against Stx2/LPS-induced podocyte dysregulation. Similarly, pretreatment with a C3a receptor antagonist limited podocyte loss and changes in ILK, Snail, and α-actinin-4 expression. In cultured podocytes, treatment with C3a reduced α-actinin-4 expression and promoted ILK-dependent nuclear expression of Snail and cell motility. These results suggest that Stx-induced activation of the alternative pathway of complement and generation of C3a promotes ILK signaling, leading to podocyte dysfunction and loss in Stx-HUS.     

The Association of Surgical Margins and Local Recurrence in Women with Early-Stage Invasive Breast Cancer Treated with Breast-Conserving Therapy: A Meta-Analysis

Purpose

There is no consensus on what constitutes adequate negative margins in breast-conserving therapy (BCT). We systematically review the evidence on surgical margins in BCT for invasive breast cancer to support the development of clinical guidelines.

Methods

Study-level meta-analysis of studies reporting local recurrence (LR) data relative to final microscopic margin status and the threshold distance for negative margins. LR proportion was modeled using random-effects logistic meta-regression.

Results

Based on 33 studies (LR in 1,506 of 28,162), the odds of LR were associated with margin status [model 1: odds ratio (OR) 1.96 for positive/close vs negative; model 2: OR 1.74 for close vs. negative, 2.44 for positive vs. negative; (P < 0.001 both models)] but not with margin distance [model 1: >0 mm vs. 1 mm (referent) vs. 2 mm vs. 5 mm (P = 0.12); and model 2: 1 mm (referent) vs. 2 mm vs. 5 mm (P = 0.90)], adjusting for study median follow-up time. There was little to no statistical evidence that the odds of LR decreased as the distance for declaring negative margins increased, adjusting for follow-up time [model 1: 1 mm (OR 1.0, referent), 2 mm (OR 0.95), 5 mm (OR 0.65), P = 0.21 for trend; and model 2: 1 mm (OR 1.0, referent), 2 mm (OR 0.91), 5 mm (OR 0.77), P = 0.58 for trend]. Adjustment for covariates, such as use of endocrine therapy or median-year of recruitment, did not change the findings.

Conclusions

Meta-analysis confirms that negative margins reduce the odds of LR; however, increasing the distance for defining negative margins is not significantly associated with reduced odds of LR, allowing for follow-up time. Adoption of wider relative to narrower margin widths to declare negative margins is unlikely to have a substantial additional benefit for long-term local control in BCT.     

Impact of Margin Assessment Method on Positive Margin Rate and Total Volume Excised

Background

For breast-conserving surgery, the method of margin assessment that most frequently achieves negative margins without increasing the volume of tissue excised is uncertain. We examined our institutional experience with three different margin assessment methods used by six experienced breast surgeons.

Methods

Patients undergoing breast-conserving surgery for invasive carcinoma during July to December of a representative year during which each method was performed (perpendicular, 2003; tangential, 2004; cavity shave, 2011) were included. The effect of margin method on the positive margin rate at first excision and the total volume excised to achieve negative margins were evaluated by multivariable analysis, by surgeon, and by tumor size and presence of extensive intraductal component (EIC).

Results

A total of 555 patients were identified, as follows: perpendicular, 140; tangential, 124; and cavity shave, 291. The tangential method had a higher rate of positive margins at first excision than the perpendicular and cavity-shave methods (49, 15, 11 %, respectively; p < 0.0001). Median volumes to achieve negative margins were similar (55 ml perpendicular; 64 ml tangential; 62 ml cavity shave; p = 0.24). Four of six surgeons had the lowest rate of positive margins with the cavity-shave method, which was significant when compared to the tangential method (p < 0.0001) but not the perpendicular method (p = 0.37). The volume excised by the three methods varied by surgeon (p < 0.0001). The perpendicular method was optimal for T1 tumors without EIC; the cavity-shave method tended to be superior for T2–T3 tumors and/or EIC.

Conclusions

Although the cavity-shave method may decrease the rates of positive margins, its effect on volume is variable among surgeons and may result in an increase in the total volume excised for some surgeons and for small tumors without EIC.     

Diabetes Mellitus and Renal Transplantation in Adults: Is There Enough Evidence for Diagnosis,Treatment, and Prevention of New-Onset Diabetes After Renal Transplantation?

BackgroundNew-onset diabetes after renal transplantation (NODAT) is one of the most frequent metabolic complications after transplantation; it is present in ～25% of kidney transplant recipients, increasing their cardiovascular risk and inducing graft damage. The medical approach of this entity is still a matter of controversy, so our aim was to review the evidence available and offer a practical approach for diagnosis, treatment, and follow-up.MethodsA systematic review of the literature in the Medline, Embase, Cochrane, and Lilacs databases was carried out with the use of the terms “Diabetes Mellitus,” “Kidney Transplantation,” “Drug Therapy,” “Prognosis,” “Therapeutics,” and “Risk Factors.” Randomized controlled trials, meta-analyses, and observational studies were included.ResultsThe main risk factors were elevated body mass index, family history of diabetes, recipient >60 years old, hepatitis C virus infection, and treatment with tacrolimus/corticosteroids or sirolimus. Some small studies suggest that thiazolidinediones, sulfonylureas, glinides, and dipeptidyl peptidase 4 inhibitors could be useful in the treatment of the disease. NODAT constitutes a prognostic factor for the renal transplant. Although there is a higher risk of developing diabetes in kidney transplant recipients than in the general population, both populations share the same diagnostic criteria.ConclusionsThere is no consensus on the treatment regimen for these patients. It is necessary to review the diagnostic criteria and the screening methods for NODAT, given the higher susceptibility of kidney transplant recipients to develop this entity; therefore, an earlier intervention could be implemented to decrease the negative effects that this disease has on the kidney graft and the recipient.     

Mechanical Circulatory Support in Advanced Heart Failure: Single-Center Experience

Background

Currently, ventricular assist device (VAD) or total artificial heart (TAH) mechanical support provides an effective treatment of unstable patients with advanced heart failure. We report our single-center experience with mechanical circulatory support therapy.

Methods

From March 2002 to December 2012, 107 adult patients (mean age, 56.8 ± 9.9 y; range, 31–76 y) were primarly supported on temporary or long-term VAD or TAH support as treatment for refractory heart failure at our institution. Temporary extracorporeal radial VAD support (group A) was established in 49 patients (45.7%), and long-term paracorporeal and intracorporeal VAD or TAH (group B) in 58 patients (54.2%). Left ventricular (LVAD) support was established in 55 patients (51.4%; n = 33, Heartmate II; n = 6, Heartmate I XVE; n = 4, Heartware HVAD; and n = 12, Centrimag) and biventricular (BVAD/TAH) support (group B) in 28 patients (26.1%; n = 10, Thoratec paracorporeal; n = 2, Heartware HVAD, n = 1, Thoratec implantable; n = 1, Syncardia TAH; and n = 14, Centrimag). The temporary Centrimag was the only device adopted as isolated right ventricular (RVAD) support, and it was inserted in 24 patients (22.4%).

Results

In group A, overall mean support time was 10.2 ± 6.6 days (range, 3–43 d). In group B, LVAD mean support time was 357 ± 352.3 days (range, 1–902 d) and BVAD/TAH support time was 98 ± 82.6 days (range, 8–832 d). In group A, the overall success rate was 55.1% (27 patients). In group B, LVAD overall success rate was 74.4% (32 patients) and BVAD/TAH success rate was 50% (7 patients). Overall heart transplantation rate for both groups was 27.1% (n = 2, group A; n = 27, group B). Overall 1-year and 5-year survivals after heart transplantation were 72.4% (n = 21) and 58.6% (n = 17), respectively.

Conclusions

Mechanical circulatory support is an effective strategy even in cases of end-stage heart failure according to our experience. Further improvement of VAD and TAH technologies may support their adoption as an encouraging alternative to heart transplantation in the near future.     

Microbial keratitis in Sydney,Australia: risk factors,patient outcomes,and seasonal variation

Graefe's Archive for Clinical and Experimental Ophthalmology - To provide recent data on patient demographics, clinical profile and outcomes of patients with microbial keratitis over a 5-year...     

Post-operative delay in return of function following guided growth tension plating and use of corrective physical therapy

Purpose

Guided growth has long been used to treat growth deformities, but the Eight-Plate^® system has recently become more widely used by pediatric orthopaedists. Because the current literature lacks evaluation of functional status in the immediate post-operative period, we investigated functional status following use of the Eight-Plate^® system.

Methods

We evaluated post-operative delay in return of function following treatment with the Eight-Plate^® system at two weeks after surgery. Fifty-one consecutive patients with a growth deformity were treated with the Eight-Plate^® system. Patients were comprised of 32 male and 19 female patients with an average age of 11 years (range 2–17.9 years).

Results

Among study participants, 19 patients (37.3 %) had post-operative delay of function. The rate of delayed function for patients 10 years of age or younger and 11 years of age or older was respectively 11.8 and 50 % (P = 0.002). Six of the 19 patients were treated with four or more plates, of which five patients (83.3 %) developed delayed return of function. The rate of delayed function in patients with at least one femoral plate compared to no femoral plate was respectively 45 and 9.1 % (P = 0.006). Bilateral operations were associated with a 66.7 % rate of delayed function compared to 25 % with unilateral operations (P = 0.004). When patients with delay of function were treated with physical therapy, 12 of 13 patients (92.3 %) had complete resolution of their symptoms.

Conclusion

Statistical significance demonstrated that patients at the greatest risk were 11 years of age or older, with four or more plates, with femoral plates, or with bilateral operations. Patients with delayed function were readily corrected by physical therapy.     

Effects of patupilone on the pharmacokinetics and pharmacodynamics of warfarin in patients with advanced malignancies: a phase I clinical trial

Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug-drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m(2) i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for C(max) and area under the curve(0-168) of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer.     

Health visitors' assessments of parent-child relationships: a focus group study

BACKGROUND: Health visitors (HVs), also known as public health nurses, in the UK provide a universal community-based service to preschool children and their parents. Since they have ongoing supportive contact with almost all mothers and young children they have opportunities to identify problems in the parent-infant relationship: for example during developmental screening, home visits and immunisation clinics. Research into the role of screening for problems in the parent-child relationship in early childhood is sparse and little is known about how such problems are currently identified in the community. OBJECTIVE: To explore the approaches taken by health visitors (HVs) to identifying problems in the parent-child relationship. DESIGN: Focus group study. SETTING: Glasgow, Scotland. Participants: 24 health visitors sampled purposively. RESULTS: Multiple sources of information were used by health visitors in assessing parent-child relationships. These include use of known risk factors, knowledge of local norms, direct observations of behaviour, reflection on the relationship between the parent and health visitor, as well as more intuitive reactions. In many cases understanding difficulties in parent-child relationships involved piecing together a jigsaw over a considerable time span. Continuity of relationships appeared to be crucial in this task. Home visits were described as the most informative setting in which to develop an understanding of the parent-child relationship. Participants reported a lack of formal training in the assessment of parent-child relationships and were keen to obtain more training. CONCLUSIONS: Health visitors use complex strategies to integrate information about parent-child relationships. These strategies are acquired in a variety of ways, but receive little emphasis during basic professional training.