Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.     

A clinicopathologic study of thrombotic microangiopathy in IgA nephropathy

Thrombotic microangiopathy (TMA) occurs in IgA nephropathy, but its clinical significance is not well described. We retrospectively examined a series of 128 patients diagnosed with IgA nephropathy between 2002 and 2008 who had a mean follow-up of 44±27 months. In our series, 53% presented with lesions of TMA, acute or organized, in arteries and/or arterioles. Among patients with TMA, 4% were normotensive, 25% had controlled hypertension, and 71% had uncontrolled hypertension. Of those with uncontrolled hypertension, 26% had malignant hypertension. Histologically, the group with TMA had a significantly greater percentage of sclerotic glomeruli and worse tubulointerstitial fibrosis than those of the group without TMA. However, a significant minority of patients had near-normal histology, with minimal tubular atrophy (20%) and/or <20% interstitial fibrosis (24%). TMA rarely occurred in the absence of significant proteinuria. During follow-up, a doubling of serum creatinine or ESRD occurred in all patients with laboratory evidence of TMA, in 42% of those with morphologic evidence but no laboratory evidence of TMA, and in 11% of those without TMA. In summary, lesions of TMA are frequent in IgA nephropathy and may occur in normotensive patients with near-normal renal histology. Although the pathophysiologic mechanisms involved remain undetermined, the current study rules out severe hypertension or advanced renal disease as sole causes.     

Axillary Recurrence After a Tumor-Positive Sentinel Lymph Node Biopsy Without Axillary Treatment: A Review of the Literature

Background

Sentinel lymph node biopsy (SLNB) has become standard of care as a staging procedure in patients with invasive breast cancer. A positive SLNB allows completion axillary lymph node dissection (cALND) to be performed. The axillary recurrence rate (ARR) after cALND in patients with positive SLNB is low. Recently, several studies have reported a similar low ARR when cALND is not performed. This review aims to determine the ARR when cALND is omitted in SLNB-positive patients.

Methods

A literature search was performed in the PubMed database with the search terms ??breast cancer,?? ??sentinel lymph node biopsy,?? ??axillary?? and ??recurrence.?? Articles with data regarding follow-up of patients with SLNB-positive breast cancer were identified. To be eligible, patients should not have received cALND and ARR should be reported.

Results

Thirty articles were analyzed. This resulted in 7,151 patients with SLNB-positive breast cancer in whom a cALND was omitted (median follow-up of 45?months, range 1?C142?months). Overall, 41 patients developed an axillary recurrence. 27 studies described 3,468 patients with micrometastases in the SLNB, of whom 10 (0.3?%) developed an axillary recurrence. ARR varied between 0 and 3.7?%. Sixteen studies described 3,268 patients with macrometastases, 24 (0.7?%) axillary recurrences were seen. ARR varied between 0 and 7.1?%. Details regarding type of surgery and adjuvant treatment were lacking in the majority of studies.

Conclusions

ARR appears to be low in SLNB-positive patients even when a cALND is not performed. Withholding cALND may be safe in breast cancer selected patients such as those with isolated tumor cells or micrometastatic disease.     

Range of motion in femoroacetabular impingement

Recent epidemiological studies have demonstrated that radiographic features specific to femoroacetabular impingement appear far more frequently in healthy and asymptomatic cohorts than previously anticipated. It remains unclear how incidental findings should be interpreted clinically. In addition, several authors have suggested that a decreased range of motion is part of the clinical presentation of femoroacetabular impingement. The purpose of the present study was to describe and analyze differences in range of motion between femoroacetabular impingement patients, asymptomatic individuals with incidental radiographic findings and healthy controls, using a validated electromagnetic tracking system. Furthermore, it was evaluated which motions were clinically relevant and could be used to differentiate between these three groups. We found all evaluated motions to differ significantly between patients and controls. The anterior impingement test showed a significant difference between patients and asymptomatic cases. In conclusion, functional evaluation of the range of motion appeared in this study as a useful tool in the diagnostic work-up of femoracetabular impingement.     

Expression of minichromosome maintenance MCM6 protein in meningiomas is strongly correlated with histologic grade and clinical outcome

The 2007 World Health Organization histologic grading of meningiomas is associated with recurrence and clinical outcome. However, distinction of grade I from grade II (atypical) meningiomas can be challenging. In the World Health Organization classification, there are 4 parameters on the basis of which grade II status can be determined: mitotic rate, cytoarchitectural features, brain invasion, and/or histologic subtype. Furthermore, this classification fails to detect grade I recurrent meningiomas, for which other prognostic criteria would be needed. The aim of this study was to evaluate the respective value of several markers involved in cell cycle as effective tools to predict recurrence. This retrospective study was based on a series of 59 meningiomas (grade I: 32 of 59, grade II: 27 of 59, all harboring ≥4 mitoses/1.6 mm), analyzed with the following immunohistochemical markers: MCM6, Ki-67, PHH3, cyclin D1, and p53. We found a significant correlation between histologic grade and mean labeling index for MCM6 (grade I: 21.8% vs. grade II: 65.8%; P<0.001), Ki-67 (3.2% vs. 16.9%; P<0.001), PHH3 (0.7‰ vs. 2.8‰; P<0.001), cyclin D1 (50.4% vs. 70.0%; P=0.005), and p53 (17.3% vs. 32.4%; P=0.017). Histologic grading and mitotic index were correlated with progression-free survival (P=0.010 and P=0.020, respectively). A nearly linear correlation was found between progression-free survival and staining for MCM6 (P<0.001), Ki-67 (P=0.003), and PHH3 (P=0.037) but not for cyclin D1 (P=0.400) and p53 (P=0.758). The interobserver agreement coefficients for MCM6, Ki-67, PHH3, cyclin D1, and p53 were, respectively, 0.97 (95% confidence interval, 0.95-0.98), 0.93 (0.89-0.96), 0.81 (0.70-0.88), 0.90 (0.83-0.94), and 0.84 (0.73-0.90). In conclusion, because of its strong level of expression and sharp difference in labeling index between indolent and recurrent tumors, MCM6 is the most efficient marker to identify tumors with a high risk of recurrence.     

Anterior suspension combined with posterior reconstruction during robot-assisted laparoscopic prostatectomy improves early return of urinary continence: a prospective randomized multicentre trial

Study Type – Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Urinary incontinence is one of the major drawbacks of radical prostatectomy, regardless of the procedure used (i.e. open, laparoscopic or robotic‐assisted). Several technical modifications have been described to improve postoperative continence, highlighting the role of puboprostatic ligaments and posterior reconstruction of the rhabdomyosphincter. The results obtained are inconsistent when applied to robotic surgery. The present multicentre randomized study shows that anterior suspension combined with posterior reconstruction is a safe and easy‐to‐perform technique for improving early continence after robotic‐assisted laparoscopic prostatectomy.

OBJECTIVE

• ? To assess the impact on urinary continence of anterior retropubic suspension with posterior reconstruction during robot‐assisted laparoscopic prostatectomy (RALP).

PATIENTS AND METHODS

• ? In total, 72 patients who were due to undergo prostatectomy between July 2009 and July 2010 were prospectively randomized into two groups: group A underwent a standard RALP procedure and group B had anterior suspension and posterior reconstruction during RALP.
• ? The primary outcome measure was urinary continence, assessed using the University of California Los Angeles Prostate Cancer Index questionnaire at 15 days, and at 1, 3 and 6 months, after surgery. Other data recorded were operation duration, blood loss, length of hospital stay, duration of bladder catheterization, complications and positive margin rate.

RESULTS

• ? The continence rates at 15 days, and at 1, 3 and 6 months, after surgery were 3.6%, 7.1%, 15.4% and 57.9%, respectively, in group A, and 5.9%, 26.5%, 45.2% and 65.4%, respectively, in group B. The continence rates differed statistically between groups at 1 and 3 months (P = 0.047 and P = 0.016, respectively).
• ? There was no significant difference between groups regarding complications (P = 0.8) or positive margin rate (P = 0.46).

CONCLUSION

• ? Anterior suspension associated with posterior reconstruction during RALP improved the early return of continence, without increasing complications.

     

The effect of gender on outcomes after lower extremity revascularization

Objective

The effect of gender on outcomes after lower extremity revascularization is controversial. The aim of our systemic review and meta-analysis was to evaluate the gender-related outcomes after peripheral vascular interventions.

Explaining endograft shortening during endovascular repair of abdominal aortic aneurysms in severe aortoiliac tortuosity

Objective

During endovascular aneurysm repair (EVAR), severely tortuous aortoiliac anatomy can alter the deployment and conformability of the endograft. The accuracy of treatment length measurements is commonly recognized to be affected by severe tortuosity. However, the exact mechanism of the postintervention length discrepancy is poorly understood. The objective of this study was to determine the mechanism of how severe aortoiliac tortuosity influences the endograft and native aorta during EVAR and its impact on the distal sealing zone.