Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Weaning from mechanical ventilation: a cross-sectional study of reference values and the discriminative validity of aging

[Purpose] To evaluate pre-extubation variables and check the discriminative validity of age as well as its correlation with weaning failure in elderly patients. [Subjects and Methods] Two hundred thirty-nine consecutive patients (48% female) who were on mechanical ventilation and had undergone orotracheal intubation were divided into four subgroups according to their age: <59 years, 60–69 years, 70–79 years, and >80 years old. The expiratory volume (V_E), respiratory frequency (f), tidal volume (V_T), and respiratory frequency/tidal volume ratio (f/V_T) were used to examine differences in weaning parameters between the four subgroups, and age was correlated with weaning failure. [Results] The rate of weaning failure was 27.8% in patients aged >80 years and 22.1% in patients aged <60 years old. Elderly patients presented higher f/V_T and f values and lower V_T values. The areas under the receiver operating characteristic curves for f/V_T ratio were smaller than those published previously. [Conclusion] Our results indicate that aging influences weaning criteria without causing an increase in weaning failure.Key words: Weaning, Mechanical ventilation, Aging     

Workers' Compensation Patients After Total Joint Arthroplasty : Do They Return to Work?

Clinicians identify patients receiving Workers' Compensation (WC) as unlikely to fully benefit from total joint arthroplasty (TJA), with possibly decreased ability to return to work. We completed follow-up for 164 patients undergoing 177 arthroplasties while receiving WC between 2000 and 2009. Inquiry was made regarding work status, nature of work, and return to work time frame. Patients undergoing primary versus revision TJA returned to work 70.2% versus 43.9%, respectively (p = 0.002). The mean time frame for return to work following primary TJA was 16.4 weeks. Manual laborers versus sedentary workers returned to work 67.1% versus 84.8%, respectively (p = 0.05). As this group is limited by the strenuous nature of their employment, clinicians should be aware that receiving WC may modestly impact return to work following arthroplasty.     

Predicting Dysplasia and Invasive Carcinoma in Intraductal Papillary Mucinous Neoplasms of the Pancreas: Development of a Preoperative Nomogram

Background

Clinical decision making for patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas is challenging. Even with strict criteria for resection, most resected lesions lack high-grade dysplasia (HGD) or invasive carcinoma.

Methods

We evaluated patients who underwent resection of histologically confirmed IPMN and had preoperative imaging available for review. A hepatobiliary radiologist blinded to histopathologic subtype reviewed preoperative imaging and recorded cyst characteristics. Patients with mixed-type IPMN were grouped with main-duct lesions for this analysis. Based on an ordinal logistic regression model, we devised two independent nomograms to predict the findings of adenoma, high-grade dysplasia (HGD–CIS), and invasive carcinoma, separately in both main and branch-duct IPMN. Bootstrap validation was used to evaluate the performance of these models, and a concordance index was derived from this internal validation.

Results

There were 219 patients who met criteria for this study. Branch-duct IPMN (bdIPMN) comprised 56 % of the resected lesions. The proportion of HGD–CIS was 15 % for bdIPMN and 33 % for main-duct lesions (mdIPMN); P = 0.003. Invasive carcinoma was identified in 15 % of bdIPMN and 41 % of main-duct lesions (P < 0.001). On multivariate regression, patient gender, history of prior malignancy, presence of solid component, and weight loss were found to be significantly associated with the ordinal outcome for patients with mdIPMN and built into the nomogram (concordance index 0.74). For patients with bdIPMN weight loss, solid component, and lesion diameter were associated with the outcome; (concordance index 0.74).

Conclusion

Based on the analysis of patients selected for resection, two nomograms were created that predict a patient’s individual likelihood of harboring HGD or invasive malignancy in radiologically diagnosed IPMN. External validation is ongoing.     

Prophylactic Radical Cystectomy for the Management of Keratinizing Squamous Metaplasia of the Bladder in a Man With Tetraplegia

Abstract

Background/Objective: To report a case of keratinizing squamous metaplasia of the bladder treated with radical cystectomy.

Design: Case report and discussion of management options.

Methods: Keratinizing squamous metaplasia of the bladder is a rare entity that can result from chronic irritative stimuli involving the bladder. It is considered a premalignant condition associated with invasive squamous cell carcinoma. A case report is presented describing the diagnosis and management of keratinizing squamous metaplasia of the bladder in a tetraplegic man with a chronic indwelling urinary catheter.

Results: Radical cystectomy with an Indiana continent reservoir was performed after cystoscopy with biopsy confirmed keratinizing squamous metaplasia. Final pathology revealed focal erosion and diffuse keratinizing squamous metaplasia of the bladder with prostatic adenocarcinoma as an incidental finding.

Conclusions: Patients with spinal cord injury who use indwelling catheters for bladder management are at higher risk of developing keratinizing squamous metaplasia. Surveillance for early detection of this entity is recommended. Prophylactic cystectomy is sometimes warranted; however, observation and frequent cystoscopic surveillance to identify potential malignant transformation can be an alternative strategy. An interdisciplinary approach is recommended before consideration of bladder resection.