A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice.

piRNAs and Piwi proteins have been implicated in transposon control and are linked to transposon methylation in mammals. Here we examined the construction of the piRNA system in the restricted developmental window in which methylation patterns are set during mammalian embryogenesis. We find robust expression of two Piwi family proteins, MIWI2 and MILI. Their associated piRNA profiles reveal differences from Drosophila wherein large piRNA clusters act as master regulators of silencing. Instead, in mammals, dispersed transposon copies initiate the pathway, producing primary piRNAs, which predominantly join MILI in the cytoplasm. MIWI2, whose nuclear localization and association with piRNAs depend upon MILI, is enriched for secondary piRNAs antisense to the elements that it controls. The Piwi pathway lies upstream of known mediators of DNA methylation, since piRNAs are still produced in dnmt3L mutants, which fail to methylate transposons. This implicates piRNAs as specificity determinants of DNA methylation in germ cells.

Utility of lateral scapular radiographs in initial evaluation of nontraumatic shoulder conditions.

Background: Lateral scapular radiographs have been routinely included in the initial radiographic examination of both traumatic and nontraumatic shoulder conditions. With the advance of modern imaging modalities, the clinical utility of the lateral scapular view has become questionable. The purpose of the study was to assess the utilization of the lateral scapular view among the members of the American Shoulder and Elbow Surgeons (ASES) and to determine the clinical utility of the lateral scapular view in the initial evaluation of nontraumatic shoulder conditions. Methods: The study consisted of two parts. The first part involved an online survey of ASES members, which asked them 3 questions regarding their preference for radiographic evaluation of new patients with nontraumatic shoulder pain. The second part involved a clinical vignette-based survey, where 4 shoulder surgeons at our institution were given 50 clinical vignettes and asked to independently answer 4 questions regarding the most probable diagnosis, abnormal radiographic findings, further imaging studies, and treatment plan for each case. The survey was repeated twice; the first was given without a lateral scapular view, and the second given 4 weeks later with a lateral scapular view included. We obtained diagnostic accuracy and percent agreement of each surgeon over two surveys and intraobserver and interobserver reliability on each variable. Results: Of a total of 235 ASES members who responded to the online survey, 193 (82.1%) indicated their routine use of a lateral scapular view. The most common reason for obtaining the view was better characterization of acromion morphology (75.4%). The clinical vignette-based survey showed substantial intrarater reliability (κ > 0.6) of the 4 surgeons between the two surveys for the most probable diagnosis, abnormal x-ray findings, and further imaging studies, while the intrarater reliability for treatment plan was moderate (κ = 0.548). The mean diagnostic accuracy of the 4 surgeons was almost equal (74% vs. 75%) between the surveys. Overall, each surgeon's percent agreement across the 2 surveys was over 70%. None of the 4 surgeons recommended a lateral scapular view for further imaging during the first survey; each wanted either advanced imaging (computed tomography, magnetic resonance imaging) or none. Discussion: The addition of a lateral scapular radiograph in the presence of other orthogonal views does not appear to improve surgeons' diagnostic accuracy or affect their decision-making on the treatment plan in nontraumatic shoulder conditions. The clinical utility of the lateral scapular view may need to be reassessed in this setting.

Neoadjuvant checkpoint inhibition in renal cell carcinoma associated Stauffer's syndrome.

Stauffer's syndrome is a paraneoplastic phenomenon associated with renal cell carcinoma (RCC) characterized by cholestatic hepatitis. We explore the effects of perioperative immunotherapy in a case of Stauffer's syndrome. A 70-year-old female with a locally advanced clear cell RCC (ccRCC) developed severe hyperbilirubinemia. The patient's cholestasis progressed despite initial systemic immunotherapy, but improved after cytoreductive nephrectomy. The patient continued immunotherapy post-operatively and regained normalized hepatic function. To our knowledge, this is the first case reporting use of systemic immunotherapy with surgery in Stauffer's syndrome, and we provide clinical insight into a treatment regimen which may be employed in future cases.

Tolerability and effects of OROS® MPH (Concerta ®) on functioning, severity of disease and quality of life in children and adolescents with ADHD: results from a prospective, non-interventional trial.

Attention-deficit/hyperactivity disorder may have substantial impact on family life, peer interactions, and quality of life. Stimulants are recommended as first-line pharmacotherapy for ADHD. OROS(®) MPH (Concerta(®)) is a long-acting preparation with duration of effect for up to 12 h. In this 8-week, prospective, open-label, non-interventional trial the impact of therapy with OROS(®) MPH on functioning in four different areas of life (school, recreation, family life, and peer interaction), severity of disease, and quality of life (QoL) as well as tolerability were investigated under daily routine care. 306 patients, aged 10.2±2.3 years, were either transitioned to OROS(®) MPH from short-acting, immediate-release MPH (-IR) preparations (n=231; 75%), or treatment was initiated with OROS(®) MPH in MPH-naïve patients (n =75; 25%). In both groups, therapy with OROS(®) MPH was associated with significant improvements in daily functioning, severity of disease, and QoL. Adverse events (AE) were documented in 160 patients (52.3%). In 95 patients (31.0%) a causal relationship was assessed as at least possible. Four serious AEs were reported in 2 patients and rated as doubtfully related to study medication. Most frequent AEs (≥5% of patients) were insomnia, anorexia, ineffectiveness of medication, and headache. In 12.1% of patients AE led to discontinuation of study participation. Considering the limitations of this non-interventional study, the results refer to the importance of a therapy that covers not only school-time, but also takes other areas of life into account. Initiating treatment with long-acting preparations, such as OROS(®) MPH in MPH-naïve patients might be a feasible option.

Epigenetic decisions in mammalian germ cells.

Specific sequences are designated for de novo DNA methylation at CpG dinucleotides in mammalian germ cells. The result is the long-term transcriptional silencing of the methylated sequences, most of which are retrotransposons and CpG-rich sequences associated with imprinted genes. There is profound sexual dimorphism in both the nature of the sequences that undergo de novo methylation in germ cells and in the mechanism by which de novo methylation is regulated. The restriction of future gene expression by the imposition of heritable methylation patterns in germ cell genomes is characteristic of mammals but is rare in other taxa.