LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11 Y279C/+ (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.

Study Type – Therapy (case control)
Level of Evidence 3b What's known on the subject? and What does the study add? The risks of delayed radical prostatectomy for men who progress on active surveillance are largely unknown. Two series have reported that prostatectomy after active surveillance has similar results to immediate therapy. Our data add to this growing body of evidence that appropriately selected men with prostate cancer can undergo active surveillance with delayed prostatectomy without added risk of missing an opportunity for cure as the majority of tumours remain organ confined. OBJECTIVE • To compare the pathological outcomes of men undergoing radical prostatectomy (RP) after a period of active surveillance (AS) with those of a similar risk group undergoing immediate surgery. PATIENTS AND METHODS • We identified men through our institutional database who underwent RP within 6 months of diagnosis or after a period of AS. The primary outcome of the present study was Gleason upgrade to ≥7 after prostatectomy. • Pathological stage and positive surgical margin rate were assessed as secondary outcomes. Binomial logistic regression models were used to determine associations of treatment subgroups with pathological upgrade, upstage and positive margins. RESULTS • Thirty‐three men with initially low‐risk cancer features underwent RP after a median (range) of 18 (7–76) months of AS. A total of 278 men with low‐risk disease features underwent immediate RP within 6 months of diagnosis. Rates of Gleason upgrading to ≥7, pathological category pT3 and positive surgical margins did not differ significantly from the immediate RP group. • On multivariate analysis of low‐risk patients, adjusting for baseline pathological features, treatment group (AS followed by prostatectomy vs immediate prostatectomy) was not associated with Gleason upgrading (odds ratio, OR, 0.35; 95% CI, 0.12–1.04), non‐organ‐confined disease (OR, 1.67; 95% CI, 0.32–8.65) or positive surgical margins at prostatectomy (OR, 0.95; 95% CI, 0.16–5.76). CONCLUSION • The present analysis did not show an association between RP after a period of AS and adverse pathological features for men with low‐risk disease.

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Fifteen patients admitted to hospital with acute purulent exacerbations of chronic bronchitis were treated with enoxacin by mouth (three 200 mg capsules twice daily) for ten days. Sputum was cultured before, during and after the treatment course. Serum and sputum concentrations were measured microbiologically at intervals on the first treatment day. Blood was assayed before, and 1, 1 1/2, 2, 2 1/2, 3, 5 and 7 h after the first dose and purulent unhomogenized sputum was tested in samples collected 0-2, 2-4, 4-6 and 6-8 h after this dose. The highest concentrations in serum were usually noted 2 or 2 1/2 h after the medication and ranged from approximately 3 to 6 mg/l (average 4.08 mg/l). The highest sputum concentrations were generally found in the 2-4 or 4-6 h portions, and ranged from 2.2 to 6 mg/l (average 3.68 mg/l). The areas under the serum and sputum concentration-time curves were both calculated to be 17.03 mg/l.h (0-7 h values) whereas the projected 0-12 h values were 25.2 and 26.9 mg/l.h, respectively. The drug concentrations declined slowly in serum and sputum with half-lives of approximately 5 and 4 h. Penetration from blood to sputum as judged on peak to peak ratios was approximately 90%, whereas the AUC value ratios showed penetration ranging from 100 to 107.5%. Unfortunately, 9 of the 15 patients had to abandon the treatment (mostly on the third day) due to unwanted drug effects (principally nausea, but some patients had hallucinations, dizziness or epileptiform attacks) possibly related to interference with theophylline metabolism.