The incidence of deep brain stimulator hardware infection: the effect of change in antibiotic prophylaxis regimen and review of the literature

The complication of hardware infection related to deep brain stimulator implantation (or revision) varies between 0 and 15.2% in the literature. However, no national guidelines exist at present to define an average or acceptable rate of infection associated with, nor the preferred antibiotic prophylaxis required for, this procedure. The aim of this study was to examine the effect of changing the antibiotic prophylaxis regimen used in a single neurosurgical centre on the incidence and outcome of hardware infection. A prospective cohort of 38 patients undergoing deep brain stimulation (DBS) implantation or internal pulse generator (IPG) replacement and receiving perioperative vancomycin (including intravenous gentamicin on induction) and pouch-installed gentamicin, was compared to a historical cohort of 35 patients receiving perioperative cefuroxime in the same unit. The infection rate over 2 years in the prospective group for DBS surgery was 0 compared to 1 (5.6%) in the historical cohort (p?=?0.11, χ(2)); the infection rate for IPG replacements was 1(3.6%) in the prospective cohort, versus 3 (17.6%) in the historical (p?=?0.44, χ(2)). In this article, we have also systematically reviewed the literature to date and derived an average infection rate of 4.7% (PI 0.9-22%, Random Effects Meta-analysis, Stata) for 35 studies comprising 3550 patients. There is no significant difference in infection rates between DBS procedures that are primarily internalised (n?=?9) compared to those in which there is a period of electrode externalisation (n?=?23) (p?=?0.9, Meta-regression analysis, Stata).     

Selective deletion of long but not short Cypher isoforms leads to late-onset dilated cardiomyopathy

Cypher long (CypherL) and short (CypherS) isoforms are distinguished from each other by the presence and absence of three C-terminal LIM domains, respectively. Cypher isoforms are developmentally regulated, and mutations affecting both long and short isoforms are linked to muscle disease in humans. Given these data, we hypothesized that various Cypher isoforms play overlapping and unique roles in striated muscle. To determine the specific role of Cypher isoforms in striated muscle, we generated two mouse lines in which either CypherS or CypherL isoforms were specifically deleted. Mice specifically, deficient in CypherS isoforms had no detectable muscle phenotype. In contrast, selective loss of CypherL isoforms resulted in partial neonatal lethality. Surviving mutants exhibited growth retardation and late-onset dilated cardiomyopathy, which was associated with cardiac fibrosis and calcification, leading to premature adult mortality. At a young age, preceding development of cardiomyopathy, hearts from these mutants exhibited defects in both Z-line ultrastructure and specific aberrations in calcineurin-NFAT and protein kinase C pathways. Earlier onset of cardiac dilation relative to control wild-type mice was observed in young CypherL isoform knockout mice consequent to pressure overload, suggesting a greater susceptibility to the disease. In summary, we have identified unique roles for CypherL isoforms in maintaining Z-line ultrastructure and signaling that are distinct from the roles of CypherS isoforms, while highlighting the contribution of mutations in the long isoforms to the development of dilated cardiomyopathy.     

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus,or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours

Background:

Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation.

Methods:

A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg^–1) and escalating doses of MK-2206 (90–200 mg) or escalating doses of dalotuzumab (7.5–10 mg kg^–1) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752.

Results:

A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles.

Conclusions:

Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.     

Cerebral and muscle MRI abnormalities in myotonic dystrophy

Pathophysiological mechanisms underlying the clinically devastating CNS features of myotonic dystrophy (DM) remain more enigmatic and controversial than do the muscle abnormalities of this common form of muscular dystrophy. To better define CNS and cranial muscle changes in DM, we used quantitative volumetric and diffusion tensor MRI methods to measure cerebral and masticatory muscle differences between controls (n=5) and adults with either congenital (n=5) or adult onset (n=5) myotonic dystrophy type 1 and myotonic dystrophy type 2 (n=5). Muscle volumes were diminished in DM1 and strongly correlated with reduced white matter integrity and gray matter volume. Moreover, correlation of reduced fractional anisotropy (white matter integrity) and gray matter volume in both DM1 and DM2 suggests that these abnormalities may share a common underlying pathophysiological mechanism. Further quantitative temporal and spatial characterization of these features will help delineate developmental and progressive neurological components of DM, and help determine the causative molecular and cellular mechanisms.