Choice of Vein‐Harvest Technique for Coronary Artery Bypass Grafting: Rationale and Design of the REGROUP Trial

The Randomized Endo‐vein Graft Prospective (REGROUP) trial ( ClinicalTrials.gov  NCT01850082) is a randomized, intent‐to‐treat, 2‐arm, parallel‐design, multicenter study funded by the Cooperative Studies Program (CSP No. 588) of the US Department of Veterans Affairs. Cardiac surgeons at 16 Veterans Affairs (VA) medical centers with technical expertise in performing both endoscopic vein harvesting (EVH) and open vein harvesting (OVH) were recruited as the REGROUP surgeon participants. Subjects requiring elective or urgent coronary artery bypass grafting using cardiopulmonary bypass with use of ≥1 saphenous vein graft will be screened for enrollment using pre‐established inclusion/exclusion criteria. Enrolled subjects (planned N = 1150) will be randomized to 1 of the 2 arms (EVH or OVH) after an experienced vein harvester has been assigned. The primary outcomes measure is the rate of major adverse cardiac events (MACE), including death, myocardial infarction, or revascularization. Subject assessments will be performed at multiple times, including at baseline, intraoperatively, postoperatively, and at discharge (or 30 days after surgery, if still hospitalized). Assessment of leg‐wound complications will be completed at 6 weeks after surgery. Telephone follow‐ups will occur at 3‐month intervals after surgery until the participating sites are decommissioned after the trial's completion (approximately 4.5 years after the full study startup). To assess long‐term outcomes, centralized follow‐up of MACE for 2 additional years will be centrally performed using VA and non‐VA clinical and administrative databases. The primary MACE outcome will be compared between the 2 arms, EVH and OVH, at the end of the trial duration.     

Hyperthermic intraperitoneal chemotherapy in conjunction with surgery for the treatment of recurrent ovarian carcinoma

OBJECTIVES: To review experience of secondary surgical cytoreduction (SSC) with hyperthermic intraperitoneal chemotherapy (IPHC). METHODS: Eligible patients with ovarian cancer in whom pre-operative evaluation indicated that there was a good possibility that disease could be resected to < or = 5 mm underwent surgery followed by intraperitoneal perfusion of cisplatin (100 mg/m2) or mitomycin C (30-40 mg total dose) heated to 41-43 degrees C (105.8-109.4 degrees F) for 90 min. Data for analysis were extracted from retrospective chart review. RESULTS: Eighteen patients underwent surgery and IPHC between 9/02 and 3/05. Characteristics were median age 64 (37-77) years, mean prior laparotomies 1.4 (0-3), mean chemotherapy regimens 3.2 (0-7), mean time from initial therapy to IPHC 30.6 (1-88) months. Original histology: papillary serous 12, poorly differentiated adenocarcinoma 1, serous low malignant potential 2, mucinous 1 and mixed subtypes 2. 13 had recurrent disease and 5 had persistent disease following front-line therapy. 15 received cisplatin and 3 mitomycin C. The mean duration of surgery was 9.8 (5-16) h. The maximum dimension of residual lesions at the end of surgery prior to IPHC was nil (n=11), < or = 2 mm (n=4), < or = 5 mm (n=2) and < or = 10 mm (n=1). Mean time to return of bowel function was 7 (5-20) days and mean time to hospital discharge 11.5 (5-49) days. All patients developed CTEP grade 1 or 2 metabolic or hematologic toxicities. CTEP grade 3 or 4 metabolic toxicity occurred in 72% and a hematologic toxicity in 28%.There was one peri-operative death due to pulmonary embolus. Median progression-free interval was 10 months and median overall survival was 31 months. Improved outcome was significantly related to the size of residual disease prior to IPHC and postoperative chemotherapy. CONCLUSIONS: IPHC is a relatively well-tolerated procedure with the majority of the morbidity being related to associated surgery. When combined with SSC it has the potential to extend quality life in some patients with recurrent ovarian cancer and warrants continued research. Randomized studies are needed earlier in the course of the disease.     

Potential allergens stimulate the release of mediators of the allergic response from cells of mast cell lineage in the absence of sensitization with antigen-specific IgE

A number of structurally diverse antigens preferentially stimulate the synthesis of IgE antibodies, but no unifying principle has been proposed that explains the nature of isotype selection. In the present study, we show that common allergens present in bee venom, house dust mite emanations and parasite proteins induce mast cell and basophil degranulation and stimulate interleukin-4 synthesis, and secretion in the absence of antigen-specific IgE. These data point to a linkage between the initial activation of cells of the innate immune system and subsequent adaptive immune responses. They suggest that IgE-independent mast cell and basophil degranulation is predictive of potential allergenicity and can be evaluated by means of a cellular assay. Our study indicates that non-immunological degranulation by prototypic allergens, such as bee venom phos-pholipase A₂ or proteases associated with house dust mite emanations, is critically dependent on enzymatic activity. These findings have potentially important implications for vaccine design in allergic and parasitic disease.     

Diminished left ventricular dyssynchrony and impact of resynchronization in failing hearts with right versus left bundle branch block.

OBJECTIVES: We compared mechanical dyssynchrony and the impact of cardiac resynchronization therapy (CRT) in failing hearts with a pure right (RBBB) versus left bundle branch block (LBBB). BACKGROUND: Cardiac resynchronization therapy is effective for treating failing hearts with conduction delay and discoordinate contraction. Most data pertain to LBBB delays. With RBBB, the lateral wall contracts early so that biventricular (BiV) pre-excitation may not be needed. Furthermore, the magnitude of dyssynchrony and impact of CRT in pure RBBB versus LBBB remains largely unknown. METHODS: Dogs with tachypacing-induced heart failure combined with right or left bundle branch radiofrequency ablation were studied. Basal dyssynchrony and effects of single and BiV CRT on left ventricular (LV) function were assessed by pressure-volume catheter and tagged magnetic resonance imaging, respectively. RESULTS: Left bundle branch block and RBBB induced similar QRS widening, and LV function (ejection fraction, maximum time derivative of LV pressure [dP/dt(max)]) was similarly depressed in failing hearts with both conduction delays. Despite this, mechanical dyssynchrony was less in RBBB (circumferential uniformity ratio estimate [CURE] index: 0.80 +/- 0.03 vs. 0.58 +/- 0.09 for LBBB, p < 0.04; CURE 0-->1 is dyssynchronous-->synchronous). Cardiac resynchronization therapy had correspondingly less effect on hearts with RBBB than those with LBBB (i.e., 5.5 +/- 1.1% vs. 29.5 +/- 5.0% increase in dP/dt(max), p < 0.005), despite similar baselines. Furthermore, right ventricular-only pacing enhanced function and synchrony in RBBB as well or better than did BiV, whereas LV-only pacing worsened function. CONCLUSIONS: Less mechanical dyssynchrony is induced by RBBB than LBBB in failing hearts, and the corresponding impact of CRT on the former is reduced. Right ventricular-only pacing may be equally efficacious as BiV CRT in hearts with pure right bundle branch conduction delay.     

Characterization of a virus-specific proteolytic activity processing the gag precursor of the simian sarcoma-associated virus

The proteolytic processing of the gag precursor polypeptide pr65gag of simian sarcoma-associated virus (SSAV) has been studied in vivo and in vitro. In SSAV-infected cells (i.e., in vivo) proteins of 52 and 38 kDa and the viral protein p30 could be immunoprecipitated with anti-p30 serum. This cleavage pattern is only in part imitated by in vitro cleavage of the isolated pr65gag with avian myeloblastosis virus (AMV) protease p15. However, in vitro incubation of isolated pr65gag with detergent-disrupted SSAV particles generated products identical in size to those found in vivo, i.e., proteins of 52 and 38 kDa and p30. The extent of cleavage is dependent on the concentration of the disrupted virions added to the incubation mixture. Studies with protease inhibitors suggest that the SSAV enzyme is a serine-type protease like that of other mammalian retroviruses and unlike the protease of avian viruses. The SSAV protease activity eluted from a molecular sieve column in a range of about 10-15 kDa reflecting the molecular weight of the murine leukemia virus (MuLV) protease (Mr = 13.5K). Thus, it appears that there is a close similarity between the proteolytic enzymes present in different mammalian retroviruses such as MuLV and SSAV.     

Distinct Aβ pathology in the olfactory bulb and olfactory deficits in a mouse model of Aβ and α‐syn co‐pathology

Several degenerative brain disorders such as Alzheimer''s disease (AD), Parkinson''s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid‐β (Aβ) and α‐synuclein (α‐syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α‐syn in Aβ aggregation and the arising characteristic olfactory impairments observed during the progression of these diseases is still not well understood. Therefore, we assessed Aβ load in olfactory bulbs of APP‐transgenic mice expressing APP695 ^KM670/671NL and PSEN1 ^L166P under the control of the neuron‐specific Thy‐1 promoter (referred to here as APPPS1) and APPPS1 mice co‐expressing SNCA ^A30P (referred to here as APPPS1 × [A30P]aSYN). Furthermore, the olfactory capacity of these mice was evaluated in the buried food and olfactory avoidance test. Our results demonstrate an age‐dependent increase in Aβ load in the olfactory bulb of APP‐transgenic mice that go along with exacerbated olfactory performance. Our study provides clear evidence that the presence of α‐syn significantly diminished the endogenous and seed‐induced Aβ deposits and significantly ameliorated olfactory dysfunction in APPPS1 × [A30P]aSYN mice.     

Experimental studies of the effect of bupivacaine on peripheral nerves

0.5% Bupivacaine was administered around the sciatic nerve of rabbits by means of a catheter, over a period of ten days. Twenty nerves showed no histological changes, but in three there were areas of demyelination and axonal degeneration, especially near the surface of the nerve. However, similar changes occurred in two out of six nerves to which normal saline was administered instead, and it is suggested that the damage may have been caused by mechanical trauma from movement of the catheter.