Oophorectomy in primary colorectal cancer

Colorectal cancer is a common cancer affecting women which may metastasize to the ovaries. We present five cases of ovarian metastases requiring surgery and review the debate regarding oophorectomy at the primary resection for colorectal cancer. Although prophylactic oophorectomy has not been proven to affect survival, further surgery for symptomatic ovarian metastases may be avoided and the increased risk of developing primary ovarian cancer is abolished.     

Fasting medium chain acyl-coenzyme A dehydrogenase--deficient children can make ketones

Medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency classically presents as hypoketotic hypoglycemia. Under-production of ketones has been presumed to be the cause of hypoketosis, but this has never been proven. Stable isotope dilution studies of ketone kinetics were performed on three well children with homozygous 985G MCAD deficiency using 1,3-13C2 sodium acetoacetate and 1,2,3,4-13C4 sodium 3-hydroxybutyrate to ascertain the rates of ketone production, interconversion, and use. All children were fasted for 9 to 11.5 hours before the beginning of the study period. Euglycemia was maintained in all cases. Ketone kinetics were calculated using a two-accessible pool model and showed normal ketone production in all three children compared with published control data from children fasted for a similar length of time. There is no evidence for underproduction or overuse of ketones in these MCAD-deficient children, at least when they are well. We propose that another factor, such as fever, may be required to reduce ketone production and result in the biochemical phenotype recognized in unwell children.     

Actin-containing sera from patients with adult respiratory distress syndrome are toxic to sheep pulmonary endothelial cells

Actin released from damaged cells after a variety of tissue injuries appears to be involved in multiple organ dysfunction syndrome. Under experimental conditions, when the quantity of actin present in plasma is made to exceed the protective capacity of the actin-scavenging mechanism, microembolism and pulmonary vascular angiopathy have been noted in rats. It remains to be determined whether this injury is a result of a direct toxic effect or occurs indirectly via platelet activation or fibrin interactions. We examined the effect of sera from patients with adult respiratory distress syndrome (ARDS), as well as G-actin added to normal serum, on the viability, morphology, and function of cultured sheep pulmonary artery endothelial cells (SPAEC). Both patient sera and normal sera to which actin was added were toxic in the cell culture model; this toxicity could be abrogated, at least partially, by preincubation with gelsolin, which is known to complex with actin. A significant portion of the toxicity of sera from patients with ARDS was sensitive to heat (56 degrees C), suggesting an important role of complement. Sera from patients with ARDS were shown to contain filaments of F-actin by immunoblot and rhodamine phalloidin staining after ultracentrifugation. Thus, saturation of the actin-scavenging system by addition of exogenous G-actin to plasma produces direct pulmonary endothelial cell injury. Furthermore, plasma from patients with ARDS secondary to bacterial pneumonia is toxic to SPAEC, and a small but significant contributory role of actin is apparent in these studies.     

Radionuclide Angiography in Evaluation of Left Ventricular Function Following Aortic Valve Replacement

Congestive heart failure in patients surviving aortic valve replacement has been associated with a high late mortality. To determine whether myocardial dysfunction in these patients occurred preoperatively, perioperatively, or during the early postoperative period, 19 consecutive patients undergoing aortic valve replacement using cardioplegia and hypothermia were studied by multiple-gated cardiac blood pool imaging. The resting ejection fractions for 8 patients with aortic stenosis did not show significant changes following operation. The 11 patients with aortic insufficiency had resting preoperative values of 58 ± 15%, which fell to 38 ± 18% immediately postoperatively (p < 0.01), with the late values being 51 ± 16%. Eight of the 18 patients (44%) showed deterioration of regional wall motion immediately after operation, which persisted in 3 during the late evaluation. The occurrence of new perioperative regional wall motion abnormalities and persistent perioperative depression in left ventricular function in some patients suggest the need for further improvement in myocardial protection during cardiopulmonary bypass for aortic valve replacement.     

Experimental autoimmune encephalomyelitis (EAE) in CCR2(-/-) mice: susceptibility in multiple strains

Chemokines are low molecular weight cytokines which act as chemoattractants for infiltrating cells bearing appropriate receptors (CCR) to sites of inflammation. It has been proposed that CCR2 on monocytes is responsible for their recruitment into the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, and two previous reports have described resistance of CCR2(-/-) mice to EAE. The present study examined three different mouse strains with CCR2 deletions for susceptibility to EAE. Animals were studied up to 4 months post-sensitization and were examined by neuropathology, RNase protection assay, in situ hybridization, and in vitro assays. All three strains were found to be susceptible to EAE: C57BL/6 x J129 and Balb c strains, 100%; and C57BL/6, 67%. Unusual in CNS lesions of CCR2(-/-) mice was an overabundance of neutrophils versus monocytes in wild-type animals. An attempt of the immune system to develop compensatory mechanisms for the lack of CCR2 was evidenced by a corresponding increase in mRNA for other chemokines and CCR. Inasmuch as neutrophils replaced monocytes and led to demyelination, our findings support the concept that promiscuity of chemokines and CCR was able to surmount the deletion of CCR2, still resulting in full expression of this autoimmune disease.     

Axial tensile fracture of microcrystalline cellulose compacts

An adapted tensile stress methodology for the fracture of microcrystalline cellulose (MCC) tablets has been investigated and implemented. The application of the generally applied linear elastic fracture mechanic (LEFM) parameters used to describe the fracture behaviour of these porous systems has been discussed. The application of an effective crack length concept, comprising of the notch depth and a process zone length designated delta c, has enabled the localised non-linear response of the MCC tablets to be characterised in a quantified manner. The requirement of the composite value delta c is postulated to be a direct result of the internal properties of the tablet formed during the compaction process due to its strong dependence on porosity. The high compact relative density creates a greater possibility for both local small-scale plastic yielding at the crack tip, commonly found in polymer materials and microcracking ahead of the crack tip, typically observed in the fracture of ceramics. The extrapolated value of KIC0 of 0.72 MPa m0.5 found in this work lies within the range found in literature for this material indicating that the adopted procedure is acceptable for the determination of the resistance to fracture of MCC compacts.     

Ultrasonic drug delivery--a general review

Ultrasound has an ever-increasing role in the delivery of therapeutic agents, including genetic material, protein and chemotherapeutic agents. Cavitating gas bodies, such as microbubbles, are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilise cell membranes and disrupt the vesicles that carry drugs. Thus, the presence of microbubbles enormously enhances ultrasonic delivery of genetic material, proteins and smaller chemical agents. Numerous reports show that the most efficient delivery of genetic material occurs in the presence of cavitating microbubbles. Attaching the DNA directly to the microbubbles, or to gas-containing liposomes, enhances gene uptake even further. Ultrasonic-enhanced gene delivery has been studied in various tissues, including cardiac, vascular, skeletal muscle, tumour and even fetal tissue. Ultrasonic-assisted delivery of proteins has found most application in transdermal transport of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; and makes cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has on cells and drug-carrying vesicles.     

Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays

A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.     

Effects of contract management on hospital performance.

The performance of contract-managed (CM) hospitals is compared to that of a set of internally managed hospitals matched on a variety of hospital and market area characteristics. The performance of the study hospitals was similar to that of the matches in the years before the onset of contract management. Among 12 performance indicators, only occupancy rates differed significantly in the two samples in the years before contract management. Occupancy rates were lower on average in the hospitals which later became contract managed. During the 3 years following the onset of contract management, the CM hospitals showed no improvement in productive efficiency but did show changes in the way services were priced. The ratio of gross patient revenue to total expense increased significantly in the CM hospitals relative to their matches. This increase also appears to be associated with an increase in net profits in the CM hospitals relative to their matches.