Effect of blood transfusion on survival in a mouse bacterial peritonitis model

Allogeneic blood transfusions can result in alloimmunization or immunosuppression. A previous study demonstrated a deleterious effect of allogeneic blood transfusion on tumor growth in mice that was dependent, in part, on the dose of tumor cells with which the host animal was inoculated. The current study examined the effect of a similar allogeneic blood transfusion protocol on survival in a mouse bacterial peritonitis model. C57Bl/6J mice were transfused with 0.2 mL of heparinized fresh whole blood from C57Bl/6J (syngeneic) or Balb/c (allogeneic) mice. Transfusions were given on Days -10 and -7. On Day 0, mice were injected intraperitoneally with 10(7) Escherichia coli. Survival at Day 7 was 61 percent in the allogeneic blood transfusion group and 55 percent in the syngeneic blood transfusion group (p = 0.52). Experiments using different strains of mice, different transfusion protocols, and different doses of bacteria also failed to demonstrate an effect of allogeneic blood transfusion on survival. The results demonstrate that blood transfusion does not influence survival after a septic challenge with bacteria. The data obtained in the present study, together with those obtained in the tumor model, suggest that the mechanisms by which the allogeneic blood transfusion impedes host defense against bacterial infections is different from the mechanisms involved in tumor growth.     

Measurement of de novo hepatic lipogenesis in humans using stable isotopes.

Direct measurement of de novo lipogenesis has not previously been possible in humans. We measured de novo hepatic lipogenesis in normal men by means of stable isotopes and by combining the acetylated-xenobiotic probe technique with mass isotopomer analysis of secreted very low density lipoprotein-fatty acids (VLDL-FA). Sulfamethoxazole (SMX) was administered with [13C]acetate during an overnight fast followed by refeeding with intravenous glucose (7-10 mg/kg of weight per min), oral Ensure (7-10 mg of carbohydrate/kg of weight per min), or a high-carbohydrate mixed-meal breakfast (3.5 g of carbohydrate/kg of weight). Respiratory quotients remained less than 1.0. High-performance liquid chromatography/mass spectrometry-determined enrichments in SMX-acetate attained stable plateau values, and hepatic acetyl-coenzyme A (CoA) dilution rate did not increase with refeeding (approximately 0.024 mmol/kg per min). The fraction of VLDL-palmitate derived from de novo lipogenesis was only 0.91 +/- 0.27% (fasted) and 1.64-1.97% (fed). For stearate, this was 0.37 +/- 0.08% and 0.47-0.64%. Precursor enrichments predicted from isotopomer ratios were close to measured SMX-acetate enrichments, indicating that SMX-acetate samples the true lipogenic acetyl-CoA pool. Stearate synthesis was less than palmitate and the two did not move in parallel. Estimated total VLDL-FA synthesis is less than 500 mg/day. Thus, de novo hepatic lipogenesis is a quantitatively minor pathway, consistent with gas exchange estimates; fatty acid futile cycling (oxidation/resynthesis) is not thermogenically significant; and synthesis rates of different nonessential fatty acids by human liver are not identical in nonoverfed normal men. The contribution and regulation of de novo lipogenesis in other settings can be studied using this technique.     

Combined 17-hydroxylase and 17,20-desmolase deficiencies: evidence for synthesis of a defective cytochrome P450c17

We studied in vivo and in vitro steroidogenesis in six phenotypic female children with 17-hydroxylase deficiency. The diagnosis was suspected as a likely cause of familial low renin hypertension and was confirmed by findings of reduced basal and ACTH-stimulated serum and urinary levels of cortisol and other 17-hydroxysteroids, together with hypergonadotropic hypogonadism in both 46,XY and 46,XX patients, and abnormally increased secretion of 17-desoxysteroids, such as progesterone, 11-deoxycorticosterone, and corticosterone. ACTH stimulation testing demonstrated a lesser degree of 17-hydroxylase deficiency in the obligate heterozygous parents; one father had increased basal serum 17-hydroxyprogesterone values, unresponsive to ACTH, suggesting partial Leydig cell 17,20-desmolase deficiency. In vitro kinetic analysis of testicular microsomal enzymes in the affected 46,XY male pseudohermaphrodites confirmed that both 17-hydroxylase and 17,20-desmolase activities were less than 2% of those in age-matched normal subjects. However, in spite of this virtual absence of both enzymatic activities of cytochrome P450c17, Northern blot analysis demonstrated abundant amounts of RNA in these tests that hybridized to a cDNA specific for this P450 enzyme. Moreover, immunoblot analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-resolved testicular microsomes showed an apparently normal content of an immunoreactive protein with a mol wt similar to that of authentic P450c17. These results suggest that these patients have a point mutation in the gene for P450c17; the mutant gene is transcribed, but gives rise to a protein defective in normal 17-hydroxylase and 17,20-desmolase activities.     

Diagnosis of Autoimmune Pancreatitis vs Neoplasms in Children With Pancreatic Mass and Biliary Obstruction

Autoimmune pancreatitis (AIP) is a rare autoimmune disorder that resembles pancreatic neoplasia and occurs primarily in adults. Management strategies and diagnostic criteria are being revised for adult patients; there are no clear diagnostic criteria for pediatric patients. We describe 3 cases of AIP in children, on the basis of clinical and pathology records. We also performed a literature review to determine the incidence of biliary obstruction in pediatric patients with pancreatic tumors. We found that children with AIP present with a variety of symptoms, and that diagnostic and therapeutic strategies also vary. Furthermore, on the basis of the many studies published on pediatric patients with pancreatic tumors, only a small percentage of the patients have biliary obstructions. Cytologic analysis of samples collected by fine-needle aspiration cytology does not accurately identify AIP in children. However, frozen section needle core biopsy samples can be used to distinguish children with AIP from those with neoplasia. Children with pancreatic mass and biliary obstruction are more likely to have AIP than neoplasms.     

A non-canonical role for desmoglein-2 in endothelial cells: implications for neoangiogenesis

Desmogleins (DSG) are a family of cadherin adhesion proteins that were first identified in desmosomes and provide cardiomyocytes and epithelial cells with the junctional stability to tolerate mechanical stress. However, one member of this family, DSG2, is emerging as a protein with additional biological functions on a broader range of cells. Here we reveal that DSG2 is expressed by non-desmosome-forming human endothelial progenitor cells as well as their mature counterparts [endothelial cells (ECs)] in human tissue from healthy individuals and cancer patients. Analysis of normal blood and bone marrow showed that DSG2 is also expressed by CD34⁺CD45^dim hematopoietic progenitor cells. An inability to detect other desmosomal components, i.e., DSG1, DSG3 and desmocollin (DSC)2/3, on these cells supports a solitary role for DSG2 outside of desmosomes. Functionally, we show that CD34⁺CD45^dimDSG2⁺ progenitor cells are multi-potent and pro-angiogenic in vitro. Using a ‘knockout-first’ approach, we generated a Dsg2 loss-of-function strain of mice (Dsg2 ^lo/lo) and observed that, in response to reduced levels of Dsg2: (i) CD31⁺ ECs in the pancreas are hypertrophic and exhibit altered morphology, (ii) bone marrow-derived endothelial colony formation is impaired, (iii) ex vivo vascular sprouting from aortic rings is reduced, and (iv) vessel formation in vitro and in vivo is attenuated. Finally, knockdown of DSG2 in a human bone marrow EC line reveals a reduction in an in vitro angiogenesis assay as well as relocalisation of actin and VE-cadherin away from the cell junctions, reduced cell–cell adhesion and increased invasive properties by these cells. In summary, we have identified DSG2 expression in distinct progenitor cell subpopulations and show that, independent from its classical function as a component of desmosomes, this cadherin also plays a critical role in the vasculature.     

MANAGEMENT OF CONCURRENT GLAUCOMA AND CATARACT BY PHACOTRABECULECTOMY TECHNIQUE: AN EFFECTIVE ALTERNATIVE APPROACH

30 cases of open angle glaucoma with cataract who underwent phacoemulsification, PMMA phaco profile IOL implantation and trabeculectomy through same incision were critically evaluated. The mean controlled, preoperative intra ocular pressure was 20 mm of Hg (range 18 to 35 mm of Hg) by aplanation method. Mean post operative pressure after 12 months was 13 mm of Hg (range 11 to 22 mm of Hg) intra operative hyphaema, post operative uveitis were noted problems. Periodic, post operative optic disc and field evaluation remained static in 66% cases. Visual acuity of 6/12 or better was achieved in 60% cases. Failure to restore glaucoma control without medication was seen in 13.3% cases after 9–12 months. The combined phacotrabeculectomy is an effective single step technique of managing concurrent glaucoma with cataract.Key words: Single incision, Phacotrabeculectomy     

Allogeneic blood transfusion-induced enhancement of tumor growth: two animal models showing amelioration by leukodepletion and passive transfer using spleen cells [see comments]

Allogeneic blood transfusions have been reported to induce immunomodulation in recipients of blood products. While the mechanism(s) of this immunomodulatory effect is unknown, it has been suggested that this effect of allogeneic blood transfusions could adversely affect patients with a malignant disorder. These concerns have been supported by a number of nonrandomized, mainly retrospective, clinical studies which indicate that allogeneic blood transfusions can adversely affect prognosis following the surgical treatment of oncology patients. Recently, we have shown that allogeneic blood transfusions enhance primary tumor growth and increase metastatic pulmonary nodule formation in inbred mice. The tumor growth-promoting activity of allogeneic blood transfusions was studied also using outbred rabbits. In this present study, we demonstrate that the tumor growth-promoting effect of allogeneic blood transfusions is mediated by donor leukocytes and that this effect can be abolished by their removal before transfusion. We show also that the allogeneic blood transfusion tumor growth-promoting effect can be passively transferred to naive animals (both mice and rabbits) using spleen cells from allogeneically transfused animals. In these experiments, numbers of metastatic pulmonary nodules were significantly increased in both mice and rabbits that had received spleen cells from allogeneically transfused animals compared with those that had received spleen cells from syngeneically transfused animals, or from animals that had been transfused with leukodepleted allogeneic blood.     

DOES THE METHOD OF TRANSLUMINAL CORONARY REVASCULARISATION INFLUENCE RE-STENOSIS? BALLOON ANGIOPLASTY,ATHERECTOMY AND STENTS COMPARED

SUMMARY Luminal renarrowing after successful coronary angioplasty is now recognised as a continuously distributed process which is determined largely by the extent of luminal increase achieved at angioplasty. In this study an alternative analytical approach is applied to determine whether luminal renarrowing following coronary intervention is related to the mechanism of luminal increase (ie by balloon, by atherectomy, by a self-expanding stainless steel mesh stent, or by a balloon-expandable tantalum coil stent). The results confirm the known proportional relationship between luminal renarrowing during follow-up and luminal improvement at intervention, regardless of the device used. However, significant differences were observed between the devices, which may reflect device-specific characteristics of the hyperplastic response to vessel injury and may have clinical implications.