Nutritional immunomodulation leads to enhanced allograft survival in combination with cyclosporine A and rapamycin, but not FK506

BACKGROUND: Recently, specific immunonutrients were found to increase experimental allograft survival when combined with cyclosporine A (CsA). This study compared the effect on rat cardiac allograft survival when nutritional immunomodulation was used with CsA, rapamycin (Rapa), or tacrolimus (FK506). METHODS: Intra-abdominal ACI to Lewis cardiac allografts were performed and assessed daily by palpation. Study groups included untreated controls and those receiving CsA, Rapa, or FK506. Rats were fed ad libitum with Impact diet (fortified with fish oil, arginine, and RNA) or standard rat food. Further study groups were transplanted that received a donor-specific transfusion in addition to immunosuppression and diet. RESULTS: Allograft survival was extended by combining Impact with CsA (45.3+/-19 days) and Rapa (165.3+/-52 days), but not FK506 (12.4+/-3.2 days). Mean graft survival in the Rapa/Impact group met criteria for functional tolerance. The addition of a donor-specific transfusion did not lead to graft survival advantages over similar groups not receiving a donor-specific transfusion. CONCLUSIONS: The use of immunonutrients improves transplant outcome in animals treated with short courses of CsA and Rapa, but not FK506. These findings highlight the potential differences in the effects of nutritional immunomodulation with different immunosuppressive drugs in the treatment of transplant patients.     

Thalidomide metabolites in mice and patients with multiple myeloma.

PURPOSE:This research examines the profile of metabolites of thalidomide that are formed in refractory multiple myeloma patients undergoing thalidomide therapy in comparison with those that are detected in healthy mice. EXPERIMENTAL DESIGN: Urine or plasma samples from patients during thalidomide therapy (100-400 mg daily), or from mice treated i.p. (100 mg/kg) or p.o. with thalidomide (50 mg/kg) were analyzed using liquid chromatography-mass spectrometry. Metabolites in each of the peaks observed in the UV- and mass spectrometry-detected high-performance liquid chromatography traces were identified by comparison of retention times and spectra with those of authentic standards. RESULTS: Plasma and urine samples from mice 4 h after treatment with thalidomide contained eight major metabolites formed by hydroxylation and/or hydrolysis of thalidomide. In contrast, urine samples from seven multiple myeloma patients at steady state levels of thalidomide therapy showed the presence of only three hydrolysis breakdown products and no hydroxylated metabolites. CONCLUSIONS: Our results show that thalidomide metabolite profiles in multiple myeloma patients differ considerably from those in mice. The lack of measurable hydroxylated metabolites in urine and in 1 case plasma of these patients suggests that such metabolites are not responsible for the therapeutic effects of thalidomide in multiple myeloma. We suggest that thalidomide may act directly, down-regulating growth factors essential for multiple myeloma growth.     

Review of Percutaneous Tracheostomy

The purpose of this study is to assess the safety and efficacy of the four known methods of percutaneous tracheostomy. Perioperative, postoperative, and late complication rates were generated for each method after a complete literature review identified 1684 percutaneous tracheostomy patients reported in 40 series. Two methods, the Toye and the guide wire dilator forceps (GWDF) methods, have been the subject of few investigations. Two other methods have been extensively studied. A high perioperative complication rate was calculated for the Rapitrac? method, whereas percutaneous dilational tracheostomy (PDT) has complication rates similar to those reported for standard operative tracheostomy. A retrospective review of 22 patients who underwent PDT at a local community hospital confirmed a “learning curve” for this technique that had been previously suggested. Review of the literature suggests that PDT can be safe and cost-effective for selected patients, but a learning curve for this technique exists that dictates caution, experience, and preparation on the part of any surgeon who wishes to add percutaneous tracheostomy to his or her repertoire.     

Changes in the expression of the type-2 but not the type-1 cyclo-oxygenase enzyme in chorion-decidua with the onset of labour

Objective To determine the relative expression of cyclo-oxygenase (COX)-1 and COX-2 in the chorion-decidual part of human fetal membranes following delivery at term and to identify any changes in expression associated with labour.
Methods Fetal membranes were collected from 12 term pregnancies before labour following elective caesarean section and from 12 spontaneous vaginal deliveries. Expression of COX-1 and COX-2 mRNA was measured using a previously validated quantitative RT-PCR assay.
Results COX-2 expression exceeded that of COX-1 by approximately eight-fold. COX1 expression did not change but COX-2 expression was found to increase four-fold with labour.
Conclusions Chorion-decidua has the capacity to contribute to the increase in prostaglandin synthesis within the uterus associated with labour. As in the amnion, it is COX-2 and not COX-1 which is upregulated with labour. COX-2 selective anti-prostaglandins should therefore be as effective as nonselective drugs in inhibition of fetal membrane prostaglandin synthesis.     

Abnormal vascular tone in infants and children with lung hypoplasia: Findings from cardiac catheterization and the response to chronic therapy.

OBJECTIVE: We describe four cases of chronic pulmonary hypertension in infants and children with chronic lung disease and pulmonary hypoplasia due to severe congenital diaphragmatic hernia (CDH) or congenital cystic adenomatoid malformation (CCAM). We report data from cardiac catheterization under various conditions: baseline respiratory support and room air, hyperoxic and inhaled nitric oxide challenge. We further report cardiac catheterization measures after chronic pulmonary vasodilator therapy with sildenafil alone or a combination of sildenafil and inhaled nitric oxide (three patients). DESIGN: Case series. SETTING: Tertiary academic center. PATIENTS: Infants and children ages 0-11 yrs with CDH (n = 3) or CCAM (n = 1) with evidence of chronic pulmonary hypertension by echocardiogram and cor pulmonale (n = 3). INTERVENTIONS: Catheterization and pulmonary vasodilator therapy. MEASUREMENTS AND MAIN RESULTS: Pulmonary vascular resistance, pulmonary arterial pressure, and changes in these measures were assessed. A 20% change in pulmonary vascular resistance was considered a clinically significant response. Ten catheterizations were performed in four patients. All patients had elevated pulmonary vascular resistance and pulmonary arterial pressures at initial catheterizations and significant vasodilation during inhaled nitric oxide. CONCLUSIONS: Chronic lung disease following pulmonary hypoplasia from CDH and CCAM is associated with abnormal pulmonary vascular tone in infants and children with evidence of chronic pulmonary hypertension. Chronic pulmonary vasodilator therapy may improve pulmonary vascular function and enhance lung growth in infants and children who are treated during their period of potential for rapid lung growth.     

Ophthalmoscopic contact lenses for transpupillary thermotherapy

Ophthalmoscopic contact lenses for transpupillary thermotherapy (TTT) must provide effective visualization of retinal treatment sites and transmission of infrared diode laser radiation. Selection and proper use of retinal laser lenses requires knowledge of their lateral magnification, laser beam magnification factor, field of view and resolution. Optical performance is analyzed for Goldmann-type lenses and a series of inverted image lenses of differing magnification. Goldmann lenses have the highest resolution, but inverted image lenses of comparable magnification have 2.5 times or more their field of view. Inverted image lenses of similar magnification can differ in resolution. They require 2-4% more incident laser power to produce the same retinal irradiance as a Goldmann lens, but this difference is small in comparison to other clinical variables. Tilting an ophthalmoscopic contact lens up to 15° causes little distortion in the circularity of the retinal spot formed by a laser beam or difference in retinal irradiance across the spot. Inverted image lenses produce higher anterior segment irradiances than Goldmann-type lenses, but anterior segment injuries are less likely in TTT than conventional visible light, short-pulse retinal photocoagulation because of the comparatively low irradiances used in TTT and the decreased absorption of diode laser infrared radiation in ocular media and melanin.     

Feasibility of an early Alzheimer's disease immunosignature diagnostic test

A practical diagnostic test is needed for early Alzheimer's disease (AD) detection. Immunosignaturing, a technology that employs antibody binding to a random-sequence peptide microarray, generates profiles that distinguish transgenic mice engineered with familial AD mutations (APPswe/PSEN1-dE9) from non-transgenic littermates. It can also detect an AD-like signature in humans. Here, we assess the changes in the immunosignature at different time points of the disease in mice and humans. We also evaluate the accuracy of the late-stage signature as a test to discriminate between young mice with familial AD mutations from non-transgenic littermates. Plasma samples from AD patients were assayed 3–12 months apart, while APPswe/PSEN1-dE9 and non-transgenic controls supplied plasma at monthly intervals until they reached 15 months of age. Microarrays with 10,000 random-sequence peptides were used to compare antibody binding patterns. These patterns gradually changed over the life-span of mice. Strong, characteristic signatures were observed in transgenic mice at early, mid and late stages, but these profiles had minimal overlap. The signature of young transgenic mice had an error rate of 18% at classifying plasma samples from late-stage transgenic mice. Conversely, the late-stage transgenic mice signature discriminated between young transgenic mice and littermates with an error rate of 21%. Less distinctive profiles were recognizable throughout the transgenic mice lifespan, being detectable as early as 2 months. The human signature had minimal change on short-term follow-up. Our results call for a reappraisal of the way incipient AD is studied, as biomarkers seen in late-stages of the disease may not be relevant in earlier stages.