Identification of high and low responders to allografts

The immune response to an allograft varies from one individual to another. This individual variation is, at least in part, due to genetic variation in the regulation of cytokine gene expression. High and low cytokine responses in vitro for tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta 1 (TGF-beta1) and other cytokines can be predicted from an individual's cytokine genotype. Using the same genetic markers we have been able to show associations, in particular between TNF-alpha genotype of the recipient and acute allograft rejection and, similarly, between TGF-beta1 genotype and chronic rejection. The ability to identify high and low responders to allografts by a simple genetic test, and to predict who will suffer acute and chronic rejection, has implications for donor selection and recipient treatment as well as for the design and interpretation of clinical trials of new immunosuppressive agents.     

Interleukin-10 (IL10) promoter polymorphisms and multiple sclerosis

Interleukin-10 (IL10) is an anti-inflammatory cytokine which may modulate disease expression in multiple sclerosis (MS). Three dimorphic polymorphisms within the IL10 promoter region at positions - 1082, -819 and -519 have previously been identified. The - 1082*A allele has been associated with low and the - 1082*G allele with high in vitro IL10 production. We have genotyped 185 Caucasian MS patients and 211 ethnically matched controls for each of these three dimorphisms. MS patients were stratified for severity of disease outcome. No associations were found for any IL10 promoter polymorphisms when the MS cases were compared with controls or with disease outcome with regards to disability. IL10 polymorphism does not appear to be associated with MS or to influence disease progression.     

Adenosine coronary vasodilation quantitative technetium 99m methoxy isobutyl isonitrile myocardial tomography in the identification and localization of coronary artery disease

Background

Exercise and dipyridamole ^99mTc-labeled methoxy isobutyl isonitrile (MIBI) myocardial scintigraphy have been widely used for the diagnosis of coronary artery disease (CAD). However, only limited data on adenosine ^99mTc-labeled MIBI cardiac imaging are currently available. This study was designed to assess the accuracy of quantitative adenosinerest ^99mTc-labeled MIBI tomography in the diagnosis and localization of CAD.

Methods and Results

Fifty-seven consecutive patients with suspected CAD who underwent coronary angiography and 22 normal volunteers were studied. All patients underwent ^99mTc-labeled MIBI tomography after administration of adenosine (140 μg/kg intravenously for 6 minutes) and at rest. A total of 171 vascular coronary territories were analyzed quantitatively. All patients with CAD (≥50% luminal stenosis) (n=55) had abnormal ^99mTc-labeled MIBI tomograms. The normalcy rate was 86% by quantitative analysis. Overall sensitivity, specificity, and diagnostic accuracy for detection of individual stenosed vessels were 84%, 87%, and 85%, respectively. In patients with one-vessel CAD (n=24), sensitivity and diagnostic accuracy in the detection of individual stenosed vessels were significantly (p<0.05) higher compared with patients with multivessel CAD (n=31). Moreover, 75% of patients with one-vessel disease showed a scintigraphic pattern characterized by the presence of perfusion defects in only one coronary artery territory, and 74% of patients with multivessel disease showed a scintigraphic pattern characterized by the presence of perfusion defects in two or more coronary artery territories. Sensitivity, specificity, and diagnostic accuracy for detecting individual diseased vessels were similar in patients without previous myocardial infarction (n=18) compared with those with previous myocardial infarction (n=39). In myocardial territories related to noninfarcted areas (n=124), sensitivity and specificity in the detection of stenosed vessels were 75% and 88%. In infarcted areas (n=47), sensitivity and specificity in the detection of stenosed vessels were 98% and 80% (differences not significant vs noninfarcted areas).

Conclusions

Adenosine-controlled coronary vasodilation combined with quantitative ^99mTc-labeled MIBI tomography is accurate for identifying patients with CAD and localizing individual stenosed coronary arteries.     

Quantitative exercise technetium-99m tetrofosmin myocardial tomography for the identification and localization of coronary artery disease

The aim of this study was to evaluate the accuracy of quantitative 1-day exercise-rest technetium-99m tetrofosmin tomography in the identification of patients with coronary artery disease (CAD) and in the detection of individual stenosed coronary vessels. Sixty-one patients with suspected CAD who underwent coronary angiography and 13 normal volunteers were studied. All patients were submitted to two i.v. injections of^99mTc-tetrofosmin, one at peak exercise (370 MBq) and the other (1110 MBq) at rest 3 h after exercise (images 15–30 min after injection for both studies). All patients with CAD (0% luminal stenosis) (n=50) had an abnormal^99mTc-tetrofosmin tomogram. Only one patient without significant coronary narrowing showed abnormal findings. Overall sensitivity, specificity and diagnostic accuracy in the detection of individual stenosed vessels were 77%, 93% and 85%, respectively. Sensitivity and diagnostic accuracy in the identification of individuals stenosed coronary vessels were significantly higher (P<0.05) in patients with single-vessel disease (n=21) than in those with multivessel disease (n=29). Sensitivity, specificity and accuracy for detecting individual diseased vessels were similar in patients without previous myocardial infarction (n=26) and in those with previous myocardial infarction (n=35). In myocardial territories related to non-infarcted areas (n=128), sensitivity and specificity in the detection of stenosed vessels were 70% and 95%, respectively. In infarcted areas (n=55), sensitivity and specificity in the detection of stenosed vessels were 85% (P=NS vs non-infarcted areas) and 75% (P<0.05 vs non-infarcted areas), respectively. Finally, sensitivity was significantly lower (P<0.05) in vascular territories supplied by vessels with moderate stenosis (50%–75%) than in those supplied by vessels with severe stenosis (>75%). The results of this study demonstrate that quantitative 1-day exercise-rest^99mTc-tetrofosmin single-photon emission tomographic imaging is a suitable and accurate technique to identify patients with CAD and to detect individual stenosed coronary vessels.     

Primary gastric lymphoid proliferations: immunological criteria to distinguish gastric lymphoma from reactive hyperplasia.

A group of six patients with a marked gastric lymphoid "hyperplasia", two of these with generalised lymphoma and the others suspected for primary gastric lymphoma, were investigated to discriminate between simple reactive hyperplasias and lymphomatous proliferations. Microscopical and ultrastructural examinations were not useful for this purpose but immunological data can give evidence of a two-fold nature of gastric lymphoid hyperplasia. Some cases are without immunological disorders, others are met with peripheral blood signs of immunological alterations similar to those observed in malignant lymphomas and in chronic lymphocytic leukemia. Only these latter cases should, in our opinion, be regarded as primitive gastric lymphomas.     

Addition of sodium bicarbonate to lidocaine decreases the duration of peripheral nerve block in the rat

BACKGROUND: Adding sodium bicarbonate to lidocaine to enhance its efficacy during peripheral nerve block is controversial. The authors studied the effect of adding sodium bicarbonate to lidocaine with and without epinephrine versus equivalent alkalinization by sodium hydroxide (NaOH) on onset, degree, and duration of peripheral nerve block. METHODS: Part I examined alkalinization by sodium bicarbonate versus NaOH to pH 7.8 on 0.5% lidocaine, with and without epinephrine (1:100,000), prepared from crystalline salt. Part II examined 0.5% and 1.0% commercial lidocaine solutions, with and without epinephrine, either unalkalinized or alkalinized with sodium bicarbonate or NaOH. With NaOH, pH was adjusted to 7.8, but with sodium bicarbonate, no pH adjustments were made to simulate clinical conditions. RESULTS: In part I, addition of either NaOH or sodium bicarbonate to 0.5% lidocaine without epinephrine produced a faster onset than did unalkalinized lidocaine, without effecting degree or duration of block. In solutions with epinephrine there were no differences in onset, degree, or duration between lidocaine alkalinized with sodium bicarbonate versus NaOH. In part II, addition of sodium bicarbonate or NaOH to 1.0% commercial lidocaine without epinephrine did not accelerate onset compared with the unalkalinized solution. However, adding sodium bicarbonate decreased the degree and duration of block by 25% and more than 50%, respectively, compared with lidocaine unalkalinized and alkalinized with NaOH. With epinephrine, sodium bicarbonate hastened onset without effecting degree and duration compared with the unalkalinized solution. CONCLUSIONS: With 1% commercial lidocaine without epinephrine, sodium bicarbonate decreases the degree and duration of block. However, in solutions with epinephrine, sodium bicarbonate hastens onset, without effecting degree or duration.     

Signaling modulation of bile salt-induced necrosis in isolated rat hepatocytes.

Hydrophobic bile salts induce either necrosis or apoptosis depending on the severity of the injury caused by them. Since bile salt-induced apoptosis is influenced by Ca2+- and protein kinase-signaling pathways, and both necrosis and apoptosis share common initiating mechanisms, we analyzed whether these signaling cascades also influence bile salt-induced necrosis in isolated rat hepatocytes. Taurochenodeoxycholate (TCDC, 0.25-1.50 mM, 2 h) reduced, in a dose-dependent manner, the percentage of viable hepatocytes, and increased the release of the cytosolic enzyme, lactate dehydrogenase (LDH) and alanine aminotransferase (ALAT), and that of the plasma membrane enzyme, alkaline phosphatase (AP). The PKC inhibitors, H7 (100 microM) and chelerythrine (2.5 microM), both prevented significantly TCDC-induced necrosis. On the contrary, the PKA activator, dibutyryl-cAMP, exacerbated TCDC-induced cell damage in a dose-dependent manner; this effect was more likely due to cAMP-mediated PKA activation, as the PKA inhibitor, KT5720 (1 microM), counteracted this effect. Instead, the intracellular Ca2+ chelator, BAPTA/AM (20 microM), was without effect. TCDC (1 mM) increased lipid peroxidation from 0.7 +/- 0.2 to 7.5 +/- 0.9 nmol of malondialdehyde per mg of protein, p < 0.001; the addition of the free radical scavenger, diphenyl-p-phenylendiamine, completely blocked this increase and prevented significantly TCDC-induced necrosis. PKC inhibition induced only a slight attenuation of TCDC-induced lipid peroxidation. Possible mechanisms accounting for the modulatory effect of signal transduction pathways on TCDC-induced necrosis, including signaling influence on TCDC transport events and TCDC-induced oxidative stress, are discussed.     

Use of the Location-Based Social Networking Application GRINDR as a Recruitment Tool in Rectal Microbicide Development Research

Mobile phone social networking applications such as GRINDR are potential tools for recruitment of men who have sex with men (MSM) for HIV prevention research. Demographics and sexual risk behaviors of men recruited through GRINDR and through traditional media were compared. GRINDR participants were younger (mean age 31 vs. 42, p?<?0.0001), more White identified (44 vs. 30?%, p?<?0.01), and had more sex partners in the previous 14 days (1.88 vs. 1.10, p?<?0.05) than other recruits. Email responses were less successful for enrollment than phone calls (5 vs. 50?%). This approach resulted in successful recruitment of younger and more educated, White identified MSM.