In Vivo Effects of Dexmedetomidine on Laser-Doppler Flow and Pial Arteriolar Diameter

Background: The alpha2 -adrenergic agonist dexmedetomidine alters global cerebral blood flow (CBF). However, few studies have investigated the action of dexmedetomidine on the cerebral microcirculation. This investigation examined the effects of dexmedetomidine on (1) regional CBF in the rat cerebral cortex using laser-Doppler flowmetry and (2) on pial arteriolar diameter.

Methods: Halothane-anesthetized rats were fitted with instruments to measure CBF as determined by laser-Doppler flow (CBFldf) or to measure pial arteriolar diameter by preparing a cranial hollow deepened until a translucent plate of skull remained, thereby maintaining the integrity of the cranial vault. In both groups, 20 micro gram/kg dexmedetomidine was infused intravenously. Thirty minutes later, the mean arterial pressure was restored to control values with an infusion of phenylephrine (0.5 to 5 micro gram/kg/min).

Results: Administration of dexmedetomidine was associated with decreases in end-tidal and arterial carbon dioxide. The CBFldf and pial arteriolar diameter were measured during normocapnia (controlled carbon dioxide) and during dexmedetomidine-induced hypocapnia. Intravenous administration of dexmedetomidine significantly decreased systemic arterial pressure concurrent with a decrease in CBFldf (22% in normocapnic animals, 36% in hypocapnic animals). Restoration of mean arterial pressure increased CBFldf in normocapnic but not in hypocapnic animals. Similarly, dexmedetomidine significantly reduced pial vessel diameter in both normocapnic (9%) and hypocapnic animals (17%). However, vessel diameters remained decreased in the normocapnic and hypocapnic animals after the mean arterial pressure was restored.     

SPECT of serotonin transporters using 123I-ADAM: optimal imaging time after bolus injection and long-term test-retest in healthy volunteers.

(123)I-ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)-5-(123)I-iodophenylamine) has been recently proposed as a new serotonin transporter (SERT) ligand for SPECT. The objective of this study was to characterize (123)I-ADAM in healthy volunteers. (123)I-ADAM distribution in the normal brain, pseudoequilibrium interval after a single injection, normal specific uptake values, and long-term test-retest variability and reliability were investigated. METHODS: Ten healthy volunteers underwent 2 SPECT sessions under the same conditions 47.6 +/- 24.0 d apart. Scans were sequentially acquired from the time of (123)I-ADAM intravenous injection up to 12 h after injection. Regions of interest (ROIs) for cerebellum (C), midbrain, thalamus, striatum, mesial temporal region, and cortex were drawn on MR images and pasted to corresponding SPECT slices after coregistration. Specific uptake ratios (SURs) at pseudoequilibrium and the simplified reference tissue model (SRTM) methods were used for quantification. SURs were obtained as ([region - C]/C) at each time point. Test-retest variability and reliability (intraclass correlation coefficient [ICC]) were calculated. RESULTS: The highest (123)I-ADAM specific uptake was found in the midbrain and thalamus, followed by the striatum and mesial temporal region. Quantification results using SUR and SRTM were correlated with R = 0.93 (test) and R = 0.94 (retest). SURs remained stable in all regions from 4 to 6 h after injection. Using SUR, test-retest variability/ICC were 13% +/- 11%/0.74 in midbrain, 16% +/- 13%/0.63 in thalamus, 19% +/- 18%/0.62 in striatum, and 22% +/- 19%/0.05 in mesial temporal region. CONCLUSION: (123)I-ADAM accumulates in cerebral regions with high known SERT density. The optimal imaging time for (123)I-ADAM SPECT quantification is suggested to be from 4 to 6 h after a single injection. Long-term test-retest variability and reliability found in the midbrain are comparable to that reported with other (123)I-labeled SPECT ligands. These results support the use of (123)I-ADAM SPECT for SERT imaging after a single injection in humans.     

Squamous cell carcinoma of the renal pelvis presenting as duodenal obstruction

A 78-year-old woman with duodenal obstruction was studied with plai addominal X-rays, barium examination ultrasonography, CT, and incisional biopsy. The pathologic report revealed an infiltrating squamous cell carcinoma of the renal pelvis, Palliative gastroenterostomy was performed.     

HLA antigens in spanish type 1 diabetic population. correlations with clinical,biological and autoimmune markers

Summary The HLA haplotype and its relationships with clinical, biological and immunological parameters were analyzed in a group of 87 Spanish type I diabetic patients at the clinical onset of the disease. The frequency of HLA-B18, DR3 and DR4 antigens was significantly increased whereas DR2, DR5 and DR7 were decreased in comparison with 189 healthy unrelated controls without family history of diabetes. DR3 showed a maximum relative risk for diabetes (5.5) whereas DR4 had a lower one (4.0). HLA-DR4 patients were younger at the time of diagnosis than DR4 negative (16.7vs 21.4 years). We found no statistically significant relationship between HLA antigens and the other variables studied including the presence of islet cell antibodies, complement fixing islet cell antibodies, insulin autoantibodies, organ-specific antibodies, fasting and maximal glucagon stimulated C-peptide levels, initial glycemia and glycosylated hemoglobin.     

CD34+-enriched-CD19+-depleted autologous peripheral blood stem cell transplantation for chronic lymphoproliferative disorders: high purging efficiency but increased risk of severe infections

OBJECTIVE: The main objective of this work was to decrease the incidence of relapse after autologous stem cell transplantation with a "double purging" procedure. METHODS: We used a "positive" (CD34) and "negative" (CD19) double selection method to improve the efficacy of "single purging" of hematopoietic harvests in poor-prognosis lymphoproliferative disorders. All patients included in the study had a positive molecular marker of their disease. Minimal residual disease (MRD) was studied by flow cytometry and PCR techniques during the purging procedure and after transplantation. RESULTS: Twenty-six patients fulfilled entry criteria. Median age of patients was 50 years (range: 33-66); 17 were male and 9 female. Thirteen (50%) of the patients mobilized an adequate number of CD34+ cells (>or=3 x 10(6)/kg) to proceed with the double-selection protocol. Twelve of the 13 harvests became PCR negative after purging. Ten patients were grafted with the selected products and all but one engrafted without delay. After a median follow-up of 30 months, 2 of 10 patients suffered a molecular relapse at 7 and 19 months respectively. The earlier relapse was observed in the patient who received a MRD+ product. Only one patient experienced a clinical relapse. Three patients died due to obliterans bronchiolitis, pneumococcal sepsis, and septic shock of unknown origin, respectively, and three others presented life-threatening infections. CONCLUSION: Therefore, CD34+/CD19+ positive/negative selection is an effective purging approach in patients with chronic lymphoproliferative disorders. This favorable effect is, however, counterbalanced by the high frequency of life-threatening infections.     

The role of natriuretic peptides in volume assessment and mortality prediction in Haemodialysis patients

Background

Maintaining optimal fluid balance is essential in haemodialysis (HD) patients but clinical evaluation remains problematic. Other technologies such as bioimpedance are emerging as valuable adjuncts. This study was undertaken to explore the potential utility of the natriuretic peptides – atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the assessment of fluid status and cardiovascular risk in this setting.

Methods

This was a cross-sectional study carried out in an unselected cohort of 170 prevalent HD patients. Volume status was assessed by clinical parameters – the presence or absence of peripheral oedema, raised jugular venous pressure and basal lung crepitations; by extracellular fluid volume (ECFV) status determined by whole body bioimpedance; and by serum levels of BNP and ANP (pre- and post –dialysis). The relationships of ANP and BNP levels to clinical and bioimpedance parameters of volume status was determined. Patients were followed up for 5 years to assess the relationship of natriuretic peptide levels to mortality.

Results

Bioimpedance estimates of ECFV expansion (>105 % of ideal ECFV) was present in 52 % of patients pre-dialysis. A significant proportion (21 %) of pre-dialysis patients had a depleted ECFV (<95 % of ideal ECFV) pre-dialysis. The situation was reversed post-dialysis. A raised JVP >3 cm was the most reliable clinical sign of ECFV expansion inferred from bioimpedance measurements and natriuretic peptide levels. The vast majority of patients with this sign also had lung crepitations or peripheral oedema or both. BNP was a stronger predictor of ECFV expansion than either pre- or post-dialysis ANP. BNP was also a stronger predictor of five-year survival.

Conclusion

Serum levels of BNP have a strong relationship to both volume status and survival in HD patients. We found no clear role for measurement of ANP, though changes in blood levels may be a sensitive indicator of acute changes in volume status. Whether monitoring levels of these peptides has a role in the management of volume status and cardiovascular risk requires further study.

     

A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention

Background

To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation.

Methods

We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON–OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF–ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation.

Results

We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ²₁ = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria.

Limitations

The small sample size limited the statistical power and external validity.

Conclusion

These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects.     

Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults

OBJECTIVE: To investigate the GH response to glucagon in adult patients with GH deficiency and in controls compared with the GH response to the insulin tolerance test (ITT) in patients with GH deficiency and to determine whether the use of glucagon results in a diagnostic utility test. PATIENTS AND DESIGN: Seventy-three patients with adult GH deficiency and organic hypothalamic-pituitary disease were recruited, along with 46 controls. The patients were divided into five groups according to the number of associated hormone deficiencies present. MEASUREMENTS: Hypopituitary subjects underwent assessment of GH secretory status by the ITT, the glucagon test and measurement of serum IGF-I concentration. Controls underwent the glucagon test. After the ITT, glucose and GH levels were measured at baseline, 30, 60 and 90 minutes, and after glucagon at baseline, 90, 120, 150, 180, 210 and 240 minutes. RESULTS: The highest GH value after the ITT in the patient group was 3 microg/l (0.76 +/- 0.82 microg/l), and after the glucagon test the highest GH peak value was 2.9 microg/l (0.64 +/- 0.79 microg/l). A correlation was found between the GH peak and the progressive number of hormone deficiencies. After the glucagon test, the GH peak obtained in the controls at 180 minutes was 9.8 +/- 4.6 microg/l and, on an individual basis, none of the 46 controls failed to achieve peak GH levels higher than 3 microg/l. In the controls, a negative correlation was observed between the GH response to glucagon and age (r = -0.389, P = 0.0075) and body mass index (r = -0.329, P = 0.0254). The accuracy of the glucagon test for differentiating patients from controls, estimated by receiver operating characteristics (ROC) curve methodology, showed that the cut-off of 3 microg/l for the GH peak provides 100% sensitivity and 100% specificity and is a reliable decision threshold. CONCLUSIONS: The glucagon GH test is reliable and provides a clear separation between GH-deficient and normal adults. A single glucagon test with a cut-off of 3 microg/l for the GH peak is diagnostic of GH deficiency in adults and could be considered and studied as an alternative to the ITT.     

Induction of tumor NK-cell immunity by anti-CD69 antibody therapy

The leukocyte activation marker CD69 is a novel regulator of the immune response, modulating the production of cytokines including transforming growth factor-beta (TGF-beta). We have generated an antimurine CD69 monoclonal antibody (mAb), CD69.2.2, which down-regulates CD69 expression in vivo but does not deplete CD69-expressing cells. Therapeutic administration of CD69.2.2 to wild-type mice induces significant natural killer (NK) cell-dependent antitumor responses to major histocompatibility complex (MHC) class I low RMA-S lymphomas and to RM-1 prostatic carcinoma lung metastases. These in vivo antitumor responses are comparable to those seen in CD69(-/-) mice. Enhanced host NK cytotoxic activity correlates with a reduction in NK-cell TGF-beta production and is independent of tumor priming. In vitro studies demonstrate the novel ability of anti-CD69 mAbs to activate resting NK cells in an Fc receptor-independent manner, resulting in a substantial increase in both NK-cell cytolytic activity and interferon gamma (IFNgamma) production. Modulation of the innate immune system with monoclonal antibodies to host CD69 thus provides a novel means to antagonize tumor growth and metastasis.     

The Syndrome of Veno-occlusive Disease After Blood or Marrow Transplantation

Veno-occlusive disease of the liver (VOD) was originally described in patients who drank infusions made with plants containing pyrrolizidine alkaloids [1]. This disease was characterized, histologically, by a progressive and concentric non-thrombotic narrowing of the lumina of small intrahepatic veins. Later, VOD was related to other pathogens such as alcohol, contraceptives, toxic oil, liver radiation and several antineoplastic drugs [2–3]. The first case of veno-occlusive disease following bone marrow transplantation (BMT) was reported in 1979 [4]. Since then, BMT has proved to be the main cause of VOD which is one of the leading causes of morbidity and mortality after transplant [5–7]. Clinical manifestations of VOD are very characteristic (jaundice, painful hepatomegaly and fluid retention) but indistinguishable from those produced by other regime-related morphological changes on zone 3 of the liver acinus. For this reason, the term “syndrome of veno-occlusive disease of the liver” has been adopted to designate the clinical manifestations of conditioning regimen toxicity on this zone [8]. This review focuses on the present knowledge of VOD syndrome after BMT.