Evaluation of [11C]GB67, a novel radioligand for imaging myocardial α1-adrenoceptors with positron emission tomography

Dysfunction of the sympathetic nervous system underlies a number of myocardial disorders. Positron emission tomography (PET) offers a way of assessing receptor function non-invasively in humans, but there are no PET radioligands for assessing myocardial α-adrenoceptors. GB67, a structural and pharmacological analogue of the α₁-adrenoceptor antagonist prazosin, was labelled with positron-emitting carbon-11 (t _1/2=20.4 min) by ¹¹C-methylation of N-desmethylamido-GB67 (GB99). [¹¹C]GB67 was injected intravenously into conscious rats. Serial arterial blood samples were taken. Rats were killed and tissues removed to determine radioactivity. The percentages of unchanged [¹¹C]GB67 and its radioactive metabolites in plasma and tissues were assessed by HPLC. Plasma clearance of radioactivity was rapid. Myocardial uptake was maximal at 1–2 min and decreased slowly during 60 min. Predosing with adrenoceptor antagonists demonstrated selectivity for myocardial α₁-adrenoceptors. GB67 and prazosin blocked uptake of radioactivity; the non-selective antagonist, phentolamine, partially blocked uptake; the α₂-adrenoceptor antagonist, RX 821002, only blocked uptake at high dose and the β-adrenoceptor antagonist, CGP 12177, had no effect. Additionally, injection of prazosin at 20 min after radioligand displaced radioactivity. In vivo competition curves obtained by injecting [¹¹C]GB67 with varying amounts of either unlabelled GB67 or its precursor GB99 were fitted to a competitive binding model to provide estimates of the maximum number of binding sites (B _max) and half saturation doses (K) for myocardium. Assuming a tissue protein content of 10%, the values of B _max [∼13 pmol·(g tissue)^–1] were similar to those [50–170 fmol·(mg protein)^–1] reported for myocardial α₁-adrenoceptors assessed in vitro. Both GB67 and its precursor GB99 had high affinity for α₁-adrenoceptors [K _GB67=1.5 nmol·(kg body weight)^–1, K _GB99=4.8 nmol· (kg body weight)^–1]. HPLC demonstrated four radioactive metabolites in plasma. [¹¹C]GB67 was 80% of the radioactivity at 5 min and 50% at 45 min. No radioactive metabolites were detected in myocardium up to 60 min after injection. [¹¹C]GB67 was assessed in two male human volunteers. PET demonstrated high myocardial uptake. The profile of radioactive metabolites in plasma was comparable to that in the rat, although metabolism was slower in humans. Thus, [¹¹C]GB67 is a promising radioligand for assessing α₁-adrenoceptors in human myocardium with PET. Received 7 May and in revised form 9 August 1999     

Geriatric hemodialysis rehabilitation care

The 2 objectives of this review are to provide background information about functional status in older dialysis patients and to discuss the utility of geriatric dialysis rehabilitation. We performed a literature search using PubMed and MedLine. All relevant texts were reviewed for information on functional status and disability in the renal population and in the general population. Data pertaining to geriatric rehabilitation and geriatric dialysis rehabilitation were also reviewed. We show how disability and functional limitations are more prevalent in populations with advanced stages of chronic kidney disease (CKD) compared with those with only mild stages of CKD. We describe data showing that dedicated geriatric dialysis rehabilitation units, using interdisciplinary care models, result in more than 70% of patients meeting their rehabilitation goals and being successfully discharged home. Nephrologists increasingly will be faced with problems arising from functional decline. We conclude by offering suggestions for future changes that may help to stem the rising tide of dialysis disability.     

Identifying injuries and motor vehicle collision characteristics that together are suggestive of diaphragmatic rupture

BACKGROUND: Diaphragmatic rupture (DR) remains a diagnostic challenge because of the lack of an accurate test demonstrating the injury. Our purpose was to identify motor vehicle collision (MVC) characteristics and patient injuries that collectively could identify the presence of a DR. METHODS: The National Automotive Sampling System was used to identify occupants involved in MVCs from 1995 to 1999 who sustained abdominal (Abbreviated Injury Scale score >or= 2) and/or thoracic injuries (Abbreviated Injury Scale score >or= 2). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to quantify the association between patient injuries, vehicle collision characteristics, and DR. Sensitivity and specificity were also calculated to determine the ability of organ injury and MVC characteristics to correctly classify patients with and without DR. RESULTS: Overall, occupants sustaining a DR had a significantly higher delta-V (DeltaV) (49.8 kilometers per hour [kph] vs. 33.8 kph, p< 0.0001) and a greater degree of occupant compartment intrusion (70.6 cm vs. 48.3 cm, p< 0.0001). Specific abdominal and thoracic organ injuries were associated with DR, including thoracic aortic tears (OR, 5.2; 95% CI, 2.2-12.5), splenic injury (OR, 8.4; 95% CI, 3.9-17.8), pelvic fractures (OR, 4.7; 95% CI, 2.7-8.0), and hepatic injuries (OR, 4.2; 95% CI, 1.7-10.6). Combining frontal or near-side lateral occupant compartment intrusion >or= 30 cm or DeltaV >or= 40 kph with specific organ injuries generated a sensitivity for indicating the likelihood of diaphragm injury ranging from 68% to 89%. Patients with any of the following characteristics had a sensitivity for detecting DR of 91%: splenic injury, pelvic fracture, DeltaV >or= 40 kph, or occupant compartment intrusion from any direction >or= 30 cm. CONCLUSION: Specific MVC characteristics combined with patient injuries have been identified that are highly suggestive of DR. For this subpopulation, additional invasive procedures including exploratory laparotomy, laparoscopy, or thoracoscopy may be warranted to exclude DR.     

GIV/Girdin Links Vascular Endothelial Growth Factor Signaling to Akt Survival Signaling in Podocytes Independent of Nephrin

Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Gα–interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Gαi3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Gαi3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Gαi3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases.     

Role of Fusion of Prone FDG‐PET and Magnetic Resonance Imaging of the Breasts in the Evaluation of Breast Cancer

Abstract: The purpose of this study is to report further about the statistically significant results from a prospective study, which suggests that fusion of prone F‐18 Fluoro‐deoxy‐glucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) breast scans increases the positive predictive value (PPV) and specificity for patients in whom the MR outcome alone would be nonspecific. Thirty‐six women (mean age, 43 years; range, 24–65 years) with 90 lesions detected on MR consented to undergo a FDG‐PET scan. Two blinded readers evaluated the MR and the computer tomography (CT) attenuation‐corrected prone FDG‐PET scans side‐by‐side, then after the volumes were superimposed (fused). A semiautomatic, landmark‐based program was used to perform nonrigid fusion. Pathology and radiologic follow‐up were used as the reference standard. The sensitivity, specificity, PPV, negative predictive value (NPV), and accuracy (with 95% confidence intervals) for MR alone, FDG‐PET alone, and fused MR and FDG‐PET were calculated. The median lesion size measured from the MR was 2.5 cm (range, 0.5–10 cm). Histologically, 56 lesions were malignant, and 15 were benign. Nineteen lesions were benign after 20–47 months of clinical and radiologic surveillance. The sensitivity of MR alone was 95%, FDG‐PET alone was 57%, and fusion was 83%. The increase in PPV from 77% in MR alone to 98% when fused and the increase in specificity from 53% to 97% were statistically significant (p < 0.05). The false‐negative rate on FDG‐PET alone was 26.7%, and after fusion this number was reduced to 9%. FDG‐PET and MR fusions were helpful in selecting which lesion to biopsy, especially in women with multiple suspicious MR breast lesions.     

Erythropoietin response to anaemia is not altered by surgery or recombinant human erythropoietin therapy

Summary. Recombinant human erythropoietin (EPO) therapy has been shown to increase red blood cell (RBC) production and facilitate autologous blood donation before elective surgery. However, recent reports have suggested that surgery and/or EPO therapy may suppress endogenous erythropoietin secretion in response to anaemia. We therefore analysed the haemoglobin/erythropoietin relationship preoperatively and postoperatively in 71 autologous blood donors subjected to aggressive phlebotomy and six treatments with either EPO (150U/kg, n=16, 300U/kg, n=18, or 600 U/kg, n=19) or placebo (n=18). Using data from the three prepoerative study visit, the linear relationship between log erythropoietin and haemoglobin was determined for each of the 18 placebo patients. We found no significant differences in the slopes of the relationships in this group during aggressive phlebotomy. Furthermore, there was no evidence of a significant difference in the erythropoietin level recorded postoperatively for each patient to that predicted from the patient's postoperative haemoglobin level, based on the haemoglobin/log erythropoietin relationship preoperatively. Similarly, for each of the EPO-treated groups, there was no evidence of a significant difference when comparing the recorded erythropoietin level to that predicted from each patient's postoperative haemoglobin level, based on the haemoglobin/log erythropoietin relationship preoperatively. We conclude that preoperative recombinant human erythropoietin therapy and/or surgery do not adversely affect the postoperative erythropoietin response to anaemia.