Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle

To determine the relationship between circulating metabolic fuels and their local concentrations in peripheral tissues we measured glycerol, glucose, and amino acids by microdialysis in muscle and adipose interstitium of 10 fasted, nonobese human subjects during (a) baseline, (b) euglycemic hyperinsulinemia (3 mU/kg per min for 3 h) and, (c) local norepinephrine reuptake blockade (NOR). At baseline, interstitial glycerol was strikingly higher (P < 0.0001) in muscle (3710 microM) and adipose tissue (2760 microM) compared with plasma (87 microM), whereas interstitial glucose (muscle 3.3, fat 3.6 mM) was lower (P < 0.01) than plasma levels (4.8 mM). Taurine, glutamine, and alanine levels were higher in muscle than in adipose or plasma (P < 0.05). Euglycemic hyperinsulinemia did not affect interstitial glucose, but induced a fall in plasma glycerol and amino acids paralleled by similar changes in the interstitium of both tissues. Local NOR provoked a fivefold increase in glycerol (P < 0.001) and twofold increase in norepinephrine (P < 0.01) in both muscle and adipose tissues. To conclude, interstitial substrate levels in human skeletal muscle and adipose tissue differ substantially from those in the circulation and this disparity is most pronounced for glycerol which is raised in muscle as well as adipose tissue. In muscle, insulin suppressed and NOR increased interstitial glycerol concentrations. Our data suggest unexpectedly high rates of intramuscular lipolysis in humans that may play an important role in fuel metabolism.     

Two-year experience with rate-modulated pacing controlled by mixed venous oxygen saturation

Mixed venous oxy-hemoglobin saturation (MVO2) is a physiological variable with several features that might be desirable as a control parameter for rate adaptive pacing. Despite these desirable characteristics, the long-term reliability of the MVO2 sensor in vivo is uncertain. We, therefore, designed a study to prospectively evaluate the long-term performance of a permanently implanted MVO2 saturation sensor in patients requiring VVIR pacing. Under an FDA approved feasibility study, eight patients were implanted with a VVIR pulse generator and a right ventricular pacing lead incorporating an MVO2 sensor. In order to accurately assess long-term stability of the sensor, patients underwent submaximal treadmill exercise using the Chronotropic Assessment Exercise Protocol (CAEP) at 2 weeks, 6 weeks, and 3, 6, 9, 12, 18, and 24 months following pacemaker implantation. Paired maximal exercise testing using the CAEP was also performed with the pacing system programmed to the VVI and VVIR modes in randomized sequence with measurement of expired gas exchange after 6 weeks and 12 months of follow-up. During maximal treadmill exercise the peak exercise heart rate (132 +/- 9 vs 71.5 +/- 5 beats/min, P < 0.00001) and maximal rate of oxygen consumption (1,704 +/- 633 vs 1382 +/- 407 mL/min, P = 0.01) were significantly greater in the VVIR than in the VVI pacing mode. Similarly, the duration of exercise was greater in the VVIR than the VVI pacing mode (8.9 +/- 3.6 min vs 7.6 +/- 3.7 min, P = 0.04). The resting MVO2 and the MVO2 at peak exercise were similar in the VVI and VVIR pacing modes (P = NS). However, the MVO2 at each comparable treadmill exercise stage was significantly higher in the VVIR mode than in the VVI mode (CAEP stage 1 (P = 0.005), stage 2 (P = 0.04), stage 3 (P = 0.008), and stage 4 (P = 0.04). The correlation between MVO2 and oxygen consumption (VO2) was excellent (r = -0.93). Telemetry of the reflectance of red and infrared light and MVO2 in the right ventricle during identical exercise workloads revealed no significant change over the first 12 months of follow-up (ANOVA, P = NS). The chronotropic response to exercise remained proportional to VO2 in all patients over the first 12 months of follow-up. The time course of change in MVO2 during maximal exercise was significantly faster than for VO2. At the 18- and 24-month follow-up exercise tests, a significant deterioration of the sensor signal with attenuation of chronotropic response was noted for 4 of the 8 subjects with replacement of the pacing system required in one patient because of lack of appropriate rate modulation. Rate modulated VVIR pacing controlled by right ventricular MVO2 provides a chronotropic response that is highly correlated with VO2. This parameter responds rapidly to changes in workload with kinetics that are more rapid than those of VO2. Appropriate rate modulation provides a higher MVO2 at identical workloads than does VVI pacing. Although the MVO2 sensor remains stable and accurate over the first year following implantation, significant deterioration of the signal occurs by 18-24 months in many patients.     

Ultrasound screening for deep venous thrombosis after total knee arthroplasty. 2-year reassessment

The efficacy of ultrasound compared with ascending venography for the detection of deep venous thrombosis immediately after total knee arthroplasty was assessed after a 2-year interval. One hundred thirty-seven patients were eligible for the study; however, 31 patients received only one of the screening methods and a color Doppler examination was inconclusive in six patients. Therefore, 100 patients had a Doppler examination and a venogram. Overall, the sensitivity of ultrasound was 85%, the specificity 97%, the positive predictive value 85%, the negative predictive value 97%, and the accuracy 95%. The sensitivity in the calf was 83%, in the popliteal vein 86%, and in the femoral vein 100%. Two years ago, the initial assessment of ultrasound for the detection of deep venous thrombosis after surgery in patients who had total joint arthroplasty revealed a 75% sensitivity, 99% specificity, 91% positive predictive value, 97% negative predictive value, and 97% accuracy. The sensitivity in the calf was 83%; the sensitivity in the popliteal vein was 40%; and the sensitivity in the femoral vein was 50%. After 2 years of using this screening test with one technician and one radiologist, an improvement with this noninvasive technique was shown. However, it was found that Doppler imaging is not as sensitive as venography for detecting calf thrombi. Any imaging technique should be validated by each institution to determine the validity of the instrument and the learning curve of the technician administering the examination.     

Impact of gender on coronary bypass operative mortality

I examine trends in single mothers' living arrangements using data from the 1970-1995 Current Population Surveys. I create a consistent trend by correcting a coding problem that stemmed from the misidentification of children living in multigenerational households before 1984. Revised estimates show that the number of single mothers in each of these years was undercounted by 200,000-300,000. All of these women were subfamily heads living with their parents, and the problem occurred disproportionately among teens and black women. The uncorrected trend falsely indicates a large increase in the share of single mothers living with their parents. In reality, there was little change in the percentage of single mothers living in this arrangement over the time period. However, the data indicate a large increase in the rate of cohabitation and a comparable decline in the rate of living independently among this population.     

Major histocompatibility complex class I presentation of exogenous soluble tumor antigen fused to the B-fragment of Shiga toxin

Targeting exogenous antigen into the MHC class I-restricted presentation pathway is a prerequisite for the induction of cytotoxic T lymphocytes (CTL) which have been shown to represent an important component of the protective and therapeutic immune response to viral infections and tumors. In this study, we produced recombinant proteins composed of the receptor-binding non-toxic B-fragment of bacterial Shiga toxin derived from Shigella dysenteriae associated with an epitope from a model tumor antigen, Mage 1. We show that Shiga B-Mage 1 fusion proteins carrying an active or inactive endoplasmic reticulum retrieval signal (the C-terminal peptides KDEL or KDELGL, respectively) could be presented by peripheral blood mononuclear cells in an MHC class I-restricted manner to Mage 1-specific CTL. After pulsing B lymphoblastoid cells or dendritic cells with Shiga B-Mage 1 fusion protein, activation of the MHC class I-restricted Mage 1-specific CTL was also demonstrated. In further analysis, we showed that treatment with brefeldin A or paraformaldehyde fixation of Epstein-Barr virus-transformed B cells prevented the presentation of the Mage 1 T cell epitope, which excluded extracellular processing of the antigen. Immunofluorescence analysis also revealed that the Shiga B-Mage 1 fusion protein was largely excluded from Lamp-2-positive lysosomal structures. Therefore, the ability of Shiga toxin B-fragment to target dendritic cells and B cells and to direct antigen into the exogenous class I-restricted pathway makes it an attractive non-living and non-toxic vaccine vector.     

Diagnostic significance of 'benign pairs' and signet ring cells in fine needle aspirates (FNAs) of the breast

Most breast mass lesions are readily characterized by FNA with cytodiagnosis. Occasionally, benign but markedly proliferative lesions are diagnostically difficult to separate from well differentiated malignancies. We present information pertaining to the diagnostic significance of two cytologic findings observed in breast aspiration specimens, namely pairs of stripped bipolar nuclei and signet ring cells (SRC). We have evaluated aspirate smears from 219 cases of histologically proven benign (n = 114) and malignant (n = 105) breast lesions. Both singlets and pairs of bipolar nuclei and SRC were enumerated, and their numbers were correlated to histological diagnosis. Closely associated pairs of stripped bipolar nuclei were found in 68% of benign lesions compared with only 3.8% of carcinomas, establishing their presence as a highly specific indicator of a benign process. Large numbers of such 'benign pairs' also favoured the diagnosis of fibroadenoma. SRC were identified in 66% of histologically proven carcinomas (67% of ductal and 70% of lobular). SRC were also present in 10% of histologically benign cases. In the malignant cases, SRC were most frequently noted in a single cell distribution or within small, loosely cohesive tissue fragments. In the benign instances, SRC were most commonly noted within large fragments, and many of these cells were proved by immunohistochemical reactions to be vacuolated myoepithelial cells. We conclude that the presence of bipolar nuclei in closely associated pairs suggests benignity and aids in the subclassification of benign breast masses. In addition, the presence of SRC does not aid in the classification of tumour subtype (ductal vs lobular), and the occurrence of such cells in the proper context should prompt surgical biopsy.