Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo.

Killer lymphocytes play a major role in host defense against tumors and infectious diseases. Previously, we reported that delta-9-tetrahydrocannabinol (THC) and II-hydroxy-delta-9-tetrahydrocannabinol (II-hydroxy-THC) suppressed the cytolytic activity of cultured natural killer (NK) cells. Also, we showed that the drugs appeared to be affecting a stage in the killing process subsequent to the binding of the killer cell to the target cell. In the present report, we have extended these studies to an examination of the effect of cannabinoids on the activity of cytotoxic T lymphocytes (CTLs). The cytolytic activity of CTLs generated by cocultivation with either allospecific stimulators or TNP-modified-self stimulators were suppressed by both THC and II-hydroxy-THC treatment. Allospecific CTLs generated in vivo were also inhibited by an in vitro exposure to either THC or II-hydroxy-THC, and the sensitivity of these cells to drug effects appeared to be greater than the sensitivity of the in vitro generated CTLs. Suppression of cytolytic function by THC and II-hydroxy-THC was maximal after a 4-h drug treatment, suggesting that the drug effects were inducible and therefore required a finite period of time to develop maximally. As seen in previous studies involving NK cells, drug treatment of mature CTLs appears to have little effect on the binding capacity of these cells for the target. However, the maximal killing capacity of the cells and the frequency of CTLs were significantly reduced by drug treatment. In addition to suppressing the cytolytic activity of mature effector CTLs, we also show that drug treatment inhibits both the proliferation of lymphocytes responding to an allogeneic stimulus and the maturation of these lymphocytes to mature CTLs. Similarly, CTL activity developing in vivo could be inhibited by THC injection. These results suggest that CTLs are inhibited by cannabinoids by at least two mechanisms. First, the cytolytic activity of mature killers is suppressed at some point beyond the binding to the target cell. Second, the cannabinoids appear to suppress the normal development of these mature effector cells from less mature precursor cells.     

Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy.

PURPOSE: A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP. METHODS: Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy. RESULTS: The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < .0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = .030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79. CONCLUSION: We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.     

Significance of coupling intervals of spontaneous ventricular arrhythmias in long-term ECG in patients with coronary heart disease

Coupling intervals of premature ventricular beats and complex arrhythmias were studied by 24-h ambulatory electrocardiographic recordings in 76 patients (35 sudden death patients and 41 survivors) with coronary artery disease. A first Holter (HM 1) was recorded at the time of left ventricular angiography and a second Holter (HM 2) after a mean interval of 34.4 +/- 11.2 months (range 2-61 months). All patients were only treated medically. The mean heart rate was significantly faster in patients who died suddenly than in survivors in both HM 1 and HM 2 (p less than 0.01). In HM 1, there were no significant differences in mean coupling intervals between patients who died suddenly and survivors, whereas in HM 2, coupling intervals of premature ventricular beats and couplets were significantly shorter in patients who died suddenly than in survivors (p less than 0.05). Patients with coupling intervals for couplets less than 500 ms died significantly earlier than those patients with coupling intervals greater than 500 ms (p less than 0.05). Our data show that there is a relationship between heart rate, coupling intervals and sudden death. Patients with fast heart rates and coupling intervals for couplets less than 500 ms represent a group at high risk of sudden death.     

Atypical extraspinal musculoskeletal tuberculosis in immunocompetent patients: part II, tuberculous myositis, tuberculous bursitis, and tuberculous tenosynovites.

Tuberculosis involving the soft tissue from adjacent bone or joint is well recognized. However, primary tuberculous pyomyositis, tuberculous bursitis, and tuberculous tenosynovitis are rare entities constituting 1% of skeletal tuberculosis. Tuberculous tenosynovitis involves most commonly the tendon sheaths of the hand and wrist, and tuberculous bursitis occurs most commonly around the hip. The greater trochanteric bursa and the greater trochanter are the most frequent sites of tuberculous bursitis. Cases of primary tuberculous pyomyositis and tenosynovitis of the tendons of the ankle and foot are seldom reported in the radiology literature. All imaging modalities-plain radiography, bone scan, computed tomography, and magnetic resonance imaging (MRI)--provide information that is helpful in determining therapy. MRI in particular, with its multiplanar capabilities and superb contrast of soft tissue, can demonstrate the extent of the soft tissue mass and access the adjacent bones and joints. However, MRI has no diagnostic specificity in regard to tuberculosis, and in nonendemic areas, biopsy is strongly recommended. All patients in this review were permanent residents of North America or Western Europe and were immunocompetent. Examples of atypical presentations of the above entities are demonstrated.     

Body fat in normal adults estimated by oxygen-18- and deuterium-dilution and by anthropometry: a comparison

We estimated body fat in 20 normal adults (10 males and 10 females) from 18O- and 2H-dilution spaces and from the equations of Durnin & Womersley and Pollock, Schmidt & Jackson based on skinfold thickness measurements. Differences between methods for body fat estimation were found to be sex-dependent: subsequent analyses indicated significant differences between methods within each sex. Regardless of sex, the highest fat estimates were obtained with the 18O-dilution method, followed by those obtained with the 2H-dilution method or the Durnin & Womersley equation. The lowest fat estimates were obtained using the Pollock, Schmidt & Jackson equation. The 18O-dilution method and the Durnin & Wormersley anthropometric method are both suitable and appropriate for body fat estimation in adults studied under field conditions.     

Voltage dependence of the pattern and frequency of discrete Ca2+ release events after brief repriming in frog skeletal muscle

Applying a brief repolarizing pre-pulse to a depolarized frog skeletal muscle fiber restores a small fraction of the transverse tubule membrane voltage sensors from the inactivated state. During a subsequent depolarizing test pulse we detected brief, highly localized elevations of myoplasmic Ca²⁺ concentration (Ca²⁺ “sparks”) initiated by restored voltage sensors in individual triads at all test pulse voltages. The latency histogram of these events gives the gating pattern of the sarcoplasmic reticulum (SR) calcium release channels controlled by the restored voltage sensors. Both event frequency and clustering of events near the start of the test pulse increase with test pulse depolarization. The macroscopic SR calcium release waveform, obtained from the spark latency histogram and the estimated open time of the channel or channels underlying a spark, exhibits an early peak and rapid marked decline during large depolarizations. For smaller depolarizations, the release waveform exhibits a smaller peak and a slower decline. However, the mean use time and mean amplitude of the individual sparks are quite similar at all test depolarizations and at all times during a given depolarization, indicating that the channel open times and conductances underlying sparks are essentially independent of voltage. Thus, the voltage dependence of SR Ca²⁺ release is due to changes in the frequency and pattern of occurrence of individual, voltage-independent, discrete release events.     

Comparison of energy expenditure estimated in healthy infants using the doubly labelled water and energy balance methods

The doubly labelled water method was used to estimate energy expenditure in 20 formula-fed infants (10 aged 1 month and 10 aged 4 months). We then compared the energy expenditure values with energy balance values calculated from energy intake and energy cost of growth. Our purpose was to compare various published equations for calculating CO2 expiration rates (and thus energy expenditure values) from the isotopic data. Those equations in which we used measured values for 18O and 2H isotope dilution spaces and estimated or measured values for insensible water losses yielded energy expenditure values (69.7 +/- 8.4 kcal/kg/d) that agreed most closely with energy balance data (70.3 +/- 11.9 kcal/kg/d). Equations in which we used a constant ratio of 1.03 between the 2H and 18O isotope dilution spaces resulted in energy expenditure values (66.3 +/- 10.2 kcal/kg/d) lower than those predicted by the energy balance data. Data analysis by nonlinear curve fitting compared to logarithmic transformation did not alter the estimates of energy expenditure obtained in these infants.