Interleukin-1alpha synergistic in vivo enhancement of cyclophosphamide- and carboplatin-mediated antitumor activity

Interleukin-1alpha (IL-1alpha) has potent acute antitumor activity in vivo and can enhance the efficacy of chemotherapeutic drug-mediated antitumor responses. Studies were undertaken to examine the ability of IL-1alpha to enhance the activity of cyclophosphamide (CTX) administered in combination with carboplatin. To determine the in vivo effect of IL-1alpha, CTX and/or carboplatin, mice bearing 14-day RIF-1 tumors were treated on day 0 with a concurrent i.p. injection of varying doses of CTX (5-150 mg/kg), human IL-1alpha (125 microg/kg), and carboplatin (50 mg/kg) and examined 24 h later for the surviving fraction by the in vivo excision clonogenic-tumor-cell assay. Even at the lowest doses of CTX, IL-1alpha significantly enhanced the clonogenic tumor cell kill when compared to treatment with CTX alone. When carboplatin was added to the treatment schema, significantly greater clonogenic cell killing and tumor regrowth delay were observed as compared to any agent alone or a two-drug combination (CTX/IL-1alpha or CTX/carboplatin). Significant enhancement was observed even at low doses of CTX in combination with carboplatin and IL-1alpha. The interaction between the three-drug combination was found to be synergistic as determined by the median dose effect with significant dose reduction apparent for IL-1alpha and CTX when used in this combination. These results demonstrate that IL-1alpha can synergistically enhance the antitumor efficacy of CTX and the combination of CTX and carboplatin.     

A controlled study of leukocyte activation in septic patients

OBJECTIVE: Qualitative and quantitative evaluation of leukocyte activation in septic patients in comparison to two control groups. DESIGN: A prospective clinical study in which the leukocyte oxidative output of whole blood was measured in three groups of patients. Two chemiluminescence markers (luminol or lucigenin), indicative of either total oxidant output or superoxide production, and three stimuli (opsonized zymosan, formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate) (PMA), representing different pathways of leukocyte activation, were used. Tumor necrosis factor, interleukin-6 and C-reactive protein (TNF, IL-6, and CRP) were determined to evaluate the severity of the inflammatory process. SETTING: Intensive care and surgical units of a university hospital. PATIENTS: Seventy-four healthy patients, ten ICU patients without signs of sepsis or systemic inflammatory response syndrome and 19 septic patients were studied. MEASUREMENT AND MAIN RESULTS: With all three stimuli, whole blood total oxidative output and superoxide production were generally increased in septic patients. This was most likely due to the increased leukocyte numbers in these patients. When the chemiluminescence values were normalized per phagocyte (granulocytes and monocytes), the total oxidative output of septic phagocytes decreased with opsonin and fMLP but increased with PMA, while superoxide output decreased regardless of the stimuli used. TNF, IL-6 and CRP, although increased in septic patients as compared to ICU controls, correlated weakly with oxidant output. CONCLUSIONS: The oxidative output of whole blood was increased in septic patients compared to controls because of elevated leukocyte numbers. However, oxidant output normalized for phagocyte numbers generally decreases during sepsis for most stimuli. Cytokines and CRP do not appear to be associated with the extent of oxidant output during sepsis.     

Endothelial cell analysis of corneas from donor eyes with an intraocular lens: a comparative study

OBJECTIVES: To examine the relationship between patient-reported depression and adherence to therapy with interferon beta-1b (IFN beta-1b) and to test the hypothesis that treatment of depression is associated with improved adherence. DESIGN: Patients with multiple sclerosis were followed up 6 months after initiating therapy with IFN beta-1b. SETTING: A university outpatient multiple sclerosis center, an academic group practice, and a health maintenance organization. PATIENTS: Eighty-five patients with clinically evident multiple sclerosis taking IFN beta-1b. MAIN OUTCOME MEASURE: Follow-up questionnaire. RESULTS: Thirty-five (41%) of the 85 patients reported new or increased depression within 6 months of initiating therapy with IFN beta-1b. Patients experiencing symptoms of depression were more likely to discontinue therapy. Among the patients reporting new or increased depression, 86% who received psychotherapy or antidepressant medication and 38% of the patients who received no therapy for depression continued the IFN beta-1b therapy (P = .003). Although psychotherapy was used as a treatment option more frequently in university and academic group practice-based multiple sclerosis clinics than in the health maintenance organization (P = .02), the treatment adherence patterns were similar across sites. CONCLUSIONS: These findings support previous findings that patients report increased depression after initiating therapy with IFN beta-1b. Although the source of this depression is unclear, these findings suggest that treating patient-reported depression increases adherence to treatment.     

Compliance with cyclosporine in adolescent renal transplant recipients

The percentage of non-tasters for phenylthiocarbamide in 915 Japanese students was 9.4%. The thresholds of the edge and back of the tongue to quinine hydrochloride were significantly smaller in the non-tasters than in the tasters. The thresholds of any tongue portions to NaCl, acetic acid or sucrose did not differ between the tasters and the non-tasters.     

Identification and localization of slow, natural, cooperative unfolding in the hematopoietic cell kinase SH3 domain by amide hydrogen exchange and mass spectrometry

Protein unfolding on a fast time scale (milliseconds-minutes) has been widely reported, but slower unfolding events (10 min-hours) have received less attention. Amide hydrogen exchange (HX) and mass spectrometry (MS) were used to investigate the unfolding dynamics of the hematopoietic cell kinase (Hck) SH3 domain. Analysis of mass spectra after deuterium exchange into intact Hck SH3 indicates a cooperative unfolding event involving 24-61% of the domain and occurring with a half-life of approximately 20 min under physiological conditions. To identify the unfolding region, SH3 was incubated in D2O and proteolytically fragmented into peptides that were analyzed by mass spectrometry. Correlation of HX rates and isotope patterns reveals cooperative unfolding in several regions, including the C-terminal half of the RT-loop and a beta-sheet flanking the binding site. Binding of a prolyl-rich segment from the HIV Nef protein slows unfolding by a factor of 3. Further analysis yields a KD of 25 microM for the Nef peptide. These results demonstrate that an inherent flexibility in the SH3 domain may assist interconversion of the closed, intramolecularly ligated state and the open, active state of Src family kinases. Furthermore, this type of previously undetectable, slow unfolding process may provide the basis for new mechanisms in which kinetics of local unfolding combines with thermodynamics to regulate enzymatic activity. The combination of hydrogen exchange and mass spectrometry appears to be the only general method capable of examining these slow unfolding processes.     

Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.     

Ehrlichiosis: findings on chest radiographs in three pediatric patients

OBJECTIVES: Ehrlichiosis is a newly recognized tick-borne infection affecting both children and adults. The disease is usually mild, with flulike symptoms, but can be fatal. We present the chest radiographs and, in one case, the chest CT scan of all recognized pediatric cases of ehrlichiosis to date from our institution. CONCLUSION: Ehrlichiosis should be included in the differential diagnosis of acutely ill pediatric patients with a history of possible tick exposure and radiographic patterns of interstitial prominence, alveolar opacities, or consolidation that may be associated with pleural effusion.     

A reverse transcriptase polymerase chain reaction assay for the detection of thermophilic Campylobacter spp

The purpose of this study was to determine the most appropriate method of normalisation for dual fine wire electromyography of shoulder muscles. Five healthy subjects were studied, with one muscle investigated in each subject (2 supraspinatus, 2 infraspinatus, 1 subscapularis). Three dual fine wire electrodes were inserted 1 cm apart around the recognised insertion points. Each subject performed five types of cyclic exercise on an isokinetic muscle dynamometer with an isometric maximal voluntary contraction (MVC) being performed before and after the exercise protocol. The EMG signal was normalised using each of the MVC voltage, the peak voltage and the whole-cycle mean voltage. There was a considerable difference (5-143%) between the MVC signals pre- and post-protocol, although no systematic trend was demonstrable. The overall mean between electrode variation in the normalised signal measured at the peak of the cycle ranged from 48-71% when normalised to pre-protocol MVC, but only 4-13% when normalised to the peak voltage and 9-17% using the whole-cycle mean voltage. However the pattern of activation within the movement cycle, which was preserved by normalisation using the peak or mean signal, was consistent between different electrode positions. It was concluded that the EMG signal depended on electrode position even when near the recognised insertion point, and that the MVC signal is highly variable in magnitude between electrodes and between pre- and post-protocol measurements.     

Use of peer ratings to assess sociability among inpatients with severe psychiatric disorders

OBJECTIVE: A critical component of inpatient treatment for persons with severe psychiatric disorders is an evaluation of their social impairments. Most existing methods for such evaluations involve staff input and can be both time-consuming and expensive. This paper reports on the use of peer ratings as a method for assessing sociability, an aspect of social functioning in this clinical population. METHODS: Thirty-two inpatients with severe psychiatric disorders who had spent an average of 18 months on an inpatient unit in a state facility rated the popularity of their inpatient peers by completing a 7-point scale measuring how much they enjoyed visiting with each patient. The reliability of peer ratings and their association with staff ratings of patients' behavior on the unit were assessed. RESULTS AND CONCLUSIONS: The peer ratings had excellent test-retest reliability and were highly associated with staff members' independent evaluations of patients' behavior. Peer ratings appear to have promise as a measure of social functioning among inpatients with severe psychiatric disorders.