Inhibition of interleukin-1 but not tumor necrosis factor suppresses neovascularization in rat models of corneal angiogenesis and adjuvant arthritis

OBJECTIVE: To assess the capacities of the cytokine inhibitors interleukin-1 receptor antagonist (IL-1Ra; anakinra) and PEGylated soluble tumor necrosis factor receptor I (PEG sTNFRI; pegsunercept) to suppress neovascularization. METHODS: A corneal angiogenesis assay was performed by implanting nylon discs impregnated with an angiogenic stimulator (basic fibroblast growth factor or vascular endothelial growth factor) into one cornea of female Sprague-Dawley rats. Animals were treated with IL-1Ra or PEG sTNFRI for 7 days, after which new vessels were quantified. In a parallel study, male Lewis rats with mycobacteria-induced adjuvant-induced arthritis were treated with IL-1Ra or PEG sTNFRI for 7 days beginning at disease onset, after which scores for inflammation and bone erosion as well as capillary counts were acquired from sections of arthritic hind paws. RESULTS: Treatment with IL-1Ra yielded a dose-dependent reduction in growth factor-induced corneal angiogenesis, while PEG sTNFRI did not. IL-1Ra, but not PEG sTNFRI, significantly reduced the number of capillaries in arthritic paws, even though both anticytokines reduced inflammation and bone erosion to a similar degree. CONCLUSION: These data support a major role for IL-1, but not TNFalpha, in angiogenesis and suggest that an additional antiarthritic mechanism afforded by IL-1 inhibitors, but not anti-TNF agents, is the suppression of the angiogenic component of pannus.     

Effects of negative and positive mood phrases on priming of alcohol words in young drinkers with high and low anxiety sensitivity

This study investigated whether potential emotional cues for drinking activate alcohol concepts in young drinkers. Participants were 84 university freshmen with high or low levels of anxiety sensitivity (AS). A verbal priming task measured activation (i.e., priming) of alcohol concepts (e.g., beer) by positive and negative mood phrases. Time to read alcohol target words was the dependent measure. Negative mood phrases consistently primed alcohol targets; positive mood phrases did not. Degree of negative mood priming did not differ as a function of gender or AS. Reported tendency to drink in bad moods predicted negative mood priming in women, whereas men showed negative mood priming irrespective of their reported drinking tendency. A general association between negative mood priming and severity of alcohol problems also emerged.     

The Centers for Disease Control and Prevention's Healthy Days Measures – Population tracking of perceived physical and mental health over time

To promote the health and quality of life of United States residents, the U.S. Department of Health and Human Services' Centers for Disease Control and Prevention (CDC) - with 54 state and territorial health agencies - has supported population surveillance of health-related quality of life (HRQOL). HRQOL was defined as "perceived physical and mental health over time." Commonly-used measures of health status and activity limitation were identified and a set of "Healthy Days" HRQOL measures was developed and validated. A core set of these measures (the CDC HRQOL-4) asks about self-rated general health and the number of recent days when a person was physically unhealthy, mentally unhealthy, or limited in usual activities. A summary measure combines physically and mentally unhealthy days. From 1993 to 2001, more than 1.2 million adults responded to the CDC HRQOL-4 in each state-based Behavioral Risk Factor Surveillance System (BRFSS) telephone interview. More than one fifth of all BRFSS respondents also responded to a set of related questions - including five items that assess the presence, main cause and duration of a current activity limitation, and the need for activity-related personal and routine care; as well as five items that ask about recent days of pain, depression, anxiety, sleeplessness, and vitality.     

Gamma knife stereotactic radiosurgery for synchronous versus metachronous solitary brain metastases from non-small cell lung cancer

A retrospective study was conducted analyzing the clinical outcome and various prognostic factors in patients treated with gamma knife stereotactic radiosurgery (GK-SRS) for solitary brain metastasis from non-small cell lung carcinoma (NSCLC). A total of 72 patients from June of 1992 to January of 1999 were treated. All patients received GK-SRS to a median dose of 18Gy, with 45 patients receiving additional whole-brain radiation therapy. No one had evidence of extra-cranial metastasis at the time of diagnosis of brain metastases. The median follow-up was 15.7 months for the entire population and 99.5 months for those who were alive at the last follow-up. Univariate and multivariate analyses were used to test the impact of various prognostic factors on survival. The median and 5-year actuarial survivals for the entire cohort were 15.7 months and 10.4%, respectively. The presence of a metachronous versus a synchronous brain metastasis was the only factor significant in the univariate (P=0.045) and multivariate (P=0.002) analyses. Patients with metachronous solitary brain metastases had a significant median survival advantage compared to those with synchronous metastases (33.3 months versus 8.6 months, P=0.001). However, there was no statistically significant difference in median survival from the time of metastasis when treated with GK-SRS in these groups (12.5 months versus 8.4 months, P=0.50). The addition of WBRT did not improve overall survival (12.0 months versus 7.7 months, P=0.73). The 5-year actuarial survival for the metachronous and synchronous groups were 13.2 and 8.1%, respectively. In conclusion, patients presenting with a solitary metachronous brain metastasis from NSCLC achieved longer survivals than those with a synchronous metastasis. The tail in the survival curves demonstrates that a prolonged survival may be attained in patients with solitary metastases from NSCLC. This study adds to the growing body of literature that supports the use of SRS in the management of this patient population.     

Effects of abstinence and smoking on information processing in adolescent smokers

RATIONALE: Although adolescent smokers appear to display some of the hallmark features of dependence, the biological and behavioral effects of smoking in this population are poorly understood. OBJECTIVES: This study aimed to define empirically the effects of abstinence and smoking in adolescent smokers, using indices validated in adult smokers. METHODS: Subjects were 16 young novice smokers (five male, 11 female), ages 14-18 years. A modified Stroop task measured the ability to inhibit attention to smoking-related cues; the classic Stroop task measured the ability to inhibit a pre-potent response (i.e. reading a word); a rapid information processing (RIP) task measured vigilance. RESULTS: Abstinence increased and smoking decreased the intrusiveness of smoking cues. Parallel effects were seen in commission errors on the RIP task. These effects were restricted to heavier smokers (>11 cigarettes/day). Subjective withdrawal effects predicted the intrusiveness of smoking words during abstinence. The number of cigarettes smoked per day predicted the beneficial effect of smoking on the classic as well as modified Stroop tasks. The physiological effects of abstinence and smoking predicted RIP performance. CONCLUSIONS: Abstinence impairs and smoking improves inhibitory information processing in young novice smokers in a manner similar to adult smokers. Daily frequency of smoking is a critical moderator of these effects.     

Ocular MR imaging and spectroscopy: an ex vivo study

Six eyes, freshly enucleated because of choroidal melanoma, were imaged on a 1.4-T superconducting magnetic resonance (MR) imaging system, and relaxation times were calculated for various parts of the eye. Unfixed fresh tissue samples were obtained for nuclear magnetic resonance spectroscopy (NMRS) on a variable-field (0.19-1.4 T) resistive unit. Detailed ocular anatomy was demonstrated. The NMRS relaxation times correlated with the MR imaging intensity patterns. The sensitivity of MR imaging to states of hydration provides an excellent window for appreciation of ocular anatomy.     

Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis

Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma. Rarely, however, primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma, based on the presence of myxoid areas and vascular crow's feet pattern, which has resulted in a debate on the classification of liposarcoma in the retroperitoneum. Genetically, myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases. Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion, whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes. As myxoid/round cell liposarcoma is highly radio- and chemosensitive, differentiation between subtypes is important to optimize treatment. We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma. Primary retroperitoneal myxoid/round cell liposarcoma (n=16) were compared to primary extremity myxoid/round cell liposarcoma (n=20). Histopathological and immunohistochemical features were studied. Amplification status of the 12q13-15 region was studied using a multiplex ligation-dependent probe amplification analysis, and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR. In primary retroperitoneal myxoid/round cell liposarcoma, MDM2 and CDK4 staining was both positive in 12 of 15 cases. In primary extremity myxoid/round cell liposarcoma, MDM2 was negative in 18/20 and CDK4 was negative in all cases. Multiplex ligation-dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas. Translocation was present in all (18/18) primary extremity myxoid/round cell liposarcomas, but absent in all primary retroperitoneal myxoid/round cell liposarcomas. On the basis of immunohistochemical and molecular characteristics, apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma. In these cases, treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma. Moreover, finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum.     

Comparative Efficacies of Liposomal Amikacin (MiKasome) plus Oxacillin versus Conventional Amikacin plus Oxacillin in Experimental Endocarditis Induced by Staphylococcus aureus: Microbiological and Echocardiographic Analyses

Optimal treatment strategies for serious infections caused by Staphylococcus aureus have not been fully characterized. The combination of a beta-lactam plus an aminoglycoside can act synergistically against S. aureus in vitro and in vivo. MiKasome, a new liposome-encapsulated formulation of conventional amikacin, significantly prolongs serum half-life (t1/2) and increases the area under the concentration-time curve (AUC) compared to free amikacin. Microbiologic efficacy and left ventricular function, as assessed by echocardiography, were compared in animals administered either oxacillin alone or oxacillin in combination with conventional amikacin or MiKasome in a rabbit model of experimental endocarditis due to S. aureus. In vitro, oxacillin, combined with either free amikacin or MiKasome, prevented the bacterial regrowth observed with aminoglycosides alone at 24 h of incubation. Rabbits with S. aureus endocarditis were treated with either oxacillin alone (50 mg/kg, given intramuscularly three times daily), oxacillin plus daily amikacin (27 mg/kg, given intravenously twice daily), or oxacillin plus intermittent MiKasome (160 mg/kg, given intravenously, a single dose on days 1 and 4). The oxacillin-alone dosage represents a subtherapeutic regimen against the infecting strain in the endocarditis model (L. Hirano and A. S. Bayer, Antimicrob. Agents Chemother. 35:685-690, 1991), thus allowing recognition of any enhanced bactericidal effects between oxacillin and either aminoglycoside formulation. Treatment was administered for either 3 or 6 days, and animals were sacrificed after each of these time points or at 5 days after a 6-day treatment course (to evaluate for posttherapy relapse). Left ventricular function was analyzed by utilizing serial transthoracic echocardiography during treatment and posttherapy by measurement of left ventricular fractional shortening. At all sacrifice times, both combination regimens significantly reduced S. aureus vegetation counts versus control counts (P < 0.05). In contrast, oxacillin alone did not significantly reduce S. aureus vegetation counts after 3 days of therapy. Furthermore, at this time point, the two combinations were significantly more effective than oxacillin alone (P < 0.05). All three regimens were effective in significantly decreasing bacterial counts in the myocardium during and after therapy compared to controls (P < 0.05). In kidney and spleen abscesses, all regimens significantly reduced bacterial counts during therapy (P < 0.0001); however, only the combination regimens prevented bacteriologic relapse in these organs posttherapy. By echocardiographic analysis, both combination regimens yielded a significant physiological benefit by maintaining normal left ventricular function during treatment and posttherapy compared with oxacillin alone (P < 0.001). These results suggest that the use of intermittent MiKasome (similar to daily conventional amikacin) enhances the in vivo bactericidal effects of oxacillin in a severe S. aureus infection model and preserves selected physiological functions in target end organs.