The competitive NMDA antagonists CGP 43487 and APV potentiate dopaminergic function

The administration to rats of different doses of the non competitive NMDA receptor blocker MK-801 (0.03–1 mg/kg IP) induced stimulation or reduction of locomotor activity, depending on the dose, whereas the competitive NMDA antagonists CGP 43487 (0.188–6 mg/kg IP) and APV (2.5–20 g/rat ICV) inhibited locomotion at the highest doses. Unlike MK-801 and APV treatment, the administration of CGP 43487 did not induce impairment of rota-rod test performance. Both competitive and non-competitive NMDA antagonists, at doses devoid of any behavioral effect per se, potentiated the responses elicited by apomorphine (0.25 mg/kg SC). In particular, the occurrence of episodes of licking was weakly affected by MK-801 administration, but significantly increased by CGP 43487 and APV treatment; the presence of gnawing was augmented by all the pretreatments; sniffing, locomotion, grooming and rearing occurrence were not affected by the administration of NMDA antagonists. The results suggest that the competitive antagonists which facilitated dopaminergic function without causing motor impairment could be useful supplements in the treatment of Parkinson's disease.     

The Massachusetts Behavioral Health Program Year 5: Transition to a New Managed Care Organization

Year 5 of the Massachusetts Behavioral Health Program was a transition to management by a new private managed care organization. Fifty-eight providers interviewed for an ongoing panel survey reported slightly lower levels of quality, access, utilization, and length of stay than a year earlier. Relationships with providers and advocates improved after an initial difficult period, while consumer and family involvement at all levels remained low. The greatest changes in managed care appeared to take place during the initial transition from fee-for-service care, but intractable problems continue, and full participation of stakeholders seems difficult to achieve.     

Studentschool bonding and adolescent problem behavior

Adolescent problem behavior, including substance use, schoolmisconduct and delinquency, is a national concern. Implicitin the concept of middle school is the recognition that studentswho develop positive social bonds with their school are morelikely to perform well academically, and refrain from misconductand other antisocial behavior. However, little scientific attentionhas been given to the complex interactions between middle schoolstudents and the school environment. Prior to implementing amiddle school problem behavior prevention program we conducteda survey in the seven middle schools in one US school district.Out of 4668 grade 6–8 students enrolled, 4263 (91.3%)completed the survey. Student–school bonding was positivelycorrelated with school adjustment (r = 0.49) and perceived schoolclimate (r = 0.77), but inversely correlated with problem behavior(r = –0.39 to –0.43). Problem behavior was significantlyhigher (P < 0.001) among males than females and among studentsin higher grades. Conversely, school bonding, climate and adjustmentwere significantly higher (P < 0.001) among females thanmales, but declined significantly from one grade to the next.The data support the conclusion that school bonding is associatedwith problem behavior. We describe the development of a multiple-componentintervention in middle schools designed to increase student–schoolbonding and prevent problem behavior.     

Visual function correlates with nerve fiber layer thickness in eyes affected by ocular hypertension.

PURPOSE: To test whether the high variability observed when measuring pattern electroretinogram (PERG), visual evoked potentials (VEP), and spatial contrast sensitivity (SCS) in eyes with ocular hypertension is associated with variation in nerve fiber layer thickness, as measured by optical coherence tomography (OCT). METHODS: The study involved 32 untreated eyes (32 patients; age range, 29-64 years) showing a normal whiteon-white 24/2 Humphrey (San Leandro, CA) perimetry, IOP between 23 and 28 mm Hg, best corrected acuity of 20/20 or better, and none of the following papillary signs on conventional color stereo slides: rim notch(es), peripapillary splinter hemorrhages, or increased vertical-to-horizontal cup-to-disc ratio. On recruitment, each eye underwent SCS testing, OCT, PERG, and VEP recordings. Linear regression (Pearson's test) or Spearman's rank regression was adopted for the analysis of the data. RESULTS: The 95% confidence limits of the electrophysiological data were: PERG P50 latency, 59.3 to 63 msec; PERG P50 to N95 amplitude, 0.74 to 1.15 cmV; VEP P100 latency, 113 to 118 msec; VEP N75 to P100 amplitude, 3.81 to 4.90 micromV. The 360 degrees nerve fiber layer thickness overall (NFLO) ranged between 113 and 169 microm (145+/-16 microm; mean+/-SD) and significantly correlated with PERG P50 to N95 amplitude (r: 0.518; P = 0.002), PERG P50 latency (r: -0.470; P = 0.007), VEP N75 to P100 amplitude (r: 0.460; P = 0.008), VEP P100 latency (r = -0.422; P = 0.016) and SCS at 3 cyc/deg (r: -0.358; P = 0.044). CONCLUSIONS: The variability of PERG, VEP, and SCS testing observed in eyes with ocular hypertension is associated with differences in NFL thickness (the thinner the layer, the worse the visual function).     

Anti-Angiogenic Activity of Selected Receptor Tyrosine Kinase Inhibitors, PD166285 and PD173074: Implications for Combination Treatment with Photodynamic Therapy

Angiogenesis, the formation of new blood vessels from an existing vasculature, is requisite for tumor growth. It entails intercellular coordination of endothelial and tumor cells through angiogenic growth factor signaling. Interruption of these events has implications in the suppression of tumor growth. PD166285, a broad-spectrum receptor tyrosine kinase (RTK) inhibitor, and PD173074, a selective FGFR₁TK inhibitor, were evaluated for their anti-angiogenic activity and anti-tumor efficacy in combination with photodynamic therapy (PDT). To evaluate the anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in vitro tumor cell growth and microcapillary formation assays, in vivo murine angiogenesis and anti-tumor efficacy studies utilizing RTK inhibitors in combination with photodynamic therapy were performed. PD166285 inhibited PDGFR--, EGFR-, and FGFR₁TKs and c-src TK by 50% (IC₅₀) at concentrations between 7–85nM. PD173074 displayed selective inhibitory activity towards FGFR₁TK at 26nM. PD173074 demonstrated (>100 fold) selective growth inhibitory action towards human umbilical vein endothelial cells compared with a panel of tumor cell lines. Both PD166285 and PD173074 (at 10nM) inhibited the formation of microcapillaries on Matrigel-coated plastic. In vivo anti-angiogenesis studies in mice revealed that oral administration (p.o.) of either PD166285 (1–25 mg/kg) or PD173074 (25–100 mg/kg) generated dose dependent inhibition of angiogenesis. Against a murine mammary 16c tumor, significantly prolonged tumor regressions were achieved with daily p.o. doses of PD166285 (5–10 mg/kg) or PD173074 (30–60 mg/kg) following PDT compared with PDT alone (p<0.001). Many long-term survivors were also noted in combination treatment groups. PD166285 and PD173074 displayed potent anti-angiogenic and anti-tumor activity and prolonged the duration of anti-tumor response to PDT. Interference in membrane signal transduction by inhibitors of specific RTKs (e.g. FGFR₁TK) should result in new chemotherapeutic agents having the ability to limit tumor angiogenesis and regrowth following cytoreductive treatments such as PDT.     

Phase II trial of circadian infusion floxuridine (FUDR) in hormone refractory metastatic prostate cancer

Circadian administration of chemotherapy has been reported to decrease toxicity and possibly enhance efficacy. Between March 1991 and December 1993, 18 evaluable patients with progressive, hormone-refractory metastatic prostate cancer were treated in this phase II trial of circadian infusion floxuridine (FUDR). The drug was delivered through a central venous catheter using a CADD-Plus computerized pump such that approximately 70% of the drug was administered between 3 and 9 p.m. and the rest (30%) was administered between 9 p.m. and 3 p.m. The dose of FUDR was 0.15 mg/kg/day × 14 days every 4 weeks. A total of 79 complete cycles was administered.Two of 18 evaluable patients (11.1%) had decreases in PSA lasting five and eight months. No objective responses or improvement in bone scans was noted. The major toxicity observed was diarrhea. Although circadian infusion FUDR is feasible and tolerable, it has limited activity in hormone refractory prostate cancer.     

Hypoxaemia in adults in the post-anaesthesia care unit

Continuous pulse oximetry was performed on 173 adults after general anaesthesia for elective inpatient surgery, throughout their post-anaesthesia care unit (PACU) stay. Supplemental oxygen was administered for greater than or equal to 30 min after arrival and subsequently discontinued before discharge to the ward. The mean and minimum oxyhaemoglobin saturation (SpO2) after discontinuing oxygen were lower than those values achieved during oxygen administration and preoperatively (P less than 0.001). At least one hypoxaemic episode (SpO2 less than or equal to 90% for greater than or equal to 15 sec) occurred in 70 subjects (41%) and 45 of these had a moderate-severe episode (SpO2 greater than or equal to 90% for less than or equal to 2 min or SpO2 less than or equal to 85%). The hypoxaemic episodes began 20 +/- 20 min (range 1-100; median 15) after discontinuing supplemental oxygen. Cyanosis was detected in only four of the 70 patients who desaturated. Factors associated with hypoxaemia were: ASA physical status class; surgical duration greater than or equal to 90 min; and preoperative mean SpO2 less than 95%. Factors not associated with hypoxaemia were: age, sex, % ideal body weight, smoking history, preoperative minimum SpO2, premedication and type of surgery. In conclusion, after discontinuing supplemental oxygen in the PACU, hypoxaemia was common, difficult to detect clinically, and associated with ASA class, surgical duration and preoperative mean SpO2.     

Practices surrounding syringe acquisition and disposal: effects of Syringe Exchange Programmes from different Brazilian regions—the AjUDE-Brasil II Project

The study describes practices relating to syringe acquisition and disposal by Syringe Exchange Programme (SEP) participants. A cross-sectional multi-city study enrolled 857 injection drug users (IDUs) from six SEPs in different Brazilian regions, and assessed self-reported acquisition and disposal behaviours. Seven hundred and nine males (82.9%) and 146 females (17.1%) were recruited through outreach and interviewed, most from the streets or their neighbourhoods (54.1%). The average age was 28.5 years; 76.4% reported injecting cocaine in the past 6 months. Sources for acquiring new syringes differed significantly between time of injection drug use debut and the 6 months prior to interview. Fifty-three percent of IDUs reported acquiring their syringes in pharmacies when they initiated injection drug use, whereas most reported acquiring new syringes in the 6 months before interview from several simultaneous sources: 69% through SEPs; 58% through pharmacies; 36% from friends and/or sexual partners; and 17% from other health services. Across SEPs, acquisition and disposal varied widely. Most interviewees discarded their syringes on the streets, in open fields, or in the garbage or sewage. Restrictions on syringe availability and unsafe practices may be functioning as barriers to the public health recommendation of one-time use of sterile syringes for IDUs and discouraging community support to SEPs. Further increase in access to legal, inexpensive and timely sterile syringes, as well as counselling about the merits of one-time use and safer disposal must be reinforced as part of efforts to minimise high-risk behaviours and curb the spread of blood-borne infections.     

Effects of a high-selenium yeast supplement on celecoxib plasma levels: a randomized phase II trial.

A combination of celecoxib and selenium was used in a randomized double-blind Phase II trial as a preliminary study to a multicenter Phase III colorectal cancer chemoprevention trial using these two agents together. The purpose of this trial was to determine whether high-selenium baker's yeast [(Saccharomyces cerevisiae) 200 microg once daily] in combination with celecoxib (400 mg once daily) altered the steady-state plasma concentration of celecoxib or produced clinically significant toxicities. Seventy-three healthy subjects (ages 40-75 years) were recruited to the 6-week study from the general local population and were randomized to either the celecoxib plus selenized baker's yeast group or the celecoxib plus placebo group after a 2-week run in period of celecoxib only. Blood samples were taken at baseline (to document that there was no evidence of celecoxib intake), after the 2-week run-in period on celecoxib to verify steady-state blood levels of this agent, and at end of study (4 weeks postrandomization). Toxicities were monitored at 2 weeks after initiation of celecoxib, at 4 weeks after initiation, and at the end of the study. Blood level concentrations of celecoxib did not differ between the two groups as determined by high-performance liquid chromatography analysis nor were there significant differences in blood chemistry values between the two groups. Subjects' self-report of general physical toxicities was uncommon and limited to National Cancer Institute toxicity grade 2 or less; however, 2 female participants (3%) were removed from the study medications because of grade 2 edema and significant weight gain after 2 and 2.5 weeks of celecoxib administration. In conclusion, high-selenium yeast and celecoxib can be taken at the described doses with minimum short-term negative effects. In future Phase III chemoprevention trials of celecoxib, weight gain should be carefully monitored, and participants should be made aware of this potential side effect before study entry.