Long-term inhibition of glioma growth by systemic administration of human PEX

AIM: The growth of gliomas depends on the balance of factors stimulating or inhibiting angiogenesis, tumor cell invasion and proliferation. The administration of endogenous inhibitors to experimental human gliomas in animal models resulted in a significant inhibition of tumor growth. It is becoming apparent that resistance can develop over time to many types of endogenous inhibitors and seems to be influenced by the tumor type and system of delivery. METHODS: We recently isolated a potent endogenous inhibitor, called human PEX, from human glioma cells in culture. Human PEX is a potent inhibitor of angiogenesis, tumor and endothelial cell proliferation and migration. In this paper, we investigated the ability of human PEX to sustain inhibition of glioma growth for a prolonged period of time. We initially developed a recombinant form of the inhibitor and showed that this form had similar in vitro and in vivo activities to the natural one. Human PEX was then administered to nude mice intracranial human glioma model, in combination with metronomic chemotherapy, for a period of 185 days, starting 15 days after tumor cells implantation. RESULTS: Our data showed that the systemic administration of human PEX mantained a very prolonged inhibition of glioma growth (50% survival of animals treated with 2 mg/kg/days was 160 days vs 24 days of the control) and had a synergistic effect with low dose chemotherapy. Histological analysis of tumors, showed that treatment with PEX was associated with a decrease of vascularity, cell proliferation, and increase in apoptosis. CONCLUSION: These data indicate that human PEX controls tumor growth by separate mechanisms. In addition, treatment with PEX produced well delineated tumors, indicating the persistence of a direct anti-invasive effect of the molecule even after a prolonged period of treatment.     

Open-angle glaucoma: variations in the intraocular pressure after visual field examination

PURPOSE: To evaluate intraocular pressure (IOP) variations after automated visual field examination in patients with primary open-angle glaucoma and in healthy subjects. PATIENTS AND METHODS: Intraocular pressure was measured in 49 patients (94 eyes) with primary open-angle glaucoma and in 13 healthy subjects (26 eyes) before and immediately after automated visual field examination. All patients had stable IOP and were using local medication to treat glaucoma. The visual field test was performed with a Humphrey 630 VF analyzer and the Central 30-2 full-threshold program. RESULTS: Mean IOP increased significantly in glaucomatous patients immediately after automated visual field examination (P < 0.01), and returned to pretest values after 1 hour (P = 0.2). Mean IOP variation was 2.38 (range, -6-11) mm Hg. In 42 (44.68%) glaucomatous eyes, IOP increased more than 2 mm Hg, with a mean increase of 5.5 mm Hg. Elderly glaucoma patients showed a significantly higher IOP rise than younger patients. No significant IOP variation was detected in healthy subjects. CONCLUSION: Intraocular pressure varied significantly and tended to increase immediately after automated visual field examination in patients with primary open-angle glaucoma. Age seemed to contribute to these IOP changes, but other factors could be involved.     

Comparison of the plasma pharmacokinetics of lamivudine during twice and once daily administration in patients with HIV

OBJECTIVE: To compare the plasma pharmacokinetics of lamivudine 150mg twice daily and 300mg once daily in patients with HIV-1 infection. DESIGN: Nonblind, sequential, pharmacokinetic study. PARTICIPANTS: 13 patients with HIV-1 infection (median age 36 years). METHODS: Patients were tested during twice daily and then once daily regimens of lamivudine. In both regimens, the total daily dose of lamivudine was identical (300 mg/day). Blood samples for pharmacokinetic analysis were taken over a 12-hour period after > or =7 days of twice daily administration, and again over a 24-hour period after 7 days of once daily administration,. RESULTS: 12 patients completed the study. Lamivudine pharmacokinetic parameters (mean +/- SD) after administration of 150mg twice daily were: peak plasma concentration (Cmax) 2077+/-816 microg/L; trough plasma concentration (Cmin) 332+/-219 microg/L; elimination half-life (t 1/2beta) 6.1+/-1.9h; time to Cmax (t(max)) 1.6+/-0.7h; average concentration over the dosage interval (Cav) 711+/-269 microg/L; and area under the concentration-time curve (AUC) over 2 dosage intervals (24h) 17085+/-6464 microg x h/L. Corresponding values after administration of 300mg once daily were: Cmax 3461+/-854 microg/L; Cmin 146+/-87 microg/L; t1/2 7.9+/-3.4h; t(max) 2.2+/-1.3h; Cav 705+/-177 microg/L; and AUC over 1 dosage interval (24h) 16644+/-4150 microg x h/L. Statistical analysis showed a significant difference (p < 0.05) between the 2 schedules for Cmax and Cmin values, whereas no significant differences emerged for the other parameters. CONCLUSIONS: Once daily lamivudine leads to a similar exposure in plasma as twice daily administration of the same total daily dose. Since once daily administration may result in improved compliance, these results provide the pharmacokinetic basis for using lamivudine in a once daily regimen. Randomised clinical studies are needed to confirm this pharmacokinetic finding.     

Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo

This study evaluates the efficacy of the combination of an antiangiogenic drug and conventional chemotherapeutics for the treatment of experimental human gliomas. As an antiangiogenic, we used recombinant human PEX, a fragment of matrix metalloproteinase-2 that we have previously shown to have a significant antimitotic, anti-invasive, and antiangiogenic properties against human glioblastoma in vitro and in vivo. We used carboplatin and etoposide as the two chemotherapeutic drugs routinely used in our institution (Ospedale Maggiore de Milano) for the treatment of malignant gliomas. Conventional chemotherapeutic drugs were administered at high dose or at a low and semicontinuous regimen. Combined treatment of high-dose chemotherapy and PEX did not produce an improvement of survival in comparison with chemotherapy alone, but it was associated with a decrease in tumor volume, vascularity, and proliferative index and an increased apoptosis. All of these animals experienced severe side effects. The longest survival was documented in animals submitted to low and semicontinuous chemotherapy and antiangiogenic treatment. This regimen was associated with no side effects, marked decrease in tumor volume, vascularity, and proliferative index, and an increased apoptosis. Our data suggest that low-dose chemotherapy in combination with PEX can be successfully used against human malignant glioma in vivo.     

MPTP-Induced apoptosis in the retina of goldfish

Neuronal degeneration, observed in the goldfish retina after MPTP administration, displays features of apoptosis, a physiological mechanism of cell death that occurs during development. The ultrastructural features of degenerating retinal neurons, that are seen in the inner nuclear layer two days after intravitreal MPTP administration, are consistent with classic changes observed in the programmed cell death. The DNA strand breaks that characterize apoptotic death are in situ detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling.     

Child and adolescent mental health emergency services in Eastern European former Iron Curtain countries

This paper describes the evolution of child and adolescent mental health emergency services in Eastern European countries over the past decade since the dissolution of the Iron Curtain. The process of helping countries to organize services, as facilitated by the authors through their training and mentoring of Eastern European mental health professionals, organized by the Children's Mental Health Alliance Foundation, with funding from the Soros Foundation, is described. This paper is a prelude to reports from six Eastern European countries which describe in more detail how child and adolescent mental health emergencies are evaluated and treated locally.     

The prognostic significance of acetowhitening of the vulva and HPV-DNA test. A multicentre study

Acetowhitening of the vulva has been related to a subclinical human papillomavirus (HPV) infection. No consense has been reached about undertaking -or not- any therapy for these acetowhite changes. We have observed from our clinical experience and in a 10 years observational follow-up, that acetowhitening of the vulva regarding high risk (16-18) and low risk (6-11) HPV groups (as assessed by PCR analysis) significantly decreased; and acetowhitening areas negative to polymerase chain reaction (PCR), significantly increased from 53% (202/382) to 85% (276/325) (P<0.001). Our findings suggest that independently from HPV type and in the absence of cofactors, there is a statistically significant spontaneous remission of these areas.     

The frequency and severity of cardiac involvement in myotonic dystrophy type 2 (DM2): Long-term outcomes

Background

Frequency and severity of cardiac involvement in DM2 are still controversial. The aims of our study were to determine the frequency and progression of cardiac and muscle involvement in a relatively large cohort of patients with DM2 throughout Italy and Germany and to provide long-term outcomes in this disorder.

Methods

104 DM2 and 117 DM1 patients underwent baseline and follow-up assessments of, ECG, 24 h Holter monitoring, 2D echocardiography and electrophysiological study (EPS) when appropriate, and manual muscle strength testing (mean follow-up: 7.4 ± 4.1 for DM2 and 5.7 ± 4 years for DM1).

Results

Overall, 10% of DM2 patients vs 31% of DM1 patients had PR ≥ 200 ms and 17% of DM2 patients vs 48% of DM1 patients had QRSD ≥ 100 ms. Six patients with DM2 vs 28 patients with DM1 required PM/ICD implantations. DM2 patients were stronger than DM1 patients at baseline, but muscle strength worsened significantly over time (p < 0.0001), just as in DM1, although at a slower annual rate.

Conclusion

Our data demonstrate that the frequency and severity of cardiac involvement and of muscle weakness are reduced in DM2 compared to DM1 and that progression is slower and less severe. Nonetheless, careful cardiac evaluation is recommended in this patient population to identify patients at risk for potential major cardiac arrhythmias.     

Association of Polypharmacy With 1-Year Trajectories of Cognitive and Physical Function in Nursing Home Residents: Results From a Multicenter European Study

Objectives

To test the association between polypharmacy and 1-year change in physical and cognitive function among nursing home (NH) residents.