The in-vitro and in-vivo characterization of PLGA:L-PLA microspheres containing dexamethasone sodium phosphate

Dexamethasone sodium phosphate (DSP) is a widely used corticosteroid in the treatment of brain oedema associated with brain tumours. DSP has many side effects that limit its usage at an effective concentration. The objective of this study was to minimize these side effects by encapsulating DSP using biodegradable synthetic polymers, to extend the release time from microspheres and to evaluate the effectiveness in the treatment of brain oedema. Microspheres containing 5% DSP were formulated by the solvent evaporation method by using a 1:1 mixture of two synthetic polymers, poly(lactic-co-glycolic acid) and L-polylactic acid (PLGA and L-PLA). The surface morphologies and particle size distribution of the microspheres were investigated. The in-vitro release studies were performed in pH 7.4 phosphate buffer solution. For determining the effectiveness of microspheres in the treatment of brain oedema, Sprague-Dawley rats weighing 200-250g were used as an animal model. Brain oedema was generated by the cold lesion method, and the effectiveness of the microspheres in treatment of oedema was investigated by the wet-dry weight method, lipid peroxidation ratios and histological evaluations. The average particle size of the microspheres was 13.04 +/- 2.05 microm, and the in-vitro release time of the microspheres was 8 h for 100/release. The degree of oedema was significantly different from the control group for the wet-dry weight method and lipid peroxidation ratio (p < 0.05). Similarly, histological evaluation of the tissues shoved that degree of oedema was significantly decreased with respect to the control group. All these results showed that implantation of microspheres was significantly more effective with respect to the systemic administration of DSP.     

p53, p21 and metallothionein immunoreactivities in patients with malignant pleural mesothelioma: correlations with the epidemiological features and prognosis of mesotheliomas with environmental asbestos exposure.

The aim of this study is to investigate immunoreactivity for p53, p21 and metallothionein in diffuse malignant pleural mesothelioma (DMPM) and to determine the relationships between the age, sex, asbestos exposure time, survival of DMPM patients with environmental asbestos exposure and immunoreactivity to p53, p21 and metallothionein. Sixty-seven histopathologically-confirmed DMPMs, 38 of whom had environmental and 29 had occupational asbestos exposure, were included. The tumour tissue samples were immunostained with antibodies against p53, p21 and metallothionein. Epidemiological data and the survival times for the DMPM patients with environmental asbestos exposures were obtained from hospital records. Thirty-three per cent of the DMPMs were positive for p53, 35% for p21 and 52% for metallothionein. There was no statistical difference between the histological subtypes of DMPM in terms of immunoreactivity for p53, p21 and metallothionein. For p21 and metallothionein there was a statistically significant difference between the exposure characteristics: patients with environmental asbestos exposure had shown more immunopositivity. There were statistically significant differences between age groups and between asbestos exposure times for metallothionein, and between asbestos exposure times and p21. The patients with positive immunostaining had longer exposure times and were older than those having negative immunostaining. The differences between survival of the patients were not statistically significant in terms of the immunohistochemical results for p53, p21 and metallothionein.     

Safety and efficacy of calcium carbonate in children with chronic renal failure

The safety and clinical efficacy of calcium carbonate therapy in children with chronic renal failure were assessed in 68 patients (average age 8.38 years) during a mean follow-up period of 19.9 months (range 1.2-49.4). Forty-seven episodes of hypercalcaemia occurred in 29 children (3.5 episodes per 100 patient-months). There were no significant differences in mean GFR or biochemical parameters between these patients at the start of calcium carbonate therapy and the group of children who never experienced hypercalcaemia. Good control of secondary hyperparathyroidism and a significant reduction in serum aluminum were achieved. Two of 23 hypercalcaemic patients showed nephrocalcinosis on ultrasonography. 99Tc pyrophosphate scanning failed to detect any other ectopic calcification. The incidence of hypercalcaemia increased significantly when the GFR was less than 15 ml/min per 1.73 m2 and was most frequent in children receiving dialysis (48 episodes per 100 patient-months). The decrease in GFR during therapy was significantly more in the hypercalcaemic group compared to the normocalcaemic group (P less than 0.01), despite no irreversible acute effects of hypercalcaemia being observed on the rate of decline of GFR. We believe that the reduced renal homeostatic reserve is a major factor predisposing to hypercalcaemia. Consequently calcium carbonate is safe to use in children with severe chronic renal failure with close biochemical monitoring; the benefits over aluminium phosphate binders far outweigh the risks of hypercalcaemia and ectopic calcification.     

Hemoglobinopathies among the Gond tribal groups of central India; interaction of alpha- and beta-thalassemia with beta chain variants.

We have investigated the frequencies and types of alpha-thal, beta-thal, and Hb variants among nearly 200 inhabitants of villages in the Mandla and Jabalpur districts of Madhya Pradesh in Central India. Over 85% were tribals of the Gond group. alpha-Thal, as -alpha 3.7/and -alpha 4.2/, and the nondeletional Koya Dora mutation were present at the combined frequency of 0.54. There were indications for the presence of other nondeletional types of alpha-thal. alpha-Globin gene triplications were not observed. Four of the six beta-thal alleles observed were in the tribal groups; two (G----C at codon 30 and G----A at IVS-I-1) were found for the first time. The simultaneous presence of an alpha-thal (-alpha/alpha alpha or -alpha/-alpha) greatly improved the clinical and hematological condition of the patients with Hb S-beta(+)-thal (IVS-I-5; G----C). The lower frequency of alpha-thal among the beta-thal heterozygotes (f = 0.32) may indicate that some of the beta-thal alleles in the tribal populations originated from an outside source. Forty-one subjects had SS; all but one had beta S with haplotype #31, while one chromosome had haplotype #17. The presence of an alpha-thal-2 (f = 0.53) in the SS patients did not affect hematological data. The Hb F levels varied between 7.5% and 42.5% with high G gamma values. No difference in Hb F level between males and females was observed. Lower Hb F levels were present in 10 SS patients with an alpha-thal-2 homozygosity (average 16% versus 23.5% for eight SS patients with alpha alpha/alpha alpha) suggesting a decreased formation of alpha gamma dimers in severe alpha chain deficiency. Several younger SS patients (less than 10 years) also had high Hb F levels (32-42%). Variations in the sequence at -530 of the beta-globin gene; i.e. in the so-called silencer sequence, were present in all beta S chromosomes with haplotype #31, but were not considered important for understanding the variability in the Hb F level. gamma-Globin gene deletions (gamma-thal) and triplications were not observed.     

The G----A mutation at position +22 3' to the Cap site of the beta-globin gene as a possible cause for a beta-thalassemia.

We describe the occurrence of a chromosome with a G----A mutation at position +22 relative to the Cap site that was found in five patients with beta-thalassemia. All patients had a common type of beta-thalassemia mutation on the second chromosome, namely the frameshift at codon 8 (-AA), the IVS-I-110 (G----A) and the IVS-II-1 (G----A) mutations. The beta genes of two patients, including the 5' and 3' untranslated regions, were completely sequenced and no other mutations, except a few polymorphic sites, were observed. Dot-blot analyses failed to demonstrate this G----A mutation at +22 in nearly 400 beta-thalassemia chromosomes and 180 normal chromosomes. Heterozygotes have the features of a high Hb A2-beta-thalassemia heterozygosity, although the hematological parameters might be less abnormal than observed in heterozygotes for the more common beta-thalassemia mutations. The possibility has been presented suggesting that this mutation might impair the binding of mRNA to ribosomes. Another mutation in this segment of DNA, i.e. a C----G mutation at position +20, is observed exclusively on a chromosome which also carries the C----G mutation at IVS-II-745. It is postulated that the +20 C----G mutation accentuates the beta-thalassemia condition caused by the IVS-II-745 mutation; the mechanism might be similar to that suggested for the G----A at +22 mutation.     

The status of alternative treatment in cancer patients in Turkey

This study was designed to measure the frequency at which Turkish patients with cancer resort to complementary and alternative medicine (CAM). A total of 704 patients referred to the Gülhane Military Medical Academy and Ankara Numune Training Hospital between September 2002 and January 2003 were asked about the CAM therapies they used. Of these, 276 patients (39.2%) had used CAM. Gender, marital status, educational status, age, financial status, severity of pain, history of cancer in the family, and their own ideas concerning CAM therapies were found to be correlated with the frequency of resorting to CAM. Resorting to CAM may lead to delayed diagnosis and treatment, adverse drug interactions, treatment withdrawal, and disease progression. Therefore, it is very important to inform patients about these potential dangers. Further studies are needed to clarify the reasons that lead patients to resort to CAM.     

Serum prolidase I activity and some bone metabolic markers in patients with breast cancer: in relation to menopausal status

OBJECTIVES: The purpose of this study was to investigate the diagnostic value of some osteoblastic/osteoclastic biochemical markers and serum prolidase I activity in breast cancer (BC). DESIGN AND METHODS: Serum bone gla protein (BGP), prolidase I activity, urinary deoxypyridinoline (Dpy) and calcium excretions were measured, in metastatic and nonmetastatic BC patients, and in 52 healthy women. RESULTS: In patients with metastases, bone turnover markers were found to be significantly higher than those in the control group and in patients without metastases. Serum prolidase activity in patients with and without metastases was also significantly higher than those in the control group, but there was no difference between the two patient groups. CONCLUSIONS: Bone turnover has been suggested to be accelerated in BC patients with the more pronounced osteolytic activation, especially in metastatic state. Serum prolidase in premenopausal period appears to be valuable in discriminating cancer patients from controls. BGP and to a lesser degree of Dpy, may be useful markers for predicting the metastatic bone involvement, as well as for the more cost effective management of BC patients and monitoring the effects of antiresorptive therapy of malignant osteolysis before any metastasis could be detected by other invasive techniques.