The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children

OBJECTIVE: The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet developed in the 1920s for the treatment of children with difficult to control seizures. Despite advances in both the pharmacotherapy and the surgery of epilepsy, many children continue to have difficult-to-control seizures. This prospective study sought to determine the ketogenic diet's effectiveness and tolerability in children refractory to today's medications. METHODS: One hundred fifty consecutive children, ages 1 to 16 years, virtually all of whom continued to have more than two seizures per week despite adequate therapy with at least two anticonvulsant medications, were prospectively enrolled in this study, treated with the ketogenic diet, and followed for a minimum of 1 year. Seizure frequency was tabulated from patients' daily seizure calendars and seizure reduction calculated as percentage of baseline frequency. Adverse events and reasons for diet discontinuation were recorded. RESULTS: The children (mean age, 5.3 years), averaged 410 seizures per month before the diet, despite an exposure to a mean of 6.2 antiepileptic medications. Three months after diet initiation, 83% of those starting remained on the diet and 34% had >90% decrease in seizures. At 6 months, 71% still remained on the diet and 32% had a >90% decrease in seizures. At 1 year, 55% remained on the diet and 27% had a >90% decrease in seizure frequency. Most of those discontinuing the diet did so because it was either insufficiently effective or too restrictive. Seven percent stopped because of intercurrent illness. CONCLUSIONS: The ketogenic diet should be considered as alternative therapy for children with difficult-to-control seizures. It is more effective than many of the new anticonvulsant medications and is well tolerated by children and families when it is effective.     

Role for glucose transporter 1 protein in human breast cancer

Glycolysis is increased in cancer cells compared with normal cells. It has been shown that glucose enters cells via a family of five functional glucose transporters (GLUT). However, GLUT expression appears to be altered in human breast cancer, which may serve as a selective advantage and facilitate the metastatic potential of these cells. The relationship of GLUT isoform expression and breast cancer cell invasiveness has not been adequately addressed. Thus, the purpose of this study was to investigate whether an association exists between GLUT expression and human breast cancer cell invasiveness. Invasiveness of the human breast cancer lines MCF-7, MDA-MB-435 and MDA-MB-231 was measured using anin vitro assay and compared with cellular GLUT isoform expression, assessed by Western blot analysis and verified by immunohistochemistry in a poorly differentiated human ductal breast cancer. Cell surface GLUT-1 expression was associated with the invasive ability of MCF-7 (2.0 ± 0.02%), MDA-MB-435 (6.4 ±0.4%), and MDA-MB-231 (19.3 ± 2.0%). However, GLUT-2 and GLUT-5 were inversely associated with invasiveness; GLUT-3 expression was variable; and GLUT-4 was undetected. In a poorly differentiated human ductal breast cancer,in situ GLUT-1 staining was intense. GLUT-1 expression was associated with the in vitro invasive ability of human breast cancer cells which was validatedin situ. If this relationship is found to exist in a larger number of human breast cancer tissues, it may be possible to develop diagnostic and therapeutic strategies based on targeted GLUT isoform expression.     

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.      

Protein kinase C activation reduces the function of the Na(+):K(+):2Cl(-) cotransporter in Xenopus laevis oocytes

BACKGROUND: The basolateral isoform of the Na(+):K(+):2Cl(-) cotransporter is expressed in several epithelial and non-epithelial cells, in which it is involved in ion secretion processes and in cell volume regulation. In humans, this cotransporter has been implicated in the development of primary hypertension. The major goal of the present study was to characterize the effect of protein kinase C activation on the function of the Na(+):K(+):2Cl(-) cotransporter isoform present in Xenopus laevis oocytes. METHODS: Oocytes were surgically harvested from adult female Xenopus laevis frogs, defolliculated by incubation in frog ringer containing collagenase B (2 mg/mL) under vigorous shaking, and by hand under the microscope. Only stage V-VI oocytes were used in the study. After overnight incubation in regular frog Ringer, oocytes were switched to a Cl(-)-free ringer for at least 12 h before beginning uptake experiments. The function of the Na(+):K(+):2Cl(-) cotransporter was determined by assessing tracer 22Na(+) uptake in the control group as well as under several experimental conditions, such as changes in extracellular osmolarity, absence of one of the cotransported ions, or the presence of drugs such as the specific cotransporter inhibitor bumetanide, phorbol esters (TPA, PDBu, or 4alphaPDD), and the PKC inhibitor bisindolylmaleimide I. At the end of the uptake period, tracer Na(+) uptake was counted by liquid scintillation of each individual oocyte previously dissolved in SDS. RESULTS: Xenopus oocytes exhibited a bumetanide-sensitive Na(+):K(+):2Cl(-) cotransporter in the plasma membrane activated by hypertonicity and inhibited by hypotonicity. The bumetanide-sensitive fraction of Na(+) uptake was significantly reduced by the addition of phorbol esters TPA or PDBu to the uptake media. This inhibitory effect of PKC activators was dose- and time-dependent. Phorbol ester 4alphaPDD, which cannot activate PKC, exhibited no effect on Na(+):K(+):2Cl(-) cotransporter function. In addition, pretreatment of oocytes with the PKC inhibitor bisindolylmaleimide I partially abolished TPA-induced reduction in the cotransporter function. CONCLUSION: In defolliculated Xenopus laevis oocytes, phorbol esters reduce the function of the Na(+):K(+):2Cl(-) cotransporter by a mechanism that includes the activation of an endogenous PKC.     

FISH Preimplantation Diagnosis of Chromosome Aneuploidy in Recurrent Pregnancy Wastage

Purpose: Our purpose was to detect aneuploidy for chromosomes 13, 16,18, 21, 22, X, and Y in preimplantation embryos from patients with a history of unexplained recurrent miscarriage. Methods: Three patients with a history of unexplained recurrent spontaneous abortion were included in this study. Embryos were biopsied at the eight-cell stage, individually fixed on slides, and processed for fluorescent in situ hybridization (FISH). A multiple FISH protocol for seven chromosomes pairs (13, 16, 18, 21, 22, X, and Y) has been developed. Results: A total of 39 embryos was studied with the multiple FISH protocol developed. Successful analysis of the biopsied embryos was achieved within the time limits usually allowed in a preimplantation diagnosis program. Analysis of the blastomeres showed that 17 embryos were chromosomally normal for the probes used, 16 embryos were aneuploid, and in 6 embryos no informative results were obtained. Conclusions: In the patients studied, a large proportion of embryos (41%) exhibited chromosomal abnormalities for the probes used. Preimplantation diagnosis to screen for chromosome abnormalities could be a feasible approach to improve the possibility of successful pregnancy in these couples.     

Effects of sub-chronic combined treatment with pergolide and caffeine on contralateral rotational behavior in unilateral 6-hydroxydopamine-denervated rats

We studied the synergistic effects of pergolide and bromocriptine with caffeine on turning behavior in 6-OHDA denervated rats. Both pergolide and bromocriptine were synergistic with caffeine, and prevented tolerance to caffeine-induced turning. When caffeine was removed, tolerance to bromocriptine effects was observed for 1 day only, while no tolerance was observed to pergolide. These results suggest that caffeine could be useful in the treatment of Parkinson's disease, preferentially as an adjuvant of mixed dopaminergic agonists like pergolide.     

Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study.

BACKGROUND: The aim of this study was to determine whether the response rate for the paclitaxel-carboplatin combination is superior to carboplatin alone in the treatment of patients with platinum-sensitive recurrent ovarian carcinoma. PATIENTS AND METHODS: Patients with recurrent ovarian carcinoma, 6 months after treatment with a platinum-based regimen and with no more than two previous chemotherapy lines, were randomized to receive carboplatin area under the curve (AUC) 5 (arm A) or paclitaxel 175 mg/m(2) + carboplatin AUC 5 (arm B). The primary end point was objective response, following a 'pick up the winner' design. Secondary end points included time to progression (TTP), overall survival, tolerability and quality of life (QoL). RESULTS: Eighty-one patients were randomized and included in the intention-to-treat analysis. The response rate in arm B was 75.6% [26.8% complete response (CR) + 48.8% partial response (PR)] [95% confidence interval (CI) 59.7% to 87.6%] and 50% in arm A (20% CR + 30% PR) (95% CI 33.8% to 66.2%). No significant differences were observed in grade 3-4 hematological toxicity. Conversely, mucositis, myalgia/arthralgia and peripheral neurophaty were more frequent in arm B. Median TTP was 49.1 weeks in arm B (95% CI 36.9-61.3) and 33.7 weeks in arm A (95% CI 25.8-41.5). No significant differences were found in the QoL analysis. CONCLUSIONS: Paclitaxel-carboplatin combination is a tolerable regimen with a higher response rate than carboplatin monotherapy in platinum-sensitive recurrent ovarian carcinoma.