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Infantile Nutritional Rickets has disappeared almost completely in France since 1992 as vitamin D enriched formula availability and previous vitamin D supplementation of infants. The search of evocative symptoms of rickets should be a routine procedure in infants, in particular in case of insufficient vitamin D intake i.e. breastfeeding, and the possibility of vitamin D resistant rickets. Hypocalcaemia occurs not only at the first but also the advanced stages of vitamin D deficiency, and may be responsible for severe cardiologic, neurologic or respiratory complications with possibility of infant death. For the young children between 1 and 5 years and for adolescents, vitamin D insufficiency is responsible for poor skeletal mineralization, loss of bone strength, and a reduction of peak of bone mineral mass at the end of puberty. The new Dietary Reference Intakes (DRI, 2011) increased greatly the Recommended Dietary allowances (RDA) from 200 to 600 IU/d (15 μg/d) for individuals from 1 to 70 years of age. These levels are not reached in winter, even in countries, like USA and Canada, where vitamin D milk fortification is mandatory and others like Japan and North-European countries despite high fish consumption. From 1 to 5 years of age and during adolescence, a winter vitamin D3 supplementation is necessary with 80.000 or 100.000 IU periodic loads every 3 months i.e. in November and February. In cases of an underlying risk, i.e. insufficient vitamin D photosynthesis in summertime (dark skin, wearing heavily skin-covering clothes, or several skin diseases), or digestive, renal or nutritional pathologies, use of some drugs, loading dose of 80.000 or 100.000 IU, every 3 months should be administered over the year., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Continuous sedation is an acknowledged medical practice in the management of refractory symptoms at the end of life. Guidelines and recommendations have been proposed in palliative care. This paper presents the state-of-the-art (definitions, indications, technical aspects) on continuous sedation followed by an ethical reflection essentially based on the "double effect" principle, on the impact on life expectancy and the assimilation of continuous sedation as a "natural death". Distinction between continuous sedation and legal euthanasia is clarified.

Chronic primary headache often cause significant interference with function and quality of life despite acute and preventive medicines. New treatments are emerging for pharmacologically intractable cluster headache and migraine. Occipital nerve stimulation in chronic cluster headache and botulinum toxin in chronic migraine represent the most promising therapies.

Antiepileptic drugs allow controlling seizures in 70% of patients. For the others, a presurgical work-up should be undertaken, especially if a focal seizure origin is suspected; however, only a fraction of pharmacoresistant patients will be offered resective (curative) surgery. In the last 15 years, several palliative therapies using extra- or intracranial electrical stimulations have been developed. This article presents the vagal nerve stimulation, the deep brain stimulation (targeting the mesiotemporal region or the thalamus), and the cortical stimulation "on demand". All show an overall long-term responder rate between 30-50%, but less than 5% of patients becoming seizure free. It is to hope that a better understanding of epileptogenic mechanisms and of the implicated neuronal networks will lead to an improvement of these proportions.

Therapeutic strategies for essential tremor (ET) and Parkinson's disease (PD) can be divided into two successive steps, one based on oral medications and the other, more invasive, using pumps or functional neurosurgery. When ET becomes refractory to propranolol, primidone and other, second-choice compounds, deep brain stimulation of the VIM nucleus of the thalamus can be considered. When PD becomes resistant to dopamine replacement therapy using various combinations of dopaminergic agents, then three options can be discussed: first, a subcutaneous apomorphine mini-pump, second, a jejunal levodopa-delivery system by means of percutaneous gastrostomy, and third, bilateral deep brain stimulation of the subthalamic nucleus. The above interventions are successful in about 80% of cases.

The role of the sympathetic nervous system (SNS) in the control of blood pressure and the occurrence of hypertension has been established both in animal models and in clinical practice. Patients resistant to treatment are common in clinical practice and require a new approach to optimize blood pressure control. The development of a catheter-based technique to denervate the kidneys for the treatment of high blood pressure was introduced recently. The concept was based on old data of surgical renal denervation which was effective but associated with important morbidity. Recent data shows that catheter-based renal denervation is feasible and safe in humans and preliminary clinical studies are very promising. These data need confirmation in larger randomised controlled trials with longer-term follow-up.

Treatment-resistant epilepsy, a very currently evoked concept in the literature, is frequently discussed in clinical practice. However, is there any valid definition for it? The large bibliography study of the Agency for Healthcare Research and Quality published in 2003 does not provide any consensual definition. Moreover, it points out the heterogeneous nature of the considered criteria. We report an expert's position on these criteria and the data related to the risk factors for treatment-resistance in the pediatric population.

Patients suffering from inflammatory or dysimmunitary diseases may develop various clinical responses to corticotherapy. This brief article describes the various cellular and molecular mechanisms which underly the genetic, endocrine and immunitary factors involved in corticosensitivity, corticoresistance and corticodependence.

Drug resistant malaria is mostly due to Plasmodium falciparum, a species highly prevalent in tropical Africa, Amazonia and South-East Asia and responsible for severe involvement of fever or anemia prompting more than a million death per year. Resistance originate from chromosomic mutations. Antimetabolite-resistant mutants (pyrimethamine and proguanil) are highly prevalent in Asia, America and East Africa. One to 3 point mutations on the dihydrofolate-reductase gene, the target enzyme, give moderate to high level of resistance. Molecular biology furnishes sensitive tools for population-based studies of resistance to these compounds. Four-aminoquinolines resistant mutants (chloroquine and amodiaquine) were encountered more than 10 years after a huge amount of these drugs has been sold. The level of resistance varies among parasites isolates populations. Impaired uptake of the drug by the parasite vacuole is a common characteristic of resistant strains. This phenotype is poorly correlated with PfMDR1 gene mutations on chromosome 5 but is strongly associated with a particular RFLP profile on chromosome 7. Amino-alcohol resistant falciparum malaria is scarce (quinine, mefloquine, halofantrine) and supposed to be associated with impaired uptake of the drug by the parasite, the mechanism of which is still unclear. In each of these three antimalarial drugs groups, the highly resistant level to a peticular compound, the highly prevalence of cross resistance of the malaria isolate. An established and strong drug pressure probably explains the multi-chemoresistance encoutered in South-East Asia and forests of South America. In Africa, frequent genetic recombinations in Plasmodium originates from a high level of malaria transmission, and falciparum chloroquine-resistance prevalence seems to stabilize at an equal level as chloroquine-sensitive malaria.

Resistance is often defined as a lack of therapeutic response. Cellular resistance involves a decrease in intracellular levels of the antitumor agent due to a variety of mechanisms. These mechanisms are active in tumors with initial resistance as well as in those which respond initially but fail to be completely destroyed by chemotherapy. Although acquired forms of resistance seem to be the result of selection, some studies suggest that antitumor agents may induce resistance. Four main mechanisms of resistance are currently being investigated: 1) multidrug resistance, involving expression of a membrane P-glycoprotein, responsible for resistance to hydrophobic cationic agents; 2) detoxification of hydrophilic agents by the enzyme glutathione-S-transferase; 3) increased production of enzymes targeted by antimetabolites; 4) mutation or decreased synthesis of topoisomerases I and II which are the targets of very recent antitumor agents. New data were presented at the 1992 symposium of the American Association for Cancer Research; expression of P-glycoprotein is controlled by the mutant protein P53, the oncogene ras and differentiation agents. Physiological effects of this molecule are related to the chloride pump. Bone marrow stem cells from transgenic mice obtained by transfection of the gene MDR1 in germ cells exhibit resistance. Many agents can reverse P-glycoprotein-related resistance. Results from three phase I trials with Cyclosporin A as reversion agent were reported. It is essential to conduct clinical trials in order to assess the true value of these new data which hold promise for improving the performance of antitumor agents.