[Cognitive decline in geriatric oncology: Trends, evaluation and treatment]. / Cancer de la personne âgée : rechercher, évaluer et prendre en charge le déclin cognitif.

Cancer prevalence increases with aging. Prevalent or incident neurocognitive disorders are frequent in geriatric oncology. Cognitive decline associated with cancer increases the risk of under or over-cancer treatment and makes therapeutic decisions complex. In this context, we present tools to optimize cognitive impairment screening, identification of underlying mechanisms and specific treatments. Geriatric specialists intervention can help global care, social services utilization and patient's orientation when ambulatory cares become difficult.

No evidence for the presence of genetic variants predisposing to psychotic disorders on the non-deleted 22q11.2 allele of VCFS patients.

The velo-cardio-facial syndrome (VCFS) is caused by hemizygous deletions on chromosome 22q11.2. The VCFS phenotype is complex and characterized by frequent occurrence of neuropsychiatric symptoms with up to 25-30% of cases suffering from psychotic disorders compared with only ~1% in the general population (odds ratio≈20-25). This makes the 22q11.2 deletion one of the most prominent risk factors for schizophrenia. However, its penetrance for neuropsychiatric phenotypes is incomplete suggesting that additional risk factors are required for disease development. These additional risk factors could lie anywhere on the genome, but by reducing the normal diploid to a haploid state, the 22q11.2 deletion could result in the unmasking of otherwise recessive alleles or functional variants on the non-deleted 22q11.2 allele. To test this hypothesis, we captured and sequenced the whole 22q11.2 non-deleted region in 88 VCFS patients with (n=40) and without (n=48) psychotic disorders to identify genetic variation that could increase the risk for schizophrenia. Single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variants were called and their distributions were compared between the two diagnostic groups using variant-, gene- and region-based association tests. None of these tests resulted in statistical evidence for the existence of a genetic variation in the non-deleted allele that would increase schizophrenia risk in VCFS patients. Power analysis showed that our study was able to achieve >80% statistical power to detect association of a risk variant with an odd ratio of ⩾22. However, it is certainly under-powered to detect risk variant of smaller effect sizes. Our study did not provide evidence that genetic variants of very large effect size located on the non-deleted 22q1.2 allele in VCFS patients increase the risk for developing psychotic disorders. Variants with smaller effects may be located in the remaining 22q11.2 allele and elsewhere in the genome. Therefore, whole exome or even genome sequencing for larger sample size would appear to be the next logical steps in the search for the genetic modifiers of the 22q11.2-deletion neuropsychiatric phenotype.

Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders.

BACKGROUND: In order to optimally integrate the use of high-throughput sequencing (HTS) as a tool in clinical diagnostics of likely monogenic disorders, we have created a multidisciplinary "Genome Clinic Task Force" at the University Hospitals of Geneva, which is composed of clinical and molecular geneticists, bioinformaticians, technicians, bioethicists, and a coordinator. METHODS AND RESULTS: We have implemented whole exome sequencing (WES) with subsequent targeted bioinformatics analysis of gene lists for specific disorders. Clinical cases of heterogeneous Mendelian disorders that could potentially benefit from HTS are presented and discussed during the sessions of the task force. Debate concerning the interpretation of identified variants and the content of the final report constitutes a major part of the task force's work. Furthermore, issues related to bioethics, genetic counseling, quality control, and reimbursement are also addressed. CONCLUSIONS: This multidisciplinary task force has enabled us to create a platform for regular exchanges between all involved experts in order to deal with the multiple complex issues related to HTS in clinical practice and to continuously improve the diagnostic use of HTS. In addition, this task force was instrumental to formally approve the reimbursement of HTS for molecular diagnosis of Mendelian disorders in Switzerland.

Multiplex targeted high-throughput sequencing for Mendelian cardiac disorders.

Mendelian cardiomyopathies and arrhythmias are characterized by an important genetic heterogeneity, rendering Sanger sequencing very laborious and expensive. As a proof of concept, we explored multiplex targeted high-throughput sequencing (HTS) as a fast and cost-efficient diagnostic method for individuals suffering from Mendelian cardiac disorders. We designed a DNA capture assay including all exons from 130 genes involved in cardiovascular Mendelian disorders and analysed simultaneously four samples by multiplexing. Two patients had familial hypertrophic cardiomyopathy (HCM) and two patients suffered from long QT syndrome (LQTS). In patient 1 with HCM, we identified two known pathogenic missense variants in the two most frequently mutated sarcomeric genes MYH7 and MYBPC. In patient 2 with HCM, a known acceptor splice site variant in MYBPC3 was found. In patient 3 with LQTS, two missense variants in the genes SCN5A and KCNQ were identified. Finally, in patient 4 with LQTS a known missense variant was found in MYBPC3, which is usually mutated in patients with cardiomyopathy. Our results showed that multiplex targeted HTS works as an efficient and cost-effective tool for molecular diagnosis of heterogeneous disorders in clinical practice and offers new insights in the pathogenesis of these complex diseases.

Increase in 20-50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation.

OBJECTIVE: Though vagus nerve stimulation (VNS) is an important option in pharmaco-resistant epilepsy, its mechanism of action remains unclear. The observation that VNS desynchronised the EEG activity in animals suggested that this mechanism could be involved in VNS antiepileptic effects in humans. Indeed VNS decreases spiking bursts, whereas its effects on the EEG background remain uncertain. The objective of the present study is to investigate how VNS affects local and inter regional syncronization in different frequencies in pharmaco-resistant partial epilepsy. METHODS: Digital recordings acquired in 11 epileptic subjects 1 year and 1 week before VNS surgery were compared with that obtained 1 month and 1 year after VNS activation. Power spectrum and synchronization were then analyzed and compared with an epileptic group of 10 patients treated with AEDs only. RESULTS: VNS decreases the synchronization of theta frequencies (P < 0.01), whereas it increases gamma power spectrum and synchronization (< 0.001 and 0.01, respectively). CONCLUSIONS: The reduction of theta frequencies and the increase in power spectrum and synchronization of gamma bands can be related to VNS anticonvulsant mechanism. In addition, gamma modulation could also play a seizure-independent role in improving attentional performances. SIGNIFICANCE: These results suggest that some antiepileptic mechanisms affected by VNS can be modulated by or be the reflection of EEG changes.

[The expanded program of vaccination: 25 years tomorrow]. / Le programme élargi de vaccination: 25 ans demain.

The expanded program on immunization will soon celebrate its 25th anniversary. The original program included vaccination against diphtheria, tetanus, pertussis, poliomyelitis, measles, and tuberculoses. It was expanded to include first yellow fever and hepatitis B and later haemophilus. Results are mixed. Diphtheria was under control but has made a major comeback since vaccination was halted in eastern Europe. Tetanus in newborns should no longer be a public health problem by 2005. Control of pertussis has not been achieved because the vaccine has been unsuccessful in interrupting transmission. Poliomyelitis is no longer reported in the Americas. Hopefully transmission of the wild virus will be stopped by 2003 and total eradication of poliomyelitis will be achieved by 2005. For several reasons, there has been an alarming increase in tuberculosis with an estimated annual incidence of 5 million cases worldwide. Eradication of measles was achieved in the Americas in 2000 and is expected in the European region by 2007 and in the east Mediterranean area by 2010. Current data on yellow fever and hepatitis B is inadequate, these vaccination being still poorly implemented in endemic areas. A more widespread use of the vaccine will be needed. However spending cutbacks and changing priorities in the Health Ministries will require a renewal of commitment to this immunization policy.

Radiolabelled monoclonal antibodies in clinical and surgical oncology: a review.

Over the past decade, the role of immunoscintigraphy using radiolabelled monoclonal antibodies has been steadily growing in clinical oncology, and in particular, in radioimmunotherapy and radioimmunoguided surgery for the treatment of primary, recurrent, and metastatic colorectal, ovarian, gastric, and prostate cancer. Herein, the authors review the requirements for successful tumour radioimmunodetection and related procedures.

Evidence of a kallikrein inhibitor in human kidney. A new ring of the kallikrein-renin-angiotensin-aldosterone chain.

By means of immunohistochemical reactions, the authors proved the inhibitor II-related immunoreactivity in distal convoluted tubules of human kidney. A sharp inhibitor II-related immunoreactivity was also present in the blood vessels' wall. On the contrary, in the wall of proximal tubules and glomeruli only low reactivity was found. The demonstration of an inhibitor II-related immunoreactivity in the distal convoluted tubules and vessels of human kidney represents a strong evidence that an inhibitor of kallikrein exists and acts also in humans as an important key in the kallikrein-renin-angiotensin-aldosterone chain and hitherto confirms the experimental data of the literature. The proved inhibitor in the human kidney may intervene in the modulation of the kallikrein-kinin system and thus represents a key role in the intrarenal mechanisms related to the blood flow and arterial pressure regulation.

[Intravascular surgery in the treatment of peripheral arteriopathies: our experience]. / La chirurgia endovascolare nel trattamento delle arteriopatie periferiche: la nostra esperienza.

The Authors, through a review of their vascular surgery experience in the treatment of PAOD at the III General Surgery Institute directed by Prof. G. Di Matteo (University, of Rome), focus their attention on endovascular surgery. Initially considered as an effective complement to "traditional surgery" rapidly its role has grown as an effective alternative for a number of vascular patients.

The immunolocalization of PGP 9.5 in normal human kidney and renal cell carcinoma.

The Authors studied the localization of protein gene product (PGP) 9.5-like immunoreactivity in normal human kidney tissue and compared the results with the same immunostaining in renal cell carcinoma. PGP 9.5-like immunoreactivity was found in cells of distal convoluted tubules and in some glomerular capillaries. The cells of proximal convoluted tubules did not show any immunostaining. Sections from renal cell carcinoma showed a very low immunostaining or were negative for PGP 9.5. As PGP 9.5 is a marker of the diffuse endocrine system, the Authors believe that the stained cells of distal tubules should be considered as neuroendocrine cells. The negative reaction to PGP 9.5 antibodies in renal cell carcinoma is rather surprising since not only tumours of neuroectodermal origin, but also tumours of other origin and tissues from some chronic degenerative diseases show a positive reaction. The explication of a negative reaction in renal cell carcinoma remains open: one of the possible explanations could be the specific histogenesis of this tumour.

[Method of biopsy and ultrastructural study of the parathyroid gland in patients with primary hyperparathyroidism]. / Tecnica di prelievo e studio ultrastrutturale della ghiandola paratiroide nei pazienti con iperparatiroidismo primario.

The authors suggest a new method of biopsy of a seemingly normal human parathyroid gland during surgery for parathyroid adenoma. Such a method provides adequate surgical specimen to rule out a likely diffuse hyperplastic disease associated with the parathyroid adenoma, and for the ultrastructural study of the gland, without any risk of postoperative complication. In all patients, ultrastructural examination showed an abnormal cell population and signs of glandular atrophy as a consequence of the high level of serum calcium due to hormonal hyperfunction of the parathyroid adenoma.

[Fibrous tumors localized in the pleura]. / Tumori fibrosi localizzati della pleura (TFLP).

Localized fibrous tumour of the pleura is an uncommon condition which in few cases may exhibit malignant behaviour. Herein the Authors report a large review on this intrathoracic neoplasm focusing, in particular, on differential diagnosis between benign and malignant variants.

Parenteral magnesium sulphate restores regional contractile function in the post-ischaemic canine myocardium.

The effects of parenteral magnesium sulphate (MS) on the regional contractile response of stunned myocardium was examined in 45 pentobarbital anaesthetized dogs. The hearts were instrumented to measure left ventricular pressure (LVP), coronary flow velocity (CFV), mean arterial blood pressure (MAP), and regional contractile function (percent segment shortening, %S; and end-diastolic segment length, EDL). Stunning was produced by a 10 min occlusion of the first descending branch of the left circumflex coronary artery. Immediately upon release of the occlusion, either magnesium sulphate or a dextrose vehicle (D5W, n = 15) was infused. Magnesium sulphate was given intravenously (IV-MS, 100 mg/kg, n = 15) or intracoronarily (IC-MS, 1.5 mg/kg, n = 15). Coronary occlusion was consistently associated with significant decreases in coronary flow velocity and %S in all groups. Following IV-MS, heart rate (HR) and mean arterial blood pressure decreased significantly from preocclusion values, whereas end-diastolic segment length tended to increase and left ventricular pressure remained constant. IC-MS did not produce any changes in heart rate, mean arterial blood pressure, end- diastolic segment length or left ventricular pressure. At the end of the magnesium sulphate infusion (IV or IC), and for the next 60 min, %S returned to or above pre-occlusion values (P < 0.05 vs. D5W). Dyskinesia and hypokinesia were abolished in the magnesium sulphate groups, but were still present in the D5W group at the end of the 60 min period (P < 0.05 vs. pre-occlusion). We conclude that parenteral magnesium sulphate significantly improves regional contractile function in the stunned myocardium. Data from the IC-MS group would suggest a direct myocardial effect, independent of changes in preload, afterload, heart rate or flow.

On the use of parenteral magnesium salts in the treatment of acute ischaemic heart disease: a brief review.

With the advent of pharmacological, mechanical and surgical revascularization as firstline therapies in acute coronary artery disease syndromes, the search for adjunctive pharmacotherapy against reocclusion and reperfusion injury has intensified. In addition, safe pharmacotherapeutic intervention conferring survival advantage is required for those at high risk ineligible for recanalization or beta blockade. Of major importance, in this vein, is the intriguing association between parenteral magnesium and the amelioration of myocardial ischaemia and the eradication of lethal ischaemic ventricular arrhythmias reasserted in both animal and human studies. In addition, in more recent years, parenteral magnesium has been linked to the amelioration of reperfusion injury in animal experiments. In this paper we shall review the literature with respect to myocardial ischaemia, its pathophysiology and treatments. In doing so, we shall present data that strongly supports the logistic use of parenteral magnesium compounds as essential therapy in the treatment of acute ischaemic heart disease associated with necrosis, and a potential role in ablating reperfusion injury.

[Diffuse cortical nephroblastomatosis. Apropos of a case]. / La néphroblastomatose corticale diffuse. A propos d'une observation.

The authors report a case of massive bilateral, and asymmetric nephroblastomatosis which was treated successfully by nephrectomy and chemotherapy. The authors discuss the clinico-pathologic significance of the present case and insist upon the requirement of a treatment (i-e-chemotherapy) in every case.