Multifocalité du carcinome épidermoïde sur les voies digestive supérieure et respiratoire distale : technicité du diagnostic endoscopique [Multiple squamous cell carcinoma of the upper digestive and lower respiratory tracts : methodology of endoscopic screening]

L'étude porte sur 951 porteurs d'un cancer primaire bucco-pharyngo-laryngé, et révèle un taux de multifocalité du carcinome épidermoïde sur les voies digestive supérieure (bouche-pharynx-oesophage) et aérienne distale (larynx-trachée-bronches) s'élevant à 14,5 %. Les secondes localisations peuvent être simultanées (6,4 %) ou successives (8,1 %) à la découverte du premier cancer: dès la deuxième année du follow-up leur incidence dépasse celle des récidives. Elles se localisent tant au niveau ORL (8,5 %) qu'oesophagien (3 %) ou bronchique (3 %). Le cancer du voile présente un taux de multifocalité particulièrement élevé (51 %). Les auteurs décrivent un type d'endoscopie de dépistage (bucco-pharyngo-oesophago-laryngo-trachéobronchoscopie) dont la fiabilité repose sur une technicité spécifique d'une part, et sur la connaissance des caractéristiques propres aux secondes localisations d'autre part. Ce dépistage systématique permet de détecter les tumeurs secondaires à un stade le plus souvent précoce et encore asymptomatique.

Cytokine mRNA profile of Epstein-Barr virus-stimulated highly differentiated T cells in multiple sclerosis: a pilot study.

The reason why EBV-specific cellular immune responses are abnormal in multiple sclerosis (MS) patients is still missing. In this exploratory pilot study, we assessed IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-17, IFN-gamma, TGF-beta1 and FOXP3 mRNA expression in EBV-stimulated highly differentiated T cells (T(HD)) of MS patients and healthy controls (HC). We found increased levels of IFN-gamma and IL-4 mRNA in CD8+ T(HD) cells of MS patients. All the other tested molecules were expressed similarly in MS patients and HC. Interestingly, increased IFN-gamma and IL-4 suggest that the control of EBV replication may be insufficient in MS patients.

African tick-bite fever: a new entity in the differential diagnosis of multiple eschars in travelers. Description of five cases imported from South Africa to Switzerland.

African tick-bite fever (ATBF) is a newly described spotted fever rickettsiosis that frequently presents with multiple eschars in travelers returning from sub-Saharan Africa and, to a lesser extent, from the West Indies. It is caused by the bite of an infected Amblyomma tick, whose hunting habits explain the typical presence of multiple inoculation skin lesions and the occurrence of clustered cases. The etiological agent of ATBF is Rickettsia africae, an emerging tick-borne pathogenic bacterium. We describe herein a cluster of five cases of ATBF occurring in Swiss travelers returning from South Africa. The co-incidental infections in these five patients and the presence of multiple inoculation eschars, two features pathognomonic of this rickettsial disease, suggested the diagnosis of ATBF. Indeed, the presence of at least one inoculation eschar is observed in 53-100% of cases and multiple eschars in 21-54%. Two patients presented regional lymphadenitis and one a mild local lymphangitis. Though a cutaneous rash is described in 15-46% of cases, no rash was observed in our series. ATBF was confirmed by serology. Thus, ATBF has recently emerged as one of the most important causes of flu-like illness in travelers returning from Southern Africa. The presence of one or multiple eschars of inoculation is an important clinical clue to the diagnosis. It can be confirmed by serology or by PCR of a biopsy of the eschar. Culture can also be done in reference laboratories. Dermatologists and primary care physicians should know this clinical entity, since an inexpensive and efficient treatment is available.

Increased EBV Reactivation in the Cerebrospinal Fluid of Patients with Early Multiple Sclerosis

Epstein-Barr virus (EBV) has been consistently associated with multiple sclerosis (MS), but whether this virus is a trigger of MS remains undetermined. Recently, EBV-infected B cells recognized by activated CD8_ T cells have been detected in the meninges of autopsied MS patients. In addition, a strong EBV-specific CD8_ T cell response in the blood of patients with MS of recent onset was reported. Here, to further explore the putative relationship between MS and EBV, we assessed the EBV-specific cellular and humoral immune responses in the blood and the cerebrospinal fluid (CSF) of patients with early MS or other neurological diseases, separated into inflammatory (IOND) and non-inflammatory (NIOND) groups. The MS non-associated neurotropic herpesvirus cytomegalovirus (CMV) served as a control. Fifty-eight study subjects were enrolled, including 44 patients (13 with early MS (onset of MS less than one year prior to the assay), 15 with IOND and 16 with NIOND) in the immunological arm of the study. The cellular immune response was investigated using a functional CFSE cytotoxic T lymphocyte (CTL) assay performed with short-term cultured EBV- or CMVspecific effector T cells from the CSF and the blood. The humoral immune response specific for these two viruses was also examined in both the blood and the CSF. The recruitment of a given virusspecific antibody in the CSF as compared to the blood was expressed as antibody indexes (AI). We found that, in the CSF of early MS patients, there was an enrichment in EBV-, but not CMV-specific, CD8_ CTL as compared to the CSF of IOND (P_ 0.003) and NIOND patients (P_0.0009), as well as compared to paired blood samples (P_0.005). Additionally, relative viral capsid antigen (VCA)-, but not EBV encoded nuclear antigen 1 (EBNA1)- or CMV-specific, AI were increased in the CSF of early MS as compared to IOND (P_0.002) or NIOND patients (P_0.008) and correlated with the EBVspecific CD8_ CTL responses in the CSF (rs_0.54, P_0.001). Fourteen additional patients were enrolled in the virological arm of the study: using semi-nested PCR, EBV-encoded nuclear RNA1 (EBER1)-a transcript expressed during all stages of EBV infection-was detected in the CSF of 2/4 early MS, but only 1/6 IOND and 0/4 NIOND patients. Altogether, our data suggest that a reactivation of EBV, but not CMV, is taking place in the central nervous system of patients with MS of recent onset. These data significantly strengthen the link between EBV and MS and may indicate a triggering role of EBV in this disease. This work was supported by grants from the Swiss National Foundation and from the Swiss Society for Multiple Sclerosis.

Modifications neurocomportementales secondaires à la sclérose en plaques [Neurobehavioral changes occurring during multiple sclerosis]

Behavioral changes occurring in patients affected by multiple sclerosis (MSI are often neglected by physicians but are actually part of the clinical spectrum of the disease. In addition, they are known to be responsible for a decline in the quality of life of MS patients. Recently, there has been a growing interest to investigate changes in the emotional experience of MS patients and their decision making, showing that the ability to take advantageous decisions was altered in MS. This paper reviews existing data on this topic.

Origin and outcome of multiple pregnancies in Bern, Switzerland, 1995-2006 and the current proposal of the Swiss parliament to revise the Swiss law of reproductive medicine: Switzerland quo vadis?

INTRODUCTION: Infertility treatments are a major source of the increase in multiple pregnancies (MPs). AIMS: The aims of the present study were (1.) to investigate the origin and maternal/neonatal outcomes of MP and (2.) to review the different measures that can be adopted to reduce these serious complications. METHODS: The study included all women with multiple births between 1 January 1995 and 31 December 2006 at the University Hospital of Bern, Switzerland. The outcomes associated with the various origins of MP (natural conception, ovarian stimulation [OS] ‒ in-vitro fertilisation [IVF-ICSI]) were analysed using a multinomial logistic regression model. An analysis of the Swiss law on reproductive medicine and its current proposed revision, as well as a literature review using Pubmed, was carried out. RESULTS: A total of 592 MP were registered, 91% (n = 537) resulted in live births. There was significantly more neonatal/maternal morbidity in MP after OS compared with natural conception and even with the IVF-ICSI group. With a policy of elective single embryo transfer (eSET), twin rates after IVF-ICSI can be reduced to <5% and triplets to <1%. CONCLUSIONS: After OS, more triplets are found and the outcome of MP is worse. MP is known to be associated with morbidity, mortality, and economic and social risks. To counteract these complications (1.) better training for physicians performing OS should be encouraged and (2.) the Swiss law on reproductive medicine needs to be changed, with the introduction of eSET policies. This would lead to a dramatic decrease in neonatal and maternal morbidity/mortality as well as significant cost reductions for the Swiss healthcare system.

A step-by-step tutorial to use HierFstat to analyse populations hierarchically structured at multiple levels.

The populations of parasites and infectious agents are most of the time structured in complex hierarchy that lies beyond the classical nested design described by Wright's F-statistics (F(IS), F(ST) and F(IT)). In this note we propose a user-friendly step-by-step notice for using recent software (HierFstat) that computes and test fixation indices for any hierarchical structure. We add some tricks and tips for some special data kind (haploid, single locus), some other procedure (bootstrap over loci) and how to handle crossed factors.

Monitoring multiple angiogenesis-related molecules in the blood of cancer patients shows a correlation between VEGF-A and MMP-9 levels before treatment and divergent changes after surgical vs. conservative therapy.

Anti-angiogenic therapies are currently in cancer clinical trials, but to date there are no established tests for evaluating the angiogenic status of a patient. We measured 11 circulating angiogenesis-associated molecules in cancer patients before and after local treatment. The purpose of our study was to screen for possible relationships among the different molecules and between individual molecules and tumor burden. We measured VEGF-A, PlGF, SCF, MMP-9, EDB+ -fibronectin, sVEGFR-2, sVEGFR-1, salphaVbeta3, sTie-2, IL-8 and CRP in the blood of 22 healthy volunteers, 17 early breast, 17 early colorectal, and 8 advanced sarcoma/melanoma cancer patients. Breast cancer patients had elevated levels of VEGF-A and sTie-2, colorectal cancer patients of VEGF-A, MMP-9, sTie-2, IL-8 and CRP, and melanoma/sarcoma patients of sVEGFR-1. salphaVbeta3 was decreased in colorectal cancer patients. A correlation between VEGF-A and MMP-9 was found. After tumor removal, MMP-9 and salphaVbeta3 significantly decreased in breast and CRP in colorectal cancer, whereas sVEGFR-1 increased in colorectal cancer patients. In sarcoma/melanoma patients treated regionally with TNF and chemotherapy we observed a rise in VEGF-A, SCF, VEGFR-2, MMP-9, Tie-2 and CRP, a correlation between CRP and IL-8, and a decreased in sVEGFR-1 levels. In conclusion, among all factors measured, only VEGF-A and MMP-9 consistently correlated to each other, elevated CRP levels were associated with tumor burden, whereas sVEGF-R1 increased after tumor removal in colorectal cancer. Treatment with chemotherapy and TNF induced changes consistent with an angiogenic switch. These results warrant a prospective study to compare the effect of surgical tumor removal vs. chemotherapy on some of these markers and to evaluate their prognostic/predictive value.

Complete Maxillo-Mandibular Syngnathia in a Newborn with Multiple Congenital Malformations.

Syngnathia is an extremely rare condition involving congenital fusion of the maxilla with the mandible. Clinical presentations vary from simple mucosal bands (synechiae) to complete bony fusion (synostosis). Most cases are unilateral incomplete fusions. We report the case of a severely growth-retarded newborn infant with complete synostosis of the mandible with the maxilla and the zygoma associated with cleft palate, choanal atresia, deafness, delayed cerebral white matter development, and genital and limb malformations. Extensive genetic analysis did not reveal any mutations. This association of multiple congenital malformations may represent an entity distinct from previously described syndromes associated with syngnathia.

In vitro effect of malachite green on Candida albicans involves multiple pathways and transcriptional regulators UPC2 and STP2.

In this study, we show that a chemical dye, malachite green (MG), which is commonly used in the fish industry as an antifungal, antiparasitic, and antibacterial agent, could effectively kill Candida albicans and non-C. albicans species. We have demonstrated that Candida cells are susceptible to MG at a very low concentration (MIC that reduces growth by 50% [MIC(50)], 100 ng ml(-1)) and that the effect of MG is independent of known antifungal targets, such as ergosterol metabolism and major drug efflux pump proteins. Transcriptional profiling in response to MG treatment of C. albicans cells revealed that of a total of 207 responsive genes, 167 genes involved in oxidative stress, virulence, carbohydrate metabolism, heat shock, amino acid metabolism, etc., were upregulated, while 37 genes involved in iron acquisition, filamentous growth, mitochondrial respiration, etc., were downregulated. We confirmed experimentally that Candida cells exposed to MG resort to a fermentative mode of metabolism, perhaps due to defective respiration. In addition, we showed that MG triggers depletion of intracellular iron pools and enhances reactive oxygen species (ROS) levels. These effects could be reversed by the addition of iron or antioxidants, respectively. We provided evidence that the antifungal effect of MG is exerted through the transcription regulators UPC2 (regulating ergosterol biosynthesis and azole resistance) and STP2 (regulating amino acid permease genes). Taken together, our transcriptome, genetic, and biochemical results allowed us to decipher the multiple mechanisms by which MG exerts its anti-Candida effects, leading to a metabolic shift toward fermentation, increased generation of ROS, labile iron deprivation, and cell necrosis.

Mass casualty incidents with multiple burn victims: rationale for a Swiss burn plan.

INTRODUCTION: Mass casualty incidents involving victims with severe burns pose difficult and unique problems for both rescue teams and hospitals. This paper presents an analysis of the published reports with the aim of proposing a rational model for burn rescue and hospital referral for Switzerland. METHODS: Literature review including systematic searches of PubMed/Medline, reference textbooks and journals as well as landmark articles. RESULTS: Since hospitals have limited surge capacities in the event of burn disasters, a special approach to both prehospital and hospital management of these victims is required. Specialized rescue and care can be adequately met and at all levels of needs by deploying mobile burn teams to the scene. These burn teams can bring needed skills and enhance the efficiency of the classical disaster response teams. Burn teams assist with both primary and secondary triage, contribute to initial patient management and offer advice to non-specialized designated hospitals that provide acute care for burn patients with Total Burn Surface Area (TBSA) <20-30%. The main components required for successful deployments of mobile burn teams include socio-economic feasibility, streamlined logistical implementation as well as partnership coordination with other agencies including subsidiary military resources. CONCLUSIONS: Disaster preparedness plans involving burn specialists dispatched from a referral burn center can upgrade and significantly improve prehospital rescue outcome, initial resuscitation care and help prevent an overload to hospital surge capacities in case of multiple burn victims. This is the rationale behind the ongoing development and implementation of the Swiss burn plan.

Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: A challenge for neuroprotection.

There is currently no approved neuroprotective pharmacotherapy for acute conditions such as stroke and cerebral asphyxia. One of the reasons for this may be the multiplicity of cell death mechanisms, because inhibition of a particular mechanism leaves the brain vulnerable to alternative ones. It is therefore essential to understand the different cell death mechanisms and their interactions. We here review the multiple signaling pathways underlying each of the three main morphological types of cell death - apoptosis, autophagic cell death and necrosis - emphasizing their importance in the neuronal death that occurs during cerebral ischemia and hypoxia-ischemia, and we analyze the interactions between the different mechanisms. Finally, we discuss the implications of the multiplicity of cell death mechanisms for the design of neuroprotective strategies.

Recessive multiple epiphyseal dysplasia (rMED) with homozygosity for C653S mutation in the DTDST gene - phenotype, molecular diagnosis and surgical treatment of habitual dislocation of multilayered patella: case report.

BACKGROUND: Multiple epiphyseal dysplasia (MED) is one of the more common generalised skeletal dysplasias. Due to its clinical heterogeneity diagnosis may be difficult. Mutations of at least six separate genes can cause MED. Joint deformities, joint pain and gait disorders are common symptoms. CASE PRESENTATION: We report on a 27-year-old male patient suffering from clinical symptoms of autosomal recessive MED with habitual dislocation of a multilayered patella on both sides, on the surgical treatment and on short-term clinical outcome. Clinical findings were: bilateral hip and knee pain, instability of femorotibial and patellofemoral joints with habitual patella dislocation on both sides, contractures of hip, elbow and second metacarpophalangeal joints. Main radiographic findings were: bilateral dislocated multilayered patella, dysplastic medial tibial plateaus, deformity of both femoral heads and osteoarthritis of the hip joints, and deformity of both radial heads. In the molecular genetic analysis, the DTDST mutation g.1984T > A (p.C653S) was found at the homozygote state. Carrier status was confirmed in the DNA of the patient's parents. The mutation could be considered to be the reason for the patient's disease. Surgical treatment of habitual patella dislocation with medialisation of the tibial tuberosity led to an excellent clinical outcome. CONCLUSIONS: The knowledge of different phenotypes of skeletal dysplasias helps to select genes for genetic analysis. Compared to other DTDST mutations, this is a rather mild phenotype. Molecular diagnosis is important for genetic counselling and for an accurate prognosis. Even in case of a multilayered patella in MED, habitual patella dislocation could be managed successfully by medialisation of the tibial tuberosity.

Male reproductive success and multiple paternity in wild, low-density populations of the adder (Vipera berus).

We studied for the first time the occurrence of multiple paternity, male reproductive success, and neonate survival in wild, low-density adder (Vipera berus) populations using 13 microsatellite loci. Paternity was assigned for 15 clutches, collected during 3 years. Our data demonstrated that multiple paternity can occur at a high level (69%) in natural populations of V. berus, even if the density of adults is low. The high proportion of multiple sired clutches was comparable to the proportion observed in captive populations. Male reproductive success significantly increased with body length, and only the largest males successfully sired entire clutches. Finally, no relationship was detected between the number of fathers per clutch and neonate survival. These results suggest that multiple matings could be beneficial in populations with high level of inbreeding or low male fecundity.