Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH). In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the ENG gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients. This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.

Immunological abnormalities associated with hereditary haemorrhagic telangiectasia.

OBJECTIVE: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder related to mutations in one of the coreceptors to the transforming growth factor-ß superfamily (ALK1 or endoglin). Besides the obvious vascular symptoms (epistaxis and arteriovenous malformations), patients have an unexplained high risk of severe bacterial infections. The aim of the study was to assess the main immunological functions of patients with HHT using the standard biological tests for primary immunodeficiencies. DESIGN, SETTING AND SUBJECTS: A prospective single-centre study of 42 consecutive adult patients with an established diagnosis of HHT was conducted at the National French HHT Reference Center (Lyon). Lymphocyte subpopulations and proliferation capacity, immunoglobulin levels and neutrophil and monocyte phagocytosis, oxidative burst and chemotaxis were assessed. RESULTS: Innate immunity was not altered in patients with HHT. With regard to adaptive immunity, significant changes were seen in immunological parameters: primarily, a lymphopenia in patients with HHT compared with healthy control subjects affecting mean CD4 (642 cells µL(-1) vs. 832 cells µL(-1) , P < 0.001), CD8 (295 cells µL(-1) vs. 501 cells µL(-1) , P < 0.0001) and natural killer (NK) cells (169 cells µL(-1) vs. 221 cells µL(-1) , P < 0.01), associated with increased levels of immunoglobulins G and A. This lymphopenia mainly concerned naïve T cells. Proliferation capacities of lymphocytes were normal. Lymphopenic patients had a higher frequency of iron supplementation but no increase in infection rate. Lower levels of immunoglobulin M and a higher rate of pulmonary arteriovenous malformations were found amongst patients with a history of severe infection. CONCLUSIONS: Patients with HHT exhibit immunological abnormalities including T CD4, T CD8 and NK cell lymphopenia and increased levels of immunoglobulins G and A. The observed low level of immunoglobulin M requires further investigation to determine whether it is a specific risk factor for infection in HHT.

[Radiation pneumonitis: a rare and potentially severe pneumonia. Usefulness of corticosteroids]. / Pneumopathie post-radique aiguë: une pneumopathie rare, potentiellement grave et très corticosensible.

We report a 80-year-old woman who presented with asthenia, confusion and abdominal pain, leading to a diagnosis of severe pneumonia complicated by a colonic pseudo-obstruction. The unfavourable outcome with antibiotic treatment and a recent past medical history of thoracic radiotherapy pointed to a possible diagnosis of radiation pneumonitis. Absence of other explanation and the rapid improvement with corticosteroids confirmed this rare and potentially serious diagnosis, especially among elderly people.

Measurement of glucose in blood with a phenylboronic acid optical sensor.

BACKGROUND: Current methods of glucose monitoring rely predominantly on enzymes such as glucose oxidase for detection. Phenylboronic acid receptors have been proposed as alternative glucose binders. A unique property of these molecules is their ability to bind glucose in a fully reversible covalent manner that facilitates direct continuous measurements. We examined (1) the ability of a phenylboronic-based sensor to measure glucose in blood and blood plasma and (2) the effect on measurement accuracy of a range of potential interferents. We also showed that the sensor is able to track glucose fluctuations occurring at rates mimicking those experienced in vivo. METHOD: In vitro static measurements of glucose in blood and blood plasma were conducted using holographic sensors containing acrylamide, N,N'-methylenebisacrylamide, 3-acrylamidophenylboronic acid, and (3-acrylamidopropyl) trimethylammonium chloride. The same sensors were also used for in vitro measurements performed under flow conditions. RESULTS: The opacity of the liquid had no affect on the ability of the optical sensor to measure glucose in blood or blood plasma. The presence of common antibiotics, diabetic drugs, pain killers, and endogenous substances did not affect the measurement accuracy, as shown by error grid analysis. Ex vivo flow experiments showed that the sensor is able to track changes accurately in concentration occurring in real time without lag or evidence of hysteresis. CONCLUSIONS: The ability of phenylboronic acid sensors to measure glucose in whole blood was demonstrated for the first time. Holographic sensors are ideally suited to continuous blood glucose measurements, being physically and chemically robust and potentially calibration free.

Continuous blood glucose monitoring with a thin-film optical sensor.

BACKGROUND: We recently described a holographic optical sensor with improved selectivity for glucose over fructose that was based on a thin-film polymer hydrogel containing phenylboronic acid receptors. The aim of the present work was to measure glucose in human blood plasma as opposed to simple buffers and track changes in concentration at a rate mimicking glucose changes in vivo. METHODS: We used holographic sensors containing acrylamide, N,N'-methylenebisacrylamide, 3-acrylamidophenylboronic acid, and (3-acrylamidopropyl)trimethylammonium chloride to measure 7 human blood plasma samples at different glucose concentrations (3-33 mmol/L) in static mode. Separately, using a flow cell, the glucose concentration was varied at approximately 0.17-0.28 mmol(-1) x L(-1) x min(-1), and the sensor's ability to continuously monitor glucose was investigated over an extended period. RESULTS: We subjected the results of the ex vivo static measurements to error grid analysis. Of 46 measurements, 42 (91.3%) fell in zone A of a Clarke error grid, and the remainder (8.7%) fell in zone B. The ex vivo flow experiments showed that the sensor is able to accurately track changes in concentration occurring in real time without lag or evidence of hysteresis. CONCLUSIONS: We demonstrate the ability of a phenylboronic acid-based sensor to measure glucose in human blood plasma for the 1st time in vitro. Holographic glucose sensors can be used without recourse to recalibration. Their robust nature, coupled with their format flexibility, makes them an attractive alternative to conventional electrochemical enzyme-based methods of glucose monitoring for people with diabetes.

[Engineering of osseous cells and bioartificial tissues]. / Ingénierie des cellules osseuses et tissus bioartificiels.

The association of osteogenic stem cells to a synthetic carrier makes possible the elaboration of bioartificial tissue. Numerous phosphocalcic ceramics does not trigger a foreign body reaction when implanted in bone tissue and thus, a number of materials are available osteogenic stem cell carriers to replace the bone tissue. Several methods can be used to harvest these cells. Their multiplication in vitro can lead to the appearance of anomalies of their metabolism or their karyotype. The culture method also seems to have a major influence on their appearance. The presence of these anomalies could explain the variability of results in terms of bone extracellular matrix synthesis after cell reimplantation. The surgical technique used for the implantation is also of influence. A method suppressing the in vitro period has been developed to avoid any cell metabolism modification. This method allows for a very reproducible bone synthesis in ectopic site. The availability of human embryonic stem cells could help to develop cell graft techniques for bone reconstruction.

Degradation of hydroxylapatite, fluorapatite, and fluorhydroxyapatite coatings of dental implants in dogs.

Calcium phosphate coatings on dental implants enhance integration of the material. Resorption of the ceramic coatings has raised some concern about the behavior of the bone-implant interfaces after the coating disappearance. Substitution of the OH- ions by fluoride in the hydroxylapatite (HA) lattice makes the calcium phosphate more stable. We investigated the degradation rate of dental implants with 50- and 100-microm coatings of HA, fluorapatite (FA), or fluorhydroxylapatite (FHA). The implants were inserted in dog jaws and retrieved for histological analysis after 3, 6, and 12 months. The thickness of the calcium phosphate coatings was evaluated using an image analysis device. A relative resorption index and its standard deviation were studied. HA and FA coatings (even at 100-microm thickness) were almost totally degraded within the implantation period. In contrast, the FHA coatings did not show significant degradation during the same period. The standard deviation showed that the resorption process for FHA with thicknesses of 50 or 100 microm was the same. Such a difference was not observed between the 50- and 100-microm thick coatings of FA and HA. In conclusion, the FHA coatings showed good integration in the bone tissue and lasted much longer than classic calcium phosphate coatings.

[Tartrate-resistant acid phosphatases (TRAP) and cytology of pseudosynovial membranes]. / Phosphatases acides tartrate résistantes (TRAP) et cytologie des membranes pseudo-synoviales.

Pseudo-synovial membranes are found at the interface between bone and aseptically lost prostheses. They are supposed to be due to the release of material debris at the interface with bone. They are mostly composed of macrophages and giant cells, and some fibrocytes in the deep layer of the membrane. The different histological structures present in these membranes have been largely described. Very recently, Kadoya et al. have demonstrated that a lot of giant cells present in the pseudo-synovial membranes show a tartrate resistant acid phosphatase activity in the presence of more than 100 mM tartrate. They have also shown that some of these cells were responsible for bone degradation. We have studied the tartrate acid phosphatase activity of a series of 10 membranes containing various material debris: titanium alloy, stainless steel, polymethylmethacrylate, polyethylene. Many mono or multinucleated cells showed a TRAP activity in their lysosomes in the presence of a 400 mM tartrate concentration. In certain membranes, these cells showed a TRAP activity located in the nucleus. This study shows that the macrophage population is very heterogeneous and the difference between osteoclasts and giant cells may be unclear.

A study of structure and degradation of nonpolymeric biomaterials implanted in bone using reflected and transmitted light microscopy.

Orthopedic biomaterials currently are made of metal alloy coated with one or more thin layers of dense or porous ceramic or metal. Sections of these materials implanted in human bone were made without altering the implant or bone-implant interfaces. Bone containing an implant was fixed and then embedded in polymethylmethacrylate. Thick sections were made using a cooled, low speed diamond saw, then ground and polished. Some were stained by fuchsin-toluidine staining solution, others were acid etched to reveal the structure of the metal contained in the prosthesis. Observation by reflected and transmitted light microscopy revealed microstructure of the implant material as well as features of the surrounding tissues.

[Histological analysis of the bone/prosthesis interface in man after implantation of a hip prosthesis coated with plasma-sprayed hydroxyapatite]. / Analyse histologique de l'interface os/prothèse après implantation humaine de prothèses de hanche revêtues d'hydroxyapatite par projection plasma.

Thin coatings of calcium phosphate hydroxyapatite on metal alloys provide to these materials biological properties of calcium phosphates. We have analysed, using histological techniques or newly developed scanning electronic microscopy techniques, hip prostheses implanted into humans for periods from a few days up to twenty six months. The results of these analyses confirm the good osteointegration of these prostheses observed during clinical studies. Moreover, an active remodeling of the bone in contact with the ceramic-coating was observed. The coating was also concerned by the remodeling process and evolved once implanted.

New observations on middle term hydroxyapatite-coated titanium alloy hip prostheses.

HA-coated hip prostheses were retrieved from elderly patients after death. Histological analysis, scanning electron microscopy and microanalysis by energy-dispersive X-ray spectrometry were performed on the same sections. These revealed good osseointegration of the implant material and evolution of bone and material.

Bonding of hydroxyapatite-coated femoral prostheses. Histopathology of specimens from four cases.

We examined specimens of hydroxyapatite-coated femoral prostheses from four patients who had died within nine months of implantation for fractured neck of femur. Histology showed newly formed immature bone overlying the hydroxyapatite coating with new trabeculae bridging to the endosteal bone layer. In the diaphysis, where there had been contact between the hydroxyapatite and the cortex, there was dense, firmly anchored bone with an haversian architecture. In other places the newly formed bone had a trabecular structure, containing bone marrow tissue with normal cellularity. It appeared that biological osseointegration had taken place.

Physicochemical characterization of deposits associated with HA ceramics implanted in nonosseous sites.

Pellets of well-characterized microporous hydroxyapatite (HA) ceramic were implanted in hamsters in two nonosseous sites: (1) in the fatty tissue of the gingival crease, far from bony tissue and (2) in intraperitoneal sites. The implants in site 1 were placed directly in contact with tissues, cells, and extracellular fluids while the implants in site 2 were placed in special chambers made of plexiglass cylinders covered in both ends with millipore filters, preventing contact with tissues and cells, but not with extracellular fluids. The hamsters were sacrificed and the implants recovered after 8, 16, 30, 150, and 365 days. The pellets were characterized using x-ray diffraction, infrared absorption, thermogravimetry, scanning and transmission electron microscopy, and calcium and phosphate analyses before and after implantation. Physicochemical analyses of HA ceramic implants before and after implantation demonstrated the formation of new material which was significantly different from the HA ceramic in terms of the following: (a) morphology (size of shape) of crystals; (b) intimate association of the inorganic phase of the new material with an organic phase similar to inorganic/organic association in bone; (c) the inorganic phase of the new material is a CO3-apatite, similar to that of bone, while the HA in ceramic is CO3-free; (d) electron diffraction of apatite of new material is similar to that of bone apatite. This study also demonstrated that the new material associated with the HA ceramics implanted in two different nonosseous sites were identical in spite of the differences in their microenvironment (cellular and acellular).

[Make-up of the posterior branches of the spinal nerves]. / La constitution des branches postérieures des nerfs rachidiens.

By opposition to the anterior branches of spinal nerves which are constituted by motor, sensitive and autonomic fibers, some of the posterior branches have not or have few of sensitive territory: C1, C5, C6, C7, D1, L4, L5 are like that. This particularity ought to be reflected in their histogram. In a first analyse authors study number of fibers, in a second their caliber.

Influence of 3-methoxy 5,7,3',4'-tetrahydroxyflavan (ME) on experimental periodontitis in the golden hamster.

Experimental periodontal disease was induced in golden hamsters by feeding the animals with a Keyes 2 000 diet. The aim of the present study was to investigate the effect of 3-methoxy 5,7,3',4'-tetrahydroxyflavan (ME), a flavanoid derivative, on periodontally induced changes by this diet which was fed ad libitum to half of the animals for 2 months prior to the start of drug therapy. The animals were then divided into 4 groups: A) control animals on normal diet; B) ME-treated (200 mg/kg 3 times a week i.p.) animals on normal diet; C) animals on Keyes 2 000 diet; D) ME-treated (200 mg/kg 3 times a week i.p.) animals on Keyes 2 000 diet. ME inhibited the diminution of bone volume as measured morphometrically. The growth of dental plaque as evaluated by a sensitive index (PII) appeared to be retarded by ME. The average PII in the ME-treated animals reached after 2 months of diet remained unchanged during the drug therapy period (4 months); whereas it was significantly increased in the group C hamsters. The biochemical data further suggest that the resorption process of the alveolar bone was decreased by ME.

Salud escolar en el partido de Quilmes. / School health in the municipality of Quilmes

Se examinaron 13.181 ninos en el Area Medica y 13.471 en el Area Odontologica, encontrando 15,5% y 63,7% respectivamente de patologia. Se considera necesario extender los estudios a los ninos en edad pre-escolar, implementar concomitantemente un programa de Educacion para la Salud y la creacion de servicios especializados en Ortopedia y Ortodoncia

[Kurloff's thymic inclusion : action on rat gonads in culture]. / Inclusion thymique de Kurloff: action sur les gonades du rat en culture.

Thymic and splenic extracts rich in FOA-KURLOFF (F.K.) body cells, obtained from guinea-pigs treated with oestrogen, were added to rat testis or ovaries in culture. Controls were prepared with extracts from thymus and spleen of non treated animals and from kidneys of treated or non treated animals. After five hours the level of sexual hormones and the germinal cells were studied. The F.K. substance has no effect on germinal cells and on progesterone and testosterone secretion. The F.K. substance induces a significative decrease of oestrogen secretion. In an other paper we established that F.K. bodies induced a hyperactivity of internal theca folliculi and of ovarian interstitial cells. It is a false image of activity in connection with a hypersecretion of FSH. The F.K. substance inhibits oestrogen synthesis.

[Neoplasm-resistance of guinea pigs: demonstration of a principle ensuring destruction of human cancer cells in culture]. / Carcino-résistance du cobaye: mise en évidence d'un principe assurant la destruction des cellules cancéreuses humaines en culture.

The thymus and the spleen of guinea Pigs treated with oestrogen were rich in cells showing a special inclusion, the Foa-Kurloff body cell (F.K.). Thymic, spleen and renal cellular extracts were obtained by tissue crushing and ultra-centrifugation from healthy or oestrogen treated animals. The extracts were added to carcinomatous (HeLa) or to non-carcinomatous cells (MRC5 fibroblasts or foetal human lung cells). The thymic extracts in the non-treated animals and the splenic extracts rich in F.K. body cells induced an inhibition in the growth of carcinomatous cells. These effects were increased with the thymus extracts rich in F.K. bodies. The thymic inclusion of F.K. seems therefore to concentrate tumorous thymic fractions.

[Action of thymic extracts on the growth of different cell populations in vitro]. / Action d'extraits thymiques sur la croissance de différentes populations cellulaires in vitro.

Thymic, splenic and renal cellular extracts were obtained by tissular grinding and ultra centrifugation, from animals having undergone diverse hormonal treatments. These extracts were added to different cellular populations in culture (carcinomatous HeLa strain, established MRCs strain, primo-culture of human foetal lung strain). The thymic extracts of non treated animals and the splenic extracts rich in FK substance from intact guinea pigs treated by oestrogenes or FSH, provoque an inhibition of tumoral cell growth. The most important effects are obtained with thymus extracts rich in FK substance. The FK substance seems capable of concentrating certain antitumoral thymic fractions.