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Les méthodes dites de dustiness sont de plus en plus reconnues comme pertinentes dans le cadre de l'évaluation a priori des expositions des travailleurs manipulant des nanomatériaux en poudre. Dans ce projet européen impliquant six instituts européens référents en santé au travail, une approche harmonisée appliquée aux quatre méthodes qui coexistent en Europe a été définie. Cette approche a été mise en oeuvre sur une série de dix nanomatériaux produits et utilisés à grande échelle dans l'industrie. Sur la base des résultats obtenus, cinq normes CEN ont été proposées., The so-called dustiness methods are increasingly recognized as relevant in the a priori evaluation of the exposures of workers handling nanomaterials in powder form. In this European project involving six European reference institutes in occupational health, a harmonized approach was elaborated and applied to the four dustiness methods that coexist in Europe. This approach was implemented on a series of ten nanomaterials produced and used on a large scale in the industry. On the basis of the results obtained, five CEN standards were proposed.

Les méthodes dites de dustiness sont de plus en plus reconnues comme pertinentes dans le cadre de l'évaluation a priori des expositions des travailleurs manipulant des nanomatériaux en poudre. Jusqu'à présent, les méthodes prescrites dans les normes européennes proposent des indices relatifs à la seule métrique masse [mg/kg], alors que la surface est de plus en plus reconnue comme un déterminant approprié pour évaluer la toxicité pulmonaire des nanomatériaux insolubles ou peu solubles ainsi que les expositions professionnelles. Dans ce contexte, nous proposons un nouvel indice de dustiness basé sur la métrique surface [m2/kg]. Cet indice repose sur l'hypothèse d'équivalence entre la surface spécifique d'une poudre et son aérosol, ce que nous démontrons au travers d'expériences de laboratoire sur différents nanomatériaux produits et utilisés à grande échelle dans l'industrie. Ce nouvel indice de dustiness devrait être proposé lors de la future révision des normes européennes., The so-called dustiness methods are increasingly recognized as relevant in the a priori evaluation of the exposures of workers handling nanomaterials in powder form. Until now, the methods prescribed in the current European standards propose only mass-based dustiness indices [mg/kg], while the surface area is increasingly recognized as an appropriate determinant for assessing the pulmonary toxicity of insoluble or poorly soluble nanomaterials, as well as the workplace exposures. In this context, a new surface-based dustiness index [m2/kg] is proposed. This index is based on the assumption of the equivalence between the specific surface area of a powder and its aerosol, which is demonstrated through laboratory experiments on various nanomaterials produced and used on a large scale in industry. We recommend that this new dustiness index is proposed in the future revision of the European standards.

Background— Variation within a single gene might produce different congenital heart defects (CHDs) within a family, which could explain the previously reported familial aggregation of discordant CHDs. We investigated whether certain groups of discordant CHDs are more common in families than others. Methods and Results— Using Danish national population and health registers, we identified CHDs among all singletons born in Denmark during 1977–2005 and their first-degree relatives. In a cohort of 1 711 641 persons, 16 777 had CHDs, which we classified into 14 phenotypes. We estimated relative risks of discordant CHDs by history of specific CHDs in first-degree relatives. The relative risk of any dissimilar CHD given the specified CHD in first-degree relatives was as follows: heterotaxia, 2.00 (95% CI, 0.96 to 4.17); conotruncal defects, 2.78 (95% CI, 2.12 to 3.66); atrioventricular septal defects, 2.25 (95% CI, 1.39 to 3.66); anomalous pulmonary venous return, 1.76 (95% CI, 0.66 to 4.64); left- and right-ventricular outflow tract obstruction, 2.55 (95% CI, 1.87 to 3.48) and 3.09 (95% CI, 2.03 to 4.71), respectively; isolated atrial septal defects, 2.76 (95% CI, 2.11 to 3.61); isolated ventricular septal defects, 2.27 (95% CI, 1.75 to 2.94); persistent ductus arteriosus, 1.92 (95% CI, 1.32 to 2.79); other specified CHDs, 3.29 (95% CI, 2.51 to 4.32); and unspecified CHDs, 2.30 (95% CI, 1.76 to 3.00). Relative risks for all pairwise combinations of discordant CHD phenotypes gave no indications that certain constellations of CHDs cluster more in families than others. Conclusion— We documented strong familial aggregation of discordant CHD phenotypes. However, we observed no excess clustering of specific CHD phenotypes among the first-degree relatives.

Background— Knowledge of the familial contribution to congenital heart diseases (CHD) on an individual and population level is sparse. We estimated an individual’s risk of CHD given a family history of CHD, as well as the contribution of CHD family history to the total number of CHD cases in the population. Methods and Results— In a national cohort study, we linked all Danish residents to the National Patient Register, the Causes of Death Register, the Danish Central Cytogenetic Register, and the Danish Family Relations Database, yielding 1 763 591 persons born in Denmark between 1977 and 2005, of whom 18 708 had CHD. Individuals with CHD were classified by phenotype. We estimated recurrence risk ratios and population-attributable risk. Among first-degree relatives, the recurrence risk ratio was 79.1 (95% confidence interval [CI] 32.9 to 190) for heterotaxia, 11.7 (95% CI, 8.0 to 17.0) for conotruncal defects, 24.3 (95% CI,12.2 to 48.7) for atrioventricular septal defect, 12.9 (95% CI, 7.48 to 22.2) for left ventricular outflow tract obstruction, 48.6 (95% CI, 27.5 to 85.6) for right ventricular outflow tract obstruction, 7.1 (95% CI, 4.5 to 11.1) for isolated atrial septal defect, and 3.4 (95% CI, 2.2 to 5.3) for isolated ventricular septal defect. The overall recurrence risk ratio for the same defect was 8.15 (95% CI, 6.95 to 9.55), whereas it was 2.68 (95% CI, 2.43 to 2.97) for different heart defects. Only 2.2% of heart defect cases in the population (4.2% after the exclusion of chromosomal aberrations) were attributed to CHD family history in first-degree relatives. Conclusions— Specific CHDs showed highly variable but strong familial clustering in first-degree relatives, ranging from 3-fold to 80-fold compared with the population prevalence, whereas the crossover risks between dissimilar cases of CHD were weaker. Family history of any CHD among first-degree relatives accounted for a small proportion of CHD cases in the population.

Germline mutations in BRCA1 and BRCA2 predispose female carriers to breast and ovarian cancer. The majority of mutations identified are small deletions or insertions or are nonsense mutations. Large genomic rearrangements in BRCA1 are found with varying frequencies in different populations, but BRCA2 rearrangements have not been investigated thoroughly. The objective in this study was to determine the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large group of Danish families with increased risk of breast and ovarian cancer. A total of 617 families previously tested negative for mutations involving few bases were screened with multiplex ligation-dependent probe amplification (MLPA). Two deletions in BRCA1 were identified in three families; no large rearrangements were detected in BRCA2. The large deletions constitute 3.8% of the BRCA1 mutations identified, which is low compared to several other populations.

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominantly inherited skin disorders characterized by the development of intra-epidermal skin blisters on mild mechanical trauma. The three major clinical subtypes (Weber-Cockayne, Koebner and Dowling-Meara) are all caused by mutations in either the keratin 5 (KRT5) or keratin 14 (KRT14) gene. Previously, we identified three novel KRT14 missense mutations in Danish EBS patients associated with the three different forms of EBS (1). The identified KRT14 mutations represent the full spectrum of the classical EBS subtypes. In the present study we investigated these mutations in a cellular expression system in order to analyse their effects on the keratin cytoskeleton. KRT14 expression vectors were constructed by fusing the nucleotide sequence encoding the FLAG reporter peptide to the 3' end of the KRT14 cDNA sequences. The expression vectors were transiently transfected into normal human primary keratinocytes (NHK), HaCaT or HeLa cells in order to analyze the ability of the mutant K14 proteins to integrate into the existing endogenous keratin filament network (KFN). No effect on the keratin cytoskeleton was observed upon transfection of NHK with the various K14 constructs neither with nor without a subsequently induced heat-stress. In contrast, all constructs, including wild-type K14, caused collapse of the endogenous KFN in a small fraction of the transfected HeLa and HaCaT cells. However, overexpression of the mutation associated with the most severe form of the disease, EBS Dowling-Meara, resulted in a higher number of transfected HaCaT cells with KFN collapse (P < 0.001). Thus, although a background KFN perturbance was observed upon transfection with the wild-type K14 construct, the mutant protein associated with the most severe form of EBS worsened the KFN perturbation significantly compared with the mutant proteins associated with the milder forms of the disease and the normal K14 protein. This shows that the clinical severity of disease-associated mutations identified in patients can be tested using this expression system, although it can not at present be used to discriminate between the milder forms. Assessment of the endogenous K14 protein expression in NHK and HaCaT cells indicated that the higher level of endogenous keratin expression in NHK might make these cells more resistant to perturbation of the keratin cytoskeleton by overexpressed K14 protein than HaCaT cells.

We report on a 2-year-old girl presenting with a severe form of hypohidrotic ectodermal dysplasia (HED). The patient presented with hypotrichosis, anodontia, hypohidrosis, frontal bossing, prominent lips and ears, dry, pale skin, and dermatitis. The patient had chronic rhinitis with malodorous nasal discharge. The girl was the second born child of first-cousin immigrants from Northern Iraq. A novel homozygous mutation (c.84delC) in the EDAR gene was identified. This mutation most likely causes a frameshift in the protein product (p.S29fs*74). This results in abolition of all ectodysplasin-mediated NF-kB signalling. This complete loss-of-function mutation likely accounts for the severe clinical abnormalities in ectodermal structures in the described patient. (C) 2014 Wiley Periodicals, Inc. We report on a 2-year-old girl presenting with a severe form of hypohidrotic ectodermal dysplasia (HED). The patient presented with hypotrichosis, anodontia, hypohidrosis, frontal bossing, prominent lips and ears, dry, pale skin, and dermatitis. The patient had chronic rhinitis with malodorous nasal discharge. The girl was the second born child of first-cousin immigrants from Northern Iraq. A novel homozygous mutation (c.84delC) in the EDAR gene was identified. This mutation most likely causes a frameshift in the protein product (p.S29fs*74). This results in abolition of all ectodysplasin-mediated NF-kB signalling. This complete loss-of-function mutation likely accounts for the severe clinical abnormalities in ectodermal structures in the described patient.

The full-length primary structure and expression profile of a novel unconventional myosin heavy chain, human myosin-IXb, is described. The primary structure of this myosin predicts a 229 kDa protein that together with its recently described rat homolog, myr 5, is the ninth class of myosins to be identified. In comparison to skeletal muscle myosin-II, the myosin-IXb ‘head’ has two unusual features: a novel N-terminal domain of 140 amino acids, which includes a 60 amino acid extension, and a large insertion of 126 amino acids in the putative actin-binding site. The ‘neck’ contains four tandemly repeated IQ motifs, suggesting that this myosin may have four associated light chains. The ‘tail’ contains a region similar to regions found in the chimerins, with a putative zinc and diacylglycerol binding domain, homologous to the regulatory domain of protein kinase C and a putative GTPase-activating protein (GAP) domain of the rho/rac family of ras-like G-proteins. Northern blot analysis of 16 different human tissues revealed an approximately 8 kb transcript that is most highly expressed in peripheral blood leukocytes, with somewhat lower levels of expression in thymus and spleen, suggesting that myosin-IXb is most abundant in cells of myeloid origin. Myosin-IXb was also expressed in a number of other tissues at significantly lower levels. Analysis of myosin-IXb protein expression, using a tail-domain directed antibody, was performed in HL-60 cells, a human leukocyte cell. Myosin-IXb expression increases by 4- to 5-fold upon induced differentiation of these cells into macrophage-like cells. The localization of myosin-IXb is also altered upon differentiation. In undifferentiated HL-60 cells, myosin-IXb colocalizes with F-actin in the cell periphery, while in differentiated cells its localization becomes more cytoplasmic, with the highest levels in the perinuclear region.

A number of chromated Zn-Fe (0.3% Fe) samples were corrosion tested in a 3% NaCl solution of pH 5.000 by means of simultaneous corrosion measurements by titration and electrochemical measurements. In one experiment lasting 95 h the corrosion rate was constant, although the dissolution valence fell from nearly two to one, while the corrosion potential increased by some 120 mV. A reaction scheme consistent with these observations is proposed.

Species of Lactobacillus were isolated and identified from commercial Washington state grapes and wines including L. brevis (4 strains), L. hilgardii (4), L. plantarum (3), and L. fructivorans (1). Unlike other strains, L. brevis and L. plantarum grew in media at relatively low pH (pH 3.16 and 3.34). Sulfur dioxide inhibited all strains as growth was delayed in 33 mg/L total SO 2 (pH 3.5). None of the strains grew in 12% or 14% ethanol. Alcoholic fermentations of two grape musts were not slowed in the presence of strains of L. brevis, L. hilgardii, or L. plantarum

Background Time trends in congenital heart defects (CHD) by specific phenotype and with long follow-up time are rarely available for an entire population. We present trends in national CHD prevalences over the past 3 decades. Methods We linked information from the National Patient Register, the Causes of Death Register, and the Danish Cytogenetic Central Register for all persons born in Denmark, 1977 to 2005, and registered in the Civil Registration System, yielding a cohort of 1,763,591 persons—18,207 with CHD. Individuals with CHDs were classified by phenotype (heterotaxia, conotruncal defect, atrioventricular septal defect, anomalous pulmonary venous return, left and right ventricular outflow tract obstructions, septal defects, complex defects, associations, patent ductus arteriosus, unspecified, and other specified) by combining International Classification of Diseases codes using a hierarchical approach. Results From 1977 to 2005, the overall CHD birth prevalence increased from 73 to 113 per 10,000 live births. Generally, prevalence increased for defects diagnosed in infancy, until 1996–1997, and then stabilized. For each 5-year interval, isolated septal defects and severe defects increased by 22% (95% CI, 20%-25%) and 5% (95% CI, 4%-7%), respectively. Among the severe defects, conotruncal defects and atrioventricular septal defect showed the largest prevalence increases. Women had a lower prevalence of severe defects during the 1980s. The CHD prevalence increase was unchanged when persons with extracardiac defects or chromosomal aberrations were excluded. Conclusions CHD birth prevalence increased from the beginning of the 1980s but stabilized in the late 1990s.

We report here the functional characterisation of a missense mutation c.7235G>A in BRCA2. By reverse transcriptase polymerase chain reaction the mutation is demonstrated to cause skipping of exon 13. We conclude that the mutation is most likely deleterious.

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant inherited skin diseases caused by mutations in either the keratin 5 (K5) or the keratin 14 (K14) genes and characterized by development of intraepidermal skin blisters. The three major subtypes of EBS are Weber-Cockayne, Koebner, and Dowling-Meara, of which the Dowling-Meara form is the most severe. We have investigated five large Danish families with EBS and two sporadic patients with the Dowling-Meara form of EBS. In the sporadic Dowling-Meara EBS patients, a novel K14 mutation (N123S) and a previously published K5 mutation (N176S) were identified, respectively. A novel K14 mutation (K116N) was found in three seemingly unrelated families, whereas another family harbored a different novel K14 mutation (L143P). The last family harbored a novel K5 mutation (L325P). The identified mutations were not present in more than 100 normal chromosomes. Six polymorphisms were identified in the K14 gene and their frequencies were determined in normal controls. These polymorphisms were used to show that the K14 K116N mutation was located in chromosomes with the same haplotype in all three families, suggesting a common ancestor. We observed a strict genotype-phenotype correlation in the investigated patients as the same mutation always resulted in a similar phenotype in all individuals with the mutation, but our results also show that it is not possible to predict the EBS phenotype merely by the location (i.e., head, rod, or linker domains) of a mutation. The nature of the amino acid substitution must also be taken into account.

We have examined the analgesic effects of indo-methacin in a double-blind study of 56 patients undergoing surgery for lumbar disc prolapse. The patients were allocated randomly to receive either indomethacin 100 mg i.v. before surgery, followed by 100 mg rectally 6 and 12 h after surgery and at 08:00, 16:00 and 23:00 on the next day, or placebo. Postoperative pain was assessed using a 10-cm visual analogue scale at fixed times. Side effects and consumption of supplementary analgesics were recorded. Patients receiving placebo had significantly greater pain scores and significantly more patients in the placebo group required supplementary analgesics.

The infrared spectra of Ni(IV), Fe(IV), Mn(IV) and V(IV) complexes with the formaldoximate ion of the type M I 2 [M IV (CH 2 NO) 6 ] (M I = Li, Na. K, Rb, Cs) have been measured in the region 4000–4030 cm −1 . Vibrational assignments for the infrared active fundamentals of the complex ions assuming S 6 symmetry have been based on the isotopic frequency shifts due to H/D, 14 N/ 15 N and 58 Ni/ 62 Ni substitutions and on the assignment of the fundamental bands observed in the infrared spectrum of sodium formaldoximate, CH 2 NONa, and CD 2 NONa (4000–4200 cm −1 ). The assignments of the ligand Skeletal modes of vibration compare well with the results obtained for sodium hexanitrocobaltate (III) , Na 3 [Co(NO 2 ) 6 ] [1].

The configuration of Ni(IV), Fe(IV), Mn(IV) and V(IV) complexes of the type MI2[MIVL2] where MI=Li, Na, K, Rb and Cs and the ligand L is the anion C3H6N3O3−3 of hexahydro-1,3,5-triazine-1,3,5-triol has been obtained by studying the infrared spectra of the complexes in the region 4000-50 cm−1. Vibrational assignments for the observed bands of the complex ions have been made assuming the molecular symmetry D3d. The assignments have been based on the observed isotopic frequency shifts due to the substitutions H/D, 14N/15N, 12C/13C, 58Ni/62Ni and 54Fe/57Fe and on the assignment of the bands in the infrared spectrum of hexahydro-1,3,5-triazine-1,3,5-triol, C3H6N3 (OH)3.

The infrared spectra of complexes of some transition metals (V, Mn, Fe and Ni) in tne oxidation state +4 with the formaldoximate ion CH 2 NO − have been studied in the region 4000–4030 cm − . Spectra of isotopic substituted compounds ( 58 Ni, 62 Ni, 54 Fe, 57 Fe, 15 N and D) have also been recorded. The complexes have been shown to be of the type M 2 I [M IV (CH 2 NO) 6 ] (M I = Li, Na, K, Rb and Cs) with the nitrogen atoms bonded to the central atom. The molecular structure of the complex ions belonging to the point group S 6 and the frequency values of the metal-ligand stretching vibrations seem to have been established.

Summary In an attempt to simplify the Mantoux test, studies have been carried out in connection with the stability of the three dilutions of Old Tuberculin previously, employed for the Mantoux test. By diluting the tuberculin in a buffer solution pH 7·38, with the addition of 0·01 per cent quinosol, the dilution containing 1/100 mg. per 0·1 c.c. keeps well for about two months. Investigations were carried out into the serviceability of purified tuberculin (prepared on the principles of F. Seibert) in attempts to find two doses to replace the usual three doses of Old Tuberculin used for the complete Mantoux test. A description is given of the preparation of a purified tuberculin that dissolves as a clear solution in a buffer solution pH 7·38, with the addition of 0·01 per cent quinosol. In contrast to other preparations of purified tuberculin, including P.P.D., this solution gives no precipitate when quinosol is added as antiseptic. Standardization of purified tuberculin in relation to the international standard tuberculin is not practicable by means of the intracutaneous method usually employed. A comparison of the standard tuberculin with the purified tuberculin on the same principles followed by the American investigators has shown that for practical purposes it is safe to assume that: 1/100 mg. standard Old Tuberculin = 1/50000 mg. purified tuberculin 1/10 mg. standard Old Tuberculin = 1/5000 mg. purified tuberculin 1 mg. standard Old Tuberculin = 1/500 mg. purified tuberculin In Denmark it has proved practicable to use two doses of purified tuberculin for the performance of the Mantoux test, namely: 1/50000 mg. and 1/500 mg. Since 1935 these two doses of purified tuberculin have been employed in extensive serial examinations in various parts of this country, comprising about 10,000 examinations, without causing any particular inconvenience. These two doses together give approximately the same number of positive reactions as do the usual three doses of Old Tuberculin (1/100 mg., 1/10 mg. and 1 mg.). By using a third dose of purified tuberculin-namely, 1/50 mg. (corresponding to about 10 mg. of Old Tuberculin)—a few more positive reactions will be obtained (less than 5 per cent). For serial examinations and for work in tuberculosis clinics, where the use of two doses will greatly facilitate the rational performance of the Mantoux test, it may be considered sufficient to use only the doses 1/50000 mg. and 1/500 mg. As dilutions in a buffer solution pH 7·38 (with the addition of 0·01 per cent quinosol), containing 1/50000 mg. per 0·1 c.c., are stable for about one month, it is quite possible to prepare all the dilutions in a central institute and distribute them to hospitals and physicians ready for use. To supply the hospitals in Denmark with these solutions regularly once a month it is estimated that the yearly consumption of purified tuberculin will amount to something between one and two grams. This method therefore offers the following advantages: (1) It is quite inexpensive. (2) Uniform dilutions are distributed all over the country. (3) Mistakes in the preparation of tuberculin dilutions are avoided. Finally, a suggestion is made as to the preparation of an international standard purified tuberculin of the same strength as P.P.D. or the Danish preparation R.II. As we have made a preparation that is stronger than P.P.D., it will be necessary to standardize preparations of purified tuberculin in relation to the standard tuberculin, and to prepare the dilutions with a view to the strength thus assayed.

Summary Report is made of 26 cases of bovine pulmonary tuberculosis. The patients are all from Copenhagen, admitted to the hospital during the period from February, 1931 to July, 1933. The strains of tubercle bacilli isolated from these patients are type-determined in the State Serum Institute (K. A. Jensen). Ten of these 26 patients were under 5 years, none over 32 years. Only in one of these cases could infectious tuberculosis be demonstrated in the home of the patient, namely: open pulmonary tuberculosis in the father that on type-determination proved tobe of human origin. Thus, not even in one of these cases could infection from another person be demonstrate—not even with merely a fair degree of probability—and this fact is in sharp contrast to the findings reported in previous investigations on the occurrence of probable sources of infection in the surroundings of consumptives. In 13 of these 26 cases the patients had been drinking raw milk for some length of time, while only three patients denied they had ever taken raw milk. Cervical adenitis was ascertained prior to or coincident with the demonstration of the lung affection in 11 (perhaps 13) of these cases. Five of the 10 children under 5 years had previously shown abdominal symptoms that might be interpreted as due to abdominal tuberculosis. The pulmonary processes that were demonstrated by X-ray examination appeared not to show any particular features that would differentiate them from the changes characteristic of the respective age-classes as generally seen in pulmonary tuberculosis. In 18 of the 26 cases the tubercle bacilli were cultivated from gastric lavage alone. Sources of error with this method are mentioned and discussed. Six of the patients died within the observation period (concluded in April, 1934), and all six died of generalised tuberculosis; three of them were under 5 years of age, two between 5 and 15 years, and one over 15 years. As there are no available mortality statistics for these age-classes based on a type-determined material of patients with human tuberculosis, it is not practicable to make any comparison in this respect with the small figures here presented. It seems evident, however, that the prognosis of bovine pulmonary tuberculosis in the age-class under 5 years is serious, probably just as serious as the prognosis of pulmonary tuberculosis due to the human type of the bacillus.

Publisher Summary This chapter deals with the chemistry of 1,2,3,4-thiatriazoles. The chapter discusses the synthesis and chemical properties of 1,2,3,4-thiatriazoles. The most general route to 1,2,3,4-thiatriazoles involves the treatment of a thiohydrazide with nitrous acid. Some of the chemical properties of 1,2,3,4-thiatriazoles include (1) they are unstable, and (2) they decompose on heating—in some cases even at room temperature—and in many cases they melt with detonation. The 1,2,3,4-thiatriazoles substituted with C-radicals are also presented. The 1,2,3,4-thiatriazole-5-thiol and its derivatives are provided in a tabulated form. The synthesis of 5-substituted-amino-1,2,3,4-thiatriazoles is discussed. Such thiatriazoles are formed quite generally from 4-substituted-thiosemicarbazides. When the substituent is an aryl group these initial products are isomerized to 5-mercaptotetrazoles on treatment with alkali. The chapter also presents the (1) decomposition of 5-amino-1,2,3,4-thiatriazole and its derivatives, and (2) the constitution of 5-amino-1,2,3,4-thiatriazole and its derivatives.