A clustering approach to improve our understanding of the genetic and phenotypic complexity of chronic kidney disease.

Chronic kidney disease (CKD) is a complex disorder that causes a gradual loss of kidney function, affecting approximately 9.1% of the world's population. Here, we use a soft-clustering algorithm to deconstruct its genetic heterogeneity. First, we selected 322 CKD-associated independent genetic variants from published genome-wide association studies (GWAS) and added association results for 229 traits from the GWAS catalog. We then applied nonnegative matrix factorization (NMF) to discover overlapping clusters of related traits and variants. We computed cluster-specific polygenic scores and validated each cluster with a phenome-wide association study (PheWAS) on the BioMe biobank (n = 31,701). NMF identified nine clusters that reflect different aspects of CKD, with the top-weighted traits signifying areas such as kidney function, type 2 diabetes (T2D), and body weight. For most clusters, the top-weighted traits were confirmed in the PheWAS analysis. Results were found to be more significant in the cross-ancestry analysis, although significant ancestry-specific associations were also identified. While all alleles were associated with a decreased kidney function, associations with CKD-related diseases (e.g., T2D) were found only for a smaller subset of variants and differed across genetic ancestry groups. Our findings leverage genetics to gain insights into the underlying biology of CKD and investigate population-specific associations.

A clustering approach to improve our understanding of the genetic and phenotypic complexity of chronic kidney disease.

Chronic kidney disease (CKD) is a complex disorder that causes a gradual loss of kidney function, affecting approximately 9.1% of the world's population. Here, we use a soft-clustering algorithm to deconstruct its genetic heterogeneity. First, we selected 322 CKD-associated independent genetic variants from published genome-wide association studies (GWAS) and added association results for 229 traits from the GWAS catalog. We then applied nonnegative matrix factorization (NMF) to discover overlapping clusters of related traits and variants. We computed cluster-specific polygenic scores and validated each cluster with a phenome-wide association study (PheWAS) on the BioMe biobank (n=31,701). NMF identified nine clusters that reflect different aspects of CKD, with the top-weighted traits signifying areas such as kidney function, type 2 diabetes (T2D), and body weight. For most clusters, the top-weighted traits were confirmed in the PheWAS analysis. Results were found to be more significant in the cross-ancestry analysis, although significant ancestry-specific associations were also identified. While all alleles were associated with a decreased kidney function, associations with CKD-related diseases (e.g., T2D) were found only for a smaller subset of variants and differed across genetic ancestry groups. Our findings leverage genetics to gain insights into the underlying biology of CKD and investigate population-specific associations.

Mono- and biallelic variant effects on disease at biobank scale.

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

Comparative safety study of three inactivated BTV-8 vaccines in sheep and cattle under field conditions.

After massive epidemics of bluetongue disease in 2006 and 2007, Germany has started a compulsory vaccination program against bluetongue virus serotype 8 (BTV-8). Since the available vaccines had not yet been registered and only limited data were available on their performance, a safety study was conducted with three different inactivated monovalent vaccines under consideration for use in Germany. A total of 1007 sheep and 893 cattle were vaccinated and subsequently compared with 638 control animals (324 sheep and 314 cattle). During the study, all animals remained in good health condition. After the initial immunisation, only local swellings were observed in a small number of animals. Following revaccination, several sheep developed more distinct local reactions and a temporary rise in body temperature. Severe systemic reactions were not detected in any of the study groups. Among cattle, neither fever, nor a decrease in milk production and only temporary low-grade local reactions were observed. Overall, our results demonstrate a high level of safety of all vaccines tested.

Oral immunisation of wild boar against classical swine fever: concluding analysis of the recent field trials in Germany.

The recent oral immunisation trials in wild boar against classical swine fever (CSF) in Germany are described and evaluated in summary. After the first field study in Lower Saxony from 1993-1995 further immunisation trials started in Mecklenburg-Western Pomerania, Brandenburg, Lower Saxony, Baden-Württemberg and Saxony-Anhalt. The immunisation strategies and the size of the vaccination zones were different in the individual federal states. In principle, the bait vaccine based on the CSF virus strain "C" were laid out by hand. Later also the aerial distribution was carried out in selected areas of Mecklenburg-Western Pomerania. The application of baits by plane was introduced at the beginning of the immunisation measures in Saxony-Anhalt apart from the manual distribution. Up to now, the field trials show that the oral immunisation can be an additional tool for CSF control by increasing of herd immunity and reduction of the CSFV prevalence. However, the immunisation was not sufficient enough for young boars in the most field studies. Based on the evaluation of the immunisation experiments an improved immunisation procedure is recommended.

First report of a parasitic mite, Leptotrombidium (Hypotrombidium) subquadratum (Lawerence) (Acari: Trombiculidae: Trombiculinae), from dogs and children in the Bloemfontein area, South Africa.

Leptotrombidium subqunadratum larvae were collected for the first time in 1994 from dogs in Bloemfontein. The larvae have been collected annually, during the summer months, over a period of 6-7 years. Previously the only known hosts were scrub hare (Lepus saxatilis) (locality unknown) and short-snouted elephant shrew (Elephantulus brachyrhynchus) (Kruger National Park). These mites cause severe itching and dermatitis in humans and dogs.

Rinderpest in South Africa--100 years ago.

To commemorate the centenary of the outbreak of rinderpest in South Africa, the historical events leading up to and following this major epidemic are recounted. Its impact on livestock and human populations, as well as initial and eventual successful attempts to control it are discussed.

Adult ixodid ticks on two cattle breeds in the south-western Free State, and their seasonal dynamics.

A study was conducted to compare the species of adult ixodid ticks on Friesian and Bonsmara cattle and their seasonal dynamics. Between five and ten animals of each breed were kept on natural False Upper Karoo vegetation, typical of the south-western Free State. Between May 1990 and October 1991, the animals were examined once or twice a month for the presence of adult ticks which were removed, counted and identified. Six species of ixodid ticks were recorded. The species composition on the two cattle breeds was remarkably similar. Ixodes rubicundus was dominant (55-57.7% of all ticks collected), followed by Hyalomma marginatum rufipes (28.9-31.5%) and Rhipicephalus punctatus *6.2-6.7%). Only small numbers of Hyalomma truncatum, Rhipicephalus evertsi evertsi and Rhipicephalus gertrudae were recorded. Almost twice as many ticks were collected from Friesian as from Bonsmara cattle. Ixodes rubicundus showed a typical winter-activity period. The other species were either active mostly during the warmer months, or their numbers were to low to determine any seasonal pattern. Apart from information on the diversity of ticks which infest cattle in the region, the study has also shown a greater resistance by Bonsmara cattle (a mixed Bos taurus/Bos indicus breed) to tick infestation. Bos indicus cattle can play an increasingly important role in integrated tick-management practices in southern Africa.

Rhipicephalus exophthalmos sp. nov., a new tick species from southern Africa, and redescription of Rhipicephalus oculatus Neumann, 1901, with which it has hitherto been confused (Acari: Ixodida: Ixodidae).

Rhipicephalus exophthalmos sp. nov., a species which has in the past been confused with Rhipicephalus oculatus Neumann, 1901, is described and illustrated from laboratory-reared specimens. Preferred hosts for the adults of this tick are various domestic and wild ungulates and hares. It is widely distributed in Namibia and in the southeastern Cape Province, South Africa, with only scattered records from elsewhere. The adults of R. oculatus are redescribed and illustrated, and the immature stages are described and illustrated for the first time. All stages feed virtually exclusively on leporids. It is common in parts of the eastern and southern Cape Province, with few records as yet from other parts of South Africa and Namibia.

The prehatch period and larval survival of Boophilus decoloratus (Koch, 1844) (Acarina: Ixodidae) under natural conditions in the Transvaal, South Africa.

Studies were made on the duration of the prehatch period of Boophilus decoloratus and on the subsequent survival and viability of larvae under natural conditions. The length of the prehatch and larval survival periods was found to be inversely dependent on increased temperature. A high initial temperature at the time of female drop decreased the prehatch period further, resulting in synchronous hatching of eggs laid at different times. Oviposition occurred but no eggs hatched during mid-winter months with mean temperatures below 10 degrees C. Eggs laid after mid-winter hatched because of the higher temperatures during subsequent months. Diapause occurs at the egg stage in areas with mean winter temperatures below 10 degrees C. Larvae survived for 10-35 weeks during periods of high and low seasonal temperatures respectively. Larval viability decreased concomitantly with larval survival. The results suggest that pasture spelling alone would be impractical as a control measure for this tick species.

Paralysis of laboratory rabbits by nymphae of Ixodes rubicundus, Neumann 1904 (Acarina: Ixodidae) and some effects on the life-cycle following feeding under different temperature conditions.

Feeding under constant cold conditions resulted in a marginal shortening of feeding period and a major shortening of the subsequent developmental phase of all stages of Ixodes rubicundus Neumann 1904, the Karoo paralysis tick. Paralysis occurred in laboratory rabbits when nymphae were fed on them under constant warm, constant cold and fluctuating ambient winter conditions. This paralysis was found to be dependent on infestation rate and feeding conditions. Under constant cold conditions paralysis resulted from lower levels of infestation than under warm or under fluctuating winter conditions. Neurological parameters used in assessing the progression of the paresis are discussed.

A survey of Karoo tick paralysis in South Africa.

Recent research interest in Karoo tick paralysis and its vector. Ixodes rubicundus, prompted this survey to determine the economic implications of this disease. The survey indicated relatively high losses caused by the condition, identified the stock involved and provided data on the incidence of paralysis and on the control methods employed. Recommendations are made to institute chemical control earlier in the season to attempt better containment of the problem.

[Coagulase-negative Staphylococcus species in mixed fodder and on grain]. / Koagulase-negative Staphylokokken-Spezies in Mischfuttermitteln und auf Getreide.

For valuation of microbially-altered combined fodder from the veterinary point of view beside the total number of germs also the diagnosis of the species of veterinary relevant indicator germs is of importance. Coagulase-negative staphylococci are the main and indicator flora in spoiling of combined fodder. According to the biochemical and physiological characterization the majority of the coagulase-negative staphylococci occurring in connection with spoiling of combined fodder belongs to the species S. xylosus. Beside the species also other coagulase-negative species as S. sciuri, S. cohnii, S, warneri and S. saprophyticus have been demonstrated. These bacterial species were also found in the single components of combined fodder as ripe grain, green unripe cereal plants, in soil samples and in the dust inside the mills for combined fodder production.

Rearing and infection techniques for Amblyomma species to be used in heartwater transmission experiments.

Techniques for the rearing of Amblyomma species to be used in heartwater (Cowdria ruminantium) transmission experiments are discussed. These involve the breeding and maintenance of infected and non-infected strains of ticks. They include the feeding of ticks on sheep, rabbits, mice, tortoises and guinea fowl.

[The synthesis of 3-amino-5-(4-pyridinyl)-1,2-dihydropyrid-2-one (Cordemcura) from a technical mixture of pyridines]. / Untersuchungen zur Synthese von 3-Amino-5-(pyrid-4-yl)-1,2-dihydro-pyrid-2-on (Cordemcura) aus technischen Pyridinbasengemischen.

For preclinical and clinical research the headline compound 6 has been synthesized from pyrid-4-yl-malondialdehyde (3) and its bis-N,N-dimethyl)-aldimin-derivative 1 by cyclization with cyanoacetamide giving 4, partial hydrolysis to the amide 5, and degradation by sodiumhypochlorite to the amine 6, concerning to the way described in patent literature. Starting product was a mixture of alkyl pyridines from which 4-picoline reacted selectively with the Vilsmeyer-complex of phosgene/DMF to give cristalline 1. Optimization in all steps resulted in a procedure that gives us the intermediates in good yields and qualities and the final product 6 with high purity, suitable for pharmaceutical use.

The use of frequency diagrams in the survey of resistance to pesticides in ticks in Southern Africa.

A method whereby resistance data can be analysed by means of frequency distributions is described. This method established that Rhipicephalus appendiculatus and R. evertsi evertsi show either little or only developing resistance to the pesticides chlorfenvinphos and dioxathion. Boophilus spp., however, show more instances and higher levels of resistance to these 2 pesticides.