A novel KRT71 variant in curly-coated dogs.

Curly fur is a common phenotype in many dog breeds, known to result from a missense variant (c.451C>T) in exon 2 of the keratin 71 (KRT71) gene. During screening for this variant across various breeds, we found that Curly Coated Retrievers (CCRs) fixed with the trait did not carry the known variant. By analysis of whole-genome sequencing data of one CCR we identified a novel genetic cause for curly fur. We found a novel structural variant in exon 7 of the KRT71 gene (c.1266_1273delinsACA) that was predicted to result in a frameshift and stop loss, therefore significantly affecting the structure of the protein, if translated. The variant was also found at lower frequencies in five other breeds, including Lagotto Romagnolo, Bichon Frise, Spanish Water Dog, Chesapeake Bay Retriever and Irish Terrier. One curly-coated Lagotto carried neither of the two KRT71 variants. These results identify a second variant for curly coat in KRT71 and suggest the existence of additional alleles. This study enables the development of an additional KRT71 gene test for breeders to understand and manage coat types.

Oral findings in paediatric patients with severe heart, liver, and kidney failure prior to organ transplantation.

PURPOSE: Organ transplantation is an effective treatment for children with severe heart, liver, and kidney diseases. These patient groups may have more oral and dental diseases than healthy controls. It is important to eliminate oral infection foci before transplantation and to maintain good oral health to avoid potential post-transplant complications. The aim of this study was to describe and compare oral health in Finnish paediatric heart, liver, and kidney transplant recipients prior to organ transplantation. METHODS: Eighty-six children who received a heart (n = 21), liver (n = 19), or kidney (n = 46) transplant in Finland during the years 2014-2018 were included in this study. The inclusion criterion was a pre-transplantation oral examination. Oral hygiene, enamel anomalies, and the number of decayed, missing, and filled teeth (dmft/DMFT) were analyzed retrospectively from medical and dental records and compared between the three patient groups. RESULTS: Children with liver (p = 0.043) or heart (p = 0.047) disease had higher combined primary and permanent dentition dmft/DMFT scores compared to children with kidney disease. A higher combined dmft/DMFT score was associated with poor oral hygiene (p = 0.005). No significant differences in oral hygiene between the patient groups were found. Furthermore, all patient groups had a high prevalence of developmental dental defects. CONCLUSION: Children with liver or heart disease seem to have a higher combined dmft/DMFT score, indicating a higher prevalence of caries compared to children with kidney disease. Prevention of dental caries, along with promoting a good oral hygiene routine and regular check-ups, is suggested in these patient groups.

Population structure in contemporary Sweden--a Y-chromosomal and mitochondrial DNA analysis.

A population sample representing the current Swedish population was analysed for maternally and paternally inherited markers with the aim of characterizing genetic variation and population structure. The sample set of 820 females and 883 males were extracted and amplified from Guthrie cards of all the children born in Sweden during one week in 2003. 14 Y-chromosomal and 34 mitochondrial DNA SNPs were genotyped. The haplogroup frequencies of the counties closest to Finland, Norway, Denmark and the Saami region in the north exhibited similarities to the neighbouring populations, resulting from the formation of the Swedish nation during the past millennium. Moreover, the recent immigration waves of the 20th century are visible in haplogroup frequencies, and have led to increased diversity and divergence of the major cities. Signs of genetic drift can be detected in several counties in northern as well as in southern Sweden. With the exception of the most drifted subpopulations, the population structure in Sweden appears mostly clinal. In conclusion, our study yielded valuable information of the structure of the Swedish population, and demonstrated the usefulness of biobanks as a source of population genetic research. Our sampling strategy, nonselective on the current population rather than stratified according to ancestry, is informative for capturing the contemporary variation in the increasingly panmictic populations of the world.

Two novel genomic regions associated with fearfulness in dogs overlap human neuropsychiatric loci.

Anxiety disorders are among the leading health issues in human medicine. The complex phenotypic and allelic nature of these traits as well as the challenge of establishing reliable measures of the heritable component of behaviour from the associated environmental factors hampers progress in their molecular aetiology. Dogs exhibit large natural variation in fearful and anxious behaviour and could facilitate progress in the molecular aetiology due to their unique genetic architecture. We have performed a genome-wide association study with a canine high-density SNP array in a cohort of 330 German Shepherds for two phenotypes, fear of loud noises (noise sensitivity) and fear of strangers or in novel situations. Genome-widely significant loci were discovered for the traits on chromosomes 20 and 7, respectively. The regions overlap human neuropsychiatric loci, including 18p11.2, with physiologically relevant candidate genes that contribute to glutamatergic and dopaminergic neurotransmission in the brain. In addition, the noise-sensitivity locus includes hearing-related candidate genes. These results indicate a genetic contribution for canine fear and suggest a shared molecular aetiology of anxiety across species. Further characterisation of the identified loci will pave the way to molecular understanding of the conditions as a prerequisite for improved therapy.

Subpopulation difference scanning: a strategy for exclusion mapping of susceptibility genes.

BACKGROUND: Association mapping is a common strategy for finding disease-related genes in complex disorders. Different association study designs exist, such as case-control studies or admixture mapping. METHODS: We propose a strategy, subpopulation difference scanning (SDS), to exclude large fractions of the genome as locations of genes for complex disorders. This strategy is applicable to genes explaining disease incidence differences within founder populations, for example, in cardiovascular diseases in Finland. RESULTS: The strategy consists of genotyping a set of markers from unrelated individuals sampled from subpopulations with differing disease incidence but otherwise as similar as possible. When comparing allele or haplotype frequencies between the subpopulations, the genomic areas with little difference can be excluded as possible locations for genes causing the difference in incidence, and other areas therefore targeted with case-control studies. As tests of this strategy, we use real and simulated data to show that under realistic assumptions of population history and disease risk parameters, the strategy saves efforts of sampling and genotyping and most efficiently detects genes of low risk--that is, those most difficult to find with other strategies. CONCLUSION: In contrast to admixture mapping that uses the mixing of two different populations, the SDS strategy takes advantage of drift within highly related subpopulations.

Interindividual variability of coumarin 7-hydroxylation in healthy volunteers.

A test designed to estimate the extent and rate of formation of 7-hydroxycoumarin by measuring the urinary excretion of the metabolite in humans after administering 5 mg coumarin was developed. Coumarin was rapidly metabolized after oral administration and more than 95% of the 7OHC formed was excreted in 4 h. The total amount of 7OHC formed was 64 +/- 15% (mean +/- SD, variation 20-100%) of the dose given. The percentage of 7OHC excreted in 2 h, as compared with the 7OHC excretion in 4 h, was found to be a constant and stable individual characteristic for the rate of the formation of 7OHC ('2 h coumarin test'). In 110 volunteers, there was a great interindividual variability in the extent and rate of 7OHC formation. Four individuals had relatively 'slow' coumarin test values (50-60%), but much larger populations would be needed for the demonstration of polymorphism.

Repair of an aneurysm of the left main coronary artery.

Coronary artery aneurysms are rare, especially in the left main coronary artery. Coronary artery aneurysms may rupture or cause myocardial infarction. There are only a few reports of coronary artery aneurysms of the left main coronary artery treated surgically. We report a case in which an arterial graft from the internal iliac (hypogastric) artery was used for the reconstruction of a congenital coronary artery aneurysm of the left main coronary artery. After a follow-up of 5 years, the patient is well and in good condition.

A prospective study of tissue polypeptide specific antigen (TPS) in breast cancer diagnosis.

The aim of the present study was to evaluate the clinical value of a new tumour marker TPS in sera from patients with breast cancer and patients with benign breast disease. The results for TPS were compared with those for TAG 12, CA 15-3 and MCA. The cutoff levels (90% specificity) determined for each test were 108.0 U/1 for TPS, 57.5 KU/1 for TAG 12, 24.8 KU/1 for CA 15-3 and 9.7 KU/1 for MCA. The diagnostic sensitivity of the TPS test was 0.21, for the TAG 12 test it was 0.2, 0.13 for the CA 15-3 test and 0.12 for the MCA test in detecting breast cancer. TPS, TAG 12, CA 15-3 and MCA tests were tested in a multivariate analysis to find the best combination of independent predictors of breast cancer. The most important predictor of breast cancer was TAG 12 followed by TPS. In order to calculate the contributions of tumour marker tests, a diagnostic score (DS) was developed. The diagnostic score (DS) was: DS = TPS x 0.0085 x TAG 12 x 0.0596 - CA 15-3 x 0.0866 - MCA x 0.2938 + 0.1738. The sensitivity of the DS in detecting breast cancer was 55% with a specificity of 90% and an efficiency of 64%. In conclusion, new tumour markers TPS and TAG 12 may have some value in breast cancer diagnosis. In particular, the results indicate the usefulness of computer assistance and a simple diagnostic score when tumour markers are used in breast cancer diagnosis.

Comparison of tumour markers TAG 12 with CA 15-3 and MCA in breast cancer diagnosis.

The aim of the present study was to evaluate the clinical value of the new tumour marker TAG 12 in sera from patients with breast cancer (n = 123), patients with benign breast disease (n = 30) and normal controls (n = 38). The results for TAG 12 were compared with those for CA 15-3 and MCA. The cut-off levels (90% specificity) determined for each test in the benign and control groups were 57.5 kU/1 for TAG 12, 24.8 kU/1 for CA 15-3 and 11.8 kU/1 for MCA. The diagnostic sensitivity of the TAG 12 test was 0.30, 0.19 for CA 15-3 test and 0.20 for MCA test in detecting breast cancer. TAG 12, CA 15-3 and MCA tests were tested in a multivariate analysis to find the best combination of independent predictors of breast cancer. The most important predictor of breast cancer was TAG 12. In order to evaluate the contributions of different tumour marker serum tests a stepwise discriminant analysis was carried out. The discriminant function is DF = TAG 12 x 0.0349 + CA 15-3 x 0.0568 + MCA x (-0.33) - 0.53. The sensitivity of the DF in detecting breast cancer was 31% with a specificity of 91% and a efficiency of 52%. The correlation coefficient in breast cancer patients between TAG 12 and CA15-3 measurements was 0.95, and 0.90 between TAG 12 and MCA measurements. In conclusion, the results indicate that TAG 12, CA 15-3 and MCA have only limited value in the diagnosis of breast cancer, but their role in monitoring and follow up of breast cancer patients is a subject for further investigation.

Clinical value of serum tumour markers TPA, TPS, TAG 12, CA 15-3 and MCA in breast cancer diagnosis; results from a prospective study.

The aim of this study was to assess the clinical value of five serum tumour markers, TPA, TPS, TAG 12, CA 15-3 and MCA, in the diagnosis of breast cancer. The serum values were measured in a prospective series of patients with breast cancer (n = 82) and benign breast disease (n = 25). The cut-off levels (90% specificity) determined for each test were 109.0 U/1 for TPA, 156.0 U/1 for TPS, 52.5 kU/1 cut-off level for TAG 12 and 24.9 kU/1 cut-off level for CA 15-3, and at the 12.0 kU/1 cut-off level for MCA. Using these cut-off levels the diagnostic sensitivity of the TPA test was 0.23, for the TPS test 0.15, 0.44 for the TAG 12 test, 0.13 for the CA 15-3 test and 0.10 for the MCA test in detecting breast cancer. When the cut-off levels were determined at 95th percentile level for each test, the cut-off level for TPA was 143.0 U/1, 279.0 U/1 cut-off level for TPS, 105.0 kU/1 cut-off level for TAG 12 and 36.7 kU/1 cut-off level for CA 15.3, and at the 15.3 kU/1 cut-off level for MCA. Using these cut-off levels the diagnostic sensitivity of the TPA test was 0.12, 0.01 for the TPS test, 0.06 for the TAG 12 test, 0.06 for the CA 15-3 test and 0.06 for the MCA test in detecting breast cancer. The correlation coefficients in breast cancer patients between TPA and TPS measurements was 0.82, between TPA and TAG 12 measurements it was 0.09, between TPA and CA 15-3 measurements it was 0.08, and 0.11 between TPA and MCA measurements. None of the serum markers studied were significant predictors in breast cancer diagnosis in a logistic regression analysis or in the discriminant analysis. Thus it seems that TPA, TPS, TAG 12, CA 15-3 and MCA have only limited value in breast cancer diagnosis, but their role in the follow-up and prediction of prognosis of breast cancer patients is a subject for further investigation.

Migration waves to the Baltic Sea region.

In this study, the population history of the Baltic Sea region, known to be affected by a variety of migrations and genetic barriers, was analyzed using both mitochondrial DNA and Y-chromosomal data. Over 1200 samples from Finland, Sweden, Karelia, Estonia, Setoland, Latvia and Lithuania were genotyped for 18 Y-chromosomal biallelic polymorphisms and 9 STRs, in addition to analyzing 17 coding region polymorphisms and the HVS1 region from the mtDNA. It was shown that the populations surrounding the Baltic Sea are genetically similar, which suggests that it has been an important route not only for cultural transmission but also for population migration. However, many of the migrations affecting the area from Central Europe, the Volga-Ural region and from Slavic populations have had a quantitatively different impact on the populations, and, furthermore, the effects of genetic drift have increased the differences between populations especially in the north. The possible explanations for the high frequencies of several haplogroups with an origin in the Iberian refugia (H1, U5b, I1a) are also discussed.

Morphological, cytogenetic, and molecular evidence for introgressive hybridization in birch.

Extensive morphological variation of tetraploid birch (Betula pubescens) in Iceland is believed to be due to gene flow from diploid dwarf birch (B. nana) by means of introgressive hybridization. A combined morphological and cytogenetic approach was used to investigate this phenomenon in two geographically separated populations of natural birch woodland in Iceland. The results not only confirmed introgressive hybridization in birch, but also revealed bidirectional gene flow between the two species via triploid interspecific hybrids. The populations showed continuous morphological variation connecting the species, but karyotypically they consisted of only three types of plants: diploids, triploids, and tetraploids. No aneuploids were found. Some of the tetraploid plants had B. pubescens morphology as expected, but most of them had intermediate characters. Most of the diploid plants were B. nana, but some were intermediates and a few had B. pubescens morphology. The triploid plants were either intermediates or they resembled one of the two species. Similar introgressive variation was observed among the diploid and triploid progeny of open-pollinated B. nana in a garden. Birch samples including field plants and artificial hybrids were further examined using a molecular method based on genomic Southern hybridization. The experiments verified introgression at the DNA level.

Options for the management of poststernotomy mediastinitis.

The management of 27 consecutive deep sternotomy wound infections is reviewed. In 22 cases the initial treatment was debridement, sternal refixation and dilute antibiotic irrigation via multiple irrigation-suction catheters. In the nine cases (41%) in which these measures failed, more extensive sternal and costal cartilage debridement and closure with a muscle flap were performed. Five cases were initially managed with major reconstructive surgery. For reconstruction, a bilateral pectoralis major myocutaneous flap was used alone in eight cases, while in six the flap was insufficient to obliterate the whole poststernectomy space, and was supplemented with rectus abdominis muscle. Early mediastinitis can be effectively treated with thorough wound debridement and mediastinal irrigation, but if there is a two-week delay from the initial sternotomy to manifestation of infection, radical debridement with muscle flap closure should be seriously considered.

Magnesium substitution in elective coronary artery surgery: a double-blind clinical study.

Magnesium may be beneficial in the control of ventricular ectopy and supraventricular tachyarrhythmias after coronary artery bypass graft (CABG) surgery, but it is not known whether a high-dose magnesium regimen is superior to a regimen keeping the patient normomagnesemic. A prospective randomized and double-blind clinical comparison was performed in 81 elective CABG patients in order to assess the effects of two different magnesium infusion regimens on electrolyte balance and postoperative arrhythmias. Forty-one patients (high-dose group, H) received 4.2 +/- 0.7 g (mean +/- SD), of magnesium sulfate before cardiopulmonary bypass, followed by an infusion of 11.9 +/- 2.8 g of magnesium chloride until the first postoperative (PO) morning, and a further 5.5 +/- 1.0 g until the second PO morning. Forty patients (low-dose group, L) received magnesium sulfate only after bypass to a total of 2.9 +/- 0.5 g at the first, and 1.4 +/- 0.1 g at the second PO morning. A blood cardioplegia technique was used in both groups, including bolus doses of magnesium chloride to a total of 2.4 +/- 0.6 g and 2.3 +/- 0.6 g to H and L patients, respectively. Continuous Holter tape-recording was used for 12 to 15 hours preoperatively, and for 48 hours postoperatively. Serum magnesium peaked in H patients on the first PO morning at 1.60 +/- 0.25 mmol/L, whereafter it declined to the normal level on the third PO morning. Patients in the L group were normomagnesemic, except after the start of bypass.(ABSTRACT TRUNCATED AT 250 WORDS)