Paweł Krajewski

M34T and V37I mutations in GJB2 associated hearing impairment: Evidence for pathogenicity and reduced penetrance

Despite research the role of the M34T and V37I variants of GJB2 in causing hearing impairment (HI) remains controversial. Our purpose was to test a hypothesis that M34T and V37I are pathogenic but have distinct features resulting in a reduced penetrance. We screened for known GJB2/GJB6 mutations 233 Polish consecutive unrelated subjects with non‐syndromic, sensorineural HI who were previously found to carry 35delG mutation on one chromosome. The most frequent mutations were also analyzed in ∼1,000 controls. We found that M34T and V37I were significantly (P ≪ 10−6) overrepresented among patients, but their penetrance was estimated as 1/10 relative to mutations of undisputed pathogenicity. This finding apparently could not be explained by low degree of HI associated with M34T and V37I since another mutation causing comparably mild HI (L90P) did not have reduced penetrance. Subsequent analyses showed that the patients with M34T/35delG and V37I/35delG had significantly later onset of HI than patients with other genotypes (P < 10−6) including the L90P/35delG (P = 0.006). Also, among these patients (but not others) a strong correlation between the degree of HI and its duration was found (r = 0.79, P < 10−5). We tentatively suggest that M34T and V37I might cause mild HI characterized by relatively late onset and progression.

Fascicles of the adult human Achilles tendon - an anatomical study.

The Achilles or calcaneal tendon is the structural base for the biomechanical work of the ankle joint. The purpose of this study is to describe the internal structure of the human Achilles tendon. The anatomy of the Achilles tendon has been described in lower mammals in which it has three parts which can be dissected from its beginning to the insertion onto the calcaneus. The partial ruptures of each part suggest that the human Achilles tendon may also be composed of parts. The Achilles tendon is one of the most commonly torn tendons in the human body. Each segment of the Achilles tendon described by us can be ruptured separately, which can cause a partial dysfunction in flexion of the ankle joint as observed in clinical practice. We dissected 20 Achilles tendons previously fixed in 10% formaldehyde and 20 fresh-frozen Achilles tendons, paying particular attention to the relationship between the lateral and medial heads of the gastrocnemius and the soleus muscles. The layer-by-layer method and a microscope were used in our study. We found that the medial group of fibers from the medial head of the gastrocnemius muscle constitutes the posterior layer of the tendon. The lateral border of the tendon is composed of the fibers from the lateral part of the medial head of the gastrocnemius muscle. The fibers from the lateral head of the gastrocnemius muscle constitute the anterior layer of the Achilles tendon. The fibers from the soleus muscle are located in the anteromedial part of the Achilles tendon. Our findings are supported by clinical descriptions and observations of the partial rupture of the Achilles tendon.

Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence.

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is an autosomal‐recessive autoimmune disease caused by autoimmune regulator gene mutations. The aim of this study was to examine the mutation profile of Polish APECED patients, determine the carrier rate of the most frequent mutation(s) and estimate disease prevalence. While studying 14 unrelated patients, we identified three novel mutations (c.1A>T, affecting the start codon; [IVS1 + 1G>C; IVS1 + 5delG], a complex mutation affecting splice site; c. 908G>C, p.R303P, a missense mutation in plant homeodomain (PHD) and three previously reported mutations (c.769C>T, p.R257X; c.967_979del13bp, C322fsX372; c.931delT, p.C311fsX376). Eleven patients had mutations on both chromosomes, whereas in three patients only a single alteration with proven or likely pathogenic effect was detected. The most frequent was the p.R257X mutation (71% of chromosomes); its carriage rate was assessed in the background population. Analysis of 2008 samples showed eight heterozygotes, indicating the frequency of 0.40% (1:250) and the disease prevalence – 1:129,000 (95% confidence interval: 1:555,000 to 1:30,000). Comparison with an epidemiological estimate (1:619,000, derived for women) suggested that in Poland, APECED is underdiagnosed. Among the patients, no genotype/phenotype correlations were found, but we noted that women had earlier onset of hypoparathyroidism (p < 0.02) and were younger at diagnosis (p < 0.05) than men.

The Role of Recent Admixture in Forming the Contemporary West Eurasian Genomic Landscape

Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have described the genomes of ancient humans across West Eurasia, demonstrating the presence of large-scale, dynamic population movements over the last 10,000 years, such that ancestry across present-day populations is likely to be a mixture of several ancient groups [1-7]. While these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled or have been either too regional or global in their outlook [8-11]. Here, using recently described haplotype-based techniques [11], we present the results of a systematic survey of recent admixture history across Western Eurasia and show that admixture is a universal property across almost all groups. Admixture in all regions except North Western Europe involved the influx of genetic material from outside of West Eurasia, which we date to specific time periods. Within Northern, Western, and Central Europe, admixture tended to occur between local groups during the period 300 to 1200 CE. Comparisons of the genetic profiles of West Eurasians before and after admixture show that population movements within the last 1,500 years are likely to have maintained differentiation among groups. Our analysis provides a timeline of the gene flow events that have generated the contemporary genetic landscape of West Eurasia.Summary Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have described the genomes of ancient humans across West Eurasia, demonstrating the presence of large-scale, dynamic population movements over the last 10,000 years, such that ancestry across present-day populations is likely to be a mixture of several ancient groups [1, 2, 3, 4, 5, 6, 7]. While these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled or have been either too regional or global in their outlook [8, 9, 10, 11]. Here, using recently described haplotype-based techniques [11], we present the results of a systematic survey of recent admixture history across Western Eurasia and show that admixture is a universal property across almost all groups. Admixture in all regions except North Western Europe involved the influx of genetic material from outside of West Eurasia, which we date to specific time periods. Within Northern, Western, and Central Europe, admixture tended to occur between local groups during the period 300 to 1200 CE. Comparisons of the genetic profiles of West Eurasians before and after admixture show that population movements within the last 1,500 years are likely to have maintained differentiation among groups. Our analysis provides a timeline of the gene flow events that have generated the contemporary genetic landscape of West Eurasia.

Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves' disease.

Objective  To investigate whether a polymorphism in the ESR2 gene (rs4986938, previously associated with endometriosis, ovulatory dysfunction and premature onset of coronary heart disease) increases the risk of Graves’ disease (GD).

Association between Tryptophan Hydroxylase 2 Gene Polymorphism and Completed Suicide

The association between suicide and a single nucleotide polymorphism (rs1386483) was examined in the recently identified tryptophan hydroxylase 2 (TPH2) gene. Blood samples of 143 suicide victims and 162 age- and sex-matched controls were examined. The frequency of the TT genotype in the TPH2 polymorphism was higher in suicide victims than in controls (17.5% vs. 8.6%; p = 0.02), particularly in those with a history of repeated suicide attempts (53.3% vs. 8.6%; p < 0.0001). The examined TPH2 polymorphism was found to be associated with suicide. This genetic marker may be particularly important in understanding risk of multiple suicide attempts. Further analyses are needed to confirm these results.

Angiotensin-Converting Enzyme Polymorphism and Completed Suicide: An Association in Caucasians and Evidence for a Link with a Method of Self-Injury

Background/Aims: An association between the II genotype of the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism and suicide was found among Japanese men. Our purpose was to replicate this finding in Caucasians and explore other putative genotypic associations among suicides. Methods: The ACE genotypes were studied by a 2-stage PCR method in 150 completed suicides and 165 age- and sex-matched controls. Results: We found an increase in the frequency of the ACEI allele among male victims of suicide compared to male controls (odds ratio, OR = 1.69, p < 0.006), female suicides (OR = 2.01, p = 0.006) and pooled controls (OR = 1.77, p = 0.001). Analysis of genotype distribution showed that the codominant model had the best fit (p = 0.7) whereas the recessive model could be rejected (p = 0.04). Among males we found an association between the number of the ACE I allele and the method of suicide: OR = 17.98, pcorrected = 0.00003, for jumping from a height; OR = 0.36, pcorrected = 0.048, for hanging. We also observed a trend for a negative effect of the number of copies of the ACE I allele on prevalence of depression (OR = 0.36, p = 0.013) and a trend for an effect on age at death (p = 0.021). Conclusions: Our results suggest that low ACE activity associated with the I allele is a risk factor for suicide, especially in a subset of males. This may be of concern given the widespread use of drugs lowering ACE activity.

Population Carrier Rates of Pathogenic ARSA Gene Mutations: Is Metachromatic Leukodystrophy Underdiagnosed?

Background Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100 000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data. Methodology We studied two independently ascertained cohorts from the Polish background population (N∼3000 each) and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2). Principal Findings Taking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100 000 and 4.1/100 000, respectively for the 1st and the 2nd cohort with a pooled estimate of 4.1/100 000 (CI: 1.8–9.4) which was higher than the estimate of 0.38 per 100 000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients). Conclusions/Significance The observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms.

A comparison of a traditional endotracheal tube versus Etview Sl in endotracheal intubation during different emergency conditions: A randomized, crossover cadaver trial

Background:Airway management is a crucial skill essential to paramedics and personnel working in Emergency Medical Services and Emergency Departments: Lack of practice, a difficult airway, or a trauma situation may limit the ability of paramedics to perform direct laryngoscopy during cardiopulmonary resuscitation. Videoscope devices are alternatives for airway management in these situations. The ETView VivaSight SL (ETView; ETView Ltd., Misgav, Israel) is a new, single-lumen airway tube with an integrated high-resolution imaging camera. To assess if the ETView VivaSight SL can be a superior alternative to a standard endotracheal tube for intubation in an adult cadaver model, both during and without simulated CPR. Methods:ETView VivaSight SL tube was investigated via an interventional, randomized, crossover, cadaver study. A total of 52 paramedics participated in the intubation of human cadavers in three different scenarios: a normal airway at rest without concomitant chest compression (CC) (scenario A), a normal airway with uninterrupted CC (scenario B) and manual in-line stabilization (scenario C). Time and rate of success for intubation, the glottic view scale, and ease-of-use of ETView vs. sETT intubation were assessed for each emergency scenario. Results:The median time to intubation using ETView vs. sETT was compared for each of the aforementioned scenarios. For scenario A, time to first ventilation was achieved fastest for ETView, 19.5 [IQR, 16.5–22] sec, when compared to that of sETT at 21.5 [IQR, 20–25] sec (p = .013). In scenario B, the time for intubation using ETView was 21 [IQR, 18.5–24.5] sec (p < .001) and sETT was 27 [IQR, 24.5–31.5] sec. Time to first ventilation for scenario C was 23.5 [IQR, 19–25.5] sec for the ETView and 42.5 [IQR, 35–49.5] sec for sETT. Conclusions:In normal airways and situations with continuous chest compressions, the success rate for intubation of cadavers and the time to ventilation were improved with the ETView. The time to glottis view, tube insertion, and cuff block were all found to be shorter with the ETView. Trial Registration:clinicaltrials.gov Identifier: NCT02733536.

Analysis of forensically used autosomal short tandem repeat markers in Polish and neighboring populations

The purpose of this study was to evaluate the homogeneity of Polish populations with respect to STRs chosen as core markers of the Polish Forensic National DNA Intelligence Database, and to provide reference allele frequencies and to explore the genetic interrelationship between Poland and neighboring countries. The allele frequency distribution of 10 STRs included in the SGMplus kit was analyzed among 2176 unrelated individuals from 6 regional Polish populations and among 4321 individuals from Germany (three samples), Austria, The Netherlands, Sweden, Czech Republic, Slovakia, Belarus, Ukraine and the Russian Federation (six samples). The statistical approach consisted of AMOVA, calculation of pairwise Rst values and analysis by multidimensional scaling. We found homogeneity of present day Poland and consistent differences between Polish and German populations which contrasted with relative similarities between Russian and German populations. These discrepancies between genetic and geographic distances were confirmed by analysis of an independent data set on Y chromosome STRs. Migrations of Goths, Viking influences, German settlements in the region of Volga river and/or forced population resettlements and other events related to World War II are the historic events which might have caused these finding.