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Try out PMC Labs and tell us what you think. Learn More. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Among Croatian islands, there are several which are known for unusual autochthonous diseases and specific medical conditions that result from the reproductive isolation and specific population genetic structure. These populations are characterized by high degree of genetic isolation, consanguinity, and inbreeding. The reported diseases include Mal de Meleda on Mljet island, hereditary dwarfism on Krk island, familial learning disability on Susak island, familial ovarian cancer on Lastovo island, and several other rare diseases and conditions inherited in Mendelian fashion. We present a historical perspective on how these conditions were first described, interpreted, and assessed. We reviewed the information obtained through genetic research in the past several years, when the genetic etiology of some of these conditions was explained. The genetic etiology of dwarfism on the island of Krk is explained by a mutation in the PROP1 gene, responsible for the short stature. The search for mutations underlying other monogenic diseases in Croatian islands is under way. Unusual autochthonous diseases and specific medical conditions on Croatian islands result from the reproductive isolation and specific genetic structure of their populations, characterized by high degree of genetic isolation, consanguinity, and inbreeding. In this review, we present historical perspective on how these conditions were first described, interpreted, and assessed. It was named after Croatian island of Mljet, previously called Meleda, where the first cases were reported by Stulli 1 - 4. According to Schnyder et al 5 , 6 , the disease originated on the island of Mljet between and , when the island was used by the Dubrovnik Republic for quarantining people suffering from plague and leprosy 7. This resulted in reproductive isolation and high consanguinity, which increased the frequency of homozygous genotypes on the island and thus increased the incidence of Mal de Meleda 8. Among the island population, it was historically thought that Mal de Meleda arises as a contact dermatitis with an unknown endemic plant on the island 6. It was recently revealed that the disease is not exclusively found on Mljet island. In the past two decades, several sporadic cases have also been reported in Italy 9 , Tunisia 10 , western region of Saudi-Arabia 11 , and United Arab Emirates A recent analysis showed that Croatian and Algerian families with the disease share the common haplotype that presents the same mutation in both populations This is consistent with a genetic epidemiological view that a causal mutation originated on Mljet at least years ago, and was then spread by sailors through trade routes of the medieval Dubrovnik Republic. This explains the sporadic cases of the disease in the Middle East and northern Africa An alternative hypothesis is that the mutation responsible for Mal de Meleda could be much older and more widespread. However, other sporadic cases of recessive palmoplantar keratoderma were reported in Sweden 15 , 16 , Japan 17 , and a Chinese family in Taiwan 18 , but their clinical presentation was milder than in original Mal de Meleda and some of the usual signs were absent. This implies possible founder mutations in other genes involved in the same genetic pathway. Recently, two new mutations and four ancestral haplotypes were observed in 69 patients from the countries of the Mediterranean basin, whereas an additional haplotype was found in the German and Scottish patients 19 , which supports the view that the disease could have a possible etiological complexity and allelic heterogeneity. The first changes in keratinization of the skin become clinically manifest several months after birth, typically affecting palms and soles, with the characteristic skin thickening Table 1. A diffuse palmoplantar keratosis is the most prominent feature, which at first presents as yellowish, smooth skin on palms and soles. Eventually, painful fissures develop, which do not necessarily correspond to creases of the skin. Hyperkeratosis extends to the sides and the dorsa of the feet and hands, and interdigital spaces are macerated, with a sharp delineation from healthy skin. An intense hyperhidrosis produces unpleasant fetid smell which is present only in the affected areas of the skin 8. Contractures of variable severity due to hyperkeratosis are usually present on the fifth finger, and they are associated with bilateral brachytelephalangia in the majority of cases. Other symptoms and signs are less common and they may involve papulous keratoses, hyperkeratotic changes similar to lichenification, perioral erythema, and a cystic osteolysis and acroosteolysis of the wrist and tarsal bones and phalanges Typically, orthohyperkeratosis, hypergranulosis, and acanthosis are observed on histological examination, with no signs of epidermal or spongiotic atypia 5 , Electron microscopy shows increased amount of tonofibrils and keratohyalin granules Symptoms progress very slowly and there are no indications that life expectancy among the affected is reduced 21 , They merely attempted to demonstrate the increased homozygosity in the patients in comparison with control population, to show that the disease may be caused in some way by increased consanguinity. However, their results were inconclusive due to a very small sample and a small number of analyzed genetic markers. An analysis of the pedigrees of 12 cases living on the island of Mljet showed that the disease had an autosomal recessive inheritance pattern 8. Based on the knowledge of pedigree structure, an analysis of two large consanguineous families from Algeria, which included 10 affected individuals, localized a disease gene to chromosome 8qter The maximum two-point lod score for D8S was found in this study, and it amounted to 8. An analysis of 5 affected individuals originating from the island of Mljet confirmed the segment of homozygosity in the same region, implying a founder effect A subsequent study on 12 individuals from Mljet further confirmed the findings 8. SLURP-1 shows a high degree of structural similarity with the three fingers motif of snake neurotoxins, which suggests its interaction with the neuronal acetylcholine receptors. SLURP-1 potentiates human alpha 7 nicotinic acetylcholine receptors present in keratinocytes Therefore, SLURP-1 is likely to be a secreted epidermal neuromodulator that influences both epidermal homeostasis and inhibition of tumor necrosis factor TNF -alpha release by macrophages during wound healing. Such roles would explain hyperproliferative and inflammatory clinical phenotype in Mal de Meleda There is a number of clinically similar phenotypes, which can now all be easily distinguished from Mal de Meleda based on genetic mutations involved. Papillon-Lefevre syndrom, also recessive palmoplantar keratosis, has a candidate genetic region on the chromosome 11q14, and subsequent genetic analyses identified the mutations in the gene encoding cathepsin C 8 , 28 - Another recessive palmoplantar keratoderma, characterized by additional cardiac symptoms such as cardiomegaly and ventricular tachycardia, and found in 4 families from the island of Naxos, Greece, is due to a mutation in plakoglobin 31 , The first report on hereditary dwarfism on the Island of Krk was written by Jauregg in Two more cases were born in and in Jurandvor. Since then, 23 dwarfs have descended from the two villages 36 , The systematic study of the condition was then performed by Vojska in A group from the Rijeka School of Medicine, Croatia, reinitiated the studies of the cases in the s and published their results recently 37 , 40 , The total population of the villages in amounted to and inhabitants, respectively, and the share of autochthonous inhabitants was Twice removed parental consanguinity was Consanguineous marriages were pronouncedly common in the past. The motivation for this phenomenon was preservation of the land within a family 40 , A total of 53 children lived in the two villages at the time of Census, totaling only The percentage of people older than 65 years was The average number of members of a household was extremely low, 1. Most men were laborers and agriculture workers, and most women were housewives. The population of both villages seems to have a large share of relatively short people in comparison with the other 9 villages from the islands of Rab, Vis, Lastovo, and Mljet Figure 1 Eight percent of men were shorter than cm. An increase in height could be noted in younger age groups, corresponding to the general trend In the s, when the research was conducted, there were 8 dwarfs in the population of the two villages. Dwarfs were found in six different families, three of which had a positive family history of nanism. The youngest dwarf was 17 years old and the oldest was It seems that the condition does not influence the life expectancy of the affected. Socio-economic conditions in which the dwarfs lived differed greatly. In , all 73 children from both villages underwent auxological examination, with the purpose of exploring hereditary dwarfism. Height below the 10th percentile was found in 13 children, 4 of which showed growth retardation 3rd percentile or lower. Of those 13 children, 10 were revisited 2 years later. The retardation of growth was still present in 4 of these children After this, the growth hormone curve was established, and a lack of somatotropin was determined to be the cause of retardation of growth in two of the four children. One of these children came from a family with known history of hereditary dwarfism 40 , All other clinical and biochemical tests were normal for their age The genetic etiology of the condition was revealed in , when it was shown that a mutation in a candidate gene PROP1 is responsible for the short stature of the dwarfs from the Krk island Similarly, familial dwarfism in a highly consanguineous family, where PROP1 was also responsible for the condition, was recently observed in Tunisia Generally, dwarfism can be caused by isolated growth hormone deficiency or multiple pituitary hormone deficiency MPHD When found in more than one member of the same family, it can show autosomal dominant, autosomal recessive, or X-linked modes of inheritance. Studies also suggested that familial MPHD dwarfism constituted a genetically and pathogenetically highly heterogenous group Mutations in POU1F1 result in a total deficiency of growth hormone and prolactin, and a variable deficiency of thyroid stimulating hormone. The small island of Susak is a unique example of extreme isolation and inbreeding. Founded by only two families of settlers, the island's population rose to in the year of , then to in , in , and in After the World War II, a most of the population emigrated, and the current population is estimated to be less than inhabitants. Therefore, the population of Susak and its emigration in Hoboken represent an outstanding example of genetically very homogenous group, separated some half a century ago and living in different environmental setting which, although limited in size, could be a suitable model for studies of genetic vs environmental impacts on human health While studying consanguinity, the researchers were able to reconstruct genealogies, which covered the entire island population, most of the emigration, and usually four in some cases up to six generations of ancestors. The family trees showed many cases of consanguinity, indicating that the island population is extremely inbred. A basic analysis of blood polymorphisms was performed through analysis of frequency distribution of blood groups. These data are significantly different from those found in the surrounding populations, with a low proportion of blood group B and high proportion of blood group A in comparison with neighboring Croatian, Slovenian, and Italian populations A systematic medical check-up was performed on the entire island population 50 , Among children examined in , multiple congenital anomalies were present in 25 cases, clustering in 12 families, and a detailed description of each particular case, along with the results of examination in siblings was presented Special attention was also given to psychiatric disorders, presumably common on the island. Among the entire population some at the time , there were persons fulfilling the criteria for some psychiatric diagnosis: 57 cases of oligophrenia, 33 cases of senile dementia, 21 cases of psychoses, 16 cases of schizophrenia, and 2 other undefined cases In many of those cases, there had been striking evidence of familial clustering of the diseases, with learning disability being a common feature in most of them 14 , Learning disability was defined as the inability to attend the public school system. As the elementary schools grade in the place of the study are both public and compulsory, the assessment of child's ability to attend the school is performed at the age of six, based on a combination of IQ score measurement and behavioral assessment. The assessment is based on standard set of tests, as required by Croatian Ministry of Science, Education, and Sports These tests include: perception test, test of point linkage, general knowledge test, drawing test, and numerical test; intelligence test based on drawing a human image; Bender Gestalt test; and Raven's progressive colored matrices Data on the individuals unable to attend school were retrieved from local general practitioners and were considered to be complete. The prevalence of learning disability was calculated as the proportion of individuals unable to attend school in the total population of each village as of January It was shown that the prevalence of learning disability in Susak was 2. One of the most frequently documented and repeated findings in human biology is the association between consanguinity and cognitive dysfunction and learning disability The genetics of human cognition is still in its early development, but it is likely to be a highly complex and multifactorially determined polygenic human trait. In some way, increased individual genome-wide homozygosity reduces the biological potential of cognition in all human populations, and the specific mechanisms are still to be revealed. The investigations of genetic diversity on Susak based on microsatellite DNA markers, as compared to the same markers in smaller samples of other populations, revealed that the average heterozygosity and allelic diversity in Susak are considerably smaller 54 , and that Susak island represents an extreme example of reduced genetic diversity in global terms Table 2. In some way, this places its population at a greater risk of cognitive dysfunction in comparison to general Croatian population. Comparison of Susak gene diversity based on autosomal microsatellite markers, with corresponding published gene diversities from isolates or outbred populations. Rudan 55 investigated the incidence of cancer in isolate island populations of the Eastern Adriatic. The population of coastal Dalmatia, characterized by similar environmental factors but quite different population genetic structure, represented a control population of over The most striking finding in these analyses was a 7-fold increase in the incidence of ovarian cancer in Lastovo in comparison to the general population The disease affects mainly younger women on the island up to 45 years of age , and shows familial clustering, which further supports the primarily genetic etiology. Histologically, the disease does not differ from the ovarian cancer cases seen in the general population 55 , As the prognosis of the disease is rather poor, and epidemiological analysis covered the period from , there were no cases or specimens left for further studies. However, it is highly likely that a mutation in a gene similar to BRCA1 is present in the island, possibly a novel and unique variant, with a very high lifetime penetrance. A genetic screening program of the candidate genes is planned among the women in the island to detect early those at increased lifetime risk of ovarian cancer 55 , A number of other monogenic diseases and conditions have been described on Croatian islands. Table 3 lists the evidence for those conditions, and also for extremely rare mutations that were observed in unusually high frequencies in specific Croatian island isolates. Prevalence of albinism and progressive spastic quadriplegia is much higher in the island of Krk than in the general Croatian population Familial congenital hip dislocation was present in unusually high frequencies at the island of Lastovo 57 , while increased incidence of glucosephosphate dehydrogenase deficiency was encountered on Vis island Overview of the evidence of extremely rare mutations present in unusually high frequencies in specific Croatian island isolates. Apart from disease-causing mutations, there are many examples in the literature on very unusual and extremely rare genetic variants present in Croatian island populations. Although these mutations are extremely rare in outbred, general population, and therefore have no effect on the total disease burden, the understanding of their effect on the phenotype could be of great general interest. These extremely rare mutations of large effect can reveal entirely new and unknown molecular and metabolic pathways from genes via expression profiles to proteomics, metabolomics, and eventually phenotype Such understanding could provide new targets for development of drugs and novel therapeutic approaches, which are currently in short supply Therefore, isolated human populations can be of great value in finding such new and unusual genetic variants, which would not be possible in general population There are no conflicts of interest related to this manuscript. National Center for Biotechnology Information , U. Journal List Croat Med J v. Croat Med J. Author information Article notes Copyright and License information Disclaimer. Received Jun 23; Accepted Jul All rights reserved. This article has been cited by other articles in PMC. Abstract Among Croatian islands, there are several which are known for unusual autochthonous diseases and specific medical conditions that result from the reproductive isolation and specific population genetic structure. History and genetic epidemiology of Mal de Meleda It was recently revealed that the disease is not exclusively found on Mljet island. Features of disease The first changes in keratinization of the skin become clinically manifest several months after birth, typically affecting palms and soles, with the characteristic skin thickening Table 1. Autosomal recessive inheritance Onset at birth or in early infancy Characteristic glove-like and sock-like hyperkeratosis with sharp margination Occasional hyperkeratotic plaques on elbows, knees. Open in a separate window. Features of the condition The population of both villages seems to have a large share of relatively short people in comparison with the other 9 villages from the islands of Rab, Vis, Lastovo, and Mljet Figure 1 Figure 1. New insights into genetic etiology The genetic etiology of the condition was revealed in , when it was shown that a mutation in a candidate gene PROP1 is responsible for the short stature of the dwarfs from the Krk island Learning Disability Island of Susak History and genetic epidemiology of learning disability on Susak The small island of Susak is a unique example of extreme isolation and inbreeding. New insights into genetic etiology One of the most frequently documented and repeated findings in human biology is the association between consanguinity and cognitive dysfunction and learning disability Table 2 Comparison of Susak gene diversity based on autosomal microsatellite markers, with corresponding published gene diversities from isolates or outbred populations. Familial Ovarian Cancer Island of Lastovo History and genetic epidemiology of ovarian cancer on Lastovo island Rudan 55 investigated the incidence of cancer in isolate island populations of the Eastern Adriatic. Figure 2. Features of disease The disease affects mainly younger women on the island up to 45 years of age , and shows familial clustering, which further supports the primarily genetic etiology. New insights into genetic etiology As the prognosis of the disease is rather poor, and epidemiological analysis covered the period from , there were no cases or specimens left for further studies. Other Mendelian diseases and conditions Islands of Krk, Pag, Silba, and Lastovo A number of other monogenic diseases and conditions have been described on Croatian islands. Table 3 Overview of the evidence of extremely rare mutations present in unusually high frequencies in specific Croatian island isolates. References 1. Stulli L. On a skin variety \\\\\\\\\[in Italian\\\\\\\\\]. Antologia di Firenze. Bosnjakovic S. Fatovic-Ferencic S, Holubar K. Mal de Meleda: from legend to reality. The portrait and paper of a forgotten hero — Luca Stulli and the Mal de Meleda of yesteryear: a year anniversary. J Invest Dermatol. Autochthonous Meleda disease. Ann Dermatol Syphiligr Paris ; 96 — Mljet disease Mal de Meleda Lijec Vjesn. The Meleda disease — an acroerythrokeratodermy. Z Hautkr. Mal de Meleda: genetic haplotype analysis and clinicopathological findings in cases originating from the island of Mljet Meleda , Croatia. Unusual cases of Meleda keratoderma treated with aromatic retinoid etretinate. Palmoplantar keratoses type Meleda. Sem Hop Paris. Mal de Meleda. Int J Dermatol. Mal de Meleda: a report of four cases from the United Arab Emirates. Pediatr Dermatol. Hum Mol Genet. Genetic epidemiological studies of eastern Adriatic island isolates, Croatia: objective and strategies. Coll Antropol. Gamborg Nielsen P. Two different clinical and genetic forms of hereditary palmoplantar keratoderma in the northernmost county of Sweden. Clin Genet. Hereditary palmoplantar keratosis of the Gamborg Nielsen type. Clinical and ultrastructural characteristics of a new type of autosomal recessive palmoplantar keratosis. Arch Dermatol Res. Nagashima M. Palmoplantar keratoses. In: Miura O, Ochiai K, editors. Clinics and genetics. Inheritance of dermatological and urological diseases. Tokyo: Igaku — Shoin Publishers; Report of a family with Mal de Meleda in Taiwan: a clinical, histopathological and immunological study. Meleda disease: report of two cases investigated by electron microscopy. Kogoj F. Mljet disease \\\\\\\\\[in Croatian\\\\\\\\\]. Zagreb: JAZU; Genetic linkage of Meleda disease to chromosome 8qter. Eur J Hum Genet. Homozygosity at chromosome 8qter in individuals affected by mal de Meleda Meleda disease originating from the island of Meleda. Br J Dermatol. Mapping of Papillon-Lefevre syndrome to the chromosome 11q14 region. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet. Papillon-Lefevre syndrome: mutations and polymorphisms in the cathepsin C gene. Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair Naxos disease maps to 17q Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair Naxos disease. A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness Vohwinkel's syndrome in three unrelated families. J Am Acad Dermatol. Jauregg VW. Wien Klin Wochenschr. Zergollern L. A follow-up on Hanhart's dwarfs of Krk. Birth Defects Orig Artic Ser. Enclaves of hereditary dwarfism on the island of Krk, Croatia. Hanhart E. Krk island disease. Vojska V. A report on the so-called small people from Krk \\\\\\\\\[in German\\\\\\\\\]. Archiven den Rassen-Geselschaft in Biologie Rajh-Gustincic M, Kopajtic B. Auxological examination of children in the region of hereditary nanism on Krk. Strategy for mapping quantitative trait loci QTL using human metapopulations. Etiology of hypopituitarism revealed. J Endocr Genet. A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies. J Clin Endocrinol Metab. Dattani MT. Novel insights into the aetiology and pathogenesis of hypopituitarism. Horm Res. Clin Endocrinol Oxf ; 62 —8. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Long-term growth hormone therapy in adulthood results in significant linear growth in siblings with a PROP-1 gene mutation. Susak Island \\\\\\\\\[in Croatian\\\\\\\\\]. Lost in transition — the Island of Susak Bohacek N. Tristan da Cunha and Susak. Lijec Vjesn. Inbreeding and learning disability in Croatian island isolates. Narodne novine. Rudan I. Inbreeding and cancer incidence in human isolates. Hum Biol. Ancestral kinship and cancer in Lastovo island, Croatia. Maricevic A. Incidence of congenital hip dislocation in Lastovo High incidence of glucosephosphate dehydrogenase deficiency in Croatian island isolate: example from Vis Island, Croatia. Anthropogenetical analysis of abnormal human alpha-globin gene cluster arrangement on chromosome Hum Hered. Y chromosomal heritage of Croatian population and its island isolates. Gamulin S. Impact of molecular medicine on pathophysiology, medical practice, and medical education. Campbell H, Rudan I. Interpretation of genetic association studies in complex disease. Pharmacogenomics J. Population choice in mapping genes for complex diseases. Support Center Support Center. External link. Please review our privacy policy. Onset at birth or in early infancy. Characteristic glove-like and sock-like hyperkeratosis with sharp margination. Occasional hyperkeratotic plaques on elbows, knees. Marked hyperhidrosis, maceration, and malodor. Slow progression without remissions. Ortohyperkeratosis, hypergranulosis, and acanthosis on histological examination, with no signs of epidermal or spongiotic atypia. Increased amount of tonofibrils and keratohyalin granules on electron microscopy. G6PD deficiency. Reports of high population frequencies of extremely rare genetic variants:.
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