Another rare case of a child with de novo terminal 9p deletion and co-existing interstitial 9p duplication: clinical findings and molecular cytogenetic study by array-CGH.

Trisomy 9p is the fourth most common chromosome abnormality found in liveborns. We report on a rare case of partial trisomy 9p complicated by partial monosomy 9p. Clinical manifestation included craniofacial abnormalities typical for trisomy 9p syndrome, developmental delay, mental retardation and brain anomaly in the form of Dandy-Walker malformation. The cytogenetic abnormality was investigated with FISH and array-CGH to characterize the breakpoints of the complex rearrangement. The patient's karyotype was 46,XX,der(9)del(9)(p24)dup(9)(p21p24)dn.arr 9p24.3p24.2 (1-2,414,485)×1,9p24.2p21.3(2,414,485-24,101,280)×3. The cytogenetic rearrangement led to a 2.4-Mb deletion of 9p24.2pter and a 21.6-Mb duplication of 9p24.2p21.3. The clinical and cytogenetic findings in our and other similar patients are compared.

Common polymorphism (81Val>Ile) and rare mutations (257Arg>Ser and 335Ile>Ser) of the MC3R gene in obese Polish children and adolescents.

The predisposing role to human obesity of the MC3R gene polymorphism is controversial. In this report we present the first study focused on the search for the MC3R polymorphism in the Polish population. Altogether 257 obese children and adolescents (RBMI>120) and 94 adults, who were never obese or overweight (BMI<25), were studied. For all subjects the entire coding sequence was analyzed by direct DNA sequencing. One common polymorphism (81Val>Ile) and two rare mutations (257Arg>Ser and 335Ile>Ser) were identified. The common polymorphism was widely distributed in the obese and control cohorts, while the mutations were identified in four obese subjects only. In case of the 335Ile>Ser substitution a three-generation family, consisting of 20 members, was also analyzed. It was found that all carriers of the 335Ser mutation were obese, but among non-carriers obese subjects also were found. Our study suggests that the predisposing effect to obesity of the 81Ile polymorphic variant is rather unlikely. With regard to the studied rare mutations we suggest that the 335Ser allele may have a small predisposing effect.

Prevention and control of childhood asthma and allergy in the EU from the public health point of view: Polish Presidency of the European Union.

The leading priority for the Polish Presidency of the Council of the European Union was to reduce health inequalities across European societies, and, within its framework, prevention and control of respiratory diseases in children. This very important paper contain proposal of international cooperation on the prevention, early detection and monitoring of asthma and allergic diseases in childhood which will be undertaken by the EU member countries as a result of EU conclusion developed during the Polish Presidency of the Council of the European Union. This will result in collaboration in the field of chronic diseases, particularly respiratory diseases, together with the activity of the network of national institutions and NGOs in this area. Paper also contains extensive analysis of the socio-economic, political, epidemiological, technological and medical factors affecting the prevention and control of childhood asthma and allergy presented during Experts presidential conference organized in Warsaw-Ossa 21-22 September 2011.

The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant.

In this multicenter study, we assessed the use of palifermin (recombinant human-keratinocyte growth factor 1) in the prevention of oral mucositis (OM) and acute GvHD (aGvHD) induced by a hematopoietic stem cell transplant (HSCT). Fifty-three patients with hematological diseases received three doses of palifermin (60 mug/kg once daily i.v.) pre- and post-conditioning regimens (total six doses). A retrospective control group of 53 transplant patients received no palifermin. There was a significant reduction in the incidence of OM of WHO (World Health Organization) grades 1-4 (58 vs 94%, P<0.001), 3-4 (13 vs 43%, P<0.001) and the median duration of OM (4 vs 9 days, P<0.001) in the palifermin group compared to the control group. The incidence of analgesics (32 vs 75.5%, P<0.001), opioid analgesics (24 vs 64%, P<0.001) and total parenteral nutrition (11 vs 45%, P<0.001) was also significantly reduced. The analysis of distribution of affected organs revealed that aGvHD was less prevalent in the palifermin group (P=0.036). There was no significant difference in the onset of any OM after HSCT, time to engraftment and length of hospitalization between groups. The drug was generally well tolerated and safe. Our results suggest that the use of palifermin reduces OM and probably aGvHD after HSCT, but a randomized trial is needed.

Novel sporadic and recurrent mutations in KRT5 and KRT14 genes in Polish epidermolysis bullosa simplex patients: further insights into epidemiology and genotype-phenotype correlation.

Epidermolysis bullosa simplex (EBS) is a hereditary genodermatosis characterised by trauma-induced intraepidermal blistering of the skin. EBS is mostly caused by mutations in the KRT5 and KRT14 genes. Disease severity partially depends on the affected keratin type and may be modulated by mutation type and location. The aim of our study was to identify the molecular defects in KRT5 and KRT14 in a cohort of 46 Polish and one Belarusian probands with clinical suspicion of EBS and to determine the genotype-phenotype correlation. The group of 47 patients with clinical recognition of EBS was enrolled in the study. We analysed all coding exons of KRT5 and KRT14 using Sanger sequencing. The pathogenic status of novel variants was evaluated using bioinformatical tools, control group analysis (DNA from 100 healthy population-matched subjects) and probands' parents testing. We identified mutations in 80 % of patients and found 29 different mutations, 11 of which were novel and six were found in more than one family. All novel mutations were ascertained as pathogenic. In the majority of cases, the most severe genotype was associated with mutations in highly conserved regions. In some cases, different inheritance mode and clinical significance, than previously reported by others, was observed. We report 11 novel variants and show novel genotype-phenotype correlations. Our data give further insight into the natural history of EBS molecular pathology, epidemiology and mutation origin.

Second malignancies and Richter's syndrome in patients with chronic lymphocytic leukaemia treated with cladribine.

The increased frequency of second malignancies in chronic lymphocytic leukaemia (CLL) is well known. Moreover, antineoplastic therapy additionally increases the risk of secondary cancers. In this study, we analysed whether treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA) during the course of CLL had an impact on the subsequent occurrence of either secondary solid tumours or Richter's syndrome. There were 1487 eligible patients, 251 treated with 2-CdA alone, 913 treated with alkylating agents (AA)-based regimens alone and 323 treated with both 2-CdA and AA. Median time from the start of CLL treatment to the diagnosis of secondary malignancy was 1.9 years (0.5-5.1 years) for the 2-CdA group, 1.8 years (0.3-7.9 years) for the AA group and 3.9 years (0.3-8.4 years) for the 2-CdA+AA group. A total of 68 malignancies were reported in 65 patients. Ten events were non-melanotic skin cancers and were excluded from the analysis, leaving 58 events in 58 patients. In the group of patients treated with 2-CdA alone, there were 15 (6.0%) cases, in the group of patients treated with AA alone there were 26 (2.8%) cases, and in the group treated with 2-CdA+AA there were 17 (5.3%) cases of secondary malignancies. The differences between the frequency of secondary malignancies in the 2-CdA and 2-CdA+AA versus AA alone groups were not significant (P=0.05 and P=0.06, respectively). Only lung cancers occurred significantly more frequently in the 2-CdA (2.8%) and 2-CdA+AA (2.2%) treated groups compared with the AA patients (0.3%) (P<0.001 and P<0.01, respectively). In conclusion, 2-CdA in CLL patients does not seem to increase the risk of secondary malignancies except for lung cancers. However, further studies are necessary to establish the real risk of lung cancer in CLL patients treated with 2-CdA.

Concomitant staining of mast and parietal cells in human gastric mucosa.

A simple technique for concomitant staining of mast and parietal cells in the same section is described. Mast cells were stained by alcian blue or astra blue in methanol-formalin-acetic acid fixed biopsies of gastric mucosa. Parietal cells were visualized by Dolichos biflorus lectin binding.

[Identification of mutation and polymorphic changes in the CFTR gene of patients with obstructive azoospermia]. / Identyfikacja mutacji i zmian polimorficznych w genie CFTR u pacjentów z azoospermia obstrukcyjna.

Obstructive azoospermia is one of the symptoms of congenital bilateral absence of the vas deferens (CBAVD)--disease which is suggested as primarily genital form of cystic fibrosis. CBAVD is a result of mutations and polymorphisms in CFTR gene. We studied 9 the most common mutations and identified 3 mutations (delta F508, R117H, G542X). The study showed that: 37.1% of CBAVD patients (13 out of 35 examined patients) carried mutations in a single or both copies of the gene. We also found the increased frequency of IVS8-5T allele in this group. No increased frequency of mutations in CFTR gene was found in group of men with incorrect spermatogenesis.

Characterisation of the supraorbital foramen and notch as an exit route for the supraorbital nerve in populations from different climatic conditions.

The aim of this study was to obtain morphological data on the supraorbital foramina and notches related to sex and side of the skull in populations from different climatic conditions. We assume that the type and frequency of these supraorbital structures may depend on the climatic conditions in which the population lived. Populations from colder regions should have a higher frequency of foramina and populations from warmer climates should have a higher frequency of supraorbital notches than other populations. This may be a result of adaptive changes and developmental responses to ambient temperatures, for prevention of heat loss in the supraorbital neurovascular bundle passing through these supraorbital structures. Localisation of the supraorbital neurovascular bundle is higher and deeper when it passes through the foramen than in the notch. A total of 1978 orbits from 989 skulls collected in three climatic regions: warm, temperate and cold, were analysed. The highest frequency of supraorbital foramina (35.4%) was in skulls from cold climatic conditions. In samples from warm climates, the frequency of supraorbital foramina was lowest (16.4%). In contrast, the frequency of supraorbital notches was highest in the sample from warm climates (54.5%), and lowest in the sample from cold climatic conditions (44.0%). Statistically significant differences in the frequency of supraorbital structures were found between cold climate sample and the other two samples (p<0.05). Our results suggest a relationship between the type of supraorbital structure and climatic conditions as an adaptation to cold climate and thermoregulatory processes concerning the human head. This research is of direct relevance to clinical practice, and drawing attention to the differences in the frequency of these supraorbital structures may help surgeons to avoid injuring the neurovascular bundles. These data and studies may also contribute to the understanding of the impact of climate on the morphology of modern European skulls.

Physical and mathematical modelling of implant-fascia system in order to improve laparoscopic repair of ventral hernia.

BACKGROUND: This paper describes an investigation of biomechanical behaviour of hernia repair, which is focused on the selection of safe linking of certain type of implant with fascia in laparoscopic operation. The strength of various fixations of the implant to the fascia is analysed. METHODS: The research is based on experimental observations of operated hernia model behaviour during a dynamic impulse load corresponding to post-operative cough. Fifty seven different types of models of implanted mesh are considered. Five types of implants and five types of connectors are used. Mechanical properties of the implants as well as limit tearing forces of joints are identified in uni-axial tensile tests. Mathematical model of implanted mesh based on finite element method is proposed. The identified mechanical properties of the materials are applied and the model is calibrated using quantities measured during experiments. FINDINGS: The presented results point at trans-abdominal sutures and ProTacks (connectors) and at DynaMesh (implant) as the most reliable materials used in ventral hernia operation, in the tested materials group. Desired properties of implants seem to be: elastic properties similar to the properties of tissues and high local strength, as fixation have a local character. The proposed mathematical model can be applied to simulate real behaviour of an implant with appropriate accuracy and to estimate the number of tacks for the implantation of hernia meshes. INTERPRETATION: The presented results may help in the deeper understanding of the fascia-mesh system behaviour, and thus may lead to improve the fixation methods.

Steroid-sparing effect of extracorporeal photopheresis in the therapy of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Steroid-refractory graft-versus-host disease (GVHD) remains a challenging therapeutic problem after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the clinical effect of extracorporeal photopheresis (ECP), and its impact on intensivity of immunosuppresive therapy in allogeneic HSCT patients. PATIENTS AND METHODS: In this study 443 Therakos ECP procedures were performed in 21 patients after allogeneic HSCT with acute (aGVHD, 8 patients) or chronic (cGVHD, 13 patients) therapy-refractory GVHD. The median age at ECP onset was 20.5 years (range, 10-55). Venous access was provided by a nontunelized central venous catheter (12 patients) or 9.6-French portacath (9 patients). RESULTS: In the cGVHD group 9/13 patients were improved with a 4-year overall survival rate of 67.7%. ECP led to steroid discontinuation in 6 and substantial dose reduction in 5 patients. The prednisone dose equivalent per kilogram body weight decreased from 0.32 mg to 0.07 mg after therapy. Therapy of aGVHD led to complete or partial symptom remission in 3/9 subjects. The change in steroid dose in the aGVHD group was not significant, there were no long-term survivors. Portacath access was well tolerated and provided adequate blood flow rates. CONCLUSIONS: The ECP therapy significantly reduced the rates of remissions with steroid discontinuation among cGVHD but not aGVHD patients. Rare ECP-related complications were either catheter related or anticoagulation induced during ECP procedures. Photopheresis was a safe, effective method to treat steroid-resistant cGVHD.

Acute glomerulonephritis in a donor as a side effect of allogeneic peripheral blood stem cell mobilization with granulocyte colony-stimulating factor.

Following on from the recently published articles reported side effects occurring due to donation of stem cells, we describe a case of a donor with transient, biopsy-proved acute focal segmental proliferative glomerulonephritis (GN) due to peripheral blood stem cells (PBSC) mobilization with granulocyte colony-stimulating factor (G-CSF). A 44-year-old woman with no relevant past medical history suffering from obesity and hypertension well controlled with metoprolol without hypertensive retinopathy was admitted to our hospital as a donor of PBSC. She received G-CSF subcutaneously-filgrastim (Amgen)-at a dose of 5 microg/kg twice a day for 6 days. The macroscopic hematuria and proteinuria occurred on 5th day of G-CSF administration. Due to mobilization and collection of stem cells, proteinuria was becoming more intense and reached the nephrotic range. The immunological, infectious, urological and gynecological causes of such complication were excluded. The final histological recognition was early stage of focal segmental proliferative GN. To our knowledge this a first report of GN in a donor due to mobilization of PBSC confirmed with renal biopsy. These findings suggest that filgrastim may induce transient urinary excretion of protein and hematuria in PBSC donors as the symptoms of acute GN without adversely affecting renal function.

Prostaglandin-endoperoxide synthase genes COX1 and COX2 - novel modifiers of disease severity in cystic fibrosis patients.

Cystic fibrosis (CF) is one of the most common autosomal recessive diseases among Caucasians caused by a mutation in the CFTR gene. However, the clinical outcome of CF pulmonary disease varies remarkably even in patients with the same CFTR genotype. This has led to a search for genetic modifiers located outside the CFTR gene. The aim of this study was to evaluate the effect of functional variants in prostaglandin-endoperoxide synthase genes (COX1 and COX2) on the severity of lung disease in CF patients. To the best of our knowledge, it is the first time when analysis of COX1 and COX2 as potential CF modifiers is provided. The study included 94 CF patients homozygous for F508del mutation of CFTR. To compare their clinical condition, several parameters were recorded, e.g. a unique clinical score: disease severity status (DSS). To analyse the effect of non-CFTR genetic polymorphisms on the clinical course of CF patients, the whole coding region of COX1 and selected COX2 polymorphisms were analysed. Statistical analysis of genotype-phenotype associations revealed a relationship between the heterozygosity status of identified polymorphisms and better lung function. These results mainly concern COX2 polymorphisms: -765G>C and 8473T>C. The COX1 and COX2 polymorphisms reducing COX protein levels had a positive effect on all analysed clinical parameters. This suggests an important role of these genes as protective modifiers of pulmonary disease in CF patients, due to inhibition of arachidonic acid conversion into prostaglandins, which probably reduces the inflammatory process.

Relationship between mast cells/parietal cells and maximal/basal acid output ratio in chronic gastritis.

Mast and parietal cells were concomitantly demonstrated in biopsies from corpus mucosa of patients with various forms of chronic gastritis. The ratio of mast/parietal cells and the ratio of maximal and basal acid output were negatively correlated.