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BASCULE ( I b i ier I a i naemic I s i pots and I c i yanosis with I u i rticarial- I l i ike I e i ruption) syndrome was first described by Bessis I et al i in 2016.1 Other case reports were subsequently published, but no successful therapeutic interventions have yet been documented.2-4 We report the use of bilastine in an adolescent boy with BASCULE syndrome. Br J Dermatol 2016; 175: 218 - 20. 2 Bessis D, Pallure V, Jeziorski E. BASCULE syndrome, orthostatic cyanosis and postural orthostatic tachycardia syndrome: time for decanting old wine? Bier anaemic spots, cyanosis with urticaria-like eruption (BASCULE) syndrome on trunk and upper limbs. [Extracted from the article]

A biopsy was not undertaken as the distribution and rate of progression over 2 months were felt to favour the latter, representing an early presentation of linear scleroderma en coup de sabre. Linear scleroderma en coup de sabre is a rare form of localized scleroderma occurring in the frontoparietal area of the forehead and scalp, with the potential to result in ophthalmological, neurological and dental complications. Development of consensus treatment plans for juvenile localized scleroderma: a roadmap toward comparative effectiveness studies in juvenile localized scleroderma. [Extracted from the article]

A letter to the editor is presented regarding the case study of a nine-year-old white female with generalized pustular psoriasis (GPP) who were treated with infliximab.

Abstract Background Independent studies have shown that several single nucleotide polymorphisms (SNP) in the human FTO (fat mass and obesity associated) gene are associated with obesity. SNP have also been identified in the pig FTO gene, among which some are associated with selected fat-deposition traits in F2 crosses and commercial populations. In this study, using both commercial pig populations and an experimental Meishan × Pietrain F2 population, we have investigated the association between one FTO SNP and several growth and carcass traits. Association analyses were performed with the FTO polymorphism either alone or in combination with polymorphisms in flanking loci. Methods SNP (FM244720:g.400C>G) in exon 3 of porcine FTO was genotyped by PCR-RFLP and tested for associations with some growth, carcass and fat-related traits. Proportions of genetic variance of four pig chromosome 6 genes (FTO, RYR1, LIPE and TGFB1) on selected traits were evaluated using single- and multi-locus models. Results Linkage analysis placed FTO on the p arm of pig chromosome 6, approximately 22 cM from RYR1. In the commercial populations, allele C of the FTO SNP was significantly associated with back fat depth and allele G with muscling traits. In the Meishan × Pietrain F2 pigs, heterozygotes with allele C from the Pietrain sows and allele G from the Meishan boar were more significantly associated with fat-related traits compared to homozygotes with allele G from the Pietrain and allele G from the Meishan breed. In single- and multi-locus models, genes RYR1, TGFB1 and FTO showed high associations. The contribution in genetic variance from the polymorphism in the FTO gene was highest for back fat depth, meat area on the musculus longissimus lumborum et thoracis tissues and metabolite glucose-6-phosphate dehydrogenase. Conclusions Our results show that in pig, FTO influences back fat depth in the commercial populations, while in the Meishan × Pietrain F2 pigs with a CG genotype, heterosis occurs for several fat-related traits.

Spontaneous tumor regression is a recognized phenomenon across various cancer types. Recent research emphasizes the alterations in autoantibodies against carbonic anhydrase I (CA I) (anti-CA I) levels as potential prognostic markers for various malignancies. Particularly, autoantibodies targeting CA I and II appear to induce cellular damage by inhibiting their respective protein's catalytic functions. Our study illuminates the profound impact of anti-CA I autoantibodies from patient serum on the esterase activity of human CA I, exhibiting inhibitory effects akin to the acetazolamide inhibitor. Concurrently, our newly synthesized mouse monoclonal IgG antibody, mAb 2B8, against human CA I showcased a potent inhibitory action. An in-depth exploration into mAb 2B8's binding dynamics with its target enzyme was undertaken. Leveraging epitope extraction and phage display library techniques, we identified the amino acid sequence DFWTYP (positions 191-196 of CA I) as crucial for mAb 2B8's interaction. In 3-D structural analysis, this sequence is spatially adjacent to a previously identified epitope (DFWTYP) that interacts with patient-derived autoantibodies. Critically, mAb 2B8 demonstrated an ability to infiltrate eukaryotic cells, engaging specifically with its intracytoplasmic target. This positions mAb 2B8 as a promising model for future studies aimed at tumor cell eradication., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Petra Chalova et al.)

The Dermatology: 'Getting It Right the First Time' (GIRFT) Programme National Specialty Report recommended improving access to, and the quality of, paediatric dermatology services. Understanding referral patterns makes it easier to identify areas that can be improved. This study analysed 292 new referrals to a national care centre that provides secondary care to 50% of all Irish children. Results showed that 51% of new referrals could have been managed in primary care and 41% of new referrals were inappropriate, including 5.5% having no abnormal skin findings. These results indicate that up to 876 referrals could have been avoided over a 13-month period, freeing up resources and reducing wait times for cases more appropriate for a secondary and tertiary care centre. This would improve access for children, allowing them to be diagnosed at the right place and time, in alignment with GIRFT values., Competing Interests: Conflicts of interest A.D.I. has received personal fees from AbbVie, Aslan, Connect Biopharma, LEO Pharma, Lilly, Novartis, Pfizer, RAPT Pharma, Sanofi/Regeneron and UCB, and has received a grant from the UK National Institute for Health Research (research arm of the UK Department of Health) as co-principal investigator of a clinical trial comparing methotrexate with ciclosporin in children with severe atopic dermatitis. He has received research support from Pfizer and Regeneron. N.F., F.B., V.D. and A.C. have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest A.D.I. has received personal fees from AbbVie, ASLAN Pharmaceuticals, Connect Biopharma, LEO Pharma, Lilly, Novartis, Pfizer, RAPT Therapeutics, Sanofi/Regeneron and UCB, and has received a grant from the UK National Institute for Health Research (research arm of the UK Department of Health) as coprincipal investigator of a clinical trial comparing methotrexate with ciclosporin in children with severe atopic dermatitis. He has received research support from Pfizer and Regeneron. The remaining authors declare no conflicts of interest.

Background: Hypertension challenges arise in part from poor adherence due to inadequate patient education. VR offers immersive learning to improve hypertension knowledge., Objective: To compare VR education with traditional verbal education to improve hypertension knowledge., Methods: In this randomised trial, 182 patients with hypertension were assigned to receive either traditional physician-led education (n = 88) or VR education (n = 94) with equivalent content. The VR group experienced a 3D video using Oculus Quest 2 headsets. Knowledge was assessed post-intervention using a 29-item questionnaire. The primary outcome was the objective score. Subjective satisfaction and responder characteristics were secondary outcomes., Results: Median objective scores were significantly higher for VR (14, IQR 3) versus traditional education (10, IQR 5), p < 0.001, indicating superior hypertension knowledge acquisition with VR. Subjective satisfaction was high in both groups. Participants were categorized into low (first quartile) and medium-high (second to fourth quartiles) responders based on their scores. Low responders had a significantly higher prevalence of older women than medium-high responders (57% vs. 40% female, p = 0.024; 68 vs. 65 years), p = 0.036)., Conclusions: VR outperforms traditional education. Tailoring to groups such as older women can optimise learning.

To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations., Methods: VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings., Results: The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies., Conclusion: The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/)., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.)

Background: Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA -related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA- mutated patients, analysing our new data with previous literature to give a comprehensive picture., Methods: We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ , GNA11 , RASA1 and TEK . Additionally, 914 patients previously reported were systematically reviewed., Results: 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ , GNA11 , RASA1 or TEK ., Conclusion: We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping 'vascular' phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This article is the fourth and last part of a series aimed at extending and correcting the anatomical nomenclature. Because of the rapid development of internet and the use of electronic formats in communication in anatomy, embryology, histology, medical education, and clinical medicine, an appropriate, precise, and concise anatomical nomenclature is required. Such tool enables to avoid any potential confusion and possible scientific/medical mistakes. The up-to-date official anatomical terminology, Terminologia Anatomica, is available longer than 20 years and needs to be refined and extended. The authors have collected and listed 210 terms and completed them with definitions and/or explanations. We aimed to start a discussion about their potential incorporation into the new revised version of the Terminologia Anatomica. This article is primarily focused on the vessels of the human body (arteries, veins, and lymphatic system).

Background: PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods., Results: Two patients, one with CLOVES variant (P1) and one with facial infiltrating lipomatosis and hemimegalencephaly (P2), were commenced on miransertib treatment on a compassionate use basis. In patient one, intra-abdominal and paraspinal overgrowth had resulted in respiratory compromise, obstructive uropathy, dysfunctional seating and lying postures, and chronic pain. In patient two, hemifacial overgrowth and hemimegalencephaly had caused difficulties with articulation and oral function, and refractory epilepsy. Miransertib treatment was continued for a median duration of 22 months (range 22-28). In patient one, alleviation of respiratory compromise was observed and functionally, seating and lying postures improved. Serial volumetric MRI analysis revealed 15% reduction in calculated volumes of fatty overgrowth between treatment commencement and end. In patient two, reduction in seizure burden and improved parent-reported quality of life measures were reported. Treatment was discontinued in both patients due to lack of sustained response, and poor compliance in year two of treatment (P2). No significant toxicities were reported., Conclusion: We report the first paediatric case series of the use of miransertib in two children with PROS. Objective clinical response was observed in patient one, and improvement in key qualitative outcomes was reported in patient two. Treatment was well tolerated with no significant toxicities reported. This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).

Pain is a medical and nursing problem that is common in surgical departments. Inadequate pain management can lead to patient distress, as well as extending the period in which the patient's quality of life is reduced. The standardized SF-MPQ-2 questionnaire provides nurses with the opportunity to assess pain within a broader context. The aim of this descriptive and exploratory study was to describe the state of pain assessment in surgical patients in the South Bohemian Region and to highlight the benefits of using a standardized tool for proper pain assessment. The research was carried out using a quantitative survey within the South Bohemian Region (Czech Republic). The participants in the study were nurses working in surgical departments in hospitals in the region as well as hospitalized patients. The results show that nurses pay slightly more attention to pain assessments than doctors. We know that, generally, pain decreases with time after surgery. Nonetheless, returning pain, as well as continuous pain, can occur, both of which have an emotional component. The results of this study are directed at nurses and include a call for more effective pain management through improved assessment.

Background: Capillary malformation-arteriovenous malformation is an autosomal dominant disorder, characterised by capillary malformations and increased risk of fast-flow vascular malformations, caused by loss-of-function mutations in the RASA1 or EPHB4 genes. Around 25% of the patients do not seem to carry a germline mutation in either one of these two genes. Even if other genes could be involved, some individuals may have mutations in the known genes that escaped detection by less sensitive techniques. We tested the hypothesis that mosaic mutations could explain some of previously negative cases., Methods: DNA was extracted from peripheral blood lymphocytes, saliva or vascular malformation tissues from four patients. RASA1 and EPHB4 coding regions and exon/intron boundaries were analysed by targeted custom gene panel sequencing. A second panel and/or Sanger sequencing were used to confirm the identified mutations., Results: Four distinct mosaic RASA1 mutations, with an allele frequency ranging from 3% to 25%, were identified in four index patients with classical capillary malformation-arteriovenous malformation phenotype. Three mutations were known, one was novel. In one patient, a somatic second hit was also identified. One index case had three affected children, illustrating that the mosaicism was also present in the germline., Conclusion: This study shows that RASA1 mosaic mutations can cause capillary malformation-arteriovenous malformation. Thus, highly sensitive sequencing techniques should be considered as diagnostic tools, especially for patients with no family history. Even low-level mosaicism can cause the classical phenotype and increased risk for offspring. In addition, our study further supports the second-hit pathophysiological mechanism to explain the multifocality of vascular lesions in this disorder., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

This article is the third part of a series aimed at correcting and extending the anatomical nomenclature. Communication in clinical medicine as well as in medical education is extensively composed of anatomical, histological, and embryological terms. Thus, to avoid any confusion, it is essential to have a concise, exact, perfect and correct anatomical nomenclature. The Terminologia Anatomica (TA) was published 20 years ago and during this period several revisions have been made. Nevertheless, some important anatomical structures are still not included in the nomenclature. Here we list a collection of 156 defined and explained technical terms related to the anatomical structures of the human body focusing on the digestive, respiratory, urinary and genital systems. These terms are set for discussion to be added into the new version of the TA.

This article details our experience with the Terminologia Histologica (TH) and its utility in the teaching of histology, cytology, and clinical medicine (e.g., pathology and hematology). Latin histological nomenclature has been used for 43years, and the latest version of the TH has been in use for 15years (although it was only issued publicly within the past 10years). The following findings and ensuing proposals allow us to discuss key points pertaining to the TH and make important suggestions for potential changes to the TH (such as the exclusion and inclusion of various terms). We classify these changes into six groups: 1.) mistakes in the TH, 2.) discrepancies among various Terminologiae, 3.) discrepancies within the TH, 4.) the repetition of terms, 5.) synonyms in the TH, and 6.) missing terms in the TH. Surprisingly, unlike the anatomical nomenclature, the histological nomenclature has been neglected in the literature. This article addresses this problem by reviewing and summarizing the state of this field, pointing out key discrepancies, offering solutions, and highlighting topics for further discussion., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Generalized lymphatic anomaly is a rare, complex, lymphatic anomaly generally involving soft tissues, spleen, and bones. It can lead to focal skeletal fragility and pathologic effusions. A recent prospective trial of sirolimus for complicated vascular anomalies showed partial response in seven patients with generalized lymphatic anomaly treated with sirolimus with a target trough level of 10-15 ng/mL for 1 year (Adams et al). We describe successful treatment of generalized lymphatic anomaly with a lower-dose, long-term course of sirolimus., (© 2018 Wiley Periodicals, Inc.)

A novel enzyme-free electrochemical immunosensor was developed for highly sensitive detection and quantification of human epididymis protein 4 (HE4) in human serum. For the first time, core/shell CdSe/ZnS quantum dots were conjugated with anti-HE4 IgG antibodies for subsequent sandwich-type immunosensing with superparamagnetic microparticles functionalized with anti-HE4 IgG antibodies, which allow rapid and efficient HE4 capture from the sample. Electrochemical detection of anti-HE4 IgG - HE4 - anti-HE4 IgG CdSe/ZnS immunocomplex was performed by recording the current response of Cd(II) ions, released from dissolved quantum dots at screen-printed carbon electrode (SPCE), modified with mercury or bismuth film. The linear range of the detection was from 20 pM to 40 nM with limit of detection of 12 pM using three times the standard deviation of blank criterion at mercury-film SPCE and from 100 pM to 2 nM with limit of detection of 89 pM at bismuth-film SPCE. Proposed electrochemical immunosensor meets the requirements for fast and sensitive quantification of HE4 biomarker in early stage of ovarian cancer and due to the proper sensitivity and specificity presents a promising alternative to enzyme-based probes used routinely in clinical diagnostics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/objectives: Atopic dermatitis (AD) affects up to 20% of children. Although the majority of patients are adequately controlled using emollients, topical corticosteroids, topical calcineurin inhibitors, or phototherapy, children with moderate to severe AD may require systemic treatment for control. The objective of the current study was to evaluate the efficacy and safety of methotrexate in children with severe AD attending a tertiary referral center., Methods: A retrospective chart review was undertaken of all children who received methotrexate for severe AD at our tertiary referral center from November 2010 to August 2015., Results: Forty-seven children were started on methotrexate for AD during this period. The mean Investigator Global Assessment (IGA) at the 3- to 5-month follow-up improved from 4.25 to 2.8, with further improvement to 1.9 in the patients that continued therapy beyond 10 months. Changes in the Children's Dermatology Life Quality Index (CDLQI) mirrored changes in the IGA, with improvement in the mean CDLQI from 14.4 at the start of the treatment to 7.5 at the 3- to 5-month follow-up. Further improvement in the CDLQI to 6.6 in patients who continued methotrexate beyond 10 months confirmed continued improvement in disease control beyond medium-term therapy. The treatment was well tolerated., Conclusions: Methotrexate appears to be an effective, safe treatment for severe pediatric AD. Its therapeutic effects continue beyond the medium-term treatment period, as reflected by further improvement in IGA and CDLQI scores in patients who continued methotrexate therapy beyond 10 months., (© 2017 Wiley Periodicals, Inc.)

Hyperglycemia, a major metabolic disturbance present in diabetes, promotes oxidative stress. Activation of antioxidant defense is an important mechanism to prevent cell damage. Levels of heavy metals and their binding proteins can contribute to oxidative stress. Antiradical capacity and levels of metallothionein (MT), metals (zinc and copper), and selected antioxidants (bilirubin, cysteine, and glutathione) were determined in 70 type 2 diabetes mellitus (T2DM) subjects and 80 healthy subjects of Caucasian origin. Single nucleotide polymorphism (rs28366003) in MT gene was detected. Antiradical capacity, conjugated bilirubin, and copper were significantly increased in diabetics, whereas MT and glutathione were decreased. Genotype AA of rs28366003 was associated with higher zinc levels in the diabetic group. The studied parameters were not influenced by renal function. This is the first study comprehensively investigating differences in MT and metals relevant to oxidative stress in T2DM. Ascertained differences indicate increased oxidative stress in T2DM accompanied by abnormalities in non-enzymatic antioxidant defense systems., (© 2017 Wiley Periodicals, Inc.)

Background: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific., Aims/methods: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry., Results: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only)., Conclusions: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.

Objectives: TMEM70 deficiency is the most common nuclear-encoded defect affecting the ATP synthase. In this multicentre retrospective study we characterise the natural history of the disease, treatment and outcome in 48 patients with mutations in TMEM70. Eleven centers from eight European countries, Turkey and Israel participated., Results: All 27 Roma and eight non-Roma patients were homozygous for the common mutation c.317-2A > G. Five patients were compound heterozygotes for the common mutation and mutations c.470 T > A, c.628A > C, c.118&#95;119insGT or c.251delC. Six Arab Muslims and two Turkish patients were homozygous for mutations c.238C > T, c.316 + 1G > T, c.336 T > A, c.578&#95;579delCA, c.535C > T, c.359delC. Age of onset was neonatal in 41 patients, infantile in six cases and two years in one child. The most frequent symptoms at onset were poor feeding, hypotonia, lethargy, respiratory and heart failure, accompanied by lactic acidosis, 3-methylglutaconic aciduria and hyperammonaemia. Symptoms further included: developmental delay (98%), hypotonia (95%), faltering growth (94%), short stature (89%), non-progressive cardiomyopathy (89%), microcephaly (71%), facial dysmorphism (66%), hypospadias (50% of the males), persistent pulmonary hypertension of the newborn (22%) and Wolff-Parkinson-White syndrome (13%). One or more acute metabolic crises occurred in 24 surviving children, frequently followed by developmental regression. Hyperammonaemic episodes responded well to infusion with glucose and lipid emulsion, and ammonia scavengers or haemodiafiltration. Ten-year survival was 63%, importantly for prognostication, no child died after the age of five years., Conclusion: TMEM70 deficiency is a panethnic, multisystemic disease with variable outcome depending mainly on adequate management of hyperammonaemic crises in the neonatal period and early childhood.

Objectives: Mitochondrial disorders of energetic metabolism (MD) represent a heterogeneous group of diseases manifesting at any age with a broad spectrum of clinical symptoms, including psychiatric disorders., Methods: The aim of the study was to characterize psychiatric symptoms and diagnoses in five patients with MELAS syndrome between the ages of 17 and 53 years., Results: Four of MELAS patients them harbored the prevalent mitochondrial DNA (mtDNA) mutation 3243A>G, and one patient had the mtDNA mutation 12706T>C. Three patients had positive family histories for MELAS syndrome. In one patient, depression was diagnosedas the first symptom ofMELAS syndrome. Depression also preceded a stroke-like episode in one patient. Four patients had disturbed cognitive functions, confusional states occurred in three patients. One patient manifested psychotic (schizophrenia-like) symptoms., Conclusion: Mitochondrial disorders deserve consideration as part of the differential diagnosis, especially, if there is suspected involvement of other organ groups or positive family history of MD.

Differences in the antioxidant system, apoptotic mechanism and in cell cycle between prostatic cell lines could partially elucidate the development of cisplatin resistance. The aim of this study was to identify the most characteristic parameter for a particular cell line and/or a particular cisplatin treatment using a general regression model and to assess whether it is possible to use measured parameters as markers of cisplatin resistance. This study integrates the results of viability, antioxidant, flow cytometric and quantitative PCR assays in order to characterize the resistance of prostate cancer to cisplatin. Cell growth using metabolic- (MTT) and impedance-based assays, the expression of key cell death signaling proteins (p53, Bax and Bcl-2), cell cycle, activity of antioxidant system-related proteins (superoxide dismutase, glutathione peroxidase, glutathione reductase and metallothionein) and free radical scavenging capacity assays [free radicals (FR), ferric reducing antioxidant power (FRAP), ABTS] were analyzed in the cell lines 22Rv1, PC-3 and PNT1A with respect to rising concentrations (0-150 µM) and different length of cisplatin treatment (12-72 h). The non-functional-p53 PC-3 cell line showed decreased BAX (p<0.05) and, in contrast to PNT1A and 22Rv1, no cisplatin-induced effects on cell cycle. All cell lines showed increasing levels of free radical scavenging activity by ABTS, FRAP and FR assays in a time- and dose-dependent manner (r>0.76 at p<0.001 for ABTS, FRAP and FR at p<0.001). PC-3 showed increased (p<0.05) levels of free radical scavenging activity by ABTS and FR methods. These findings, together with significantly elevated MT, decreased p53 and Bax indicate PC-3 to be cisplatin-resistant. The differences in the antioxidant system and apoptotic mechanisms in PC-3 cells may elucidate the development of cisplatin resistance and indicate that this cell line may be further studied as a model of cytostatic resistance.