Peer assessment as a method for measuring harmful internet use.

Harmful Internet use (HIU) describes unintended use of the Internet. It could be both self-harm and harming others. Our research goal is to develop a more accurate method for measuring HIU by this novel peer assessment. As such, it may become, with our call for more research, a paradigm shift supplementing every rating scale or other type of Internet use assessment. In addition to classic statistical analysis, structural equations have been employed. Results indicate that the true positive rate (TPR) is substantially higher than assessed in other studies.•Peer assessment improvement.•AUC for ROC was computed to establish cut-off points for the used scale.•Results obtained by the Structural Equation model indicate that parental care has a moderate influence on subjects' attempts to fight HIU.

Audiological and radiological study of eight polish patients with alpha-mannosidosis.

Alpha-mannosidase catalyze lysosomal cleaving of mannose residues from glycoproteins. The enzyme is encoded by the MAN2B1 gene. Biallelic pathogenic variants cause enzymatic deficiency, which clinically results in alpha-mannosidosis (AM), an autosomal recessively inherited condition. Typical features observed in AM patients include intellectual disability, loss of speech, dysmorphic features, progressive motor problems, ataxia, hearing impairment and recurrent otitis. The cause of the latter is mainly attributed to immunodeficiency. The aim of our study was to demonstrate the otolaryngologic and hearing outcomes in patients with AM. The study group consisted of 8 AM patients: 6 males and 2 females, aged 2.5-37 yrs. The clinical course, dysmorphic ENT features, hearing status and the HRCT scans of the temporal bones were analyzed. MS Excel for Windows and Statistica software package were used for the comparison of interaural audiometric loss, mean hearing loss and mean hearing threshold for each patient's audiometric frequency tested. We identified ENT dysmorphic features in all of our AM patients, while the hearing loss was detected in 6 out of our 8 patients. For those cases, the onset of deafness was noted in the first decade of life, this impairment was sensorineural, of cochlear origin, bilateral, of a moderate degree (mean loss 62.76 dB; median 60 dB, standard deviation 12.5 dB), symmetrical and stable. The shape of the audiometric curves of our patients can be described as slightly sloping towards the higher tested frequencies, with a marked improvement at 4 kHz. The radiological examination revealed normal structures of the ears, with the exception of one case where a persistent otitis generated a cochlear gap. We therefore concluded that the hearing loss in our AM patients derived from cochlear impairment unrelated with recurrent otitis.

Transformative effect of a Humanitarian Program for individuals affected by rare diseases: building support systems and creating local expertise.

Rare diseases affect > 400 million people globally with a disproportionate burden falling on children, resulting in high morbidity and mortality rates. Affected individuals in some under-resourced countries have limited access to expert care or treatments; moreover, they suffer long diagnostic journeys during which debilitating and life-threatening complications occur. Lysosomal storage disorders (LSD) are prototype rare diseases due, in the main, to inherited deficiencies of lysosomal enzymes/transporters that affect up to 1 in 5000 newborns. Recognizing the need to provide treatment access to people with LSDs everywhere, a collaborative partnership was pioneered and set up 30 years ago. Partnering with local authorities, non-government organizations across six continents, local as well as international experts, a robust, sustainable Humanitarian Program emerged that now represents the most enduring charitable access program for LSD treatment. Here we present the history, process, lasting beneficial effect of the program to develop healthcare systems and infrastructures, and the lessons learned from addressing major unmet needs for LSDs.

Impact of high-volume, intermediate-volume and low-volume bowel preparation on colonoscopy quality and patient satisfaction: An observational study.

Background: Although optimal bowel preparation is essential for high-quality screening colonoscopy, documentation of preparation quality, patient satisfaction and adherence is scarce. Aim: The aim of this article is to compare low-volume (LV, 300 ml sodium picosulfate), intermediate-volume (IV, 2 l polyethylene glycol, PEG + ascorbic acid and sodium ascorbate), and high-volume (HV, 4 l PEG) purgatives. Results: A total of 5000 individuals (50.5% women) were enrolled between March 2015 and July 2017 (LV:IV:HV = 3.61:1.54:1). Overall sex- and age-adjusted adenoma detection rate was 25.4% (LV 23.8%, IV 25.4%, HV 29.8%), median age was 59.6 years, and cleansing was successful in 96.8%. Success rates of bowel cleansing were highest with HV (97.6%), followed by LV (97.2%) and IV (95.3%) with OR 2.04 (CI 95% 1.20-3.45, p = 0.008) and OR 1.79 (CI 95% 1.27-2.50, p = 0.001), respectively, compared to IV. A total of 93.5% of the LV group would use the same purgative in the future, 73.2% of IV and 69.4% of HV. A total of 84.4% would prefer overnight preparation, 12.1% same-day preparation. Conclusion: All purgatives investigated showed good bowel cleansing quality results, patient satisfaction and compliance. Improvement in patient information might lead to even higher participation rates in screening colonoscopy since one in five patients stated that bowel preparation worried him or her most prior to colonoscopy.

Recognition of alpha-mannosidosis in paediatric and adult patients: Presentation of a diagnostic algorithm from an international working group.

Alpha-mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for alpha-mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique. Two proposals were developed for diagnostic algorithms of alpha-mannosidosis, one for patients ≤10 years of age and one for those >10 years of age. In younger patients, hearing impairment and/or speech delay are the cardinal symptoms that should prompt the clinician to look for additional symptoms that may provide further diagnostic clues. Older patients have different clinical presentations, and the presence of mental retardation and motor impairment progression and/or psychiatric manifestations should prompt the clinician to assess for other symptoms. In both younger and older patients, either additional metabolic monitoring or referral for testing is warranted upon suspicion of disease. Oligosaccharides in urine (historically performed) or serum were considered as an initial screening procedure, while enzymatic activity may also be considered as first choice in some centres. Molecular testing should be performed as a final confirmatory step. The developed algorithms can easily be applied in a variety of settings, and may help to favour early diagnosis of alpha mannosidosis and treatment.

The identification of discontinuous epitope in the human cystatin C - Monoclonal antibody HCC3 complex.

Human cystatin C (hCC) is a cysteine proteinase inhibitor involved in pathophysiological processes of dimerization and amyloid formation. These processes are directly associated with a number of neurodegenerative disorders such as Alzheimer disease or hereditary cystatin C amyloid angiopathy (HCCAA). One of the ideas on how to prevent amyloid formation is to use immunotherapy. HCC3 is one of a group of antibodies binding to hCC and reducing the in vitro formation of cystatin C dimers. Therefore, identification of the binding sites in the hCC-HCC3 complex may facilitate a search of effective drugs against HCCAA as well as understanding the mechanisms of neurodegenerative disorders. In this work we present epitope identification of the hCC-HCC3 complex using methods such as affinity chromatography, epitope excision and extraction MS approach, enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry (HDX MS). Comprehensive analysis of the obtained results allowed us to identify the epitope sequence with the key fragment covering hCC L1 loop and two potential epitopic fragments - α-helical part, hCC (17-28) and ß4 strand in C-terminal part of hCC. The presence of the L1 loop in the epitope sequence accounts for the significant reduction of hCC dimer formation in the presence of HCC3 antibody. SIGNIFICANCE OF THE STUDY: Deciphering the mechanism of the cystatin C aggregation process and detailed analysis of the interactions between hCC, or its pathogenic variant, and monoclonal antibodies, potentially constituting aggregation inhibitors, might be of great value as there still is a complete lack of any kind of efficient therapy for young people with the pathogenic mutation of hCC.

Holistic Long-Term Care Over Elderly Kidney Transplant Recipients.

Kidney transplantation is an optimal method of renal replacement therapy in patients with phase V chronic kidney disease. Elderly patients (older than 60 years) with a kidney transplant create a significant and constantly growing pool of patients with this type of organ transplantation. In this group of patients, long-term care should be particularly stringent and vigilant. Apart from typical conditions associated with chronic kidney disease and possible post-transplant complications as well as side effects of immunosuppressive treatment, the patient also experiences changes and limitations associated with the progress of age and diseases typical for old age, characterized by a higher risk of infection, and changed pharmacokinetics/pharmacodynamics. Undoubtedly, patients should remain under the medical care of qualified transplantologists, but constant cooperation with a general practitioner and geriatrician would be of added value. Study results show that although most of the elderly kidney recipients have constant contact with their general practitioners, and almost half of them use private care, contribution of the geriatrician to the transplant care system is unsatisfactory, and elderly kidney recipients would expect more extensive outpatient care.

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

How to reduce the number of rating scale items without predictability loss?

Rating scales are used to elicit data about qualitative entities (e.g., research collaboration). This study presents an innovative method for reducing the number of rating scale items without the predictability loss. The "area under the receiver operator curve method" (AUC ROC) is used. The presented method has reduced the number of rating scale items (variables) to 28.57% (from 21 to 6) making over 70% of collected data unnecessary. Results have been verified by two methods of analysis: Graded Response Model (GRM) and Confirmatory Factor Analysis (CFA). GRM revealed that the new method differentiates observations of high and middle scores. CFA proved that the reliability of the rating scale has not deteriorated by the scale item reduction. Both statistical analysis evidenced usefulness of the AUC ROC reduction method.

Non-paraganglioma tumors of the jugular foramen - Growth patterns, radiological presentation, differential diagnosis.

OBJECTIVE: Most common tumors of the jugular foramen are paragangliomas. However, other lesions, also malignant, may involve the jugular foramen and mimic radiographic presentation of paragangliomas. Therefore, a correct preoperative diagnosis is crucial for best treatment planning. This study analyzes imaging characteristics of non-paraganglioma neoplasms involving the jugular foramen, with attention given to features helpful in differential diagnosis. STUDY DESIGN: A retrospective chart search. SETTING: Teritary referral university centre. SUBJECTS AND METHODS: During the years 1997-2010, 11 cases of jugular foramen tumors other than paragangliomas, with available imaging studies, were identified. Histopathology revealed: 3 schwannomas, 1 malignant schwannoma, 2 meningiomas, 1 hemangiopericytoma, 1 ependymoma, 1 endolymphatic sac carcinoma (ELST) and 2 nasopharyngeal carcinoma metastases. CT, MRI and angiography were assessed to determine tumor growth directions, bone involvement, tumor morphology and vascular composition. RESULTS: Schwannomas were characterized by parapharyngeal space involvement, jugular foramen expansion, preservation of cortical margins, irregular contrast enhancement. Meningiomas presented diffuse bone infiltration, sclerotic changes, erosion of the cortical bone. Ependymoma showed diffuse skull base infiltration, permeative erosion, heterogeneity, abundant vascularization. Hemangiopericytoma radiologically imitated paraganglioma. ELST showed permeative/geographic bony destruction, heterogeneity, intratumoral bony fragments. Metastases were lytic, solid lesions characterized by circumferential growth, internal carotid artery encasement and stenosis. CONCLUSIONS: A combination of certain radiological features including tumor epicenter, growth vectors, skull base infiltration, bony changes and tumor morphology help establish correct preoperative diagnosis and differentiate less common jugular foramen tumors, from most common paragangliomas. Hemangiopericytoma may radiologically mimic paraganglioma.

The nutritional status and the height of the arch of the foot in preschool children.

AIM: Childhood obesity is an increasingly common problem. It is associated with poor posture especially with lower limb deformities. The study aimed at assessing the prevalence of overweight and obesity in preschoolers, the analysis also contained the relationship between the nutritional status and the foot arching. METHODS: One thousand two hundred ninety-four children at the age from 3 to 6 years took part in the study. The height and weight of the children were measured. From these measurements, the BMI and Cole Index values were calculated. The prevalence of overweight and obesity were estimated. The degree of foot arching was measured using a podoscope and categorised according to Clarke's angle (CA). Differences in CA between right and left foot were analysed across all groups according to age and gender. Secondly CA for both feet was compared between girls and boys from all age groups. Thirdly, CA was compared for the same gender but between different age groups. Finally, nutritional status and CA for the right and left foot were correlated. Basic descriptive statistics, the U Mann-Whitney test, a one-way ANOVA and the linear correlation study were used to verify the presence of trend. RESULTS: Twenty percent of boys and 15.7% of girls were found overweight, and 9.8% of both male and female subjects were found obese. The prevalence of overweight increased with age. The longitudinal arch of the foot was higher in girls. It increased with age. The height of the longitudinal arch of the foot was smaller in overweight and obese children. CONCLUSION: A substantial number of overweight and obese preschoolers took part in the study, in which a significant dependence between excessive body weight and flat feet was found. The preschool education programmes should include pro-health exercises combining aerobic training with exercises developing good body posture habits.

Osteoimmunology in mucopolysaccharidoses type I, II, VI and VII. Immunological regulation of the osteoarticular system in the course of metabolic inflammation.

BACKGROUND: Mucopolysaccharidoses (MPSs) are rare genetic diseases caused by a deficient activity of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. These metabolic blocks lead to the accumulation of GAGs in various organs and tissues, resulting in a multisystemic clinical picture. The pathological GAG accumulation begins a cascade of interrelated responses: metabolic, inflammatory and immunological with systemic effects. Metabolic inflammation, secondary to GAG storage, is a significant cause of osteoarticular symptoms in MPS disorders. OBJECTIVE AND METHOD: The aim of this review is to present recent progress in the understanding of the role of inflammatory and immune processes in the pathophysiology of osteoarticular symptoms in MPS disorders and potential therapeutic interventions based on published reports in MPS patients and studies in animal models. RESULTS AND CONCLUSIONS: The immune and skeletal systems have a number of shared regulatory molecules and many relationships between bone disorders and aberrant immune responses in MPS can be explained by osteoimmunology. The treatment options currently available are not sufficiently effective in the prevention, inhibition and treatment of osteoarticular symptoms in MPS disease. A lot can be learnt from interactions between skeletal and immune systems in autoimmune diseases such as rheumatoid arthritis (RA) and similarities between RA and MPS point to the possibility of using the experience with RA in the treatment of MPS in the future. The use of different anti-inflammatory drugs requires further study, but it seems to be an important direction for new therapeutic options for MPS patients.

Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study.

BACKGROUND: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. METHODS: This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. RESULTS: Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS). CONCLUSIONS: These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.

The impact of a ketogenic diet and liver dysfunction on serum very long-chain fatty acids levels.

Peroxisomes play an essential role in mammalian cellular metabolism, particularly in oxidation fatty acid pathways. Serum very long-chain fatty acids (VLCFA), the main biochemical diagnostic parameters for peroxisomal disorders, were examined in 25 neurological patients with epilepsy on a ketogenic diet and 27 patients with liver dysfunction. The data show that patients on a ketogenic diet have increased levels of C22:0 and C24:0, but not C26:0, and normal C24:0/C22:0 and C26:0/C22:0. Patients with liver insufficiency showed a slightly elevated level of C26:0, a normal level of C24:0 and a decreased level of C22:0; thus in 21/27 the ratio of C24:0/C22:0 was increased and 15/27 the ratio of C26:0/C22:0 was increased.

Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up.

AIM: We present a 3-year follow-up of a boy with mucopolysaccharidosis type II (MPS II) who had idursulfase therapy initiated at the age of 3 months and compare his clinical course to his healthy twin brother. METHODS: Detailed anthropometric features, ultrasound studies of liver and spleen volumes, echocardiography and audiological examinations, psychological tests, joint range of motion (ROM) and skeletal radiographs were monitored. RESULTS: After 3 years of treatment, the patient has not developed any clinical manifestations of MPS II. He did not develop coarse facial features, joint disease, or organomegaly, and his cardiac function remained normal. There were no pronounced signs of dysostosis multiplex on radiographs. The only difference when compared with his healthy twin brother was lower IQ (Termann-Merrill 98 vs. 118) and mild deformity of one vertebrae. CONCLUSION: Our study suggests that early initiation of enzyme replacement therapy may significantly slow or prevent the development of irreversible disease manifestations and therefore modify the natural history of MPS II.

The effect of physical training on static balance in young people with intellectual disability.

Intellectual disability affects all spheres of people's lives who suffer from it. It lowers the level of intellectual functioning, often stigmatizes, characteristically changing features, and decreases motor performance. Unfortunately, modern medicine cannot cure intellectual disability; however, there is a chance to improve the quality of life of people with mental retardation by means of physical exercises and by enhancing coordination, the quality of gait and efficiency in performing everyday activities. This paper deals with observations of static balance in 40 young females and males with mild Down syndrome, out of which 20 were subjected to a three-month sensorimotor training programme. The participants performed exercises with rehabilitation balls and air pillows twice a week, and the remaining persons constituted a control group. The balance platform test conducted at the beginning of the experiment revealed that the level of static one-legged balance was similar in both groups. A significant difference was noted in the length of the path of the general centre of gravity (COG) and the time frame in which the vertical projection of COG remained within the 13 mm radius circle, between the result of the test conducted under visual control and with the eyes closed, both in the group of the participants performing exercises and the ones who did not do them. After the training sessions the results of both tests improved in the group of the persons subjected to the training programme, however differences between the groups were not statistically significant, apart from the comparison of the time of keeping COG within the 13 mm radius circle at the beginning and at the end of the experiment by the participants who were physically active. Our results lead to a conclusion that exercises with the use of unstable surfaces improve deep sensibility in people with mild mental retardation.

Reproductive function in men affected by X-linked adrenoleukodystrophy/adrenomyeloneuropathy.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is the most frequent, severely neurodegenerative, clinically heterogeneous peroxisomal disorder, the signs of which are a consequence of myelin, adrenal cortex, and testes impairment. OBJECTIVE: We studied testosterone, LH, and FSH levels in X-ALD/adrenomyeloneuropathy (AMN) patients. We evaluate the ability to procreate of these patients by analysis of pedigree and family screening by detection of very long-chain fatty acid (VLCFA) levels. SUBJECT AND METHODS: Seventeen patients with X-ALD/AMN (16 with AMN and one asymptomatic) aged 24-48 (mean±S.D., 34.7±5.9) years, were identified based on the clinical picture, magnetic resonance imaging, and the presence of increased serum VLCFA levels. Nine X-ALD/AMN patients' daughters, mean ages ±S.D.=7.7±3.8 years, were identified as heterozygote by elevated VLCFA levels. Serum VLCFA levels were determined as ester derivatives by a gas chromatography method. Serum testosterone, LH, and FSH levels in X-ALD/AMN patients were detected by IRMAs. RESULTS: Serum testosterone levels were at the lowest levels of normal range but serum LH and FSH concentrations were increased in 57.1 and in 42.9% of X-ALD/AMN patients respectively. Among the 11 investigated of X-ALD/AMN married adult men, nine had produced offspring, a total of 13 children. All patients' daughters showed elevated serum VLCFA at heterozygote levels. CONCLUSION: In this study, we report that in a group of X-ALD/AMN married adult men, we did not find a significant decrease in fertility compared with the Polish population (18.2 vs 15%).

Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders.

Familial X-chromosome inactivation (XCI) skewing was investigated in a family in which a female mucopolysaccharidosis type II (MPS II) (Hunter syndrome, an X-linked genetic disease) occurred. Among eight related females aged under 60 years from three generations who were tested, four revealed a non-random pattern of XCI. Detailed genetic analysis failed to find mutations in genes that were previously reported as important for the XCI process. Haplotype analysis excluded linkage of non-random XCI with genes localized on the X-chromosome. We propose that analysis of the XCI pattern should be taken into consideration when assessing risk factors for X-linked recessive genetic disorders.

Management of neuronopathic Gaucher disease: revised recommendations.

The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease.

Molecular and clinical consequences of novel mutations in the arylsulfatase A gene.

Metachromatic leukodystrophy (MLD), a severe neurodegenerative metabolic disorder, is caused by deficient activity of arylsulfatase A (ARSA; EC 3.1.6.8), which leads to a progressive demyelinating process in central and peripheral nervous systems. In this study, a DNA sequence analysis was performed on six Polish patients with different types of MLD. Six novel mutations were identified: one nonsense (p.R114X), three missense (p.G122C, p.G293C, p.C493F) and two frameshift mutations (g.445_446dupG and g.2590_2591dupC). Substitutions p.G293C and p.C493F and duplication g.445_446dupG caused a severe reduction of enzyme activity in transient transfection experiments on mammalian cells (less than 1% of wild-type (WT) ARSA activity). Duplication 2590_2591dupC preserved low-residual ARSA activity (10% of WT ARSA). In summary, the novel MLD-causing mutations in the exons 2, 5 and even in 8 of the ARSA gene described here can be classified as severe type 0, leading in homozygosity to the late infantile form MLD. Growth retardation, delayed motor development, gait disturbances, tonic-clonic seizures and non-epileptic muscle spasms were the first onset symptoms in patients with late infantile form of MLD. In individual with juvenile type MLD gait disturbances evidenced the onset of the disease, while in a patient with late juvenile MLD, difficulties at school were displayed.