Sensory experiences questionnaire unravels differences in sensory profiles between MECP2-related disorders.

The methyl CpG-binding protein-2 (MECP2) gene is located on the Xq28 region. Loss of function mutations or increased copies of MECP2 result in Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. Individuals with both disorders exhibit overlapping autism symptoms, yet few studies have dissected the differences between these gene dosage sensitive disorders. Further, research examining sensory processing patterns in persons with RTT and MDS is largely absent. Thus, the goal of this study was to analyze and compare sensory processing patterns in persons with RTT and MDS. Towards this goal, caregivers of 50 female individuals with RTT and 122 male individuals with MDS, between 1 and 46 years of age, completed a standardized measure of sensory processing, the Sensory Experiences Questionnaire. Patterns detected in both disorders were compared against each other and against normative values. We found sensory processing abnormalities for both hyper- and hypo-sensitivity in both groups. Interestingly, abnormalities in MDS were more pronounced compared with in RTT, particularly with items concerning hypersensitivity and sensory seeking, but not hyposensitivity. Individuals with MDS also exhibited greater sensory symptoms compared with RTT in the areas of tactile and vestibular sensory processing and for both social and nonsocial stimuli. This study provides a first description of sensory symptoms in individuals with RTT and individuals with MDS. Similar to other neurodevelopmental disorders, a variety of sensory processing abnormalities was found. These findings reveal a first insight into sensory processing abnormalities caused by a dosage sensitive gene and may ultimately help guide therapeutic approaches for these disorders.

Development and validation of parent-reported gastrointestinal health scale in MECP2 duplication syndrome.

BACKGROUND/AIMS: We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials. METHODS: MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale. RESULTS: A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis (CFA). The final MDS-specific GHS included 38 items and 7 factors that underwent further reliability and validity assessments. The power of the study was at least 0.982. The Cronbach's alphas of the instruments were General Health: 0.799, Eating-Chewing-Swallowing: 0.809, Reflux: 0.794, Motility: 0.762, Mood: 0.906, Medication: 0.595, Parenting: 0.942 and all items together: 0.928. The correlation coefficient between total and individual item scores ranged from 0.215 to 0.730. Because of the ordinal nature of the variables, the diagonal weighted least squares estimation (DWLS) method was used to execute the CFA and Structural Equation Modeling. The GHS had excellent model fit with the acceptable range of fit indices values. CONCLUSIONS: We developed a parent-reported, reliable, and valid MDS-specific GHS. This scale can be utilized in clinical settings or as an outcome measure in translational and clinical research.

Exploring gastrointestinal health in MECP2 duplication syndrome.

BACKGROUND: MECP2 duplication syndrome (MDS) is a rare neurogenetic syndrome caused by duplications of MECP2 at the Xq28 region. Although constipation and gastrointestinal reflux are reported in MDS, a comprehensive characterization of gastrointestinal health has not been fully explored. METHODS: We conducted a parent survey to explore the characteristics of gastrointestinal health in individuals with MDS using a secure online registry and compared differences in gastrointestinal symptoms between individuals with MDS and those with Rett syndrome (RTT). KEY RESULTS: One hundred six surveys were analyzed. Symptoms commonly associated with constipation occurred in 72% to 89% of MDS individuals. Eleven percent of MDS individuals underwent surgery for complications associated with constipation. We observed a bimodal distribution for gastroesophageal reflux disease (GERD) and gastrostomy feeding, with higher prevalence in 0-3 and >12-year-old MDS individuals. Constipation and GERD were significantly more common, and gas bloating was significantly less common in MDS than in RTT. Biliary tract disease requiring surgery was an unrecognized problem in 5% of MDS individuals. We determined that gastrointestinal problems in MDS individuals contribute to caretaker burden. CONCLUSION AND INFERENCES: Our study is the first in-depth investigation that characterizes gastrointestinal health in MDS and enumerates differences in gastrointestinal symptoms between MDS and RTT. Strategies to reduce gastrointestinal symptoms will alleviate caregiver burden in MDS. Further studies are needed to examine the mechanisms that cause gastrointestinal problems in MDS.

Assessing the Burden on Caregivers of MECP2 Duplication Syndrome.

BACKGROUND: MECP2 duplication syndrome (MDS) is a rare neurogenetic disorder characterized by severe neurodevelopmental disorder, refractory epilepsy, recurrent infections, and functional gastrointestinal problems. Because of the significant clinical problems and lifelong disability of children with this disorder we hypothesized that the burden on parents/caregivers of these children is significant. However, there are no reports of the impact on caregivers of individuals with MDS. METHODS: We developed and validated a burden scale to investigate the challenges of caregivers of children and adults with MDS and identified factors contributing to the burden on caregivers. We developed a Health Insurance Portability and Accountability Act-compliant patient registry for families with MDS and delivered caregiver burden survey through the registry. RESULTS: Of 237 completed surveys, 101 were eligible for the study. We identified increased levels of self-perceived anxiety, depression, and emotional exhaustion in caregivers that correlated with higher burden scores. Epilepsy was the only clinical feature that caused a higher burden in caregivers of individuals with MDS. In addition, a higher burden was found in Hispanic caregivers. The duration of care negatively correlated with burden score. CONCLUSIONS: This is the first study to investigate the burden on caregivers of individuals with MDS and identify several factors contributing to increased burden. Addressing these concerns has the potential to improve the health of individuals with MDS and contribute to the well-being of their caretakers.

Exploring the characteristics and most bothersome symptoms in MECP2 duplication syndrome to pave the path toward developing parent-oriented outcome measures.

BACKGROUND: MECP2 Duplication Syndrome (MDS), resulting from the duplication of Xq28 region, including MECP2, is a rare disorder with a nascent understanding in clinical features and severity. Studies using antisense oligonucleotides revealed a broad phenotypic rescue in transgenic mice. With human clinical trials on the horizon, there is a need to develop clinical outcome measures for MDS. METHODS: We surveyed caregivers of MDS individuals to explore the frequency and severity of MDS clinical features, and identify the most meaningful symptoms/domains that need to be included in the outcome measure scales. RESULTS: A total of 101 responses were eligible for the survey. The top six most meaningful symptoms to caregivers in descending order included epilepsy, gross motor, fine motor, communication, infection, and constipation problems. Epilepsy was present in 58.4% of the subjects and 75% were drug-resistant, Furthermore, ~12% required intensive care unit (ICU) admission. Infections were present in 55% of the subjects, and one-fourth of them required ICU admission. Constipation was present in ~85% of the subjects and one-third required enemas/suppositories. CONCLUSION: Our study is one of the largest cohorts conducted on MDS individuals characterizing the frequency and severity of MDS symptoms. Additionally, these study results will contribute to establishing a foundation to develop parent-reported outcomes in MDS.

Factors influencing insulin usage among type 2 diabetes mellitus patients: A study in Turkish primary care.

BACKGROUND: DM (diabetes mellitus) patients with poorly regulated blood glucose levels are at risk of increased morbidity and mortality. There are different factors that cause resistance to the initiation of insulin therapy such as beliefs and perceptions concerning diabetes and its treatment and the nature and consequences of insulin therapy. OBJECTIVES: We aimed to explore the reasons for this reluctance and how these obstacles could be overcome so that DM patients who require insulin could initiate therapy. METHODS: This was a cross-sectional, descriptive study of diabetic patients with glycated haemoglobin A1c (HbA1C) levels above 7.0%, who were followed-up at a primary care and endocrinology outpatient clinic. RESULTS: Ninety-four patients (57.4% females, 42.6% males) were recruited for this study. Most patients (57.4%) considered that insulin was a drug of last resort. Among all patients, 34.1% thought that insulin lowered blood glucose levels to an extreme degree and 14.9% disagreed. The patients thought that self-injection was hard (27.6%), required someone else to administer the injection (27.6%), insulin injection was painful (33.0%). 59.6% of all patients believed that their religion did not restrict the use of insulin, 52.1% stated that their family physicians had sufficiently informed them. CONCLUSION: Our most significant finding is that a lack of adequate information relating to insulin appears to be the major factor behind DM patients' refusal of insulin treatment. The fact that patients consider insulin treatment as a final solution to DM could be related to resistance to the initiation of insulin therapy. [Box: see text].

What primary care physicians think about insulin initiation in type 2 diabetes: a field-based study.

BACKGROUND/AIM: A significant number of patients with type 2 diabetes mellitus require insulin and little is known about the possible physician-related factors that could cause a delay in the initiation of insulin treatment in patients with type 2 diabetes. This study aimed to evaluate those factors. MATERIALS AND METHODS: A total of 87 family physicians working at 36 family health centers in urban Malatya participated in our study on a voluntary basis. A self-administered survey form was structured to gather the views of the primary care physicians. The survey was developed based on a review of the literature. The survey consisted of Likert scale item questions regarding knowledge about the disease of diabetes mellitus and the views of the primary care physicians regarding insulin initiation for type 2 diabetic patients. RESULTS: Almost half of the participants (42.5%, n = 37) felt incompetent in the starting dosage adjustment and 40.2% (n = 35) of the participants felt incompetent in maintaining the appropriate dosage adjustment. In terms of sex, female family physicians were found to be more uncertain about the timing of initiating insulin treatment for diabetic patients. CONCLUSION: This study shows the necessity of continuous education activities and interventions to promote motivation in family physicians to improve care of diabetic patients in primary care.

Human milk banking and milk kinship: Perspectives of mothers in a Muslim country.

AIM: The present study aims to determine the knowledge, attitudes and views of mothers regarding infant feeding, breast milk, wet-nursing, milk kinship and human milk banks. METHODS: This descriptive cross-sectional study was composed of 1042 mothers who delivered at two different hospitals in Turkey. RESULTS: Almost half of the participating mothers, 49.9%, agreed with the establishment of alternative HMBs in Turkey. Only 7.7% of the mothers in this study expressed views in favour of the establishment of Western-style HMBs. Approximately half of the mothers (42.4%) indicated that they were against the establishment of any kind of HMBs in Turkey. Only 9.2% of the mothers in this study stated that they would volunteer to donate their breast milk to the Western-style HMBs, and only 6.9% of the mothers approved obtaining milk from this type of HMB. Finally, 44.2% of the mothers stated that they would donate their breast milk to the alternative HMBs, and 31.9% of the mothers approved obtaining milk from this type of HMB. CONCLUSION: This is the first study conducted among mothers in a Muslim community about issues such as infant feeding, breast milk, wet-nursing, milk kinship and HMBs. The majority of the mothers in this study are against the establishment of Western-style HMBs, whereas they have a more positive response to an alternative HMB when their religious concerns are relieved.

ß-Glucan treatment prevents progressive burn ischaemia in the zone of stasis and improves burn healing: an experimental study in rats.

Saving the zone of stasis is one of the major goals of burn specialists. Increasing the tissue tolerance to ischaemia and inhibiting inflammation have been proposed to enable salvage of this zone. After a burn, excessive inflammation, including increased vascular permeability, local tissue oedema and neutrophil activation, causes local tissue damage by triggering vascular thrombosis and blocking capillaries, resulting in tissue ischaemia and necrosis. Oxygen radicals also contribute to tissue damage after a burn. However, macrophages play a pivotal role in the response to burn. We studied ß-glucan because of its many positive systemic effects that are beneficial to burn healing, including immunomodulatory effects, antioxidant effects (free-radical scavenging activity) and effects associated with the reduction of the inflammatory response. There were four test groups in this study with eight rats in each group. Group 1 was the control group, group 2 was administered a local pomade (bacitracin+neomycin sulphate), group 3 received ß-glucan (50 mg kg(-1), orally) + the local pomade and group 4 received ß-glucan. Burns were created using a brass comb model. Macroscopic, histopathological and statistical assessments were performed. Samples were harvested on the 3rd, 7th and 21 days for analysis. The neutrophilic infiltration into the zone of stasis was analysed on day 3. Macrophage infiltration, fibroblast proliferation, angiogenesis and re-epithelialisation ratios in the zone of stasis were analysed on days 7 and 21. The ß-glucan groups (groups 3 and 4) exhibited lower neutrophil counts on the 3rd day, and macrophage infiltration, fibroblast proliferation, angiogenesis and re-epithelialisation were very high in these groups on the 7th day. In particular, re-epithelialisation on the 21st day was significantly better in the ß-glucan groups. This study demonstrated that ß-glucan may prevent neutrophil-dependent tissue damage and burn-induced oxidative injury through its anti-inflammatory and antioxidant properties. We speculate that the inhibition of neutrophil activation preserves vascular patency by preventing capillary blockage. ß-Glucan is also a powerful macrophage stimulator, and is therefore very effective in saving the zone of stasis.

A case report of cutaneous larva migrans.

Cutaneous larva migrans (CLM) is a helminthic infection most commonly found in tropical and subtropical geographic areas. However, with the ease and increase of foreign travel by many around the world, CLM is no longer confined to these areas. CLM is an erythematous, serpiginous, cutaneous eruption caused by accidental percutaneous penetration and subsequent migration of larvae. Here, we present a case diagnosed as CLM and treated with Albendazole.

Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-L-cysteine--preparation of S-substituted thiosuccinic acid esters.

Dimethyl fumarate (DMF) is used successfully to treat psoriasis. In spite of its proven clinical efficacy, the mode of metabolism and the pharmacodynamics of DMF are still not completely understood. Some previous studies have indicated that orally applied DMF for a considerable part is quickly hydrolysed to methylhydrogen fumarate (MHF) at basic pH conditions as present in the upper intestine, especially in the presence of biological fluids containing esterases. On the other hand it was shown that DMF due to its high lipophilicity rapidly penetrates into cells and may thus at least in part be absorbed after po application without being hydrolysed. On the other hand, no detectable amounts of DMF were hitherto found in plasma samples after po administration. In order to shed light on possible further routes of presystemic metabolism of DMF, studies on the reactivity towards glutathione (GSH) were carried out. GSH is present in millimolar concentrations in almost all cells. DMF due to its nature as an alpha,beta-unsaturated carboxylic acid ester can react spontaneously with thiols via a Michael-type addition. It could be shown that DMF reacts at high rates under near-physiological conditions. Studies on the reaction kinetics at pH 7.4 show that GSH addition proceeds rapidly to yield a 1:1 mixture of both diastereomeric 2-(S-glutathionyl)-succinic acid dimethyl esters. MHF under identical conditions was shown to react with GSH as well leading to a mixture of four products (2 diastereomeric pairs). However, MHF reacted at a much lower rate. The structures of all thiol conjugates were confirmed unambiguously by extensive NMR measurements. GSH conjugates and the corresponding mercapturic acids on grounds of the high spontaneous reactivity observed may be expected to be major metabolites of unhydrolysed DMF which makes its way into enterocytes. On the other hand, MHF, due to its slow reaction with GSH, may have higher chances than DMF to react with more essential thiol groups in macromolecules.

Levels of minimal residual disease detected by quantitative molecular monitoring herald relapse in patients with multiple myeloma.

BACKGROUND AND OBJECTIVES: Detection of minimal residual disease (MRD) has helped to improve the treatment of patients with leukemia. At present MRD testing in patients with multiple myeloma (MM) is not applied as a standard diagnostic or prognostic method. DESIGN AND METHODS: Immunoglobulin heavy chain (IgH) polymerase chain reaction (PCR) using patient-specific TaqMan probes together with LightCycler technology was performed to quantify minimal residual disease in MM. Relative levels of clonotypic cells were assessed as IgH/2beta-actin ratios with a sensitivity of 10(-4) to 10(-5). RESULTS: Following stem cell transplantation, a significant reduction of clonotypic cells was observed in bone marrow (BM) and peripheral blood (PB) samples of 11 patients, comparing pre-treatment values with those of best response (median: 13% to 0.09% and 0.03% to 0%, respectively). In 5 patients with ongoing clinical remission IgH/2beta-actin ratios remained stable at a low level, while in 6 patients an increase to 2% in BM and 0.4% in PB was associated with progression of the disease. In 4 of these 6 patients the increase of clonotypic cells in PB was detectable a median of 3 months (range: 0.5-6) before relapse. Furthermore, time-to-progression of patients with pre-transplantation IgH/2b-actin ratios > 0.03% in BM was significantly shorter than that of patients with lower MRD levels. INTERPRETATION AND CONCLUSIONS: MRD in patients with MM can be quantified reliably using TaqMan chemistry adapted to the LightCycler system. Residual tumor cell levels before transplantation as well as results of sequential molecular monitoring are predictive of relapse.