Report of severe accidental baclofen intoxication in a healthy 4-year-old boy and review of the literature.

The number of reports on baclofen intoxication has increased in recent years. Here we report the case of a 4-year-old boy in deep coma who was referred to the pediatric intensive care unit. The patient was intubated and mechanically ventilated. A computerized tomography scan without contrast showed a collapsed appearance of the ventricular system suggesting diffuse cerebral edema. A multichannel electroencephalogram registered 6 h after admission showed a very slow and ample continuous pattern, without structure, nonreactive to stimulations, expressing diffuse and severe nonspecific cerebral pain. A targeted analysis to determine the baclofen plasma levels was performed. Test results of plasma samples were highly positive for baclofen (2009 ng/mL). Following 36 h of mechanical ventilation, the patient rapidly regained consciousness and recovered normal neurological behavior. The present case demonstrates the importance of considering baclofen overdosage in cases of deep coma with areflexia, and emphasizes the importance of warning parents about the potential toxicity of baclofen when prescribing the drug to a family member. A review of the literature on pediatric baclofen overdose is included.

"Ears of the Lynx" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia.

BACKGROUND AND PURPOSE: The "ears of the lynx" MR imaging sign has been described in case reports of hereditary spastic paraplegia with a thin corpus callosum, mostly associated with mutations in the spatacsin vesicle trafficking associated gene, causing Spastic Paraplegia type 11 (SPG11). This sign corresponds to long T1 and T2 values in the forceps minor of the corpus callosum, which appears hyperintense on FLAIR and hypointense on T1-weighted images. Our purpose was to determine the sensitivity and specificity of the ears of the lynx MR imaging sign for genetic cases compared with common potential mimics. MATERIALS AND METHODS: Four independent raters, blinded to the diagnosis, determined whether the ears of the lynx sign was present in each of a set of 204 single anonymized FLAIR and T1-weighted MR images from 34 patients with causal mutations associated with SPG11 or Spastic Paraplegia type 15 (SPG15). 34 healthy controls, and 34 patients with multiple sclerosis. RESULTS: The interrater reliability for FLAIR images was substantial (Cohen κ, 0.66-0.77). For these images, the sensitivity of the ears of the lynx sign across raters ranged from 78.8 to 97.0 and the specificity ranged from 90.9 to 100. The accuracy of the sign, measured by area under the receiver operating characteristic curve, ranged from very good (87.1) to excellent (93.9). CONCLUSIONS: The ears of the lynx sign on FLAIR MR imaging is highly specific for the most common genetic subtypes of hereditary spastic paraplegia with a thin corpus callosum. When this sign is present, there is a high likelihood of a genetic mutation, particularly associated with SPG11 or SPG15, even in the absence of a family history.

Renal Operational Tolerance Is Associated With a Defect of Blood Tfh Cells That Exhibit Impaired B Cell Help.

Renal operationally tolerant patients (TOL) display a defect in B cell differentiation, with a deficiency in plasma cells. Recently described, T follicular helper (Tfh) cells play a critical role in B cell differentiation. We analyzed blood Tfh subsets in TOL and transplanted patients with stable graft function under immunosuppression (STA). We observed a reduced proportion of blood activated and highly functional Tfh subsets in TOL, without affecting Tfh absolute numbers. Functionally, Tfh cells from TOL displayed a modified gene expression profile, failed to produce interleukin-21, and were unable to induce IgG production by naive B cells. This Tfh defect is linked to a low incidence of postgraft de novo donor-specific antibody (dnDSA) immunization, suggesting that the lack of Tfh cells in TOL may induce a protolerogenic environment with reduced risk of developing dnDSA. Finally, we showed that elevated Tfh in STA precedes the occurrence of dnDSA during an alloresponse. These data provide new insights into the mechanisms of antibody response in operational tolerance. Disrupted homeostasis and impaired Tfh function in TOL could lead to a reduced risk of developing dnDSA and suggest a predictive role of blood Tfh cells on the occurrence of dnDSA in transplant recipients.

[Lessons learned from the implementation of Dutch national healthcare guidelines on childhood obesity]. / Lessen geleerd van de implementatie van Zorgstandaard Obesitas voor kinderen.

OBJECTIVE: To describe the implementation and feasibility of the national healthcare guidelines on childhood obesity in a region with a high prevalence of overweight and obesity in children. DESIGN: Descriptive, implementation study. METHOD: The implementation of the guidelines took place in the borough Amsterdam West. In total, 17 general practitioners (GP) from the Academic General Practice Network (ANH) of the VU University Medical Center, Amsterdam, participated in the study, along with 19 child healthcare practitioners and 3 paediatricians. A number of measures were taken to promote implementation. Feasibility was evaluated using both qualitative and quantitative methods. RESULTS: The participating healthcare providers found the training in application of the guidelines and case study discussions useful. GPs found that their role as central caregiver was not feasible. All participants expressed a preference for child healthcare practitioners as the central caregiver. A total of 327 obese children were invited to attend the GP's surgery; only 65 of them participated in the study and only 28 children were monitored for a whole year. Collaboration agreements between involved healthcare providers were rarely fulfilled. CONCLUSION: Implementation of the national healthcare guidelines on childhood obesity in the current form appears not to be feasible in Amsterdam West, despite the many implementation-enhancing measures that were applied. It is questionable whether the national healthcare guidelines on childhood obesity in its current form can contribute to addressing the societal problem of overweight and obesity in children.

Effects of self-monitoring of glucose on distress and self-efficacy in people with non-insulin-treated Type 2 diabetes: a randomized controlled trial.

AIMS: To investigate the effects of self-monitoring of glucose in blood or urine, on diabetes-specific distress and self-efficacy, compared with usual care in people with non-insulin-treated Type 2 diabetes mellitus. METHODS: One hundred and eighty-one participants with non-insulin-treated Type 2 diabetes mellitus [diabetes duration ≥ 1 year, age 45-75 years, HbA1c ≥ 53.0 mmol/mol (7.0%), self-monitoring frequency < 3 times in the previous year] were randomly assigned to blood self-monitoring (n = 60), urine self-monitoring (n = 59) or usual care (n = 62). Primary outcomes were between-group differences in diabetes-specific distress [Problem Areas in Diabetes scale (PAID)] and self-efficacy [Confidence in Diabetes Self-Care questionnaire (CIDS-2)] after 12 months. Secondary outcomes included changes in HbA1c , treatment satisfaction and depressive symptoms. RESULTS: There were no statistically significant between-group differences in changes in PAID and CIDS-2 after 12 months. Mean difference in PAID between blood monitoring and control was -2.2 [95% confidence interval (CI) -7.1 to 2.7], between urine monitoring and control was -0.9 (95% CI -4.4 to 2.5) and between blood monitoring and urine monitoring was -2.0 (95% CI -4.1 to 0.1). Mean difference in CIDS-2 between blood monitoring and control was 0.6 [95% CI (-2.0 to 2.1), between urine monitoring and control was 2.8 (95% CI -2.3 to 7.9)] and between blood monitoring and urine monitoring was -3.3 (95% CI -7.9 to 1.3). No statistically significant between-group differences in change in any of the secondary outcome measures were found. CONCLUSIONS: This study did not find statistical or clinical evidence for a long-term effect of self-monitoring of glucose in blood or urine on diabetes-specific distress and self-efficacy in people with moderately controlled non-insulin-treated Type 2 diabetes mellitus. (Current Controlled Trials ISRCTN84568563).

Perspectives of obese children and their parents on lifestyle behavior change: a qualitative study.

BACKGROUND: In order to improve and optimize future behavioral family lifestyle intervention programs, more information on the perceptions of obese children and their parents of these programs is needed. As such, the aim of this qualitative study is 1) to explore the expectations of obese children and their parents in relation to lifestyle interventions; 2) to identify barriers to making lifestyle changes that parents and children face within their social context (within the family, at school and amongst friends and peers) as well as the things that facilitate these changes and 3) to identify the needs of obese children and their parents in the context of a lifestyle intervention. METHODS: A qualitative study using semi-structured interviews was conducted. Interviewees were participants in a lifestyle intervention program in the Netherlands. RESULTS: Eighteen children (mean age 10 years) and 24 parents were interviewed. The respondents expected to lose weight by being physically active or by eating healthily. Parents struggled with adopting and adhering to new rules and the absence of support of family members. Children struggled with inconsistent parenting and a lack of support from their parents. Bullying experienced at school impeded the children in their ability to make the necessary changes. Support from peers, on the other hand, stimulated their progress. Parents identified the need for the general practitioner to discuss overweight in a non-offensive way and to show an interest in the process of weight loss. CONCLUSIONS: Participants in a lifestyle behavior intervention program benefit from parental support and help from their (extended) family, peers and friends. They would also profit from the sustained involvement of their general practitioner in assisting in the maintenance of lifestyle behavior changes.

ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes.

SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs.

Experience of hypoglycaemia is associated with changes in beliefs about diabetes in patients with type 2 diabetes.

AIM: Hypoglycaemia may have a detrimental impact on quality of life for patients with Type 2 diabetes. There are few clinical studies exploring the impact of experiencing hypoglycaemia on beliefs about diabetes and health status. The aim of this study was to explore associations between experience of hypoglycaemia and changes in diabetes beliefs and self-reported health status in patients with non-insulin-treated Type 2 diabetes using a blood glucose meter. METHODS: One-year prospective cohort analysis of 226 patients recruited to a randomized trial evaluating the impact of self-monitoring of blood glucose. Self-reported hypoglycaemia over 1 year was categorized into three groups: (1) no experience of hypoglycaemia; (2) blood glucose measurements < 4 mmol/l with no associated symptoms of hypoglycaemia (grade 1); and (3) symptomatic hypoglycaemia (grade 2 and 3). Measures of beliefs about diabetes (Revised Illness Perception Questionnaire) and health status (EuroQol-5D) were assessed at baseline and 1 year. Differences in mean changes over 1 year were explored with analyses of covariance. RESULTS: There was a significant increase in mean score in beliefs about personal control (1.14; 95%CI 0.14-2.14) among those experiencing grade 1 hypoglycaemia compared with those not experiencing hypoglycaemia. There were no significant differences in changes in health status between groups, with small overall changes that were inconsistent between groups. CONCLUSIONS: This study does not provide support for a long-term adverse impact on beliefs about diabetes or health status from the experience of mild symptomatic hypoglycaemia, in well-controlled, non-insulin-treated patients with Type 2 diabetes using self-monitoring of blood glucose.

Hereditary spastic paraplegia due to SPAST mutations in 151 Dutch patients: new clinical aspects and 27 novel mutations.

BACKGROUND: In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form. OBJECTIVE: To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4). METHODS: SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed. RESULTS: 151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype. CONCLUSIONS: Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed.

[From psychiatric symptoms to paraneoplastic syndrome]. / Van psychiatrisch symptoom tot paraneoplastisch syndroom.

Two patients, a 38-year-old man and a 32-year-old woman, were admitted to a psychiatric ward. The first patient suffered from a mood disorder, personality changes and complained of several, hitherto unexplained physical symptoms. Finally the patient was diagnosed with paraneoplastic cerebellar degeneration associated with Hodgkin's disease. The second patient presented with psychosis and panic disorders, but the condition was later found to be caused by paraneoplastic limbic encephalitis due to ovarian teratomas. These cases illustrate that patients with paraneoplastic neurological syndromes may present with psychiatric symptoms which can hamper an early diagnosis.

The incidences of and consultation rate for lower extremity complaints in general practice.

OBJECTIVE: To estimate the incidence and consultation rate of lower extremity complaints in general practice. METHODS: Data were obtained from the Second Dutch National Survey of General Practice, in which 195 general practitioners (GPs) in 104 practices recorded all contacts with patients during 12 consecutive months in computerised patient records. GPs classified the symptoms and diagnosis for each patient at each consultation according to the International Classification of Primary Care (ICPC). Incidence densities and consultation rates for different complaints were calculated. RESULTS: During the registration period 63.2 GP consultations per 1000 person-years were attributable to a new complaint of the lower extremities. Highest incidence densities were seen for knee complaints: 21.4 per 1000 person-years for women and 22.8 per 1000 person-years for men. The incidence of most lower extremity complaints was higher for women than for men and higher in older age. CONCLUSIONS: Both incidences of and consultation rates for lower extremity complaints are substantial in general practice. This implies a considerable impact on the workload of the GP.

Course and prognosis of elbow complaints: a cohort study in general practice.

OBJECTIVE: To describe the course of new episodes of elbow complaints in general practice, and to identify predictors of short term and long term outcome in terms of pain intensity and functional disability. METHODS: 181 patients with elbow complaints filled in questionnaires at baseline and at 3, 6, and 12 months of follow up. Baseline scores of pain and disability, characteristics of the complaint, sociodemographic and psychosocial factors, physical activity, general health, and comorbidity were investigated as possible predictors of outcome. Outcome measures were analysed separately using multiple regression analyses. RESULTS: 13% of the patients reported recovery at the 3 month follow up and 34% at 12 months. Irrespective of outcome and length of follow up, a longer duration of the complaint before consulting the general practitioner, having musculoskeletal comorbidity, and using "retreating" as coping style increased the likelihood of an unfavourable outcome. Less social support was associated with an unfavourable outcome at 3 months, and having a history of elbow complaints and using "worrying" as coping style were associated with an unfavourable outcome at 12 months. The explained variance of the models ranged from 46% to 49%. CONCLUSIONS: Recovery of patients with elbow complaints in general practice was poor. Besides characteristic of the complaint, passive coping and less social support were related to a worse prognosis. The results of this study may help general practitioners to provide patients with more accurate information about their prognosis.

Incidence and prevalence of complaints of the neck and upper extremity in general practice.

OBJECTIVE: To study the incidence and prevalence of neck and upper extremity musculoskeletal complaints in Dutch general practice. METHODS: Data were obtained from the second Dutch national survey of general practice. In all, 195 general practitioners (GPs) from 104 practices across the Netherlands recorded all contacts with patients during 12 consecutive months. Incidence densities and consultation rates were calculated. RESULTS: The total number of contacts during the registration period of one year was 1 524 470. The most commonly reported complaint was neck symptoms (incidence 23.1 per 1000 person-years), followed by shoulder symptoms (incidence 19.0 per 1000 person-years). Sixty six GP consultations per 1000 person-years were attributable to a new complaint or new episode of complaint of the neck or upper extremity (incidence density). In all, the GPs were consulted 147 times per 1000 registered persons for complaints of the neck or upper extremity. For most complaints the incidence densities and consultation rates were higher for women than for men. CONCLUSIONS: Neck and upper extremity symptoms are common in Dutch general practice. The GP is consulted approximately seven times each week for a complaint relating to the neck or upper extremity; of these, three are new complaints or new episodes. Attention should be paid to training GPs to deal with neck and upper limb complaints, and to research on the prognosis and treatment of these common complaints in primary care.

Internal consistency and validity of a new physical workload questionnaire.

AIMS: To examine the dimensionality, internal consistency, and construct validity of a new physical workload questionnaire in employees with musculoskeletal complaints. METHODS: Factor analysis was applied to the responses in three study populations with musculoskeletal disorders (n = 406, 300, and 557) on 26 items related to physical workload. The internal consistency of the resulting subscales was examined. It was hypothesised that physical workload would vary among different occupational groups. The occupations of all subjects were classified into four groups on the basis of expected workload (heavy physical load; long lasting postures and repetitive movements; both; no physical load). Construct validity of the subscales created was tested by comparing the subscale scores among these occupational groups. RESULTS: The pattern of the factor loadings of items was almost identical for the three study populations. Two interpretable factors were found: items related to heavy physical workload loaded highly on the first factor, and items related to static postures or repetitive work loaded highly on the second factor. The first constructed subscale "heavy physical work" had a Cronbach's alpha of 0.92 to 0.93 and the second subscale "long lasting postures and repetitive movements", of 0.86 to 0.87. Six of eight hypotheses regarding the construct validity of the subscales were confirmed. CONCLUSIONS: The results support the internal structure, internal consistency, and validity of the new physical workload questionnaire. Testing this questionnaire in non-symptomatic employees and comparing its performance with objective assessments of physical workload are important next steps in the validation process.

Clinimetric evaluation of shoulder disability questionnaires: a systematic review of the literature.

OBJECTIVE: To identify all available shoulder disability questionnaires designed to measure physical functioning and to evaluate evidence for the clinimetric quality of these instruments. METHODS: Systematic literature searches were performed to identify self administered shoulder disability questionnaires. A checklist was developed to evaluate and compare the clinimetric quality of the instruments. RESULTS: Two reviewers identified and evaluated 16 questionnaires by our checklist. Most studies were found for the Disability of the Arm, Shoulder, and Hand scale (DASH), the Shoulder Pain and Disability Index (SPADI), and the American Shoulder and Elbow Surgeons Standardised Shoulder Assessment Form (ASES). None of the questionnaires demonstrated satisfactory results for all properties. Most questionnaires claim to measure several domains (for example, pain, physical, emotional, and social functioning), yet dimensionality was studied in only three instruments. The internal consistency was calculated for seven questionnaires and only one received an adequate rating. Twelve questionnaires received positive ratings for construct validity, although depending on the population studied, four of these questionnaires received poor ratings too. Seven questionnaires were shown to have adequate test-retest reliability (ICC >0.70), but five questionnaires were tested inadequately. In most clinimetric studies only small sample sizes (n<43) were used. Nearly all publications lacked information on the interpretation of scores. CONCLUSION: The DASH, SPADI, and ASES have been studied most extensively, and yet even published validation studies of these instruments have limitations in study design, sample sizes, or evidence for dimensionality. Overall, the DASH received the best ratings for its clinimetric properties.

Infection-triggered regulatory mechanisms override the role of STAT 4 in control of the immune response to influenza virus antigens.

Accurate control of the balance of the T1 and T2 cells during antiviral immunity is essential for optimizing immune effector functions and for avoiding potentially severe immunopathology. We examined the in vivo role of the signal transducer and activator of transcription (STAT) 4 in regulating the T1/T2 balance during the response to live influenza virus and isolated viral proteins. We found that the differentiation of gamma interferon (IFN-gamma)-producing Th1 and Tc1 cells after inoculation of live virus occurred independently of STAT 4 expression. Influenza virus-specific T2 and Tc2 responses were well controlled in such STAT 4-deficient mice unless IFN-gamma was eliminated as well. In contrast, the STAT 4-dependent signaling pathway played a more essential role in regulating the T1/T2 balance after immunization with viral proteins and, in particular, inactivated nonreplicating virus. Pulmonary infection was cleared even in the absence of both functional STAT 4 genes and functional IFN-gamma genes because virus-neutralizing antibodies were still generated, consistent with a substantial redundancy in different antiviral effector pathways. Thus, replicating agents such as live influenza virus can elicit IFN-gamma and control T2 immunity independently of STAT 4, whereas the profile of immunity to isolated proteins is more reliant on an intact STAT 4 signaling pathway.

Receptor-mediated targeting of spray-dried lipid particles coformulated with immunoglobulin and loaded with a prototype vaccine.

PURPOSE: Spray-dried lipid-based microparticles (SDLM) serve as a platform for delivery of a wide variety of compounds including peptides, proteins, and vaccines to the respiratory mucosa. In the present study, we assessed the impact of IgG-mediated targeting to phagocytic cells of inactivated influenza virus formulated in SDLM, on subsequent immune responses. METHODS: SDLM were produced containing inactivated influenza virus strain A/WSN/32/H1N1 (WSN), with or without IgG. Using phagocytic antigen presenting cells (APC) and a T cell hybridoma (TcH) line specific for a dominant influenza virus epitope, we compared the in vitro responses elicited by ligand-formulated (SDLM-IgG-WSN) and non-ligand particles (SDLM-WSN). The effect of including the IgG ligand in the formulation was further characterized by measuring the immune responses of rodents vaccinated with SDLM. RESULTS: SDLM-IgG-WSN were internalized in an Fc receptor (FcR)-dependent manner by phagocytic APC that were then able to effectively present a dominant, class II-restricted epitope to specific T cells. While SDLM-WSN elicited a lower response than administration of plain inactivated virus in saline, the level of the T cell response was restored both in vitro and in vivo by incorporating the APC FcR ligand, IgG, in the SDLM. CONCLUSIONS: Incorporation of FcR ligand (IgG) in SDLM restored the limited ability of formulated virus to elicit T-cell immunity, by receptor-mediated targeting to phagocytes.

Plasmid vaccination with insulin B chain prevents autoimmune diabetes in nonobese diabetic mice.

The insulin B (InsB) chain bears major type 1 diabetes-associated epitopes of significance for disease in humans and nonobese diabetic (NOD) mice. Somatic expression of InsB chain initiated early in life by plasmid inoculation resulted in substantial protection of female NOD mice against disease. This was associated with a T2 shift in spleen, expansion of IL-4-producing and, to a lesser extent, of IFN-gamma-secreting T cells in pancreatic lymph nodes, as well as intermolecular Th2 epitope spreading to glutamic acid decarboxylase determinants. A critical role of IL-4 for the Ag-specific protective effect triggered by plasmid administration was revealed in female IL-4(-/-) NOD mice that developed diabetes and higher Th1 responses. Coadministration of IL-4-expressing plasmid or extension of the vaccination schedule corrected the unfavorable response of male NOD mice to DNA vaccination with InsB chain. Thus, plasmid-mediated expression of the InsB chain early in diabetes-prone mice has the potential to prevent transition to full-blown disease depending on the presence of IL-4.