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Patients with Langerhans cell histiocytosis (LCH) may develop progressive neurodegeneration in the central nervous system (ND-CNS-LCH). Neurofilament light protein (NFL) in cerebrospinal fluid (CSF) is a promising biomarker to detect and monitor ND-CNS-LCH. We compared paired samples of NFL in plasma (p-NFL) and CSF in 10 patients (19 samples). Nine samples had abnormal CSF-NFL (defined as ≥380 ng/l) with corresponding p-NFL ≥ 2 ng/l. Ten samples had CSF-NFL 380 ng/l; eight (80%) with p-NFL 2 ng/l (p 0.001; Fisher's exact test). Thus, our results suggest that p-NFL may be used to screen for ND-CNS-LCH. Further studies are encouraged, including the role of p-NFL for monitoring of ND-CNS-LCH.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterised by the accumulation into granulomas of apoptosis-resistant pathological dendritic cells (LCH-DCs). LCH outcome ranges from self-resolving to fatal. Having previously shown that, (i) monocyte-derived DCs (Mo-DCs) from LCH patients differentiate into abnormal and pro-inflammatory IL-17A-producing DCs, and (ii) recombinant IL-17A induces survival and chemoresistance of healthy Mo-DCs, we investigated the link between IL-17A and resistance to apoptosis of LCH-DCs. In LCH granulomas, we uncovered the strong expression of BCL2A1 (alias BFL1), an anti-apoptotic BCL2 family member. In vitro, intracellular IL-17A expression was correlated with BCL2A1 expression and survival of Mo-DCs from LCH patients. Based on the chemotherapeutic drugs routinely used as first or second line LCH therapy, we treated these cells with vinblastine, or cytarabine and cladribine. Our preclinical results indicate that high doses of these drugs decreased the expression of Mcl-1, the main anti-apoptotic BCL2 family member for myeloid cells, and killed Mo-DCs from LCH patients ex vivo, without affecting BCL2A1 expression. Conversely, neutralizing anti-IL-17A antibodies decreased BCL2A1 expression, the downregulation of which lowered the survival rate of Mo-DCs from LCH patients. Interestingly, the in vitro combination of low-dose vinblastine with neutralizing anti-IL-17A antibodies killed Mo-DCs from LCH patients. In conclusion, we show that BCL2A1 expression induced by IL-17A links the inflammatory environment to the unusual pro-survival gene activation in LCH-DCs. Finally, these preclinical data support that targeting both Mcl-1 and BCL2A1 with low-dose vinblastine and anti-IL-17A biotherapy may represent a synergistic combination for managing recurrent or severe forms of LCH.

The 11th International Conference on Rare Diseases and Orphan Drugs (ICORD), South Africa, included the Africa-Rare initiative launch and facilitated multi-stakeholder engagement in the challenges facing, and opportunities for, Africans living with rare diseases. The following ICORD Global Call to Action, developed in collaboration with the International Rare Diseases Research Consortium, synthesizes the outcomes of the deliberations and emphasizes the international collaborative efforts required to address the global effects of rare diseases on public health.

Langerhans cell histiocytosis (LCH) is a granulomatous inflammatory myeloid neoplasia associated with a cytokine storm in both serum and lesions. Increased levels of plasma interleukin-17A (IL-17A) in LCH patients have been reported, but this finding was not confirmed in all studies. Neurodegeneration is a devastating complication of LCH (ND-LCH). We aimed to revisit the issue of plasma IL-17A levels in LCH, by using a larger number of patients, and also to investigate the relationship between IL-17A and LCH sequelae, especially ND-LCH.Plasma samples from 68 LCH patients and 127 controls were analyzed for IL-17A levels by two ELISAs with different anti-IL-17A capture antibodies: either polyclonal or neutralizing monoclonal antibodies in 17polyAb-ELISA or 17mAb-ELISA, respectively.Both ELISAs had a similar capacity to specifically detect recombinant or native human IL-17A, as well as plasma IL-17A from LCH patients. We confirmed the finding of higher levels of plasma IL-17A in LCH patients compared to controls (p 0.0001). The association of IL-17A with LCH was independent of the ELISA used, and of gender, age, disease class activity, and pattern of tissue-organ involvement (single-system versus multi-system). ROC analyses (p 0.0001) allow to discriminate LCH patients from the control group, supporting the notion that IL-17A may be a potential biomarker for LCH. More interestingly, high IL-17A levels were significantly associated with LCH patients having sequelae, with the highest plasma levels in patients with ND-LCH (p 0.0001).The association between high levels of IL-17A and LCH was confirmed. IL-17A may be associated with ND-LCH development. This might have therapeutic implications, offering a novel target for precision therapy of ND-LCH.

To the editor: Langerhans cell histiocytosis (LCH) has been described as an inflammatory myeloid neoplasia that affects various organs. Central nervous system involvement may result in endocrinopathies and progressive neurodegeneration (ND-LCH), characterized by low-grade inflammation and

Objective In IBD, interleukin-23 (IL-23) and its receptor (IL-23R) are implicated in disease initiation and progression. Novel insight into which cells produce IL-23 at the site of inflammation at an early stage of IBD will promote the development of new tools for diagnosis, treatment and patient monitoring. We examined the cellular source of IL-23 in colon tissue of untreated newly diagnosed paediatric patients with IBD. Design Colon tissues from IBD and non-IBD patients were analysed by quantitative real-time PCR (qPCR), immunofluorescence confocal microscopy and flow cytometry after appropriate sample preparation. Blood samples from IBD and non-IBD patients and healthy controls were analysed using flow cytometry and qPCR. Results We discovered that tissue-infiltrating neutrophils were the main source of IL-23 in the colon of paediatric patients with IBD, while IL-23 + human leucocyte antigen-DR + or IL-23 + CD14 + cells were scarce or non-detectable, respectively. The colonic IL-23 + neutrophils expressed C-X-C motif (CXC)R1 and CXCR2, receptors for the CXC ligand 8 (CXCL8) chemokine family, and a corresponding CXCR1 + CXCR2 + IL-23 + subpopulation of neutrophils was also identified in the blood of both patients with IBD and healthy individuals. However, CXCL8-family chemokines were only elevated in colon tissue from patients with IBD. Conclusions This study provides the first evidence of CXCR1 + CXCR2 + IL-23-producing neutrophils that infiltrate and accumulate in inflamed colon tissue of patients with IBD. Thus, this novel source of IL-23 may play a key role in disease progression and will be important to take into consideration in the development of future strategies to monitor, treat and prevent IBD.

Background/Aims: National Plans for Rare Diseases (RDs) are the common denominator of current public health policy concerns on RDs across the EU. With the aim of a better distribution of the available resources, they conjugate the European objective that aims at ensuring that patients with RDs have access to high-quality care - including diagnostics, treatment and rehabilitation - with the national priorities of selecting specific measures for adoption and implementation. Methods: The European Project for Rare Diseases National Plans Development (EUROPLAN, www.europlanproject.eu) is cofunded by the EU Commission (DG-SANCO) and is coordinated by the Italian National Center for Rare Diseases of the Istituto Superiore di Sanità (ISS). The EUROPLAN goal is to promote the implementation of National Plans or Strategies to tackle RDs and share relevant experiences within countries, linking national efforts, through a common strategy at a European level. In order to fulfill these objectives, EUROPLAN involved health authorities, clinicians, scientists, the European Organisation for Rare Diseases (EURORDIS), and many other patient groups as associated and collaborating partners from several European countries. Results: The project was launched in 2008 and foresaw 2 implementation phases: phase 1 (2008-2011) to build the consensus definition of operational tools (recommendations and indicators), and the ongoing phase 2 (2012-2015), mainly aimed at capacity building with the proactive involvement of multilevel stakeholders. EUROPLAN is facilitating and accelerating the implementation of National Plans in almost all EU and several non-EU Countries. Conclusions: EUROPLAN is a European and an international process more than a project, and it could be defined as a ‘litmus test' demonstrating how the collaboration between institutions and patients' associations can accelerate the process of awareness and development of policies and actions.

Aim: In a recent Swedish study, comparing data from the Swedish Cancer Register with the Medical Birth Register including data on IVF, an increased risk of Langerhans cell histiocytosis (LCH) was f ...

Aim: There is currently no well-accepted therapy for central nervous system Langerhans cell histiocytosis (CNS-LCH), a neuroinflammatory disease clinically characterized by often progressive, neurological symptoms including ataxia, dysarthria, dysphagia, hypertonicity, intellectual impairment and behavioural abnormalities. We applied immunomodulative/anti-inflammatory treatment on a patient with progressive CNS-LCH disease. Method: Intravenous immunoglobulin (IVIG) was administered monthly for 15 years to a patient with severe, image-verified neurodegenerative CNS-LCH. Results: During the IVIG treatment, the neurological deterioration initially appeared to be haltered, but over time there was still some deterioration. Conclusions: IVIG may be beneficial in partly haltering CNS-LCH neurodegeneration, but further studies are needed.

Background Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and other central nervous system (CNS) dysfunctions revealed by brain magnetic resonance imaging (MRI). We estimated the incidence and pattern of pathological brain MRI findings in a well-defined, population-based cohort of children with LCH. Methods Among children under 15 years of age diagnosed with LCH in the Stockholm County during 1992–2001, brain MRI was performed at a single center in children with clinical and/or laboratory signs of CNS involvement, including endocrine dysfunction. Results Out of the 29 children (16 males, 13 females) diagnosed with LCH, brain MRI was performed based on clinical indications in 16 children (55%) with either abnormal endocrine findings (n = 6), such as diabetes insipidus (n = 5), low IGF-1 (n = 1), or panhypopituitarism (n = 1), or clinical CNS symptoms (n = 10). CNS MRI abnormalities were demonstrated in eight children (28%), at a median time of 3.5 years after LCH diagnosis (range 1–11.4 years). Altogether 7 of the 29 children (24%) had MRI findings associated with neurodegeneration, corresponding to a minimal incidence of 2.1/106 children per year. Neurodegenerative abnormalities tended to be more frequent in patients with craniofacial involvement (P = 0.12). Conclusions The minimal annual incidence rate of neurodegenerative associated radiographic findings in LCH is estimated at 2.1/106 children (24% of all children with LCH). An important question is whether all patients with LCH, or certain forms of LCH, should be recommended for a late follow-up examination including MRI. In patients with CNS-LCH, neurological, neuropsychological, neurophysiological, neurochemical and neuroradiological follow-up assessment is suggested. Pediatr Blood Cancer 2011;56:250–257. © 2010 Wiley-Liss, Inc.

Background. Progressive neurodegeneration may result in potentially severe cognitive and motor dysfunctions as a complication of Langerhans cell histiocytosis (LCH), a suggested IL-17A-associated inflammatory condition. To detect this complication (CNS-LCH) early and to evaluate the potential efficacy of therapeutic interventions, biomarkers detecting and measuring ongoing neurodegeneration Would be valuable. We evaluated cerebrospinal fluid (CSF) biomarkers of ongoing neurodegeneration in CNS-LCH patients. Procedure. Nine patients with endocrine, neuromotor, cognitive or/and behavioral abnormalities as well as neuroradiological evidence of CNS-LCH were evaluated 4-12 years after LCH diagnosis for CSF levels of neurofilament protein light chain (NF-L), glial fibrillary acid protein (GFAp), and total tau protein (TAU). Two patients were analyzed longitudinally. One hundred ten children with newly diagnosed acute lymphoblastic leukemia (ALL) served as controls. Results. NF-L, TAU, and GFAp levels were elevated in four, six, and eight of nine patients studied, respectively. NF-L (P < 0.001) and GFAp (P < 0.001) were higher in patients than in controls (TAU not analyzed in controls). The patient with most severe clinical and neuroradiological CNS-LCH displayed the highest levels of NF-L and GFAp whereas three patients without signs of systemic disease had low TAU levels and normal/slightly elevated NF-L. NF-L tended to be higher at radiological progression of neurodegeneration than at Status quo (P = 0.07). Notably, we experienced frequent lumbar puncture complications in these patients. Conclusions. CSF levels of NF-L, TAU, and GFAp appear to be elevated in CNS-LCH. It would be valuable if these markers were validated in order to serve as markers for early CNS-LCH, to monitor disease progression and to evaluate various treatment attempts for CNS-LCH. Pediatr Blood Cancer 2009;53:1264-1270. (C) 2009 Wiley-Liss, Inc.

A survey of workstation layout and work postures among 156 computer operators was performed in 16 call centers (CCs) in Sweden, relating data to operators’ comfort, symptoms and existing ISO-standards, EU-directives and National Work Environment Law. The quality of the furniture and equipments was generally good and mainly fulfilled the demands of the law, directives and standards. The main problem was how these were used—how they were positioned and adjusted to fit the individual operator and to allow good and flexible work postures. Awkward postures were, therefore, seen in shoulder joints and wrists. Lack of easy height adjustability of many desks was noted. This was associated with more seated postures and back pain. Desk and chair quality were associated with operators’ satisfaction and work postures and thick keyboards with dissatisfaction and neck or back pain. Optimal adjustments were associated with operators’ satisfaction and good work postures and in some aspects also with fewer symptoms. The conditions were more optimal at internal CCs as opposed to freestanding external (outsourced) enterprises. Relevance to industry CCs are one of the fastest expanding business sectors. Besides, investments in more flexible desks, optimizing basic adjustments would improve conditions substantially in many cases. There is thus a potential for improvements in the conditions for CC work with possibilities for gain in comfort, health and productivity.

Langerhans cell histiocytosis is a rare disease of unknown etiology. We wanted to assess the population-based incidence of LCH in a well-defined cohort of children.We identified all children15-years old treated with LCH during the 10 years period 1992-2001 at the Department of Pediatrics, Karolinska University Hospital in Stockholm, the referral center for children with LCH in Stockholm County. We also contacted the Departments of Dermatology, Orthopedics, and Neurosurgery for possible additional patients.Twenty-nine children (16 males) with LCH were identified, with a median age at diagnosis of 3.8 years (2 months-13.7 years). All children but one had a definitive diagnosis of LCH. The minimum incidence of LCH is estimated to 8.9/10(6) children per year. At diagnosis, 20 children (69%) had single system (SS) and 9 (31%) multisystem (MS) manifestations. Five of the 20 children with SS eventually developed MS disease, thus 14 (48%) had MS involvement at the maximal extent of disease (4.3/10(6) children per year). Interestingly, 22 children (76%) were diagnosed during the fall (September-November, n = 12) and winter (December-February, n = 10) seasons, as compared to seven children during the spring (March-May = 1) and summer (June-August = 6) seasons (P = 0.005, Chi-square).The incidence of childhood LCH in our study is higher than previously reported. In our patient cohort, LCH was more commonly diagnosed during the fall and winter season as compared to the spring and summer season. Whether this seasonal variation can be confirmed in larger studies and whether it has relevance for LCH pathophysiology remains to be elucidated.

A survey of physical work conditions was performed in a strategic sample of call centres in Sweden. Extensive observations including measurements of work environment factors took place at 16 companies, involving 156 operators and their workstations. Observed conditions were compared with current directives and recommendations and also with the operators’ ratings of comfort and reported symptoms. Internal and external call centres working in the whole range of task complexity were compared. The air quality and thermal climate in the workplace were mainly satisfactory, but air humidity was low. Sound levels were often high at many workstations and illuminance too low. Glare and reflexions in the VDU-screens were common. The observations indicate that the conditions quite often were out of range of current directives and recommendations for sound working environment. The indoor climate, the air quality, the ambient noise level and the illumination created dissatisfaction of comfort among about 74% the operators. Correlations between the ratings of comfort and the observations were moderate, but most were statistically significant. No significant associations between symptoms (eyes, ears, throat, skin or headache) and the observations were found. Relevance to industry The study provides useful data both for designing call centres and similar offices and for improvement of the physical work environment. It points out which physical factors and environment-related symptoms one should be especially aware of among call centre workers.

Fire fighting work comprises work tasks requiring an energy yield at maximal or close to maximal levels of the individual. Due to the very nature of fire fighting more complex physiological variables are difficult to measure. We measured metabolic and respiratory responses in 15 male, professional fire fighters during simulated work tasks on a test ground. Work time was on the average 22 min with individual components of work tasks lasting 2-4 min. The mean oxygen consumption for the whole exercise (22 min) was 2.75+/-0.29 l/min. The most demanding work task demanded an oxygen uptake of 3.55+/-0.27 l/min. Corresponding values for respiratory minute volumes were 82+/-14 and 102+/-14l/min, respectively. Heart rates averaged 168+/-12 for the whole test and 179+/-13 beats/min for the heaviest work task. Two new classes for classification of intensive and exhausting, short term physical work are proposed for inclusion in ISO8996 and values for relevant parameters are proposed.

The aim of the study was to examine the effects of wearing an ice-vest (ca 1 kg) on physiological and subjective responses in fire fighters. The experiments were carried out on a treadmill in a hot-dry environment. The physical cooling effect of the ice-vest was measured with a thermal manikin. The ice-vest effectively reduced skin temperatures under the vest. On average, heart rate was 10 beats/min lower, the amount of sweating was reduced by 13%, and subjective sensations of effort and warmth were lower during work with the ice-vest compared to work without it. Thermal manikin tests indicated that the useful energy available from the vest for body cooling was rather high (58%). In conclusion, the ice-vest reduces physiological and subjective strain responses during heavy work in the heat, and may promote efficient work time by 10%.

The effects of low to moderate wind speeds on face temperature, thermal and pain sensations while subjects walked on a treadmill during cold exposure were studied in eight healthy men. The purpose of the study was to evaluate further the risk of frostbite at different activity levels. The walking speed was 2.8 km h(-1) and two inclination levels were used, 0 degrees and 6 degrees. The subjects were exposed to -10 degrees C and 0, 1 or 5 m s(-1) wind for 60 min dressed in cold-protective clothing with only the face unprotected. Results from previous experiments with the same subjects standing for 30 min were included in the analysis of the data. Each individual was exposed to all combinations of air velocity and activity level. The exposure to -10 degrees C and the highest wind speed used would carry no risk of frostbite according to the wind chill index. Cold lowered the skin temperature of the face significantly and wind further increased skin cooling. The activity level did not affect forehead and cheek temperatures, but the average nose skin temperature was higher and pain sensations were reduced at a higher work rate. The predicted risk of frostbite in the nose, based on average responses, would thus be less at a higher work rate. However, the results indicate that exercise does not necessarily protect all individuals from frostbite at moderate air speeds, since the nose skin temperature of 25% of the subjects dropped to 0 degrees C at 5 m s(-1) during both standing and walking. Thus the potential individual risk of frostbite in the nose is similar during light exercise and standing. Moreover, the risk of frostbite seems to be underestimated by the wind chill index under the conditions tested in this study.

Objectives. The present study sought to identify firefighters’ rated physical demands for the most frequently occurring work tasks and to determine if the ratings differed between full-time and part-time firefighters to help create a basis for the development of physical employment tests for firefighters. Methods. An extensive questionnaire was completed by 125 and 68 firefighters in 2000 and 2010, respectively. The data were analysed with the Mann–Whitney U test and binominal test and ranked on the basis of the responses in each category. Results. Significant differences were seen between the full- and part-time firefighters. The work tasks rated as the most physically strenuous in terms of aerobic fitness, muscle strength, work posture and body control by most respondents were smoke diving upstairs (carrying a hose), victim rescue in different ways, carrying a stretcher over terrain and pulling a hose. Conclusions. Physically strenuous work tasks should be included in the end-point performance variables used to select physical performance tests for firefighters. The part-time firefighters with no experience in several of the work tasks suggests that work-related exercises are important if both groups of firefighters are expected to do similar work. emergency personnel ergonomics physical demand performance tests

The study aimed to find out the problems connected with feet during work in cold loose housing barns in wintertime. Thirteen dairy farms and 20 workers were studied. Skin temperatures and subjective responses were collected, and at the end of a work period the subjects filled in a questionnaire about the workday. The foot skin temperatures were measured on dorsal foot and second toe. Most of the workers used rubber boots. The ambient temperature outdoors varied from +5 to −11°C. Indoor temperatures could be the same as outdoors (cold barns and fodder storage) but also close to +30°C (milk room). The lowest mean foot and toe skin temperatures were 24.1±2.6°C and 16.0±1.4°C. The lowest measured values were 20.1°C and 12.8°C, respectively. The toe temperatures were on average 7.3°C colder than foot temperatures (mean 28.8°C). The low foot skin temperature was well related to cold sensation. Low toe temperatures fitted well with wetness sensation. On average the thermal sensation of feet over the work period was neutral. The lowest ratings were cold (−2). The combination of various environmental factors in farms complicates finding of perfect footwear for work. Recommendations on the choice of footwear and their care are given. Relevance to industry Dairy farms function as small enterprises. The owners’ family usually does the work. The workdays are often long. In spite of modern machinery and industrial methods, several work moments are heavy and the work conditions are considered to be harsh.

The effects of exercise intensity on thermoregulatory responses in cold (-10 degrees C) in a 0.2 (still air, NoWi), 1.0 (Wi1), and 5.0 (Wi5) m x s(-1) wind were studied. Eight young and healthy men, preconditioned in thermoneutral (+20 degrees C) environment for 60 min, walked for 60 min on the treadmill at 2.8 km/h with different combinations of wind and exercise intensity. Exercise level was adjusted by changing the inclination of the treadmill between 0 degrees (lower exercise intensity, metabolic rate 124 W x m(-2), LE) and 6 degrees (higher exercise intensity, metabolic rate 195 W x m(-2), HE). Due to exercise increased heat production and circulatory adjustments, the rectal temperature (T(re)), mean skin temperature (Tsk) and mean body temperature (Tb) were significantly higher at the end of HE in comparison to LE in NoWi and Wi1, and T(re) and Tb also in Wi5. Tsk and Tb were significantly decreased by 5.0 m x s(-1) wind in comparison to NoWi and Wi1. The higher exercise intensity was intense enough to diminish peripheral vasoconstriction and consequently the finger skin temperature was significantly higher at the end of HE in comparison to LE in NoWi and Wi1. Mean heat flux from the skin was unaffected by the exercise intensity. At LE oxygen consumption (VO2) was significantly higher in Wi5 than NoWi and Wi1. Heart rate was unaffected by the wind speed. The results suggest that, with studied exercise intensities, produced without changes in walking speed, the metabolic rate is not so important that it should be taken into consideration in the calculation of wind chill index.

The effects of the thermal state of the body (slightly cool and neutral) and moderate wind speeds on face temperature, blood pressure, respiratory function and pain sensation during cold exposure were studied on eight healthy male subjects. They were dressed in cold-protective clothing and preconditioned at + 20 degrees C (TN) and -5 degrees C (CO) for 60 min, then exposed to -10 degrees C and 0 m x s(-1) (NoW), 1 (W1) and 5 (W5) m x s(-1) wind for 30 min. Thus, each individual was exposed six times. The exposure to wind entailed a combination of strong cooling of the bare face and mild body cooling. The forehead, cheek and nose temperatures decreased during cold exposure, and the decrease was greater at higher air velocities (P0.0001). All subjects reported pain sensations at 5 m x s(-1). At the end of exposure only the nose temperature was significantly lower in CO than in TN subjects; it was about 2 degrees C and reached 0 degrees C in two experiments. The systolic and diastolic blood pressure (SBP and DBP, respectively) increased significantly by 7.7 and 5.9 mmHg, respectively, during preconditioning at -5 degrees C, but did not change at + 20 degrees C. SBP and DBP increased during exposure to -10 degrees C in TN by approximately 9 mmHg. However, the total average increase of blood pressure (1-90 min) was similar in TN and CO (SBP 15 mmHg and DBP 13 mmHg). SBP and DBP increased more during exposure to 5 m x s(-1) at -10 degrees C than NoW. Blood pressure responses as observed in this study (SBP and DBP up to 51 and 45 mmHg, respectively) are potential health risks for hypertensive individuals and angina patients. Respiratory functions (FVC, FEV1) were reduced by about 3% by the cold (-5 and -10 degrees C) compared to pre-experiment values. Furthermore, the Wind Chill Index seems to underestimate the cooling power of 5 m x s(-1) at -10 degrees C of bare skin (e.g. face). Therefore it needs to be revised and we suggest that it is expanded to include risk levels for pain sensation.

The objective of the study was to validate the DLE (duration limited exposure) index, which provides a method to determine acceptable time limits when, in a cold environment, clothing insulation is not sufficient to protect the wearer from body cooling. The thermal responses of ten male subjects dressed in winter clothing to −6, −14 and −22°C during very light exercise were studied. The individual variation of peripheral temperature responses was large. The majority of the subjects stated that they would accept the exposure once a day, but not continuously. DLE was on the `safe side' according to the body net heat debt and rectal temperature, but at the same time it allowed for low skin temperatures, especially of the extremities at low ambient temperatures. At predicted time limits, the mean skin temperature criteria of DLE suggested in the ISO document ISO/TR 11079 were not met at −14 and −22°C. Introduction of limit criteria for extremity cooling in prediction models would render a more complete assessment of cold stress. Relevance to industry Since the protective clothing worn by the worker is not always sufficient for the actual low ambient temperature there is a need for accurate predictions of exposure time.

In a recent Swedish study, comparing data from the Swedish Cancer Register with the Medical Birth Register including data on IVF, an increased risk of Langerhans cell histiocytosis (LCH) was found in children born 1982-2005 after IVF. Here, we aimed to verify the LCH diagnoses and examine whether any special forms of the disease were overrepresented in this population.Medical records for all children with LCH conceived by IVF were acquired and the diagnosis confirmed or discarded. Disease characteristics were compared with data from children diagnosed with LCH 1992-2001 in the Stockholm County.We verified LCH in seven children born after IVF, all born prior to 2002. These children did not have milder disease forms. The odds ratio (OR) to develop LCH for the whole group born after IVF was 3.2 [95% confidence interval (CI), 1.4-7.3] and for children born before 2002, 5.2 [95% CI, 2.3-11.9], compared with children in Stockholm County 1992-2001.LCH was overrepresented in children born after IVF prior to 2002. Affected children did not have milder disease forms. These findings may be valuable to understand LCH aetiology. Additional studies on a putative correlation between IVF and LCH in the offspring are encouraged.

There is currently no well-accepted therapy for central nervous system Langerhans cell histiocytosis (CNS-LCH), a neuroinflammatory disease clinically characterized by often progressive, neurological symptoms including ataxia, dysarthria, dysphagia, hypertonicity, intellectual impairment and behavioural abnormalities. We applied immunomodulative/anti-inflammatory treatment on a patient with progressive CNS-LCH disease.Intravenous immunoglobulin (IVIG) was administered monthly for 15 years to a patient with severe, image-verified neurodegenerative CNS-LCH.During the IVIG treatment, the neurological deterioration initially appeared to be haltered, but over time there was still some deterioration.IVIG may be beneficial in partly haltering CNS-LCH neurodegeneration, but further studies are needed.

Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and other central nervous system (CNS) dysfunctions revealed by brain magnetic resonance imaging (MRI). We estimated the incidence and pattern of pathological brain MRI findings in a well-defined, population-based cohort of children with LCH.Among children under 15 years of age diagnosed with LCH in the Stockholm County during 1992-2001, brain MRI was performed at a single center in children with clinical and/or laboratory signs of CNS involvement, including endocrine dysfunction.Out of the 29 children (16 males, 13 females) diagnosed with LCH, brain MRI was performed based on clinical indications in 16 children (55%) with either abnormal endocrine findings (n = 6), such as diabetes insipidus (n = 5), low IGF-1 (n = 1), or panhypopituitarism (n = 1), or clinical CNS symptoms (n = 10). CNS MRI abnormalities were demonstrated in eight children (28%), at a median time of 3.5 years after LCH diagnosis (range 1-11.4 years). Altogether 7 of the 29 children (24%) had MRI findings associated with neurodegeneration, corresponding to a minimal incidence of 2.1/10(6) children per year. Neurodegenerative abnormalities tended to be more frequent in patients with craniofacial involvement (P = 0.12).The minimal annual incidence rate of neurodegenerative associated radiographic findings in LCH is estimated at 2.1/10(6) children (24% of all children with LCH). An important question is whether all patients with LCH, or certain forms of LCH, should be recommended for a late follow-up examination including MRI. In patients with CNS-LCH, neurological, neuropsychological, neurophysiological, neurochemical and neuroradiological follow-up assessment is suggested.

Progressive neurodegeneration may result in potentially severe cognitive and motor dysfunctions as a complication of Langerhans cell histiocytosis (LCH), a suggested IL-17A-associated inflammatory condition. To detect this complication (CNS-LCH) early and to evaluate the potential efficacy of therapeutic interventions, biomarkers detecting and measuring ongoing neurodegeneration would be valuable. We evaluated cerebrospinal fluid (CSF) biomarkers of ongoing neurodegeneration in CNS-LCH patients.Nine patients with endocrine, neuromotor, cognitive or/and behavioral abnormalities as well as neuroradiological evidence of CNS-LCH were evaluated 4-12 years after LCH diagnosis for CSF levels of neurofilament protein light chain (NF-L), glial fibrillary acid protein (GFAp), and total tau protein (TAU). Two patients were analyzed longitudinally. One hundred ten children with newly diagnosed acute lymphoblastic leukemia (ALL) served as controls.NF-L, TAU, and GFAp levels were elevated in four, six, and eight of nine patients studied, respectively. NF-L (P0.001) and GFAp (P0.001) were higher in patients than in controls (TAU not analyzed in controls). The patient with most severe clinical and neuroradiological CNS-LCH displayed the highest levels of NF-L and GFAp whereas three patients without signs of systemic disease had low TAU levels and normal/slightly elevated NF-L. NF-L tended to be higher at radiological progression of neurodegeneration than at status quo (P = 0.07). Notably, we experienced frequent lumbar puncture complications in these patients.CSF levels of NF-L, TAU, and GFAp appear to be elevated in CNS-LCH. It would be valuable if these markers were validated in order to serve as markers for early CNS-LCH, to monitor disease progression and to evaluate various treatment attempts for CNS-LCH.

Background Patients with Langerhans cell histiocytosis (LCH) may develop neurodegeneration and significant CNS sequelae, affecting a significant proportion of the patients. We here aimed to investigate the neuropsychological consequences in more detail. Methods Using an extensive neuropsychological test battery, we evaluated nine LCH patients, 6–20 years old, with radiological signs indicative of neurodegeneration. Results Altogether 3/9 patients performed below 1 SD of normal for age on full IQ. Detailed analysis revealed that 4/9 had deficient performance IQ, whereas 1/9 had subnormal verbal IQ (defined as below 1 SD). Furthermore, 3/8 patients showed slow speed of performance for age. Notably, 8/9 (89%) had deficient verbal working memory and 7/8 (88%) performed below normal on visual-spatial working memory. Conclusions The results indicate a specific, uneven neuropsychological profile in patients affected by CNS-LCH, with a decline particularly on perceptual tasks whereas the verbal performance was not as negatively influenced. Furthermore, verbal and visual-spatial working memory functions were below normal for age in all but one patient studied. LCH may easily be misdiagnosed, but it is important that individuals affected by CNS-LCH are diagnosed to provide advice and support. It remains a challenge to find a treatment reducing this unfortunate neurodegeneration. Pediatr Blood Cancer 2008;51:669–674. © 2008 Wiley-Liss, Inc.

Dry air in office workplaces has been the target for discomfort complaints and a number of symptoms in the skin and the mucous membranes, such as eye irritation. To investigate the effects of dry ambient air, 39 office workers, working in the same building on two floors (23 on one floor and 16 on the other), were asked to participate in a study (single-blind design). The air temperature was 20–22°C during the whole 12-week test period. The relative humidity (RH) was changed from about 43%, which was the regulated normal RH of the particular office building (NORMAL), to about 15% (DRY) and was then changed back to NORMAL. Each humidity level was maintained for 4 weeks. Comfort and symptoms of the skin, eyes, mouth and throat were evaluated by a questionnaire at each RH level, and before and after each shift of air humidity. A few symptoms were already reported under NORMAL RH. 54% of the subjects reported that the air was ‘too dry’ in DRY conditions compared to 5% in NORMAL conditions. DRY resulted in more frequent perceived dryness of the mouth and throat (31% vs. 10%) and facial skin (44% vs. 15%), and more frequent symptoms of the eyes (36% vs. 8%), lips (38% vs. 10%) and running nose (46% vs. 8%) than did NORMAL. Some workers also reported sensations of heat/red skin in their faces more often in DRY conditions. Low relative air humidity resulted in more discomfort and more frequent symptoms in facial skin and the mucous membranes. This indicates that humidification of dry air most probably would reduce the number and frequency of air-related symptoms.

The aim of this study was to validate the Edholm scale (Edholm, 1966) and the ISO 8996 standard (International Organization for Standardization [ISO], 1990) by comparing the metabolic rates estimated for both methods with the actual measured metabolic rate (MMeas) in 6 manual material handling tasks simulated under laboratory conditions. The metabolic rate was calculated from oxygen consumption VO2 (19 participants) according to Standard No. ISO 8996 (ISO, 1990). Additionally, the participants estimated perceived exertion using the Borg scale. The metabolic rates derived from the Edholm scale (MEdh) overestimated 5 of 6 activities by 34-50% (alpha = .05). The metabolic rates derived from ISO 8996 (MISO) overestimated all activities by 7-38% (alpha = .05).

The effects of initial thermal state on thermoregulatory responses to cold (-10 degrees C) in a 0.2 (still air), 1.0, and 5.0 m. S(-1) wind speed were studied. Eight young male subjects were first preconditioned in thermoneutral (+20 degrees C, TN) or cool (-5 degrees C, CO) environment for 60 min. After preconditioning the subjects were exposed to wind at -10 degrees C in a standing position, facing the wind, for 30 min. Precooling decreased mean skin temperature (Tsk) by 4.0 (SEM 0.1) degrees C (P0.001) and increased heat flux by 57 (SEM 2) W x m(-2) (P0.001) in comparison to TN. Cooling rate of Tsk was faster (P0.001) in TN than in CO at every wind speed. Even so, Tsk ended up at a lower level in CO (P0.001-0.01) than in TN at every wind speed. Local skin temperatures of hand, finger, foot and toe were significantly lower in CO than in TN at the end of all exposures to wind. Heat flux from the skin was 8% higher (NS) in TN at 5.0 m x s(-1) wind speed in comparison to CO. A 5.0 m x s(-1) wind speed increased oxygen consumption significantly (P0.001) in both CO and TN in comparison to still air. At 5.0 m x s(-1) wind speed the general thermal sensation was the same (cold) in both TN and CO, despite the higher Tsk in TN. In conclusion, Tsk decreased more rapidly in TN, probably due to rapid skin vasoconstriction and redistribution of circulation to the central body. Probably for the same reason, dry heat loss from the skin was at nearly the same level in both TN and CO. Although the initial thermal state did not affect the amount of heat loss, it significantly affected the peripheral temperatures and thermal sensations and should therefore be taken into consideration in the prediction of thermophysiological responses to wind.

Prolonged exposure to cold air may induce a chronic asthma-like condition in healthy subjects as has been demonstrated in cross-country skiers. In the present controlled study, our aim was to elucidate further the link between cold air exposure and airway inflammation by assessing the cellular influx and mediator levels within the airways following acute exposure to cold air. Bronchoalveolar (BAL) and nasal lavages were performed after exposure to cold air (-23 degrees C) and normal indoor air (+22 degrees C) during a light, intermittent work for 2 h in a cross-over design in eight healthy, nonsmoking, subjects. Analyses of inflammatory cell number, cell activation markers, pro-inflammatory cytokines, albumin and interleukin (IL)-8 in lavage fluids were performed. The number of granulocytes and of alveolar macrophages in BAL fluid was significantly higher after cold air exposure (p

Beta2-agonists are frequently used by elite cross-country skiers, a group of athletes with a high prevalence of asthma. It has been claimed that beta2-agonists have a positive effect on physical performance. The aim of the present study was to investigate whether inhalation of a beta2-agonist increases physical performance at low temperature in healthy, nonasthmatic athletes with normal bronchial responsiveness. Twenty elite male athletes (cyclists, cross-country skiers, middle and long distance runners) with no history of allergy or airway disease and who had normal spirometry and methacholine bronchial provocation tests performed a maximal exercise test on a treadmill in a climate chamber at approximately 10 degrees C on two subsequent days. Before exercise they inhaled terbutaline (3 mg from MDI) or placebo in a randomized, single blind manner. After 10-min warm-up on the treadmill, a submaximal work preceded a stepwise increase of the workload until exhaustion. Lung function, ventilation, oxygen uptake, and heart rate were determined and blood samples for lactate and potassium analyses were drawn before, during, and after exercise. Terbutaline induced a significant bronchodilatation; FEV1 increased from 4.8 (4.4-5.1) L to 5.0 (4.6-5.4) L, mean (95% CI). There were no significant differences between the two treatments with regard to exercise time, 25.1 (24.3-25.8) min vs 24.9 (24.1-25.6) min, oxygen uptake and ventilation during exercise, or heart rate at maximal workload. Terbutaline induced an increase in serum lactate concentration but did not influence the lactate response to exercise. The serum potassium increase was attenuated at low workload but not at maximal work. The postexercise decrease in serum potassium concentration was significantly greater after terbutaline (-0.52 (-0.29 to -0.76) mmol x L-1) than after placebo (-0.13 (0.06 to -0.32) mmol x L-1 (P < 0.001). We conclude that inhalation of a beta2-agonist (terbutaline) in a dose that yields significant bronchodilatation does not influence physical performance at low temperature in healthy athletes. Acute inhalation of the beta2-agonist amplified the postexercise hypokalemia, a finding of unclear significance. Although there is a slight bronchodilatation and potential negative airways effect of cold air inhalation, a beta2-agonist does not increase physical performance in top athletes.

In cold conditions variations in the physical activity of clothed individuals and rest periods in a moderate temperature may result in a disturbance of heat balance and thermal comfort of the individual, in particular when sweating occurs. The purpose of the study was to examine thermal responses in persons dressed in winter clothing during changes of exercise intensity (high to low) and ambient temperature, and to investigate whether there were any effects on these responses due to fibre material (wool and synthetic). Two types of transient condition were studied, an exercise level transient (E) and a temperature transient (T). Ten healthy male subjects dressed in multi-layer winter clothing ensembles with different levels of total insulation walked on a treadmill at an ambient temperature of -10 degrees C. The garments were manufactured from wool, giving insulations of 2.6 clo, in T only and otherwise of 3.2 clo, or synthetic fibres, giving insulations of 2.4 clo in T only and otherwise of 3.1 clo. In E the subjects exercised at a high intensity for 50 min followed by 60 min walking at low intensity. In T they walked at a moderate speed for 90 min in ambient temperature of -10 degrees C, rested in temperatures of +22 degrees C for 30 min and walked in the cold climatic chamber for another 45 min. The skin temperature, sweating responses and thermal sensations were higher/warmer with increasing insulation during exercise. The wool fibre material resulted in a slightly higher mean skin temperature (about 0.3 degree C) during exercise, but no differences in subjective responses were found. The rest period had only a small influence on the subsequent thermal responses. The interindividual variations in thermal responses were large.

Thermoregulatory and thermal subjective responses were studied in ten male, clothed subjects during continuous (C) and intermittent (I) exercise at the same average level of oxygen consumption. The subjects performed both I and C twice, dressed in two different three-layer cold-protective clothing ensembles of two thermal insulation levels [total clothing insulation = 2.59 clo (L) and 3.20 clo (H)]. Experiments were carried out at an ambient temperature of -10 degrees C. Rectal temperatures increased similarly in both types of exercise. Mean skin temperature (Tsk) was lower in I compared to C with both levels of clothing insulation. Over the last 0.5 h of the experiment Tsk was approximately 1.3 degrees C lower in I than in C for clothing L. The skin evaporation rate was higher in clothing H than L but did not differ between I and C. Subjective ratings for thermal sensations of the whole body (BTS) and hands were close to neutral in I and around slightly warm in C. The BTS was lower in I than in C and was lower in L compared to H. It was concluded that, at equal average energy expenditure, thermal responses to intermittent and continuous exercise in the cold differ in clothed subjects, principally as a result of different patterns of heat exchange.

A tight-fitting crewneck undergarment (U) and a loose-fitting shirt (S) were studied as part of a commonly used clothing ensemble (Itot = 0.22 m2 K W-1). Ten clothed male subjects performed standardized packing work (VO2 = 0.761 min-1) at three climatic conditions, 20 degrees C and Va = 0.45 m s-1 (0-30 min), at 5 degrees C and Va = 0.39 m s-1 (30-60 min) and at 5 degrees C and Va = 1.23 m s-1 (76-90 min). From 60-75 min the subjects rested at 20 degrees C. The physiological and subjective responses varied with the environment from slightly warm to cool. U resulted in warmer responses than S: torso and upper arm skin temperatures were higher at both 5 degrees C and 20 degrees C, evaporation rate was higher at 20 degrees C, mean skin temperature was higher during work at 20 degrees C, sweating tended to begin earlier and skin wettedness to be higher with U than with S. No differences were observed in core temperature, heart rates, and subjective thermal evaluations. It was concluded that a tight-fitting inner layer (U) compared to a loose-fitting one (S) allows for less cooling of the skin in both a cool and a slightly warm environment.

Over the last decade the European Union has been coordinating actions addressing various aspects of rare diseases and has funded several cross-border research projects. Recently has initiated the biggest rare disease international collaborative effort by launching the International Rare Diseases Research Consortium (IRDiRC). RARE-Bestpractices is one of the more than 100 collaborative research projects on rare diseases funded under the Seventh Framework Programme for Research and Technological Development (FP7; 2007-2013) (1). As a wide, open and inclusive network, RARE-Bestpractices will build on the knowledge of the experts in rare disease research area and experts in guideline development and health technology assessment area, brought together, for the first time, from academic institutions, agencies, organizations, patient advocacy groups, governmental bodies. The project aims at building a platform to collect and exchange information on best practices for the management of rare diseases; to identify relevant research needs; to promote the development of high quality guidelines; and to contribute in making patients, health professionals and policy makers “informed guideline users”. Besides, RARE-Bestpractices will intend to define the extent to which conclusions from cost-effectiveness analyses for pharmaceuticals are accounted for and implemented in guidelines across a range of countries.