A. R. Gwosdow

Osteopenia in Gaucher disease develops early in life: Response to imiglucerase enzyme therapy in children, adolescents and adults

BACKGROUND In Gaucher disease (GD), acid-β-glucosidase (GBA1) gene mutations result in defective glucocerebrosidase and variable combinations of hematological, visceral, and diverse bone disease. Osteopenia is highly prevalent, but its age of onset during the natural course of GD is not known. It is also unclear if the degree of improvement in osteopenia, secondary to imiglucerase enzyme therapy, differs by the age of the patient. OBJECTIVE We hypothesized that osteopenia develops early in life, during the natural course of type 1 Gaucher disease (GD1), and that its response to treatment is maximal during this period. METHODS We examined data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry of patients treated with imiglucerase between the ages of 5 and 50 years. Lumbar spine bone mineral density (BMD) (determined by dual-energy X-ray absorptiometry (DXA) and expressed as Z-scores) at baseline and for up to 10 years on imiglucerase were analyzed in children (ages ≥ 5 to <12 years), adolescents (≥ 12 to <20 years), young adults (≥ 20 to < 30 years), and older adults (≥ 30 to < 50 years). BMD was correlated with other disease characteristics. Pre-treatment, descriptive statistics were applied to 5-year age categories. Non-linear mixed effects regression models were used to analyze DXA Z-scores over time after treatment with imiglucerase. RESULTS Pre-treatment, low BMD was prevalent in all age groups, most strikingly in adolescents. DXA Z-scores were at or below -1 in 44% of children (n=43), 76% of adolescents (n=41), 54% of young adults (n=56) and 52% of older adults (n=171). The most common GBA1 genotype was N370S heteroallelic. Baseline hematological and visceral manifestations in the 4 age groups were similar. In children with DXA Z-scores ≤-1 at baseline, imiglucerase therapy for 6 years resulted in improvement of mean DXA Z-scores from -1.38 (95% CI -1.73 to -1.03) to -0.73 (95% CI -1.25 to -0.21); in young adults DXA Z-scores improved from -1.95 (95% CI -2.26 to -1.64) to -0.67 (95% CI -1.09 to -0.26). BMD also improved in older adults, but the magnitude of the improvement was lower compared to younger patients. CONCLUSIONS Low bone density is common in GD1 with the highest prevalence rate in adolescence, a developmental period critical to attainment of peak bone mass. Imiglucerase results in amelioration of osteopenia in all age groups, with the greatest improvements in younger patients.

The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry.

PURPOSE Investigate the incidence of Parkinsonism among patients with Gaucher disease type 1 (GD1) and describe demographics, genotypes, and Gaucher disease (GD)-related characteristics for affected and non-affected patients. METHODS STUDY TYPE Cohort study with age- and gender-matched nested case-control analysis. Calculation of event incidence, standardized morbidity ratio, and event-free survival (Kaplan-Meier). DATA SOURCE The International Collaborative Gaucher Group (ICGG) Gaucher Registry data as of June 2010. Study cohort: GD1 patients with any report of Parkinsonism. Pre-matching control group: All GD1 patients with no report of Parkinsonism. RESULTS The matched study cohort comprised of 68 patients with reports of Parkinsonism and 649 patients without Parkinsonism. Demographic and clinical characteristics suggest a milder GD phenotype in patients with Parkinsonism compared to the control group. The most prevalent GD1 genotype was N370S/N370S (39% for controls; 46% for patients with Parkinsonism). Patients with Parkinsonism were diagnosed with GD1 at a mean age of 37 years compared to 31 years in control patients. The standardized morbidity ratio for the development of Parkinsonism among all GD1 patients indicated an approximately 6 to 17 fold increase over that of 2 reference populations. The mean age of reported Parkinsonism onset was 57 years compared to 60 years in the general population (Lees, Hardy, and Revesz, 2009 [1]). The probability that a patient with GD1 will develop Parkinsonism before age 70 years is 5 to 7% and 9 to 12% before age 80 years. CONCLUSIONS The incidence of Parkinsonism among GD1 patients is significantly increased compared to two reference populations. GD1 patients with Parkinsonism have a later median age at GD diagnosis, later age at the start of treatment, and later age at death than patients with GD1 alone. The Gaucher-related clinical profile of GD1 patients with Parkinsonism is similar to or milder than the GD1 alone group. Therefore, severity of the common GD1 clinical manifestations does not appear to be predictive for the onset of Parkinsonism.

IL‐1 is expressed in human adrenal gland in vivo. Possible role in a local immune‐adrenal axis

IL‐1 is an important mediator in the dialogue between the immune system and the hypothalamo‐pituitary‐adrenal axis. A direct influence of IL‐1 upon adrenal steroidogenesis has been demonstrated in experimental animals. We therefore designed a study to see if IL‐1 is expressed within the normal human adrenal gland. The combination of in situ hybridization and specific immunostaining to IL‐1β was eminently suited to demonstrate both mRNA and protein production. The specific immunostaining of the different cells combined with in situ hybridization (IL‐1) allowed us to identify the exact cellular source of IL‐1. IL‐1 mRNA occurred in the zona reticularis in 17α‐hydroxyiase positive steroid cells surrounding the adrenomedullary cells. Some CD68+ macrophages in this zona showed a positive signal. A weak signal was seen to IL‐1 mRNA in few chromaffin cells, while IL‐1‐like immunoreactivity was more frequent. We conclude that in the normal situation in man IL‐1 is mainly expressed in specialized cortical cells. The occurrence of the major glucocorticoid inducing factor in the normal human adrenal gland itself provides evidence for an autocrine or paracrine reaction under physiological conditions.

The Effect of Temperature and Humidity Levels in a Protective Mask on User Acceptability During Exercise

Subjective and physiological responses were obtained from six subjects wearing a ventilated face mask while exercising (3.8 met) for 15 min on a bicycle ergometer. Different combinations of ambient air temperatures (7 degrees, 16 degrees, 25 degrees C) and mask air temperatures (22 degrees, 27 degrees, 33 degrees C) were studied together with two different air humidities inside the mask (61% and 86% RH). Control experiments were performed without the mask at the same ambient temperatures. Skin temperatures, heart rates and skin wettedness were monitored during exercise. The subjects acceptance of the mask and thermal environment, thermal sensation, sensations of discomfort, sweating and skin wettedness, and their judgment of the work of breathing were assessed at the end of the 15 min exercise period. The acceptance of both the ambient thermal environment and of the thermal microclimate in the mask primarily was determined by the ambient air temperature, but it was influenced by the air temperature and humidity inside the mask. At ambient temperatures of 7 degrees C and 25 degrees C, the acceptance of the thermal work conditions decreased. In the warm environment a mask air temperature less than or equal to 27 degrees C was 100% acceptable and increased the acceptance of thermal environment. In the cool environment, a mask air temperature greater than or equal to 27 degrees C was 100% acceptable. The humidity content of the mask air was only important when the mask air was warm. Warm humid air significantly decreased acceptance of the mask conditions.

Mechanisms of interleukin-1-induced hormone secretion from the rat adrenal gland.

The aim of these studies was to determine the intraadrenal mechanism of interleukin-1 (IL-1)-induced corticosterone release from the rat adrenal gland. To accomplish this, the role of catecholamines and eicosanoids on IL-1-induced corticosterone release was determined. Experiments were conducted on primary cultures of dispersed rat adrenal cells. Dose-dependent increases (P < 0.05) in corticosterone concentration were observed when primary adrenal cells were incubated with different doses (10(-10) to 10(-8) M) of IL-1 alpha. IL-1 alpha and IL-1 beta elevated corticosterone release after a 24 hr incubation period. ACTH elevated corticosterone levels at 4 and 24 hr. The stimulatory effect of IL-1 on corticosterone release was mimicked by epinephrine (1 microM), and was selectively blocked by the alpha-adrenergic antagonist, phentolamine (10 microM). The beta-adrenergic antagonist, propranolol (10 microM), did not change IL-1 induced corticosterone release. Neither phentolamine nor propranolol had an effect on ACTH stimulated corticosterone release. Both IL-1 alpha and IL-1 beta significantly elevated (P < 0.05) epinephrine levels after a 24 hr incubation period compared to media-treated controls. Untreated adrenal cells fixed for immunohistochemical staining with a specific anti-rat tyrosine hydroxylase antibody indicate that the primary adrenal cell preparation contained 3.1 +/- 0.45% tyrosine hydroxylase positive cells. On the ultrastructural level, the chromaffin cells were found to be in direct cellular contact with cortical cells. Although IL-1 alpha significantly increased (P < 0.05) prostaglandin E2 (PGE2) levels from primary adrenal cells, the presence of the cyclooxygenase inhibitor, indomethacin (10 microM) significantly inhibited IL-1 alpha-induced PGE2 secretion without altering the effect of IL-1 alpha on corticosterone release. Inhibitors of the lipoxygenase system (5-lipoxygenase, 10 microM) and the lipoxygenase and cytochrome P450 monooxygenase systems (nordihydroguaiaretic acid, 10 microM) did not effect IL-1 alpha-induced corticosterone or PGE2 release. These observations indicate that IL-1 stimulates the local release of catecholamines, which, in turn, stimulates corticosterone release through an alpha-adrenergic receptor; this mechanism is independent of PGE2.

Evaporative water losses through a temporary wound dressing under simulated wound conditions.

Patients with burns lose large amounts of water through evaporation from open wounds. Because the wound covering is the first line of defense for maintenance of body fluid balance in these patients, quantification of the evaporative water loss through wound coverings at the bedside would improve the accuracy of estimations of body water loss. The present experiment evaluates the use of a small ventilated capsule system automated with miniature resistance-type dew-point sensors for measurement of evaporative water loss through biologic dressings under simulated wound conditions. Evaporative water loss from wounds was simulated by pilocarpine-induced profuse sweating on the forearm. Evaporative water loss through uncovered skin was compared with that of skin covered with commercially available temporary wound dressings. Compared with an adjacent unstimulated area, forearm dew-point temperature in the capsule (Tcdp) and sweat rate increased immediately after pilocarpine exposure and remained significantly elevated and relatively constant for an additional 60 minutes. Evaporative water loss of the forearm was 29 +/- 4.8 gm/m2/hr (mean +/- SE) at baseline and rose significantly to 275 +/- 18.2 gm/m2/hr after pilocarpine exposure. The pilocarpine-stimulated sweat rate and Tcdp at neutral conditions were similar to those obtained from walking on a treadmill for 60 minutes in a 30 degrees C room. Compared with pilocarpine-induced evaporative water loss of the uncovered skin, temporary wound dressings significantly reduced evaporative water loss by 40% to 60%. No significant differences were observed between varieties of temporary wound dressings differing in thickness and/or porosity.(ABSTRACT TRUNCATED AT 250 WORDS)

The burden of familial chylomicronemia syndrome from the patients’ perspective

ABSTRACT Background: Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by high levels of plasma triglycerides and chylomicrons, which may cause life-threatening acute pancreatitis. Currently no FDA-approved treatment exists. Management is low-fat diet (<20g fat/day), which is difficult to maintain. With the restricted diet, triglycerides may remain elevated. We conducted discussions with patients and caregivers to better understand the burden of FCS from their perspectives. Methods: A panel of FCS patients and caregivers was assembled to discuss and assess the clinical and psychosocial burden of FCS. Results: Ten adults with FCS (median age 48 yr) and their spouses/caregivers were asked specific questions about their experiences living with FCS. Patients with FCS stated their symptoms were abdominal pain, nausea, diarrhea, constipation, bloating, and fatigue. Patients reported a median of 34 episodes of acute pancreatitis over their lifetimes; half of these led to hospitalizations, each with an average stay of 6.5 days. The psychosocial burden of FCS was primarily associated with the restricted diet, anxiety and stress of FCS. Conclusions: Living with FCS imposes a significant clinical and psychosocial burden on patients and caregivers, who reported reduced quality of life, limited employment opportunities, socialization and increased burden on family.

Effect of low and high doses of nitrous oxide on preproenkephalin mRNA and its peptide methionine enkephalin levels in the hypothalamus

The effect of exposure to nitrous oxide (N2O) on the levels of preproenkephalin mRNA in the hypothalamus of rats was examined. In the first experiment, rats were exposed to 1000 ppm N2O for 8 h a day over 4 days. Compared with controls (which were exposed to air over the same duration), the N2O exposed animals exhibited significant elevations in preproenkephalin mRNA levels in the hypothalamus. In a second experiment, rats were exposed to 60% N2O or air for 12, 24 and 48 h duration, and hypothalamic levels of preproenkephalin mRNA as well as methionine enkephalin were analyzed. Compared with controls, N2O exposed rats exhibited significant elevations in preproenkephalin mRNA levels. The levels on preproenkephalin mRNA were significantly higher after 48 h of N2O exposure than after 12 h of N2O exposure. Similarly, the concentration of methionine enkephalin was significantly higher after 24 and 48 h of exposure of N2O than after exposure to 12 h of N2O or air. These results indicate that (a) exposure to N2O results in significant elevations in preproenkephalin mRNA levels, (b) the increased preproenkephalin mRNA levels appear to be proportional to the concentration of N2O exposure as well as the duration of N2O exposure, and (c) N2O-induced elevation in preproenkephalin mRNA levels is associated with corresponding increase in tissue concentrations of methionine enkephalin. In total, these results suggest that N2O selectively stimulates synthesis of methionine enkephalin in the diencephalic region of the brain.

Evaluating the impact of peer support and connection on the quality of life of patients with familial chylomicronemia syndrome

ABSTRACT Background: Familial chylomicronemia syndrome (FCS) is a disease caused by impaired lipoprotein lipase function and characterized by chylomicronemia, reduced quality of life (QoL) and risk of pancreatitis. The aim of the current study is to assess if QoL can be improved by patients being connected to other patients. Methods: Respondents (N = 50) categorized into 3 groups (actively connected, passively connected and non-connected) self-reported their current or comparative assessments of QoL before and after connection with FCS-focused support organizations using a customized retrospective web-based survey. Results: Connected respondents showed significantly improved perceptions of overall health, disease severity, motivation to take care of health and emotional well-being (p ≤ 0.05). Any level of connection produced noticeable benefits, but active connection in the form of regular interaction with other patients reported the greatest improvements. Additionally, respondents reported higher levels of satisfaction with their primary treating physician after being connected. The majority of patients (62%) reported joining support groups following referrals from their physicians. Conclusions: Similar to other disease states, connecting with other patients with FCS had a positive impact on aspects of quality of life. Physicians may play a central role in referring their patients with FCS to support groups.