Frostbite: a treatment guideline for prehospital treatment in a military environment.

Frostbite remains a severe medical condition that causes long-lasting sequelae and can threaten military operations. Information on prehospital treatment of frostbite is scarce and existing guidelines are aimed at the general population.This paper provides a guideline on prehospital emergency care of frostbite in the (Netherlands) Armed Forces. The insights gained from studies reporting on frostbite treatment in the prehospital setting were combined with the expert opinions of the authors and applied to the military context. The resulting guideline consists of two stages: (prolonged) field care and care at a Medical Treatment Facility. The cornerstones are rewarming in warm water and evacuation to a medical facility. Additional aspects of prehospital treatment are rehydration, proper analgesia, non-steroidal anti-inflammatory drugs and wound care.We suggest further collaboration among North Atlantic Treaty Organization partners and other affiliated nations, focusing on the full spectrum of military injury management including state-of-the-art aftercare, long-lasting sequelae and return to duty after frostbite.

Frostbite: a systematic review on freezing cold injuries in a military environment.

BACKGROUND: Military practice or deployment in extreme conditions includes risks, dangers and rare disorders. One of the challenges is frostbite; however, current literature does not provide an overview of this condition in a military context. This review aims to map the incidence, risk factors and outcome of frostbite in military casualties in the armed forces. METHODS: A systematic literature search on frostbite (freezing cold injuries) in military settings from 1995 to the present was performed. A critical appraisal of the included articles was conducted. Data on incidence, risk factors, treatment and outcome were extracted. RESULTS: Fourteen studies were included in our systematic review. Most studies of frostbite in a military setting were published nearly half a century ago. Frostbite incidence has declined from 7% to around 1% in armed forces in arctic regions but could be as high as 20% in small-scale arctic manoeuvres. Overall and military-specific risk factors for contracting frostbite were identified. CONCLUSION: During inevitable arctic manoeuvres, frostbite is a frequently diagnosed injury in service members. Postfreezing symptoms often persist after severe frostbite injury, which decreases employability within the service. Over time, military practice has changed considerably, and modern protective materials have been introduced; therefore, re-evaluation and future study in the military field are appropriate, preferably with other North Atlantic Treaty Organization partners.

Effects of repeated freeze-thaw cycles on endocrine parameters in plasma and serum.

Background Repeated freezing and thawing of plasma (or serum) may influence the stability of plasma (or serum) constituents. Despite the alarming warnings from commercial manuals that freeze-thaw cycles affect the stability of hormones in plasma (or serum), surprisingly little, consistent information about this concept is available in literature. Methods We studied the stability of 15 endocrine parameters (adrenocorticotropic hormone, osteocalcin, plasma renin activity, α-subunits, cortisol binding globulin, glucagon, inhibin B, fT4, TT4, TT3, rT3, TBG, TSH, chromogranin A and thyroglobulin upon repeated freeze-thaw cycles in plasma (or serum) samples from 10 volunteers. Blood was collected by venipuncture and after centrifugation and aliquoting, all samples were frozen at -20℃. Aliquots were thawed up to four times and changes in concentrations of endocrine parameters were compared to baseline condition. Results Repeated freeze-thaw cycling resulted in significant and relevant increases of plasma renin activity and a small decrease of adrenocorticotropic hormone. Conclusions For most of the analysed endocrine parameters, we found no effects of multiple freeze-thaw cycles despite alarming notifications in assay manuals. Plasma renin activity was the only endocrine parameter that showed significant and relevant changes following repeated freeze-thaw cycling.

Rapid effects of deep brain stimulation reactivation on symptoms and neuroendocrine parameters in obsessive-compulsive disorder.

Improvement of obsessions and compulsions by deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) is often preceded by a rapid and transient mood elevation (hypomania). In a previous study we showed that improvement of mood by DBS for OCD is associated with a decreased activity of the hypothalamus-pituitary adrenal axis. The aim of our present study was to evaluate the time course of rapid clinical changes following DBS reactivation in more detail and to assess their association with additional neuroendocrine parameters. We included therapy-refractory OCD patients treated with DBS (>1 year) and performed a baseline assessment of symptoms, as well as plasma concentrations of thyroid-stimulating hormone (TSH), prolactin, growth hormone, copeptin and homovanillic acid. This was repeated after a 1-week DBS OFF condition. Next, we assessed the rapid effects of DBS reactivation by measuring psychiatric symptom changes using visual analog scales as well as repeated neuroendocrine measures after 30 min, 2 h and 6 h. OCD, anxiety and depressive symptoms markedly increased during the 1-week OFF condition and decreased again to a similar extent already 2 h after DBS reactivation. We found lower plasma prolactin (41% decrease, P=0.003) and TSH (39% decrease, P=0.003) levels during DBS OFF, which increased significantly already 30 min after DBS reactivation. The rapid and simultaneous increase in TSH and prolactin is likely to result from stimulation of hypothalamic thyrotropin-releasing hormone (TRH), which may underlie the commonly observed transient mood elevation following DBS.

Clonidine increases bone resorption in humans.

SUMMARY: Inhibition of sympathetic signaling to bone reduces bone resorption in rodents. In contrast, we show that pharmacological reduction of the sympathetic tone increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct pharmacological effect on the osteoclast. INTRODUCTION: Inhibition of sympathetic signaling to bone reduces bone resorption in rodents. It is uncertain whether a similar role for the sympathetic nervous system exists in humans. The sympathetic tone can be reduced by clonidine, which acts via alpha-2-adrenergic receptors in the brainstem. Our objective was to determine the effect of clonidine on bone turnover in humans. METHODS: The acute effect of a single oral dose of 0.3 mg clonidine on serum bone turnover markers (C-terminal cross-linking telopeptides of collagen type I (CTx), a marker for bone resorption, and procollagen type 1 N propeptide (P1NP), a marker for bone formation) was determined in a randomized crossover design in 12 healthy volunteers, aged 18-70 years. In addition, we assessed the effect of clonidine on the number of tartrate-resistant acid phosphatase-positive multinucleated cells (TRAcP(+) MNCs) and bone resorption. RESULTS: CTx concentrations increased after clonidine treatment compared to the control condition (p = 0.035). P1NP concentrations were not affected by clonidine (p = 0.520). In vitro, clonidine had no effect on the number of TRAcP(+) MNCs (p = 0.513) or on bone resorption (p = 0.996). CONCLUSIONS: We demonstrated that clonidine increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct effect on the osteoclast.

The water deprivation test and a potential role for the arginine vasopressin precursor copeptin to differentiate diabetes insipidus from primary polydipsia.

The water deprivation test is the gold standard test to differentiate central or nephrogenic diabetes insipidus (DI) from primary polydipsia (PP) in patients with polyuria and polydipsia. Few studies have addressed the diagnostic performance of this test. The aim of this retrospective cohort study was to evaluate the diagnostic performance of the standard water deprivation test, including plasma arginine vasopressin (AVP) measurements, in 40 consecutive patients with polyuria. We compared initial test results with the final clinical diagnosis, i.e., no DI, central DI, or nephrogenic DI. The median length of follow-up was 8 years. In a subset of ten patients, the novel marker copeptin (CP) was measured in plasma. Using the final diagnosis as a gold standard, a threshold for urine osmolality of >800 mOsmol/kg after water deprivation yielded a sensitivity and specificity of 96 and 100%, respectively, for diagnosing PP. Sensitivity increased to 100% if the cut-off value for urine osmolality was set at 680 mOsmol/kg. Plasma AVP levels did not differ between patient groups and did not differentiate among central DI, nephrogenic DI, or PP. In all three patients with central DI, plasma CP was <2.5 pmol/l with plasma osmolality >290 mOsmol/kg, and >2.5 pmol/l in patients without DI. The optimal cut-off value for differentiating PP from DI during a water deprivation test was urine osmolality >680 mOsmol/kg. Differentiating between central and nephrogenic DI should be based on clinical judgment as AVP levels did not discriminate.

The effects of beta-2 adrenergic agonist and antagonist on human bone metabolism: a randomized controlled trial.

PURPOSE: Genetic knockout or pharmacological inhibition of the beta-2 adrenergic receptor (B2AR) increased bone mass, whereas stimulation decreased bone mass in rodents. In humans, observational studies support sympathetic nervous system regulation of bone metabolism, but intervention studies are lacking. We aimed to determine the effects of a selective beta-2 adrenergic agonist and non-selective antagonist on human bone metabolism. METHODS: 32 healthy postmenopausal women were included in a randomized controlled trial conducted in the Academic Medical Center Amsterdam. Participants were randomized to receive treatment with 17-ß estradiol 2mg/day; 17-ß estradiol 2mg/day and terbutaline 5mg/day (selective B2AR agonist); propranolol 80mg/day (non-selective B-AR antagonist); or no treatment during 12weeks. Main outcome measure was the change in serum concentrations of procollagen type I N propeptide (P1NP) and C-terminal crosslinking telopeptides of collagen type I (CTx) as markers of bone formation and resorption after 12weeks compared between the treatment groups. Data were analyzed with mixed model analysis. RESULTS: 17-ß estradiol decreased bone turnover compared to control (P1NP p<0.001, CTx p=0.003), but terbutaline combined with 17-ß estradiol failed to increase bone turnover compared to 17-ß estradiol alone (P1NP p=0.135, CTx p=0.406). Propranolol did not affect bone turnover compared to control (P1NP p=0.709, CTx p=0.981). CONCLUSION: Selective beta-2 adrenergic agonists and non-selective beta-antagonists do not affect human bone turnover although we cannot exclude small changes below the detection limit of this study.

The IGSF1 deficiency syndrome: characteristics of male and female patients.

CONTEXT: Ig superfamily member 1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. OBJECTIVE: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes. METHODS: All patients (n = 42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. RESULTS: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. CONCLUSION: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Bone resorption is increased in pheochromocytoma patients and normalizes following adrenalectomy.

CONTEXT: The sympathetic nervous system (SNS) controls bone turnover in rodents, but it is uncertain whether a similar role for the SNS exists in humans. Pheochromocytomas are catecholamine-producing neuroendocrine tumors. Because catecholamines are the neurotransmitters of the SNS, we hypothesized that pheochromocytoma patients have increased bone turnover. OBJECTIVE: Our objective was to compare bone turnover in pheochromocytoma patients and controls. DESIGN AND SETTING: This retrospective case-control study was performed at the Endocrine Department of the Academic Medical Center of the University of Amsterdam in The Netherlands from 2007 until 2011. PATIENTS: All patients were screened for pheochromocytoma. Cases (n = 21) were identified by 24-h urinary excretion of fractionated metanephrines above the institutional reference value and confirmed by histology after adrenalectomy. All patients screened and diagnosed as not having pheochromocytoma served as controls (n = 126). MAIN OUTCOME MEASURE: The difference in bone turnover markers C-terminal cross-linking telopeptides of collagen type I (CTx) and procollagen type 1 N propeptide (P1NP) between cases and controls was the main outcome measure. RESULTS: CTx concentrations were higher in cases [343 ng/liter; interquartile range (IQR), 295 ng/liter] than in controls (232 ng/liter; IQR, 168 ng/liter; P < 0.001) and decreased after adrenalectomy [before, 365 ng/liter (IQR, 450 ng/liter); after, 290 ng/liter (IQR, 241 ng/liter); P = 0.044]. The effect remained after adjustment for possible confounders. P1NP concentrations did not differ. CONCLUSIONS: This study shows that pheochromocytoma patients have increased bone resorption, which normalizes after adrenalectomy. This finding supports the concept of regulation of bone remodeling by the SNS in humans.

Determination of unbound prednisolone, prednisone and cortisol in human serum and saliva by on-line solid-phase extraction liquid chromatography tandem mass spectrometry and potential implications for drug monitoring of prednisolone and prednisone in saliva.

Prednisolone (PLN) and prednisone (PN) are widely used glucocorticoids. Drug monitoring of PLN and PN is not routinely done owing to the need for multiple blood sampling and challenging measurement of unbound PLN and PN in blood. Here we present a robust method for quantification of cortisol, PLN and PN in serum, ultrafiltrate and saliva by on-line solid-phase extraction LC-MS/MS. The method is linear for the three analytes over the range of 6-1400 nmol/L for serum and 2-450 nmol/L for ultrafiltrate and saliva. Within-run precision of all three analytes was <10% and total precision was <15%. This method was applied to create time-concentration profiles of cortisol, PLN and PN after an oral dose of prednisolone in a healthy volunteer. Salivary levels of PLN correlated well with ultrafiltrate levels (p < 0.01), while this correlation was only marginal for PN (p = 0.052). The PN/PLN ratio was significantly higher in saliva than in ultrafiltrate and serum (p < 0.01). Addition sums of both metabolites in saliva showed excellent correlation with those of ultrafiltrate (p < 0.01). These findings have not been presented before and may have important implications for future studies concerning drug monitoring of PLN and PN in saliva.

Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis.

The pronounced daily variation in the release of adrenal hormones has been at the heart of the deciphering and understanding of the circadian timing system. Indeed, the first demonstration of an endocrine day/night rhythm was provided by Pincus (1943), by showing a daily pattern of 17-keto-steroid excretion in the urine of 7 healthy males. Twenty years later the adrenal gland was one of the very first organs to show, in vitro, that circadian rhythmicity was maintained. In the seventies, experimental manipulation of the daily corticosterone rhythm served as evidence for the identification of respectively the light- and food-entrainable oscillator. Another 20 years later the hypothalamo-pituitary-adrenal (HPA)-axis was key in furthering our understanding of the way in which rhythmic signals generated by the central pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) are forwarded to the rest of the brain and to the organism as a whole. To date, the adrenal gland is still of prime importance for understanding how the oscillations of clock genes in peripheral tissues result in functional rhythms of these tissues, whereas it has become even more evident that adrenal glucocorticoids are key in the resetting of the circadian system after a phase-shift. The HPA-axis thus still is an excellent model for studying the transmission of circadian information in the body.

Determination of thyroid hormones and their metabolites in tissue using SPE UPLC-tandem MS.

A solid-phase liquid chromatography tandem mass spectrometry (SPE LC-MS/MS) method was developed to determine thyroid hormones and their metabolites in tissue samples. The separation was achieved using reversed-phase ultra-performance liquid chromatography (UPLC); the mass spectrometric detection was achieved by positive electrospray ionization and multiple reaction monitoring. Prior to the UPLC separation a sample cleanup with a cation exchange was performed. ¹³C6 labeled internal standards were used for the thyroid hormones and their metabolites. The method was linear over a range from 0.23 to 90 nmol/L for thyroxine and from 0.23 to 9 nmol/L for the metabolites. The lower limit of quantification ranged from 0.98 to 1.73 pg on column. Intra- and total assay variation were <10 and <15%, respectively. This method enables us to link thyroid hormone tissue concentrations to local iodothyronine deiodinase expressions, which will enhance our understanding of the regulation of thyroid hormone metabolism on the tissue level.

Familial neurohypophyseal diabetes insipidus due to a novel mutation in the arginine vasopressin-neurophysin II gene.

BACKGROUND: Familial neurohypophyseal (central) diabetes insipidus (DI) is caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. The majority of cases is inherited in an autosomal dominant way. In this study, we present the clinical features of a mother and her son with autosomal dominant neurohypophyseal DI caused by a novel mutation. CASE: A thirty-four-year-old woman and her three-year-old son were evaluated because of polyuria and polydipsia since the age of 1.5 years onwards. Both patients were subjected to a water deprivation test confirming the diagnosis of central DI. Magnetic resonance imaging of the brain of the mother showed a hypothalamus without apparent abnormalities and a relatively small neurohypophysis without a hyperintense signal. Mutation analysis showed a c.322G>T (p.?/p.Glu108X) in Exon 2 of the AVP-NPII gene in both mother and son. DISCUSSION: This study reports neurohypophyseal DI in a mother and her son due to a novel mutation in Exon 2 of the AVP-NPII gene. Clinical and pathophysiological aspects of this disease are shortly reviewed and discussed.

Interference by antiruthenium antibodies in the Roche thyroid-stimulating hormone assay.

There are many causes of interference in immunoassays causing erratic patient results. A method-specific interference due to antiruthenium antibodies in Roche free thyroxine (fT4) and free triiodothyronine (fT3) assays has been described previously. As a result, a new generation fT4 assay has been introduced by Roche. We describe six cases of interference due to antiruthenium antibodies, where in four cases interference in the Roche thyroid-stimulating hormone (TSH) assay was found as well. This raised the question as to whether other assays on this platform would also give incorrect results in patients with antiruthenium antibodies. Interference due to antiruthenium antibodies was suspected because of discrepancies between clinical presentation and/or TSH, fT4 and fT3 results. Samples of these six patients were re-analysed in Roche Diagnostics Laboratory, where it was demonstrated that the found discrepancies were indeed caused by interfering antiruthenium antibodies. Subsequently, these patients were asked to donate some blood once more for further evaluation, and three subjects agreed to participate. Their plasma was used to assay 18 analytes on Modular E and on a ruthenium-independent platform. The results were compared taking into account the known differences between distinct methods. As expected, significant interference was found in TSH. Also, in the new generation fT4 assay, ruthenium-induced interference was still present. However, the other assays, both competitive and immunometric, did not show clear interference. We therefore conclude that although antiruthenium antibodies theoretically can interfere in all assays on the Modular E platform, this kind of interference is found in the thyroid hormone assays, without marked interference in the other assays.

An online solid-phase extraction-liquid chromatography-tandem mass spectrometry method to study the presence of thyronamines in plasma and tissue and their putative conversion from 13C6-thyroxine.

Thyronamines are exciting new players at the crossroads of thyroidology and metabolism. Here, we report the development of a method to measure 3-iodothyronamine (T(1)AM) and thyronamine (T(0)AM) in plasma and tissue samples. The detection limit of the method was 0.25 nmol/l in plasma and 0.30 pmol/g in tissue both for T(1)AM and for T(0)AM. Using this method, we were able to demonstrate T(1)AM and T(0)AM in plasma and liver from rats treated with synthetic thyronamines. Although we demonstrated the in vivo conversion of (13)C(6)-thyroxine ((13)C(6)-T(4)) to (13)C(6)-3,5,3'-triiodothyronine, we did not detect (13)C(6)-T(1)AM in plasma or brain samples of rats treated with (13)C(6)-T(4). Surprisingly, our method did not detect any endogenous T(1)AM or T(0)AM in plasma from vehicle-treated rats, nor in human plasma or thyroid tissue. Although we are cautious to draw general conclusions from these negative findings and in spite of the fact that insufficient sensitivity of the method related to extractability and stability of T(0)AM cannot be completely excluded at this point, our findings raise questions on the biosynthetic pathways and concentrations of endogenous T(1)AM and T(0)AM.

Evaluation of endocrine tests. D: the prolonged fasting test for insulinoma.

OBJECTIVE: To establish the diagnostic performance of the prolonged fasting test in patients suspected of insulinoma. METHODS: We included all patients who were referred to our department between August 1995 and August 2006 with a clinical suspicion of insulinoma. Insulinoma was diagnosed by a positive Whipple's triad during the prolonged fast in combination with an insulin/C-peptide ratio below 1. The presence of insulinoma was confirmed by histopathological data, which was considered the golden standard. If the prolonged fast was negative, long-term follow-up was obtained. RESULTS: Ten patients had a positive Whipple's triad during the prolonged fast: eight had a histologically proven insulinoma, and two had factitious hypoglycaemia (insulin/C-peptide ratio >1.0) One additional patient likely had an insulinoma, but the Whipple's triad remained absent at up to 56 hours of fasting. Follow-up (median 53 months (3 to 142) in 76% of patients with a negative fasting test revealed no missed cases of insulinoma. During the prolonged fast the glucose, insulin and C-peptide concentrations overlapped in patients with and without insulinoma. CONCLUSION: In our centre, the prolonged fasting test defined as a positive Whipple's triad in combination with an insulin/C-peptide ratio <1 had a sensitivity of 88.9% and a specificity of 100% for the diagnosis of insulinoma.

Establishment of reference values for endocrine tests. Part VII: growth hormone deficiency.

BACKGROUND: Plasma insulin-like growth factor (IGF-I) concentration can be used as a rough indicator of the growth-hormone status. However, for the diagnosis of growth hormone deficiency, dynamic tests are required. The growth hormone (GH) response in the insulin tolerance test (ITT) is considered to be the gold standard in this respect. An alternative for the ITT is the GHRH/ GHRP-6 test, which has fewer side effects. In this study we established reference values for IGF-I levels and for the GH response in both dynamic tests. METHODS: We studied 296 subjects recruited from the general population, equally distributed according to sex and aged between 20 and 70 years. Serum IGF-I level was measured in all subjects and an insulin tolerance test (0.15 U/kg Actrapid iv) and GHRH/GHRP-6 test (1 microg GHRH/kg and 1 microg GHRP-6/kg) were performed in 49 subjects. RESULTS: In multivariate analyses both IGF-I and the GH response in the ITT were significantly influenced by age, whereas the GH response in the GHRH/GHRP-6 test was significantly affected by BMI. There was no sex difference in IGF-I and in the GHRH/GHRP-6 test, but in the ITT males had a higher GH peak. There was a significant correlation between the GH responses in both tests, and the GH response was significantly higher in the GHRH/GHRP-6 test than in the ITT. Age-adjusted reference values were established for each test. CONCLUSION: We have established age-adjusted reference values for serum IGF-I and for the GH response in the ITT and GHRH/GHRP-6 test.

Evaluation of Endocrine Tests. C: glucagon and clonidine test in phaeochromocytoma.

BACKGROUND: The diagnosis of phaeochromocytoma is based on the demonstration of catecholamine excess. Urine and plasma metanephrine measurements are highly sensitive tests for the diagnosis of phaeochromocytoma, but moderate elevations in metanephrines lack optimal specificity. In this study we aimed to evaluate the diagnostic value of additional tests, i.e. glucagon stimulation and clonidine suppression test, in patients with moderately elevated catecholamines and/or metanephrines. METHODS: Patients with suspected phaeochromocytoma with moderately elevated catecholamines and/or metanephrines in plasma or urine were subjected to the glucagon stimulation and clonidine suppression test. The presence of phaeochromocytoma was confirmed by histology and the absence by a disease-free extended follow-up. RESULTS: Fifty-five patients were included. Phaeochromocytoma was diagnosed in 11 patients. The follow-up period in patients without phaeochromocytoma was 56 (19 to 154) months. The sensitivity of the glucagon test was 30% and the specificity 100%. The clonidine test had no discriminative power, because the area under the ROC curve was not significantly different from 0.5. CONCLUSION: The clonidine suppression test without normetanephrine measurements and the glucagon stimulation test are not sensitive enough to safely exclude phaeochromocytoma in patients with mildly elevated plasma or urine catecholamines.

Plasma insulin concentrations during a hyperinsulinaemic clamp: what do we measure?

BACKGROUND: The aim of this study is to compare the performance of three commonly used insulin assays with respect to the detection of exogenous human and porcine insulin added to human or rat plasma. METHODS: The DPC Immulite human insulin assay, the Mercodia rat insulin enzyme-linked immunosorbent assay and the Linco rat insulin radioimmunoassay were tested. RESULTS: The mean cross-reactivity of exogenous insulin ranged from 25% to 92%. The mean cross-reactivity of Actrapid in human plasma on the DPC Immulite was 56% and was independent of the endogenous insulin concentration. CONCLUSIONS: The measurement of exogenous insulin varies according to the source of exogenous insulin, matrix and insulin assay.

Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels.

Type I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T(3), elevated rT(3), normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24 h) was not correlated with circulating levels of T(3), rT(3) or fT(4). Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT(4) levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT(4) and T(3).