Effect of different head and neck positions on behaviour, heart rate variability and cortisol levels in lunged Royal Dutch Sport horses.

Different head-and-neck positions (HNPs) are discussed in relation to potential welfare issues. To evaluate the effect on welfare, seven Royal Dutch Sport horses were studied in five predetermined HNPs: (1) unrestrained (HNP1); (2) neck raised, bridge of nose around the vertical (HNP2); (3) neck lowered and considerably flexed, bridge of nose pointing towards the chest (HNP4); (4) neck raised and extended, bridge of nose in front of the vertical (HNP5), and (5) neck lowered and flexed, bridge of nose pointing towards the carpus (HNP7). A standardised exercise test (SET) of 34 min consisted of trot, canter and walk. Behaviour was recorded with a pre-defined ethogram and R-R intervals measured using telemetry. Cortisol concentrations were taken at the start, 5 and 30 min after the SET. Behaviour around the SET was scored separately. Conflict behaviours increased significantly during HNP2 when compared with HNP1, HNP4 and HNP7 during the SET, and there was significant negative anticipation before HNP2 and HNP7. The heart rate variability (HRV) frequency domain for HNP2 showed a significantly increased low frequency peak (LFpeak) compared with other HNPs, and there was a decrease in very low frequency (VLF%) compared with HNP1. HNP4 showed a significant increase in LF% and decrease in VLF% compared with HNP1. Saliva cortisol concentrations were significantly increased in HNP2 at 5 and 30 min after exercise. Increased conflict behaviour was mostly observed in HNP2, but there was a raised HRV suggesting a sympathetic shift in HNP2 and HNP4, and increased cortisol concentrations during HNP2 indicated a stress response.

Gonadal function in male and female patients with classic galactosemia.

BACKGROUND: Hypergonadotropic hypoestrogenic infertility is the most burdensome complication for females suffering from classic galactosemia. In contrast, male gonadal function seems less affected. The underlying mechanism is not understood and several pathogenic mechanisms have been proposed. Timing of the lesion, prenatal or chronic post-natal, or a combination of both are not yet clear. METHODS: This review focuses on gonadal function in males and females, ovarian imaging and histology in this disease. It is based on the literature known to the authors and a Pubmed search using the keywords galactosemia, GALT deficiency, (premature) ovarian failure/insufficiency/dysfunction, testicular function, gonadotrophins, FSH, LH (published between January 1971 and April 2009). RESULTS: Male gonads are less affected, boys spontaneously reach puberty, although onset can be delayed. Semen quality has not been extensively studied. Several affected males are known to have fathered a child. Female gonads are invariably affected, although to a varied extent (hypergonadotropic hypoestrogenic ovarian dysfunction). Intriguingly, FSH is often already increased in infancy. Imaging usually shows hypoplastic and streak-like ovaries. Histological findings in some cases reveal the presence of morphologically normal but decreased numbers of primordial follicles, with the absence of intermediate and Graafian follicles. CONCLUSION: Gonads in males seem less affected than in females who exhibit hypergonadotropic hypoestrogenic subfertility. FSH can be elevated in infancy, and ovarian histology sometimes shows the presence of normal primordial follicles with absence of intermediate and Graafian follicles. These findings are similar to other genetic diseases primarily affecting the ovary.

Overtrained horses alter their resting pulsatile growth hormone secretion.

The influence of intensified and reduced training on nocturnal growth hormone (GH) secretion and elimination dynamics was studied in young (1.5 yr) Standardbred geldings to detect potential markers indicative for early overtraining. Ten horses trained on a treadmill for 32 wk in age-, breed-, and gender-matched fixed pairs. Training was divided into four phases (4, 18, 6, and 4 wk, respectively): 1) habituation to high-speed treadmill trotting, 2) normal training, in which speed and duration of training sessions were gradually increased, 3) in this phase, the horses were divided into 2 groups: control (C) and intensified trained (IT) group. In IT, training intensity, duration, and frequency were further increased, whereas in control these remained unaltered, and 4) reduced training (RT). At the end of phases 2, 3, and 4, blood was sampled overnight every 5 min for 8 h for assessment of GH secretory dynamics using pulse detection, deconvolution analysis, and approximate entropy (ApEn). Intensified training induced overtraining (performance decreased by 19% compared with C), which was associated with an increase in concentration peaks number (3.6 vs. 2.0, respectively), a smaller peak secretion pattern with a prolonged half-life (15.2 vs. 7.3 min, respectively), and an increased ApEn (0.89 vs. 0.49, respectively). RT did not lead to full recovery for the overtrained horses. The increased irregularity of nocturnal GH pulsatility pattern is indicative of a loss of coordinated control of GH regulation. Longer phases of somatostatin withdrawal are hypothesized to be the underlying mechanism for the observed changes in GH pulsatility pattern.

The endocrine system in treated patients with classical galactosemia.

Endocrine abnormalities in classical galactosemia, female hypergonadotropic hypogonadism and low thyroxin in neonates, have been reported. Galactosemia is a secondary glycosylation disorder and hypoglycosylation of glycoproteins has a role in this dysfunction. Hypoglycosylation, improves but does not completely disappear with dietary treatment. Our aim was to evaluate the endocrine system in treated patients (n = 37, 25 females, 12 males, age 5-19 years). Endocrine determinations were compared to age and gender matched reference ranges. Sample t-test (to test differences with reference population) and linear regression analysis between hGH (growth hormone), IGF-1 (insulin-like growth factor), IGFBP-3 (insulin growth factor binding protein), FSH (follicle stimulating hormone), LH (luteinizing hormone) and GALT activity, and soy intake, was carried out. Mean IGF-1 Z-score was -0.98 +/- 0.84 (range -2.59 to 1.21) (P < 0.001) in females and 0.03 +/- 0.55 (range -1.0 to 0.89) (P = 0.84) in males. Mean IGFBP-3 Z-score was -0.98 +/- 1.3 (range -3.0 to 2.0) (P < 0.001) in females and 0.26 +/- 0.93 (range -0.94 to 2.0) (P = 0.35) in males. IGF-1 and IGFBP-3 were positively correlated (P < 0.001). IGF-1 or IGFBP-3 Z-scores and age, hGH, estradiol, GALT activity or soy intake were not correlated. FSH was elevated in females, other axes were normal. Besides the hypergonadotropic hypogonadism in females, IGF-1 and IGFBP-3 are in the low to normal ranges in girls. Hypoglycosylation in galactosemia is diet dependent and could worsen when galactose intake increases either because of poor compliance or diet liberalization.

Tibolone and metabolites induce prolactin production in human endometrial stromal cells in vitro: evidence for cell-specific metabolism.

In this study, we assessed the effects of tibolone and its metabolites on the production of a progesterone sensitive parameter, prolactin, in human endometrium stroma cells in vitro. In addition, the metabolism of the compounds by isolated stromal and epithelial cells was evaluated. The reference compounds, progesterone, Org 2058, and DHT all induced prolactin production. Oestradiol also slightly induced prolactin production and enhanced the response to Org 2058. Tibolone and Delta4-tibolone were similar with regard to potency to induce prolactin levels in the culture supernatant. Their potency was lower than that of Org 2058, similar to that of progesterone and higher than that of DHT. The efficacies of tibolone, Delta4-tibolone and Org 2058 were similar (approximately 200-fold induction). The estrogenic tibolone metabolites 3alpha- and 3beta-OH tibolone also significantly stimulated prolactin production. Their potency, however, was low since significance was reached only at the highest concentrations tested. The PR antagonist Org 31710 inhibited both tibolone- and Delta4-tibolone-induced prolactin production. The responses of tibolone and Delta4-tibolone were not affected by co-incubation with the androgen receptor antagonist OH-flutamide. The effect of tibolone, but not Delta4-tibolone, was antagonized approximately 50% in combination with the highest dose (1 microM) estrogen receptor antagonist, ICI 164384. The induction of prolactin by 3alpha- and 3beta-OH tibolone was antagonized most potently by Org 31710, but also by ICI 164384 and OH-flutamide. Tibolone is metabolized differently in epithelial and stromal cells of the human endometrium. The epithelial cells mostly produce the progestagenic/androgenic Delta4-tibolone. The stromal cells produce predominantly the 3beta-OH tibolone, and some Delta4-tibolone, but the net effect observed with regard to prolactin production is progestagenic. When the metabolites 3alpha-OH, 3beta-OH, and Delta4-tibolone were added to the cultures no conversions were observed. The HPLC analyses showed no evidence for the production of sulfated metabolites. In conclusion, the net effects on endometrial stromal cells are predominantly progestagenic. Tibolone is converted by epithelial cells into Delta4-tibolone which displays progestagenic and androgenic activities, whereas in stromal cells also the estrogenic metabolites 3alpha- and 3beta-OH tibolone are formed.

Bone metabolism in galactosemia.

Classical galactosemia is an autosomal recessively inherited disorder of galactose metabolism. Treatment consists of life-long dietary restriction of galactose. Despite treatment, long-term complications occur such as a decreased bone mineral density (BMD). A decreased BMD might be the result of either dietary deficiencies secondary to the galactose-restricted diet or unknown intrinsic factors. In this study, 40 children with classical galactosemia (13 males and 27 females, aged 3-17 years) on dietary treatment were included to gain insight in the bone metabolism of galactosemics. We found weight and height Z scores significantly decreased in galactosemics. Mean areal BMD Z scores of lumbar spine and of femoral neck as measured by Dual energy X-ray Absorptiometry (DXA) were -0.6 (P < 0.001) and -0.3 (P = 0.066), respectively. Mean volumetric BMD of the femoral neck was significant lower in galactosemics (P < 0.001). The recommended dietary allowances (RDA) for calcium, magnesium, zinc, vitamin D, and protein were met in all patients. Mean serum levels of calcium, phosphate, magnesium, zinc, 1,25-dihydroxy vitamin D (1,25OHD), parathormone (PTH), 17-beta estradiol, bone alkaline phosphatase (BAP), and under-carboxylated osteocalcin (ucOC) were normal. Serum levels of IGF-1 Z score, carboxylated osteocalcin (cOC), N-terminal telopeptide (NTX), and C-terminal telopeptide (CTX) were significantly lower in galactosemics than in control subjects. The different bone markers were strongly correlated. The low levels of IGF-1 Z score, formation marker cOC, and resorption markers NTX and CTX suggest a decreased bone metabolism in galactosemics.

Determinants of neonatal IgE level: parity, maternal age, birth season and perinatal essential fatty acid status in infants of atopic mothers.

OBJECTIVE: The hygiene hypothesis suggests that the protective 'siblings effect' against atopic diseases such as atopic dermatitis, allergic asthma and hay fever is a result of recurrent infections during early childhood. A recent study and review have indicated that this protective effect may already arise in utero. Lower n-3 essential fatty acid (EFA) status is associated with increased parity, and EFA status has also been related to atopy. The present study confirms the negative association between parity and neonatal immunoglobulin E (IgE) levels and further unravel the role of perinatal EFA status. METHODOLOGY: In a prospective cohort study in 184 atopic mothers and their neonates, we simultaneously measured serum total IgE and EFA levels in plasma phospholipids, both in the mother at 34-36 weeks of gestation and in the neonate at the age of 1 week. Linear regression analysis was used to estimate the effect of parity on maternal and neonatal IgE and EFA status, and the independent effects of parity and EFA status on IgE, controlling for confounding factors such as maternal age and birth season. RESULTS: Parity was associated with lower neonatal IgE level (P < 0.01), as well as with lower docosahexanoic acid (DHA, 22:6n-3) status of the mother (P = 0.01) but not of the neonate (P > 0.69). In the multivariate analysis, higher parity, higher maternal IgE, lower maternal age and birth in the first 3 months of the year were independently associated with neonatal IgE level. No association was detected between maternal or neonatal EFA status and neonatal IgE. CONCLUSIONS: As neonatal total serum IgE is predictive of later atopy, our results support the hypothesis that the sibling effect in atopy is already being programmed in utero. Our data also confirm earlier findings that DHA status is lower in multiparous women, but this did not confound the relation between parity and neonatal IgE.

Thyroid function, depressed mood, and cognitive performance in older individuals: the Maastricht Aging Study.

The hypothesis was tested that thyroid function, as indicated by serum thyroid-stimulating hormone (TSH) level, is associated with cognitive performance in a healthy aging population. In a random sample of 120 participants recruited from the Maastricht Aging Study (MAAS), aged between 49 and 71 years, we assessed TSH level, mood state (Symptom Check List, subscale depression), and three domains of cognitive function: verbal memory, general sensorimotor speed, and complex flexibility. After correction for age, sex, and educational level, a negative association between TSH and memory function was apparent: higher levels of TSH predicted lower levels of memory performance. Exclusion of individuals with TSH levels suspect for thyroid disorder (n=2) or who were on thyroid replacement (n=3) attenuated this association. Furthermore, additional control for mood status reduced the association below the significance level. No interaction between age and TSH on cognition was found, which indicated that the TSH-memory association was independent of age group level. We conclude that the association between TSH level and memory performance was small and dependent on mood status and the presence of (possible) thyroid disease in this relatively healthy population based sample. Prospective studies are needed to address the role of thyroid function in age-related cognitive decline.

Olfactory function after mild traumatic brain injury.

OBJECTIVE: The aim of this study was to determine the incidence of olfactory dysfunction after mild traumatic brain injury (MTBI). Damage to the olfactory bulbs or frontal cortex has been reported in MTBI, but olfactory dysfunction after MTBI has not been studied in a prospective way before. DESIGN: Patients with first-time MTBI were included. Patients' olfactory threshold values (Hyposmia Utility Kit by Olfacto-Labs) were measured 2 weeks after the trauma. Associations between olfactory threshold values and individual symptoms and S-100B and NSE concentrations were examined, using multiple linear regression analysis, adjusting for the influence of age. RESULTS: Twenty-two per cent of 111 included patients had hyposmia and 4% had anosmia. Thresholds at 2 weeks showed no significant associations with the presence of symptoms at the ER, nor with early concentrations of S-100B or NSE. CONCLUSIONS: Although a high prevalence of olfactory dysfunction was found, no correlation was found between olfactory dysfunction and acute parameters of MTBI.

Prediction of post-traumatic complaints after mild traumatic brain injury: early symptoms and biochemical markers.

OBJECTIVES: To identify parameters at first presentation after mild traumatic brain injury (MTBI) that are predictive of the severity of post-traumatic complaints (PTC) after six months. Early recognition of patients with MTBI who are at risk of developing PTC would be useful because early follow up at the outpatient clinic may help to reduce the severity of these complaints in the long run. METHODS: The presence of symptoms in the emergency room (ER) (headache, dizziness, nausea, vomiting, and neck pain) and biochemical markers (neurone specific enolase and S-100B) in serum were assessed as possible predictive variables for the severity of PTC. Outcome variables were the severity of 16 PTC six months after the trauma. RESULT: After six months, the severity of most complaints had declined to pretrauma levels but medians for headache, dizziness, and drowsiness were still increased. In a series of 79 patients, 22 (28%) reported one or more PTC after six months. After adjustment for baseline variables, an at least twofold increased severity of all PTC subgroups was reported by those patients reporting headache, dizziness, or nausea in the ER. A twofold increased severity of "cognitive" and "vegetative" PTC was also found in those with increased concentrations of biochemical serum markers at first presentation. The prevalence of full recovery after six months increased from 50% in patients with three symptoms to 78% in those with no symptoms in the ER. Inclusion of biochemical markers showed that all 10 patients with no symptoms in the ER and normal markers recovered fully. CONCLUSIONS: The presence of headache, dizziness, or nausea in the ER after MTBI is strongly associated with the severity of most PTC after six months. Identifying MTBI patients in the ER without headache, dizziness, nausea, or increased serum marker concentrations may be a promising strategy for predicting a good outcome.

Dissociable hormonal, cognitive and mood responses to neuroendocrine challenge: evidence for receptor-specific serotonergic dysregulation in depressed mood.

Fifteen patients with major depression, dysthymia, or anxiety disorder with depressed mood (DSM-IV diagnoses) and 16 controls received single oral doses of 0.5mg/kg metachlorophenylpiperazine (m-CPP), a 5-HT(2C) agonist, and 10 mg ipsapirone, a 5-HT(1A) agonist, according to double-blind, placebo-controlled, cross-over design. The groups' levels of cortisol, adrenocorticotrophic hormone (ACTH) and prolactin did not differ at baseline. Both 5-HT agonists significantly elevated cortisol, ACTH, and prolactin. The cortisol response to ipsapirone was significantly blunted in major depression and dysthymia patients. Neuroendocrine responses to m-CPP did not differ between groups, but m-CPP selectively increased profile of mood states (POMS) depression and tenseness scores in patients. No effects of ipsapirone on mood were found. However, ipsapirone impaired memory performance in controls, but tended to improve memory performance in patients. The results support the evidence for both hypothalamic and possibly hippocampal 5-HT(1A) receptor desensitisation and non-hypothalamic, 5-HT(2C) receptor sensitisation, probably fronto-cortical, in patients with major depression and dysthymia.

Decreased plasma orexin-A levels in obese individuals.

Orexin-A and -B stimulate appetite and food intake in rats. Orexins and orexin receptors are present in the hypothalamus as well as the enteric nervous system, the pancreas and the gut. The presence of orexins in peripheral blood, however, has not yet been reported. To determine whether orexin-A is present in human plasma and is related to body weight, we measured plasma orexin-A and leptin levels in a population with a body mass index (BMI) range from 19.8 to 59 kg/m(2). Plasma orexin-A levels correlated negatively and plasma leptin levels correlated positively with BMI. In obese and morbidly obese individuals, orexin-A levels were significantly lower and leptin levels were significantly higher when compared to normal. Our results support previous data suggesting that orexin-A acts also in a peripheral manner. The fact that lower levels of plasma orexin-A are present in obese individuals suggests that it is involved in the regulation of human energy metabolism.

[Successful treatment and pregnancy in a women with the non-classic form of congenital adrenal hyperplasia]. / Succesvolle behandeling en zwangerschap bij een vrouw met de niet-klassieke vorm van het adrenogenitaal syndroom.

In an 18-year-old woman non-classic 21-hydroxylase deficiency was diagnosed and dexamethasone treatment was instituted. Ten years later, she became pregnant for the first time; at 37 weeks unexpected intrauterine foetal death was found to have occurred. A second pregnancy ended with a spontaneous abortion following a 12-week period of amenorrhoea. At the third pregnancy, the medication was replaced with hydrocortisone as it was suspected that the use of dexamethasone may have played a role in the intrauterine foetal death and the spontaneous abortion. The patient gave birth to a healthy, but dysmature, daughter. Female patients with non-classic congenital adrenal hyperplasia present with signs of androgen excess. Treatment with glucocorticoids reduces the symptoms and restores the menstrual cycle and fertility. Preconceptional advice by a clinical geneticist is recommended, because of the risk of an affected child. If there is no risk of having a child with congenital adrenal hyperplasia, hydrocortisone or prednisone is the treatment of choice during pregnancy as neither cross the placenta.

Clinical experience with Sandostatin LAR in patients with acromegaly.

Patients with acromegaly, who are not cured after transsphenoidal adenomectomy, may be treated with external irradiation and/or octreotide injections. Recently, a long-acting formulation of octreotide (Sandostatin LAR has become available in clinical practice. We assessed the effects of treatment with this long-acting octreotide in 18 consecutive patients with acromegaly treated in our center, who had persistent signs and symptoms of acromegaly despite transsphenoidal surgery with (n=7) or without irradiation (n=11). Twelve had already been treated with regular Sandostatin for a period of 0.5-8 years in dosages of 3 x 50 to 3 x 300 mcg s.c. (median daily dose 300 mcg). All patients started with i.m. injections of 20 mg Sandostatin LAR every 4 weeks. In the patients who started treatment with octreotide for the first time, mean serum IGF-1 levels (measured by IRMA, Nichols Diagnostics) decreased from 634+/-229 to 255+/-88 ng/ml after 3 months, 271+/-81 ng/ml after 1 year and 263+/-97 ng/ml after 2 years (all P<0.05), while random GH levels (DELFIA, Wallac) decreased from 6.6 (range 3.1-67.0) to 2.1 (0.5-3.1) mU/l after 2 years (P<0.05). In the 12 patients who had already been treated with octreotide, mean IGF-1 also fell, from 367+/-193 to 331+/-195 ng/ml (P=0.023) after 3 months, to 342+/-191 ng/ml after 1 year and 277+/-169 ng/ml (P=0.002) after 2 years, while random GH levels decreased from 4.5 (1.1-46) mU/l at baseline to 2.1 (0.4-23.0) after 2 years (P=0.003). Therefore, the average decrease of IGF-1 was 10% after 3 months and 25% after 2 years. One patient had a decrease of less than 5% (but her IGF-1 was normal, 193 ng/ml), and one patient showed no response to both regular and long-acting Sandostatin (ave. IGF-1, 755 ng/ml). No specific side-effects occurred. One patient chose to return to t.i.d. injection of regular octreotide because of slight worsening of her complaints of headache despite normal IGF-1 levels. All other patients favoured continuation of the monthly injections. In six patients, the dose had to be increased to 30-40 mg monthly because the IGF-1 levels still remained elevated. Sandostatin LAR may be considered a great improvement for the treatment of patients with (symptomatic) acromegaly.

Are children with cystic fibrosis who are treated with a proton-pump inhibitor at risk for vitamin B(12) deficiency?

BACKGROUND: In a recent study, the authors demonstrated the beneficial effect of proton-pump inhibitors (PPI) on fat malabsorption and bone mineral content in children with cystic fibrosis (CF). Prolonged use of PPI could result in vitamin B(12) deficiency as a consequence of impaired release of vitamin B(12) from food in a nonacid environment. The aim of this study was to evaluate the vitamin B 12 status of CF patients either treated with a PPI or not by measuring vitamin B(12) and homocysteine blood levels, the latter being a sensitive indicator of vitamin B(12) deficiency. METHODS: The study population consisted of 20 CF patients, 11 patients treated with a PPI for at least 2 years and 9 patients not treated with a PPI, and 10 healthy, age-matched control participants. Homocysteine blood levels were measured by high-performance liquid chromatography, and vitamin B(12) levels were measured by a competitive protein-binding assay. RESULTS: Vitamin B(12) levels were significantly higher in both CF groups compared with the control participants (PPI+, P = 0.02; PPI-, P = 0.009). There was no significant difference in vitamin B(12) levels between both CF groups. Homocysteine levels were normal and similar in all groups. CONCLUSIONS: Cystic fibrosis patients treated with a PPI for at least 2 years show no signs of vitamin B(12) deficiency.

[Macroprolactinemia, a benign form of hyperprolactinemia]. / Macroprolactinemie, een onschuldige vorm van hyperprolactinemie.

In a 34-year-old woman with primary subfertility, a strongly increased serum concentration of prolactin was found in combination with normal levels of oestradiol, which is an indication for the presence of prolactin forms without clinical effect. She appeared to have macroprolactinaemia, i.e. the presence of circulating large forms of prolactin (up to > 100 kDa), which may be detected by the immunoassays currently used. They give no clinical signs or symptoms. Diagnosing macroprolactinaemia means that further diagnostic tests for hypopituitarism abnormalities using MRI need not be carried out and unjustified treatment of otherwise healthy persons may be prevented.

S-100B and neuron-specific enolase in serum of mild traumatic brain injury patients. A comparison with health controls.

OBJECTIVES: The aim of the study was to determine whether serum concentrations of neuron-specific enolase (NSE) and S100-B in mild traumatic brain injury (MTBI) patients are higher than in serum of healthy controls. MATERIAL AND METHODS: Blood samples from 104 MTBI patients were taken shortly after the trauma for measurement of S-100B and NSE in serum. In 92 healthy persons these markers were also measured. Marker concentrations in serum of patients and controls were compared. In the patient group the relation between serum-marker concentrations and clinical symptoms and signs, that occurred shortly after the traumatic event, were evaluated. RESULTS: Median NSE concentration was only slightly higher in patients (9.8 microg/l; 10 to 90 percentile range 6.9 to 14.3 microg/ l) than in controls (9.4 microg/l; 6.3 to 13.3 microg/l). Median S-100B concentration was significantly higher in patients (0.25 microg/l; 0.00 to 0.68 microg/l) than in controls (0.02 microg/l; 0.00 to 0.13 microg/l). An association was found between S-100B concentrations and vomiting in patients. CONCLUSIONS: S-100B is a useful marker for brain damage in MTBI patients and seems to be associated with the presence of vomiting after the trauma.

Factors contributing to alterations in skeletal muscle and plasma amino acid profiles in patients with chronic obstructive pulmonary disease.

BACKGROUND: There is increasing evidence of abnormal protein metabolism in patients with chronic obstructive pulmonary disease (COPD), as reflected by lower plasma branched-chain amino acid (BCAA) concentrations and different muscle amino acid (AA) patterns than in age-matched control subjects. OBJECTIVE: We examined whether the low plasma BCAA concentrations in COPD reflect an imbalance between anabolic and catabolic processes as evidenced by a low fat-free mass (FFM) and alterations in the anabolic hormone insulin and whether discrepancies in muscle AA concentrations between studies are related to different patient characteristics. DESIGN: AA profiles in arterial plasma and quadriceps femoris muscle and insulin concentrations in venous plasma were analyzed in 28 postabsorptive COPD patients (14 with and 14 without macroscopic emphysema) and in 28 control subjects. FFM was measured by dual-energy X-ray absorptiometry. RESULTS: The lower sum of plasma BCAAs in the COPD group than in the control subjects was the result of a lower leucine concentration (P: < 0.001); no significant difference in valine and isoleucine was found between the groups. In the COPD group, the lower leucine concentrations were associated with low FFM (P: < 0.01). Compared with the control group, the muscle-to-plasma leucine gradient was higher in the COPD group (P: < 0.001) and was associated with a higher insulin concentration (P: < 0.01). Several muscle AA concentrations were higher or tended to be higher in the group without emphysema than in the control group, whereas nearly all AA concentrations were lower in the group with emphysema. CONCLUSIONS: Leucine metabolism is altered in COPD patients and is associated with low FFM and high insulin concentrations. There were striking differences in the skeletal muscle AA profile between the COPD subtypes.

Prognostic factors for successful insulin therapy in subjects with type 2 diabetes.

OBJECTIVE: To assess which factors influence or predict the efficacy of insulin therapy in subjects with type 2 diabetes, who were poorly controlled despite maximal doses of oral glucose lowering agents. RESEARCH DESIGN AND METHODS: Seventy-five patients with type 2 diabetes participated (mean age (+/- SD), 67 +/- 8 years; body mass index, 25.8 +/- 5.0 kg/m2; median time since diagnosis of diabetes, 8 years (range 1-36); 27 males and 48 females). They were transferred to insulin therapy, in which case either insulin alone, or a combination of insulin and glibenclamide was employed. The importance of baseline parameters (glycaemic control, beta-cell function, measures of insulin resistance) was assessed by comparing good and poor responders (defined as achieved HbA1c < 8.0 or > 9.0%) to insulin therapy, and by multiple logistic regression analysis of these baseline parameters and achieved metabolic control. RESULTS: During insulin therapy, HbA1c levels decreased from 10.9 +/- 1.3 to 8.2 +/- 1.1% (p < 0.001), and fasting blood glucose levels decreased from 14.0 +/- 2.3 to 8.2 +/- 2.1 mmol/l (p < 0.001). Thirty patients reached HbA1c levels < 8.0%, 21 of them even < 7.5%. The mean increase in body weight was 4.5 kg. HbA1c after 6 months was 7.0 +/- 0.6% in the good responders, and 9.8 +/- 0.6% in the poor responders (p < 0.001), despite a comparable insulin dose. Baseline metabolic control was similar in both groups. Also, glucagon-stimulated and calculated insulin secretion, as well as parameters of insulin resistance, such as fasting serum insulin levels, free fatty acids, and serum triglycerides, were not different between both groups, and certainly not higher in the poor responders. Also previous metformin use was not different. However, poor responders were more obese than good responders, and had significantly longer known duration of diabetes. Multiple logistic regression confirmed that only duration of diabetes and body mass index were independent predictors of response to insulin therapy. CONCLUSIONS: We conclude that in elderly patients with type 2 diabetes improvement of glycaemic control can be achieved at the expense of some weight gain. Measurement of residual insulin secretion prior to institution of insulin treatment does not discriminate between good and poor responders to this model of therapy. Especially in obese patients with longer duration of diabetes more attention is needed in order to achieve optimal glycaemic control. Combination of insulin with newer drugs, like thiazolidinediones, may perhaps achieve this.