Continuous subcutaneous infusion of low dose growth hormone decreases serum sex-hormone binding globulin and testosterone concentrations in moderately obese middle-aged men

OBJECTIVE   Sex-hormone binding globulin (SHBG) is a liver derived protein whose concentration has been shown to be affected by a number of factors. The aim of the present study was to investigate the possible effect of increased basal GH concentrations on serum concentrations of SHBG, testosterone and thyroid hormones.
DESIGNS  Recombinant human growth hormone (rhGH) was given as a continuous subcutaneous infusion in a low dose (0.02 U/kg/day) over a period of 14 days in an open study.
PATIENTS  Eight middle-aged (42–59 years) overweight (body mass index 26.1–33.8 kg/m²) but otherwise healthy men were studied.
MEASUREMENTS  Blood samples were obtained after an over-night fast before and after 2, 7 and 14 days of treatment. Serum was separated and stored at −20°C until assay.
RESULTS  Serum GH concentrations increased to a steady level of 2–4 mU/l. Serum SHBG concentration decreased between 2 and 7 days of treatment and serum testosterone concentration changed in parallel. There was no change in the ratio between serum SHBG and serum testosterone. Serum T4 and free T4 concentrations decreased, and that of T3 increased as a result of continuous GH infusion. Simple correlations between changes in SHBG concentrations and other hormonal changes showed positive significant correlations between changes of SHBG and of testosterone.
CONCLUSIONS  Low dose continuously infused GH resulted in a parallel decrease in serum SHBG and testosterone concentrations. Thyroid hormone concentrations were affected in a similar way to that previously demonstrated following daily injections of GH.     

Gastric mucosal recognition of Helicobacter pylori is independent of Toll-like receptor 4

Little is known about the interactions between Helicobacter pylori, which specializes in colonizing the mucin layer that covers the gastric mucosa, and primary gastric epithelial cells. The expression pattern of Toll-like receptors (TLRs) in primary gastric epithelial cells and cell lines was compared. Primary cells did not express TLR4, whereas all cell lines expressed a nonsignaling form of TLR4. Because other cells within the mucosa expressed TLR4, it was next investigated whether H. pylori can be recognized by TLR4--they cannot. Moreover, H. pylori infection of primary cells induced a regulated production of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha, whereas infection of cell lines only resulted in IL-8 production. The cytokine production in all cell types was strictly cag dependent. These findings indicate that, although the epithelium is important in directing the immune response against H. pylori infections, the response is independent of TLR4.     

Defective activation of skeletal muscle and adipose tissue lipolysis in type 1 diabetes mellitus during hypoglycemia

The increased risk of hypoglycemia during intensified treatment of type 1 diabetes mellitus (T1DM) patients, who have a deficient glucagon secretory response, is largely attributed to the development of suppressed adrenomedullary responses. A consequence of this impairment of catecholamine secretion might be reduced lipolysis in major target tissues (muscle and adipose) and, in turn, increased glucose metabolism. To test this hypothesis, we used microdialysis to monitor glycerol (index of lipolysis) in the extracellular fluid of skeletal muscle and adipose tissue and assessed whole-body glucose use by measuring [6,6-(2)H(2)]glucose enrichment in plasma in seven intensively treated T1DM patients and eight nondiabetic subjects who received a 3-h insulin infusion (0.8 mU/kg.min) on two occasions: during mild-moderate hypoglycemia or euglycemia. In the hypoglycemic study, the rise in plasma epinephrine was approximately 50% less in the T1DM patients despite a greater fall in plasma glucose (to 3.0 vs. 3.5 mM in controls; P < 0.05). Moreover, the rate of glucose flux and the plasma-extracellular fluid glucose gradient in muscle was increased during hypoglycemia in T1DM subjects compared with controls. Glycerol levels in muscle, adipose, and plasma fell similarly in both groups in the first hour. Thereafter, tissue glycerol remained suppressed in the T1DM patients but rebounded significantly (P < 0.01) in the control subjects. The glycerol response in muscle and adipose tissue was significantly correlated with plasma epinephrine concentration (r = 0.73, P = 0.002; and r = 0.52, P = 0.04, respectively), and inversely correlated with whole-body glucose disposal (r = -0.51, P = 0.05; and r = -0.50, P = 0.05). To determine whether the absence of the lipolytic response is limited to deficient catecholamine release, we perfused muscle and adipose tissue in situ with the selective beta(2)-agonist terbutaline during hyperinsulinemic euglycemia. Local addition of agonist increased glycerol and blood flow in both muscle and adipose (P < 0.01 and P < 0.05, respectively) similarly in T1DM and control subjects. We conclude that deficient release of (rather than impaired responsiveness to) catecholamines in T1DM prevents the local fat breakdown within muscle and adipose tissue that normally occurs during mild-moderate hypoglycemia. This defect within peripheral tissues may lead to a delayed increase in glucose disposal that could contribute to the severity of hypoglycemia when it is prolonged.     

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome

Purpose

In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m²) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

Child maltreatment: variation in trends and policies in six developed countries

We explored trends in six developed countries in three types of indicators of child maltreatment for children younger than 11 years, since the inception of modern child protection systems in the 1970s. Despite several policy initiatives for child protection, we recorded no consistent evidence for a decrease in all types of indicators of child maltreatment. We noted falling rates of violent death in a few age and country groups, but these decreases coincided with reductions in admissions to hospital for maltreatment-related injury only in Sweden and Manitoba (Canada). One or more child protection agency indicators increased in five of six countries, particularly in infants, possibly as a result of early intervention policies. Comparisons of mean rates between countries showed five-fold to ten-fold differences in rates of agency indicators, but less than two-fold variation in violent deaths or maltreatment-related injury, apart from high rates of violent child death in the USA. These analyses draw attention to the need for robust research to establish whether the high and rising rates of agency contacts and out-of-home care in some settings are effectively reducing child maltreatment.     

The Adolescent Adjustment Profile (AAP) in comparisons of patients with obesity,phenylketonuria or neurobehavioural disorders

Psychosocial development in children with chronic disease is a key issue in paediatrics. This study investigated whether psychosocial adjustment could be reliably assessed with the 42-item Adolescent Adjustment Profile (AAP) instrument. The study mainly focused on adjustment-to-obesity measurement, although it compared three patient groups with chronic conditions. All phenylketonuria (PKU) patients in Sweden between ages 9 and 18 and their parents and teachers were invited to participate. Patients with neurobehavioural syndromes and obesity were age- and gender-matched with PKU patients. Healthy children constituted a reference group. Psychosocial adjustment was measured using the AAP, which is a multi-informant questionnaire that contains four domains. Information concerning parents’ socio-economic and civil status was requested separately. Respondents to the three questionnaires judged the PKU patients to be normal in all four domains. Patients with neurobehavioural syndromes demonstrated less competence and the most problems compared with the other three groups. According to the self-rating, the parent rating and the teacher rating questionnaires, obese patients had internalizing problems. The parent rating and the teacher rating questionnaire scored obese patients as having a lower work capacity than the reference group. Compared with the reference group, not only families with obese children but also families with children with neurobehavioural syndromes had significantly higher divorce rates. Obese patients were also investigated with the Strength and Difficulties Questionnaire (SDQ), another instrument that enables comparison between two measures of adjustment. The AAP had good psychometric properties; it was judged a useful instrument in research on adolescents with chronic diseases.     

Workplace NO and NO2 during combined treatment of infants with nasal CPAP and NO

Objective To determine the workplace concentrations of NO and NO₂ in and around a paediatric incubator during inhaled NO (iNO) treatment and during an accidental emptying of NO cylinders into room air.Design We simulated iNO–nasal CPAP treatment in order to assess the impact on the occupational environment. Furthermore, two full NO cylinders for therapy, 1,000 ppm, 20 litres, 150 bar and 400 ppm, 10 litres, 150 bar, were emptied as rapidly as possible into an intensive care unit (ICU) room.Setting University hospital ICU.Measurements and results To correctly gauge the contribution from iNO–CPAP we constructed a system measuring breathing zone and room ventilation inlet-outlet values during a 10-ppm iNO treatment of a simulated infant. Maximal breathing zone values were 17.9 ± 7.0 (mean ± 95% CI) ppb for NO and 25.2 ± 4.8 ppb for NO_2. If room inlet values were subtracted, the contributions to breathing zone values emanating from iNO–CPAP were 14.8 ± 4.6 ppb for NO and 14.6 ± 4.6 ppb for NO₂. At the ventilation outlet the maximal contributions were 4.2 ± 2.9 ppb NO and 9.6 ± 4.3 ppb NO₂. During rapid total release of a gas cylinder in the ICU room, simulating an accident, we found transient NO levels comparable to the high therapeutic dosing range, but only low NO₂ levels.Conclusions Neither 8-h time-weighted average (TWA) nor 15 min short-term exposure limits (STEL) were exceeded during normal operation or during a simulated accident. The contribution of nitrogen oxides from treatment to workplace air were minor compared to those from ambient air.     

Carotid atherosclerosis is correlated with extent and severity of coronary artery disease evaluated by myocardial perfusion scintigraphy

Increased intima-media thickness (IMT) in the common carotid artery (CCA) correlates with conventional risk factors for cardiovascular disease and is an independent predictor of cardiac events. However, correlation between IMT and degree of ischemic heart disease evaluated by coronary angiogram is weak. The purpose of this study was to investigate the relationship between measures of carotid atherosclerosis and the extent and severity of coronary artery disease (CAD) in 111 consecutive patients (60 men and 51 women, mean age 60 years) with known or suspected CAD who were investigated with adenosine-stress myocardial perfusion scintigraphy. Common carotid artery lumen diameter (LD) and IMT of the carotid bulb and distal CCA were measured with ultrasound, and CCA cross-sectional intima-media area (CIMA) was calculated. Seventy-two of 110 patients (65%) had significant perfusion defects. Increasing carotid plaque occurrence (absence, unilateral or bilateral occurrence) correlated with more advanced CAD (p<0.01). The extent and severity of myocardial hypoperfusion correlated significantly with presence of carotid plaque (r=0.23 and 0.24 respectively, p<0.05), CIMA (r=0.23 and 0.22, p<0.05), and LD (r<0.26 and 0.25, p<0.01) but not with IMT. In contrast to CIMA, LD failed to show an independent relation to extent of CAD after adjustment for age, sex, and body mass index. In conclusion, in subjects with intermediate to high risk of ischemic heart disease, occurrence of carotid plaques and increased cross-sectional intimamedia area in the common carotid artery are the best parameters for predicting CAD expressed as myocardial hypoperfusion.     

Different catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner

Background

Takotsubo cardiomyopathy (TCM) is characterized by regional left ventricular dysfunction that cannot be explained by an occlusive lesion in a coronary artery. Catecholamines are implicated in the pathogenesis of TCM but the mechanisms involved are unknown. Because the endogenous and the most commonly used exogenous catecholamines have well defined adrenoceptor subtype affinities, inferences can be made about the importance of each adrenoceptor subtype based on the ability of different catecholamines to induce TCM. We therefore studied which of five well-known catecholamines, that differ in receptor subtype affinity, are able to induce TCM-like cardiac dysfunction in the rat.

Methods

255 rats received intraperitoneally isoprenaline (β₁/β₂-adrenoceptor agonist), epinephrine (β₁/β₂/α-adrenoceptor agonist), norepinephrine (β₁/α-adrenoceptor agonist), dopamine (α/β₁/β₂-adrenoceptor agonist) or phenylephrine (α-adrenoceptor agonist). Each catecholamine was given in five different doses. We measured blood pressure through a catheter inserted in the right carotid artery and studied cardiac morphology and function by echocardiography.

Results

All catecholamines induced takotsubo-like cardiac dysfunction. Isoprenaline induced low blood pressure and predominantly apical dysfunction whereas the other catecholamines induced high blood pressure and basal dysfunction. In another set of experiments, we continuously infused hydralazine or nitroprusside to rats that received epinephrine or norepinephrine to maintain systolic blood pressure < 120 mm Hg. These rats developed akinesia of the apex instead of the base. Infusion of phenylephrine to maintain blood pressure > 120 mm Hg after isoprenaline administration prevented apical TCM-like dysfunction.

Conclusions

Catecholamine-induced takotsubo-like cardiac dysfunction appears to be afterload dependent rather than depend on stimulation of a specific adrenergic receptor subtype.