Mats Ryberg

Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation

CONTEXT Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile. OBJECTIVE The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets. DESIGN AND SETTING We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers. PATIENTS The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM). INTERVENTION The same daily dose of hydrocortisone was administered as OD dual-release or TID. MAIN OUTCOME MEASURE We evaluated cortisol pharmacokinetics. RESULTS Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7 kg, P = 0.005), systolic blood pressure (difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004). CONCLUSION The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.

The Association of Bacterial Adhesion with Dental Caries

Saliva adhesion of bacteria is a key event in oral biofilm formation. Here, we used partial least-squares (PLS) analysis to correlate adhesion of cariogenic (Streptococcus mutans Ingbritt) and commensal (Actinomyces naeslundii LY7) model bacteria, and their agglutinin and acidic proline-rich protein ligands, respectively, with high and low caries experiences in 38 children reflecting todays skewed caries distribution. Adhesion of S. mutans was among the factors correlating strongest with high caries experience when PLS modeled together with traditional factors (e.g., sugar intake, lactobacilli counts). Saliva phenotypes with high agglutinin levels and Db-s (an acidic PRP variant) coincided with both high caries experience and S. mutans adhesion. A. naeslundii adhesion correlated with low caries experience. Non-Db phenotypes (i.e., acidic PRP-1 and PRP-2 variants) coincided with both low caries experience and S. mutans, but high A. naeslundii, adhesion. Thus, bacterial adhesion may modulate susceptibility and resistance to dental caries.

Effect of β2-Adrenoceptor Agonists on Saliva Proteins and Dental Caries in Asthmatic Children

Twenty-four children, from 10 to 20 years old, with asthma treated with β2-adrenoceptor agonists were matched with healthy controls of the same age, sex, and social background. Stimulated whole and parotid saliva was collected, and decayed and filled tooth surfaces as well as oral hygiene habits were recorded. The dietary and sugar intake was carefully checked by a four-day dietary record. The asthmatic children had a 26% lower (p<0.05) value for secretion rate of whole saliva. Seventy percent of the children with Streptococcus mutans counts >2×105 colony-forming units/mL of whole saliva belonged to the asthmatic group (p<0.05). The concentrations of total protein and amylase in parotid saliva were significantly lower for the asthmatic children. The concentrations of potassium, salivary peroxidase, bacteria-aggregating glycoproteins, and secretory IgA were not affected, but the secretion rate of parotid saliva was 36% lower in the asthma group (p<0.05). Oral hygiene and dietary habits did not differ between the groups. The asthmatic children had higher DFS scores, but these were not significantly different from those of the healthy controls (p = 0.07). We suggest that subjects with asthma treated with β2-receptor agonists should receive special prophylactic attention.

Long-term effects of a Palaeolithic-type diet in obese postmenopausal women: a 2-year randomized trial

Background/Objectives:Short-term studies have suggested beneficial effects of a Palaeolithic-type diet (PD) on body weight and metabolic balance. We now report the long-term effects of a PD on anthropometric measurements and metabolic balance in obese postmenopausal women, in comparison with a diet according to the Nordic Nutrition Recommendations (NNR).Subjects/Methods:Seventy obese postmenopausal women (mean age 60 years, body mass index 33 kg/m2) were assigned to an ad libitum PD or NNR diet in a 2-year randomized controlled trial. The primary outcome was change in fat mass as measured by dual-energy X-ray absorptiometry.Results:Both groups significantly decreased total fat mass at 6 months (−6.5 and−2.6 kg) and 24 months (−4.6 and−2.9 kg), with a more pronounced fat loss in the PD group at 6 months (P<0.001) but not at 24 months (P=0.095). Waist circumference and sagittal diameter also decreased in both the groups, with a more pronounced decrease in the PD group at 6 months (−11.1 vs−5.8 cm, P=0.001 and−3.7 vs−2.0 cm, P<0.001, respectively). Triglyceride levels decreased significantly more at 6 and 24 months in the PD group than in the NNR group (P<0.001 and P=0.004). Nitrogen excretion did not differ between the groups.Conclusions:A PD has greater beneficial effects vs an NNR diet regarding fat mass, abdominal obesity and triglyceride levels in obese postmenopausal women; effects not sustained for anthropometric measurements at 24 months. Adherence to protein intake was poor in the PD group. The long-term consequences of these changes remain to be studied.

Preserved hippocampus activation in normal aging as revealed by fMRI

The hippocampus is deteriorated in various pathologies such as Alzheimers disease (AD) and such deterioration has been linked to memory impairment. By contrast, the structural and functional effects of normal aging on the hippocampus is a matter of debate, with some findings suggesting deterioration and others providing evidence of preservation. This constitutes a crucial question since many investigations on AD are based on the assumption that the deterioration of the hippocampus is the breaking point between normal and pathological aging. A growing number of fMRI studies specifically aimed at investigating hippocampal engagement in various cognitive tasks, notably memory tasks, but the results have been inconclusive. Here, we optimized the episodic face‐name paired‐associates task in order to test the functioning of the hippocampus in normal aging. Critically, we found no difference in the activation of the hippocampus between the young and a group of older participants. Analysis of individual patterns of activation substantiated this impression. Collectively, these findings provide evidence of preserved hippocampal functioning in normal aging.

A Palaeolithic-type diet causes strong tissue-specific effects on ectopic fat deposition in obese postmenopausal women

Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause. We hypothesized that a diet containing a relatively high content of protein and unsaturated fat [mainly monounsaturated fatty acids (MUFAs)] but limited carbohydrates and saturated fat would reduce lipid content in liver and muscle and increase insulin sensitivity in postmenopausal women.

Possible Release of an ArgGlyArgProGln Pentapeptide with Innate Immunity Properties from Acidic Proline-Rich Proteins by Proteolytic Activity in Commensal Streptococcus and Actinomyces Species

ABSTRACT This study suggests degradation of salivary acidic proline-rich proteins (PRPs) into potential innate-immunity-like peptides by oralStreptococcus and Actinomyces species. PRP degradation paralleled cleavage of Pro-containing substrates. PRP degradation by S. gordonii strain SK12 instantly released a Pyr1-Pro104Pro105 and a Gly111-Pro149Gln150 peptide together with a presumed Arg106Gly107Arg108Pro109Gln110pentapeptide. The synthetic Arg106Gly107Arg108Pro109Gln110peptide desorbed bound bacteria and counteracted sucrose-induced decrease of dental plaque pH in vitro.

Comprehensive medical examination of a group of patients with alleged adverse effects from dental amalgams.

Mercury from dental amalgams does not seem to cause dose-related intoxications. However, animal studies have shown that high-dose exposure to mercury may support various types of immunologic reactions. Ten patients claiming that their symptoms were caused and aggravated by amalgam therapy were selected for a study of the effects of removal of one amalgam restoration followed by placing of a composite filling. Clinical symptoms and the result of laboratory tests were recorded. Six patients had contact allergies to metals, three of them to mercury ammonium chloride. The comparison of pre- and post-experimental test results showed significant reductions in p-IgE and dU-albumin and significant increases in p-C3d and dU-beta 2-microglobulin. There was no laboratory evidence of a direct toxic effect by mercury on the patients. The observed response by some of the studied factors to the low acute exposure to amalgam may imply that an activation of the immune system occurred.

Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

Objective The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). Design Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. Methods Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). Results In stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. Conclusions This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy.

Saliva composition in asthmatic patients after treatment with two dose levels of a β2-adrenoceptor agonist

Changes are known to occur in the salivary composition of asthmatic patients treated with beta 2-adrenoceptor agonists. To evaluate the precise contribution of the agonist to the impaired saliva secretion, 15 asthmatic patients, 15-23 yr old, were given two dose levels of agonist, either terbutaline or salbutamol. The lower dose, 0.15-3.0 mg/day, represented the therapeutic level used by the patients. During a wash-out period of one month, the asthma was treated with budesonide, a corticosteroid spray. Then a daily dose of 32 mg of terbutaline or salbutamol was given for one month. Samples of whole saliva, stimulated by chewing, and parotid saliva, stimulated by citric acid, were collected on three occasions: (1) at the end of the low-dose agonist treatment; (2) at the end of the wash-out period; and (3) at the end of the high-dose agonist treatment. During the high dosing the secretion rate of parotid saliva decreased and the concentrations of its total protein, amylase, hexosamine and the ratio of hexosamine/total protein were lowered. The output per minute of total protein, amylase, hexosamine, peroxidase, lysozyme, secretory IgA and potassium decreased. There were only small differences in secretion rates or saliva composition between samples collected at the end of the low-dose and at the end of the wash-out period. Thus, treatment with beta 2-adrenoceptor agonists impairs saliva secretion in asthmatics.