Strong and persistent effect on liver fat with a Paleolithic diet during a two-year intervention.

BACKGROUND/OBJECTIVES: Our objective was to investigate changes in liver fat and insulin sensitivity during a 2-year diet intervention. An ad libitum Paleolithic diet (PD) was compared with a conventional low-fat diet (LFD). SUBJECTS/METHODS: Seventy healthy, obese, postmenopausal women were randomized to either a PD or a conventional LFD. Diet intakes were ad libitum. Liver fat was measured with proton magnetic resonance spectroscopy. Insulin sensitivity was evaluated with oral glucose tolerance tests and calculated as homeostasis model assessment-insulin resistance (HOMA-IR)/liver insulin resistance (Liver IR) index for hepatic insulin sensitivity and oral glucose insulin sensitivity (OGIS)/Matsuda for peripheral insulin sensitivity. All measurements were performed at 0, 6 and 24 months. Forty-one women completed the examinations for liver fat and were included. RESULTS: Liver fat decreased after 6 months by 64% (95% confidence interval: 54-74%) in the PD group and by 43% (27-59%) in the LFD group (P<0.01 for difference between groups). After 24 months, liver fat decreased 50% (25-75%) in the PD group and 49% (27-71%) in the LFD group. Weight reduction between baseline and 6 months was correlated to liver fat improvement in the LFD group (rs=0.66, P<0.01) but not in the PD group (rs=0.07, P=0.75). Hepatic insulin sensitivity improved during the first 6 months in the PD group (P<0.001 for Liver IR index and HOMA-IR), but deteriorated between 6 and 24 months without association with liver fat changes. CONCLUSIONS: A PD with ad libitum intake had a significant and persistent effect on liver fat and differed significantly from a conventional LFD at 6 months. This difference may be due to food quality, for example, a higher content of mono- and polyunsaturated fatty acids in the PD. Changes in liver fat did not associate with alterations in insulin sensitivity.

Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women.

BACKGROUND/OBJECTIVES: Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women. SUBJECTS/METHODS: Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11ß hydroxysteroid dehydrogenase type 1 (11ßHSD1) in subcutaneous adipose tissue were studied. RESULTS: Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11ßHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11ßHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months. CONCLUSIONS: Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.

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

OBJECTIVES: 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. SUBJECTS: Ten healthy, nonsmoking postmenopausal women with a body mass index (BMI) >27 (28-35) kg m(-2) were included in the study. INTERVENTIONS: Participants were instructed to consume an ad libitum Palaeolithic-type diet intended to provide approximately 30 energy percentage (E%) protein, 40 E% fat (mainly MUFAs) and 30 E% carbohydrate. Intramyocellular lipid (IMCL) levels in calf muscles and liver triglyceride levels were quantified using proton magnetic resonance spectroscopy ((1) H-MRS) before and 5 weeks after dietary intervention. Insulin sensitivity was estimated by homoeostasis model assessment (HOMA) indices and the euglycaemic hyperinsulinaemic clamp technique. RESULTS: Mean energy intake decreased by 25% with a weight loss of 4.5 kg. BMI, waist and hip circumference, waist/hip ratio and abdominal sagittal diameter also decreased significantly, as did diastolic blood pressure (mean -7 mmHg), levels of fasting serum glucose, cholesterol, triglycerides, LDL/HDL cholesterol, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), urinary C-peptide and HOMA indices. Whole-body insulin sensitivity did not change. Liver triglyceride levels decreased by 49%, whereas IMCL levels in skeletal muscle were not significantly altered. CONCLUSIONS: A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women.

Four new nodulose-spored species of Inocybe (Agaricales) from West Africa.

We describe four new nodulose-spored species of Inocybe from tropical regions of Africa: I. beninensis, I. flavipes, I. fuscobrunnea and I. pallidiangulata. The new species are recognised based on morphological data and phylogenetic analyses of ITS, 28S and RPB2 sequences. Phylogenetic analyses indicated that I. flavipes and I. beninensis are part of a subclade leading to the I. calida group. Inocybe fuscobrunnea appears sister to the I. asterospora group. Inocybe pallidiangulata is nested within a clade of mainly tropical species from South Asia, Africa, and South America, close to the subclade of I. lilacinosquamosa and I. ayangannae from Guyana. Complete descriptions and illustrations, including photographs and line drawings, and a key to nodulose-spored taxa of tropical African species of Inocybe are provided. Citation: Aïgnon HL, Jabeen S, Verbeken A, Matheny PB, Yorou NS, Ryberg M (2022). Four new nodulose-spored species of Inocybe (Agaricales) from West Africa. Fungal Systematics and Evolution 10: 1-18. doi: 10.3114/fuse.2022.10.01.

Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper.

BACKGROUND: Comorbidities and risk factors likely to complicate treatment are common in elderly cancer patients. Anthracyclines remain the cornerstone of first-line therapy for non-Hodgkin's lymphoma (NHL) and metastatic and early breast cancer but can cause congestive heart failure. Elderly patients are at increased risk of this event and measures to reduce it should be considered. METHODS: A committee of experts in breast cancer and NHL met under the auspices of the International Society for Geriatric Oncology to review the literature and make recommendations, based on level of evidence, for the assessment, treatment and monitoring of elderly patients requiring anthracyclines. RESULTS AND RECOMMENDATIONS: Use of anthracycline-based chemotherapy illustrates many of the dilemmas facing elderly cancer patients. Age in itself should not prevent access to potentially curative treatment or treatment that prolongs life or improves its quality. The risk of cardiotoxicity with conventional anthracyclines is increased by the following factors: an existing or history of heart failure or cardiac dysfunction; hypertension, diabetes and coronary artery disease; older age (independent of comorbidities and performance status); prior treatment with anthracyclines; higher cumulative dose of anthracyclines and short infusion duration. The fact that cumulative and irreversible cardiotoxicity is likely to be greater in this population than among younger patients calls for effective pretreatment screening for risk factors, rigorous monitoring of cardiac function and early intervention. Use of liposomal anthracycline formulations, prolonging the infusion time for conventional anthracyclines and cardioprotective measures should be considered. However, when treatment is being given with curative intent, care should be taken to ensure reduced cardiotoxicity is not achieved at the expense of efficacy.

A Paleolithic-type diet results in iodine deficiency: a 2-year randomized trial in postmenopausal obese women.

BACKGROUND/OBJECTIVES: Different diets are used for weight loss. A Paleolithic-type diet (PD) has beneficial metabolic effects, but two of the largest iodine sources, table salt and dairy products, are excluded. The objectives of this study were to compare 24-h urinary iodine concentration (24-UIC) in subjects on PD with 24-UIC in subjects on a diet according to the Nordic Nutrition Recommendations (NNR) and to study if PD results in a higher risk of developing iodine deficiency (ID), than NNR diet. SUBJECTS/METHODS: A 2-year prospective randomized trial in a tertiary referral center where healthy postmenopausal overweight or obese women were randomized to either PD (n=35) or NNR diet (n=35). Dietary iodine intake, 24-UIC, 24-h urinary iodine excretion (24-UIE), free thyroxin (FT4), free triiodothyronine (FT3) and thyrotropin (TSH) were measured at baseline, 6 and 24 months. Completeness of urine sampling was monitored by para-aminobenzoic acid and salt intake by urinary sodium. RESULTS: At baseline, median 24-UIC (71.0 µg/l) and 24-UIE (134.0 µg/d) were similar in the PD and NNR groups. After 6 months, 24-UIC had decreased to 36.0 µg/l (P=0.001) and 24-UIE to 77.0 µg/d (P=0.001) in the PD group; in the NNR group, levels were unaltered. FT4, TSH and FT3 were similar in both groups, except for FT3 at 6 months being lower in PD than in NNR group. CONCLUSIONS: A PD results in a higher risk of developing ID, than a diet according to the NNR. Therefore, we suggest iodine supplementation should be considered when on a PD.

Epirubicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer.

PURPOSE: To evaluate the influence of cumulative dose, dose-intensity, single-dose level, and schedule of epirubicin on the risk of developing congestive heart failure (CHF) in patients with advanced breast cancer. PATIENTS AND METHODS: Four hundred sixty-nine consecutive anthracyline-naive patients with metastatic breast cancer were included. Only patients with cardiac failure according to New York Heart Association (NYHA) function class II or more were recorded as having CHF. For each patient, the following were calculated: the cumulative dose of epirubicin, mean dose-intensity (cumulative dose of epirubicin/duration of treatment), and single-dose level (cumulative dose of epirubicin/number of injections). RESULTS: Thirty-four patients (7.2%) developed CHF. The cumulative risk of cardiotoxicity was 4% at 900 mg/m2 and increased exponentially to 15% at 1,000 mg/m2. Irradiation against the mediastinum and thoracic spine increased the risk of CHF (P=.025), but dose-intensity, single-dose level, and schedule had no influence on the risk of developing CHF. Age, previous adjuvant irradiation (to the left or right hemithorax), and previous chemotherapy (cyclophosphamide, methotrexate, and fluorouracil [CMF]) were not risk factors. The median time to onset of CHF following the last dose of epirubicin was 57 days (range, 0 to 853). Among patients with CHF, 13 (38.2%) died of cardiac failure. The median survival time for all patients with CHF was 162 days (range, 0 to +1,957). Previous irradiation directly against the heart increased the risk of death due to cardiac failure and decreased the median survival time to 125 days (range, 0 to 336). CONCLUSION: The present large retrospective study of 469 patients substantiates previous results concerning the cardiotoxicity of epirubicin. A significantly increasing risk of CHF in patients who receive cumulative doses greater than 950 mg/m2 was established. The future recommended maximum cumulative dose of epirubicin should be 900 mg/m2 in patients with metastatic breast cancer. Previous irradiation against the heart leads to an increased risk of developing CHF with an accelerated course to death, which indicates an additive cardiotoxic effect of irradiation and epirubicin.

Structure of RecA-DNA complexes studied by combination of linear dichroism and small-angle neutron scattering measurements on flow-oriented samples.

By combining anisotropy of small-angle neutron scattering (SANS) and optical anisotropy (linear dichroism, l.d.) on flow-oriented RecA-DNA complexes, the average DNA-base orientation has been determined in RecA complexes with double-stranded (ds) as well as single-stranded (ss) DNA. From the anisotropy of the two-dimensional SANS intensity representation, the second moment orientation function S is obtained. Knowledge of S is crucial for the interpretation of l.d. spectra in terms of orientation of the DNA bases and the aromatic amino acid residues. The DNA-base planes are essentially perpendicular to the fibre axis of the complex between RecA and dsDNA in the presence of cofactor ATP gamma S. A somewhat tilted base geometry is found for the RecA-ATP gamma S complexes with single-stranded poly(dT) and poly(d epsilon A). This behaviour contrasts the RecA-ssDNA complex formed without cofactor which displays a poor orientation of the bases. Well-ordered bases in the ssDNA-RecA complex is possibly reflecting the role of RecA in preparing a nucleotide strand for base-pairing in the search-for-homology process. While the central SANS intensity is essentially independent of the pitch of the helical complex, a secondary intensity maximum, which becomes focused upon flow orientation, is found to be a sensitive measure of the pitch. The pitch values for the complexes compare well with cryo-electron microscopy results but are slightly larger than those seen for uranyl-stained samples.

A cognitive-behavioral group intervention as prevention for persistent neck and back pain in a non-patient population: a randomized controlled trial.

Given the demand for interventions that may prevent the development of persistent musculoskeletal pain problems, we investigated the effects of a cognitive-behavioral program in a group of non-patients with neck or back pain symptoms. Two hundred and fifty-three people selected from a population study were invited to participate. These people had experienced four or more episodes of relatively intense spinal pain during the past year but had not been out of work more than 30 days. Participants were randomly assigned to either a cognitive-behavioral group intervention or a treatment as usual comparison group. The experimental group received a standardized six-session program, provided by a trained therapist according to a manual. A significant overall analysis at the 1-year follow-up showed that the cognitive-behavioral group produced better results on 26 of the 33 outcome variables. Group comparisons indicated that the cognitive-behavioral group, relative to the comparison group, had significantly better results with regard to fear-avoidance beliefs, number of pain-free days, as well as the key variable of sick leave. Participation in the cognitive behavioral group reduced the risk for long-term sick leave during the follow-up by threefold. Thus, despite the strong natural recovery rate for back pain, the cognitive-behavioral intervention produced a significant preventive effect with regard to disability.

ADP/ATP and protein phosphorylation dependence of phototransformable protochlorophyllide in isolated etioplast membranes.

The effects of modulated ADP/ATP and NADPH/NADP(+) ratios, and of protein kinase inhibitors, on the in vitro reformation of phototransformable protochlorophyllide, i.e. the aggregated ternary complexes between NADPH, protochlorophyllide, and NADPH-protochlorophyllide oxidoreductase (POR, EC 1.3.1.33), in etioplast membranes isolated from dark-grown wheat (Triticum aestivum) were investigated. Low temperature fluorescence emission spectra (-196 degrees C) were used to determine the state of the pigments. The presence of spectral intermediates of protochlorophyllide and the reformation of phototransformable protochlorophyllide were reduced at high ATP, but favoured by high ADP. Increased ADP level partly prevented the chlorophyllide blue-shift. The protein kinase inhibitor K252a prevented reformation of phototransformable protochlorophyllide without showing any effect on the chlorophyllide blue-shift. Addition of NADPH did not overcome the inhibition. The results indicate that protein phosphorylation plays a role in the conversion of the non-phototransformable protochlorophyllide to POR-associated phototransformable protochlorophyllide. The possible presence of a plastid ADP-dependent kinase, the activity of which favours the formation of PLBs, is discussed. Reversible protein phosphorylation is suggested as a regulatory mechanism in the prolamellar body formation and its light-dependent dispersal by affecting the membrane association of POR. By the presence of a high concentration of phototransformable protochlorophyllide, prolamellar bodies can act as light sensors for plastid development. The modulation of plastid protein kinase and protein phosphatase activities by the NADPH/NADP(+) ratio is suggested.

Do epidemiological results replicate? The prevalence and health-economic consequences of neck and back pain in the general population.

Current estimates of the prevalence and consequences of neck and back pain vary greatly between studies. It is not known whether this variance is due to differences in methodology, or if it depends on the dynamics of the problem over time. The aim of this study was consequently an attempt to replicate and extend the findings of a previous epidemiological study using the same methodology on a new population. A survey of 3000 35-45 year olds, selected at randon, was conducted to determine the prevalence, site, frequency and intensity of the pain as well as any work loss or health-care utilization. The response rate was 69% and an analysis of non-responders showed that they were very similar to responders, but had a slightly lower prevalence. The results replicated the original study: 73% reported back pain during the past year and the consequences included considerable suffering and functional impairment. Moreover, 17% of those reporting pain had utilized sick leave during the past year for the problem, while an additional 14% had been off work but had not used sick leave. Sufferers averaged 3.5 health-care visits during the past year. However, the consumption of resources was highly skewed and about 6% of the sufferers accounted for over 50% of the costs. It was concluded that when the same selection criteria and assessment techniques are employed, the results found are quite similar. This implies that much of the huge variation in reported prevalence rates and consequences of back pain may be due to methodological differences. This underscores the need for standardized methods.

Effect of beta 2-adrenoceptor agonists on saliva proteins and dental caries in asthmatic children.

Twenty-four children, from 10 to 20 years old, with asthma treated with beta 2-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 less than 0.05) value for secretion rate of whole saliva. Seventy percent of the children with Streptococcus mutans counts greater than 2 X 10(5) colony-forming units/mL of whole saliva belonged to the asthmatic group (p less than 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 less than 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 beta 2-receptor agonists should receive special prophylactic attention.

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 today's 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.

The effects of moderate protein deficiency on beta-adrenoceptor density in rat parotid and submandibular salivary glands.

The effects of moderate protein deficiency on the number and dissociation constant of beta-adrenergic receptors were investigated. One group of adult rats was fed a protein-deficient diet (5% protein), a control group was given a similar diet with 20% protein, and a third group was fed a standard pellet diet. After 21 days, the salivary glands were removed and the cell membranes were isolated. The binding of [3H]-dihydroalprenolol to cell membranes was measured, with or without the presence of timolol, a potent beta-adrenoceptor antagonist. The rats fed the 5% protein diet had fewer beta-adrenoceptors in both the parotid and the submandibular glands than did the 20% protein group, which did not differ from the standard pellet group. The dissociation constant was not affected by protein deficiency. The rats fed the 5% protein diet had a significantly lower gain in body weight, less heavy submandibular glands but heavier parotids than the rats fed 20% protein. Thus the cellular conditions for protein secretion in the salivary glands are impaired during moderate protein deficiency in the adult rat.

The effects of long-term treatment with salmeterol and salbutamol on the flow rate and composition of whole saliva in the rat.

The effect of long-acting beta 2-adrenoceptor agonists on salivary glands and saliva secretion has not been studied before. Sprague-Dawley rats were given either the long-acting beta 2-agonist salmeterol, 1 mg/kg body wt per day or the short-acting agonist salbutamol, 5 mg/kg per day. Saline solution was used as control. After 18 days pilocarpine-stimulated saliva was collected, and after 21 days saliva was collected after stimulation with isoproterol and pilocarpine in combination. The saliva was analysed for total protein, amylase, hexosamine, sialic acid, sodium, potassium and calcium. At day 25 the salivary glands were extirpated and weighed. The weight of the parotid glands increased significantly after both salmeterol and salbutamol treatment, approx. 40%; the submandibular gland weights were not affected by either beta 2-agonist treatment. Pilocarpine-stimulated salivary flow rate was increased in the salbutamol, but not in the salmeterol, group. In the salmeterol group the concentration of sialic acid was increased and that of calcium was decreased. In saliva stimulated with pilocarpine and isoproterenol in combination, the concentrations of total protein, amylase and calcium were decreased after salmeterol. In the salbutamol group, total protein and potassium were decreased. The ratio sialic acid: total protein was increased at both saliva collections in both beta 2-agonist groups. It is concluded that rats treated chronically with the long-acting beta 2-adrenoceptor agonist salmeterol have an impaired secretion of salivary proteins and calcium and that the effect resembles that of salbutamol.

Saliva composition in asthmatic patients after treatment with two dose levels of a beta 2-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.

Radiotherapy in benign uterine bleeding disorders. The Radiumhemmet metropathia cohort 1912-1977. Short and long term results.

Radiotherapy was earlier a method of choice for treatment of benign bleeding disorders (metropathia), especially in women of high surgical risk. During the period 1912 to 1977 933 women with benign bleeding disorders were treated at Radiumhemmet with intracavitary brachytherapy or external irradiation or a combination of both. The result with regard to cure of the uterine bleedings was good (48%). Hormonal withdrawal symptoms after treatment were noted in 45% of the patients. In the long term follow up an increased risk of cardiovascular death was found in women treated before menopause. Malignant tumours occurred in 107 cases versus 90.2 expected (RR 1.19). The estimated ovarian dose of ionizing radiation varied from 3.5 Gy to 6.0 Gy for the three standard techniques. Two women gave birth to a healthy child 4 and 5 years after intracavitary radium treatment. The estimated absorbed dose to the ovaries in these two women were 1 Gy and 4 Gy, respectively.

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/m(2)) 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.

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.

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.