Reduced dispensing of prescribed antibiotics during the Covid-19 pandemic has not increased severe complications from common infections.

BACKGROUND: Sweden has seen an accelerated decline in the number of dispensed antibiotic prescriptions from an already low level during the Covid-19 pandemic. This prompted us to explore whether the decrease in antibiotic prescriptions has reached a critically low level and resulted in an increase in treatment of severe complications from common infections. The aim was to study if the accelerated decrease in antibiotic sales has led to an increase in complications in outpatients with common infections. METHOD: A population-based nationwide registry study based on the Swedish Prescribed Drug Register and the National Patient Register. RESULTS: The total number of dispensed antibiotic prescriptions decreased by 17% during 2020 compared to 2019. The decrease was most pronounced in younger age groups and for antibiotics targeting respiratory tract infections. The number of hospital admissions and visits to open specialist care due to pneumonia or complications related to otitis, tonsillitis, or sinusitis decreased by 4-44%. Prescriptions and numbers of visits or admissions due to urinary tract infections and skin infections remained largely unchanged compared to previous years. CONCLUSION: No increase in complications due to common bacterial infections could be detected despite an unprecedented decline in dispensed antibiotic prescriptions in outpatient care in 2020. The decrease in dispensed antibiotic prescriptions from pharmacies was probably primarily related to a general decrease in the incidence of respiratory infections due to the recommendations and restrictions implemented to mitigate the Covid-19 pandemic in Sweden. This in return led to fewer doctors' visits and consequently to fewer occasions to prescribe antibiotics, be they warranted or not.

Induction of dynamic hyperinflation by expiratory resistance breathing in healthy subjects - an efficacy and safety study.

NEW FINDINGS: What is the central question of this study? The study aimed to establish a novel model to study the chronic obstructive pulmonary disease (COPD)-related cardiopulmonary effects of dynamic hyperinflation in healthy subjects. What is the main finding and its importance? A model of expiratory resistance breathing (ERB) was established in which dynamic hyperinflation was induced in healthy subjects, expressed both by lung volumes and intrathoracic pressures. ERB outperformed existing methods and represents an efficacious model to study cardiopulmonary mechanics of dynamic hyperinflation without potentially confounding factors as present in COPD. ABSTRACT: Dynamic hyperinflation (DH) determines symptoms and prognosis of chronic obstructive pulmonary disease (COPD). The induction of DH is used to study cardiopulmonary mechanics in healthy subjects without COPD-related confounders like inflammation, hypoxic vasoconstriction and rarefication of pulmonary vasculature. Metronome-paced tachypnoea (MPT) has proven effective in inducing DH in healthy subjects, but does not account for airflow limitation. We aimed to establish a novel model incorporating airflow limitation by combining tachypnoea with an expiratory airway stenosis. We investigated this expiratory resistance breathing (ERB) model in 14 healthy subjects using different stenosis diameters to assess a dose-response relationship. Via cross-over design, we compared ERB to MPT in a random sequence. DH was quantified by inspiratory capacity (IC, litres) and intrinsic positive end-expiratory pressure (PEEPi, cmH2 O). ERB induced a stepwise decreasing IC (means (95% CI): tidal breathing: 3.66 (3.45-3.88), ERB 3 mm: 3.33 (1.75-4.91), 2 mm: 2.05 (0.76-3.34), 1.5 mm: 0.73 (0.12-1.58) litres) and increasing PEEPi (tidal breathing: 0.70 (0.50-0.80), ERB 3 mm: 11.1 (7.0-15.2), 2 mm: 22.3 (17.1-27.6), 1.5 mm: 33.4 (3.40-63) cmH2 O). All three MPT patterns increased PEEPi, but to a far lesser extent than ERB. No adverse events during ERB were noted. In conclusion, ERB was proven to be a safe and efficacious model for the induction of DH and might be used for the investigation of cardiopulmonary interaction in healthy subjects.

Functional and structural relevance of conserved positively charged lysine residues in organic anion transporting polypeptide 1B3.

The human organic anion transporting polypeptide 1B3 (OATP1B3), located in the basolateral membrane of hepatocytes, mediates the uptake of endogenous substrates such as taurocholate and drugs from blood into hepatocytes. The transport activity of OATP1B3 is influenced by positively charged amino acids, which are facing the central pore. Molecular modeling was performed to select conserved positively charged amino acids, which may influence transport activity and anchoring of OATP1B3 in the plasma membrane. The modeling revealed that Lys361 faces the pore, and Lys399 is oriented to the plasma membrane. Therefore, the mutants L361>A, L361>R, L399>A, and L399>R were generated using site-directed mutagenesis to investigate the impact of the positive charges on transport activity and anchoring in the membrane. Transport kinetic analyses for the substrates sulfobromophthalein and taurocholate showed a loss of function for the L361>A mutant, whereas the transport activity was maintained by the L361>R mutant, indicating that the positive charge at position 361 is important for transport activity of OATP1B3. Comparative modeling with OATP1A2 and OATP2B1 revealed that the pore size around this lysine residue is larger in OATP1A2 and smaller in OATP2B1 compared with OATP1B3, which could be related to the respective substrate spectra. Cell surface expression of L399>A and L399>R was decreased to 16 and 72% compared with wild-type OATP1B3 (p < 0.001), respectively, indicating that the positive charge of lysine at position 399 is necessary for an unimpaired cell surface expression. Furthermore, we provide a summary of amino acids, which influence the transport activity of OATP1B3.

Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine.

The antimalarial drug chloroquine is eliminated to a significant extent by renal tubular secretion. The molecular mechanism of renal chloroquine secretion remains unknown. We hypothesized that organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), localized in the basolateral and luminal membranes of proximal tubule cells, respectively, are involved in chloroquine transport. The interaction of chloroquine with both transporters was investigated using single-transfected human embryonic kidney 293 (HEK293)-MATE1 cells in uptake experiments and single-transfected Madin-Darby canine kidney II (MDCK)-OCT2 and MDCK-MATE1 cells as well as double-transfected MDCK-OCT2-MATE1 cells grown as polarized monolayers on transwell filters. In HEK293-MATE1 cells, chloroquine competitively inhibited MATE1-mediated metformin uptake (K(i) = 2.8 µM). Cellular accumulation of chloroquine was significantly lower (P < 0.001) and transcellular chloroquine transport was significantly increased (P < 0.001) in MDCK-MATE1 and MDCK-OCT2-MATE1 cells compared to vector control cells after basal addition of chloroquine (0.1 to 10 µM). In contrast, no difference in cellular accumulation or transcellular transport of chloroquine was observed between MDCK-OCT2 and vector control cells. In line with an oppositely directed proton gradient acting as a driving force for MATE1, basal-to-apical transport of chloroquine by MDCK-OCT2-MATE1 cells increased with decreasing apical pH from 7.8 to 6.0. Transcellular transport of chloroquine by MDCK-OCT2-MATE1 cells was inhibited by cimetidine, trimethoprim, and amitriptyline. Our data demonstrate that chloroquine is a substrate and potent competitive inhibitor of MATE1, whereas OCT2 seems to play no role in chloroquine uptake. Concomitantly administered MATE1 inhibitors are likely to modify the renal secretion of chloroquine.

Effects of Dynamic Hyperinflation on Left Ventricular Diastolic Function in Healthy Subjects - A Randomized Controlled Crossover Trial.

Objective: Diastolic dysfunction of the left ventricle is common in patients with chronic obstructive pulmonary disease (COPD). Dynamic hyperinflation has been suggested as a key determinant of reduced diastolic function in COPD. We aimed to investigate the effects of induced dynamic hyperinflation on left ventricular diastolic function in healthy subjects to exclude other confounding mechanisms associated with COPD. Design: In this randomized controlled crossover trial (NCT03500822, https://www.clinicaltrials.gov/), we induced dynamic hyperinflation using the validated method of expiratory resistance breathing (ERB), which combines tachypnea with expiratory resistance, and compared the results to those of tachypnea alone. Healthy male subjects (n = 14) were randomly assigned to the ERB or control group with subsequent crossover. Mild, moderate, and severe hyperinflation (i.e., ERB1, ERB2, ERB3) were confirmed by intrinsic positive end-expiratory pressure (PEEPi) using an esophageal balloon catheter. The effects on diastolic function of the left ventricle were measured by transthoracic echocardiographic assessment of the heart rate-adjusted transmitral E/A-ratio and E/e'-ratio. Results: We randomly assigned seven participants to the ERB group and seven to the control group (age 26 [24-26] vs. 24 [24-34], p = 0.81). Severe hyperinflation decreased the E/A-ratio compared to the control condition (1.63 [1.49-1.77] vs. 1.85 [0.95-2.75], p = 0.039), and moderate and severe ERB significantly increased the septal E/e'-ratio. No changes in diastolic function were found during mild hyperinflation. PEEPi levels during ERB were inversely correlated with the E/A ratio (regression coefficient = -0.007, p = 0.001). Conclusions: Our data indicate dynamic hyperinflation as a determinant of left ventricular diastolic dysfunction in healthy subjects. Therapeutic reduction of hyperinflation might be a treatable trait to improve diastolic function in patients with COPD.

Influence of cyclooxygenase inhibitors on the function of the prostaglandin transporter organic anion-transporting polypeptide 2A1 expressed in human gastroduodenal mucosa.

The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E(2) with IC(50) values of 6.2 +/- 1.2 and 3.1 +/- 1.2 microM. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE(2) transport by 162.7 +/- 13.9, 77.2 +/- 3.6, and 32.3 +/- 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors.

Quality of drug prescribing in elderly people in nursing homes and special care units for dementia: a cross-sectional computerized pharmacy register analysis.

BACKGROUND: Drug prescribing to the elderly is extensive and often inappropriate. Furthermore, the number of drugs used is the most important risk factor for adverse drug reactions. Despite this, drug prescribing in the elderly in Sweden is high and increasing. In 2003 the Swedish National Board of Health and Welfare launched a set of indicators to evaluate the quality of drug therapy in the elderly. Use of this tool in combination with the Swedish computerized national register covering all persons receiving multi-dose drug dispensing (drugs dispensed in one dose unit bag for each dose occasion) would enable detection of inappropriate drug prescribing and could help reduce the risk of drug-related problems among the elderly. OBJECTIVES: To assess the extent and quality of drug prescribing in younger and older elderly residents receiving multi-dose drug dispensing in ordinary nursing homes (NHs) and special care units for dementia (NHDs), and to evaluate the relationship between the quality of prescribing and the number of prescribers per resident, in a Swedish county. METHODS: The computerized national pharmacy drug register provided the database and a cross-sectional design was used. Selected drug-specific quality indicators proposed by the Swedish National Board of Health and Welfare in 2003 were used to assess the quality of drug prescribing. RESULTS: This study included 3705 residents. Their mean age was 85 years and 72% were women. The mean number of prescribed drugs was 10.3 per resident. The proportion of residents with prescriptions for psychotropic drugs was 80% in NHs and 85% in NHDs. The prevalence of each drug-specific quality indicator was as follows: long-acting benzodiazepines 16.4% (NHs) versus 11.7% (NHDs), anticholinergic drugs 20.7% versus 18.5%, drug duplication 14.6% versus 13.6%, three or more psychotropic drugs 25.6% versus 35.3%, class C interactions (drug combinations that may require dose adjustment) 41.9% versus 38.7% and class D interactions (drug combinations that should be avoided) 8.1% versus 5.6%. Younger elderly residents (age 65-79 years) had a lower quality of drug prescribing. An increasing number of prescribers per resident was associated with a lower quality of drug therapy. CONCLUSIONS: We found a lower quality of drug prescribing, e.g. anticholinergic drugs prescribed to approximately 20% of residents of NHs and NHDs, and a higher rate of psychotropic drug use (>/=80%) compared with previous studies in NHs. Our results also demonstrated a negative correlation between quality of prescribing and number of prescribers per resident.

An EU approach to health system performance assessment: Building trust and learning from each other.

EU countries have recently joined forces to carry out common work on health systems performance assessment (HSPA). After the signature of the Tallinn Charter in 2008, a small group of countries brought the issue of HSPA on the EU agenda; this led the European commission and member states to set up an expert group on HSPA in 2014. This group started by facilitating the exchange of best practices and lessons learnt, with an eye to avoiding duplications with activities of international organisations. While progressing on its work, the group broadened its scope: it stepped into concrete work on policy priorities such as the assessment of quality of care, integrated care and primary care. It also moved into the organisation of country-tailored events and of advocacy activities. We identify three main strength factors of the EU expert group on HSPA. First, it is built through a bottom-up participatory approach, which promotes a sense of ownership by the members. Second, it developed a flexible and pragmatic attitude, which makes it able to constantly adapt to emerging needs and priorities. Finally, the group positioned itself in a niche that was still to be exploited: the identification of ways to translate HSPA findings into effective policy making.

The national program on standardized cancer care pathways in Sweden: Observations and findings half way through.

In 2015, the Swedish government initiated a national cancer reform program to standardize cancer care pathways. Primary aims included shortened waiting times among patients with suspected cancer, increased patient satisfaction and reduced regional variation. The implementation phase of the program is now more than half way through and both achievements and challenges have been identified. The ongoing evaluation demonstrates that professional engagement and adjustments on the meso- and micro-level of the system are essential to achieving sustainable improvements. Waiting times have shortened for the pathways launched first, and patients are satisfied with a more transparent process. Physicians in primary care are satisfied to inform patients about the pathways but point out problems with comorbidity and complicated diagnostic procedures related to unspecific symptoms. Mechanisms and ethical considerations behind possible crowding-out effects need to be thoroughly highlighted and discussed with staff and management. The results so far appear promising but meso- and micro-levels of the system need to be more involved in the design processes.

Developing the role of the drug and therapeutics committees: perceptions of chairs.

PURPOSE: According to Swedish law, every county is required to have a local drug and therapeutics committee (DTC) to contribute to safe and cost-effective drug use. The law presents merely a framework and gives no detailed instructions addressing, for example, organisation and methods. The aim of this study is to explore the variation of conceptions of the role of the DTCs among committee Chairs and to compare the results with an earlier study. DESIGN/METHODOLOGY/APPROACH: Data were collected by questionnaires and telephone interviews with committee chairs, which were analysed using a phenomenographic approach. FINDINGS: Four conceptions were identified, namely: traditional, patient-aware, influential, holistic and cooperative, which all involved prescribers. In one conception the DTC acted as an expert to decision-makers. One conception included the notion that cooperation across the bureaucratic borders was important. Patients were involved in two conceptions. Comparison with the earlier study showed a trend toward higher patient awareness and a higher agreement on DTC goals with an increased focus on quality issues. ORIGINALITY/VALUE: This study demonstrates an alternative research method bringing in new perspectives when exploring activities within healthcare. Patient involvement in the work of the DTCs is increasing, but should be further explored and developed.

Effects of periodic intake of a high-caloric diet on body mass and leptin resistance.

The effects of continuous or intermittent access to a high-caloric (HC) diet, always offered in addition to standard chow, on body mass and leptin resistance were analyzed in female C57BL/6J mice. Susceptibility for diet-induced obesity (DIO) was apparent from the marked preference for the HC diet. Continuous HC diet feeding of mice at 4 weeks of age induced leptin resistance within 2 weeks and massive gains in body mass, although with increasing inter-individual variability in the inbred strain considered to be isogenic. In adult mice receiving HC diet for the first time, leptin treatment failed to reduce energy intake first after 11 days of HC diet feeding, but became effective again within 3 days after HC diet withdrawal. In mice with a history of several preceding periods of access to the HC diet totalling >30 days, supplementary HC diet abolished the anorectic effect of leptin treatment within only 3 days and it reappeared not earlier than 11 days after HC diet withdrawal. Thus, in the investigated DIO-prone mouse strain both, the loss of responsiveness to leptin under HC diet and its recovery after HC diet withdrawal strongly depended on the dietary history. Recovery from leptin resistance during periods of intermittent chow feeding was associated with losses of body mass that did not completely compensate for the obesity-inducing effect of the preceding HC diet.

Gender equity in health care in Sweden--minor improvements since the 1990s.

A report by the Swedish National Committee on Gender Disparities in Patient Care (1996) identified many shortcomings in the ability of the health sector to gear patient management and treatment to the specific needs of men and women. To promote gender equity in health care, the Committee presented several proposals relating to research, education, monitoring, and evaluation of health services and the responsibilities of health authorities. In 2002, the Swedish Government authorised the National Board of Health and Welfare to review and analyse gender equity trends in health care. Data from, e.g. the national quality registers, epidemiological health data registers, population surveys, and Patient Trust Boards were compiled to identify gender disparities in the quality and accessibility of health services. The curricula of medical universities and the policies of major research funds were reviewed, as were developments in major fields of health research. The National Board found that many of the gender disparities identified in the 1990s still exist, e.g. access to advanced evidence-based technologies such as coronary interventions. As previously, women account for around 60%, and men for 40%, of complaints, e.g. to the Patients' Advisory Committees. Many of the proposals of the National Committee have not been fully implemented by the national authorities or the county councils. We conclude that promoting gender equity in health care is an important but difficult task for health authorities. To make health services more gender sensitive a combination of strategies, including enforcement by guidelines and regulations, may be needed.

The 2015 National Cancer Program in Sweden: Introducing standardized care pathways in a decentralized system.

Starting in 2015, the Swedish government has initiated a national reform to standardize cancer patient pathways and thereby eventually speed up treatment of cancer. Cancer care in Sweden is characterized by high survival rates and a generally high quality albeit long waiting times. The objective with the new national program to standardize cancer care pathways is to reduce these waiting times, increase patient satisfaction with cancer care and reduce regional inequalities. A new time-point for measuring the start of a care process is introduced called well-founded suspicion, which is individually designed for each cancer diagnosis. While medical guidelines are well established earlier, the standardisation is achieved by defining time boundaries for each step in the process. The cancer reform program is a collaborative effort initiated and incentivized by the central government while multi-professional groups develop the time-bound standardized care pathways, which the regional authorities are responsible for implementing. The broad stakeholder engagement and time-bound guidelines are interesting approaches to study for other countries that need to streamline care processes.

Patient-centredness as a quality domain in Swedish healthcare: results from the first national surveys in different Swedish healthcare settings.

OBJECTIVES: Patients' perception of the quality and patient-centredness of healthcare has gained increasing interest in the last decade in Sweden, as in other countries. The purpose of the study was to evaluate to what extent patients perceived Swedish healthcare as patient-centred and to explore the satisfaction levels related to gender, education level and to having or not having Swedish as one's mother tongue. DESIGN AND SETTINGS: This study has a cross-sectional design. Analyses were based on the first national patient surveys in Sweden, conducted between 2009 and 2010. The surveys included responses from 232,518 patients who had been in contact with primary, outpatient, inpatient, or emergency care units. Survey questions related to indicators of patient-centred care and sociodemographic variables were selected for the analysis. The patients' level of satisfaction in the selected indicators was analysed and compared by sociodemographic and background factors. Multivariable logistic regression models were used for analysis. RESULTS: The patients expressed high levels of satisfaction in questions related to the 'Respect' indicator (81-96% satisfied) but lower levels in most of the other indicators of patient-centred care. Only 25-30% of the patients reported they had been told about possible warning signs of their condition or treatment and 58-66% said they had received enough information about their condition. Group differences were detected. The most satisfied patient groups were men, individuals with low levels of education and those with Swedish as their mother tongue. CONCLUSIONS: According to these first national patient surveys, achieving patient-centred healthcare for all citizens is a challenge for Swedish healthcare authorities. Future analyses of national patient surveys should show whether national efforts to encourage acceptance of patient-centred approaches and strategies for equal care will give intended results.

[Non-invasive and invasive out of hospital ventilation in chronic respiratory failure : Consensus report of the working group on ventilation and intensive care medicine of the Austrian Society of Pneumology]. / Nichtinvasive und invasive außerklinische Beatmung beim chronisch respiratorischen Versagen : Konsensus-Report des Arbeitskreises für Beatmung & Intensivmedizin der Österreichischen Gesellschaft für Pneumologie.

The current consensus report was compiled under the patronage of the Austrian Society of Pneumology (Österreichischen Gesellschaft für Pneumologie, ÖGP) with the intention of providing practical guidelines for out-of-hospital ventilation that are in accordance with specific Austrian framework parameters and legal foundations. The guidelines are oriented toward a 2004 consensus ÖGP recommendation concerning the setup of long-term ventilated patients and the 2010 German Respiratory Society S2 guidelines on noninvasive and invasive ventilation of chronic respiratory insufficiency, adapted to national experiences and updated according to recent literature. In 11 chapters, the initiation, adjustment, and monitoring of out-of-hospital ventilation is described, as is the technical equipment and airway access. Additionally, the different indications-such as chronic obstructive pulmonary diseases, thoracic restrictive and neuromuscular diseases, obesity hypoventilation syndrome, and pediatric diseases-are discussed. Furthermore, the respiratory physiotherapy of adults and children on invasive and noninvasive long-term ventilation is addressed in detail.

The role of drug and therapeutics committees.

PURPOSE: Improved quality and safety in drug use is a public health goal of major importance. In Sweden, local drug and therapeutics committees (DTCs) have adopted the task of working for safe and rational drug use. This study aimed to explore how chairs conceived the role of the DTCs, to explore how information officers conceived their own role, and to determine whether the respondents included patients in their answers. DESIGN/METHODOLOGY/APPROACH: Data were collected using questionnaires and the answers were analysed according to phenomenographic method to identify conceptions. "Patient awareness" was studied by content analysis. FINDINGS: In both groups the prescribers were the focus of attention, and only a few respondents mentioned patients. A variation of four conceptions was found among chairs and three among information officers. It would be beneficial if DTCs used this knowledge in their development. ORIGINALITY/VALUE: The importance of "patient awareness" within DTCs must be further explored.

Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects.

Prostaglandins such as prostaglandin E2 (PGE2) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE2-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE2-mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [(3)H]-thymidine incorporation which was in line with a higher accumulation of AGS-OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE2-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible-factor 1α (HIF1α) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE2-mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa.

Hyperphagia, not hypometabolism, causes early onset obesity in melanocortin-4 receptor knockout mice.

Previous studies on mice with melanocortin-4 receptor gene (MC4r) knockout have focused on obese adults. Because humans with functional MC4r mutations show early-onset obesity, we determined the onset of excessive fat deposition in 10- to 56-day-old mice, taking into account sex and litter influences. Total body fat content of MC4r-/- on day 35 and MC4r+/- on day 56 significantly exceeds that of MC4r+/+. Plasma leptin levels increase in proportion to fat mass. According to cumulative food intake and energy expenditure measurements from day 21 to 35, onset of excessive fat deposition in MC4r-/- is fueled by hyperphagia and counteracted partially by hypermetabolism. In 35- to 56-day-old mice, arcuate nucleus neuropeptide Y (NPY) mRNA decreases and pro-opiomelanocortin (POMC) mRNA increases with fat content and plasma leptin levels independently of genotype. Taking into account fat content by ANCOVA reveals, however, increases in both NPY mRNA and POMC mRNA due to melanocortin-4 receptor (MC4R) deficiency. We conclude that hyperphagia, not hypometabolism, is the primary disturbance initiating excessive fat deposition in MC4R-deficient mice at weaning and that the overall changes in NPY and POMC expression tend to antagonize the onset of excessive fat deposition.

Age-dependent hypothalamic expression of neuropeptides in wild-type and melanocortin-4 receptor-deficient mice.

In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type (+/+) and melanocortin-4 receptor (MC4R)-deficient (+/-, -/-) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and cocaine-and-amphetamine-regulated transcript (CART) were analyzed in the arcuate nucleus (ARC) and adjacent regions comprising the dorsomedial (DMN) and ventromedial (VMN) nucleus. In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content. Adjusting for the influence of body fat content by ANCOVA showed that the levels of NPY, POMC, and CART were highest and of AGRP lowest in young -/- mice. In the middle-aged mice, feedback from body fat content was weakened. For -/- mice ANCOVA revealed higher NPY and AGRP, lower POMC, and unchanged CART expression levels relative to young -/- mice. In the DMN and VMN, POMC and AGRP signals were absent at each age. CART was expressed in the DMN independent of age, fat content, and genotype. For NPY expression, an age-dependent induction was found in the DMN and VMN; it was absent in the young but present in the middle-aged mice, showing close positive correlations between body fat content and the numbers of NPY-labeled cells which were further enhanced in -/- mice. Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content. Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency.

Inactivation of the GR in the nervous system affects energy accumulation.

The homeostatic regulation of body weight protects the organism from the negative consequences of starvation and obesity. Glucocorticoids (GCs) modulate this regulation, although the underlying mechanisms remain unclear. To address the role of central GRs in the regulation of energy balance, we studied mice in which GRs have selectively been inactivated in the nervous system. Mutant mice display marked growth retardation. During suckling age this is associated with normal fat deposition causing a 60% temporary increase of percent body fat, compared with control littermates. After weaning, fat and protein depositions are reduced so that adults are both smaller and leaner than their controls. Decreased food intake and, after weaning, reduced metabolic efficiency account for these developmental disturbances. Plasma levels of leptin and insulin, two important energy balance regulators, are elevated in young mutants but normal in adults. Leptin/body fat ratio is higher at all ages, suggesting disturbed control of circulating leptin as a consequence of chronically elevated GC levels in mutant animals. Adult mutants display increased hypothalamic CRH and NPY levels, but peptide levels of melanin concentrating hormone and Orexin A and B are unchanged. The increased levels of plasma GCs and hypothalamic CRH may act as catabolic signals most likely leading to persistently reduced energy accumulation.