When and where do hip fractures occur? A population-based study.

UNLABELLED: We investigated the effects of socio-demographic and health factors on timing and location of hip fracture among 484 subjects. Time of fracture varied between community dwellers and residential care facility dwellers, and in relation to subjects' psychotropic drug status. Indoor hip fracture incidence increased on snow-covered days. INTRODUCTION: This paper aims to describe the timing and whereabouts of hip fracture cases in a population-based setting and to relate these factors with residential and health status, seasonal variation, and snow-covered ground. METHODS: We consecutively included 484 incident hip fracture events (age ≥50 years) admitted to a Swedish orthopedic department during a 1-year period. Data concerning socio-demographic details, fall location, time of fracture, comorbidity, and medications were collected from in-patient medical records and through patient or caregiver interviews. RESULTS: The expected peak in fracture occurrence during daytime was observed among community dwellers but not among subjects living in residential care. Hip fracture was twice as likely to occur during nighttime hours among psychotropic drug users (adjusted odds ratio (Adj. OR), 2.20; 95% confidence interval (CI), 1.12-4.30) compared to those not receiving these medications. Subjects without dementia, taking psychotropic drugs, were also more likely to fracture during nighttime hours (Adj. OR, 2.91; 95% CI, 1.40-6.0). We observed an increase in indoor hip fracture incidence on snow-covered days among community dwellers (incidence rate ratio, 1.34; 95% CI, 1.02-1.74). We observed only a weak seasonal trend in hip fracture incidence, based on month, among community dwellers who fractured indoors. CONCLUSIONS: Special attention and possibly fall-preventive efforts should be directed not only toward those living in residential care facilities but also toward community-dwelling subjects taking psychotropic drugs since these groups have a higher incidence of nighttime hip fracture. Further research aiming to explain the seasonal variation of indoor fracture incidence among community dwellers is warranted.

Psychedelic drug use and schizotypy in young adults.

Despite recently resurrected scientific interest in classical psychedelics, few studies have focused on potential harms associated with abuse of these substances. In particular, the link between psychedelic use and psychotic symptoms has been debated while no conclusive evidence has been presented. Here, we studied an adult population (n = 1032) with a special focus on young (18-35 years) and healthy individuals (n = 701) to evaluate the association of psychedelic drug use with schizotypy and evidence integration impairment typically observed in psychosis-spectrum disorders. Experimental behavioural testing was performed in a subsample of the subjects (n = 39). We observed higher schizotypy scores in psychedelic users in the total sample. However, the effect size was notably small and only marginally significant when considering young and healthy subjects (Cohen's d = 0.13). Controlling for concomitant drug use, none of our analyses found significant associations between psychedelic use and schizotypal traits. Results from experimental testing showed that total exposure to psychedelics (frequency and temporal proximity of use) was associated with better evidence integration (Cohen's d = 0.13) and a higher sensitivity of fear responses (Cohen's d = 1.05) to the effects instructed knowledge in a reversal aversive learning task modelled computationally with skin conductance response and pupillometry. This effect was present even when controlling for demographics and concomitant drug use. On a group level, however, only difference in sensitivity of fear responses to instructed knowledge reached statistical significance. Taken together, our findings suggest that psychedelic drug use is only weakly associated with psychosis-like symptoms, which, in turn, is to a large extent explained by psychiatric comorbidities and use of other psychoactive substances. Our results also suggest that psychedelics may have an effect on flexibility of evidence integration and aversive learning processes, that may be linked to recently suggested therapeutic effects of psychedelic drugs in non-psychotic psychiatric populations.

Ischaemic pre-conditioning means an increased adenosine metabolism with decreased glycolytic flow in ischaemic pig myocardium.

BACKGROUND: Ischaemic pre-conditioning (IP) is a potent protective mechanism for limiting the myocardial damage due to ischaemia. It is not fully known as to how IP protects. The metabolism of adenosine may be an important mechanistic component. We study the role of adenosine turnover together with glycolytic flow in ischaemic myocardium subjected to IP. METHODS: An acute myocardial ischaemia pig model was used, with microdialysis sampling of some metabolites (lactate, adenosine, glucose, glycerol, taurine) of ischaemic myocardium. An IP group was compared with a control group before and during a prolonged ischaemia. ¹4C-labelled adenosine and glucose were infused through microdialysis probes, and lactate, ¹4C-labelled lactate, glucose, taurine and glycerol were analysed in the effluent. The glycogen content in myocardial biopsies was determined. RESULTS: The ¹4C-adenosine metabolism was higher as there was a higher production of ¹4C-lactate in IP animals compared with the controls. The glycolytic flow, measured as myocardial lactate formation, was retarded during prolonged ischaemia in IP animals. Myocardial free glucose and glycogen content decreased during the prolonged ischaemia in both groups, with higher free glucose in the IP group. We confirmed the protective effects of IP with lower myocardial concentrations of markers for cellular damage (glycerol). CONCLUSIONS: This association between increased adenosine turnover and decreased glycolytic flow during prolonged ischaemia in response to IP can possibly be explained by the competitive effect for the metabolites from both glucose and adenosine metabolism for entering glycolysis. We conclude that this study provides support for an energy-metabolic explanation for the protective mechanisms of IP.

Metabolic responses in ischemic myocardium after inhalation of carbon monoxide.

BACKGROUND: To clarify the mechanisms of carbon monoxide (CO) tissue-protective effects, we studied energy metabolism in an animal model of acute coronary occlusion and pre-treatment with CO. METHODS: In anesthetized pigs, a coronary snare and microdialysis probes were placed. CO (carboxyhemoglobin 5%) was inhaled for 200 min in test animals, followed by 40 min of coronary occlusion. Microdialysate was analyzed for lactate and glucose, and myocardial tissue samples were analyzed for adenosine tri-phosphate, adenosine di-phosphate, and adenosine mono-phosphate. RESULTS: Lactate during coronary occlusion was approximately half as high in CO pre-treated animals and glucose levels decreased to a much lesser degree during ischemia. Energy charge was no different between groups. CONCLUSIONS: CO in the low-doses tested in this model results in a more favorable energy metabolic condition in that glycolysis is decreased in spite of maintained energy charge. Further work is warranted to clarify the possible mechanistic role of energy metabolism for CO protection.

Lactate concentration in umbilical cord blood is gestational age-dependent: a population-based study of 17 867 newborns.

OBJECTIVE: To study the influence of gestational age on lactate concentration in arterial and venous umbilical cord blood at birth and to define gestational age-specific reference values for lactate in vigorous newborns. DESIGN: Population-based comparative. SETTING: University hospitals. SAMPLE: Vigorous newborns with validated umbilical cord blood samples. MATERIAL AND METHODS: From 2000 to 2004, routine cord blood gases, lactate and obstetric data from two university hospitals were available for 17 867 newborns from gestational week 24 to 43. After validation of blood samples and inclusion only of singleton pregnancies aimed for vaginal delivery, 10 700 women remained. Among those, reference values were defined in 10 169 vigorous newborns, that is in newborns with a 5-minute Apgar score corresponding to the gestational age-specific median value minus 1 point score, or better. MAIN OUTCOME MEASURES: Cord lactate concentration relative to gestational age. RESULTS: The arterial and venous lactate concentrations increased monotonously with gestational age from 34 weeks. Considerable differences were found between mean and median values, but after logarithmic transformation the log-lactate values were normally distributed. Simple linear regression analysis showed a significant association between the log-lactate values and gestational age (P < 10(-6), R(2)= 0.024). Reference curves were constructed after anti-logarithmic transformation. Both the gestational age and the time of the second stage of labour influenced, independently of each other, the lactate concentrations. CONCLUSIONS: Lactate concentrations in arterial and venous umbilical cord blood are increasing significantly with advancing gestational age.

Recombining germline-derived CDR sequences for creating diverse single-framework antibody libraries.

We constructed a single-chain Fv antibody library that permits human complementarity-determining region (CDR) gene fragments of any germline to be incorporated combinatorially into the appropriate positions of the variable-region frameworks VH-DP47 and VL-DPL3. A library of 2 x 109 independent transformants was screened against haptens, peptides, carbohydrates, and proteins, and the selected antibody fragments exhibited dissociation constants in the subnanomolar range. The antibody genes in this library were built on a single master framework into which diverse CDRs were allowed to recombine. These CDRs were sampled from in vivo-processed gene sequences, thus potentially optimizing the levels of correctly folded and functional molecules, and resulting in a molecule exhibiting a lower computed immunogenicity compared to naive immunoglobulins. Using the modularized assembly process to incorporate foreign sequences into an immunoglobulin scaffold, it is possible to vary as many as six CDRs at the same time, creating genetic and functional variation in antibody molecules.

Effect of Structured Physical Activity and Nutritional Supplementation on Physical Function in Mobility-Limited Older Adults: Results from the VIVE2 Randomized Trial.

OBJECTIVES: The interactions between nutritional supplementation and physical activity on changes in physical function among older adults remain unclear. The primary objective of this study was to examine the impact of nutritional supplementation plus structured physical activity on 400M walk capacity in mobility-limited older adults across two sites (Boston, USA and Stockholm, Sweden). DESIGN: All subjects participated in a physical activity program (3x/week for 24 weeks), involving walking, strength, balance, and flexibility exercises. Subjects were randomized to a daily nutritional supplement (150kcal, 20g whey protein, 800 IU vitamin D) or placebo (30kcal, non-nutritive). SETTING: Participants were recruited from urban communities at 2 field centers in Boston MA USA and Stockholm SWE. PARTICIPANTS: Mobility-limited (Short Physical Performance Battery (SPPB) ≤9) and vitamin D insufficient (serum 25(OH) D 9 - 24 ng/ml) older adults were recruited for this study. MEASUREMENTS: Primary outcome was gait speed assessed by the 400M walk. RESULTS: 149 subjects were randomized into the study (mean age=77.5±5.4; female=46.3%; mean SPPB= 7.9±1.2; mean 25(OH)D=18.7±6.4 ng/ml). Adherence across supplement and placebo groups was similar (86% and 88%, respectively), and was also similar across groups for the physical activity intervention (75% and 72%, respectively). Both groups demonstrated an improvement in gait speed with no significant difference between those who received the nutritional supplement compared to the placebo (0.071 and 0.108 m/s, respectively (p=0.06)). Similar effects in physical function were observed using the SPPB. Serum 25(OH)D increased in supplemented group compared to placebo 7.4 ng/ml versus 1.3 ng/ml respectively. CONCLUSION: Results suggest improved gait speed following physical activity program with no further improvement with added nutritional supplementation.

Hypoxia-independent apoptosis in neural cells exposed to carbon monoxide in vitro.

The neurotoxic effects of carbon monoxide (CO) are well known. Brain hypoxia due to the binding of CO to hemoglobin is a recognized cause of CO neurotoxicity, while the direct effect of CO on intracellular targets remains poorly understood. In the present study, we have investigated the pathways leading to neural cell death induced by in vitro exposure to CO using a gas exposure chamber that we have developed. Mouse hippocampal neurons (HT22) and human glial cells (D384) were exposed to concentrations of CO ranging from 300 to 1000 ppm in the presence of 20% oxygen. Cytotoxicity was observed after 48 h exposure to 1000 ppm, corresponding to approximately 1 microM CO in the cultured medium, as measured by gas chromatography. CO induced cell death with characteristic features of apoptosis. Exposed cells exhibited loss of mitochondrial membrane potential, release of cytochrome c into the cytosol, nuclei with chromatin condensation, and exposure of phosphatidyl serine on the external leaflet of the plasma membrane. CO also triggered activation of caspase and calpain proteases. Pre-incubation with either the pancaspase inhibitor Z-VAD-fmk (20 microM) or the calpain inhibitor E64d (25 microM) reduced by 50% the occurrence of apoptosis. When pre-incubating the cells with the two inhibitors together there was an additional reduction in the number of cells with apoptotic nuclei. These data suggest that CO causes apoptosis via activation of parallel proteolytic pathways involving both caspases and calpains. Furthermore, pre-treatment with the antioxidant MnTBAP (100 microM) significantly reduced the number of apoptotic nuclei, pointing to a critical role of oxidative stress in CO toxicity.

Crystal structure of reduced protein R2 of ribonucleotide reductase: the structural basis for oxygen activation at a dinuclear iron site.

BACKGROUND: Ribonucleotide reductases (RNRs) catalyze the formation of the deoxyribonucleotides that are essential for DNA synthesis. The R2 subunit of Escherichia coli RNR is a homodimer containing one dinuclear iron centre per monomer. A tyrosyl radical is essential for catalysis, and is formed via a reaction in which the reduced, diferrous form of the iron centre activates dioxygen. To help understand the mechanism of oxygen activation, we examined the structure of the diferrous form of R2. RESULTS: The crystal structures of reduced forms of both wild type R2 and a mutant of R2 (Ser211--> Ala) have been determined at 1.7 A and 2.2 A resolution, respectively. The diferrous iron centre was compared to the previously determined structure of the oxidized, diferric form of R2. In both forms of R2 the iron centre is coordinated by the same carboxylate dominated ligand sphere, but in the reduced form there are clear conformational changes in three of the carboxylate ligands and the bridging mu-oxo group and two water molecules are lost. In the reduced form of R2 the coordination number decreases from six to four for both ferrous ions, explaining their high reactivity towards dioxygen. The structure of the mutant Ser211--> Ala, known to have impaired reduction kinetics, shows a large conformational change in one of the neighbouring helices although the iron coordination is very similar to the wild type protein. CONCLUSIONS: Carboxylate shifts are often important for carboxylate coordinated metal clusters; they allow the metals to achieve different coordination modes in redox reactions. In the case of reduced R2 these carboxylate shifts allow the formation of accessible reaction sites for dioxygen. The Ser211--> Ala mutant displays a conformational change in the helix containing the mutation, explaining its altered reduction kinetics.

Long-term prognosis after myocardial infarction in men with diabetes.

Men (1306) who survived a first myocardial infarction (MI) were studied. The mean follow-up time was 6.5 yr, and at the end of the follow-up period survival status was known for all patients. By the time of the MI the prevalence of diabetes was 5.6%. Patients with and without diabetes were compared. There were no differences in the estimated primary or secondary risk. The cumulative survival rate 1, 2, and 5 yr after the MI was 82, 78, and 58% among the diabetic subjects compared with 94, 92, and 82% among the nondiabetic subjects (P less than 0.001). The difference remained even after allowance for age and estimated secondary risk in a multivariate regression analysis. There were no differences in mortality rates among patients with type I diabetes compared with type II diabetes, nor among patients treated with diet alone, sulfonylurea, or insulin, but the numbers were small. The cumulative rate of reinfarctions after 1, 2, and 5 yr was 18, 28, and 46% in diabetic subjects and 12, 17, and 27% in nondiabetic subjects (P = 0.004). A history of diabetes was an independent secondary risk factor among male survivors of a first MI with respect to deaths and reinfarctions.

Crystallization and preliminary crystallographic analysis of the signal recognition particle SRPphi14-9 fusion protein.

The SRPphi14-9 fusion protein, which can functionally replace the SRP9/14 heterodimer in the mammalian signal recognition particle (SRP), has been crystallized using the vapor diffusion method. Four different crystal forms were grown. SRPphi14-9 form IV crystals belong to the space group P4(1)22/ P4(3)22 with cell parameters a = b = 69.7 Angstroms, c = 95.7 Angstroms, alpha = beta = gamma = 90 degrees. A complete data set to 2.8 Angstroms resolution with an Rsym on intensities of 7.0% was collected on a single flash-frozen crystal.

Crystallization and preliminary X-ray analysis of the 9 kDa protein of the mouse signal recognition particle and the selenomethionyl-SRP9.

Two different crystal forms of the 9 kDa protein of the signal recognition particle (SRP9) have been prepared by the hanging drop vapor diffusion technique using 28% (w/v) PEG8000 or 28% saturated ammonium sulphate as precipitant. The crystals are hexagonal bipyramids with average dimensions of 0.2 X 0.1 X 0.1 mm(3) and they diffract to a resolution of 2.3 Angstroms. They belong to the space groups P6(2)22/P6(4)22 or P3(1)21/P3(2)21 with cell dimensions a = b = 63.0 Angstroms, and c = 111.5 Angstroms. Crystals have also been grown from the selenomethionyl protein and multiwavelength data sets have been collected.

Diseases and drugs causing prolongation of the QT interval.

The prolonged QT interval and its association with diseases and drugs was studied on the basis of computerized electrocardiograms recorded in the region of the Kuopio University Central Hospital, East Finland. Altogether, 33,655 persons in whom at least 1 electrocardiogram was recorded from 1975 to 1983 were found. The study population consisted of 183 persons with prolonged QT intervals (at least 470 ms) and 187 with normal QTc intervals (440 ms or less), aged 45 to 64 years. These subjects were selected from 14,990 persons eligible. No difference in the prevalence of diseases affecting the QTc interval was found between those with long QTc intervals and those with normal QTc intervals. No difference between the groups was found in use of quinidine, procainamide or disopyramide. When the comparison was made on the basis of all group 1A antiarrhythmic drugs (quinidine, procainamide and disopyramide combined), persons with prolonged QTc intervals used these drugs more often than did those with normal QTc intervals (p = 0.031). Use of sotalol was significantly more common (p less than 0.001) in subjects with long QTc intervals. The mortality rate was also higher in persons with prolonged QTc interval (p less than 0.001), and most deaths during follow-up were due to coronary artery disease.

Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris.

The effects of single doses of felodipine (5 and 10 mg) and nifedipine (10 and 20 mg) on chronic stable effort angina pectoris were assessed in a placebo-controlled, double-blind, crossover study of 24 patients receiving beta blockers and short-acting nitroglycerin. The effects were measured by repeated bicycle ergometer tests. The total work, and time until 1 mm of ST depression increased significantly by 9 to 31% after both active drugs at both dose levels in comparison with placebo. The differences were not significant between drugs or doses. At rest, blood pressure decreased (10 to 15%) and heart rate increased (5 to 10%) significantly after both active drugs. During exercise at the highest comparable work load, systolic blood pressure decreased significantly (23 to 26%), whereas heart rate was not affected after felodipine and nifedipine compared with placebo. The 2 drugs were well tolerated, and side effects were mild. Therefore, single doses of 5 and 10 mg of felodipine, and 10 and 20 mg of nifedipine have similar antianginal and anti-ischemic properties. However, felodipine has a longer duration of action, which may improve compliance.

Mononitrates as monotherapy in the prophylactic treatment of angina pectoris.

This article reviews the results of double-blind comparative studies on the therapeutic use of isosorbide 5-mononitrate as monotherapy in the prophylaxis of angina pectoris. Isosorbide 5-mononitrate appears at least as effective as the same dosage of isosorbide dinitrate and is probably superior to the calcium antagonists. Recent data have shown that isosorbide 5-mononitrate in a controlled-release formulation given once daily has a significantly better antianginal effect than placebo without inducing the development of tolerance.

Abrupt withdrawal of isosorbide 5-mononitrate (Imdur) after long term treatment in stable angina pectoris. A preliminary report.

32 patients with stable angina pectoris who had been receiving a controlled-release formulation Durules of isosorbide 5-mononitrate (Imdur) 60 to 120 mg daily with concomitant beta-blocker therapy for at least 1 year were entered into a study to evaluate possible rebound phenomena from the abrupt withdrawal of isosorbide 5-mononitrate and to determine whether nitrate tolerance had developed. Isosorbide 5-mononitrate was abruptly withdrawn and substituted with placebo for 2 weeks, after which the active drug was reintroduced. No deterioration of exercise performance could be detected during withdrawal of therapy, but an increase was seen after reinstitution. No tolerance was found for systolic blood pressure and ST segment changes or for the number of anginal attacks and short-acting glyceryl trinitrate tablets consumed. Three patients had to be hospitalised because of a sudden deterioration of symptoms on withdrawal of isosorbide 5-mononitrate. It was concluded that isosorbide 5-mononitrate in Durules has a beneficial effect and that tolerance does not appear to be clinically relevant.

Congenital malformations after the use of inhaled budesonide in early pregnancy.

OBJECTIVE: To study possible teratogenic risks with the use of an inhaled glucocorticoid, budesonide, in early pregnancy. METHODS: Using the Swedish Medical Birth Registry, congenital malformations were studied in 2014 infants whose mothers had used inhaled budesonide for asthma in early pregnancy. The presence of congenital malformations was checked further with auxiliary registries. RESULTS: No increase in the general rate of congenital malformations was observed: 3.8% (95% confidence interval [CI] 2.9, 4.6) of the infants had a congenital malformation diagnosed, which is similar to the population rate (3.5%). After exposure to budesonide, four infants were born with orofacial clefts; this also is similar to the expected number (3.3). CONCLUSION: Even though a specific teratogenic effect of use of budesonide in early pregnancy cannot be ruled out, it is unlikely that a clinically significant teratogenic risk exists.

Fetal growth is not associated with early onset of severe retinopathy in type 1 diabetes mellitus.

Reduced fetal growth has been suggested as a possible risk factor for diabetic nephropathy. The aim of the present study was to examine whether there could be an association also with rapidly progressing severe retinopathy in younger type 1 diabetic patients. Maternal pregnancy, as well as birth parameters of 27 type 1 diabetic patients with severe retinopathy diagnosis at a median age of 25 years, were studied retrospectively. The control group consisted of 22 type 1 diabetic patients with mild background retinopathy and with similar age, age at onset, and duration of diabetes. Mothers of the subjects with severe retinopathy had a higher body mass index (P = 0.03) but similar age, blood pressure levels, and weight gain during pregnancy as those of the control group. All but four babies, two in each group, were born after 37 completed gestational weeks. There were no differences regarding birth weight or of relative birth weight corrected for gestational length. Head circumference, birth length, and placenta weight were similar. The results indicate that fetal growth is not a factor of major importance for the development of severe retinopathy in younger type 1 diabetic patients.

Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes.

BACKGROUND: Diabetes type 1 is associated with an increased risk for infant congenital malformations. It is debated whether this is true also at gestational diabetes. AIMS: To study occurrence of congenital malformations in infants whose mothers had preexisting or gestational diabetes. STUDY DESIGN: A register study covering over 1.2 million Swedish births in 1987-1997 based on the Swedish health registries. SUBJECTS: We identified from the Medical Birth Registry 3864 infants born of women with preexisting diabetes and 8688 infants born of women with gestational diabetes. OUTCOMES MEASURES: Congenital malformations identified in the Medical Birth Registry, the Registry of Congenital Malformations, and the Hospital Discharge Registry. The rates of congenital malformations among these infants was compared with the population rates. RESULTS: At preexisting diabetes, the total malformation rate was 9.5% while the rate at gestational diabetes was similar to the population rate, 5.7%. At preexisting diabetes, certain conditions were more common than expected: orofacial clefts, cardiovascular defects, oesophageal/intestinal atresia, hypospadias, limb reduction defects, spine malformations, and polydactyly. For some of these conditions, an excess was found also for infants whose mothers had gestational diabetes. Infants with multiple malformations were in excess at preexisting diabetes but not at gestational diabetes but the specific type of malformations involved were similar in the two diabetes groups. CONCLUSIONS: It is suggested that in the group of gestational diabetes exists a subgroup with an increased risk for a diabetes embryopathy, perhaps due to preexisting but undetected diabetes type 2.

Caries prevalence and distribution in 3-20-year-olds in Jönköping, Sweden, in 1973, 1978, 1983, and 1993.

Four cross-sectional studies were carried out in 1973, 1978, 1983, and 1993 to collect clinical and radiographic epidemiological data on the dental health status of the inhabitants of Jönköping, Sweden. The aim of the present paper was to use these data to analyze trends in the development of caries among children and adolescents between 1973 and 1993. Approximately 500 randomly selected individuals evenly distributed among the age groups 3, 5, 10, 15, and 20 years participated in each study. The main results show that the numbers of caries-free individuals increased in all age groups. In 1993, the mean number of decayed and filled tooth surfaces in the primary (dfs) and the permanent (DFS) dentition in all age groups was less than half of that found in 1973. Most of this decrease took place during the first 5 years, i.e., between 1973 and 1978. Between 1978 and 1983, only minor changes were observed. There was a further reduction of approximately 30%-50% in dfs/DFS between 1983 and 1993 in 3-, 5-, 10-, and 20-year-olds. The frequency distributions of dfs/DFS for 5- and 15-year-olds revealed an increasing skewness over time: in 1993, a large majority of the children and adolescents had a low or moderate caries severity while only a small group had high scores of dfs/DFS.