Rib fractures after blunt thoracic trauma in patients with normal versus diminished bone mineral density: a retrospective cohort study.

This study aimed to evaluate rib fracture rate as well as rib fracture characteristics after thoracic trauma in patients with normal versus diminished bone mineral density (BMD). A retrospective cohort study of persons aged 50 years or older presenting to the Emergency Department after sustaining blunt thoracic trauma between July 1, 2014, and December 31, 2017, was performed. Patient and trauma characteristics and DXA scan results were collected. Rib fracture rate and characteristics were evaluated on a radiograph and/or CT scan of the thorax. In total, 119 patients were included for analysis. Fifty-eight of them (49%) had a diminished BMD. In the remaining 61, the BMD was normal. The diminished BMD group experienced rib fractures more often than the normal BMD group (n = 43 (74%) versus n = 31 (51%); p = 0.014). Patients with diminished BMD suffered low-energy trauma more frequently than the normal BMD group (21 (36%) versus 11 patients (15%), respectively (p = 0.011)). Rib fracture characteristics such as the median number of rib fractures, concomitant intrathoracic injury rate, and rib fracture type distribution were not different between the groups. The rate of rib fractures after blunt thoracic trauma was significantly higher in patients with diminished BMD than in patients with a normal BMD. Differences in number and location of rib fractures between groups could not be proven. When assessing patients aged 50 years or older presenting to the hospital after substantial blunt thoracic trauma, the presence of diminished BMD should be taken into account and the presence of rib fractures should be investigated with appropriate diagnostic procedures. Diminished bone mineral density (i.e., osteopenia or osteoporosis) is associated with increased fracture risk. This study evaluated if diminished BMD increases the rib fracture risk. Patients with diminished BMD have a higher risk of sustaining rib fractures after substantial blunt thoracic trauma, which implicates a lower threshold for CT imaging of the chest.

Was Eysenck right after all? A reassessment of the effects of psychotherapy for adult depression.

AIMS: In the 1950s, Eysenck suggested that psychotherapies may not be effective at all. Twenty-five years later, the first meta-analysis of randomised controlled trials showed that the effects of psychotherapies were considerable and that Eysenck was wrong. However, since that time methods have become available to assess biases in meta-analyses. METHODS: We examined the influence of these biases on the effects of psychotherapies for adult depression, including risk of bias, publication bias and the exclusion of waiting list control groups. RESULTS: The unadjusted effect size of psychotherapies compared with control groups was g = 0.70 (limited to Western countries: g = 0.63), which corresponds to a number-needed-to-treat of 4.18. Only 23% of the studies could be considered as a low risk of bias. When adjusting for several sources of bias, the effect size across all types of therapies dropped to g = 0.31. CONCLUSIONS: These results suggest that the effects of psychotherapy for depression are small, above the threshold that has been suggested as the minimal important difference in the treatment of depression, and Eysenck was probably wrong. However, this is still not certain because we could not adjust for all types of bias. Unadjusted meta-analyses of psychotherapies overestimate the effects considerably, and for several types of psychotherapy for adult depression, insufficient evidence is available that they are effective because too few low-risk studies were available, including problem-solving therapy, interpersonal psychotherapy and behavioural activation.

Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion.

Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.

Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.

De novo mutations in specific mTOR pathway genes cause brain overgrowth in the context of intellectual disability (ID). By analyzing 101 mMTOR-related genes in a large ID patient cohort and two independent population cohorts, we show that these genes modulate brain growth in health and disease. We report the mTOR activator gene RHEB as an ID gene that is associated with megalencephaly when mutated. Functional testing of mutant RHEB in vertebrate animal models indicates pathway hyperactivation with a concomitant increase in cell and head size, aberrant neuronal migration, and induction of seizures, concordant with the human phenotype. This study reveals that tight control of brain volume is exerted through a large community of mTOR-related genes. Human brain volume can be altered, by either rare disruptive events causing hyperactivation of the pathway, or through the collective effects of common alleles.

Note: femtosecond laser micromachining of straight and linearly tapered capillary discharge waveguides.

Gas-filled capillary discharge waveguides are important structures in laser-plasma interaction applications, such as the laser wakefield accelerator. We present the methodology for applying femtosecond laser micromachining in the production of capillary channels (typically 200-300 µm in diameter and 30-40 mm in length), including the formalism for capillaries with a linearly tapered diameter. The latter is demonstrated to possess a smooth variation in diameter along the length of the capillary (tunable with the micromachining trajectories). This would lead to a longitudinal plasma density gradient in the waveguide that may dramatically improve the laser-plasma interaction efficiency in applications.

Phase-space manipulation of ultracold ion bunches with time-dependent fields.

All applications of high brightness ion beams depend on the possibility to precisely manipulate the trajectories of the ions or, more generally, to control their phase-space distribution. We show that the combination of a laser-cooled ion source and time-dependent acceleration fields gives new possibilities to perform precise phase-space control. We demonstrate reduction of the longitudinal energy spread and realization of a lens with control over its focal length and sign, as well as the sign of the spherical aberrations. This creates new possibilities to correct for the spherical and chromatic aberrations which are presently limiting the spatial resolution.

Low-energy-spread ion bunches from a trapped atomic gas.

We present time-of-flight measurements of the longitudinal energy spread of pulsed ultracold ion beams, produced by near-threshold ionization of rubidium atoms captured in a magneto-optical atom trap. Well-defined pulsed beams have been produced with energies of only 1 eV and a root-mean-square energy spread as low as 0.02 eV, 2 orders of magnitude lower than the state-of-the-art gallium liquid-metal ion source. The low energy spread is important for focused ion beam technology because it enables milling and ion-beam-induced deposition at sub-nm length scales with many ionic species, both light and heavy. In addition, we show that the slowly moving, low-energy-spread ion bunches are ideal for studying intricate space charge effects in pulsed beams. As an example, we present a detailed study of the transition from space charge dominated dynamics to ballistic motion.

Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat.

To elucidate the role of intestinal bacteria in the conversion of phylloquinone into menaquinone-4 (MK-4) we investigated the tissue distribution of vitamin K in germ-free rats. The rats were made vitamin K deficient by feeding a vitamin K-free diet for 13 days. In a subsequent period of 6 days, phylloquinone and menadione were supplied via the drinking water in concentrations of 10 and 50 micromol l(-1). Menadione supplementation led to high levels of tissue MK-4, particularly in extrahepatic tissues like pancreas, aorta, fat and brain. Liver and serum were low in MK-4. Phylloquinone supplementation resulted in higher phylloquinone levels in all tissues when compared with vitamin K-deficient values. The main target organs were liver, heart and fat. Remarkably, tissue MK-4 levels were also higher after the phylloquinone supplementation. The MK-4 tissue distribution pattern after phylloquinone intake was comparable with that found after menadione intake. Our results demonstrate that the conversion of phylloquinone into MK-4 in extrahepatic tissues may occur in the absence of an intestinal bacterial population and is tissue specific. A specific function for extrahepatic MK-4 or a reason for this biochemical conversion of phylloquinone into MK-4 remains unclear thus far.

Phylloquinone and menaquinone-4 distribution in rats: synthesis rather than uptake determines menaquinone-4 organ concentrations.

To clarify the origin of organ menaquinone-4 (MK-4), the distributions of phylloquinone and MK-4 were investigated in rats fed diets containing phylloquinone, MK-4 or menadione (1.1, 2.2 and 31 mumol/kg diet, respectively, 6 rats per group). Warfarin (2 x 1 mg/kg subcutaneously) was given (3 rats per group) to study the effect of vitamin K cycle blockage. In rats fed phylloquinone the vitamin accumulated mainly in liver and heart. Additionally, the diet resulted in significantly higher organ MK-4 concentrations compared with the vitamin K-deficient controls. The epoxide of MK-4 also was significantly higher in some organs. The MK-4 diet increased MK-4 concentration primarily in the heart, liver and lung. Rats fed menadione had significantly higher MK-4 and MK-4 epoxide concentrations in all organs examined. The greatest accumulations were in nonhepatic organs, particularly the pancreas, salivary gland and brain. Generally, liver and plasma had low MK-4 concentrations. Warfarin treatment lowered significantly the MK-4 concentrations, whereas MK-4 epoxide accumulated. The study shows the following: 1) dietary phylloquinone is accumulated mainly in the heart and liver, 2) the MK-4 accumulation in nonhepatic organs is due to synthesis rather than uptake and 3) MK-4 rather than phylloquinone may be the functional vitamin in nonhepatic organs.

Vitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4.

We measured the vitamin K status in postmortem human tissues (brain, heart, kidney, liver, lung, pancreas) to see if there is a tissue-specific distribution pattern. Phylloquinone (K1) was recovered in all tissues with relatively high levels in liver, heart and pancreas (medians, 10.6 (4.8), 9.3 (4.2), 28.4 (12.8) pmol(ng)/g wet weight tissue); low levels (< 2 pmol/g) were found in brain, kidney and lung. Menaquinone-4 (MK-4) was recovered from most of the tissues; its levels exceeded the K1 levels in brain and kidney (median, 2.8 ng/g) and equalled K1 in pancreas. Liver, heart and lung were low in MK-4. The higher menaquinones, MK-6-11, were recovered in the liver samples (n 6), traces of MK-6-9 were found in some of the heart and pancreas samples. The results show that in man there are tissue-specific, vitamin-K distribution patterns comparable to those in the rat. Furthermore, the accumulation of vitamin K in heart, brain and pancreas suggests a hitherto unrecognized physiological function of this vitamin.

Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4.

The present study was undertaken to determine whether there is selective tissue distribution of vitamin K in the rat and whether this distribution mirrors the distribution of tissue vitamin K metabolism. The effects of feeding a vitamin K-free diet followed by resupplementation with phylloquinone (K1) were studied. K1 was recovered in all tissues. In K1-supplemented rats, most tissues accumulated K1 relative to plasma K1 with the highest levels in liver, heart, bone, and cartilaginous tissue (sternum). Low K1 levels were found in the brain. In the K1-free rats, relatively high K1 levels were still found in heart, pancreas, bone and sternum. Surprisingly, menaquinone-4 (MK-4) was detected in all tissues, with low levels in plasma and liver, and much higher levels in pancreas, salivary gland and sternum. MK-4 levels exceeded K1 levels in brain, pancreas, salivary gland and sternum. Supplementation with K1, orally and by intravenous infusion, caused MK-4 levels to rise. Some accumulation of K1 and MK-4 in the mitochondrial fraction was found for kidney, pancreas and salivary gland. In the liver the higher menaquinones (MK-6-9) accumulated in the mitochondria. The results indicate that: (1) there is selective tissue distribution of K1 and MK-4, (2) dietary K1 is a source of MK-4. The results also suggest there may be an as yet unrecognized physiological function for vitamin K (MK-4).

Vitamin K status and parenteral nutrition; the effect of Intralipid on plasma vitamin K1 levels.

Parenteral nutrition may affect the patient's vitamin K status. This imposes a risk when using drugs that interfere with the vitamin K-dependent clotting factor synthesis, such as N-methyl-thiotetrazole-containing cephalosporins. Intravenous lipid emulsions based on plant oils may contain phylloquinone (vitamin K1). We estimated the vitamin K1 content of the intravenous lipid emulsion product Intralipid (20%), an emulsion based on soybean oil, and estimated the vitamin K1 status of recipient patients. The emulsion was found to contain 0.6-0.7 micrograms/ml of the vitamin. Patients supplied with the product per continuous intravenous infusion, showed a steady increase of their plasma vitamin K1 levels, 3-30-fold over 4 days of infusion. In conclusion, the study shows that fat emulsions prepared from plant oils may contain vitamin K1 in sufficient amounts to meet the daily requirement.

Vitamin K metabolism and vitamin K1 status in human liver samples: a search for inter-individual differences in warfarin sensitivity.

Vitamin K-dependent parameters in human liver samples were investigated to find a clue to the inter-individual differences in sensitivity for oral anticoagulants. Vitamin K epoxide reductase and vitamin K-dependent carboxylase activity differed 2-3-fold between the samples. Microsomal warfarin binding correlated significantly with the reductase activity. Microsomal vitamin K epoxide reductase of the different samples showed equal sensitivity for warfarin inhibition, I50 about 0.1 microM. Vitamin K epoxide reductase activity stimulated by NADH/lipoamide and microsomal lipoamide dehydrogenase activity showed higher inter-subject variability than the reductase activity by itself. Liver vitamin K1 levels varied 4-5-fold. Total and liver microsomal vitamin K1 levels were correlated. One of the liver samples was obtained from a donor anticoagulated with phenprocoumon and additionally treated with vitamin K1. High levels of the vitamin and its epoxide were present. Phenprocoumon was essentially irreversibly bound to the microsomes. In general the results confirm inter-individual differences in the hepatic vitamin K-dependent systems; the differences as such were found to be small. However, as the various parameters can work synergistically in the same direction, they may well account for the wide dose range observed in oral anticoagulant therapy.

Cytokinetic analysis of lung cancer by bromodeoxyuridine labeling of cytology specimens.

Recent flow cytometric (FCM) studies have indicated the prognostic value of S-phase cells (SPF) in lung cancer. More refined cytokinetic analysis can be obtained by dual-parameter FCM, labeling S-phase cells with 5-bromodeoxyuridine (BrdUrd), which can be detected using a monoclonal antibody (MoAb) to BrdUrd. Tumor cells obtained through bronchoscopic brush were incubated for 1 hr in RPMI 1640 medium with 10% fetal calf serum and 10 microM BrdUrd. After fixation in ethanol, pepsin treatment, and DNA denaturation, the nuclei were stained with anti-BrdUrd MoAb and propidium iodide. From 14 of 20 patients, sufficient material was obtained (three adenocarcinoma and seven squamous cell, one giant cell, and three small cell carcinoma). The measured SPF ranged from 5.2% to 26%. The labeling index (LI), calculated as the ratio of the number of BrdUrd-labeled cells to the total number of aneuploid cells, or diploid cells in the case of a diploid tumor, ranged from 1.2% to 16.7%; LI and SPF correlated significantly (r = 0.69). In this study, we have demonstrated the feasibility of determining the actively DNA-synthesizing cells on brush material from lung cancer cells. In addition, some extra information can be obtained about the SPF population, including the fraction of unlabeled SPF, which could be of prognostic significance.

The effect of S-warfarin administration on vitamin K 2,3-epoxide reductase activity in liver, kidney and testis of the rat.

The dithiothreitol-dependent vitamin K 2,3-epoxide (vitamin KO) reductase activity was assayed in rat liver, kidney and testis microsomes. Rat kidney and testis showed vitamin KO reductase activity. The activity was about one tenth of the activity present in liver microsomes. The effect of in vivo S-warfarin was investigated after single doses, i.e. 0.2, 0.4 and 1 mg/kg, and after its chronic administration, i.e. 4.8 micrograms/kg/hr for 3 days. At 20 hr following the acute warfarin administration vitamin KO reductase in liver microsomes was depressed in a dose-dependent way, 50, 30 and 20% of control activity. Vitamin KO reductase in testis was not affected, and in kidney reductase activity was only reduced after the highest warfarin dose, 40% of control activity. Following chronic administration of warfarin, vitamin KO reductase activity was reduced in liver as well as in kidney and testis microsomes, 15-20, 40 and 60% of control activity in liver, kidney and testis, respectively. Blood clotting activity was about 14% of normal (thrombotest). Vitamin KO reductase activity in tissue microsomes was inhibited by warfarin added in vitro. Tissue and microsomal warfarin concentration were assayed. Following the acute administration, warfarin was poorly distributed into kidney and testis. Following the chronic administration, warfarin tissue to plasma ratio was about 3 for liver, but 0.5 for kidney and testis. The results indicate that during chronic therapy with oral anticoagulants vitamin K-dependent systems in non-hepatic tissues are reduced. However, this reduction is less than the reduction of the hepatic system. This is determined mainly by the pharmacokinetic behaviour of the 4-hydroxycoumarins.

B16 tumor cells contain a warfarin sensitive vitamin K1 2,3 epoxide reductase.

Using an adapted assay that requires an enzyme aliquot that forms only 5 pmoles vitamin K, we were able to demonstrate vitamin K1 2,3 epoxide reductase activity in cultured B16 mouse melanoma cells. The enzyme uses dithiothreitol, but not NADH as a reducing cofactor and is sensitive to inhibition by warfarin (2% residual activity at 10 micrograms/ml warfarin). Incubation of B16 cells in culture with 30 micrograms/ml warfarin leads to an 45% residual reductase as compared to normally cultured B16 cells. Combined with the reported presence of vitamin K dependent carboxylase in B16 cells and the cytotoxicity of warfarin towards B16 cells this suggests an active vitamin K cycle in these melanoma cells that may be essential for survival.

Stereoselective aspects in the pharmacokinetics and pharmacodynamics of acenocoumarol and its amino and acetamido derivatives in the rat.

The stereoselectivity of the pharmacokinetics and of the pharmacodynamics of the oral anticoagulant acenocoumarol (AC) and of two of its potential metabolites, the amino (AM) and the acetamido (AA) derivatives, were investigated in the rat. The pharmacokinetics and pharmacodynamics were investigated following the acute subcutaneous (1 mg/kg) administration of the pure enantiomers. For AC and AA, the S(-)-enantiomer was preferentially eliminated, whereas for AM the R(+)-enantiomer showed the shortest half-life. The differences in elimination between the AC enantiomers were entirely due to differences in total clearance, 183 +/- 14 and 714 +/- 148 ml X h-1 X kg-1 (+/- SD) for R(+)- and S(-)-AC. Also the differences in elimination between the AM enantiomers were mainly due to differences in body clearance, 50 +/- 13 and 18 +/- 4 ml X h-1 X kg-1 for R(+)- and S(-)-AM. For S(-)-AA the higher total clearance as well as the smaller volume of distribution accounted for its 2-fold higher rate of elimination. Acetylation of AM, i.e. the conversion to AA, which accounted for about 50% of its total clearance was stereoselective for R(+)-AM. The renal clearance of AA which accounted for 50-60% of the AA clearance was not selective for one of the AA enantiomers. Stereoselectivity in plasma protein binding was observed, the differences, however, were small. Thus, stereoselectivity in plasma protein binding did not account for the observed differences in the pharmacokinetics. The differences in anticlotting activity between the enantiomers of AC and AM were determined mainly by their pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Acenocoumarol and its amino and acetamido metabolites. Comparative pharmacokinetics and pharmacodynamics in the rat.

The elimination, distribution and anticoagulant activity of racemic acenocoumarol, its amino (AM) and acetamido (AA) derivative were determined in male Wistar rats after subcutaneous injection of a single dose of 2 mg kg-1. The effect of daily administration of acenocoumarol on the prothrombin complex activity (PCA) was also investigated. A rapid onset of the hypothrombogenic effect was observed for all three derivatives with the half-life of decline of PCA = 3.6 h. The duration of the hypothrombogenic effect was short for the drug and its AA derivative and long for the AM compound (normalization at about 24 and 70 h, respectively), parallelling the half-life of elimination of the compounds of, 3.3, 4, and 8 h respectively. Daily administration of acenocoumarol for 8 days showed no change in the kinetics of the anticoagulant effect. Elimination of the drug is solely by metabolism. Reduction of the 4'-nitro group was not a metabolic route of importance; the amount of its two derivatives cumulatively excreted in urine over 5 days accounted for 2-3% of the dose only. Elimination of AM derivative is mainly by acetylation to AA, the compound which itself is eliminated by renal excretion. The distribution of acenocoumarol between liver and plasma was determined. The liver to plasma ratio was higher than 1 beyond 10 min after administration. The elimination rate of the drug from liver was slower than from plasma giving an increase in liver to plasma ratio in time. Plasma protein binding was extensive, being the highest for the drug; 1.81, 2.84 and 3.89% free for drug, AM, and AA derivative, respectively.

Analysis of acenocoumarin and its amino and acetamido metabolites in body fluids by high-performance liquid chromatography.

Acenocoumarin and its acetamido metabolite, after extraction at pH 4.4, were analysed by isocratic reversed-phase high-performance liquid chromatography using aqueous acetonitrile (pH 4.90) as eluent. Warfarin was used as internal standard. The amino metabolite, after back-extraction into 0.5 N HCl, was derivatized by diazotization and heat treatment. The resulting product was analysed by the same reversed-phase system. The sensitivity of the method for acenocoumarin and its amino metabolite was in the range of 20 ng/ml. To achieve this sensitivity for the analysis of the acetamido compound, the acetonitrile content of the eluent had to be lowered. The assay was applied to the analysis of plasma samples of patients under acenocoumarin therapy. The disposition of the amino compound in rats was investigated.