Hemorrhagic Transformation Rates following Contrast Media Administration in Patients Hospitalized with Ischemic Stroke.

BACKGROUND AND PURPOSE: Hemorrhagic transformation is a critical complication associated with ischemic stroke and has been associated with contrast media administration. The objective of our study was to use real-world in-hospital data to evaluate the correlation between contrast media type and transformation from ischemic to hemorrhagic stroke. MATERIALS AND METHODS: We obtained data on inpatient admissions with a diagnosis of ischemic stroke and a record of either iso-osmolar or low-osmolar iodinated contrast media for a stroke-related diagnostic test and a treatment procedure (thrombectomy, thrombolysis, or angioplasty). We performed multivariable regression analysis to assess the relationship between contrast media type and the development of hemorrhagic transformation during hospitalization, adjusting for patient characteristics, comorbid conditions, procedure type, a threshold for contrast media volume, and differences across hospitals. RESULTS: Inpatient visits with exclusive use of either low-osmolar (n = 38,130) or iso-osmolar contrast media (n = 4042) were included. We observed an overall risk reduction in hemorrhagic transformation among patients who received iso-osmolar compared with low-osmolar contrast media, with an absolute risk reduction of 1.4% (P = .032), relative risk reduction of 12.5%, and number needed to prevent harm of 70. This outcome was driven primarily by patients undergoing endovascular thrombectomy (n = 9211), in which iso-osmolar contrast media was associated with an absolute risk reduction of 4.6% (P = .028), a relative risk reduction of 20.8%, and number needed to prevent harm of 22, compared with low-osmolar contrast media. CONCLUSIONS: Iso-osmolar contrast media was associated with a lower rate of hemorrhagic transformation compared with low-osmolar contrast media in patients with ischemic stroke.

Multiscale response of the human skull to quasi-static compression.

Full thickness skull specimens were extracted from the human crania, with both the inner and outer surfaces intact. The BVF-morphology (bone volume fraction) of these specimens had been previously characterized in detail and reported, with high-resolution micro-computed tomography at ~5 µm resolution. A subset of these specimens was loaded in the direction normal to the outer surface in quasi-static compression. In contrast to many previous mechanical characterization studies of skulls, following two additional procedures were used in this study. (1) Fresh skull specimens were used, which were stored refrigerated before mechanical loading, instead of using embalmed or dried specimens. (2) Furthermore, using digital image correlation, non-contact full-field inhomogeneous strain measurements were made using the speckled specimen surfaces and the compression platens, also avoiding possible errors in strain measurements from machine compliance and due to irregularities in the loading surfaces of the specimen. The averaged far-field compressive mechanical response was obtained from these local full-field measurements on the composite bone specimens. Assuming a layered structure for the skull bone, using the local averaged full-field strain measurements of each layer, a power law was used to represent the relationship between initial mechanical response and the averaged BVF of the layers. Using the measured porosity maps of the rest of the non-compressed specimens, this relationship was used to predict the modulus-depth dependency of the skull bone and the variabilities associated with the structure. The mechanical properties and density as a function of the normalized thickness of the skull are presented for use in finite element simulations to model the skull with the desired degrees of complexities, also based on the region of action, depending on the goals of the computer simulation of the impact: either as a single homogenous layer, three-layer sandwich, multilayer heterogeneous or continuous elemental structure. In addition, a power law was derived relating the compressive failure strength and bone volume fraction (BVF) for the skull bone.

Influence of the mesostructure on the compressive mechanical response of adolescent porcine cranial bone.

The Göttingen minipig has been used as a surrogate in impact experiments designed to better understand the mechanisms by which mechanical loading induces traumatic brain injury (TBI). However, the relationship between mechanical response and structural morphology of the minipig cranium must be understood relative to the human skull in order to accurately scale any quantitative results, such as injury thresholds, from non-human TBI experiments to the human anatomy. In this study, bone specimens were dissected from the crania of adolescent Göttingen minipigs. These specimens were small cubes that contained the entire thickness of the skull. The microstructure of these skull specimens was quantified at the micron-length scale using micro-computed tomography (micro-CT). The skull was found to be highly porous near the skin-side surface and became less porous nearer the brain-side surface. The skull specimens were then loaded in quasi-static compression to obtain their mechanical response. The surface strain distribution on the specimen face was measured during loading using digital image correlation (DIC). The 2-D strain field formed a gradient of iso-strain bands along the thickness (depth) dimension from the skin-most to brain-most sides of the skull. The variation of the minipig microstructure along the thickness differed significantly from that of the adult human skull; thus the mechanical load transmission through the minipig skull is expected to be quite different from that of the human skull. The objective was to develop the methodology of relating the microstructure, as quantified by the bone volume fraction (BVF), to the mechanical response. The specimen was modeled by discretizing the depth dimension into a series of layers, which enabled the calibration of a power law relating the depth-dependent BVF to the depth-varying modulus. The relationship was used to predict moduli values for the adolescent minipig skull to provide updated, biofidelic parameters for finite element simulations at varying levels of complexity. Moreover, the methodology outlined in this paper can be applied to other skulls with different structural variations, such as the human.

Structural analysis of the frontal and parietal bones of the human skull.

Bone specimens were collected from the frontal and parietal bones of 4 adult, human skulls. The microstructure was characterized using microcomputed tomography (micro-CT) at about 6-µm resolution to map the change of porosity as a function of the depth, P(d), from the inner surface nearest to the brain to the outer surface nearest to the skin. A quantifiable method was developed using the measured P(d) to objectively distinguish between the three layers of the skull: the outer table, diploë , and inner table. The thickness and average porosity of each of the layers were then calculated from the measured porosity distributions, and a Gaussian function was fit to the P(d) curves. Morphological parameters were compared between the two bone types (frontal and parietal), while accounting for skull-to-skull variability. Parietal bones generally had a larger diploë accompanied by a thinner inner table. The arrangement of the porous vesicular structure within the outer table was also obtained with micro-CT scans with longer scan times, using enhanced parameters for higher resolution and lower noise in the images. From these scans, the porous structure of the bone appeared to be randomly arranged in the transverse plane, compared to the porous structure of the human femur, which is aligned in the loading direction.

Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death.

Familial dilated cardiomyopathy is a rare cause of dilated cardiomyopathy (DCM), especially in childhood. Our aim was to describe the clinical course and the genetic variants in a family where the proband was a four-month-old infant presenting with respiratory problems due to DCM. In the family, there was a strong family history of DCM and sudden cardiac death in four generations. DNA was analyzed initially from the deceased girl using next-generation sequencing including 50 genes involved in cardiomyopathy. A cascade family screening was performed in the family after identification of the TNNT2 and the BAG3 variants in the proband. The first-degree relatives underwent clinical examination including biochemistry panel, cardiac ultrasound, Holter ECG, exercise stress test, and targeted genetic testing. The index patient presented with advanced DCM. After a severe clinical course, the baby had external left ventricular assist as a bridge to heart transplantation. 1.5 months after transplantation, the baby suffered sudden cardiac death (SCD) despite maximal treatment in the pediatric intensive care unit. The patient was shown to carry two heterozygous genetic variants in the TNNT2 gene [TNNT2 c.518G>A(p.Arg173Gln)] and BAG3 [BAG3 c.785C>T(p.Ala262Val)]. Two of the screened individuals (two females) appeared to carry both the familial variants. All the individuals carrying the TNNT2 variant presented with DCM, the two adult patients had mild or moderate symptoms of heart failure and reported palpitations but no syncope or presyncopal attacks prior to the genetic diagnosis. The female carriers of TNNT2 and BAG3 variants had more advanced DCM. In the family history, there were three additional cases of SCD due to DCM, diagnosed by autopsy, but no genetic analysis was possible in these cases. Our findings suggest that the variants in TNNT2 and BAG3 are associated with a high propensity to life-threatening cardiomyopathy presenting from childhood and young adulthood.

Proliferative responses to altered 17beta-hydroxysteroid dehydrogenase (17HSD) type 2 expression in human breast cancer cells are dependent on endogenous expression of 17HSD type 1 and the oestradiol receptors.

The primary source of oestrogen in premenopausal women is the ovary but, after menopause, oestrogen biosynthesis in peripheral tissue is the exclusive site of formation. An enzyme group that affects the availability of active oestrogens is the 17beta-hydroxysteroid dehydrogenase (17HSD) family. In breast cancer, 17HSD type 1 and type 2 have been mostly investigated and seem to be the principal 17HSD enzymes involved thus far. The question whether 17HSD type 1 or type 2 is of greatest importance in breast tumour development is still not clear. The aim of this study was to investigate how the loss of 17HSD type 2 expression, using siRNA in the non-tumour breast epithelial cells HMEC (human mammal epithelial cells) and MCF10A, and gain of 17HSD type 2 expression, using transient transfection in the breast cancer derived cell lines MCF7 and T47D, affect oestradiol conversion and proliferation rate measured as S-phase fraction. We further investigated how this was related to the endogenous expression of 17HSD type 1 and oestradiol receptors in the examined cell lines. The oestradiol level in the medium changed significantly in the MCF7 transfected cells and the siRNA-treated HMEC cells, but not in T47D or MCF10A. The S-phase fraction decreased in the 17HSD type 2-transfected MCF7 cells and the siRNA-treated HMEC cells. The results seemed to be dependent on the endogenous expression of 17HSD type 1 and the oestradiol receptors. In conclusion, we found that high or low levels of 17HSD type 2 affected the oestradiol concentration significantly. However, the response was dependent on the endogenous expression of 17HSD type 1. Expression of 17HSD type 1 seems to be dominant to 17HSD type 2. Therefore, it may be important to investigate a ratio between 17HSD type 1 and 17HSD type 2.

17beta-Hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer.

The 17beta-hydroxysteroid dehydrogenase (17HSD) enzymes are involved in the local regulation of sex steroids. The 17HSD type 1 enzyme catalyses the interconversion of the weak oestrone (E1) to the more potent oestradiol (E2), whereas 17HSD type 2 catalyses the oxidation of E2 to E1. The aim of this study was to correlate the expression of these enzymes in the tumour with the recurrence-free survival of tamoxifen-treated breast cancer patients. We used real-time reverse transcriptase PCR to investigate the mRNA expression of 17HSD types 1 and 2 in tumour samples from 230 postmenopausal patients. For the patients with oestrogen receptor (ER)-positive breast cancer, we found a statistically significant positive correlation between recurrence-free survival and expression of 17HSD type 2 (P=0.026). We examined the ratio of 17HSD types 2 and 1, and ER-positive patients with low ratios showed a significantly higher rate of recurrence than those with higher ratios (P=0.0047). ER positive patients with high expression levels of 17HSD type 1 had a significantly higher risk for late relapse (P=0.0051). The expression of 17HSD types 1 and 2 in breast cancer differs from the expression of these enzymes in normal mammary gland, and this study indicates that the expression has prognostic significance in breast cancer.

Abnormal expression of 17beta-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence.

The 17beta-hydroxysteroid dehydrogenase (17beta-HSD) enzymes are involved in the interconversion of biologically active and inactive sex steroids and are considered to play a critical role in the in situ metabolism of estrogen, especially in estrogen-dependent breast cancer. The gene encoding 17beta-HSD type 2 is located at 16q24.1-2, and earlier studies have shown that allelic loss in this region is an early and frequent event in breast cancer progression. Recurrence of hormone-dependent breast cancer frequently occurs several years after the primary treatment. The aim of this study was to investigate whether the expression of 17beta-HSD types 1 and 2 differs in tumors from patients with late relapses (>5 years) compared with controls without recurrence after long-term follow-up. Using real-time reverse transcription-PCR, we found that the normal mammary gland expressed both 17beta-HSD types 1 and 2, whereas the tumors frequently lacked detectable levels of type 2. Only 10% of the estrogen receptor-positive tumors expressed type 2, whereas 31% of the ER-negative tumors did so (P = 0.031). In a case-control series of 84 patients, a high level of 17beta-HSD type 1 indicated increased risk to develop late relapse of breast cancer (odds ratio, 3.0; 95% confidence interval, 1.0-12.6; P = 0.041), whereas retained expression of type 2 indicated decreased risk (odds ratio, 0.25; 95% confidence interval, 0.05-1.2; P = 0.050). In multivariate analysis of the estrogen receptor-positive patients, the absence of 17beta-HSD type 2 combined with a high expression of type 1 showed prognostic significance (P = 0.016) in addition to DNA aneuploidy (P = 0.0058), whereas progesterone receptor status did not (P = 0.71). These findings suggest that abnormal expression of 17beta-HSD isoforms has prognostic significance in breast cancer and that altered expression of these enzymes may have importance in breast cancer progression.

The frequency of anti-C + anti-G in the absence of anti-D in alloimmunized pregnancies.

Anti-D+C are often initially identified in sera from alloimmunized women. Anti-G may be present in these samples, mimicking anti-D+C, and therefore the differentiation of anti-D, -C and -G may be important. Sera from 27 alloimmunized women, initially identified as containing anti-D + anti-C, were analysed by adsorption/elution studies in the presence of polyethylene glycol (PEG) using R(0)r (D+C-G+) and r'r(D-C+G+) red blood cells (RBC). Additionally, 15/27 samples were tested by adsorption in the presence of PEG and subsequently warm elution, using rGr (D-C-G+) RBC. Anti-G + anti-C, without anti-D, were identified in 4/27 samples (14.8%) and none of the newborn children needed postpartum treatment. The combination of D+G, D+C and D+C+G antibodies occurred in 25.9%, 11.1% and 48.1% of the women, respectively. Overall, anti-G was detected in 24/27 samples (88.9%). Pregnant women shown to have anti-G+C but not anti-D should receive Rh immune globulin. Additionally, the finding of apparent anti-D+C during pregnancy in D-negative spouses may lead to paternity testing and therefore a correct antibody identification is necessary.

Hypersecretion of ovarian androgens may be gonadotrophin dependent many years after menopause.

BACKGROUND: In fertile women both adrenals and ovaries contribute to androgen production, whereas after the menopause the ovarian contribution normally decreases. OBJECTIVE: The objective of this case study was to assess whether ovarian androgen secretion was responsive to decreased gonadotrophin stimulation and whether gonadotrophins were sensitive to negative feedback from sex steroids many years after the menopause. METHODS: In this uncontrolled case study a 72 years old slightly overweight woman with noninsulin-dependent diabetes mellitus presented with hirsuitism and elevated serum testosterone concentrations. The woman was reluctant to have an oophorectomy, and received an oral estradiol/progestagene preparation. Serum testosterone and gonadotrophin concentrations were measured before and after steroid hormone therapy. RESULTS: Serum gonadotrophin concentrations decreased and testosterone levels returned to normal during therapy. When the hormone therapy was stopped for 1 month the high testosterone concentrations returned, but were again normalized when the hormone therapy was reinitiated. CONCLUSION: The ovaries of this woman were apparently still responsive to pituitary stimulation and her hypothalamic pituitary ovarian feed-back system still seemed to be working after 70 years of age.

Why are psychotropic drugs prescribed to out-patients? A methodological study.

The prescription of psychotropic drugs at a multidoctor district health centre in northern Sweden in 1973, was analysed by means of problem-oriented medical records. Of the 22,000 inhabitants of the district 10,700 consulted the health centre. Psychotropic drugs were prescribed for 11.3% of the patients, corresponding to 5% of the inhabitants of the area. Sixty per cent of the patients received one psychotropic prescription and 90% not more than three. Two-thirds of prescriptions were for women. Hypnotics, sedatives and minor tranquillisers constituted 64% of all prescriptions, major tranquillisers 24% and antidepressants 12%. One fifth of the patients obtained drugs belonging to more than one of the major psychotropic groups during the year. Insomnia, psychoneurosis and depression made up two-thrids of the indications for psychotropic drug therapy. More than thirty different psychotropic drugs were prescribed for the two major indications. There was considerable variation in how the different doctors prescribed drugs for the same indication. Fifty-nine different drug products were prescribed, of which the commonest five constituted more than half of the total number. Individual doctors used from 22 to 38 different psychotropic drugs.