Selective inferior petrosal sinus sampling without venous outflow diversion in the detection of a pituitary adenoma in Cushing's syndrome

Conventional MRI may still be an inaccurate method for the non-invasive detection of a microadenoma in adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) with ovine corticotropin-releasing hormone (oCRH) stimulation is an invasive, but accurate, intervention in the diagnostic armamentarium surrounding CS. Until now, there is a continuous controversial debate regarding lateralization data in detecting a microadenoma. Using BIPSS, we evaluated whether a highly selective placement of microcatheters without diversion of venous outflow might improve detection of pituitary microadenoma.

Biocompatibility assessment of the first generation PediaFlow pediatric ventricular assist device

The PediaFlow pediatric ventricular assist device is a miniature magnetically levitated mixed flow pump under development for circulatory support of newborns and infants (3-15 kg) with a targeted flow range of 0.3-1.5 L/min. The first generation design of the PediaFlow (PF1) was manufactured with a weight of approximately 100 g, priming volume less than 2 mL, length of 51 mm, outer diameter of 28 mm, and with 5-mm blood ports. PF1 was evaluated in an in vitro flow loop for 6 h and implanted in ovines for three chronic experiments of 6, 17, and 10 days. In the in vitro test, normalized index of hemolysis was 0.0087 ± 0.0024 g/100L. Hemodynamic performance and blood biocompatibility of PF1 were characterized in vivo by measurements of plasma free hemoglobin, plasma fibrinogen, total plasma protein, and with novel flow cytometric assays to quantify circulating activated ovine platelets. The mean plasma free hemoglobin values for the three chronic studies were 4.6 ± 2.7, 13.3 ± 7.9, and 8.8 ± 3.3 mg/dL, respectively. Platelet activation was low for portions of several studies but consistently rose along with observed animal and pump complications. The PF1 prototype generated promising results in terms of low hemolysis and platelet activation in the absence of complications. Hemodynamic results validated the magnetic bearing design and provided the platform for design iterations to meet the objective of providing circulatory support for young children with exceptional biocompatibility.

Pentalogy or hexalogy of Cantrell?

Pentalogy of Cantrell (PC) is a rare congenital syndrome involving the abdominal wall, sternum, diaphragm, pericardium, and heart. The embryonic period in which PC develops coincides with that of umbilical cord (UC) formation. The aim of the following study was to address the question of whether PC is associated with UC pathologies. Four cases, prenatally identified between 2002 and 2008, were enrolled in this study. Umbilical cord pathologies defined as single umbilical artery, short cord, or UC with atypical coiling pattern were retrospectively assessed on stored ultrasound images and from autopsy reports. The literature regarding PC and UC pathologies was reviewed. Three singleton pregnancies and 1 monoamniotic twin pregnancy with twin reversed arterial perfusion sequence were reviewed. All had a normal karyotype. Three showed the classical PC stigmata, with ectopia cordis. One fetus had no ectopia cordis; this case had a normal UC, whereas all others fetuses showed a short UC with atypical coiling pattern. Of 26 publications dealing with PC, the UC was described in only 8 cases, 7 of which were abnormal. There seems to be a strong correlation between the PC and UC abnormalities, in particular in cases with ectopia cordis. We speculate that the insult leading to the classical malformations of PC and UC abnormalities is the same or the sequence of malformations itself may alter the early fetoplacental blood flow and therefore the normal development of the UC angioarchitecture.

Sonographic Assessment of Fetal Cardiac Function: Indirect Measurements of Fetal Cardiac Function, Newer Techniques and Clinical Applications

Noninvasive blood flow measurements based on Doppler ultrasound studies are the main clinical tool for studying the cardiovascular status of fetuses at risk for circulatory compromise. Usually, qualitative analysis of peripheral arteries and in particular clinical situations such as severe growth restriction or volume overload also of venous vessels close to the heart or of flow patterns in the heart is being used to gauge the level of compensation in a fetus. However, quantitative assessment of the driving force of the fetal circulation, the cardiac output remains an elusive goal in fetal medicine. This article reviews the methods for direct and indirect assessment of cardiac function and explains new clinical applications. Part 1 of this review describes the concept of cardiac function and cardiac output and the techniques that have been used to quantify output. Part 2 summarizes the use of arterial and venous Doppler studies in the fetus and gives a detailed description of indirect measurements of cardiac function (like indices derived from the duration of segments of the cardiac cycle) with current examples of their application.

Pulsed-wave tissue Doppler echocardiography for the analysis of fetal cardiac arrhythmias

Rhythm analysis of the fetal heart is hampered by the inability to routinely obtain electrocardiographic recordings of the fetus. Doppler studies of fetal cardiac tissue movements, assessing cardiac movements both qualitatively and quantitatively, have recently been described. We used a conventional high-resolution ultrasound system to obtain rhythm data from pulsed-wave tissue Doppler signals of the fetal heart in normal cardiac rhythm and in a variety of fetal cardiac arrhythmias.

Sonographic Assessment of Fetal Cardiac Function: Introduction and Direct Measurement of Cardiac Function

Noninvasive blood flow measurements based on Doppler ultrasound studies are the main clinical tool for studying the cardiovascular status in fetuses at risk for circulatory compromise. Usually, qualitative analysis of peripheral arteries and, in particular clinical situations such as severe growth restriction or volume overload, also of venous vessels close to the heart or of flow patterns in the heart are being used to gauge the level of compensation in a fetus. Quantitative assessment of the driving force of the fetal circulation, the cardiac output, however, remains an elusive goal in fetal medicine. This article reviews the methods for direct and indirect assessment of cardiac function and explains new clinical applications. Part 1 of this review describes the concept of cardiac function and cardiac output and the techniques that have been used to quantify output. Part 2 summarizes the use of arterial and venous Doppler studies in the fetus and gives a detailed description of indirect measures of cardiac function (like indices derived from the duration of segments of the cardiac cycle) with current examples of their application.

Interaction of pregnancy and autoimmune rheumatic disease

During pregnancy, the fetus represents a natural allograft that is not normally rejected. While the maternal immune system retains the ability to respond to foreign antigens, tolerance mechanisms are up-regulated to protect the fetus from immunologic attacks by the mother. The profound immunologic adaptations during and after pregnancy do influence maternal autoimmune rheumatic diseases in several ways. One is triggering the onset of a rheumatic disease in the post partum period, the other influencing disease activity of established rheumatic disease. The review will discuss the mechanisms of increased susceptibility of rheumatoid arthritis (RA) in the first year post partum with a specific emphasis on the role of fetal cells or antigens persisting in the maternal circulation (so called microchimerism). Furthermore, the different influences of pregnancy on established rheumatic diseases will be highlighted. A marked beneficial effect of pregnancy is observed on RA whereas several other rheumatic diseases as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) show either no particular effect or an aggravation of symptoms during pregnancy. Differences emerging in regard to modulation of disease symptoms during pregnancy seem related to response to hormones, the type of cytokine profile and immune response prevailing as well as further downstream interactions of molecular pathways that are important in disease pathogenesis.

Preparation of intact bovine tail intervertebral discs for organ culture

The intervertebral disc (IVD) is the joint of the spine connecting vertebra to vertebra. It functions to transmit loading of the spine and give flexibility to the spine. It composes of three compartments: the innermost nucleus pulposus (NP) encompassing by the annulus fibrosus (AF), and two cartilaginous endplates connecting the NP and AF to the vertebral body on both sides. Discogenic pain possibly caused by degenerative intervertebral disc disease (DDD) and disc herniations has been identified as a major problem in our modern society. To study possible mechanisms of IVD degeneration, in vitro organ culture systems with live disc cells are highly appealing. The in vitro culture of intact bovine coccygeal IVDs has advanced to a relevant model system, which allows the study of mechano-biological aspects in a well-controlled physiological and mechanical environment. Bovine tail IVDs can be obtained relatively easy in higher numbers and are very similar to the human lumbar IVDs with respect to cell density, cell population and dimensions. However, previous bovine caudal IVD harvesting techniques retaining cartilaginous endplates and bony endplates failed after 1-2 days of culture since the nutrition pathways were obviously blocked by clotted blood. IVDs are the biggest avascular organs, thus, the nutrients to the cells in the NP are solely dependent on diffusion via the capillary buds from the adjacent vertebral body. Presence of bone debris and clotted blood on the endplate surfaces can hinder nutrient diffusion into the center of the disc and compromise cell viability. Our group established a relatively quick protocol to "crack"-out the IVDs from the tail with a low risk for contamination. We are able to permeabilize the freshly-cut bony endplate surfaces by using a surgical jet lavage system, which removes the blood clots and cutting debris and very efficiently reopens the nutrition diffusion pathway to the center of the IVD. The presence of growth plates on both sides of the vertebral bone has to be avoided and to be removed prior to culture. In this video, we outline the crucial steps during preparation and demonstrate the key to a successful organ culture maintaining high cell viability for 14 days under free swelling culture. The culture time could be extended when appropriate mechanical environment can be maintained by using mechanical loading bioreactor. The technique demonstrated here can be extended to other animal species such as porcine, ovine and leporine caudal and lumbar IVD isolation.

Hydrogels for nucleus replacement—Facing the biomechanical challenge

Hydrogels are considered promising for disc regeneration strategies. However, it is currently unknown whether the destruction of the natural interface between nucleus and surrounding structures caused by nucleotomy and an inadequate annulus closure diminishes the mechanical competence of the disc. This in vitro study aimed to clarify these mechanisms and to evaluate whether hydrogels are able to restore the biomechanical behaviour of the disc. Nucleus pressure in an ovine intervertebral disc was measured in vivo during day and night and adapted to an in vitro axial compressive diurnal (15min) and night (30min) load. Effects of different defects on disc height and nucleus pressure were subsequently measured in vitro using 30 ovine motion segments. Following cases were considered: intact; annulus incision repaired by suture and glue; annulus incision with removal and re-implantation of nucleus tissue; and two different hydrogels repaired by suture and glue. The intradiscal pressure in vivo was 0.75MPa during day and 0.5MPa during night corresponding to an in vitro axial compressive force of 130 and 58N, respectively. The compression test showed that neither the implantation of hydrogels nor the re-implantation of the natural nucleus, assumed as being the ideal implant, was able to restore the mechanical functionality of an intact disc. Results indicate the importance of the natural anchorage of the nucleus with its surrounding structures and the relevance of an appropriate annulus closure. Therefore, hydrogels that are able to mimic the mechanical behaviour of the native nucleus may fail in restoring the mechanical behaviour of the disc.

Atypical scrapie isolates involve a uniform prion species with a complex molecular signature

The pathobiology of atypical scrapie, a prion disease affecting sheep and goats, is still poorly understood. In a previous study, we demonstrated that atypical scrapie affecting small ruminants in Switzerland differs in the neuroanatomical distribution of the pathological prion protein (PrP(d)). To investigate whether these differences depend on host-related vs. pathogen-related factors, we transmitted atypical scrapie to transgenic mice over-expressing the ovine prion protein (tg338). The clinical, neuropathological, and molecular phenotype of tg338 mice is similar between mice carrying the Swiss atypical scrapie isolates and the Nor98, an atypical scrapie isolate from Norway. Together with published data, our results suggest that atypical scrapie is caused by a uniform type of prion, and that the observed phenotypic differences in small ruminants are likely host-dependant. Strikingly, by using a refined SDS-PAGE technique, we established that the prominent proteinase K-resistant prion protein fragment in atypical scrapie consists of two separate, unglycosylated peptides with molecular masses of roughly 5 and 8 kDa. These findings show similarities to those for other prion diseases in animals and humans, and lay the groundwork for future comparative research.

Microphthalmia in Texel sheep is associated with a missense mutation in the paired-like homeodomain 3 (PITX3) gene

Microphthalmia in sheep is an autosomal recessive inherited congenital anomaly found within the Texel breed. It is characterized by extremely small or absent eyes and affected lambs are absolutely blind. For the first time, we use a genome-wide ovine SNP array for positional cloning of a Mendelian trait in sheep. Genotyping 23 cases and 23 controls using Illumina's OvineSNP50 BeadChip allowed us to localize the causative mutation for microphthalmia to a 2.4 Mb interval on sheep chromosome 22 by association and homozygosity mapping. The PITX3 gene is located within this interval and encodes a homeodomain-containing transcription factor involved in vertebrate lens formation. An abnormal development of the lens vesicle was shown to be the primary event in ovine microphthalmia. Therefore, we considered PITX3 a positional and functional candidate gene. An ovine BAC clone was sequenced, and after full-length cDNA cloning the PITX3 gene was annotated. Here we show that the ovine microphthalmia phenotype is perfectly associated with a missense mutation (c.338G>C, p.R113P) in the evolutionary conserved homeodomain of PITX3. Selection against this candidate causative mutation can now be used to eliminate microphthalmia from Texel sheep in production systems. Furthermore, the identification of a naturally occurring PITX3 mutation offers the opportunity to use the Texel as a genetically characterized large animal model for human microphthalmia.

Increased placental phospholipid levels in pre-eclamptic pregnancies

Physiological pregnancy is associated with an increase in lipids from the first to the third trimester. This is a highly regulated response to satisfy energy and membrane demands of the developing fetus. Pregnancy disorders, such as pre-eclampsia, are associated with a dysregulation of lipid metabolism manifesting in increased maternal plasma lipid levels. In fetal placental tissue, only scarce information on the lipid profile is available, and data for gestational diseases are lacking. In the present study, we investigated the placental lipid content in control versus pre-eclamptic samples, with the focus on tissue phospholipid levels and composition. We found an increase in total phospholipid content as well as changes in individual phospholipid classes in pre-eclamptic placental tissues compared to controls. These alterations could be a source of placental pathological changes in pre-eclampsia, such as lipid peroxide insult or dysregulation of lipid transport across the syncytiotrophoblast.

Acute Encephalopathy with Unilateral Cortical-Subcortical Lesions in Two Unrelated Kindreds Treated with Glucocorticoids Prenatally for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Established Facts and Novel Insight

Background: Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. Case Reports: We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. Conclusion: These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed.

Air pollution during pregnancy and neonatal outcome: a review

There is increasing evidence of the adverse impact of prenatal exposure to air pollution. This is of particular interest, as exposure during pregnancy--a crucial time span of important biological development--may have long-term implications. The aims of this review are to show current epidemiological evidence of known effects of prenatal exposure to air pollution and present possible mechanisms behind this process. Harmful effects of exposure to air pollution during pregnancy have been shown for different birth outcomes: higher infant mortality, lower birth weight, impaired lung development, increased later respiratory morbidity, and early alterations in immune development. Although results on lower birth weight are somewhat controversial, evidence for higher infant mortality is consistent in studies published worldwide. Possible mechanisms include direct toxicity of particles due to particle translocation across tissue barriers or particle penetration across cellular membranes. The induction of specific processes or interaction with immune cells in either the pregnant mother or the fetus may be possible consequences. Indirect effects could be oxidative stress and inflammation with consequent hemodynamic alterations resulting in decreased placental blood flow and reduced transfer of nutrients to the fetus. The early developmental phase of pregnancy is thought to be very important in determining long-term growth and overall health. So-called "tracking" of somatic growth and lung function is believed to have a huge impact on long-term morbidity, especially from a public health perspective. This is particularly important in areas with high levels of outdoor pollution, where it is practically impossible for an individual to avoid exposure. Especially in these areas, good evidence for the association between prenatal exposure to air pollution and infant mortality exists, clearly indicating the need for more stringent measures to reduce exposure to air pollution.

Sonographic Assessment of the Umbilical Cord

The umbilical cord is not an inert structure, suspended between the fetus and placenta, but it plays an active role and it is involved in several processes afflicting the feto-placental unit. Its study has to be regarding not only its morphology and morphometry, and the impendance of blood flow by Doppler waveform analysis, but it includes also an analysis of the coiling type and the amount of the Wharton Jelly. The umbilical cord has been considered like an important and huge source of informations, useful to assess the well-being of the fetus and the outcome of pregnancy. The standardization of ultrasound techniques is the first step to speak the same language and make the study of this structure a fundamental part of well-being fetus assessment. This article is carefully focused on morphologic, morphometric and functional ultrasound examination of umbilical cord and suggests that any anomaly detected should provide an indication for an intense fetal follow-up, useful for early helpful therapy, preventing serious complication for the pregnancy.