Three novel PROC gene lesions causing protein C deficiency

Hallam PJ, Mannucci P, Tripodi A, Bevan D, Laursen B, Tengborn L, Wacey A, Cooper DN. Three novel PROC gene lesions causing protein C deficiency. Clin Genet 1998: 54: 231–233. 0 Munksgaard, 1998
Missense mutations. three of them novel (Am210→Val, Asn248→ Ile, Ah355→Val), were found in the protein c ( PROC ) genes of 7 patients with inherited protein C deficiency associated with venous thrombosis. Comparison with the phenotypic effects of mutations in the analogous residues of factor IX causing hdernophilia B and the use of molecular modelling has provided explanations as to how these lesions might alter either the structure, function or secretion of the protein C molecules encoded.     

Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome-wide association study

Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10⁻⁰⁵) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10⁻⁰⁵) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.     

Pulmonary venous flow as assessed by Doppler echocardiography: potential clinical applications

During the past few years Doppler assessment of pulmonary venous flow has gained increasing interest. The growing experience with the use of transesophageal echocardiography, the approach that nearly always yields registrations adequate for quantitative analysis, has markedly contributed in this respect. The Doppler-derived pulmonary venous flow pattern can be regarded as a measure of left atrial inflow and it augments the clinical significance of Doppler transmitral flow in the evaluation of diastolic left ventricular function. This article summarizes physiological background, possible applications, and limitations of Doppler echocardiography of pulmonary venous flow in clinical cardiology.     

Pediatric intestinal transplantation

Advancements in donor management, organ preservation and operative techniques, as well as immunosuppressive therapies, have provided children with intestinal failure and its complications a chance not only for enteral autonomy but also long-term survival through intestinal transplantation (ITx). First described in the 1960’s, experience has grown in managing these complex patients both pre- and post-transplant. The goals of this review are to provide a brief history of intestinal transplantation and intestinal rehabilitation in pediatric patients, followed by focused discussions of the indications for ITx, induction and maintenance immunosuppression therapies, common post-operative complications, and outcomes/quality of life post-transplant.     

Safety of modern oral contraception: the options for women: lessons to be learned

The relatively short history of hormonal contraception has been marked by a series of 'pill scares', all of which--after creating panic among users--were proven to be unfounded in terms of public health impact. The latest pill scare, provoked by regulatory action in the United Kingdom and the Federal Republic of Germany in response to the publication of a series of articles indicating a doubling of risk of deep venous thrombosis in users of oral contraceptives containing third-generation progestins, seems finally settled: both the British and the German Drug Regulatory Authorities have now reverted their verdict. The damage unfortunately stays: hundreds of thousands of women have been compelled to abandon the pill of their choice, often deciding to drop contraception altogether, thereby exposing themselves to unwanted pregnancy and--in a number of cases--to pregnancy termination. This latest episode should be turned into something positive: we need to learn that, in the case of drugs in widespread use, before restrictive action is taken--and except for very rare and specific instances--the scientific community must carry out an exhaustive debate on the reality and importance of the observed effects. Although the public should, in each instance, be properly informed, it is only after this process has been completed that restrictive action should be taken. It is hoped that, after this last episode, all concerned have learned this simple principle and will accept being guided by it from now on.     

Quantification of Mitral and Tricuspid Regurgitation Using Jet Centerline Velocities: An In Vitro Study of Jets in an Ambient Counterflow

A method for quantifying mitral and tricuspid regurgitant volume that utilizes a measure of jet orifice velocity U(0) - m/sec), a distal centerline velocity (U(m) - m/sec), and the intervening distance (X - cm) was recently developed; where jet flow rate (Q(cal) - L/min) is calculated as Q(cal) = (U(m)X)(2)/(26.46U(o)). This method, however, modeled the regurgitant jet as a free jet, whereas many atrial jets are counterflowing jets because of jet opposing intra-atrial flow fields (counterflows). This study concentrated on the feasibility of using the free jet quantification equation in the atrium where ambient flow fields may alter jet centerline velocities and reduce the accuracy of jet flow rate calculations. A 4-cm wide chamber was used to pump counterflows of 0, 4, and 22 cm/sec against jets of 2.3, 4.8, and 6.4 m/sec originating from a 2-mm diameter orifice. For each counterflow-jet combination, jet centerline velocities were measured using laser Doppler anemometry. For free jets (no counterflow), flow rate was calculated with 98% mean accuracy. For all jets in counterflow, the calculation was less accurate as: (i) the ratio of jet orifice velocity to counterflow velocity decreased (U(o)/U(c), where U(c) is counterflow velocity), i.e., the counterflow was relatively more intense, and (ii) centerline measurements were made further from the orifice. But although counterflow lowered jet centerline velocities beneath free jet values, it did so only significantly in the jet's distal portion (X/D > 16, i.e., >16 orifice diameters from the origin of the jet). Thus, the initial portion (X/D < 16) of a jet in counterflow behaved essentially as a free jet. As a result, even in significant counterflow, jet flow rate was calculated with >93% accuracy and >85% for jets typical of mitral and tricuspid regurgitation, respectively. Counterflow lowers jet centerline velocities beneath equivalent free jet values. This effect, however, is most significant in the distal portion of the jet. Therefore, regurgitant jets, although not classically free because of systolic atrial inflow or jet-induced intra-atrial swirling flows, will decay in their initial portions as free jets and thus are candidates for quantification with the centerline technique. (ECHOCARDIOGRAPHY, Volume 13, July 1996)     

Dopamine,dopexamine and dobutamine in liver transplant recipients: a comparison of their effects on hemodynamics,oxygen transport and hepatic venous oxygen saturation

The purpose of this study was to determine the effects of vasoactive treatment with dopamine (DO), dopexamine (DX), and dobutamine (DOB) on hemodynamics, oxygen transport and hepatic venous oxygen saturation (SvhO₂) after orthotopic liver transplantation (OLT). A pulmonary artery catheter was inserted into the right hepatic vein of 17 OLT patients. Timed infusion of DO, DX, and DOB was performed at the following rates: DO at 4 and 8 g/kg per minute, and DOB at 5 and 10 g/kg per minute. Hemodynamics, oxygen transport variables, and SvhO₂ were assessed. Each catecholamine induced a significant increase in cardiac index, oxygen delivery, and SvhO₂. Mean arterial pressure was increased during DO and DOB, but significantly reduced during DX. Each inotrope increased oxygen delivery in parallel with SvhO₂, suggesting a corresponding increase in hepatic oxygen supply. Therefore, it appears that each vasoactive drug may be utilized in OLT patients to provide oxgen delivery without impairment of splanchnic oxygenation.     

Echocardiographic and color flow Doppler assessment of systemic and pulmonary venous connection and drainage in the neonate with congenital heart disease

Systemic and pulmonary venous anomalies are frequently encountered either as isolated lesions or as a significant component of a more complex lesion in the newborn infant with congenital heart disease. Two-dimensional echocardiography and Doppler techniques (conventional and color flow) have become the primary diagnostic imaging modality in this setting. Precise pre-operative definition of these variable venous connection and drainage patterns is critical as the required surgical procedure may solely be based on exact understanding of the veins' anatomy and physiology. On the systemic venous site, anomalies of superior and inferior venae cavae, innominate vein, and coronary sinus can be equally well imaged with either echocardiography or angiography. However, on the pulmonary venous site, echocardiography and Doppler techniques including color flow mapping are superior to angiography for precise definition of the connection and drainage sites of the individual pulmonary veins.