Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

Hepatobiliary scintigraphy in a patient with bilhemia

A 4-year-old child referred for acute jaundice following percutaneous needle biopsy of the liver underwent hepatobiliary scintigraphy. Although all conventional liver tests suggested preservation of hepatocyte function, the tracer uptake in the liver appeared dramatically reduced at scintigraphy and the blood pool activity did not decrease significantly until the end of the study. Visualization of the bile ducts indicated, however, that the tracer was taken up by the hepatocyte and further excreted into the biliary tree. There was no tracer pooling in the biliary tree although no bowel activity was observed, even on delayed images. The association of persistent blood pool activity, bile duct visualization without tracer pooling, and nonvisualization of the bowel was caused by a continuous recirculation of the tracer from the biliary tree into the bloodstream. The presence of a biliovenous fistula was further proven by percutaneous transhepatic cholangiography performed 24 h later. Since 1975, only 16 cases of bilhemia have been reported. To the best of our knowledge the scintigraphic pattern of this rare but lifethreatening complication has not previously been reported.     

Intravenous Lidocaine Infusion Facilitates Acute Rehabilitation after Laparoscopic Colectomy

Background: Intravenous infusion of lidocaine decreases postoperative pain and speeds the return of bowel function. The authors therefore tested the hypothesis that perioperative lidocaine infusion facilitates acute rehabilitation protocol in patients undergoing laparoscopic colectomy.

Methods: Forty patients scheduled to undergo laparoscopic colectomy were randomly allocated to receive intravenous lidocaine (bolus injection of 1.5 mg/kg lidocaine at induction of anesthesia, then a continuous infusion of 2 mg [middle dot] kg-1 [middle dot] h-1 intraoperatively and 1.33 mg [middle dot] kg-1 [middle dot] h-1 for 24 h postoperatively) or an equal volume of saline. All patients received similar intensive postoperative rehabilitation. Postoperative pain scores, opioid consumption, and fatigue scores were measured. Times to first flatus, defecation, and hospital discharge were recorded. Postoperative endocrine (cortisol and catecholamines) and metabolic (leukocytes, C-reactive protein, and glucose) responses were measured for 48 h. Data (presented as median [25-75% interquartile range], lidocaine vs. saline groups) were analyzed using Mann-Whitney tests. P < 0.05 was considered statistically significant.

Results: Patient demographics were similar in the two groups. Times to first flatus (17 [11-24] vs. 28 [25-33] h; P < 0.001), defecation (28 [24-37] vs. 51 [41-70] h; P = 0.001), and hospital discharge (2 [2-3] vs. 3 [3-4] days; P = 0.001) were significantly shorter in patients who received lidocaine. Lidocaine significantly reduced opioid consumption (8 [5-18] vs. 22 [14-36] mg; P = 0.005) and postoperative pain and fatigue scores. In contrast, endocrine and metabolic responses were similar in the two groups.     

Spectrum of NSD1 mutations in Sotos and Weaver syndromes

Interestingly, mental retardation was consistently more severe in patients with NSD1 deletions. Macrocephaly and facial gestalt but not overgrowth and advanced bone age were consistently observed in Sotos syndrome patients. We suggest therefore considering macrocephaly and facial gestalt as mandatory criteria for the diagnosis of Sotos syndrome and overgrowth and advanced bone age as minor criteria.     

Impaired responses to toll-like receptor 4 and toll-like receptor 3 ligands in human cord blood

Toll-like receptor (TLR)-4 signaling pathway plays an essential role in host defense against gram-negative bacteria while TLR-3-mediated signaling is critically involved in anti-viral immunity. To gain insight into the defects responsible for impaired Th1 responses in human newborns, we investigated the responses of human cord blood cells to lipopolysaccharide, LPS, and to polyinosinic-polycytidylic acid, Poly (I:C), ligands of TLR-4 and TLR-3, respectively. Measurement of cytokine levels revealed a profound defect in IL-12 (p70) synthesis and an increased release of IL-10 in cord blood exposed to LPS or Poly (I:C), as compared to adult blood. Moreover, Poly (I:C)-induced IFN-alpha production was found to be significantly impaired in cord blood. Phenotypic maturation of myeloid DC in response to LPS or Poly (I:C) was next compared in cord and adult blood. We observed that neonatal myeloid DC displayed decreased upregulation of CD40, CD80 whereas CD86 and HLA-DR upregulation did not differ significantly between adults and neonates. Taken together, these findings might be relevant to the increased vulnerability of human newborns to intracellular pathogens and to their inability to develop efficient Th1-type responses.     

Automated fluorescent genotyping detects 10% of cryptic subtelomeric rearrangements in idiopathic syndromic mental retardation

Recent studies have shown that cryptic unbalanced subtelomeric rearrangements contribute to a significant proportion of idiopathic syndromic mental retardation cases. Using a fluorescent genotyping based strategy, we found a 10% rate of cryptic subtelomeric rearrangements in a large series of 150 probands with severe idiopathic syndromic mental retardation and normal RHG-GTG banded karyotype. Fourteen children were found to carry deletions or duplications of one or more chromosome telomeres and two children had uniparental disomy. This study clearly shows that fluorescent genotyping is a sensitive and cost effective method that not only detects cryptic subtelomeric rearrangements but also provides a unique opportunity to detect uniparental disomies. We suggest giving consideration to systematic examination of subtelomeric regions in the diagnostic work up of patients with unexplained syndromic mental retardation.     

Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome

Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of lens, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described for WMS. A locus for AR WMS has recently been mapped to chromosome 19p13.3-p13.2 while mutation within the fibrillin-1 gene (15q21.1) was found in one AD WMS family. In order to answer the question of whether or not genetic heterogeneity could be related to a clinical heterogeneity, we reviewed 128 WMS patients from the literature (including 57 AR, 50 AD, and 21 sporadic cases), with a particular attention to clinical features. Statistical analyses using Fischer exact test were used to compare the proportions of 12 clinical parameters between AR and AD patients. There was no significant difference between both groups for myopia, glaucoma, cataract, short stature, brachydactyly, thick skin, muscular build, and mental retardation. Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007), ectopia lentis (64% in AR, 84% in AD, Fischer 0.016), joint limitations (49% in AR, 77% in AD, Fischer 0.010), and cardiac anomalies (39% in AR, 13% in AD, Fischer 0.004). Nevertheless, we failed to distinguish AR from AD inheritance in individual cases. These results support the clinical homogeneity but the genetic heterogeneity of WMS.     

Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.