Intraoperative blood transfusions in highly alloimmunized patients undergoing orthotopic liver transplantation.

Intraoperative blood requirements were analyzed in patients undergoing primary orthotopic liver transplantation and divided into two groups on the basis of panel reactive antibody of pretransplant serum measured by lymphocytotoxicity testing. One group of highly sensitized patients (n = 25) had PRA values of over 70% and the second group of patients (n = 26) had 0% PRA values and were considered nonsensitized. During the transplant procedure, the 70% PRA group received considerably greater quantities of blood products than the 0% PRA group--namely, red blood cells: 21.1 +/- 3.7 vs. 9.8 +/- 0.8 units (P = 0.002), and platelets: 17.7 +/- 3.2 vs. 7.5 +/- 1.5 units (P = 0.003). Similar differences were observed for fresh frozen plasma and cryoprecipitate. Despite the larger infusion of platelets, the blood platelet counts in the 70% PRA group were lower postoperatively than preoperatively. Twenty patients in the 70% PRA group received platelet transfusions, and their mean platelet count dropped from 95,050 +/- 11,537 preoperatively to 67,750 +/- 8,228 postoperatively (P = 0.028). In contrast, nearly identical preoperative (84,058 +/- 17,297) and postoperative (85,647 +/- 12,445) platelet counts were observed in the 17 0% PRA patients who were transfused intraoperatively with platelets. Prothrombin time, activated partial thromboplastin time, and fibrinogen levels showed no significant differences between both groups. These data demonstrate that lymphocytotoxic antibody screening of liver transplant candidates is useful in identifying patients with increased risk of bleeding problems and who will require large quantities of blood during the transplant operation

Intraoperative blood transfusion requirements and deficient hemostasis in highly alloimmunized patients undergoing liver transplantation

During orthopic liver transplantation (OLT) a large transfusion of different blood components is frequently necessary. From 1981 to 1985 at the University Health Center in Pittsburgh, 4,318 units of RBCs and 4,788 units of platelets were administered during 366 OLT performed in adults. This results in a mean of 25 units of RBCs and 30 units of platelets per operation. The majority of adult liver transplant patients receive multiple transfusions of whole blood and/or blood components during their pretransplant course because of complications relating to their original disease. The exposure of these patients to different antigens from random donors facilitates the development of alloimmunization. The heightened alloimmune state can be identified by preoperative values of panel reacting antibodies (PRA). Since platelets possess the HLA antigens of donor specificity, platelets may function as the target of host antibodies, resulting in platelet alteration and subsequent dysfunction. Thus, the effect of alloimmunization on platelet function may be one of the factors responsible for significant blood loss after large transfusions of different blood components. In this retrospective study we compared blood loss and platelet transfusion during OLT with preoperative alloimmunization against random donor antigens, indicated by PRA values

Postictal Psychosis in Epilepsy: A Clinicogenetic Study

OBJECTIVE: Psychoses affecting people with epilepsy increase disease burden and diminish quality of life. We characterised post-ictal psychosis, which comprises about one-quarter of epilepsy-related psychoses, and has unknown causation. METHODS: We conducted a case-control cohort study including patients diagnosed with post-ictal psychosis, confirmed by psychiatric assessment, with available data regarding epilepsy, treatment, psychiatric history, psychosis profile and outcomes. After screening 3,288 epilepsy patients, we identified 83 with psychosis: 49 had post-ictal psychosis. Controls were 98 adults, matched by age and epilepsy type, with no history of psychosis. Logistic regression was used to investigate clinical factors associated with post-ictal psychosis; univariate associations with a P-value<0.20 were used to build a multivariate model. Polygenic risk scores for schizophrenia were calculated. RESULTS: Cases were more likely to have seizure clustering (OR 7.59, P<0.001), seizures with a recollected aura (OR 2.49, P=0.013) and a family history of psychiatric disease (OR 5.17, P=0.022). Cases showed predominance of right temporal epileptiform discharges (OR 4.87, P=0.007). There was no difference in epilepsy duration, neuroimaging findings or anti-seizure treatment between cases and controls. Polygenic risk scores for schizophrenia in an extended cohort of post-ictal psychosis cases (58) were significantly higher than in 1,366 epilepsy controls (R2 =3%, P=6x10-3 ), but not significantly different from 945 independent patients with schizophrenia (R2 =0.1%, P=0.775). INTERPRETATION: Post-ictal psychosis occurs under particular circumstances in people with epilepsy with a heightened genetic predisposition to schizophrenia, illustrating how disease biology (seizures) and trait susceptibility (schizophrenia) may interact to produce particular outcomes (post-ictal psychosis) in a common disease

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

Infantile Convulsions with Paroxysmal Dyskinesia (ICCA Syndrome) and Copy Number Variation at Human Chromosome 16p11

BACKGROUND: Benign infantile convulsions and paroxysmal dyskinesia are episodic cerebral disorders that can share common genetic bases. They can be co-inherited as one single autosomal dominant trait (ICCA syndrome); the disease ICCA gene maps at chromosome 16p12-q12. Despite intensive and conventional mutation screening, the ICCA gene remains unknown to date. The critical area displays highly complicated genomic architecture and is the site of deletions and duplications associated with various diseases. The possibility that the ICCA syndrome is related to the existence of large-scale genomic alterations was addressed in the present study. METHODOLOGY/PRINCIPAL FINDINGS: A combination of whole genome and dedicated oligonucleotide array comparative genomic hybridization coupled with quantitative polymerase chain reaction was used. Low copy number of a region corresponding to a genomic variant (Variation_7105) located at 16p11 nearby the centromere was detected with statistical significance at much higher frequency in patients from ICCA families than in ethnically matched controls. The genomic variant showed no apparent difference in size and copy number between patients and controls, making it very unlikely that the genomic alteration detected here is ICCA-specific. Furthermore, no other genomic alteration that would directly cause the ICCA syndrome in those nine families was detected in the ICCA critical area. CONCLUSIONS/SIGNIFICANCE: Our data excluded that inherited genomic deletion or duplication events directly cause the ICCA syndrome; rather, they help narrowing down the critical ICCA region dramatically and indicate that the disease ICCA genetic defect lies very close to or within Variation_7105 and hence should now be searched in the corresponding genomic area and its surrounding regions

Testing association of rare genetic variants with resistance to three common antiseizure medications

OBJECTIVE: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). METHODS: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. RESULTS: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. SIGNIFICANCE: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes

An Attempt to Understand Kidney's Protein Handling Function by Comparing Plasma and Urine Proteomes

With the help of proteomics technology, the human plasma and urine proteomes, which closely represent the protein compositions of the input and output of the kidney, respectively, have been profiled in much greater detail by different research teams. Many datasets have been accumulated to form “reference profiles” of the plasma and urine proteomes. Comparing these two proteomes may help us understand the protein handling aspect of kidney function in a way, however, which has been unavailable until the recent advances in proteomics technology.After removing secreted proteins downstream of the kidney, 2611 proteins in plasma and 1522 in urine were identified with high confidence and compared based on available proteomic data to generate three subproteomes, the plasma-only subproteome, the plasma-and-urine subproteome, and the urine-only subproteome, and they correspond to three groups of proteins that are handled in three different ways by the kidney. The available experimental molecular weights of the proteins in the three subproteomes were collected and analyzed. Since the functions of the overrepresented proteins in the plasma-and-urine subproteome are probably the major functions that can be routinely regulated by excretion from the kidney in physiological conditions, Gene Ontology term enrichment in the plasma-and-urine subproteome versus the whole plasma proteome was analyzed. Protease activity, calcium and growth factor binding proteins, and coagulation and immune response-related proteins were found to be enriched.The comparison method described in this paper provides an illustration of a new approach for studying organ functions with a proteomics methodology. Because of its distinctive input (plasma) and output (urine), it is reasonable to predict that the kidney will be the first organ whose functions are further elucidated by proteomic methods in the near future. It can also be anticipated that there will be more applications for proteomics in organ function research