ABSTRACT
ABSTRACT: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.
Subject(s)
Antibodies , Thrombocytopenia , Thrombosis , Thrombocytopenia/diagnosis , Thrombocytopenia/pathology , Heparin , Vaccination , Humans , Platelet Factor 4/metabolism , Antibodies/analysis , Male , Female , Child, Preschool , Child , Adult , Thrombosis/diagnosis , Thrombosis/pathologyABSTRACT
Rapid and reliable diagnosis of endometrial cancer (EC) in uterine aspirates is highly desirable. Current sensitivity and failure rate of histological diagnosis limit the success of this method and subsequent hysteroscopy is often necessary. Using quantitative reverse transcriptase-polymerase chain reaction on RNA from uterine aspirates samples, we measured the expression level of 20 previously identified genes involved in EC pathology, created five algorithms based on combinations of five genes and evaluated their ability to diagnose EC. The algorithms were tested in a prospective, double-blind, multicenter study. We enlisted 514 patients who presented with abnormal uterine bleeding. EC was diagnosed in 60 of the 514 patients (12%). Molecular analysis was performed on the remnants of aspirates and results were compared to the final histological diagnoses obtained through biopsies acquired by aspiration or guided by hysteroscopy, or from the specimens resected by hysterectomy. Algorithm 5 was the best performing molecular diagnostic classifier in the case-control and validation study. The molecular test had a sensitivity of 81%, specificity of 96%, positive predictive value (PPV) of 75% and negative predictive value (NPV) of 97%. A combination of the molecular and histological diagnosis had a sensitivity of 91%, specificity of 97%, PPV of 79% and NPV of 99% and the cases that could be diagnosed on uterine aspirate rose from 76 to 93% when combined with the molecular test. Incorporation of the molecular diagnosis increases the reliability of a negative diagnosis, reduces the need for hysteroscopies and helps to identify additional cases.
Subject(s)
Endometrial Neoplasms/diagnosis , Uterine Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Biopsy/methods , Case-Control Studies , Double-Blind Method , Endometrial Neoplasms/pathology , Female , Humans , Hysterectomy/methods , Hysteroscopy/methods , Middle Aged , Pathology, Molecular/methods , Prospective Studies , Reproducibility of Results , Sensitivity and Specificity , Uterine Hemorrhage/diagnosis , Uterine Hemorrhage/pathology , Uterine Neoplasms/genetics , Uterine Neoplasms/pathology , Young AdultABSTRACT
A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.
Subject(s)
D-Amino-Acid Oxidase/genetics , Schizophrenia/genetics , Schizophrenia/physiopathology , Amino Acid Sequence , Case-Control Studies , Chromosome Mapping , Chromosomes, Artificial, Bacterial/genetics , Chromosomes, Human, Pair 13/genetics , Cloning, Molecular , D-Amino-Acid Oxidase/metabolism , Enzyme Activation , Genetic Markers , Humans , In Vitro Techniques , Molecular Sequence Data , Polymorphism, Single Nucleotide , Receptors, N-Methyl-D-Aspartate/genetics , Sequence Homology, Amino Acid , Two-Hybrid System TechniquesABSTRACT
El diagnóstico clínico del cáncer de colon hereditario no polipósico (CCHNIP) se basa en el cumplimiento de los criterios de Amsterdam 1 o los criterios de Amsterdam modificados 2, que incluye la presencia de neoplasias extracolónicas del síndrome de Lynch II. Muchas familias presentan patrones de agregación fuertes, sospechosos de un carácter hereditario y cuyo seguimiento puede conducir a que se beneficien de un protocolo de diagnóstico precoz. Se presenta una familia inicialmente con criterios de sospecha de CCHNP que se convirtió en una familia Amsterdam 1 (familia 1) y una familia con criterios de Amsterdam 2 (familia 2) que presenta un miembro afectado a una edad muy joven. Ambas recibieron consejo genético y las recomendaciones de seguimiento. La realización de una colonoscopia total de control a un miembro asintomático de la familia 1 permitió llegar al diagnóstico de un cáncer de colon en estadio inicial y a un tratamiento quirúrgico amplio ante el elevado riesgo de una segunda neoplasia metacrónica. El caso de la familia 2 demuestra que las recomendaciones de consejo genético deben ser las mismas cuando se cumplen los criterios de Amsterdam 2. Ambas familias ilustran la importancia de realizar un cuidadoso árbol genealógico cuando se sospechen criterios de agregación familiar. (AU)
