Phenome-wide Investigation of Behavioral, Environmental, and Neural Associations with Cross-Disorder Genetic Liability in Youth of European Ancestry.

Etiologic insights into psychopathology may be gained by using hypothesis-free methods to identify associations between genetic risk for broad psychopathology and phenotypes measured during adolescence, including both markers of child psychopathology and intermediate phenotypes such as neural structure that may link genetic risk with outcomes. We conducted a phenome-wide association study (phenotype n=1,269-1,694) of polygenic risk scores (PRS) for broad spectrum psychopathology (i.e., Compulsive, Psychotic, Neurodevelopmental, and Internalizing) in youth of PCA-selected European ancestry (n=5,556; ages 9-13) who completed the baseline and/or two-year follow-up of the ongoing Adolescent Brain Cognitive Development℠ (ABCD) Study. We found that Neurodevelopmental and Internalizing PRS were significantly associated with a host of proximal as well as distal phenotypes (Neurodevelopmental: 187 and 211; Internalizing: 122 and 173 phenotypes at baseline and two-year follow-up, respectively), whereas Compulsive and Psychotic PRS showed zero and one significant associations, respectively, after Bonferroni correction. Neurodevelopmental PRS were further associated with brain structure metrics (e.g., total volume, mean right hemisphere cortical thickness), with only cortical volume indirectly linking Neurodevelopmental PRS to grades in school. Genetic variation influencing risk to psychopathology manifests broadly as behaviors, psychopathology symptoms, and related risk factors in middle childhood and early adolescence.

The circumstances in which recurrent laryngeal nerve palsy occurs after surgery for benign thyroid disease: a retrospective study of 1026 patients.

OBJECTIVE: To evaluate the circumstances in which recurrent laryngeal nerve palsy occurs after thyroid surgery. METHODS: This study assessed 1026 patients who underwent surgery for benign thyroid disease over a seven-year period in a retrospective, single-centre study. RESULTS: With a total of 1835 recurrent laryngeal nerves at risk, there were 38 cases (2.07 per cent) of transient recurrent laryngeal nerve palsy and 8 (0.44 per cent) of permanent recurrent laryngeal nerve palsy. No explanation was found for 10 of the 46 cases of recurrent laryngeal nerve palsy. Among the 38 other cases, the probable causes included poor identification of the recurrent laryngeal nerve during surgery, involuntary resection of the nerve and several other factors. CONCLUSION: Apart from accidental resection of the recurrent laryngeal nerve during thyroid surgery, the causes of post-operative recurrent laryngeal nerve palsy are often unclear and likely multifactorial. Poor identification of the recurrent laryngeal nerve during surgery is still the main cause of post-operative recurrent laryngeal nerve palsy, even when intra-operative neuromonitoring is used.

Impact of incidental parathyroidectomy and mediastinal-recurrent cellular and lymph-node dissection on parathyroid function after total thyroidectomy.

OBJECTIVES: To determine the impact of incidental parathyroidectomy and mediastinal-recurrent cellular and lymph-node dissection on parathyroid function after total thyroidectomy. MATERIAL AND METHODS: A single-center retrospective study was conducted for a 5-year period in a university hospital center, including 605 patients undergoing total thyroidectomy, 52 of whom had mediastinal-recurrent cellular and lymph-node dissection. ENDPOINTS: The main endpoint was intraoperative number of parathyroid glands as predictor of parathyroid hormone (PTH) level and postoperative hypocalcemia. The secondary endpoint was the correlation between associated mediastinal-recurrent cellular and lymph-node dissection and incidental parathyroidectomy and its impact on PTH level and calcemia in the immediate postoperative period and at 1 month. RESULTS: 161 patients (26.61%) showed hypocalcemia in the immediate postoperative period and 12 (1.98%) at 1 month. Mediastinal-recurrent cellular and lymph-node dissection increased incidental parathyroidectomy risk 4.6-fold. Mediastinal-recurrent cellular and lymph-node dissection was associated with a statistically "suggestive" decrease in day-1 calcemia (P=0.03), and no significant decrease at 1 month (P=0.52). Incidental parathyroidectomy (6.7% of cases with parathyroidectomy versus 1.3% without) did not significantly increase the rate of early hypocalcemia (P=0.28), but was associated with a "suggestive" worsening at 1 month (P=0.02). CONCLUSION: Hypocalcemia after total thyroidectomy is a complex, probably multifactorial issue. Systematic parathyroid gland identification is not recommended due to the increased risk of gland lesion, mainly by devascularization. Incidental parathyroidectomy may induce hypocalcemia at 1 month postoperatively (statistically "suggestive" association).

Head and neck squamous cell carcinoma and metachronous second primaries.

OBJECTIVES: To assess the rate of second (or more) primaries after treatment for head and neck squamous cell carcinoma (HNSCC), and survival compared to patients with a single head and neck cancer. MATERIAL AND METHOD: A single-center retrospective study was performed in a University Hospital Center in 541 patients between 2002 and 2010. RESULTS: One hundred and forty-one patients (26.06%) presented 172 metachronous cancers. Overall 5-year survival was 20.3% with and 38.1% without metachronous cancer. Median and mean survival were respectively 21.9 and 51 months in patients with a single cancer, versus 13.9 and 26.5 months in case of metachronous cancer. Specific survival was comparable to overall survival. All-cause and specific survival were significantly poorer in metachronous cancer (P=0.001; log-rank α=0.05). CONCLUSION: At least a quarter of HNSCC patients go on to develop a metachronous second primary. These are of poor prognosis, whatever their location.

Cardiovascular risk and severity factors in patients admitted to hospital for spontaneous epistaxis.

OBJECTIVES: To assess the role of cardiovascular risk factors, intake of drugs altering hemostasis and severity signs in patients admitted with spontaneous epistaxis. MATERIAL AND METHODS: A single-center retrospective study covering a 7-year period in a university hospital center included 205 patients admitted with spontaneous epistaxis. Study variables comprised: cardiovascular risk factors (cardiovascular disease or history of cardiovascular disease with hemorrhagic or thromboembolic risk, high blood pressure, type-2 diabetes, dyslipidemia), intake of drugs altering hemostasis, blood pressure and minimum hemoglobin level during hospital stay. Groups of serious and non-serious epistaxis were distinguished. RESULTS: There were no significant inter-group differences for mean age, sex ratio, history of high blood pressure or number of cardiovascular risk factors. Serious epistaxis was associated with significantly lower blood pressure and hemoglobinemia. Number of cardiovascular risk factors correlated with probability of blood transfusion. CONCLUSION: The real influence of the various study factors, including severity factors, on onset of spontaneous epistaxis remains to be elucidated.

Impact of pre-operative serum 25-hydroxyvitamin D on post-operative serum calcium in patients undergoing total thyroidectomy for benign goitre: retrospective study of 246 patients.

OBJECTIVE: To determine whether pre-operative serum 25-hydroxyvitamin D has an impact on post-operative parathyroid hormone and serum calcium levels in patients undergoing total thyroidectomy for benign goitre. METHODS: This single-centre, retrospective study comprised 246 unselected surgical patients who had undergone total thyroidectomy for bilateral, benign, multinodular goitre. The correlation between pre-operative serum 25-hydroxyvitamin D and post-operative serum parathyroid hormone and serum calcium was studied to determine whether low pre-operative serum 25-hydroxyvitamin D was predictive of post-operative hypocalcaemia. RESULTS: Seventy-nine patients (32 per cent) had post-operative hypocalcaemia. Eighteen patients (7.32 per cent) experienced unintentional parathyroidectomy (1 parathyroid gland in 15 patients, 2 parathyroid glands in 3 patients). In univariate analysis, pre-operative serum 25-hydroxyvitamin D was not correlated with post-operative serum calcium (p = 0.69) or post-operative serum parathyroid hormone (p = 0.5804). Furthermore, in multivariate analysis, which took into account unintentional parathyroidectomy, no correlation was found (p = 0.33). Bilateral unintentional parathyroidectomy was statistically associated with post-operative hypocalcaemia (p = 0.032). CONCLUSION: Pre-operative serum 25-hydroxyvitamin D did not appear to have any impact on post-operative serum calcium in patients undergoing total thyroidectomy for benign goitre.

Intra-operative neuromonitoring of the vagus nerve during thyroidectomy. A prospective study.

OBJECTIVES: To determine whether intra-operative neuromonitoring (IONM) of the vagus nerve during thyroidectomy can predict postoperative vocal fold palsy. DESIGN: A single-centre, prospective study. SETTING: University Hospital. PARTICIPANTS: A total of 95 patients underwent thyroid surgery. A total of 160 vagus nerves were studied. The amplitude of the action potential of vocal muscles was recorded intra-operatively by indirect supramaximal stimulation of the vagus nerve. All patients underwent flexible fibre-optic laryngoscopy on postoperative day 1 to detect the presence of vocal fold palsy. MAIN OUTCOME MEASURES: The primary outcome measure was the difference of the action potential amplitude of the vagus nerve before and after resection of the thyroid lobe. Statistical analysis determined the amplitude variation cut-off able to accurately predict postoperative vocal fold palsy. RESULTS: Transient vocal fold palsy was observed in 4.375% of cases, and permanent fold palsy was observed in 1.25% of cases. A decrease of the action potential amplitude by more than 61% was statistically significantly associated with postoperative vocal fold palsy. A greater than 87% decrease of the amplitude of the action potential was correlated with permanent postoperative vocal fold palsy. CONCLUSION: IONM of the vagus nerve during thyroidectomy may accurately predict postoperative vocal fold palsy.

Identification of pre-sliding friction dynamics.

The hysteretic nonlinear dependence of pre-sliding friction force on displacement is modeled using different physics-based and black-box approaches including various Maxwell-slip models, NARX models, neural networks, nonparametric (local) models and dynamical networks. The efficiency and accuracy of these identification methods is compared for an experimental time series where the observed friction force is predicted from the measured displacement. All models, although varying in their degree of accuracy, show good prediction capability of pre-sliding friction. Finally, we show that even better results can be achieved by using an ensemble of the best models for prediction.

Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura.

Platelets and sera from 12 patients with thrombotic thrombocytopenic purpura (TTP) and 12 healthy normal control subjects were examined. As determined by quantitative flow cytometry, prior to plasma exchange therapy platelet surface glycoprotein (GP) Ib levels were similar in TTP patients and normal controls (mean 20 188 and 20 226 molecules/platelet, respectively). Platelets from patients with TTP did, however, have significantly reduced levels of GPIIb/IIIa prior to plasmapheresis (mean 36 348 v 52 505 molecules/platelet in controls; P = 0.0004) and of GPIV (mean 13 321 v 26 212 molecules/platelet in controls; P = 0.0002). An increase in activated platelets, as determined by CD62 expression, was observed in 82% of patients. Increased platelet-associated immunoglobulins and/or complement was also seen in approximately 60% of the patients. In general, with return of platelet counts to normal levels following seven plasmaphereses, the above abnormalities were reversed, although often not to normal levels. Western blot analysis indicated the presence of antibodies reactive to platelet GPIV (88 kD) in 70% of pretreatment sera from patients with TTP; a similar band was observed in 80% of patient sera against microvascular endothelial cells. Immunofluorescence microscopic examination indicated the presence of antibody in pretreatment sera from patients with TTP to microvascular (73%) and large vessel (36%) endothelial cells. As measured by an indirect flow cytometric assay, pretreatment sera from 55% of patients with TTP were reactive with large vessel endothelial cells and 100% reacted with microvascular endothelial cells; reactivity was significantly greater against the microvascular endothelial cells (P = 0.0048) and was reduced following plasma exchange therapy. These results indicate abnormalities in platelet glycoprotein expression in TTP and suggest that anti-platelet and anti-endothelial cell antibodies play a role in the thrombocytopenia and vasculitis characteristic of this disorder.

Multidrug resistance-1 and p-glycoprotein in human chondrosarcoma cell lines: expression correlates with decreased intracellular doxorubicin and in vitro chemoresistance.

We report on two chondrosarcoma cell lines, FS and AQ, that may be used as models of multidrug resistance in chondrosarcoma. Multidrug resistance-1 expression was assayed with reverse transcription-polymerase chain reaction. Immunostaining for the multidrug resistance-1 product, P-glycoprotein, was performed with the monoclonal antibody C494. Intracellular levels of doxorubicin were measured by fluorescent emission at 590 nm after 1 hour of incubation with the agent and again after 1, 2, and 4-hour washout periods. Chemosensitivity was assayed by staining micropellet cultures of AQ and FS cells with fluorescein acetate before and after the cells were exposed to varying doses of doxorubicin for 48 hours. Cytotoxicity was assessed by comparison of computer-processed images before and after treatment. The FS cell line was positive for multidrug resistance-1 expression, stained heavily for P-glycoprotein, and had significantly lower intracellular levels of doxorubicin than the AQ cell line, which was negative for multidrug resistance-1 and P-glycoprotein. Chemosensitivity testing showed that the FS cell line was significantly more resistant to doxorubicin than was the AQ cell line at all doses tested. Our results show that multidrug resistance-1 expression in a human chondrosarcoma cell line results in resistance to doxorubicin in vitro.

Cleidocranial dysplasia with neonatal death due to central nervous system injury in utero: case report and literature review.

Cleidocranial dysplasia (CCD), an uncommon disorder involving membranous bones, is rarely lethal in early life. The calvaria is defective and wormian bones are present. Abnormalities of the clavicles vary in severity from a minor unilateral defect to bilateral absence. This report concerns pre- and postmortem anatomical and radiological findings in a 15-day-old female neonate with CCD. Her postnatal course was characterized by seizures and recognition of hydrocephalus during the first day of life. The calvaria was hypoplastic with numerous wormian bones. A pseudofracture of the right clavicle was present. Hydrocephalus was present in the brachycephalic brain which had a severely thinned cerebral cortex. Hemosiderin in the ventricular lining and marked subependymal gliosis were interpreted as evidence of old intraventricular hemorrhage that had occurred in utero. A CCD-related condition, Yunis-Varon syndrome (YVS), is noted for early lethality and for developmental and secondary abnormalities of the central nervous system. The present case only partially matches the phenotype of YVS and might represent a part of a spectrum of phenotypic variants ranging from viable CCD to lethal YVS.

Binding of thrombin to the G-protein-linked receptor, and not to glycoprotein Ib, precedes thrombin-mediated platelet activation.

The roles of the G-protein-linked thrombin receptor and platelet glycoprotein Ib (GPIb) as alpha-thrombin-binding sites on platelets remain controversial. alpha-Thrombin has been proposed to bind to both GPIb and the hirudin-like domain of the G-protein-linked receptor (from which it cleaves the NH2-terminal extracellular domain to release a 41-mer peptide (TR-(1-41), where TR is alpha-thrombin receptor)) to initiate platelet activation. Using affinity-purified rabbit anti-human TR-(1-41) IgG and immunoblotting, we demonstrated TR-(1-41) release from platelets suspended in Tyrode's buffer containing 2 mM CaCl2 and incubated with >/=0.5 nM alpha-thrombin for 10-60 s at 37 degrees C. As quantified by enzyme-linked immunosorbent assay, 0.32-0.59 nM TR-(1-41) was released from washed platelets (5 x 10(11) platelets/liter) after their incubation with 10 nM alpha-thrombin for 10 s. Parallel binding of alpha-thrombin to and activation of the platelets were confirmed by flow cytometry. A monoclonal antibody against the hirudin-like domain of the G-protein-linked receptor abrogated alpha-thrombin binding to platelets, cleavage of TR-(1-41), and platelet activation by

Platelet-surface glycoproteins in healthy and preeclamptic mothers and their newborn infants.

Preeclampsia, a common complication of pregnancy, contributes significantly to maternal and fetal morbidity and mortality. It may lead to both quantitative and qualitative defects of maternal and neonatal platelets. In this prospective study, flow cytometry has been used to study expression of platelet-surface glycoproteins (GPs) on maternal and neonatal platelets of both healthy and preeclamptic subjects. We studied 15 preeclamptic women, 20-44 y of age, and their newborns (median gestational age, 32 wk; range, 26-38) and seven healthy women (aged 26-41 y) and their healthy newborns (median gestational age, 38 wk; range, 38-42). Compared with their healthy and preeclamptic mothers, resting platelets from neonates expressed significantly less CD41 and CD9. Thrombin activation resulted in significant increases in platelet-surface expression of CD62P, CD63, CD41, CD9, and CD36 in neonates and their healthy mothers. Compared with neonates of healthy mothers, platelets from neonates of preeclamptic mothers expressed lower levels of CD62P, CD63, CD9, and CD36 on activated platelets. These findings suggest that preeclampsia influences the expression of platelet-surface GPs on neonatal and maternal platelets, which may affect platelet function, leading to an additional risk for bleeding in thrombocytopenic neonates of mothers with preeclampsia.

Fine needle aspiration diagnosis of ciliated hepatic foregut cysts: a report of three cases.

BACKGROUND: Ciliated hepatic foregut cysts, albeit rare, are important to consider in liver aspirates obtained for evaluation of possible neoplastic disease. CASES: In three cases, liver fine needle aspirates showed features consistent with ciliated hepatic foregut cysts. Two of these aspirates were obtained to evaluate possible metastatic disease prior to resection of primary tumors, one of the lung and one of the bladder. A third case had radiologic findings suggestive of a cystic neoplasm. The fine needle aspirate material from these cases revealed clusters of tall, columnar cells with basally oriented nuclei and prominent apical terminal plates with cilia. These features are consistent with ciliated hepatic foregut cysts. CONCLUSION: This entity, although originally described in the late 19th century, to our knowledge has not been reported to occur in fine needle aspirate material and should be included in the differential diagnosis of cystic lesions of the liver.

Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity.

Patients with both acute and chronic autoimmune thrombocytopenic purpura (AITP) have in vitro lymphocyte defects in the form of platelet-stimulated proliferation and cytokine secretion. A blinded study was performed to determine if these defects are related to serum cytokine levels and/or platelet antigen expression. Compared with controls, 53% of children with chronic AITP, but only 9% of those with acute AITP, had increased serum interleukin-2 (IL-2), interferon-gamma, and/or IL-10; however, none of the patients had detectible serum levels of IL-4 or IL-6, cytokine patterns suggesting and early CD4+ Th0 and Th1 cell activation. In children with chronic AITP, the levels of serum IL-2 correlated with in vitro platelet-stimulated IL-2 production. Few (17%) patients with AITP showed platelet activation, as measured by CD62 expression, or abnormal expression levels of platelet membrane glycoprotein (GP) IIbIIIa, but abnormal GPIb levels were observed in one-third of children with AITP. In contrast to normal controls and patients with nonimmune thrombocytopenia, a significant number of children with acute (80%), chronic (71%), or chronic-complex (55%) AITP and GPIb+ peripheral blood cells expressing HLA-DR. HLA-DR was variably coexpressed on distinct smaller and larger-sized GPIb+ cell populations with CD41, CD45, CD14, CD80, and/or glycophorin molecules. GPIb+ cells isolated from spleens of patients with chronic AITP had high expression (49% +/- 30%) of HLA-DR and splenic T cells had a high level of in vitro platelet-stimulated IL-2 secretion compared with controls. Platelet HLA-DR expression correlated inversely with platelet count, but not with therapy, serum cytokines, or in vitro lymphocyte antiplatelet reactivity. The results indicate that platelet HLA-DR expression is a common occurrence in patients with immune thrombocytopenia, whereas a large subpopulation of children with chronic AITP can be identified by increased serum cytokine levels and in vitro platelet-stimulated IL-2 secretion by lymphocytes, suggesting that differences exist in the immune pathogenesis of acute and chronic AITP, particularly at the level of platelet reactive T cells.

Plasmin accelerates platelet-dependent prothrombinase formation without activating the platelets.

Patients with acute myocardial infarction who undergo thrombolytic therapy may shortly thereafter present evidence for increased platelet activation and thrombin activity, and recurrent thrombosis. This study investigated whether plasmin activates platelets and prothrombin in recalcified platelet-rich plasma (RPRP) to cause (at least in part) these side-effects of thrombolytic therapy. Plasmin (0.1 and 1.0 CU/ml) addition to RPRP with microM r-tick anticoagulant peptide (the latter a factor Xa inhibitor which abrogates prothrombin activation by prothrombinase at the concentration used) resulted in no change in the concentration of prothrombin fragment 1 + 2, or in the expression of GMP-140, the resting and activated GP IIb-IIIa conformers, and GPIb on platelets. Thus, plasmin neither activates platelets nor prothrombin in RPRP. However, plasmin accelerated platelet activation and secretion, and prothrombin fragment 1 + 2 production in RPRP. When combined with 1 microM r-tick anticoagulant peptide and 1 or 10 mM alpha-thrombin to RPRP, plasmin also increased the number of GMP-140 molecules expressed/platelet without enhancing alpha-thrombin binding to the platelets. Additionally, plasmin accelerated prothrombin activation when it was added to washed platelets resuspended in factor V depleted plasma simultaneously with 10 mM CaCl2, 10 nM alpha-thrombin for 10 s (to activate platelets and platelet factor V), followed by 4 microM hirudin and 1 nM factor Xa. Thus, plasmin potentiates the platelet release reaction in response to alpha-thrombin (probably by increasing the availability of factor V on the platelets) to enhance prothrombin activation in RPRP. These actions of plasmin may contribute to the increased platelet activation and thrombotic side-effects that can occur after thrombolytic therapy.

Amphetamine in recovery from brain injury.

A chart review of dextroamphetamine treatment in 27 traumatic brain injury patients during rehabilitation therapy suggests that amphetamine treatment enhanced the recovery and functional status of 15 patients.