Management of Critically Ill Pregnant Patients with COVID-19 Infection in a Rural State.

OBJECTIVE: There is limited data on the treatment of coronavirus disease 2019 (COVID-19) in pregnancy. Arkansas saw an increase in COVID-19 cases in June 2020. The first critically ill pregnant patient was admitted to our institution on May 21st, 2020. The objective of this study was to evaluate outcomes in critically ill pregnant women with COVID-19 at a single tertiary care center who received remdesivir and convalescent plasma (CCP). STUDY DESIGN: This is a retrospective observational review of critically ill pregnant women with COVID-19 who received remdesivir and CCP. This study was approved by the institutional review board (#261354). RESULTS: Seven pregnant patients with COVID-19 were admitted to the intensive care unit (ICU). All received remdesivir and CCP. Six received dexamethasone. The median ICU length of stay (LOS) was 8 days (range 3-17). Patient 1 had multi-organ failure requiring vasopressors, renal dialysis, and had an intrauterine fetal demise. Patients 4 and 6 required mechanical ventilation, were delivered for respiratory distress and were extubated at 2 and 1 days postpartum, respectively. The only common risk factor was obesity. There were no adverse events noted with remdesivir or CCP. CONCLUSION: There is little data regarding the use of remdesivir or CCP for the treatment of COVID-19 in pregnant women. In our cohort, these were well tolerated with no adverse events. Previously reported median ICU LOS in critically ill pregnant women with COVID-19 was 8 days (range 4-15).1 Our study found a similar ICU LOS (8 days; range 3-17). Patient 1 did not receive remdesivir or CCP until transport to our facility on hospital day 3. Excluding patient 1, median ICU LOS was 6.5 days (range 3-9). Our institution's treatment of pregnant women with critical illness with remdesivir, CCP and dexamethasone combined with delivery in select cases has thus far had good outcomes. KEY POINTS: · Combined therapy: remdesivir, CCP, dexamethasone.. · Remdesivir, CCP and dexamethasone was effective in treating critically ill pregnant women with COVID-19.. · No adverse events were associated with combined therapy.. · Delivery improved respiratory status..

Two Epidemics and a Pandemic: The Collision of Prescription Drug Misuse and Racism during COVID-19.

The present study investigated the relationship between perceived racial discrimination and prescription drug misuse (PDM) among Asian, Black, and Latinx Americans during the COVID-19 crisis. U.S. racial/ethnic minorities may have been uniquely affected by two national and one global pandemic: the opioid crisis, racism, and COVID-19. Opioid death rates increased among many groups prior to the pandemic. This country witnessed an increase in racialized acts against people of color across the spectrum in the spring and summer months of the world's COVID-19 outbreak. While studies have shown a clear link between perceived racial discrimination and substance abuse outside of the global pandemic, no identified studies have done so against the backdrop of a global health pandemic. Separate hierarchical regressions revealed a significant association between perceived racial discrimination and PDM for Black Americans, Asian Americans, and Latinx individuals. Findings build on the scant literature on PDM in diverse samples and establish a relationship between perceived racial discrimination and PDM, as previously identified for other abused substances. Future post-pandemic substance misuse interventions should consider the influence of perceived racial discrimination as they help individuals recover from the aftermath of this stressful trifecta.

Spontaneous Renal Rupture During Pregnancy: A Contemporary Literature Review and Guide to Management.

IMPORTANCE: Spontaneous renal rupture is a rare pregnancy complication, which requires a high index of suspicion for a timely diagnosis to prevent a poor maternal or fetal outcome. OBJECTIVE: This review highlights risk factors, pathophysiology, symptoms, diagnosis, management, and complications of spontaneous renal rupture in pregnancy. EVIDENCE ACQUISITION: A literature search was carried out by research librarians using the PubMed and Web of Science search engines at 2 universities. Fifty cases of spontaneous renal rupture in pregnancy were identified and are the basis of this review. RESULTS: The first case of spontaneous renal rupture in pregnancy was reported in 1947. Rupture occurs more commonly on the right side and during the third trimester. Pain was a reported symptom in every case reviewed. Treatment usually consists of stent or nephrostomy tube placement. Conservative management has been reported. CONCLUSIONS: When diagnosed early and managed appropriately, maternal and fetal outcomes are favorable. Preterm delivery is the most common complication. RELEVANCE: Our aim is to increase the awareness of spontaneous renal rupture in pregnancy and its associated complications in order to improve an accurate diagnosis and maternal and fetal outcomes.

Development of Coagulation Factor XII Antibodies for Inhibiting Vascular Device-Related Thrombosis.

INTRODUCTION: Vascular devices such as stents, hemodialyzers, and membrane oxygenators can activate blood coagulation and often require the use of systemic anticoagulants to selectively prevent intravascular thrombotic/embolic events or extracorporeal device failure. Coagulation factor (F)XII of the contact activation system has been shown to play an important role in initiating vascular device surface-initiated thrombus formation. As FXII is dispensable for hemostasis, targeting the contact activation system holds promise as a significantly safer strategy than traditional antithrombotics for preventing vascular device-associated thrombosis. OBJECTIVE: Generate and characterize anti-FXII monoclonal antibodies that inhibit FXII activation or activity. METHODS: Monoclonal antibodies against FXII were generated in FXII-deficient mice and evaluated for their binding and anticoagulant properties in purified and plasma systems, in whole blood flow-based assays, and in an in vivo non-human primate model of vascular device-initiated thrombus formation. RESULTS: A FXII antibody screen identified over 400 candidates, which were evaluated in binding studies and clotting assays. One non-inhibitor and six inhibitor antibodies were selected for characterization in functional assays. The most potent inhibitory antibody, 1B2, was found to prolong clotting times, inhibit fibrin generation on collagen under shear, and inhibit platelet deposition and fibrin formation in an extracorporeal membrane oxygenator deployed in a non-human primate. CONCLUSION: Selective contact activation inhibitors hold potential as useful tools for research applications as well as safe and effective inhibitors of vascular device-related thrombosis.

Progesterone inhibits cytokine/TNF-α production by porcine CL macrophages via the genomic progesterone receptor.

In pigs, luteolytic sensitivity to PGF-2α (=LS) is delayed until d 13 of the estrous cycle. While the control of LS is unknown, it is temporally associated with macrophage (MAC; which secretes tumor necrosis factor [TNF]-α) infiltration into the corpora lutea (CL), and previous studies have shown that TNF-α induces LS in porcine luteal cells (LCs) in culture. This study was designed to explore the control of LS by CL macrophage (CL MAC)/TNF-α by progesterone (P4), and to examine the hypothesis that P4 acting via the genomic P4 receptor (PGR) inhibits CL MAC TNF-α and thus plays a key role in regulating LS during the pig estrous cycle. In experiment 1, the effects of LCs on CL MAC cytokine/TNF-α mRNA expression in co-culture were examined (MID cycle; ~d 7-12; no LS); results showed that LC was inhibitory to cytokine/TNF-α. In experiment 2, the effects of P4 or R5020 (PGR-agonist) on CL MAC cytokine/TNF-α mRNA expression were examined (MID cycle; ~d 7-12; no LS); results showed that both P4 and R5020 dose-dependently inhibited TNF-α. In experiment 3, CL MACs were isolated from CL at MID (~d 7-12; no LS) and LATE (~d 13-18; + LS) cycle, and TNF-α/PGR mRNA measured. Results indicated that while TNF-α mRNA was 4.2-fold greater in CL MACs from LATE vs MID cycle, PGR mRNA was 4.5-fold greater in CL MACs from MID vs LATE cycle. These data support our hypothesis and suggest that progesterone, acting via PGR, plays a critical physiological role in the control of TNF-α production by CL MACs and LS during the pig estrous cycle.

Preclinical tools for the evaluation of tuberculosis treatment regimens for children.

Tuberculosis (TB) treatment regimens have been extrapolated from adults to children. However, pediatric disease merits different treatment strategies to avoid under- or over-treatment. While animal models have been pivotal in identifying effective regimens for adult disease, pediatric TB is heterogeneous and cannot be represented by a single preclinical model. Infants and young children most commonly have disseminated disease or tuberculous meningitis (TBM), school-aged children have paucibacillary disease, and adolescents have adult-like cavitary lung disease. Models simulating these forms of pediatric TB have been developed, but their utility in assessing treatment regimens is in the early stages. Disseminated, intracellular disease can be partly reproduced by an in vitro pharmacodynamic system, TBM by a pediatric rabbit model of TBM, paucibacillary TB by the balbC mouse model, and cavitary disease by a rabbit model and a C3HeB/FeJ mouse model of pulmonary TB. Although there is no one-size-fits-all preclinical 'pediatric TB model', these models can be employed to study drug distribution to the sites of disease and, coupled with translational modeling, used to help select and optimize regimens for testing in children. Use of these models may accelerate the development of regimens for rare or hard-to-treat TB, namely drug-resistant TB and TBM.

Clinical assessment of gastric emptying and sensory function utilizing gamma scintigraphy: Establishment of reference intervals for the liquid and solid components of the Nottingham test meal in healthy subjects.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study presents the reference intervals of the modular "Nottingham test meal" (NTM) for assessment of gastric function by gamma scintigraphy (GSc) in a representative population of healthy volunteers (HVs) stratified for age and sex. METHODS: The NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and an optional solid component (12 solid agar-beads (0 kcal). Filling and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gamma scintigraphy parameters that describe early and late phase Gastric emptying (GE) were calculated from validated models. KEY RESULTS: Gastric emptying (GE) of the liquid component was measured in 73 HVs (male 34; aged 45±20). The NTM produced normal postprandial fullness (VAS ≥30 in 41/74 subjects). Dyspeptic symptoms were rare (VAS ≥30 in 2/74 subjects). Gastric emptying half-time with the Liquid- and Solid-component -NTM was median 44 (95% reference interval 28-78) minutes and 162 (144-193) minutes, respectively. Gastric accommodation was assessed by the ratio of the liquid-NTM retained in the proximal:total stomach and by Early phase emptying assessed by gastric volume after completing the meal (GCV0). No consistent effect of anthropometric measures on GE parameters was present. CONCLUSIONS AND INFERENCES: Reference intervals are presented for GSc measurements of gastric motor and sensory function assessed by the NTM. Studies involving patients are required to determine whether the reference interval range offers optimal diagnostic sensitivity and specificity.

Rapid Drink Challenge in high-resolution manometry: an adjunctive test for detection of esophageal motility disorders.

BACKGROUND/AIMS: The Chicago Classification for diagnosis of esophageal motility disorders by high-resolution manometry (HRM) is based on single water swallows (SWS). Emerging data suggest that a "Rapid Drink Challenge" (RDC) increases sensitivity for motility disorders. This study establishes normal values and diagnostic thresholds for RDC in clinical practice. METHODS: Two cohort studies were performed in patients with dysphagia or reflux symptoms (development and validation sets). Healthy subjects and patient controls provided reference values. Ten SWS and two 200-mL RDC were performed. Primary diagnosis for SWS was established by the Chicago Classification. Abnormal RDC was defined by impaired esophagogastric junction (EGJ) function (elevated integrated relaxation pressure during RDC [IRP-RDC]); incomplete inhibition of contractility during and ineffective contraction after RDC. Diagnostic thresholds identified in the development set were prospectively tested in the validation set. RESULTS: Normal values were determined in healthy (n=95; age 37.8 ± 12) and patient controls (n=44; age 46.4 ± 15). Development and validation sets included 178 (54 ± 17 years) and 226 (53 ± 16 years) patients, respectively. Integrated relaxation pressure during RDC was higher for SWS than RDC in all groups (overall P<.001), except achalasia. Rapid Drink Challenge suppressed contractility, except in achalasia type III, spasm, and hypercontractile motility disorders (P<.001). An effective after-contraction was present more often in health than disease (P<.001). Optimal diagnostic thresholds identified in the development set (IRP-RDC ≥12 mmHg achalasia, IRP-RDC ≥ 8mmHg "all cause" EGJ dysfunction), were confirmed in the validation set (both, sensitivity ~85%, specificity >95%). CONCLUSIONS: Rapid Drink Challenge contributes clinically relevant information to routine HRM studies, especially in patients with EGJ dysfunction.

The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

Development and validation of a large, modular test meal with liquid and solid components for assessment of gastric motor and sensory function by non-invasive imaging.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study introduces the large 'Nottingham Test Meal' (NTM) for assessment of gastric motor and sensory function by non-invasive imaging. METHODS: NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and 12 solid agar-beads (0 kcal) with known breaking strength. Gastric fullness and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gastric emptying (GE) were measured in 24 healthy volunteers (HVs) by gastric scintigraphy (GS) and magnetic resonance imaging (MRI). The contribution of secretion to gastric volume was assessed. Parameters that describe GE were calculated from validated models. Inter-observer agreement and reproducibility were assessed. KEY RESULTS: NTM produced moderate fullness (VAS ≥30) but no more than mild dyspeptic symptoms (VAS <30) in 24 HVs. Stable binding of meal components to labels in gastric conditions was confirmed. Distinct early and late-phase GE were detected by both modalities. Liquid GE half-time was median 49 (95% CI: 36-62) min and 68 (57-71) min for GS and MRI, respectively. Differences between GS and MRI measurements were explained by the contribution of gastric secretion. Breaking strength for agar-beads was 0.8 N/m(2) such that median 25 (8-50) % intact agar-beads and 65 (47-74) % solid material remained at 120 min on MRI and GS, respectively. Good reproducibility for liquid GE parameters was present and GE was not altered by agar-beads. CONCLUSIONS & INFERENCES: The NTM provided an objective assessment of gastric motor and sensory function. The results were reproducible and liquid emptying was not affected by non-nutrient agar-beads. The method is potentially suitable for clinical practice.

Enhancing neural stem cell response to SDF-1α gradients through hyaluronic acid-laminin hydrogels.

Traumatic brain injury (TBI) initiates an expansive biochemical insult that is largely responsible for the long-term dysfunction associated with TBI; however, current clinical treatments fall short of addressing these underlying sequelae. Pre-clinical investigations have used stem cell transplantation with moderate success, but are plagued by staggeringly low survival and engraftment rates (2-4%). As such, providing cell transplants with the means to better dynamically respond to injury-related signals within the transplant microenvironment may afford improved transplantation survival and engraftment rates. The chemokine stromal cell-derived factor-1α (SDF-1α) is a potent chemotactic signal that is readily present after TBI. In this study, we sought to develop a transplantation vehicle to ultimately enhance the responsiveness of neural transplants to injury-induced SDF-1α. Specifically, we hypothesize that a hyaluronic acid (HA) and laminin (Lm) hydrogel would promote 1. upregulated expression of the SDF-1α receptor CXCR4 in neural progenitor/stem cells (NPSCs) and 2. enhanced NPSC migration in response to SDF-1α gradients. We demonstrated successful development of a HA-Lm hydrogel and utilized standard protein and cellular assays to probe NPSC CXCR4 expression and NPSC chemotactic migration. The findings demonstrated that NPSCs significantly increased CXCR4 expression after 48 h of culture on the HA-Lm gel in a manner critically dependent on both HA and laminin. Moreover, the HA-Lm hydrogel significantly increased NPSC chemotactic migration in response to SDF-1α at 48 h, an effect that was critically dependent on HA, laminin and the SDF-1α gradient. Therefore, this hydrogel serves to 1. prime NPSCs for the injury microenvironment and 2. provide the appropriate infrastructure to support migration into the surrounding tissue, equipping cells with the tools to more effectively respond to the injury microenvironment.

WEDGE: an anticoagulant thrombin mutant produced by autoactivation.

BACKGROUND: The production of therapeutically relevant proteases typically involves activation of a zymogen precursor by external enzymes, which may raise regulatory issues about availability and purity. Recent studies of thrombin precursors have shown how to engineer constructs that spontaneously convert to the mature protease by autoactivation, without the need for external enzymes. OBJECTIVES: Autoactivation is an innovative strategy that promises to simplify the production of proteases of therapeutic relevance, but has not been tested in practical applications. The aim of this study was to provide a direct test of this strategy. METHODS: An autoactivating version of the thrombin mutant W215A/E217A (WE), which is currently in preclinical development as an anticoagulant, was engineered. RESULTS AND CONCLUSIONS: The autoactivating version of WE can be produced in large quantities, like WE made in BHK cells or Escherichia coli, and retains all significant functional properties in vitro and in vivo. The results serve as proof of principle that autoactivation is an innovative and effective strategy for the production of trypsin-like proteases of therapeutic relevance.

Evidence for factor IX-independent roles for factor XIa in blood coagulation.

BACKGROUND: Factor XIa is traditionally assigned a role in FIX activation during coagulation. However, recent evidence suggests this protease may have additional plasma substrates. OBJECTIVE: To determine whether FXIa promotes thrombin generation and coagulation in plasma in the absence of FIX, and to determine whether FXI-deficiency produces an antithrombotic effect in mice independently of FIX. METHODS: FXIa, FXIa variants and anti-FXIa antibodies were tested for their effects on plasma coagulation and thrombin generation in the absence of FIX, and for their effects on the activation of purified coagulation factors. Mice with combined FIX and FXI deficiency were compared with mice lacking either FIX or FXI in an arterial thrombosis model. RESULTS: In FIX-deficient plasma, FXIa induced thrombin generation, and anti-FXIa antibodies prolonged clotting times. This process involved FXIa-mediated conversion of FX and FV to their active forms. Activation of FV by FXIa required the A3 domain on the FXIa heavy chain, whereas activation of FX did not. FX activation by FXIa, unlike FIX activation, was not a calcium-dependent process. Mice lacking both FIX and FXI were more resistant to ferric chloride-induced carotid artery occlusion than FXI-deficient or FIX-deficient mice. CONCLUSION: In addition to its predominant role as an activator of FIX, FXIa may contribute to coagulation by activating FX and FV. As the latter reactions do not require calcium, they may make important contributions to in vitro clotting triggered by contact activation. The reactions may be relevant to FXIa's roles in hemostasis and in promoting thrombosis.

Measurement of esophago-gastric junction cross-sectional area and distensibility by an endolumenal functional lumen imaging probe for the diagnosis of gastro-esophageal reflux disease.

BACKGROUND: Measurement of esophago-gastric junction (EGJ) cross-sectional area (CSA) and distensibility by an Endolumenal Functional Lumen Imaging Probe (EndoFLIP®) may distinguish between gastro-esophageal reflux disease (GERD) patients and healthy volunteers (HV). We aimed to assess the agreement of EndoFLIP® measurements with clinical and physiologic diagnosis of GERD. METHODS: Twenty-one HV and 18 patients with typical GERD symptoms were studied. After gastroscopy, EGJ CSA, and distensibility were measured by EndoFLIP®. Forty-eight hour esophageal pH monitoring was then performed by a wireless system. The ability of EndoFLIP® to discriminate GERD patient and HVs was assessed. Planned secondary analysis then assessed whether EGJ CSA and distensibility were increased in individuals with pathologic acid exposure. KEY RESULTS: Healthy volunteers were younger and had lower body mass index (BMI; both p < 0.001). Pathologic acid exposure was present in 3/21 (14%) HVs and 9/18 (50%) patients (p = 0.126). At 30 mL EndoFLIP® bag volume, EGJ CSA was higher (p = 0.058) and EGJ distensibility was lower (p = 0.020) in HVs than patients. Secondary analysis showed that EGJ measurements were similar in participants with and without pathologic acid exposure (CSA 98 mm² vs 107 mm²; p = 0.789, distensibility; p = 0.704). An inverse association between BMI and CSA (R² = 0.2758, p = 0.001) and distensibility (R² = 0.2005, p = 0.005) was present. CONCLUSIONS & INFERENCES: Endolumenal Functional Lumen Imaging Probe is not useful for GERD diagnosis because EGJ CSA and distensibility do not distinguish between HVs and GERD patients defined by clinical presentation or pH measurement. This unexpected result may be due to an important, confounding interaction of obesity.

Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates.

BACKGROUND: Inorganic polyphosphates (polyP), which are secreted by activated platelets (short-chain polyP) and accumulate in some bacteria (long-chain polyP), support the contact activation of factor XII (FXII) and accelerate the activation of FXI. OBJECTIVES: The aim of the present study was to evaluate the role of FXI in polyP-mediated coagulation activation and experimental thrombus formation. METHODS AND RESULTS: Pretreatment of plasma with antibodies that selectively inhibit FXI activation by activated FXII (FXIIa) or FIX) activation by activated FXI (FXIa) were not able to inhibit the procoagulant effect of long or short-chain polyP in plasma. In contrast, the FXIIa inhibitor, corn trypsin inhibitor, blocked the procoagulant effect of long and short polyP in plasma. In a purified system, long polyP significantly enhanced the rate of FXII and prekallikrein activation and the activation of FXI by thrombin but not by FXIIa. In FXI-deficient plasma, long polyP promoted clotting of plasma in an FIX-dependent manner. In a purified system, the activation of FXII and prekallikrein by long polyP promoted FIX activation and prothombin activation. In an ex vivo model of occlusive thrombus formation, inhibition of FXIIa with corn trypsin inhibitor but not of FXI with a neutralizing antibodies abolished the prothrombotic effect of long polyP. CONCLUSIONS: We propose that long polyP promotes FXII-mediated blood coagulation bypassing FXI. Accordingly, some polyp-containing pathogens may have evolved strategies to exploit polyP-initiated FXII activation for virulence, and selective inhibition of FXII may improve the host response to pathogens.

Rumination variations: aetiology and classification of abnormal behavioural responses to digestive symptoms based on high-resolution manometry studies.

BACKGROUND: Rumination is the voluntary, albeit subconscious return of gastric contents to the mouth. Currently, rumination syndrome and repetitive belching disorders are considered separate diagnoses, as defined by Rome III criteria and high-resolution oesophageal manometry (HRM). AIM: To test the hypothesis that these conditions represent a common behavioural response to aversive digestive stimuli and that successful treatment can be directed at both the stimulus and the response. METHODS: Case-note review of consecutive patients with a final diagnosis of behavioural digestive disorders between August 2009 and October 2011. RESULTS: Thirty-five of 46 (76%) patients exhibited 'classical' rumination with abdomino-gastric strain (R-waves) driving gastric contents across the lower oesophageal sphincter; 5 (11%) had 'reflux-related' rumination with R-waves seen during gastro-oesophageal common cavity (reflux) events and 6 had (13%) supra-gastric belching. All received at least one biofeedback session at the time of diagnosis with a good response reported by 20/46 (43%) of the patients, which included 3 with supra-gastric belching. Additionally, rumination ceased in cases in which definitive treatment relieved the symptoms that triggered abnormal behaviour (e.g. fundoplication in 'reflux-rumination'). CONCLUSIONS: Rumination and many of its variations, excluding only some cases of supra-gastric belching, are associated with abdomino-gastric strain, a generic abnormal behavioural response to a variety of aversive digestive stimuli. All types of rumination can respond to biofeedback. High-resolution oesophageal manometry identifies subgroups with distinct mechanisms of disease that respond to specific management targeted at the symptoms that trigger the abnormal behaviour.

Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes.

DiGeorge, or 22q11 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes--particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites--the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes--especially those that influence the cell cycle or mitochondrial function--remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients.

Laminin promotes coagulation and thrombus formation in a factor XII-dependent manner.

BACKGROUND: Laminin is the most abundant non-collagenous protein in the basement membrane. Recent studies have shown that laminin supports platelet adhesion, activation and aggregation under flow conditions, highlighting a possible role for laminin in hemostasis. OBJECTIVE: To investigate the ability of laminin to promote coagulation and support thrombus formation under shear. RESULTS AND METHODS: Soluble laminin accelerated factor (F) XII activation in a purified system, and shortened the clotting time of recalcified plasma in a FXI- and FXII-dependent manner. Laminin promoted phosphatidylserine exposure on platelets and supported platelet adhesion and fibrin formation in recalcified blood under shear flow conditions. Fibrin formation in laminin-coated capillaries was abrogated by an antibody that interferes with FXI activation by activated FXII, or an antibody that blocks activated FXI activation of FIX. CONCLUSION: This study identifies a role for laminin in the initiation of coagulation and the formation of platelet-rich thrombi under shear conditions in a FXII-dependent manner.