Unanticipated differences between α- and γ-diaminobutyric acid-linked hairpin polyamide-alkylator conjugates

Hairpin polyamide–chlorambucil conjugates containing an {alpha}-diaminobutyric acid ({alpha}-DABA) turn moiety are compared to their constitutional isomers containing the well-characterized {gamma}-DABA turn. Although the DNA-binding properties of unconjugated polyamides are similar, the {alpha}-DABA conjugates display increased alkylation specificity and decreased rate of reaction. Treatment of a human colon carcinoma cell line with {alpha}-DABA versus {gamma}-DABA hairpin conjugates shows only slight differences in toxicities while producing similar effects on cell morphology and G2/M stage cell cycle arrest. However, striking differences in animal toxicity between the two classes are observed. Although mice treated with an {alpha}-DABA hairpin polyamide do not differ significantly from control mice, the analogous {gamma}-DABA hairpin is lethal. This dramatic difference from a subtle structural change would not have been predicted

Plasma-type gelsolin in subarachnoid hemorrhage: novel biomarker today, therapeutic target tomorrow?

There is growing interest in the potential neuroprotective properties of gelsolin. In particular, plasma-type gelsolin (pGSN) can ameliorate deleterious inflammatory response by scavenging pro-inflammatory signals such as actin and lipopolysaccharide. In a recent issue of Critical Care, Pan and colleagues report an important association between pGSN and subarachnoid hemorrhage (SAH) disease severity, and found pGSN to be a novel and promising biomarker for SAH clinical outcome. Previous research shows pGSN may be actively degraded by neurovascular proteases such as matrix metalloproteinases in the cerebral spinal fluid of SAH patients. Taken together, these results suggest that pGSN is not only a novel marker of SAH clinical outcome, but may also play an active mechanistic role in SAH, and potentially serve as a future therapeutic target

Fatal Hyperammonemic Brain Injury from Valproic Acid Exposure

Background: Hyperammonemia is known to cause neuronal injury, and can result from valproic acid exposure. Prompt reduction of elevated ammonia levels may prevent permanent neurological injury. We report a case of fatal hyperammonemic brain injury in a woman exposed to valproic acid. Case: A 38-year-old woman with schizoaffective disorder and recent increase in valproic acid dosage presented with somnolence and confusion and rapidly progressed to obtundation. Brain MRI showed diffuse bilateral restricted diffusion in nearly the entire cerebral cortex. She had normal liver function tests but serum ammonia level was severely elevated at 288 $\mu mol/l$. Genetic testing showed no mutation in urea cycle enzymes. Despite successful elimination of ammonia with hemodialysis she developed fatal cerebral edema. Conclusion: Cerebral edema secondary to hyperammonemia is potentially reversible if recognized early. Ammonia excretion can be facilitated by initiation of hemodialysis and administration of scavenging agents (sodium phenylacetate and sodium benzoate). Severe hyperammonemia can result from valproic acid exposure even in the absence of hepatotoxicity or inborn errors of metabolism. It is important to check serum ammonia in any patient with encephalopathy who has had recent valproic acid exposure

Seizures and antiepileptic drugs in patients with spontaneous intracerebral hemorrhages

AbstractPurposePatients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a clear indication. We compared the percentage of patients with spontaneous ICH who had seizures at onset or during hospitalization, and examined empiric use of antiepileptic drugs (AEDs) in these patients in 2 cohorts 10 years apart.MethodsUsing a clinical data registry at a tertiary care adult hospital, we retrospectively selected admissions for spontaneous ICH between 1/1/99–12/31/00 (Cohort A, n=30) and 1/1/09–12/31/10 (Cohort B, n=108). Clinical, neurophysiological and radiological data were collected in both cohorts.ResultsIn Cohorts A and B respectively, AEDs were started in 53.3% and 50.0%, and continued on discharge in 50.0% and 20.4% of patients; 86.6% and 59.1% of patients discharged on AEDs did not have a clinical/electrographic seizure or epileptiform EEG findings. Seizures occurred in 6.6% and 13.0% in Cohorts A and B respectively. The presence of a seizure at presentation (p=0.01) and during hospitalization (p=0.02) were predictors for continuing AED on discharge.ConclusionIn both cohorts, a significant number of patients were discharged on AEDs without a clear indication, though there is a change in practice between the two cohorts

Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia

Thromboembolic Risks of Recombinant Factor VIIa Use in Warfarin-Associated Intracranial Hemorrhage: A Case–Control Study

Background: Recombinant factor VIIa (rFVIIa) may be used for rapid hemostasis in life-threatening hemorrhage. In warfarin-associated intracerebral hemorrhage (wICH), FVIIa use is controversial and may carry significant thromboembolic risks. We compared incidence of baseline thromboembolic risk factors and thromboembolism rates in wICH patients treated with additional rFVIIa to those treated with standard therapy of fresh frozen plasma (FFP) and vitamin K alone. Methods: We identified 45 consecutive wICH patients treated with additional rFVIIa over 5-year period, and 34 consecutive wICH patients treated with standard therapy alone as comparison group. We compared the incidence of post-hemorrhage cardiac and extra-cardiac thromboembolic complications between two treatment groups, and used logistic regression to adjust for significant confounders such as baseline thromboembolic risk factors. We performed secondary analysis comparing the quantity of FFP transfused between two treatment cohorts. Results: Both rFVIIa-treated and standard therapy-treated wICH patients had a high prevalence of pre-existing thromboembolic diseases including atrial fibrillation (73% vs 68%), deep venous thrombosis (DVT) or pulmonary embolism (PE) (22% vs 18%), coronary artery disease (CAD) (38% vs 32%), and abnormal electrocardiogram (EKG) (78% vs 85%). Troponin elevation following wICH was prevalent in both groups (47% vs 41%). Clinically significant myocardial infarction (MI), defined as troponin > 1.0 ng/dL, occurred in 13% of rFVIIa-treated and 6% of standard therapy-treated patients (p=0.52). Past history of CAD (p=0.0061) and baseline abnormal EKG (p=0.02) were independently associated with clinically significant MI following wICH while rFVIIa use was not. The incidences of DVT/PE (2% vs 9%; p=0.18) and ischemic stroke (2% vs 0%; p=0.38) were similar between two treatment groups. Recombinant FVIIa-treated patients had lower mean INR at 3 (p=0.0001) and 6 hours (p<0.0001) and received fewer units of FFP transfusion (3 vs 5; p=0.003). Conclusions: Pre-existing thromboembolic risk factors as well as post-hemorrhage troponin elevation are prevalent in wICH patients. Clinically significant MI occurs in up to 13% of wICH patients. rFVIIa use was not associated with increased incidence of clinically significant MI or other venous or arterial thromboembolic events in this wICH cohort

Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19-A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium.

Importance The COVID-19 pandemic continues to affect millions of people globally, with increasing reports of neurological manifestations but limited data on their incidence and associations with outcome. Objective To determine the neurological phenotypes, incidence, and outcomes among adults hospitalized with COVID-19. Design, Setting, and Participants This cohort study included patients with clinically diagnosed or laboratory-confirmed COVID-19 at 28 centers, representing 13 countries and 4 continents. The study was performed by the Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID) from March 1 to September 30, 2020, and the European Academy of Neurology (EAN) Neuro-COVID Registry (ENERGY) from March to October 2020. Three cohorts were included: (1) the GCS-NeuroCOVID all COVID-19 cohort (n = 3055), which included consecutive hospitalized patients with COVID-19 with and without neurological manifestations; (2) the GCS-NeuroCOVID COVID-19 neurological cohort (n = 475), which comprised consecutive patients hospitalized with COVID-19 who had confirmed neurological manifestations; and (3) the ENERGY cohort (n = 214), which included patients with COVID-19 who received formal neurological consultation. Exposures Clinically diagnosed or laboratory-confirmed COVID-19. Main Outcomes and Measures Neurological phenotypes were classified as self-reported symptoms or neurological signs and/or syndromes assessed by clinical evaluation. Composite incidence was reported for groups with at least 1 neurological manifestation. The main outcome measure was in-hospital mortality. Results Of the 3055 patients in the all COVID-19 cohort, 1742 (57%) were men, and the mean age was 59.9 years (95% CI, 59.3-60.6 years). Of the 475 patients in the COVID-19 neurological cohort, 262 (55%) were men, and the mean age was 62.6 years (95% CI, 61.1-64.1 years). Of the 214 patients in the ENERGY cohort, 133 (62%) were men, and the mean age was 67 years (95% CI, 52-78 years). A total of 3083 of 3743 patients (82%) across cohorts had any neurological manifestation (self-reported neurological symptoms and/or clinically captured neurological sign and/or syndrome). The most common self-reported symptoms included headache (1385 of 3732 patients [37%]) and anosmia or ageusia (977 of 3700 patients [26%]). The most prevalent neurological signs and/or syndromes were acute encephalopathy (1845 of 3740 patients [49%]), coma (649 of 3737 patients [17%]), and stroke (222 of 3737 patients [6%]), while meningitis and/or encephalitis were rare (19 of 3741 patients [0.5%]). Presence of clinically captured neurologic signs and/or syndromes was associated with increased risk of in-hospital death (adjusted odds ratio [aOR], 5.99; 95% CI, 4.33-8.28) after adjusting for study site, age, sex, race, and ethnicity. Presence of preexisting neurological disorders (aOR, 2.23; 95% CI, 1.80-2.75) was associated with increased risk of developing neurological signs and/or syndromes with COVID-19. Conclusions and Relevance In this multicohort study, neurological manifestations were prevalent among patients hospitalized with COVID-19 and were associated with higher in-hospital mortality. Preexisting neurological disorders were associated with increased risk of developing neurological signs and/or syndromes in COVID-19

Nanoimprint Lithography Based Approach for the Fabrication of Large-Area, Uniformly-Oriented Plasmonic Arrays

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58080/1/1129_ftp.pd

Small molecules targeting histone H4 as potential therapeutics for chronic myelogenous leukemia

We recently identified a polyamide-chlorambucil conjugate, 1R-Chl, which alkylates and down-regulates transcription of the human histone H4c gene and inhibits the growth of several cancer cell lines in vitro and in a murine SW620 xenograft model, without apparent animal toxicity. In this study, we analyzed the effects of 1R-Chl in the chronic myelogenous leukemia cell line K562 and identified another polyamide conjugate, 6R-Chl, which targets H4 genes and elicits a similar cellular response. Other polyamide conjugates that do not target the H4 gene do not elicit this response. In a murine model, both 1R-Chl and 6R-Chl were found to be highly effective in blocking K562 xenograft growth with high-dose tolerance. Unlike conventional and distamycin-based alkylators, little or no cytotoxicities and animal toxicities were observed in mg/kg dosage ranges. These results suggest that these polyamide alkylators may be a viable treatment alternative for chronic myelogenous leukemia

PopTargs: a database for studying population evolutionary genetics of human microRNA target sites

There is an increasing interest in the study of polymorphic variants at gene regulatory motifs, including microRNA target sites. Understanding the effects of selective forces at specific microRNA target sites, together with other factors like expression levels or evolutionary conservation, requires the joint study of multiple datasets. We have compiled information from multiple sources and compared it with predicted microRNA target sites to build a comprehensive database for the study of microRNA targets in human populations. PopTargs is a web-based tool that allows the easy extraction of multiple datasets and the joint analyses of them, including allele frequencies, ancestral status, population differentiation statistics and site conservation. The user can also compare the allele frequency spectrum between two groups of target sites and conveniently produce plots. The database can be easily expanded as new data becomes available and the raw database as well as code for creating new custom-made databases is available for downloading. We also describe a few illustrative examples