Prediction of delayed cerebral ischemia followed aneurysmal subarachnoid hemorrhage. A machine-learning based study.

INTRODUCTION: Delayed Cerebral Ischemia (DCI) is a significant complication following aneurysmal subarachnoid hemorrhage (aSAH) that can lead to poor outcomes. Machine learning techniques have shown promise in predicting DCI and improving risk stratification. METHODS: In this study, we aimed to develop machine learning models to predict the occurrence of DCI in patients with aSAH. Patient data, including various clinical variables and co-factors, were collected. Six different machine learning models, including logistic regression, multilayer perceptron, decision tree, random forest, gradient boosting machine, and extreme gradient boosting (XGB), were trained and evaluated using performance metrics such as accuracy, area under the curve (AUC), precision, recall, and F1 score. RESULTS: After data augmentation, the random forest model demonstrated the best performance, with an AUC of 0.85. The multilayer perceptron neural network model achieved an accuracy of 0.93 and an F1 score of 0.85, making it the best performing model. The presence of positive clinical vasospasm was identified as the most important feature for predicting DCI. CONCLUSIONS: Our study highlights the potential of machine learning models in predicting the occurrence of DCI in patients with aSAH. The multilayer perceptron model showed excellent performance, indicating its utility in risk stratification and clinical decision-making. However, further validation and refinement of the models are necessary to ensure their generalizability and applicability in real-world settings. Machine learning techniques have the potential to enhance patient care and improve outcomes in aSAH, but their implementation should be accompanied by careful evaluation and validation.

STAT5b gain-of-function disease in a child with mycobacterial osteomyelitis of the skull: rare presentation of an emerging disease entity.

PURPOSE: STAT proteins play a key role in several cellular functions related to cell development, differentiation, proliferation, and survival. Persistent STAT activation due to somatic STAT5bN642H gain-of-function mutation is a rare mechanism of STAT dysregulation that results in hypereosinophilia, frequent infections, leukemias, and pulmonary diseases. Herein, we describe a case of a child with a rare early onset STAT5b gain-of-function disease treated with targeted JAK inhibition who developed a cranial Mycobacterium avium osteomyelitis. METHODS: A 3-year-old male with a known STAT5b gain-of-function mutation presented with a 10-day history of a firm, immobile, non-painful cranial mycobacterium mass with dural infiltration located anterior to the coronal suture. Stepwise management finalized with complete resection of the lesion with calvarial reconstruction. A case-based literature review was performed evaluating all patients with this mutation who developed cranial disease. RESULTS: The patient was symptom and lesion-free at 1 year since surgical resection and initiation of triple mycobacterial pharmacotherapy. Our literature review demonstrated the rarity of this disease, as well as other presentations of this disease in other patients. CONCLUSION: Patients with STAT5b gain-of-function mutations have attenuated Th1 responses and are treated with medications, such as JAK inhibitors, which further inhibit other STAT proteins that regulate immunity against rare infectious entities, such as mycobacterium. Our case highlights the importance of considering these rare infections in patients on JAK inhibitors and with STAT protein mutations. Possessing a clear mechanistic understanding of this genetic mutation, its downstream effect, and the consequences of treatment may enhance a physician's diagnostic and clinical management of similar patients in the future.

Pediatric brain aneurysms: a review of 1458 brain MR angiograms.

PURPOSE: To evaluate clinical and imaging characteristics of pediatric brain aneurysms. MATERIALS AND METHODS: A retrospective review of 1458 MR angiograms of pediatric patients (≤18 years old) obtained between 2006 and 2021 was performed. A non-infundibular arterial luminal outpouching larger than 1mm in size was identified as an "Intracranial aneurysm." Patient demographics, clinical presentations, and predisposing risk factors, including family history and underlying medical conditions, were reviewed. MRA images were analyzed for aneurysm location, number, maximum diameter, and interval changes on follow-up. RESULTS: Forty-nine (3.3%) patients (30 females, 19 males) with 64 intracranial aneurysms were identified with an average age of 13.71 ± 3.67 years. Eleven (22.4%) patients had multiple aneurysms. An underlying systemic illness was observed in 81.6% (40/49) cases, with sickle cell disease as the most frequent (25/49, 51%) diagnosis. A first-degree family history of intracranial aneurysms was recognized in 36/1458 (2.5%) patients. However, no intracranial aneurysm was found in this group. While 02/49 (4%) patients presented with acute SAH, headache was the most common (16/49, 32.7%) symptom at presentation in unruptured cases. The majority (47/64, 73.4%) of the aneurysms were located in the anterior circulation, with the ICA ophthalmic segment being most frequently (24/47, 51%) involved. Most (54/64, 84.4%) aneurysms were smaller than 4mm in size at the time of diagnosis. At least one follow-up MRA was obtained in 72.3% (34/47) of the unruptured aneurysms cohort. There was no change in the aneurysm size and morphology in 31/34 (91.2 %) patients over an average imaging follow-up of 39.6 months. Three (6%) patients demonstrated an interval increase in the aneurysm size. SAH patients (n=2) and two unruptured aneurysm patients with an interval increase in size were successfully treated with endovascular techniques. CONCLUSION: Female predominance with a higher frequency of small and unruptured intracranial aneurysms was recognized in our cohort. A higher incidence of an underlying systemic illness, especially sickle cell disease, was also noted. Most intracranial aneurysms in children appear to remain stable. However, there seems to be the risk of an aneurysm size increase which warrants regular clinical and imaging follow-up.

Biomarkers of Coagulation and Inflammation in COVID-19-Associated Ischemic Stroke.

[Figure: see text].

Separation surgery for metastatic epidural spinal cord compression: comparison of a minimally invasive versus open approach.

OBJECTIVE: The aim of this study was to compare outcomes of separation surgery for metastatic epidural spinal cord compression (MESCC) in patients undergoing minimally invasive surgery (MIS) versus open surgery. METHODS: A retrospective study of patients undergoing MIS or standard open separation surgery for MESCC between 2009 and 2019 was performed. Both groups received circumferential decompression via laminectomy and a transpedicular approach for partial corpectomy to debulk ventral epidural disease, as well as instrumented stabilization. Outcomes were compared between the two groups. RESULTS: There were 17 patients in the MIS group and 24 in the open surgery group. The average age of the MIS group was significantly older than the open surgery group (65.5 vs 56.6 years, p < 0.05). The preoperative Karnofsky Performance Scale score of the open group was significantly lower than that of the MIS group, with averages of 63.0% versus 75.9%, respectively (p = 0.02). This was also evidenced by the higher proportion of emergency procedures performed in the open group (9 of 24 patients vs 0 of 17 patients, p = 0.004). The average Spine Instability Neoplastic Score, number of levels fused, and operative parameters, including length of stay, were similar. The average estimated blood loss difference for the open surgery versus the MIS group (783 mL vs 430 mL, p < 0.05) was significant, although the average amount of packed red blood cells transfused was not significantly different (325 mL vs 216 mL, p = 0.39). Time until start of radiation therapy was slightly less in the MIS than the open surgery group (32.8 ± 15.6 days vs 43.1 ± 20.3 days, p = 0.069). Among patients who underwent open surgery with long-term follow-up, 20% were found to have local recurrence compared with 12.5% of patients treated with the MIS technique. No patients in either group developed hardware failure requiring revision surgery. CONCLUSIONS: MIS for MESCC is a safe and effective approach for decompression and stabilization compared with standard open separation surgery, and it significantly reduced blood loss during surgery. Although there was a trend toward a faster time to starting radiation treatment in the MIS group, both groups received similar postoperative radiotherapy doses, with similar rates of local recurrence and hardware failure. An increased ability to perform MIS in emergency settings as well as larger, prospective studies are needed to determine the potential benefits of MIS over standard open separation surgery.

Moyamoya Disease and Syndrome: A National Inpatient Study of Ischemic Stroke Predictors.

OBJECTIVES: Ischemic stroke and hemorrhagic stroke are the most common sequelae of the Moyamoya variants [Moyamoya disease (MMD) and syndrome (MMS)]. We sought to determine the rates of stroke subtypes and the predictive factors of arterial ischemic stroke (AIS) utilizing a large data sample of MMD and MMS patients in the US. MATERIALS AND METHODS: We queried the 2016 and 2017 National Inpatient Sample database for Moyamoya diagnosis plus any of the following associated conditions; sickle cell disease, neurofibromatosis type 1, cranial radiation therapy or Down Syndrome. Multivariate regression determined the risk factors for AIS onset in MMD and MMS. RESULTS: 2323 patients with a diagnosis of Moyamoya were included; 668 (28.8%) patients were classified as MMS and 1655 (71.2%) as MMD. AIS was the most common presentation in both cohorts; however, MMD patients had higher rates of AIS (20.4 vs 6%, p < 0.001), hemorrhagic stroke (7.4vs 2.5%, p < 0.001), and TIA (3.3vs 0.9%, p = 0.001) compared to MMS patients. Multivariate analysis showed that increasing age [OR = 1.017 95%CI: 1.008-1.03, p < 0.001], lipidemia [OR = 1.32 95%CI: 1.02-1.74, p = 0.049], and current smoking status [OR = 1.43 95%CI: 1.04-1.97, p = 0.026] were independent risk factors for AIS in MMD patients, whereas hypertension [OR = 2.61 95%CI: 1.29-5.25, p = 0.007] and African-American race [OR = 0.274, 95%CI: .117-.64, p = 0.003] were independent predictors in the MMS cohort. CONCLUSION: AIS is the most common presentation in both, MMD and MMS. However, MMD patients had higher rates of stroke events compared to MMS. Risk factors for AIS in MMD included increasing age, lipidemia and smoking status, whereas in MMS hypertension was the only independent risk factor.

Acid-Induced Liberation of Polysubstituted Cyclopentadiene Ligands from Cyclopentadienyl Cobalt: A [2 + 2 + 1] Cycloaddition Route toward 1,2,4-Trisubstituted Cyclopentadienes.

Here, we report that trifluoroacetic acid (TFAH) induces demetallation and protodesilylation of the cyclopentadiene ligand in cobalt-η4-cyclopentadiene complexes of general formula [(η5-C5H5)Co(η4-exo-C(TMS)═C(SO2Ph)CH═CRCH(CO2Et))] (1-Ph, R = Ph; 1-ArtBu, R = p-C6H4tBu; 1-ArNMe2, R = p-C6H4NMe2; and 1-Me, R = Me). The trisubstituted cyclopentadiene products are isolated as a mixture of two tautomers, [(CH2C(SO2Ph)═CHC(CO2Et)═CR)] (8-R-A) and [(CH═C(SO2Ph)CH2C(CO2Et)═CR)] (8-R-B). The endo isomer, [(η5-C5H5)Co(η4-endo-C(TMS)═C(SO2Ph)CH═CPhCH(CO2Et))] (1-Ph-endo), also undergoes demetallation and protodesilylation to give 8-Ph-A and 8-Ph-B in excellent yield. The cobalt-cyclopentadiene complex, [(η5-C5H5)Co(η4-exo-C(TMS)═C(SO2Ph)CH═C(CO2Me)CH(CO2Et))] (1-CO2Me), undergoes demetallation and protodesilylation upon treatment with TFAH to give a hydrogen-bonded fulvenol (8-CO2Me). Liberation of the ethoxy-substituted cyclopentadiene ligand of [(η5-C5H5)Co(η4-exo-C(TMS)═C(SO2Ph)CH═C(OEt)CH(CO2Et))] (1-OEt) leads to formation of a cyclopentenone derivative (11). Thermolysis of 8-Ph-A/8-Ph-B in the presence of maleimide leads to a highly functionalized Diels-Alder adduct, whereas 8-Ph-A/8-Ph-B serves as precursors to trisubstituted ruthenocenes by in situ deprotonation and reaction with [(η5-C5R5)Ru(NCMe)3]PF6 (16-H, R = H; 16-Me, R = Me).

Topectomy versus leukotomy: J. Lawrence Pool's contribution to psychosurgery.

Surgery of the mind has a rather checkered past. Though its history begins with the prehistoric trephination of skulls to allow "evil spirits" to escape, the early- to mid-20th century saw a surge in the popularity of psychosurgery. The 2 prevailing operations were topectomy and leukotomy for the treatment of certain mental illnesses. Although they were modified and refined by several of their main practitioners, the effectiveness of and the ethics involved with these operations remained controversial. In 1947, Dr. J. Lawrence Pool and the Columbia-Greystone Associates sought to rigorously investigate the outcomes of specific psychosurgical procedures. Pool along with R. G. Heath and John Weber believed that nonexcessive bifrontal cortical ablation could successfully treat certain mental illnesses without the undesired consequences of irreversible personality changes. They conducted this investigation at the psychiatric hospital at Greystone Park near Morristown, New Jersey. Despite several encouraging findings of the Columbia-Greystone project, psychosurgery practices began to decline significantly in the 1950s. The uncertainty of results and ethical debates related to side effects made these procedures unpopular. Further, groups such as the National Association for the Advancement of Colored People and the American Civil Liberties Union condemned the use of psychosurgery, believing it to be an inhumane form of treatment. Today, there are strict guidelines that must be adhered to when evaluating a patient for psychosurgery procedures. It is imperative for the neurosurgery community to remember the history of psychosurgery to provide the best possible current treatment and to search for better future treatments for a particularly vulnerable patient population.

Head injury in heroes of the Civil War and its lasting influence.

The Civil War era was an age-defining period in the history of the United States of America, the effects of which are still seen in the nation today. In this era, the issue of head injury pervaded society. From the president of the United States, Abraham Lincoln, to the officers and soldiers of the Union and Confederate armies, and to the population at large, head injury and its ramifications gripped the nation. This article focuses on 3 individuals: Major General John Sedgwick, First Lieutenant Alonzo Cushing, and Harriet Tubman, as examples of the impact that head injury had during this era. These 3 individuals were chosen for this article because of their lasting legacies, contributions to society, and interesting connections to one another.

Hepatoselective Nitric Oxide (NO) Donors, V-PYRRO/NO and V-PROLI/NO, in Nonalcoholic Fatty Liver Disease: A Comparison of Antisteatotic Effects with the Biotransformation and Pharmacokinetics.

V-PYRRO/NO [O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate] and V-PROLI/NO (O2-vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate), two structurally similar diazeniumdiolate derivatives, were designed as liver-selective prodrugs that are metabolized by cytochrome P450 isoenzymes, with subsequent release of nitric oxide (NO). Yet, their efficacy in the treatment of nonalcoholic fatty liver disease (NAFLD) and their comparative pharmacokinetic and metabolic profiles have not been characterized. The aim of the present work was to compare the effects of V-PYRRO/NO and V-PROLI/NO on liver steatosis, glucose tolerance, and liver fatty acid composition in C57BL/6J mice fed a high-fat diet, as well as to comprehensively characterize the ADME (absorption, distribution, metabolism and excretion) profiles of both NO donors. Despite their similar structure, V-PYRRO/NO and V-PROLI/NO showed differences in pharmacological efficacy in the murine model of NAFLD. V-PYRRO/NO, but not V-PROLI/NO, attenuated liver steatosis, improved glucose tolerance, and favorably modified fatty acid composition in the liver. Both compounds were characterized by rapid absorption following i.p. administration, rapid elimination from the body, and incomplete bioavailability. However, V-PYRRO/NO was eliminated mainly by the liver, whereas V-PROLI/NO was excreted mostly in unchanged form by the kidney. V-PYRRO/NO was metabolized by CYP2E1, CYP2C9, CYP1A2, and CYP3A4, whereas V-PROLI/NO was metabolized mainly by CYP1A2. Importantly, V-PYRRO/NO was a better NO releaser in vivo and in the isolated, perfused liver than V-PROLI/NO, an effect compatible with the superior antisteatotic activity of V-PYRRO/NO. In conclusion, V-PYRRO/NO displayed a pronounced antisteatotic effect associated with liver-targeted NO release, whereas V-PROLI/NO showed low effectiveness, was not taken up by the liver, and was eliminated mostly in unchanged form by the kidney.

PABA/NO lead optimization: Improved targeting of cytotoxicity to glutathione S-transferase P1-overexpressing cancer cells.

PABA/NO [O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate] is a nitric oxide (NO)-releasing arylating agent designed to be selectively activated by reaction with glutathione (GSH) on catalysis by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancer cells. PABA/NO has proven active in several cancer models in vitro and in vivo, but its tendency to be metabolized via a variety of pathways, some that generate inactive metabolites and hydrolysis products, limits its potential as a drug. Here we show that a simple replacement of cyano for nitro at the 4 position to give compound 4b ('p-cyano-PABA/NO') has the dual effect of slowing the undesired side reactions while enhancing the proportion of NO release and arylating activity on catalysis by GSTP1. Compound 4b showed increased resistance to hydrolysis and uncatalyzed reaction with GSH, along with a more favorable product distribution in the presence of GSTP1. It also showed significant proapoptotic activity. The data suggest p-cyano-PABA/NO to be a more promising prodrug than PABA/NO, with better selectivity toward cancer cells.

Joseph Warren: a discussion of his life and analysis of his death.

As his fellow soldiers ran past him, Joseph Warren stood bravely on Bunker Hill. It was June 17, 1775, and British troops were fighting the colonists in one of the early battles of the American Revolution. The British had already attempted two major assaults that day, and the third would end with Warren's death. He was a medical doctor, public figure, and general who spent his life and last living moments fighting for freedom for the American colonists. After the battle, there was much confusion about what had happened to Joseph Warren. Some thought he had survived the battle; other accounts differed on how exactly he had died. The details of the events on Bunker Hill remained a mystery until the following year, when Paul Revere helped identify Warren's body by the false teeth that had been implanted years earlier. Warren's remains showed that his head had been struck by a bullet. Analysis of the skull helped to sift through the differing tales of Warren's death and thus unveil the truth about what occurred that day. The smaller bullet wound in the left maxilla suggests that he was not shot while retreating with the rest of the soldiers. The larger exit wound in the right occiput illustrates that the bullet's trajectory crossed the midline of the brain and most likely injured the brainstem. Therefore, contrary to rumors that circulated at the time, Joseph Warren most likely was killed instantly at the Battle of Bunker Hill while heroically facing his enemy.

Direct reaction of amides with nitric oxide to form diazeniumdiolates.

We report the apparently unprecedented direct reaction of nitric oxide (NO) with amides to generate ions of structure R(C═O)NH-N(O)═NO(-), with examples including R = Me (1a) or 3-pyridyl (1b). The sodium salts of both released NO in pH 7.4 buffer, with 37 °C half-lives of 1-3 min. As NO-releasing drug candidates, diazeniumdiolated amides would have the advantage of generating only 1 equiv of base on hydrolyzing exhaustively to NO, in contrast to their amine counterparts, which generate 2 equiv of base.

Aminolysis of an N-diazeniumdiolated amidine as an approach to diazeniumdiolated ammonia.

Recent theoretical studies have suggested that the parent diazeniumdiolate ion, H2N-N(O)═NO(-) ("diazeniumdiolated ammonia"), might be stable enough to be isolated and that it could potentially serve as a uniquely advantageous prodrug form of bioactive nitroxyl (HNO). Here, we report on an attempt to isolate its O(2)-benzylated derivative by aminolysis of the C═N bond in PhC(NH2)═N-N(O)═NOBn. The reaction proved remarkably sluggish in comparison to aminolysis of unsubstituted benzamidine, and the desired product could not be isolated, apparently because of base sensitivity of the NH2 group. Consistent with this interpretation, O-benzylhydroxylamine and N2O were recovered from the reaction mixture in high yields, along with N,N'-dibutylbenzamidine. Theoretical calculations rationalize the observed slow aminolysis by demonstrating that the diazeniumdiolate group greatly suppresses the electrophilicity of the adjacent C═N carbon center, rendering attack at that position endothermic. The data provide significant insights into the challenges inherent to the pursuit of diazeniumdiolated ammonia.

WEB for recurrent aneurysms: a case series to review technical nuances.

Recurrent intracranial aneurysms (IAs) often present with more complex morphology such as irregular shape, shallow height, and wide neck, which can make for challenging endovascular treatments.1 Initial rupture and interventions are associated with fibrotic changes and considerable alteration in the aneurysm configuration, which limits retreatment options and increases the risk of complications during retreatment.2 The Woven Endobridge (WEB) embolization device has demonstrated high efficacy, flexibility, and safety for the treatment of wide-neck bifurcation IAs, including ruptured and recurrent IAs, as shown in multiple retrospective studies and meta-analyses.3-8 Due to its optimal barrel shape, the WEB device is useful in the setting of previously treated aneurysms, particularly with wide-neck previously coiled aneurysms.1 9 10 In this technical video of four cases (video 1), we describe the technical nuances of WEB embolization for recurrent IAs, which were initially either coiled or clipped and demonstrated progressive growth with a wide-neck presentation on follow-up. neurintsurg;16/3/226/V1F1V1Video 1Management of recurrent intracranial aneurysms via WEB: This video describes four recurrent intracranial aneurysms, which were initially either coiled or clipped but demonstrated progressive growth with a wide-neck presentation on follow-up. All cases were successfully treated via WEB.

Balloon-assisted U-turn Technique to Access Cortical Vein for Transvenous Embolization of Mixed Dural-pial Arteriovenous Malformation.

Cerebral arteriovenous malformations can be classified into pure pial, mixed dural-pial, and pure dural types. Mixed pial-dural AVMs (DPAVM) are rare and often receive blood supply from dural meningeal arteries, including branches of the internal carotid, external carotid, and vertebral arteries.1- 6 DPAVMs, which are usually large and complex, require delicate endovascular and surgical treatment methods. The cure rate is low, and recurrence is very common, leading to high morbidity and mortality. In this case video, we present a case of PDAVM that recurred after initial endovascular onyx embolization, requiring additional endovascular coiling which resulted in obliteration of the DPAVM.

Metal allergy and neurovascular stenting: A systematic review.

BACKGROUND: Intracranial stents and flow diverters contain significant amounts of metals, notably nickel, which can cause allergic reactions in a considerable portion of the population. These allergic responses may lead to complications like in-stent stenosis (ISS) and TIA/Stroke in patients receiving stents or flow diverters for intracranial aneurysms. METHODS: We conducted a systematic review of studies from inception until July 2023, which reported outcomes of patients with metal allergy undergoing neurovascular stenting. The skin patch test was used to group patients into those with positive, negative, or absent patch test results but with a known history of metal allergy. RESULTS: Our review included seven studies with a total of 39 patients. Among them, 87% had a history of metal allergy before treatment. Most aneurysms (89%) were in the anterior circulation and the rest (11%) were in the posterior circulation. Skin patch tests were performed in 59% of patients, with 24% showing positive results and 33% negative. Incidental ISS was observed in 18% of patients, and the rate of TIA/Stroke was reported in 21%. The pooled rates of ISS and TIA/Stroke were higher in the first group (43% and 38%) compared to the second (18% and 9%) and third groups (15% and 15%), but these differences were not statistically significant. CONCLUSIONS: The current neurosurgical literature does not provide a conclusive association between metal allergy and increased complications among patients undergoing neurovascular stenting. Further studies are necessary to gain a more comprehensive understanding of this topic.

Enzymatic generation of the NO/HNO-releasing IPA/NO anion at controlled rates in physiological media using ß-galactosidase.

We introduce a strategy for generating mixtures of nitric oxide (NO) and nitroxyl (HNO) at tunable rates in physiological media. The approach involves converting a spontaneously HNO/NO-generating ion to a caged (prodrug) form that is essentially stable in neutral media, but that can be activated for HNO/NO release by adding an enzyme capable of efficiently opening the cage to regenerate the ion. By judiciously choosing the enzyme, substrate, and reaction conditions, unwanted scavenging of the HNO and NO by the protein can be minimised and the catalytic efficiency of the enzyme can be maintained. We illustrate this approach with a proof-of-concept study wherein the prodrug is Gal-IPA/NO, a diazeniumdiolate of structure iPrHN-N(O)NOR, with R=ß-d-galactosyl. Escherichia coli-derived ß-d-galactosidase at concentrations of 1.9-15nM hydrolysed 56µM substrate with half-lives of 140-19min, respectively, producing the IPA/NO anion (iPrHN-N(O)NO(-), half-life ∼3min), which in turn spontaneously hydrolysed to mixtures of HNO with NO. Using saturating substrate concentrations furnished IPA/NO generation rates that were directly proportional to enzyme concentration. Consistent with these data, the enzyme/substrate combination applied to ventricular myocytes isolated from wild-type mouse hearts resulted not only in a significant positive inotropic effect, but also rescued the cells from the negative inotropy, hypercontractions, and occasional cell death seen with the enzyme alone. This mechanism represents an alternate approach for achieving controlled fluxes of NO/HNO to investigate their biological actions.

Decoding nitric oxide release rates of amine-based diazeniumdiolates.

Amine-based diazeniumdiolates (NONOates) have garnered widespread use as nitric oxide (NO) donors, and their potential for nitroxyl (HNO) release has more recently been realized. While NO release rates can vary significantly with the type of amine, half-lives of seconds to days under physiological conditions, there is as yet no way to determine a priori the NO or HNO production rates of a given species, and no discernible trends have manifested other than that secondary amines produce only NO (i.e., no HNO). As a step to understanding these complex systems, here we describe a procedure for modeling amine-based NONOates in water solvent that provides an excellent correlation (R(2) = 0.94) between experimentally measured dissociation rates of seven secondary amine species and their computed NO release activation energies. The significant difference in behavior of NONOates in the gas and solvent phases is also rigorously demonstrated via explicit additions of quantum mechanical water molecules. The presented results suggest that the as-yet unsynthesized simplest amine-based NONOate, the diazeniumdiolated ammonia anion [H2N-N(O)═NO(-)], could serve as an unperturbed HNO donor. These results provide a step forward toward the accurate modeling of general NO and/or HNO donors as well as for the identification of tailored prodrug candidates.