Citations

Background: The relationship between cortical lesions (CLs) and white matter lesions (WMLs) in multiple sclerosis (MS) is poorly understood. Pathological studies support a topographical association between CLs and underlying subcortical WMLs and suggest CLs may play a role in both disease initiation and progression. We hypothesized that cortical MS lesions are physically connected to white matter MS lesions via axonal connections. Objective: To assess the presence of CL-WML connectivity utilizing novel magnetic resonance imaging (MRI) methodology. Methods: In all, 28 relapsing-remitting MS patients and 25 controls received 3 T MRI scans, including double inversion recovery (DIR) for CL detection coupled with diffusion tensor imaging (DTI). CL and WML maps were created, and DTI was used to calculate inter-lesional connectivity and volumetric connectivity indices. Results: All patients showed inter-lesional WML connectivity (median 76% of WMLs connected to another WML; interquartile range (IQR), 58%–88%). On average, 52% of detected CLs per patient were connected to at least one WML (IQR, 42%–71%). Volumetric connectivity analysis showed significantly elevated cortical lesion ratios in MS patients (median, 2.3; IQR, 1.6–3.3) compared to null MS and healthy control datasets ( p < 0.001). Conclusion: These findings provide strong evidence of inter-lesional connectivity between CLs and WMLs, supporting our hypothesis of intrinsic CL-WML connectivity.

Background: Patients hospitalized for first acute coronary syndrome (ACS) are frequently discharged on multiple new medications. The short-term tolerability of these medications is unknown. Methods: This single-center cohort study assessed 30-day health-care utilization and how it may be impacted by medication prescribing trends. We included Olmsted County patients presenting with ACS and previously undiagnosed coronary artery disease in 2008 to 2009. All health-care contacts were reviewed 30 days after index hospital discharge for potential adverse medication effects including documented hypotension or bradycardia, or symptoms likely attributed to the medications. Results: The study included 86 patients; their mean age was 63 (standard deviation: 15.5 years). Antianginal or antihypertensive cardiovascular (CV) medications were prescribed to 98% of patients at discharge; 76% were prescribed 2 or more. There were 233 health-care contacts in 30 days; 90 (39%) of these contacts were unscheduled. More CV medications tended to be prescribed to patients with unscheduled contacts, both pre-ACS ( P = .045) and upon hospital discharge ( P = .051). Hypotension and/or bradycardia at follow-up occurred in 52 patients (60%). Surprisingly, there was no association between hypotension and/or bradycardia at follow-up and increased health-care utilization ( P = .12). Potential adverse drug effects were reported in 34 (40%) patients. These patients had significantly more total health-care contacts ( P < .001) and unscheduled health-care contacts (median 0 vs 1.5; P < .001). Conclusions: Symptoms of adverse drug effects were associated with more frequent health-care utilization after ACS. Clinicians need to consider this while striving to increase patient compliance with post-ACS medications and optimize care transitions.

OBJECTIVE Hypothalamic hamartomas (HHs) are associated with gelastic seizures and the development of medically refractory epilepsy. Magnetic resonance imaging–guided laser interstitial thermal therapy (MRg-LITT) is a minimally invasive ablative treatment that may have applicability for these deep-seated lesions. Here, the authors describe 3 patients with refractory HHs who they treated with MRg-LITT. METHODS An institutional review board–approved prospective database of patients undergoing Visualase MRg-LITT was retrospectively reviewed. Demographic and historical medical data, including seizure and medication histories, previous surgeries, procedural details, and surgical complications, along with radiological interpretation of the HHs, were recorded. The primary outcome was seizure freedom, and secondary outcomes included medication reduction, seizure frequency, operative morbidity, and clinical outcome at the latest follow-up. RESULTS All 3 patients in the multi-institutional database had developed gelastic seizures related to HH at the ages of 7, 7, and 9 years. They presented for further treatment at 25, 28, and 48 years of age, after previous treatments with stereotactic radiosurgery in all cases and partial hamartoma resection in one case. One ablation was complicated by a small tract hemorrhage, which was stable on postoperative imaging. One patient developed hyponatremia and experienced weight gain, which were respectively managed with fluid restriction and counseling. At the most recent follow-up at a mean of 21 months (range 1–32 months), one patient was seizure free while another had meaningful seizure reduction. Medication was reduced in one case. CONCLUSIONS Adults with gelastic seizures despite previous treatments can undergo MRg-LITT with reasonable safety and efficacy. This novel therapy may provide a minimally invasive alternative for primary and recurrent HH as the technique is refined.

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/ .

Abstract Lessons Learned Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials. Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC. Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. Background. Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. Methods. In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m2 intravenously or 2.3 mg/m2 orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0–2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression. Results. Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5–3.6) and 1.2 (95% CI, 1.1–1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2–7.6) and 3.4 (95% CI, 1.8–5.6) months for topotecan and linsitinib, respectively (p = .71). Grade 3/4 adverse events (&gt;5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for linsitinib. Conclusion. Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients.