The 2β Insert Perturbs Folding, Stability and Hydrophobic Exposure of Stromal Interaction Molecules

Stromal interaction molecule (STIM)1 and 2 regulate agonist-induced and basal cytosolic calcium (Ca2+) levels through oligomerization and translocation to endoplasmic reticulum (ER)-plasma membrane (PM) junctions. At these junctions, the STIM cytosolic coiled-coil domains couple to PM Orai1 protein subunits to form Ca2+ released activated Ca2+ (CRAC) channels that facilitate store-operated Ca2+ entry (SOCE). One splice variant of STIM2, STIM2β, contains an extra 8-residue (2β insert) located within the coiled-coils and inhibits SOCE through an unresolved mechanism, adding another layer of complexity to Ca2+ regulation in mammals. I hypothesize that the 2β insert perturbs the coiled-coil conformation and dynamics commensurate with an ability to activate SOCE. My data show the 2β insertion induced an overall reduction in α-helicity, thermal stability, and promoted a conformation of greater exposed hydrophobicity which affected oligomerization. Previous studies show STIM2 more weakly couples to Orai1 compared to STIM1, and STIM2β is completely incapable of binding to Orai1. My functional studies show the 2β insertion in the STIM1 context also significantly inhibits SOCE. Therefore, my data suggests that the 2β insert inhibits STIM function and SOCE through a mechanism which perturbs α-helical levels and destabilizes the cytosolic domain coiled-coil structure, independent of the requirement for weaker STIM2 coupling to Orai1

Clinical considerations in transitioning patients with epilepsy from clonazepam to clobazam: a case series.

IntroductionIn treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients' overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely.Case presentationsThe following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox-Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic-clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left-handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke.ConclusionsFrom these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful

Stones, Bones, and Groans with Cancerous Overtones - A Rare Case of Diffuse Large B Cell Lymphoma Presenting as Hypercalcemia

Diffuse large B cell lymphoma (DLBCL) is a type of non-Hodgkin lymphoma that can present in a variety of ways including fever, weight loss, weakness, and drenching night sweats. Uncommonly, hypercalcemia of malignancy can be associated with DLBCL through multiple mechanisms that include synthesis of parathyroid hormone related peptide (PTHrP) or elevated calcitriol levels. It is estimated that hypercalcemia in the setting of DLBCL is present in 18% of newly diagnosed cases. This report details a case of an 80-year-old man with history of chronic anemia and CKD stage 3b that presented with weakness, decreased oral intake, and self-reported weight loss. Initial labs showed a corrected calcium of 14.1 mg/dL and normal phosphorous and alkaline phosphatase levels. PTH was decreased at 4 pg/mL. Serum protein electrophoresis and skeletal survey were unremarkable. A continued anemia of 8.1 g/dL in the setting of hypercalcemia prompted further investigation with endoscopy and colonoscopy which showed a large malignant-appearing mass in the mid gastric body. Pathology identified the mass as DLBCL germinal center type. Labs taken after endoscopy reported elevated 1,25-dihydroxyvitamin D levels, consistent with vitamin-D induced hypercalcemia seen in DLBCL. This case report highlights an uncommon yet important presentation of DLBCL. It is imperative that a differential diagnosis for undifferentiated hypercalcemia in an older patient should include malignancies such as DLBCL and workup should include extrarenal causes of hypercalcemia such as PTHrP production and calcitriol levels

Spatio-Temporal Analysis of Roadside Transportation-Related Air Quality (StarTraq 2021): A Characterization of Bike Trails and Highways in the Fresno/Clovis Area

The San Joaquin Valley is identified as an area with a high level of particulate matter (PM) in the air, reaching above the federal and state clean air standards (EPA 2019). Many of the cities in the valley are classified as the most polluted cities in the United States for both particulate matter and ozone pollution (American Lung Association, 2021). To resolve this issue, alternative forms of transportation have been considered in transportation planning. In this study, active transportation mode air quality was monitored on selected Woodward Park and Old Clovis trails and urban bike lanes. Real-time aerosol monitors, and low-cost sensors were carried in a backpack on bicycles during the sampling. Researchers collected GPS data via a portable GPS technology called Tracksticks. Driving transportation mode air quality data was acquired from the roadways within the Fresno/Clovis area, spanning six sampling routes, and during intercity trips between Fresno, Berkeley, and Los Angeles, for a total of five sampling routes. ‘On-Road\u27 (outside vehicle) monitors were installed on the roof of a vehicle while ‘In-Vehicle’ monitors were installed inside the vehicle for comparison with the particulate pollution levels in the two contrasting microenvironments. The results showed the following three main outcomes: (1) clear relationships exist among PMs of different sizes; (2) there were greater variations in air quality of bike trails and On-Road samples than backyard and In-Vehicle samples; (3) we observed significant differences in air quality inside and outside the vehicle while driving local and intercity roadways; and (4) the road trip to the Bay area revealed that San Joaquin Valley has increased ambient PM2.5 and black carbon (BC) levels compared to those in the Bay Area on every trip, regardless of the daily change of the air quality

Spatio-Temporal Analysis of the Roadside Transportation Related Air Quality (STARTRAQ) and Neighborhood Characterization

To promote active transportation modes (such as bike ride and walking), and to create safer communities for easier access to transit, it is essential to provide consolidated data-driven transportation information to the public. The relevant and timely information from data facilitates the improvement of decision-making processes for the establishment of public policy and urban planning for sustainable growth, and for promoting public health in the region. For the characterization of the spatial variation of transportation-emitted air pollution in the Fresno/Clovis neighborhood in California, various species of particulate matters emitted from traffic sources were measured using real-time monitors and GPS loggers at over 100 neighborhood walking routes within 58 census tracts from the previous research, Children’s Health to Air Pollution Study - San Joaquin Valley (CHAPS-SJV). Roadside air pollution data show that PM2.5, black carbon, and PAHs were significantly elevated in the neighborhood walking air samples compared to indoor air or the ambient monitoring station in the Central Fresno area due to the immediate source proximity. The simultaneous parallel measurements in two neighborhoods which are distinctively different areas (High diesel High poverty vs. Low diesel Low poverty) showed that the higher pollution levels were observed when more frequent vehicular activities were occurring around the neighborhoods. Elevated PM2.5 concentrations near the roadways were evident with a high volume of traffic and in regions with more unpaved areas. Neighborhood walking air samples were influenced by immediate roadway traffic conditions, such as encounters with diesel trucks, approaching in close proximity to freeways and/or busy roadways, passing cigarette smokers, and gardening activity. The elevated black carbon concentrations occur near the highway corridors and regions with high diesel traffic and high industry. This project provides consolidated data-driven transportation information to the public including: 1. Transportation-related particle pollution data 2. Spatial analyses of geocoded vehicle emissions 3. Neighborhood characterization for the built environment such as cities, buildings, roads, parks, walkways, etc

Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study.

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period. Patients taking concomitant LEV at enrollment were excluded from this analysis. Patients were categorized by their status of prior exposure to LEV, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LTG), to investigate any consistent trend towards reduced response in AED-exposed subgroups compared to AED-naïve subgroups, regardless of the mechanism of action. Study completion rates, percent reduction from baseline in focal seizure frequency over placebo, ≥50% responder rates, and tolerability were evaluated for each subgroup. A total of 1160 patients were investigated. Study completion rates were similar in the AED-exposed subgroups and AED-naïve subgroups. In subgroups with (531 patients) or without (629 patients) prior LEV exposure, ≥50% responder rates for each dose of BRV compared with placebo were generally higher among the LEV-naïve subgroups than the previously LEV-exposed subgroups. LEV-exposed subgroups receiving BRV doses ≥50mg/day showed greater ≥50% responder rates than those receiving placebo. Similar results were observed for CBZ, TPM, and LTG. Previous treatment failure with commonly prescribed AEDs (LEV, CBZ, TPM, or LTG) is associated with a reduced response to BRV irrespective of the mechanism of action. Hence, this post-hoc analysis indicates that previous treatment failure with LEV does not preclude the use of BRV in patients with epilepsy

Cognitive effects of lamotrigine versus topiramate as adjunctive therapy in older adults with epilepsy

Older individuals may be more susceptible to cognitive side effects of antiepileptic drugs than are younger adults. This randomized, double-blind study compared the cognitive effects of lamotrigine (median maintenance dosage, 500.0 mg/d) and topiramate (median maintenance dosage, 300.0 mg/d) as adjunctive therapy for 16 weeks in patients ≥50 years of age. Fifty-one patients (lamotrigine, n=25; topiramate, n=26) were enrolled, and 28 patients (lamotrigine, n=15; topiramate, n=13) completed the study. In a combined analysis of all cognitive tests performed, no significant differences between treatment groups were noted. However, analyses of individual cognitive test results revealed that lamotrigine-treated patients had significantly better results on the Controlled Oral Word Association Test and the Symbol-Digit Modalities Test, whereas topiramate-treated patients had significantly more favorable results on the Digit Cancellation Test and the Rey Auditory-Verbal Learning Test. Larger studies are needed to further clarify the differences in the cognitive effects of lamotrigine and topiramate in older patients