UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression.

The circuit origins of aggression in autism spectrum disorder remain undefined. Here we report Tac1-expressing glutamatergic neurons in ventrolateral division of ventromedial hypothalamus (VMHvl) drive intermale aggression. Aggression is increased due to increases of Ube3a gene dosage in the VMHvl neurons when modeling autism due to maternal 15q11-13 triplication. Targeted deletion of increased Ube3a copies in VMHvl reverses the elevated aggression adult mice. VMHvl neurons form excitatory synapses onto hypothalamic arcuate nucleus AgRP/NPY neurons through a NRXN1-CBLN1-GluD1 transsynaptic complex and UBE3A impairs this synapse by decreasing Cbln1 gene expression. Exciting AgRP/NPY arcuate neurons leads to feedback inhibition of VMHvl neurons and inhibits aggression. Asymptomatic increases of UBE3A synergize with a heterozygous deficiency of presynaptic Nrxn1 or postsynaptic Grid1 (both ASD genes) to increase aggression. Targeted deletions of Grid1 in arcuate AgRP neurons impairs the VMHvl to AgRP/NPY neuron excitatory synapses while increasing aggression. Chemogenetic/optogenetic activation of arcuate AgRP/NPY neurons inhibits VMHvl neurons and represses aggression. These data reveal that multiple autism genes converge to regulate the VMHvl-arcuate AgRP/NPY glutamatergic synapse. The hypothalamic circuitry implicated by these data suggest impaired excitation of AgRP/NPY feedback inhibitory neurons may explain the increased aggression behavior found in genetic forms of autism.

Biologically Effective Dose and Rectal Bleeding in Definitive Proton Therapy for Prostate Cancer.

Purpose and Objectives: With increasing use of hypofractionation and extreme hypofractionation for prostate cancer, rectal dose-volume histogram (DVH) parameters that apply across dose fractionations may be helpful for treatment planning in clinical practice. We present an exploratory analysis of biologically effective rectal dose (BED) and equivalent rectal dose in 2 Gy fractions (EQD2) for rectal bleeding in patients treated with proton therapy across dose fractionations. Materials and Methods: From 2016 to 2018, 243 patients with prostate cancer were treated with definitive proton therapy. Rectal DVH parameters were obtained from treatment plans, and rectal bleeding events were recorded. The BED and EQD2 transformations were applied to each rectal DVH parameter. Univariate analysis using logistic regression was used to determine DVH parameters that were significant predictors of grade ≥ 2 rectal bleeding. Youden index was used to determine optimum cutoffs for clinically meaningful DVH constraints. Stepwise model-selection criteria were then applied to fit a "best" multivariate logistic model for predicting Common Terminology Criteria for Adverse Events grade ≥ 2 rectal bleeding. Results: Conventional fractionation, hypofractionation, and extreme hypofractionation were prescribed to 117 (48%), 84 (34%), and 42 (17.3%) patients, respectively. With a median follow-up of 20 (2.5-40) months, 10 (4.1%) patients experienced rectal bleeding. On univariate analysis, multiple rectal DVH parameters were significantly associated with rectal bleeding across BED, EQD2, and nominal doses. The BED volume receiving 55 Gy > 13.91% was found to be statistically and clinically significant. The BED volume receiving 55 Gy remained statistically significant for an association with rectal bleeding in the multivariate model (odds ratio, 9.81; 95% confidence interval, 2.4-40.5; P = .002). Conclusion: In patients undergoing definitive proton therapy for prostate cancer, dose to the rectum and volume of the rectum receiving the dose were significantly associated with rectal bleeding across conventional fractionation, hypofractionation, and extreme hypofractionation when using BED and EQD2 transformations.

Phase coding of spatial representations in the human entorhinal cortex.

The grid-like activity pattern of cells in the mammalian entorhinal cortex provides an internal reference frame for allocentric self-localization. The same neurons maintain robust phase couplings with local field oscillations. We found that neurons of the human entorhinal cortex display consistent spatial and temporal phase locking between spikes and slow gamma band local field potentials (LFPs) during virtual navigation. The phase locking maintained an environment-specific map over time. The phase tuning of spikes to the slow gamma band LFP revealed spatially periodic phase grids with environment-dependent scaling and consistent alignment with the environment. Using a Bayesian decoding model, we could predict the avatar's position with near perfect accuracy and, to a lesser extent, that of heading direction as well. These results imply that the phase of spikes relative to spatially modulated gamma oscillations encode allocentric spatial positions. We posit that a joint spatiotemporal phase code can implement the combined neural representation of space and time in the human entorhinal cortex.

Context-dependent spatially periodic activity in the human entorhinal cortex.

The spatially periodic activity of grid cells in the entorhinal cortex (EC) of the rodent, primate, and human provides a coordinate system that, together with the hippocampus, informs an individual of its location relative to the environment and encodes the memory of that location. Among the most defining features of grid-cell activity are the 60° rotational symmetry of grids and preservation of grid scale across environments. Grid cells, however, do display a limited degree of adaptation to environments. It remains unclear if this level of environment invariance generalizes to human grid-cell analogs, where the relative contribution of visual input to the multimodal sensory input of the EC is significantly larger than in rodents. Patients diagnosed with nontractable epilepsy who were implanted with entorhinal cortical electrodes performing virtual navigation tasks to memorized locations enabled us to investigate associations between grid-like patterns and environment. Here, we report that the activity of human entorhinal cortical neurons exhibits adaptive scaling in grid period, grid orientation, and rotational symmetry in close association with changes in environment size, shape, and visual cues, suggesting scale invariance of the frequency, rather than the wavelength, of spatially periodic activity. Our results demonstrate that neurons in the human EC represent space with an enhanced flexibility relative to neurons in rodents because they are endowed with adaptive scalability and context dependency.

Breast density measurements with ultrasound tomography: a comparison with film and digital mammography.

PURPOSE: To investigate the use of the whole-breast sound speed measurement as a marker of breast density (BD), a known risk factor for breast cancer. METHODS: As part of an ongoing study of breast cancer detection, 249 patients were scanned with a clinical prototype that operates on the principles of ultrasound tomography. Typically, 40-100 sound speed tomograms were reconstructed from the scan data, corresponding to the entire volume of the breast of each patient. The data were used to estimate the volume averaged sound speed (VASS) of the breast for each patient. The corresponding mammograms were used to calculate mammographic percent density (MPD) using CUMULUS software. Film mammograms were available for 164 patients while 85 digital mammograms were available for the remaining patients. Standard statistical techniques were used to determine associations of breast sound speed with a variety of mammographic measures such as percent density, area of dense tissue, and area of nondense tissue. Furthermore, associations of breast sound speed with continuous variables such as age and weight and dichotomous variables such as parity and menopausal status were also assessed. RESULTS: VASS was found to be significantly associated with MPD. The Spearman correlation coefficient (r(s)) between VASS and MPD was found to be 0.77 and 0.71 for film and digital mammography, respectively. VASS was positively correlated with dense areas by mammography, both digital (r(s) = 0.46) and film (r(s) = 0.56). VASS was negatively associated with nondense area by mammography, both digital (r(s) = -0.58) and film (r(s) = -0.63). BD by all methods was less in postmenopausal than in premenopausal women. The MPD was lower in the postmenopausal group (by 6.6%, p < 0.08, for the digital group and 7.73%, p < 0.007, for the film group). The VASS was also lower in the postmenopausal group (by 15 m∕s, p < 0.001 for the digital group and 8 m∕s, p < 0.08, for the film group). The association of MPD with age was characterized with r(s) = -0.06 (p < 0.6) for digital mammography and r(s) = -0.53 (p < 0.002) for film mammography. For weight, the MPD associations were characterized by r(s) = -0.53 (p < 0.0001) for digital mammography and -0.38 (p < 0.0001) for film mammography. The association of VASS with age was r(s) = -0.33 (p < 0.002) for the digital group and -0.17 (p < 0.03) for the film group. For weight, the relationship was characterized with r(s) = -0.45 (p < 0.001) for the digital group and -0.37 (p < 0.0001) for the film group. CONCLUSIONS: The association between VASS and MPD is strong for both film and digital mammography, suggesting that VASS is a viable measure of breast density. This result sets the stage for future work that will focus on directly testing the association of VASS with breast cancer risk.

Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): A comparative analysis of toxicities and clinical outcomes.

BACKGROUND: Elective nodal irradiation (ENI) and involved field radiotherapy (IFRT) are definitive radiotherapeutic approaches used to treat patients with locally advanced non-small cell lung cancer (NSCLC). ENI delivers prophylactic radiation to clinically uninvolved lymph nodes, while IFRT only targets identifiable gross nodal disease. Because clinically uninvolved nodal stations may harbor microscopic disease, IFRT raises concerns for increased nodal failures. This retrospective cohort analysis evaluates failure rates and treatment-related toxicities in patients treated at a single institution with ENI and IFRT. METHODS: We assessed all patients with stage III locally advanced or stage IV oligometastatic NSCLC treated with definitive radiotherapy from 2003 to 2008. Each physician consistently treated with either ENI or IFRT, based on their treatment philosophy. RESULTS: Of the 108 consecutive patients assessed (60 ENI vs. 48 IFRT), 10 patients had stage IV disease and 95 patients received chemotherapy. The median follow-up time for survivors was 18.9 months. On multivariable logistic regression analysis, patients treated with IFRT demonstrated a significantly lower risk of high grade esophagitis (Odds ratio: 0.31, p = 0.036). The differences in 2-year local control (39.2% vs. 59.6%), elective nodal control (84.3% vs. 84.3%), distant control (47.7% vs. 52.7%) and overall survival (40.1% vs. 43.7%) rates were not statistically significant between ENI vs. IFRT. CONCLUSIONS: Nodal failure rates in clinically uninvolved nodal stations were not increased with IFRT when compared to ENI. IFRT also resulted in significantly decreased esophageal toxicity, suggesting that IFRT may allow for integration of concurrent systemic chemotherapy in a greater proportion of patients.

Successful use of topiramate in a patient with severe postherpetic neuralgia.

OBJECTIVE: To describe the case of a patient with postherpetic neuralgia (PHN) who had a marked response to topiramate despite failure of several previous therapies. CASE SUMMARY: A 79-year-old white male with multiple medical comorbidities developed severe trigeminal territory PHN requiring treatment with opiates to maintain adequate pain relief. Topiramate was initiated after the patient failed treatment with 4 other antiepileptic medications due to various adverse events. After 3 months of topiramate therapy, with dosages up to 50 mg twice daily, PHN pain had decreased to the point that the patient was able to discontinue the use of opiates entirely. At time of writing, he continued to be maintained on topiramate 50 mg twice daily with good pain relief and no reported adverse effects. DISCUSSION: Topiramate exhibits a number of actions that may contribute to the relief of neuropathic pain, including modulation of voltage-gated sodium and calcium channels, potentiation of gamma-aminobutyric acid inhibition, and blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainite glutamate receptors. Current evidence-based recommendations consider topiramate to be a third-line agent for the treatment of neuropathic pain based on studies of its use in painful diabetic neuropathy and chronic lumbar radicular pain. A comprehensive search of MEDLINE (1950-August 2008) using the terms postherpetic neuralgia, neuralgia, and topiramate revealed only one previously published case report evaluating the use of topiramate specifically for treatment of PHN. CONCLUSIONS: While it is impossible to determine whether pain relief in this case was due to treatment with topiramate as opposed to spontaneous resolution of pain over time, this additional case report suggests that topiramate may be a useful treatment option for patients with PHN who have not responded to or are intolerant of other interventions. Further studies are needed to determine whether topiramate should receive a stronger recommendation for the treatment of PHN.

A 10-fold improvement in the precision of boron isotopic analysis by negative thermal ionization mass spectrometry.

Boron isotopes are potentially very important to cosmochemistry, geochemistry, and paleoceanography. However, the application has been hampered by the large sample required for positive thermal ionization mass spectrometry (PTIMS), and high mass fractionation for negative-TIMS (NTIMS). Running as BO(2)(-), NTIMS is very sensitive and requires only nanogram sized samples, but it has rather poor precision (approximately 0.7-2.0 per thousand) as a result of the larger mass fractionation associated with the relatively light ion. In contrast, running as the much heavier molecule of Cs(2)BO(2)(+), PTIMS usually achieves better precision around 0.1-0.4 per thousand. Moreover, there is a consistent 10 per thousand offset in the (11)B/(10)B ratio for NIST SRM 951 standard boric acid between the NTIMS and the certified value, but the cause of this offset is unclear. In this paper, we have adapted a technique we developed earlier to measure the (138)La/(139)La using LaO(+) (1) to improve the NTIMS technique for BO(2). We were able to correct for instrumental fractionation by measuring BO(2)(-) species not only at masses of 42 and 43, but also at 45, which enabled us to normalize (45)BO(2)/(43)BO(2) to an empirical (18)O/(16)O value. We found that both I(45)/I(42) = ((11)B(16)O(18)O/(10)B(16)O(16)O) and (I(43)/I(42))(C) = ((11)B(16)O(16)O/(10)B(16)O(16)O) vary linearly with (I(45)/I(43))(C) x 0.5 = ((11)B(16)O(18)O/(11)B(16)O(16)O) x 0.5 = (18)O/(16)O. In addition, different activators and different chemical forms of B yield different slopes for the fractionation lines. After normalizing (11)B(16)O(18)O/(11)B(16)O(16)O x 0.5 to a fixed (18)O/(16)O value, we obtained a mean (11)B/(10)B value of NIST SRM 951 that matches the NIST certified value at 4.0430 +/- 0.0015 (+/-0.36 per thousand, n = 11). As a result, our technique can achieve precision and accuracy comparable to that of PTIMS with only 1 per thousand of the sample required. This new NTIMS technique for B isotopes is critical to the studies of early solids in the solar system and individual foraminifera in sediments that require both high sensitivity and precision.

Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteers.

The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration-time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (+/-) values for the C(max) of lovastatin were 1.04+/-0.43, 2.03+/-0.65 and 4.03+/-3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC(0-48 h) of lovastatin were 14.6+/-7.8, 34.1 +/-13.7, and 53.9+/-35.6 ng h/ml. The same tendency was also found for C(max) and AUC(0-48 h) values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the C(max) and AUC(0-48 h) values of lovastatin as well as lovastatin acid appeared to increase linearly.

Comparative pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets in humans.

The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three-period crossover study following a single oral dose of lovastatin extended-release (ER) tablets and lovastatin immediate-release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets underfasting conditions. Serial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Lovastatin ER tablets, unlike lovastatin IR tablets, exhibited delayed- and extended-release characteristics. The relative bioavailability, in terms of area under the curve values, of lovastatin (156%) and lovastatin acid (124%) was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given with breakfast. An even greater increase in the bioavailability of lovastatin (261%) and lovastatin acid (231%) was observed when the lovastatin ER tablets were administered under fasting conditions. Thus, greater gastrointestinal tract drug absorption of lovastatin from lovastatin ER tablets was demonstrated. Ingestion of a standard breakfast prior to administration of lovastatin ER tablets decreased absorption of lovastatin by approximately 40%, relative to lovastatin ER tablets under fasting conditions.