Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood-brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 μs) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound.     

Schizophrenia comorbid with panic disorder: evidence for distinct cognitive profiles

Patients with comorbid schizophrenia and panic symptoms share a distinct clinical presentation and biological characteristics, prompting some to propose panic psychosis as a separate subtype of schizophrenia. Less is known about these patients' neuropsychological profiles, knowledge of which may facilitate target-specific treatments and research into the etiopathophysiology for such cases. A total of 255 schizophrenia patients with panic disorder (n=39), non-panic anxiety disorder (n=51), or no anxiety disorder (n=165) were assessed with the Wechsler Adult Intelligence Scale-Revised, the Wisconsin Card Sorting Test, the Trail Making Test, the Controlled Oral Word Association Test, the Animal Naming subtest of the Boston Diagnostic Aphasia Examination, and the Wechsler Memory Scale-Revised. Psychotic symptoms were assessed with the Positive and Negative Syndrome Scale. Patients with panic disorder demonstrated a higher verbal IQ and better problem solving, set switching, delayed recall, attention, and verbal fluency as compared to schizophrenia patients without comorbid anxiety. The schizophrenia-panic group reported a higher level of dysthymia on stable medication. Our findings suggest that patients with schizophrenia and comorbid panic disorder exhibit distinct cognitive functioning when compared to other schizophrenia patients. These data offer further support for a definable panic-psychosis subtype and suggest new etiological pathways for future research.     

Validation of a protein biomarker test for predicting renal decline in type 2 diabetes: The Fremantle Diabetes Study Phase II

AimsTo validate the prognostic utility of a novel plasma biomarker panel, PromarkerD, for predicting renal decline in an independent cohort of people with type 2 diabetes.MethodsModels for predicting rapid estimated glomerular filtration rate (eGFR) decline defined as i) incident diabetic kidney disease (DKD), ii) eGFR decline ≥30% over four years, and iii) annual eGFR decline ≥5 mL/min/1.73 m² were applied to 447 participants from the longitudinal observational Fremantle Diabetes Study Phase II. Model performance was assessed using discrimination and calibration.ResultsDuring 4.2 ± 0.3 years of follow-up, 5–10% of participants experienced a rapid decline in eGFR. A consensus model comprising apolipoprotein A-IV (apoA4), CD5 antigen-like (CD5L), insulin-like growth factor–binding protein 3 (IGFBP3), age, serum HDL-cholesterol and eGFR showed the best performance for predicting incident DKD (AUC = 0.88 (95% CI 0.84–0.93)); calibration Chi-squared = 5.6, P = 0.78). At the optimal score cut-off, this model provided 86% sensitivity, 78% specificity, 30% positive predictive value and 98% negative predictive value for four-year risk of developing DKD.ConclusionsThe combination of readily available clinical and laboratory features and the PromarkerD biomarkers (apoA4, CD5L, IGFBP3) proved an accurate prognostic test for future renal decline in an independent validation cohort of people with type 2 diabetes.