An atlas of itch-associated neural dynamics in the mouse brain.

The itch-scratching cycle is mediated by neural dynamics in the brain. However, our understanding of the neural dynamics during this cycle remains limited. In this study, we examine the neural dynamics of 126 mouse brain areas by measuring the calcium signal using fiber photometry. We present numerous response patterns in the mouse brain during the itch-scratching cycle. Interestingly, we find that a group of brain areas exhibit activation only at the end of histamine-induced scratching behavior. Additionally, several brain areas exhibit transient activation at the onset of scratching induced by chloroquine. Both histamine- and chloroquine-induced itch evoke diverse response patterns across the mouse brain. In summary, our study provides a comprehensive dataset for the diverse activity pattern of mouse brain during the itch-scratching cycle, paving the way for further exploration into the neural mechanisms underlying the itch-scratching cycle.

The Parabrachial Nucleus Directly Channels Spinal Nociceptive Signals to the Intralaminar Thalamic Nuclei, but Not the Amygdala.

The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.

Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation.

Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.

Adult-onset of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome with hypothyroidism and psychiatric disorders.

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a clinical syndrome associated with mitochondrial disorders (MIDs). This report illustrates a case of MELAS syndrome with hypothyroidism and psychiatric disorders, which is different from the common clinical manifestations of MELAS syndrome, such as exercise intolerance, migraine-like headaches, hearing loss and seizures etc. There are considerable interests in the possibility that mitochondrial dysfunction may play a role in the pathogenesis of endocrine dysfunctions and psychiatric disorders in MELAS syndrome.

Relationship between time to clinical response and outcomes among Pneumonia Outcomes Research Team (PORT) risk class III and IV hospitalized patients with community-acquired pneumonia who received ceftriaxone and azithromycin.

Recent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP. To address this, a retrospective cohort study was conducted among adult patients who received ceftriaxone and azithromycin for CAP of Pneumonia Outcomes Research Team (PORT) risk class III and IV at an academic medical center. The clinical response was defined as clinical stability for 24 h with improvement in at least one pneumonia symptom and with no symptom worsening. A classification and regression tree (CART) was used to determine the delay in response time, measured in days, associated with the greatest risk of a prolonged hospital length of stay (LOS) and adverse outcomes (in-hospital mortality or 30-day CAP-related readmission). A total of 250 patients were included. On average, patients were discharged 2 days following the achievement of a clinical response. In the CART analysis, adverse clinical outcomes were higher among day 5 nonresponders than those who responded by day 5 (22.4% versus 6.9%, P = 0.001). The findings from this study indicate that time to clinical response, as defined by the recent FDA guidance, is a reasonable prognostic indicator of real-world effectiveness outcomes among hospitalized PORT risk class III and IV patients with CAP who received ceftriaxone and azithromycin.

Evaluation of the pharmacodynamic profile of commonly used intravenous vancomycin dosing schemes in patients on automated peritoneal dialysis.

OBJECTIVES: The intent of this study was to evaluate the appropriateness of commonly used intravenous (iv) vancomycin dosing schemes in patients on automated peritoneal dialysis (APD) using population pharmacokinetic (PK) modelling and Monte Carlo simulation. METHODS: Data from a single-dose PK study of 10 non-infected APD patients ≥18 years old were analysed. Patients received iv vancomycin (15 mg/kg) followed by three cycler-assisted APD dwells over 8 h, followed by two 8 h dwells. Serum and dialysate samples were collected over the entire 24 h. A three-compartment model was fitted to the data with BigNPAG. Monte Carlo simulation was used to determine the probability of achieving an AUC/MIC ratio of >400 in both the serum and the peritoneal cavity for a variety of iv vancomycin dosing schemes (1-2 g every 24-48 h). RESULTS: In the probability of target attainment (PTA) analyses, only 2 g of iv vancomycin every 24 h conferred >90% probability of achieving an AUC/MIC ratio of >400 for MIC values <2 mg/L in the serum. However, this dosing regimen resulted in average trough concentrations >20 mg/L. In the peritoneal cavity, no regimen yielded PTA ≥90% for MIC values ≥0.5 mg/L. CONCLUSIONS: Although expert guidelines suggest iv vancomycin may be an acceptable empirical therapy for patients on APD with infection, these analyses indicate that iv vancomycin may not be effective for peritonitis but may be a viable option for non-peritoneal infections with MIC values ≤1 mg/L.

Effects of obesity and sex on antimicrobial pharmacokinetics and acute kidney injury: validation of a preclinical model.

Obese patients may be at a greater risk for acute kidney injury (AKI) with the use of certain antimicrobial agents that are dosed by weight. Current preclinical models of AKI utilize the male rat within a narrow weight range that limits extrapolation of the generated results. We evaluated the pharmacokinetics and AKI potential of gentamicin in 14-week-old diet-induced obesity-prone (n = 40) and obesity-resistant (n = 40) rats of both sexes. Single daily doses of gentamicin (12.5, 18.75, or 25 mg/kg of body weight) or saline (control) were administered intraperitoneally for 14 doses. Blood samples were collected after doses 1, 7, and 14, assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and analyzed using a nonparametric population pharmacokinetic approach for gentamicin. Urine was collected after doses 1, 3, and 5 and assayed for kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) and normalized to creatinine (Cr) values. Histology was performed on all animals, and the degree of proximal tubular injury was graded. The mean (minimum, maximum) weight of the rats was 330 (136, 580) g. NGAL/Cr predicted AKI better than did KIM-1/Cr and was detectable in male rats after dose 1 and in obesity-prone female rats after dose 5. Proximal tubular injury by histology was significantly higher in male than in female rats. A significant relationship between the gentamicin area under the curve from zero to 24 hours (AUC(0-24)) estimates and the maximum NGAL/Cr ratio was observed. This preclinical model has the potential to aid with dose extrapolation for body size and improve assessment of the toxicology potential of antimicrobials in development.

Selective cognitive impairments are related to selective hippocampus and prefrontal cortex deficits after prenatal chlorpyrifos exposure.

Prenatal exposure to chlorpyrifos (CPF) leads to cognitive impairments in adulthood. The cytoarchitectural basis is unclear. In the present study, we assessed the effects of prenatal CPF exposure on T-maze delayed alternation task and the win-shift/lose-shift responses associated with the morphology of the dorsal hippocampus (dHPC) and the medial prefrontal cortex (mPFC) in adult animals. Gestational ICR female mice were exposed to 0, 1 or 5mg/kg/d of CPF through gestational days 13-17. Behavioral experiments were performed on postnatal days (PD) 45-60 of the male and female offsprings; morphological samples were collected on PD 60. Our behavioral study results showed a gradual increase in the number of lose-shift errors on increased memory loads in the 5mg/kg/d CPF-treated males. A weak initial increase in the number of lose-shift errors was observed in the females. In all of the groups, no significant differences were observed in the number of win-shift errors and correct of the first choice. The morphological studies showed extensive condensed nucleus and enlarged intercellular spaces in the CA1 and DG sub-regions in the dHPC of the CPF-treated males and the DG sub-region of the CPF-treated females. The cell count was significantly reduced in these sub-regions. The morphological studies showed no obvious abnormalities at PrL and IL of mPFC in the CPF-treated males and females, but the cell count was reduced. Our findings suggest that prenatal CPF exposure at 5mg/kg/d induces selective cognitive impairments, which based on the morphological deficits in the dHPC and the mPFC.