Increased Excitability of Lateral Habenula Neurons in Adolescent Rats following Cocaine Self-Administration

Background:

The lateral habenula is a brain region that has been critically implicated in modulating negative emotional states and responses to aversive stimuli. Exposure to addictive drugs such as cocaine negatively impacts affective states, an effect persisting longer than acute drug effects. However, the mechanisms of this effect are poorly understood. We hypothesized that drugs of abuse, such as cocaine, may contribute to drug-induced negative affective states by altering the firing properties of lateral habenula neurons, thus changing the signaling patterns from the lateral habenula to downstream circuits.

Methods:

Using whole-cell current-clamp recording of acutely prepared brain slices of rats after various periods of withdrawal from cocaine self-administration, we characterized an important heterogeneous subregion of the lateral habenula based on membrane properties.

Results:

We found two major relevant neuronal subtypes: burst firing neurons and regular spiking neurons. We also found that lateral habenula regular spiking neurons had higher membrane excitability for at least 7 days following cocaine self-administration, likely due to a greater membrane resistance. Both the increase in lateral habenula excitability and membrane resistance returned to baseline when tested after a more prolonged period of 45 days of withdrawal.

Conclusion:

This is the first study to look at intrinsic lateral habenula neuron properties following cocaine exposure beyond acute drug effects. These results may help to explain how cocaine and other drugs negatively impact affect states.     

Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis: A multicenter cohort study

We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs.     

Preventive Effects of Renin-angiotensin System Inhibitors on Oxaliplatin-induced Peripheral Neuropathy: A Retrospective Observational Study

Purpose

Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin-induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy.

Mouse model of dermal fibrosis induced by one-time injection of bleomycin-poly(L-lactic acid) microspheres

Objective. Animal models are useful tools to study various aspectsof human diseases. Bleomycin (BLM)-induced scleroderma mousehas been widely investigated as an animal model of scleroderma.Repeated injections of BLM, either daily or every other day,for 3–4 weeks are required to induce scleroderma in mice.Poly(L-lactic acid) (PLA) is a biodegradable, biocompatibleand bioabsorbable device that has been widely investigated forcontrolled drug release. In this study, we fabricated BLM-containingPLA microspheres and subcutaneously injected them into C3H micefor only one time. Methods. Treated skins were harvested at days 7 and 21. Then,histological examination and collagen content measurement assaywere performed. The mRNA expression of 1(I) collagen (COL1A1),monocyte chemoattractant protein-1 (MCP-1), TGF-β₁ andconnective tissue growth factor (CTGF) were quantified by real-timePCR. Results. Dermal fibrosis was histologically observed at day7 after injection and remained present at day 21. Tissue responsesagainst BLM-PLA microspheres alone were mild. Soluble collagencontent and expression level of 1(I) collagen mRNA were significantlyelevated at day 21. Expression levels of MCP-1 mRNA and TGF-β₁mRNA at day 7 and CTGF mRNA at day 21 were also elevated. Conclusion. The present study demonstrated for the first timethat one-time injection of BLM-PLA microspheres can induce dermalfibrosis in C3H mice. BLM-PLA microspheres thus offer a labour-saving,simple and powerful tool to establish an animal model of BLM-induceddermal fibrosis. KEY WORDS: Bleomycin, Scleroderma, Mouse model, Dermal fibrosis, Drug delivery system, Poly(L-lactic acid) Submitted 11 October 2007; revised version accepted 24 January 2008.     

Perfusion-driven Intravoxel Incoherent Motion (IVIM) MRI in Oncology: Applications,Challenges, and Future Trends

Recent developments in MR hardware and software have allowed a surge of interest in intravoxel incoherent motion (IVIM) MRI in oncology. Beyond diffusion-weighted imaging (and the standard apparent diffusion coefficient mapping most commonly used clinically), IVIM provides information on tissue microcirculation without the need for contrast agents. In oncology, perfusion-driven IVIM MRI has already shown its potential for the differential diagnosis of malignant and benign tumors, as well as for detecting prognostic biomarkers and treatment monitoring. Current developments in IVIM data processing, and its use as a method of scanning patients who cannot receive contrast agents, are expected to increase further utilization. This paper reviews the current applications, challenges, and future trends of perfusion-driven IVIM in oncology.     

Evaluation of Malignant Breast Lesions Using High-resolution Readout-segmented Diffusion-weighted Echo-planar Imaging: Comparison with Pathology

Purpose:We aimed to investigate the performance of high resolution-diffusion-weighted imaging (HR-DWI) using readout-segmented echo-planar imaging in visualizing malignant breast lesions and evaluating their extent, using pathology as a reference.Methods:This retrospective study included patients who underwent HR-DWI with surgically confirmed malignant breast lesions. Two radiologists blinded to the final diagnosis evaluated HR-DWI independently and identified the lesions, measuring their maximum diameters. Another radiologist confirmed if those lesions were identical to the pathology. The maximum diameters of the lesions between HR-DWI and pathology were compared, and their correlations were calculated using Spearman’s correlation coefficient. Apparent diffusion coefficient (ADC) values of the lesions were measured.Results:Ninety-five mass/64 non-mass lesions were pathologically confirmed in 104 females. Both radiologists detected the same 93 mass lesions (97.9%). Spearman’s correlation coefficient for mass lesions were 0.89 and 0.90 (P < 0.0001 and 0001) for the two radiologists, respectively. The size differences within 10 mm were 90.3% (84/93) and 94.6% (88/93) respectively. One radiologist detected 35 non-mass lesions (54.7%) and another radiologist detected 32 non-mass lesions (50.0%), of which 28 lesions were confirmed as identical. Spearman’s correlation coefficient for non-mass lesions were 0.59 and 0.22 (P = 0.0002 and 0.22), respectively. The mean ADC value of mass lesions and non-mass lesions were 0.80 and 0.89 × 10⁻³ mm²/s, respectively.Conclusion:Using HR-DWI, malignant mass lesions were depicted with excellent agreement with the pathological evaluation. Approximately half of the non-mass lesions could not be identified, suggesting a current limitation of HR-DWI.     

Blood dendritic cells in patients with acute lymphoblastic leukaemia

Myeloid and plasmacytoid dendritic cells (MDCs, PDCs) play a key role in the initiation of immune responses. In this study, we show a severe reduction of MDCs and PDCs in patients with B lineage acute lymphoblastic leukaemia (B-ALL; P = 0.01 vs. controls). DCs from patients with T lineage ALL (T-ALL) were quantitatively and functionally comparable to healthy donors, as demonstrated by secretion of interleukin (IL)-12p70 and interferon-alpha. In vitro, the circulating CD34(+) fraction of B-ALL cases did not generate either CD1a(+) MDCs or PDCs, suggesting that DC development is probably affected in B-ALL, but not in T-ALL.     

Differentiation and proliferation of periosteal osteoblast progenitors are differentially regulated by estrogens and intermittent parathyroid hormone administration

The periosteum is now widely recognized as a homeostatic and therapeutic target for actions of sex steroids and intermittent PTH administration. The mechanisms by which estrogens suppress but PTH promotes periosteal expansion are not known. In this report, we show that intermittent PTH(1-34) promotes differentiation of periosteal osteoblast precursors as evidenced by the stimulation of the expression or activity of alkaline phosphatase as well as of targets of the bone morphogenetic protein 2 (BMP-2) and Wnt pathways. In contrast, 17beta-estradiol (E2) had no effect by itself. However, it attenuated PTH- or BMP-2-induced differentiation of primary periosteal osteoblast progenitors. Administration of intermittent PTH to ovariectomized mice induced rapid phosphorylation of the BMP-2 target Smad1/5/8 in the periosteum. A replacement dose of E2 had no effect by itself but suppressed PTH-induced phosphorylation of Smad1/5/8. In contrast to its effects to stimulate periosteal osteoblast differentiation, PTH promoted and subsequently suppressed proliferation of periosteal osteoblast progenitors in vitro and in vivo. E2 promoted proliferation and attenuated the antiproliferative effect of PTH. Both hormones protected periosteal osteoblasts from apoptosis induced by various proapoptotic agents. These observations suggest that the different effects of PTH and estrogens on the periosteum result from opposing actions on the recruitment of early periosteal osteoblast progenitors. Intermittent PTH promotes osteoblast differentiation from periosteum-derived mesenchymal progenitors through ERK-, BMP-, and Wnt-dependent signaling pathways. Estrogens promote proliferation of early osteoblast progenitors but inhibit their differentiation by osteogenic agents such as PTH or BMP-2.