Black-blood magnetic resonance imaging suggesting central nervous system vasculitis in moyamoya syndrome associated with systemic lupus erythematosus.

Moyamoya syndrome is a cerebrovascular disorder characterized by bilateral stenosis and occlusion of the internal carotid arteries and their branches. A 45-year-old woman with a history of systemic lupus erythematosus was admitted for recurrent ischemic strokes. Magnetic resonance (MR) angiography revealed moyamoya-like vasculopathy. Black-blood gadolinium-based contrast-enhanced MR images showed strong, concentric enhancement along the occluded arteries, which suggested vasculitis as the etiology of moyamoya-like vasculopathy. Intensive immunosuppressive therapy combined with anticoagulation therapy and rehabilitation led to a favorable outcome in this case. Black-blood MR imaging can be a non-invasive and prompt imaging modality when central nervous system vasculitis is suspected.

Prognostic significance of crazy paving ground grass opacities in non-HIV Pneumocystis jirovecii pneumonia: an observational cohort study.

BACKGROUND: In patients with non-HIV Pneumocystis jirovecii pneumonia (PjP), computed tomography imaging reveals ground grass opacities (GGO). Previous reports show that some patients with non-HIV PjP exhibit GGO with crazy paving. However, there have been no studies on the association between crazy paving GGO and non-HIV PjP clinical outcomes. Here, at the diagnosis of non-HIV PjP, we reviewed high-resolution computed tomography (HRCT) findings that included GGO types and evaluated the prognostic impact of crazy paving GGO on the clinical outcomes of non-HIV PjP immunocompromised patients. METHODS: We retrospectively reviewed the clinical information including the HRCT findings of patients diagnosed with non-HIV PjP from five institutions between 2006 and 2015. The GGO types included those with or without crazy paving. The associations between clinical factors such as HRCT findings and in-hospital mortality were assessed using the Cox regression model. RESULTS: Sixty-one patients were included in our study. Nineteen patients died at a hospital. All patients exhibited GGO on HRCT imaging at diagnosis of non-HIV PjP. The HRCT findings included crazy paving GGO (29 patients, 47.5%), consolidations (23 patients, 37.7%), bronchiectasis (14 patients, 23.0%), and centrilobular small nodules (30 patients, 49.2%). Cysts were not observed in any patient. Multivariate analysis revealed that crazy paving GGO and low serum albumin levels were independent risk factors for mortality. CONCLUSIONS: At the diagnosis of non-HIV PjP, patients with crazy paving GGO on HRCT imaging and low serum albumin levels may have a poor prognosis.

Accelerated nucleation of the 2014 Iquique, Chile Mw 8.2 Earthquake.

The earthquake nucleation process has been vigorously investigated based on geophysical observations, laboratory experiments, and theoretical studies; however, a general consensus has yet to be achieved. Here, we studied nucleation process for the 2014 Iquique, Chile Mw 8.2 megathrust earthquake located within the current North Chile seismic gap, by analyzing a long-term earthquake catalog constructed from a cross-correlation detector using continuous seismic data. Accelerations in seismicity, the amount of aseismic slip inferred from repeating earthquakes, and the background seismicity, accompanied by an increasing frequency of earthquake migrations, started around 270 days before the mainshock at locations up-dip of the largest coseismic slip patch. These signals indicate that repetitive sequences of fast and slow slip took place on the plate interface at a transition zone between fully locked and creeping portions. We interpret that these different sliding modes interacted with each other and promoted accelerated unlocking of the plate interface during the nucleation phase.

Frequency components of systolic blood pressure variability reflect vasomotor and cardiac sympathetic functions in conscious rats.

In this study, after confirming the suppression of autonomic nervous function by isoflurane anesthesia using autonomic antagonists, we pharmacologically investigated the involvement of vasomotor and cardiac sympathetic functions in systolic blood pressure variability (SBPV) frequency components in conscious rats at rest and during exposure to low-ambient temperature (LT-exposure, 9°C for 90 min). Under unanesthesia, phentolamine administration (α-adrenoceptor antagonist, 10 mg/kg) decreased the mid-frequency component (MF 0.33-0.73 Hz) and inversely increased the high-frequency component (HF 1.3-2.5 Hz). The increased HF was suppressed by subsequent treatment with atenolol (ß-adrenoceptor antagonist, 10 mg/kg), but not with atropine (muscarinic receptor antagonist, 10 mg/kg). Moreover, phentolamine administration after atenolol decreased MF, but did not increase HF. LT-exposure increased MF and HF; however, phentolamine pretreatment suppressed the increased MF during LT-exposure, and atenolol pretreatment dose-dependently decreased the increased HF. These results suggest that MF and HF of SBPV may reflect α-adrenoceptor-mediated vasomotor function and ß-adrenoceptor-mediated cardiac sympathetic function, respectively, in the conscious state.

Low rather than high dose lipopolysaccharide 'priming' of muscle provides an animal model of persistent elevated mechanical sensitivity for the study of chronic pain.

Experimental animal pain models involving peripheral nerve lesions have expanded the understanding of the pathological changes caused by nerve damage. However models for the pathogenesis of chronic pain patients lacking obvious nerve injuries have not been developed to the same extent. Guided by clinical observations, we focused on the initiating noxious event, the context when applying nociceptive stimulation targeting long-lasting pain elicited by muscle insult. The administration of a nociceptive agent (6% hypertonic saline: HS; 5-time repeated-injection: HS5) after pretreatment with an immuno-inflammatory agent (lipopolysaccharide: LPS, 2 µg/kg) into one gastrocnemius muscle produced markedly long-persisting biphasic sustained mechanical hypersensitivity on the plantar surface of both hindpaws. In the acute phase, the blockade of afferent inputs from the injected-site was effective in returning the contralateral enhanced-responses to baseline levels. In contrast, similar blockade during the chronic phase did not affect the contralateral enhanced-responses, indicating that the hypersensitivity in the two phases was probably induced by different mechanisms. However, increasing the dose of LPS (20 µg/kg) before applying HS5 eliminated the development of mechanical hypersensitivity in the chronic phase, while the hypersensitivity in the acute phase was significantly more severe than with low-dose LPS-pretreatment. In this model, the development of hypersensitivity could be modulated by manipulating LPS-doses prior to noxious stimulation. This novel chronic pain model based on a preceding 'priming' myalgic stimulus provides an intriguing means for studying the pathogenesis of chronic pain.

Molecular cloning of prostaglandin EP3 receptors from canine sensory ganglia and their facilitatory action on bradykinin-induced mobilization of intracellular calcium.

We previously demonstrated that the activation of prostaglandin E-prostanoid-3 (EP3) receptor sensitized the canine nociceptor response to bradykinin (BK). To elucidate the molecular mechanism for this sensitization, we cloned two cDNAs encoding EP3s with different C-terminals, from canine dorsal root ganglia, and established the transformed cell lines stably expressing them. In both transformants, EP3 agonist did not increase intracellular cAMP levels, but it attenuated forskolin-dependent cAMP accumulation in a pertussis toxin (PTX)-sensitive manner and increased intracellular calcium levels in a PTX-resistant manner, indicating that both EP3s can couple with Gi and Gq, but not with Gs proteins. As the nociceptor response to BK is mediated by BK B2 receptor, it was transfected into the transformants and the effects of EP3 agonist on BK-dependent calcium mobilization were investigated. When BK was applied twice with a 6-min interval, the second response was markedly attenuated. Pre-treatment with EP3 agonist had no effect on the initial response, but restored the second response in a PTX-sensitive manner. A protein kinase A inhibitor mimicked the effect of EP3 agonist. These results demonstrate that the activation of EP3 restores the response to BK by attenuating the desensitization of BK B2 receptor activity via Gi protein.

Norepinephrine reduces heat responses of cutaneous C-fiber nociceptors in Sprague-Dawley rats in vitro.

Nociceptors are excited or sensitized by many inflammatory mediators as well as by elevation of tissue temperature. We have shown that there is a facilitatory synergistic interaction between norepinephrine (NE) and bradykinin (BK) on cutaneous C-fiber nociceptors in normal Lewis rats. These interactions may play an important role in the mechanism of sympathetically maintained pain. In the present experiment, using skin-saphenous nerve in vitro preparations, we tested the effect of NE on the activity of nociceptive fibers and their response to heat in normal Sprague-Dawley rats. For comparison with the previous data on Lewis rats, we also examined the effect of NE on BK response. NE (10(-5) or 10(-6) M) did not excite nociceptive fibers before repeated heat stimuli or BK superfusion (10(-5) or 10(-6) M) to the receptive field. In contrast, after a few applications of heat or BK, NE excited 20-43% of nociceptive fibers to similar magnitudes. We also found that NE sensitized subsequent BK responses, but somewhat unexpectedly that it suppressed subsequent heat responses. This occurred regardless of the presence or absence of NE-induced excitation. These results suggest different mechanisms of NE modification to the BK and heat responses of cutaneous C-fiber nociceptors.

Nociceptor structural specialization in canine and rodent testicular "free" nerve endings.

The receptive fields (RFs) of polymodal nociceptor units of canine testis consist of small fascicles of branching axons ending as clusters within the thin vascular layer overlying the seminiferous tubules. This propitious arrangement enabled serial reconstruction of electron micrographs of a flat, punctate zone, identified during recording of impulse discharge of a single physiologically characterized nociceptor "unit." The RFs showed multiple axons, with some branching and sequential vesicle-containing swellings, similar to what have been called terminals and assumed to constitute impulse generating sites in other tissues. Consistent with this interpretation is the local presence of: (1) clusters of small mitochondria, (2) glycogen granules, and (3) sectors of axolemma denuded of Schwann cell processes and thus "free" endings directly contacting the epithelial basal lamina. The most distal sectors showed additional morphologic properties: (1) zones of vesicles embedded in an extensive granular matrix, (2) preterminal arrays of "axonal reticulum" derived from the smooth endoplasmic reticulum displacing axonal cytoskeletal elements, (3) a variety of sizes and electron lucency in clear, spherical vesicles and a few granular or dense-core vesicles, and (4) specialization in the last Schwann cell of the fascicle. These latter features may reflect differences in the specialized receptor mechanisms of nociceptors that are difficult to detect without extensive serial electron microscopic analysis. Alternatively, these features may constitute a regional specialization of the testis. The term free nerve ending is perhaps an insufficient and inaccurate descriptor of the morphology of nociceptors. These findings are considered in the context of their possible relation to the sensitized vanilloid receptor mechanism unique to nociceptors.

Effects of adrenoceptor antagonists on the cutaneous blood flow increase response to sympathetic nerve stimulation in rats with persistent inflammation.

There is some evidence that the sympathetic nervous system plays a role in the development and/or maintenance of painful states, and that sympathetic nervous function is altered in these conditions. Our previous experiments showed that electrical stimulation of the lumbar sympathetic trunk (sympathetic stimulation: SS), which normally induces a decrease in blood flow (BF) of plantar skin, induced its BF increase in about 50% of adjuvant-inflamed rats. To investigate the mechanism of this BF-increase response, we examined whether noradrenaline (NA) plays any role in this changed response to SS, and which receptor subtype is involved. We measured paw cutaneous BF response with a laser Doppler flowmeter in rats chronically inflamed with complete Freund's adjuvant. SS induced the BF-increase response in 50-67% of measured sites. Close-arterially injected NA induced the BF-increase response at dosages between 10-100 ng/kg only at the sites with the BF-increase response to SS. The BF-increase and -decrease responses to NA was significantly reduced after the close-arterial injection of either alpha1- or alpha2-adrenoceptor antagonists (p lt; 0.05, respectively). In contrast, although the BF-decrease responses to SS were significantly reduced by administration of alpha1- and alpha2-adrenoceptor antagonist, BF-increase response was reduced only by alpha1-adrenoceptor antagonist, and that only at a higher dose. In addition, the beta-adrenoceptor antagonist had no effects on both responses. These results suggest that the BF-increase response to SS involves, additionally to NA, a non-adrenergic mechanism.

The effects of bradykinin agonists and antagonists on visceral polymodal receptor activities.

The endogenous algesic agent bradykinin (BK) is a consistent stimulant for the polymodal receptor, a type of nociceptor. Two types of BK receptor, B1 and B2, have been proposed in smooth muscles by Regoli. The type of BK receptor mediating the BK response of the polymodal receptor was studied using 3 BK analogs, des-Arg9-BK (a B1 agonist), des-Arg9-[Leu8]-BK (a B1 antagonist), and [Thi5,8, D-Phe7]-BK (a B2 antagonist). Single- and multi-fiber activities from testicular polymodal receptors were recorded in vitro using testis-spermatic nerve preparations excised from dogs anesthetized with pentobarbital (30 mg/kg, i.v.). Neither des-Arg9-BK, des-Arg9-[Leu8]-BK, nor [Thi5,8,D-Phe7]-BK induced discharges in nociceptors at concentrations up to 9.4 x 10(-6) M. Des-Arg9-[Leu8]-BK (up to 9.4 x 10(-6) M) did not suppress responses to BK (9.4 x 10(-8 approximately -9) M), whereas [Thi5,8,D-Phe7]-BK (above 2.8 x 10(-7) M) suppressed the BK response in a concentration-dependent manner and shifted the concentration-response curve of BK to the right. It was ascertained that [Thi5,8,D-Phe7]-BK had no effect on responses to noxious heat and high K+ solution. These results suggest that the BK receptor mediating the nociceptor response to BK is of the B2 type.