Sensitization of TRPV1 by EP(1 )and IP reveals peripheral nociceptive mechanism of prostaglandins

Prostaglandin E(2 )(PGE(2)) and prostaglandin I(2 )(PGI(2)) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPV1 is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPV1 has been reported to be critical for inflammatory pain mediated through PKA- and PKC-dependent pathways. PGE(2 )or PGI(2)increased or sensitized TRPV1 responses through EP(1 )or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE(2 )or PGI(2), the temperature threshold for TRPV1 activation was reduced below 35°C, so that temperatures near body temperature are sufficient to activate TRPV1. A PKA-dependent pathway was also involved in the potentiation of TRPV1 through EP(4 )and IP receptors upon exposure to PGE(2 )and PGI(2), respectively. Both PGE(2)-induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPV1-deficient mice and EP(1)-deficient mice. IP receptor involvement was also demonstrated using TRPV1-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPV1 activity through EP(1 )or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE(2 )or PGI(2)

TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP

Transient receptor potential V3 (TRPV3) and TRPV4 are heat-activated cation channels expressed in keratinocytes. It has been proposed that heat-activation of TRPV3 and/or TRPV4 in the skin may release diffusible molecules which would then activate termini of neighboring dorsal root ganglion (DRG) neurons. Here we show that adenosine triphosphate (ATP) is such a candidate molecule released from keratinocytes upon heating in the co-culture systems. Using TRPV1-deficient DRG neurons, we found that increase in cytosolic Ca(2+)-concentration in DRG neurons upon heating was observed only when neurons were co-cultured with keratinocytes, and this increase was blocked by P2 purinoreceptor antagonists, PPADS and suramin. In a co-culture of keratinocytes with HEK293 cells (transfected with P2X(2) cDNA to serve as a bio-sensor), we observed that heat-activated keratinocytes secretes ATP, and that ATP release is compromised in keratinocytes from TRPV3-deficient mice. This study provides evidence that ATP is a messenger molecule for mainly TRPV3-mediated thermotransduction in skin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00424-009-0703-x) contains supplementary material, which is available to authorized users

DIP/WISH deficiency enhances synaptic function and performance in the Barnes maze

<p>Abstract</p> <p>Background</p> <p>DIP (diaphanous interacting protein)/WISH (WASP interacting SH3 protein) is a protein involved in cytoskeletal signaling which regulates actin cytoskeleton dynamics and/or microtubules mainly through the activity of Rho-related proteins. Although it is well established that: 1) spine-head volumes change dynamically and reflect the strength of the synapse accompanying long-term functional plasticity of glutamatergic synaptic transmission and 2) actin organization is critically involved in spine formation, the involvement of DIP/WISH in these processes is unknown.</p> <p>Results</p> <p>We found that DIP/WISH-deficient hippocampal CA1 neurons exhibit enhanced long-term potentiation via modulation of both pre- and post-synaptic events. Consistent with these electrophysiological findings, DIP/WISH-deficient mice, particularly at a relatively young age, found the escape hole more rapidly in the Barnes maze test.</p> <p>Conclusions</p> <p>We conclude that DIP/WISH deletion improves performance in the Barnes maze test in mice probably through increased hippocampal long-term potentiation.</p

Parental satisfaction and seizure outcome after corpus callosotomy in patients with infantile or early childhood onset epilepsy

AbstractPurposeTo elucidate the benefit of corpus callosotmy in terms of parental satisfaction and seizure outcome.MethodThis study included 16 consecutive patients with infantile or early childhood onset epilepsy who underwent total corpus callosotomy for alleviation of seizures. Questionnaires were sent anonymously to the parents asking about relative changes in seizures and about parental satisfaction for the post-operative outcome.ResultsThe improvements in frequency, intensity, and duration of seizures were correlated with the level of satisfaction (Spearman's rank-order correlation coefficient, ρ=0.87, 0.93, and 0.75, respectively). The highest level of satisfaction was only seen in patients who achieved freedom from all seizures or drop attacks.ConclusionComplete seizure freedom and freedom from drop attacks are important goals of corpus callosotomy for parental satisfaction. These factors should be considered in assessing post-operative outcome after corpus callosotomy

NADPH oxidase-derived reactive oxygen species are essential for differentiation of a mouse macrophage cell line (RAW264.7) into osteoclasts

Reactive oxygen species (ROS) derived from NADPH oxidase (Nox) homologues have been suggested to regulate osteoclast differentiation. However, no bone abnormalities have been documented in Nox1 deficient, Nox2 deficient, or Nox3 mutant mice. During receptor activator of nuclear factor-κB ligand (RANKL)-stimulated differentiation of a mouse macrophage cell line (RAW264.7) into osteoclasts, mRNA levels of Nox enzymes (Nox1-4) and their adaptor proteins were monitored by real-time reverse transcriptase PCR. RAW264.7 cells constitutively expressed abundant Nox2 mRNA and small amounts of Nox1 and Nox3 transcripts. RANKL markedly attenuated Nox2 mRNA expression in association with reciprocal up-regulation of Nox1 and Nox3 transcripts. Introduction of small interference RNA targeting p67phox or p22phox into RAW264.7 cells effectively downregulated ROS generation and significantly suppressed the RANKL-stimulated differentiation, which was assessed by appearance of tartrate resistant acid phosphatase (TRAP)- positive, multinucleated cells having an ability to form resorption pits on calcium phosphate thin film-coated disks, and by expression of osteoclast marker genes (TRAP, cathepsin K, Atp6i, ClC-7, and NFATc1). Our results suggest that RANKL may stimulate switching between Nox homologues during osteoclast differentiation, and Nox-derived ROS may be crucial for RANKL-induced osteoclast differentiation

The Diagnosis and Treatment Approach for Oligo-Recurrent and Oligo-Progressive Renal Cell Carcinoma

One-third of renal cell carcinomas (RCCs) without metastases develop metastatic disease after extirpative surgery for the primary tumors. The majority of metastatic RCC cases, along with treated primary lesions, involve limited lesions termed “oligo-recurrent” disease. The role of metastasis-directed therapy (MDT), including stereotactic body radiation therapy (SBRT) and metastasectomy, in the treatment of oligo-recurrent RCC has evolved. Although the surgical resection of all lesions alone can have a curative intent, SBRT is a valuable treatment option, especially for patients concurrently receiving systemic therapy. Contemporary immune checkpoint inhibitor (ICI) combination therapies remain central to the management of metastatic RCC. However, one objective of MDT is to delay the initiation of systemic therapies, thereby sparing patients from potentially unnecessary burdens. Undertaking MDT for cases showing progression under systemic therapies, known as “oligo-progression”, can be complex in considering the treatment approach. Its efficacy may be diminished compared to patients with stable disease. SBRT combined with ICI can be a promising treatment for these cases because radiation therapy has been shown to affect the tumor microenvironment and areas beyond the irradiated sites. This may enhance the efficacy of ICIs, although their efficacy has only been demonstrated in clinical trials

ホスピス トクシマ ニオケル マッキ ガン カンジャ ノ ボウシュヨウセイ シンケイ ショウコウグン ノ ハッショウ ヒンド ト ソノ リンショウテキ イギ

Neurological complications in advanced cancer occur frequently and therefore an adequate neurological assessment must always be part of patient evaluation in hospice palliative care. Paraneoplastic neurological syndromes are rare, probably affecting less than 1 per cent of patients with cancer, even if the most commonly associated neoplasms, such as small-cell lung cancer and ovarian cancer are considered. Neurological complications were studied in 127 inpatients with advanced cancers. Neurological complications were seen in up to 40 per cent of the patients. The most frequent symptom was derilium, followed in order to lethargy, paraplegia, depression, dementia, hemiplegia, restlessness, aphasia, stupor, facial palsy, recurrent laryngeal nerve palsy, convulsion, and myastenia. Those symptoms were seen in patients in hepatic encephalitis（12）, metastatic brain tumor（9）, metastatic spinal cord injury（8）, depression（4）, paraneoplastic syndrome（4）, hypercalcemia（2）, senile dementia（2）, peripheral neuritis（2）, and cerebral infarction（2）. Of the four patients with paraneoplastic syndrome, one patient had both anti-Hu antibody and anti-VGCC antibody and two patients had anti-neuronal nuclear antibodies. These results indicate that paraneoplastic neurological syndromes are associated more than 1 per cent of patients with advanced cancer

Clinical Efficacy and Safety of Sitafloxacin 200 mg Once Daily for Refractory Genitourinary Tract Infections

The aim of this ongoing trial is to evaluate the clinical efficacy and safety of sitafloxacin (STFX) 200 mg once daily (QD) for 7 days in patients with refractory genitourinary tract infections, which include recurrent or complicated cystitis, complicated pyelonephritis, bacterial prostatitis, and epididymitis. The primary endpoint is the microbiological efficacy at 5-9 days after the last administration of STFX. Recruitment began in February 2021, and the target total sample size is 92 participants

Erratum to: Expression of myeloperoxidase and gene mutations in AML patients with normal karyotype: double CEBPA mutations are associated with high percentage of MPO positivity in leukemic blasts

Erratum to: International Journal of Hematology, 94(1), pp.81-89: 2011DOI 10.1007/s12185-011-0883-yThe original version of this article unfortunately contained some errors in Table 2 in the column headed ‘‘Amino acid changes’’. The corrected table is given here