Occipital nerve stimulation (ONS) is a form of peripheral nerve stimulation used to treat refractory headaches. The trial of ONS was carried with the midline incision C1-2 level, inserted electrical lead subcutaneously to oblique and cephalad direction followed by trajectory of blunt dissection. We used 8 pole electrical lead to cover lesser occipital nerve, greater occipital nerve, third occipital nerve and great auricular nerve. We anchored the lead at the midline insertion site after confirming the stimulation of the patient. And then we looped and tightened the lead loosely, connected the lead and the extension under right supraspinatus muscle region. After 1 week trial period, we performed the permanent implantation of occipital nerve stimulator. We inserted internal pulse generator under a pocket located at right infraclavicular region. The VAS score dropped from 8/10 to 1-2/10. No serious complications were detected during 1 month follow-up.
Headache; Occipital nerve stimulation; Occipital neuralgia; Peripheral nerve stimulation
The differential diagnosis of headache is often difficult because the symptom of headache is overlapping. Superficial cervical plexus block is useful in diagnosis and treatment of headache. Headache arising from the neck and radiating to the frontotemporal regions and possibly to the supraorbital region has been defined as cervicogenic headache. A positive response to anesthetic blocks is one of the diagnostic criteria of cervicogenic headache. We experienced a case of headache arising from direct lymph node metastasis of hepatocellular carcinoma adjacent to the superficial cervical plexus during treatment of cervicogenic headache under ultrasonographic guidance. Especially in patients with medical history of cancer, practitioners should consider the possibility of metastasis to cervical lymph nodes and using ultrasonography to evaluate the cervical area prior to the practice.
Cervicogenic headache; Diagnostic block; Metastasis; Superficial cervical plexus; Ultrasonography
The evolution of brain imaging techniques over the last decade has been remarkable. Along with such technical developments, research into chronic pain has made many advances. Given that brain imaging is a non-invasive technique with great spatial resolution, it has played an important role in finding the areas of the brain related to pain perception as well as those related to many chronic pain disorders. Therefore, in the near future, brain imaging techniques are expected to be the key to the discovery of many unknown etiologies of chronic pain disorders and to the subjective diagnoses of such disorders.
brain imaging; chronic pain
Epidural steroid injection (ESI) is one of the most common procedures for patients presenting low back pain and radiculopathy. However, there is no clear consensus on what constitutes appropriate steroid use for ESIs. To investigate optimal steroid injection methods for ESIs, surveys were sent to all academic pain centers and selected private practices in Korea via e-mail.
Among 173 pain centers which requested the public health insurance reimbursements for their ESIs and were enrolled in the Korean Pain Society, 122 completed questionnaires were returned, for a rate of 70.5%; also returned were surveys from 39 academic programs and 85 private practices with response rates of 83.0% and 65.9%, respectively.
More than half (55%) of Korean pain physicians used dexamethasone for ESIs. The minimum interval of subsequent ESIs at the academic institutions (3.1 weeks) and the private practices (2.1 weeks) were statistically different (P = 0.01).
Although there was a wide range of variation, there were no significant differences between the academic institutions and the private practices in terms of the types and single doses of steroids for ESIs, the annual dose of steroids, or the limitations of doses in the event of diabetes, with the exception of the minimum interval before the subsequent ESI.
dexamethasone; dose; epidural; radiculopathy; spinal pain; steroid; survey; triamcinolone
Treatment remains uncertain for IgA nephropathy patients with mild to moderate proteinuria, for whom anti-hypertensive medication or the RAS blocker is not applicable due to low blood pressure.
A double blinded randomized trial.
The anti-proteinuric effect of tacrolimus was explored for 40 biopsy-proven mild IgA nephropathies for 16 weeks. We randomly assigned patients either to receive tacrolimus or placebo with stratification by using a renin angiotensin system blocker. The primary outcome was the percentage change of final UACR compared to the baseline value (pcUACR).
The mean value of pcUACR at 12-week and 16-week visits (primary outcome) was decreased more in the Tac group compared to the control group (–52.0±26.4 vs –17.3±29.3%, p = 0.001). At each visit, pcUACR was also decreased more in the Tac group compared to the control group. In the Tac group, the pcUACRs were –60.2±28.2%, –62.2±33.9%, –48.5±29.8%, and –55.5±24.0%, and, in the control group, –6.8±32.2%, –2.5±35.9%, –12.7±34.2%, and –21.9±30.6%, at 4-week, 8-week, 12-week, and 16-week visits, respectively. The pre-defined secondary outcomes were better in the Tac group compared to the control group. The frequency of decrease in pcUACR and percentage change of UPCR (pcUPCR) ≥50% at 16 weeks were 65.0% (13/20) and 55.0% (11/20)in the Tac group, and 25.0% (5/20) and 15.0% (3/20), in the control group, respectively (p = 0.025 for pcUACR and p = 0.019 for pcUPCR). However, tacrolimus wasn't effective with a dose of 0.05 mg/kg/day in patients taking ARB. The adverse events were tolerable.
Tacrolimus effectively reduced proteinuria in IgA nephropathy with normal blood pressure. This suggested that tacrolimus could be an alternative to corticosteroid and RAS blocker for IgA nephropathy patients who cannot endure anti-hypertensive medication.
Amyloid-β (Aβ) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer’s disease (AD); however, the cellular pathology of the disease is not fully understood. Here, we report that IgG Fcγ receptor II-b (FcγRIIb) mediates Aβ neurotoxicity and neurodegeneration. We found that FcγRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Aβ. Neuronal FcγRIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic Aβ-induced cell death in vitro. Fcgr2b deficiency ameliorated Aβ-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted Aβ. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of FcγRIIb in Aβ neurotoxicity, we demonstrated that soluble Aβ oligomers interact with FcγRIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic Aβ neurotoxicity. We conclude that FcγRIIb has an aberrant, but essential, role in Aβ-mediated neuronal dysfunction.
More than 80% of cancer patients experience cancer pain. Among them, more than 50% experience moderate to severe pain. To control cancer pain, a variety of methods have been used, including medications and nerve blocks. In some patients, however, it is impossible to perform nerve blocks due to caner metastasis into the epidural space, while in other patients, opioid dose escalation is impossible due to opioid side effects; thus, cancer pain management is difficult. Scrambler therapy is a novel approach for pain control that uses EKG-like pads, which are applied above and below the site of pain. Scrambler therapy synthesizes 16 different types of nerve action potentials that provide "non-pain" information via cutaneous nerves. The advantages of this treatment are that it is non-invasive and safe and has no significant side effects. In this case series, we report the treatment results of using scrambler therapy in three cancer patients with intractable pain.
cancer; electric stimulation/methods; intractable; pain; scrambler therapy
To investigate the role of endogenous hydrogen sulfide (H2S) in partial obstruction-induced dysfunction of the interstitial cells of Cajal (ICC) in mice ileum.
Materials and Methods
Partial intestinal obstruction was induced surgically in male imprinting control region (ICR) mice. ICC networks were studied by Immunohistochemistry. Electrical activity was recorded by intracellular recording techniques. The expression of ICC phenotype marker c-kit receptor tyrosine kinase (c-kit), membrane binding stem cell factor (mSCF), the endogenous H2S biosynthesis enzymes cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) was studied by Western blotting. The expression of tumor necrosis factor-α (TNF-α) mRNA was observed by using real-time polymerase chain reaction.
Partial intestinal obstruction resulted in ICC networks were disrupted above obstruction 14 days after the operation. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed and their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized. The expression of c-kit and mSCF was significantly decreased, also suggesting the disruption of the ICC network. The expression of TNF-α was significantly increased in the tunica muscularis of the obstructed intestine. Treatment of cultured intestinal smooth muscle cells with TNF-α caused dramatic down regulation of mSCF. The expression of CBS and CSE was significantly decreased in the tunica muscularis of the obstructed intestine. Intraperitoneal injection (i.p) of DL-propargylglycine, an irreversible inhibitor of CSE, and aminooxyacetic acid, an inhibitor of CBS, elevated the expression of TNF-α mRNA in the tunica muscularis of the ileum. Obstruction-induced over expression of TNF-α was significantly improved by supplementation of NaHS, but not the expressions of mSCF and c-kit.
The down regulation of endogenous H2S biosynthesis is related to over expression of TNF-α in obstructed small intestine. TNF-α-mediated mSCF down-regulation is not the only reason of partial intestinal obstruction-induced loss of ICC.
Site-directed mutagenesis was used to search for amino acid residues of the human P2Y1 receptor involved in the binding of the P2 receptor antagonists pyridoxal-5′-phosphate-6-azophenyl-2,4-disulfonate (PPADS), its analogue 6-(2′-chloro-phenylazo)-pyridoxal-α5-phosphate (MRS 2210), the suramin analogue 8-8′-[carbonylbis(imino-3,1-phenylene)]bis(1,3,5-naphthalene-trisulfonate) (NF023), and Reactive blue 2. Receptors containing single amino acid replacements at positions in transmembrane helical domains (TMs) 3, 5, 6, and 7 critical for the activation of the receptor by nucleotide agonists were expressed in COS-7 (African green monkey kidney) cells. Inositol phosphate accumulation was induced by 2-methylthioadenosine 5′-diphosphate (2-MeSADP). In wild type human P2Y1 receptors, PPADS (10 to 60 µM), MRS 2210 (10 µM), NF023 (100 µM), and Reactive blue 2 (10 µM) shifted the concentration-response curve of 2-MeSADP in a parallel manner to the right. For PPADS, a pA2 value of 5.2 was estimated. The shifts caused by MRS 2210, NF023, and Reactive blue 2 corresponded to apparent pKB values of 5.6, 5.0, and 5.8, respectively. In K280A mutant receptors, the affinities of PPADS, MRS 2210, NF023, and Reactive blue 2 were about 6- to 60-fold lower than those observed at wild type receptors. The K280A mutation also caused an approximately 1,000-fold increase in the EC50 value of the agonist 2-MeSADP, similar to previous observations. In contrast, no major change in antagonistic potency was observed at receptors with other mutations in TMs 3, 5, 6, and 7. Thus, the residue Lys280 (6.55), which is located within the upper third of TM 6 of the human P2Y1 receptor, is not only critical for the activation of the receptor but also plays an important role in the binding of pyridoxal derivatives and a number of other chemically unrelated P2 receptor antagonists. Lys280 seems to belong to an overlapping region of the respective binding sites.
antagonists; G protein-coupled receptors; mutagenesis; phospholipase C; nucleotides
The intrathecal drug delivery system (ITDDS), an effective treatment tool for intractable spasticity and pain, is associated with various complications but breakage of the catheter is rare. We report the case of a 50-yr-old man with ITDDS, in whom an intrathecal catheter was severed, resulting in a 28.6-cm-long intrathecal fragment. The catheter completely retracted into the intrathecal space from the anchor site. The catheter was severed during spine flexion, and the total distal fragment was repositioned in the intrathecal space. Although the outcome of ITDDS was associated with the length or diameter of the broken catheter, no neurologic complications occurred in our patient. Thus, we inserted another catheter instead of removing the old one. Thereafter, the patient has been regularly followed up, and no neurologic complications have developed during the 28 months.
Catheter; Complications; Intrathecal Injections; Implantable Infusion Pumps
The effects of putative A3 adenosine receptor antagonists of three diverse chemical classes (the flavonoid MRS 1067, the 6-phenyl-1,4-dihydropyridines MRS 1097 and MRS 1191, and the triazoloquinazo-line MRS 1220) were characterized in receptor binding and functional assays. MRS1067, MRS 1191 and MRS 1220 were found to be competitive in saturation binding studies using the agonist radioligand [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide) at cloned human brain A3 receptors expressed in HEK-293 cells. Antagonism was demonstrated in functional assays consisting of agonist-induced inhibition of adenylate cyclase and the stimulation of binding of [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTP-γ-S) to the associated G-proteins. MRS 1220 and MRS 1191, with KB values of 1.7 and 92 nM, respectively, proved to be highly selective for human A3 receptor vs human A1 receptor-mediated effects on adenylate cyclase. In addition, MRS 1220 reversed the effect of A3 agonist-elicited inhibition of tumor necrosis factor-α formation in the human macrophage U-937 cell line, with an IC50 value of 0.3 μM. Published by Elsevier Science Ltd.
Dihydropyridine; flavonoid; triazoloquinazoline; adenylate cyclase; tumor necrosis factor; guanine nucleotides; adenosine A3 receptor; adenosine
1,4-Dihydropyridines are regarded as privileged structures for drug design, i.e. they tend to bind to a wide variety of receptor sites. We have shown that upon appropriate manipulation of the substituent groups on a 1,4-dihydropyridine template, high affinity and selectivity for the A3 subtype of adenosine receptors (‘P1 receptors’) may be attained. In the present study we have begun to extend this approach to P2 receptors which are activated by ATP and other nucleotides. Nicardipine, a representative dihydropyridine, used otherwise as an L-type calcium channel blocker, was shown to be an antagonist at recombinant rat P2X2 (IC50 = 25 μM) and P2X4 (IC50 ~ 220 μM) receptors expressed in Xenopus oocytes. Thus, this class of compounds represents a suitable lead for enhancement of affinity through chemical synthesis. In an attempt to modify the 1,4-dihydropyridine structure with a predicted P2 receptor recognition moiety, we have replaced one of the ester groups with a negatively charged phosphonate group. Several 4-phenyl-5-phosphonato-1,4-dihydropyridine derivatives, MRS 2154 (2,6-dimethyl), MRS 2155 (6-methyl-2-phenyl), and MRS 2156 (2-methyl-6-phenyl), were synthesized through three component condensation reactions. These derivatives were not pure antagonists of the effects of ATP at P2X2 receptors, rather were either inactive (MRS 2156) or potentiated the effects of ATP in a concentration-dependent manner (MRS 2154 in the 0.3–10 μM range and MRS 2155 at >1 μM). Antagonism of the effects of ATP at P2X2 receptor superimposed on the potentiation was also observed at >10 μM (MRS 2154) or 0.3–1 μM (MRS 2155). Thus, while a conventional dihydropyridine, nicardipine, was found to antagonize rat P2X2 receptors ninefold more potently than P2X4 receptors, the effects of novel, anionic 5-phosphonate analogues at the receptor were more complex.
Ion channels; Oocytes; Purines; Dihydropyridine derivatives; Potentiator
We conducted a mutational analysis of residues potentially involved in the adenine nucleotide binding pocket of the human P2Y1 receptor. Mutated receptors were expressed in COS-7 cells with an epitope tag that permitted confirmation of expression in the plasma membrane, and agonist-promoted inositol phosphate accumulation was assessed as a measure of receptor activity. Residues in transmembrane helical domains (TMs) 3, 5, 6, and 7 predicted by molecular modeling to be involved in ligand recognition were replaced with alanine and, in some cases, by other amino acids. The potent P2Y1 receptor agonist 2-methylthio-ATP (2-MeSATP) had no activity in cells expressing the R128A, R310A, and S314A mutant receptors, and a markedly reduced potency of 2-MeSATP was observed with the K280A and Q307A mutants. These results suggest that residues on the exofacial side of TM3 and TM7 are critical determinants of the ATP binding pocket. In contrast, there was no change in the potency or maximal effect of 2-MeSATP with the S317A mutant receptor. Alanine replacement of F131, H132, Y136, F226, or H277 resulted in mutant receptors that exhibited a 7–18-fold reduction in potency compared with that observed with the wild-type receptor. These residues thus seem to subserve a less important modulatory role in ligand binding to the P2Y1 receptor. Because changes in the potency of 2-methylthio-ADP and 2-(hexylthio)-AMP paralleled the changes in potency of 2-MeSATP at these mutant receptors, the β- and γ-phosphates of the adenine nucleotides seem to be less important than the α-phosphate in ligand/P2Y1 receptor interactions. However, T221A and T222A mutant receptors exhibited much larger reductions in triphosphate (89- and 33-fold versus wild-type receptors, respectively) than in diphosphate or monophosphate potency. This result may be indicative of a greater role of these TM5 residues in γ-phosphate recognition. Taken together, the results suggest that the adenosine and α-phosphate moieties of ATP bind to critical residues in TM3 and TM7 on the exofacial side of the human P2Y1 receptor.
Novel analogs of the P2 receptor antagonist pyridoxal-5′-phosphate-6-phenylazo-2′,4′-disulfonate (PPADS) were synthesized. Modifications were made through functional group substitution on the sulfophenyl ring and at the phosphate moiety through the inclusion of phosphonates, demonstrating that a phosphate linkage is not required for P2 receptor antagonism. Substituted 6-phenylazo and 6-naphthylazo derivatives were also evaluated. Among the 6-phenylazo derivatives, 5′-methyl, ethyl, propyl, vinyl, and allyl phosphonates were included. The compounds were tested as antagonists at turkey erythrocyte and guinea-pig taenia coli P2Y1 receptors, in guinea-pig vas deferens and bladder P2X1 receptors, and in ion flux experiments by using recombinant rat P2X2 receptors expressed in Xenopus oocytes. Competitive binding assay at human P2X1 receptors in differentiated HL-60 cell membranes was carried out by using [35S]ATP-γ-S. A 2′-chloro-5′-sulfo analog of PPADS (C14H12O9N3ClPSNa), a vinyl phosphonate derivative (C15H12O11N3PS2Na3), and a naphthylazo derivative (C18H14O12N3PS2Na2), were particularly potent in binding to human P2X1 receptors. The potencies of phosphate derivatives at P2Y1 receptors were generally similar to PPADS itself, except for the p-carboxyphenylazo phosphate derivative C15H13O8N3PNa and its m-chloro analog C15H12O8N3ClPNa, which were selective for P2X vs. P2Y1 receptors. C15H12O8N3ClPNa was very potent at rat P2X2 receptors with an IC50 value of 0.82 μM. Among the phosphonate derivatives, [4-formyl-3-hydroxy-2-methyl-6-(2-chloro-5-sulfonylphenylazo)-pyrid-5-yl]methylphosphonic acid (C14H12-O8N3ClPSNa) showed high potency at P2Y1 receptors with an IC50 of 7.23 μM. The corresponding 2,5-disulfonylphenyl derivative was nearly inactive at turkey erythrocyte P2Y1 receptors, whereas at recombinant P2X2 receptors had an IC50 value of 1.1 μM. An ethyl phosphonate derivative (C15H15O11N3PS2Na3), whereas inactive at turkey erythrocyte P2Y1 receptors, was particularly potent at recombinant P2X2 receptors.
ATP; nucleotides; ion channels; phospholipase C; smooth muscle; guinea pig; turkey erythrocytes
Complex regional pain syndrome affects the quality of life of the patient. The aim of this study was to investigate the epidemiological features of this syndrome and evaluate its effect on the patient's working life. We demonstrated that the disease has a male preponderance and is 3 times more likely to affect the lower extremities. In this study, 11 participants (20%) retained their employment, whereas 44 (80%) became unemployed. Mean age and pain score were lower in the employment group than in the unemployment group (29.1 ± 16.8 yr vs 40.1 ± 12.6 yr, P = 0.021, and 4.5 ± 2.9 vs 7.0 ± 2.0, P = 0.002, respectively). Subjects diagnosed within 8 months (P = 0.044), those who had achieved higher levels of education (P = 0.028), and those working in white-collar jobs (P = 0.011) had higher employment-retention rates. Therefore, patients must manage their jobs (lower physical demand and decrease the number of working hours) if they are to improve their occupational life. To achieve satisfactory outcomes and a high employment-retention rate, clinicians must be aware of the importance of an early diagnosis (within 8 months), appropriate treatment, and a reduction in the patient's pain score.
Complex Regional Pain Syndromes; Work; Employment
We have synthesized a series of derivatives of the known P2 receptor antagonist PPADS (pyridoxal-5′-phosphate-6-azo-phenyl-2,4-disulfonate) and examined their ability to inhibit functional activity of the recombinant human P2Y13 nucleotide receptor expressed in 1321N1 human astrocytoma cells co-expressing Gα16 protein (AG32). Analogues of PPADS modified through substitution of the phenylazo ring, including halo and nitro substitution, and 5′-alkyl phosphonate analogues were synthesized and tested. A 6-benzyl-5′-methyl phosphonate analogue was prepared to examine the effect of stable replacement of the azo linkage. The highest antagonistic potency was observed for 6-(3-nitrophenylazo) derivatives of pyridoxal-5′-phosphate. The 2-chloro-5-nitro analogue (MRS 2211) and 4-chloro-3-nitro analogue (MRS 2603) inhibited ADP (100 nM)-induced inositol trisphosphate (IP3) formation with pIC50 values of 5.97 and 6.18, respectively, being 45- and 74-fold more potent than PPADS. The antagonism of MRS 2211 was competitive with a pA2 value of 6.3. MRS2211 and MRS2603 inhibited phospholipase C (PLC) responses to 30 nM 2-methylthio-ADP in human P2Y1 receptor-mediated 1321N1 astrocytoma cells with IC50 values of >10 and 0.245 μM, respectively. Both analogues were inactive (IC50 > 10 μM) as antagonists of human P2Y12 receptor-mediated PLC responses in 1321N1 astrocytoma cells. Thus, MRS2211 displayed >20-fold selectivity as antagonist of the P2Y13 receptor in comparison to P2Y1 and P2Y12 receptors, while MRS2603 antagonized both P2Y1 and P2Y13 receptors.
PPADS (pyridoxal-5′-phosphate-6-azo-phenyl-2,4-disulfonate); Pyridoxal phosphate derivatives; Adenine nucleotides; P2Y13 receptor; Inositol trisphosphate; Purines
Strategy, Management and Health PolicyVenture Capital Enabling TechnologyPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IV
The effects of structural modifications of adenine nucleotides previously shown to enhance either agonist (2-thioether groups) or antagonist (additional phosphate moieties at the 3′- or 2′-position) properties at P2Y1 receptors were examined at recombinant rat P2X1, P2X2, P2X3, and P2X4 receptors expressed in Xenopus oocytes. The potency of P2Y1 agonists HT-AMP (2-(hexylthio)adenosine-5′-monophosphate) and PAPET (2-[2-(4-aminophenyl)ethylthio]adenosine-5′-triphosphate) was examined at P2X receptors. Both nucleotides showed a preference for the Group I (α,β-meATP-sensitive, fast-inactivating) P2X sub-units. HT-AMP was 5-fold more potent than ATP at P2X3 receptors and a partial agonist at all except P2X2 receptors, at which it was a full agonist. The efficacy of HT-AMP was as low as 23% at P2X4 receptors. PAPET was a weak partial agonist at rat P2X4 receptors and a nearly full agonist at the other subtypes. At rat P2X3 receptors, PAPET was more potent than any other known agonist (EC50 = 17 ± 3 nM). MRS 2179 (N6-methyl-2′-deoxyadenosine 3′, 5-bisphosphate, a potent P2Y1 receptor antagonist) inhibited ATP-evoked responses at rat P2X1 receptors with an IC50 value of 1.15 ± 0.21 μM. MRS 2179 was a weak antagonist at rat P2X3 receptors, with an IC50 value of 12.9 ± 0.1 μM, and was inactive at rat P2X2 and P2X4 receptors. Thus, MRS 2179 was 11-fold and 130-fold selective for P2Y1 receptors vs. P2X1 and P2X3 receptors, respectively. MRS 2209, the corresponding 3′-deoxy-2′-phosphate isomer, was inactive at rat P2X1 receptors, thus demonstrating its greater selectivity as a P2Y1 receptor antagonist. Various adenine bisphosphates in the family of MRS 2179 containing modifications of either the adenine (P2Y1 antagonists with 2- and 6-substitutions), the phosphate (a 3′,5′-cyclic diphosphate, inactive at P2Y1 receptors), or the ribose moieties (antagonist carbocyclic analogue), were inactive at both rat P2X1 and P2X3 receptors. An anhydrohexitol derivative (MRS 2269) and an acyclic derivative (MRS 2286), proved to be selective antagonists at P2Y1 receptors, since they were inactive as agonist or antagonist at P2X1 and P2X3 receptors.
ion channel; oocytes; purines; ATP derivatives; bisphosphates; deoxyadenosine derivatives
Evidence suggests that diabetes mellitus (DM) is associated with idiopathic pulmonary fibrosis (IPF). According to the new IPF guidelines, high-resolution computed tomography (HRCT) is an essential means of diagnosing IPF. We investigated the relationship between IPF and DM in patients treated between 2003 and 2007. Newly diagnosed IPF patients in large university teaching hospitals in Korea were enrolled from January 2003 to December 2007. We retrospectively analyzed 1,685 patients using the interstitial lung disease (ILD) registry. In total, 299 IPF patients (17.8%) also had DM. The mean age of our subjects was 68.0 ± 9.4 yr. HRCT showed significantly more reticular and honeycomb patterns in IPF patients with DM than in IPF patients without DM (P = 0.014, P = 0.028, respectively). Furthermore, significantly higher incidences of hypertension, cardiovascular diseases, and other malignancies (except lung cancer) were found in IPF patients with DM than in IPF patients without DM. In conclusion, IPF patients with DM are more likely to have the usual interstitial pneumonia (UIP) pattern, including reticular and honeycomb patterns, on HRCT than are those without DM.
Idiopathic Pulmonary Fibrosis; Diabetes Mellitus; High Resolution Computed Tomography
During the last five decades, long-term therapy with immunosuppressive agents such as pulse cyclophosphamide in conjunction with high-dose corticosteroids has enhanced both patient survival and renal survival in patients with diffuse proliferative lupus nephritis. Nevertheless, severe side effects such as infectious complications remain the main cause of morbidity and mortality. Central nervous system aspergillosis is uncommon but life-threatening in lupus patients. In this single-patient case study, carotid aneurysm with sphenoidal sinusitis was suspected when severe epistaxis occurred during cyclophosphamide pulse therapy. With anti-fungal therapy, a graft stent was successfully deployed to the aneurysm and specimens of sphenoidal mucosa showed typical hyphae, indicating aspergillosis. Three months after stopping voriconazole treatment, two cerebral aneurysms that were revealed on MR images were successfully removed by aneurysmal clipping. The patient remained alive at one-year follow-up with lupus nephritis in remission. The rarity and high mortality of aspergillus-related fungal aneurysms have led to most cases being recognized postmortem. However, such aneurysms must be diagnosed early to prevent fatal complications by performing appropriate management such as surgical procedure or endovascular intervention.
Lupus Nephritis; Neuroaspergillosis; Intracranial Aneurysm; Voriconazole; Endovascular Procedure
Cell death is an important process of plant responses to development and biotic/abiotic stresses. In rice plants, PBZ1, a PR10 family protein, has been shown to accumulate in tissues undergoing cell death. However, the function of PBZ1 in cell death remains yet to be demonstrated. Here, we report that exogenous recombinant PBZ1 protein induces cell death in rice suspension-cultured cells (SCCs) and also in leaves of Nicotiana tabacum in a dosedependent manner. This finding was confirmed in vivo in transgenic Arabidopsis lines harboring the PBZ1 gene under the control of a dexamethasone (DEX)-inducible promoter. The DEX-treated leaves of transgenic Arabidopsis induced expression of PBZ1 at transcript and protein levels and showed cell death morphology. TUNEL analysis detected DNA fragmentation, a hallmark of programmed cell death, in rice SCCs treated with the PBZ1 protein. Recombinant PBZ1 protein also exhibited RNase activity and exhibited internalization inside BY-2 cells. Taken together, PBZ1 induces cell death not only in rice, but also in tobacco and Arabidopsis via its RNase activity inside the cell. PBZ1 could be used as a marker to understand the mechanism by which PBZ1 confers the cell death morphology in rice and other model plants.
dexamethasone; PBZ1; PR-10 protein family; programmed cell death; RNase activity; TUNEL
The C-arm fluoroscope is known as the most important equipment in pain interventions. This study was conducted to investigate the completion rate of education on radiation safety, the knowledge of radiation exposure, the use of radiation protection, and so on.
Unsigned questionnaires were collected from the 27 pain physicians who applied for the final test to become an expert in pain medicine in 2011. The survey was composed of 12 questions about the position of the hospital, the kind of hospital, the use of C-arm fluoroscopy, radiation safety education, knowledge of annual permissible radiation dose, use of radiation protection, and efforts to reduce radiation exposure.
In this study, although most respondents (93%) had used C-arm fluoroscopy, only 33% of the physicians completed radiation safety education. Even though nine (33%) had received education on radiation safety, none of the physicians knew the annual permissible radiation dose. In comparing the radiation safety education group and the no-education group, the rate of wearing radiation-protective glasses or goggles and the use of radiation badges or dosimeters were significantly higher in the education group. However, in the use of other protective equipment, knowledge of radiation safety, and efforts to reduce radiation exposure, there were no statistical differences between the two groups.
The respondents knew very little about radiation safety and had low interest in their radiation exposure. To make the use of fluoroscopy safer, additional education, as well as attention to and knowledge of practices of radiation safety are required for pain physicians.
education; fluoroscopy; radiation; radiation monitoring; radiation protection
The primary site of action of pregabalin, i.e. the α-2-δ subunit of the voltage-dependent calcium channel, is located at the dorsal root ganglion and dorsal horn of the spinal cord. Therefore, the epidural administration of pregabalin could have advantages over oral administration. However, the possibility of its neurotoxicity should be excluded before any attempt at epidural administration. We evaluated the neuronal safety of epidurally-administered pregabalin by observing the sensory/motor changes and examining the histopathology of spinal cord in rats.
Sixty rats of 180-230 g were divided into three groups; 3 mg of pregabalin dissolved in 0.3 ml saline (group P, n = 20), 0.3 ml 40% alcohol (group A, n = 20), or 0.3 ml normal saline (group N, n = 20) was administered epidurally to the rats in each group. Pinch-toe test, motor function evaluation, and histopathologic examination of vacuolation, chromatolysis, meningeal inflammation, and neuritis were performed at the 1st, 3rd, 7th, and 21st day after each epidural administration.
All rats enrolled in group P, like those in group N, showed neither sensory/motor dysfunction nor any histopathological abnormality over the 3-week observation period. In contrast, in group A, 80% of the rats showed abnormal response to the pinch-toe test and all rats showed decreased motor function during the entire evaluation period. In addition, all histopathologic findings of neurotoxicity were observed exclusively in group A.
The epidurally administered pregabalin (about 15 mg/kg) did not cause any neurotoxic evidence, in terms of both sensory/motor function evaluation and histopathological examination in rats.
Epidural injection; Neurotoxicity; Pregabalin
Postlaminectomy peridural fibrosis is inevitable. Some studies have compared and identified the effects of high molecular weight hyaluronic acids (HMWHA) and low molecular weight hyaluronic acids (LMWHA) on peridural fibrosis in postlaminectomy animal models. However, no studies have been found that compare pain behaviors between hyaluronic acids or among hyaluronic acids and other solid materials. The purpose of this study was to examine the correlation between pain-related behaviors and histopathologic changes in laminectomized rats using various peridurally administered materials.
Forty male Sprague-Dawley rats, laminectomized at the L5 and L6 levels, were divided into four groups: group C, laminectomy only; group L, laminectomy and LMWHA application; group H, laminectomy and HMWHA application; group F, laminectomy and fat interposition. Pain behaviors were checked before, 3 days, 1 week, and 3 weeks after surgery. Histopathological changes were checked at the L5 level 3 weeks after the surgery.
The 50% withdrawal thresholds in groups L and H were higher than that in groups C and F three days after laminectomy (P < 0.05). The paw withdrawal time did not change among the groups and in each group during the study period. Peridural fibrosis in group F was significantly lower than in the other groups (P < 0.05).
Hyaluronic acids significantly reduced mechanical allodynia but not thermal hyperalgesia. Peridural fibrosis did not show any correlation with pain behaviors. There have been limited studies on the correlation between peridural fibrosis and pain behavioral change, which should be verified by further studies.
allodynia; failed back surgery syndrome; hyaluronic acid; laminectomy
The aims of this study were; 1) to develop the final version of the Korean Roland-Morris Disability Questionnaire (RDQ), and 2) to compare the responsiveness between the RDQ and the Oswestry Disability Index (ODI) scores in patients having low back pain. The psychometric properties of the final Korean RDQ were evaluated in 221 patients. Among them, 30 patients were reliability tested. Validity was evaluated using an 11-point numerical rating scale (NRS) and the Korean ODI. The receiver operating characteristic (ROC) curve analysis of the RDQ and the ODI was compared in 54 patients with lumbar zygapophyseal (facet) joint pain. There was a moderate relationship between the RDQ and NRS (r = 0.59, P < 0.01) and a strongly positive correlation between the RDQ and the ODI (r = 0.76, P < 0.001). The Korean RDQ with the higher area under the ROC curve showed a better overall responsive performance than did the ODI in patients with lumbar facet joint pain after medial branch radiofrequency neurotomy (P < 0.01). The results of the study present the final version of the Korean RDQ is valid for assessing functional status in a Korean population with chronic low back pain.
Low Back Pain; Oswestry Disability Index; Psychometric Properties; Roland-Morris Disability Questionnaire
The P2X7 receptor is associated with the death of many cell types, and growing evidence supports its presence on neurons. Activation of the P2X7 receptor on isolated retinal ganglion cells increases intracellular calcium levels and can kill the cells. Within the intact eye, however, glia and other cell types surrounding the ganglion cells may provide protection and attenuate the effects of receptor stimulation. This investigation thus asks whether stimulation of the P2X7 receptor can actually kill retinal ganglion cells in vivo. Drugs were injected intravitreally into the superior/nasal region of Long Evans rats. Cell survival was determined by counting the number of remaining ganglion cells labeled with aminostilbamidine. The P2X7 receptor agonist BzATP reduced ganglion cell survival as compared to eyes injected with saline solution. Ganglion cell death was inhibited by co-injection of the P2X7 antagonists Brilliant Blue G and MRS 2540. The loss of ganglion cells following activation of the P2X7 receptor was also prevented by the adenosine A3 adenosine receptor agonist MRS 3558. In conclusion, stimulation of the P2X7 receptor can kill retinal ganglion cells in vivo. The neuroprotective effects of A3 activation identified in isolated ganglion cells are also receptor apparent in vivo. This implies that the balance between extracellular ATP and its protective metabolite adenosine can influence ganglion cell survival in the living eye.
P2X receptor; A3 adenosine receptor; purinergic signaling; retinal ganglion cells; neuroprotection; in vivo models