Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor

Mast cells are the major effector-cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels on stimulation through the high-affinity receptor for immunoglobulin E (IgE; FcepsilonRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FcepsilonRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production on FcepsilonRI stimulation. Analysis of 4-1BB ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca2+ flux induced by FcepsilonRI stimulation. The defective Ca2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-gamma2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FcepsilonRI-inducible 4-1BB plays a costimulatory function together with FcepsilonRI stimulation.     

Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy

Castleman's disease, an atypical lymphoproliferative disorder, can be classified into 2 types: hyaline-vascular and plasma cell types according to the histologic features of the affected lymph nodes. The plasma cell type is frequently associated with systemic manifestations and is often refractory to systemic therapy including corticosteroids and chemotherapy, particularly in multicentric form. Dysregulated overproduction of interleukin-6 (IL-6) from affected lymph nodes is thought to be responsible for the systemic manifestations of this disease. Therefore, interference with IL-6 signal transduction may constitute a new therapeutic strategy for this disease. We used humanized anti-IL-6 receptor antibody (rhPM-1) to treat 7 patients with multicentric plasma cell or mixed type Castleman's disease. All patients had systemic manifestations including secondary amyloidosis in 3. With the approval of our institution's ethics committee and the consent of the patients, they were treated with 50 to 100 mg rhPM-1 either once or twice weekly. Immediately after administration of rhPM-1, fever and fatigue disappeared, and anemia as well as serum levels of C-reactive protein (CRP), fibrinogen, and albumin started to improve. After 3 months of treatment, hypergammaglobulinemia and lymphadenopathy were remarkably alleviated, as were renal function abnormalities in patients with amyloidosis. Treatment was well tolerated with only transient leukopenia. Histopathologic examination revealed reduced follicular hyperplasia and vascularity after rhPM-1 treatment. The pathophysiologic significance of IL-6 in Castleman's disease was thus confirmed, and blockade of the IL-6 signal by rhPM-1 is thought to have potential as a new therapy based on the pathophysiologic mechanism of multicentric Castleman's disease. (Blood. 2000;95:56-61)     

Conversion of G-protein specificity of insulin-like growth factor II/mannose 6-phosphate receptor by exchanging of a short region with beta-adrenergic receptor.

The 14-residue peptide (peptide 14) corresponding to Arg2410-Lys2423 of the insulin-like growth factor II receptor (IGF-IIR) can activate the adenylate cyclase-inhibitor guanine nucleotide-binding protein Gi, and the 15-residue beta III-2 peptide Arg259-Lys273 of the beta 2-adrenergic receptor (beta 2AR) can activate the stimulatory protein Gs. In phospholipid vesicles, IGF-IIR and beta 2AR activate Gi and Gs in response to IGF-II and isoproterenol, respectively. We constructed a chimeric IGF-II receptor (beta III-2/IGF-IIR) by converting its native peptide 14 sequence to the beta III-2 sequence. In cells expressing beta III-2/IGF-IIR, membrane adenylate cyclase activity markedly increased without IGF-II and was further promoted by IGF-II. This was verified by measuring chloramphenicol acetyltransferase (CAT) activity in beta III-2/IGF-IIR cells with cotransfection of a cAMP response element-CAT construct. This study shows not only the conversion of G-protein specificity of a receptor from Gi to Gs but also the simulation of G protein-coupled receptor signals by using a short receptor region and intact cells. These findings indicate that the G protein-activation signals are interchangeable, self-determined structural motifs that function in the setting of either a single-spanning or multiple-spanning receptor.     

OFIRMEV: An Old Drug Becomes New Again

This was judged to be the first place winning submission for the American Dental Society of Anesthesiology Student Essay Award.Acetaminophen is an old drug that is now available in an intravenous formulation. Its advantages and disadvantages are reviewed, including its potential role in multimodal postoperative pain therapy.Key Words: Intravenous acetaminophen, Postoperative pain control, Multimodal analgesiaEffective treatment of acute postoperative dental pain often requires a multimodal pain management approach—the use of multiple complementary analgesics with different mechanisms and sites of action—as a means of optimizing analgesic efficacy and reducing opioid-related adverse effects.^1,2 The American Society of Anesthesiologists Task Force on Acute Pain Management advocates that unless contraindicated, patients should receive an around-the-clock regimen of nonopioid analgesics as first-line agents and for opioids to be used as adjunctive agents.³ The choices of medication, dose, route, and duration of therapy are determined by the practitioner and should be individualized taking into consideration the patient''s medical history and physical health and the surgical procedure being performed.³A new component in such a multimodal analgesic strategy is OFIRMEV (Cadence Pharmaceuticals, San Diego, Calif), an intravenous (IV) formulation of acetaminophen approved by the US Food and Drug Administration in 2011 for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever in patients 2 years and older.⁴Although IV acetaminophen is relatively new in the US, the same formulation has been used extensively in over 80 countries since 2002.⁵ Evidence from randomized clinical trials has found IV acetaminophen to be a safe, effective, and well-tolerated analgesic agent in the treatment of acute postoperative pain associated with a number of surgical procedures, including third-molar extraction and orthognathic surgery.^6,7 The goal of this paper is to examine the potential role of IV acetaminophen in dentistry.Acetaminophen, alone or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids, has been the primary and most effective analgesic therapy for the management of postoperative dental pain.^8,9 The popularity and acceptance of acetaminophen are attributed to its relative safety and effectiveness.⁸ Acetaminophen is not associated with postoperative bleeding, gastric mucosal damage, dyspepsia, or renal injury seen with NSAIDs, nor does it cause the respiratory depression, nausea, vomiting, constipation, urinary retention, and sedation seen with opioids.^10,11 The most important safety concern with acetaminophen is the potential for hepatotoxicity when it is used at higher than recommended doses (>4000 mg/d for adult patients)^4,10 Compared to oral acetaminophen, IV acetaminophen reduces initial hepatic exposure by approximately twofold because of the lack of first-pass metabolism.^7,10 Reduced hepatic exposure of IV acetaminophen thus improves its safety profile and may be of benefit to patients with compromised hepatic function.¹⁰ Nevertheless, caution must be used when administering IV acetaminophen to patients with liver dysfunction or active liver disease, alcoholism, chronic malnutrition, severe hypovolemia, or severe kidney dysfunction.⁴ IV acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease.⁴ The most common treatment-emergent adverse events associated with IV acetaminophen are nausea, vomiting, headache, and insomnia.⁴ Because of its more favorable risk/benefit profile, acetaminophen may be considered the foundation analgesic in multimodal pain management.^9,12–14Dentists can administer analgesics in a variety of ways, with safety, efficacy, speed of onset, ease of administration, and cost being important factors to consider in the drug and route of administration used. Nonopioid analgesics are most often given via the oral route; however, many surgical patients are restricted from oral intake or unable to take oral medications because of sedation or postoperative nausea and vomiting.^10,15,16 The oral route may also be less efficacious because intraoperative opioids, inhaled anesthetics, and surgical stress can delay gastric emptying, thereby reducing gastrointestinal absorption of orally administered drugs.^17,18 Intravenous administration of acetaminophen would be an ideal route in the immediate postoperative period, especially in situations where a patient is unable to take medications by mouth or when a faster onset of analgesia is desired.^10,11 IV acetaminophen is dispensed as a 100-mL single-use vial containing 1000 mg acetaminophen and is given over 15 minutes as an IV infusion.⁴The primary analgesic effect of acetaminophen is thought to be due to a central nervous system site of action involving cyclooxygenase (COX) inhibition.^5,10 Passive diffusion of acetaminophen into the central nervous system appears to be enhanced by a high plasma to cerebrospinal fluid (CSF) concentration gradient, with acetaminophen concentrations in the CSF being linearly dose proportional with plasma levels.¹⁹ IV acetaminophen has been shown to achieve higher maximum concentrations and earlier time to maximum concentration compared to bioequivalent oral doses with less intrasubject variability.^{15,16,20–22} Mean maximum concentration after a standard 15-minute infusion of 1 g acetaminophen is approximately 70% higher than the mean maximum concentration observed at equivalent oral doses.²² Peak CSF plasma concentrations of IV acetaminophen are 60% higher than with oral administration.²² Time to maximum concentration for IV acetaminophen occurs at the end of the 15-minute infusion compared to >45 minutes with oral acetaminophen.^4,22 The earlier and higher peak plasma and CSF maximum concentrations observed with IV acetaminophen may be responsible for the more rapid onset and higher peak efficacy of IV acetaminophen compared with oral acetaminophen.²² It is important to note that the higher peak concentrations achieved by IV acetaminophen remain far below the concentration considered the threshold for potential hepatotoxicity; therefore, there is no compromise in safety when administering acetaminophen intravenously.^11,15After oral surgical procedures, postoperative pain is most severe 3–5 hours following surgery and improves gradually over time.^23,24 Rapid onset of analgesic action is critical, as studies suggest that preemptively blocking postoperative pain can limit the initiation of central pain receptor sensitization, resulting in a decrease in overall pain perception, pain duration, and need for opioid analgesics.¹³ Onset of the analgesic effect of IV acetaminophen is rapid. In a randomized, double-blinded, placebo-controlled trial comparing the onset of analgesia between equivalent doses of oral and IV acetaminophen in patients with moderate to severe pain after impacted third-molar extraction, IV acetaminophen provided a clinically significant faster onset of meaningful pain relief (8 minutes IV vs 37 minutes oral) and decreased time to achieving maximal pain relief (15 minutes IV vs 1 hour oral).¹⁵ The analgesic effect of IV acetaminophen lasts for 4–6 hours.⁴ IV acetaminophen has also been shown to be superior to oral acetaminophen in reliably obtaining therapeutic concentrations and maintaining higher plasma concentrations.²⁵ In a study comparing plasma levels achieved in the early postoperative period by equivalent doses of oral and IV acetaminophen, 96% of patients given IV acetaminophen achieved therapeutic plasma concentrations versus only 67% of patients receiving an oral dose.^10,25The efficacy of IV acetaminophen in managing postoperative pain and decreasing the need for opioids has been demonstrated in a number of randomized placebo-controlled trials.^6,7 Compared with other analgesics in the treatment of moderate to severe postoperative pain, IV acetaminophen 1 g has a comparable efficacy to ketorolac 30 mg after total hip or knee replacement, diclofenac 75 mg after orthognathic surgery or orthopedic surgery, metamizol 2.5 g after aortic aneurysm repair, and morphine 10 mg after surgical removal of impacted third molar.^14,16,26 In patients who had undergone surgical third-molar extraction complaining of moderate to severe postoperative pain, the use of a 1 g dose of IV acetaminophen was compared with that of a 2 g dose of IV acetaminophen and with placebo.^15,16 In this study, both active treatment groups provided more effective and longer duration of analgesia and better scores on patients'' global evaluation (ie, good–excellent) compared to placebo.¹⁶ In another controlled study, acetaminophen administered intravenously as its prodrug propacetamol 2 g (equivalent to acetaminophen 1 g) was shown to have an analgesic effect indistinguishable from that of intramuscular morphine (10 mg) with better tolerability.²⁶Postoperative nausea and vomiting is a common and unpleasant adverse effect associated with dental surgery performed under IV sedation or general anesthesia, with reported incidence rates between 20 and 30%.²⁷ Postoperative nausea and vomiting is associated with increased morbidity (ie, bleeding, hematoma, wound dehiscence, aspiration) that may prolong recovery or result in unanticipated hospital admissions.²⁷ Decreasing opioid consumption has been suggested as the most effective, safest, and least expensive way to reduce opioid-related adverse effects.^11,27 Although systematic reviews and meta-analyses show that IV acetaminophen used in combination with patient-controlled opioid analgesia may reduce opioid requirements by 20–30%, these reductions in dose do not consistently translate into reduced incidence of opioid-related postoperative nausea and vomiting.^6,7,10Until the introduction of IV acetaminophen, the only other nonopioid injectable analgesics available in the US were NSAIDs: IV ketorolac and IV ibuprofen (Caldolor, Cumberland Pharmaceuticals Inc).^5,28 The pathogenesis of dental pain is primarily inflammation. Thus, NSAIDs have been described as being more effective analgesics in treating dental pain than acetaminophen and opioids, which lack anti-inflammatory action.^23,29 NSAIDs produce their analgesic and anti-inflammatory effects by inhibiting COX isoenzymes COX1/COX-2 and blocking peripheral and central production of prostaglandin.^11,29 Analgesic and anti-inflammatory effects of NSAIDs are primarily due to inhibition of COX-2, whereas the adverse effects (ie, renal dysfunction, gastrointestinal mucosal damage, platelet inhibition) are mediated by inhibition of COX-1.^11,29 The specificity of individual NSAIDs for the COX isoenzymes differs and has significant implications in terms of analgesic potency and incidence of adverse effects.²⁹ IV ketorolac, a preferential COX-1 inhibitor, is currently the IV nonopioid analgesic of choice in the US due to its efficacy and low cost.⁵ Due to its high degree of COX-1 selectivity, IV ketorolac is only approved for use in adult patients for the short-term (5 days or fewer) management of moderate to severe pain requiring analgesia at the opioid level; its use prior to major surgery and intraoperatively is contraindicated.⁵ IV ibuprofen is indicated for use only in adults for the management of mild to moderate pain, management of moderate to severe pain as an adjunct to opioid analgesics, and reduction of fever.^28,29 IV ibuprofen has a safer clinical profile than ketorolac due to its more balanced affinity for COX-1/COX-2 and is approved for preoperative administration with no limitations on its duration of use.^28,29 Nevertheless, all NSAIDs carry risks of serious gastrointestinal, cardiovascular, renal, and bleeding adverse effects.⁵ In situations where IV NSAIDs are not approved (ie, pediatric patients) or not clinically appropriate (ie, patients with history of peptic ulcer disease, renal disease, or surgeries with a high risk of postoperative bleeding), IV acetaminophen can serve as a viable alternative when an IV route of administration is needed.^10,28,29For many outpatient dental procedures performed under general anesthesia or IV sedation, IV acetaminophen administered in the immediate postoperative period may provide sufficient analgesia to address mild to moderate pain, obviating the need for or decreasing NSAID and opioid dosing and their associated side effects.^5,10,11 The primary advantage of IV acetaminophen is as a means to provide nonopioid analgesia in patients with mild to moderate pain in whom the oral route is not possible and IV NSAIDs are contraindicated. IV acetaminophen provides a method of achieving rapid therapeutic concentrations that can subsequently be maintained by oral acetaminophen.^30,31 In conclusion, IV acetaminophen is a new IV nonopioid analgesic, which may find a role in dentistry for the management of postoperative pain.     

Crohn’s Disease Successfully Treated With Infliximab in a Patient Receiving Hemodialysis: Case Report and Review of the Literature

There is limited information in the use of antitumor necrosis factor α, infliximab, in patients on hemodialysis. In Crohn’s disease (CD), only 3 cases are reported.A 76-year-old man on hemodialysis for renal failure caused by immunoglobulin A nephropathy developed diarrhea and abdominal pains. A marked edema was observed in the pretibia and ankle. An increase of C-reactive protein (CRP) and erythrocyte sedimentation rate, hypoalbuminemia, hypocholesterolemia, and moderate anemia was found. Ultrasonography and computed tomography (CT) found wall thickness in the left colon. Sigmoidoscopy revealed multiple ulcers in the sigmoid colon and noncaseating epithelioid granuloma was found in the biopsy specimen. Barium enema study exhibited collar button signs and longitudinal ulcers in the left colon.A severe form of CD was diagnosed. Metronidazole seemed to decrease CRP but was ineffective in ameliorating diarrhea. Infliximab rather than steroid hormone was chosen for the treatment. Standard induction therapy with infliximab was initiated. Symptoms rapidly improved then disappeared. CD activity index decreased from 747 to a remission level of 134 after 2 infusions of infliximab. Scheduled maintenance infliximab therapy was administered after the induction therapy. Ultrasonography and CT showed a disappearance of the wall thickness of the colon. Adverse reactions were not observed.Infliximab was effective and safe in a patient with CD on hemodialysis. Our case has added additional literature in accordance with previous reports supporting infliximab as effective and safe in patients on hemodialysis.     

Adrenocortical Carcinoma Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration

Adrenocortical carcinoma (ACC) is a rare malignancy with a very poor prognosis. A 77-year-old man underwent imaging studies due to poorly controlled hypertension, which revealed a mass measuring 43 mm in diameter near the left adrenal gland. There were no findings indicative of pheochromocytoma. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) was performed for the preoperative pathological evaluation, and the findings indicated a possibility of ACC. Based on these results, curative surgery was performed. If the diagnosis of pheochromocytoma is excluded, then EUS-FNA for adrenal lesions is relatively safe. It can also be used for the preoperative diagnosis of ACC.     

Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab

Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.     

Age-related changes of the function of T cell subsets: predominant defect of the proliferative response in CD8 positive T cell subset in aged persons

The proportion of CD8 positive cells in the peripheral blood AET-rosette forming T cells from aged persons was significantly reduced than that from young persons. The difference in the proportion between aged and young groups became more significant after proliferative response to a mitogen phytohemagglutinin (PHA) or a specific antigen tuberculin active peptide (TAP). The purified macrophage-deprived T cells (Twp), CD4 (T4) positive cells or CD8 positive cells were prepared from aged or young persons. These cell preparations lost proliferative response to PHA or TAP but showed marked proliferative response to the combined stimulation to 1 microM of ionomycin and 1 nM of phorbol-12-myristate-13-acetate (PMA) at usual culture cell density (2.5 X 10(5)/ml). Proliferative responses of these cell preparations to the combined stimulation were significantly reduced in the aged than those in the young and the magnitude of the difference in the proliferative responses between aged and young groups was more pronounced in CD8 positive cell population than in CD4 positive cell population. Although the cell preparations were relatively independent of exogenous IL-2 for the proliferative response to the combined stimulation of ionomycin and PMA at usual culture cell density, they needed exogenous IL-2 for sustained proliferation at lower culture cell density (5 X 10(3)/ml). These IL-2-dependent proliferative responses to the combined stimulation in the aged were significantly lower than those in the young and again the difference in the proliferative magnitude between aged and young groups was greater in CD8 positive population. The mechanism(s) of age-related change of the proportion and proliferative ability of T subsets were discussed.     

All-trans-retinoic acid inhibits the development of mesangial proliferative glomerulonephritis in interleukin-6 transgenic mice

All-trans-retinoic acid (ATRA), a vitamin A derivative, was reported to suppress the interleukin-6 (IL-6) production and to downregulate the IL-6 receptor (IL-6R) and/or its signal transducer glycoprotein 130. We investigated the in vivo antinephritic effect of ATRA on IL-6 transgenic mice which had developed mesangial proliferative glomerulonephritis (PGN) as well as its in vitro inhibitory effect on the proliferation of rat mesangial cells. In vivo experiments on IL-6 transgenic mice showed that ATRA administration suppressed proteinuria and hematuria and reduced the IL-6 concentrations; furthermore, histological examination demonstrated that it improved PGN. In vitro experiments using rat mesangial cells demonstrated that ATRA inhibited cell growth in a dose-dependent manner within a range from 10(-4) to 10(-6) M. This inhibition by ATRA was partially counteracted by the addition of IL-6. RT-PCR assay results showed that ATRA also reduced IL-6R, but not the glycoprotein 130 expression in mesangial cells. These findings indicate that, by blocking of the IL-6 function, ATRA may be therapeutically effective in PGN.     

Sensitivity and accuracy in recording His-Purkinje activity by surface-averaged electrocardiography

A clinical evaluation of the surface-averaged ECG (SAE) to record His-Purkinje activity (HPA) was made on 70 patients who underwent His bundle electrograms (HBE). The recorded signals first judged as HPA in 43 patients by the noninvasive method alone were later verified in 37 patients by HBE; the accuracy of the HPA recordings (predictive value) was 86.0%. The HPA-V interval measured noninvasively had a high correlation with the HV interval by HBE (r = 0.89, p less than 0.01). The verified detection rate in all 70 patients was 52.9%: HPA was detected in 12 of 18 patients (66.7%) with sclerotic and hypertensive heart disease (Group I), five of 19 patients (26.3%) with rheumatic heart disease (Group II), 11 of 17 patients (64.7%) with congenital heart disease (Group III), and nine of 16 patients (56.2%) with miscellaneous conditions (Group IV). The detection rate was markedly lower in Group II than in other groups (Group II vs Group I or III, p less than 0.025). The PR segment was significantly longer in the patients in whom HPA was detected than in those in whom it was not detected (71.5 +/- 22.3 msec vs 43.9 +/- 19.5 msec, p less than 0.001). His-Purkinje activity (HPA) was detected in 32 of 52 recordings (61.5%) with sinus rhythm and seven of 20 recordings (35.0%) with atrial fibrillation, including two recordings in each of two cardioverted patients (p less than 0.05). We conclude that the surface-averaged ECG (SAE) has clinically acceptable sensitivity and accuracy except in patients with rheumatic heart disease, short PR segments or atrial fibrillations.