[84] Similarly, most of other investigators have indicated less marked association between the expression of ISGs in PBMCs and treatment PF-6463922 mw outcomes, or IL28B genotype in comparison with in liver of the same patients.[80, 86] Thus, although there are several reports about the association between ISGs in liver or PBMCs and IL28B genotype or response to IFN therapy, the biological pathways linking IL28B genetic variants to spontaneous and/or treatment-induced HCV clearance remain unknown. However, recent reports suggest some possible scenarios. Using primary human hepatocytes or chimpanzee, Thomas et al. found that type III but not type I IFNs are primarily induced after HCV infection and

that their degree of induction

is closely correlated with the levels of ISGs.[87] These results strongly suggest that hepatic IFN-λ production may have important roles and could be a principal driver of ISG induction in response to HCV infection. On the other hand, in chronically HCV-infected chimeric mouse model that have the characteristic of immunodeficiency, larger amounts of IFN-λs on HCV-infected human hepatocytes were produced in liver with a favorable IL28B genotype on treatment with IFN-α.[88] However, no significant differences in HCV-RNA reduction related to IL28B variants were observed because of the lack of intrinsic immune cells in the model. In contrast, Zhang et al. and Yoshio et al. reported that a certain subset Rapamycin price of dendritic cells (DCs) within human PBMCs could recognize HCV and produce large amounts of IFN-λs.[89, 90] The ability of production of IFN-λ3 was superior in subjects with a favorable IL28B genotype.[90] Moreover, IFN-α directly affected DC function and significantly increased IFN-λ production.[89] Based on these findings, it is tempting to speculate that exogenous IFN-α would increase IFN-λ production by DCs and/or HCV-infected hepatocytes during IFN-α therapy, and this Tau-protein kinase could provide a potential explanation as to why

IL28B genetic variants predict the outcome of IFN-α therapy (Fig. 1). Recently, Olsson et al. performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. They discovered that a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG) was strongly associated with HCV clearance. The ss469415590 polymorphism is located upstream of IL28B and is in high-linkage disequilibrium with rs12979860. The ss469415590 ΔG allele is a frameshift variant that creates a novel gene, designated IFNL4, encoding the type III IFN-λ4 protein, which is fairly similar to IFN-λ3. Interestingly, compared with rs12979860, ss469415590 is more strongly associated with spontaneous and treatment-induced HCV clearance in individuals of African ancestry, whereas it did not improve prediction among Caucasians and Asians.

[84] Similarly, most of other investigators have indicated less marked association between the expression of ISGs in PBMCs and treatment GDC-0980 outcomes, or IL28B genotype in comparison with in liver of the same patients.[80, 86] Thus, although there are several reports about the association between ISGs in liver or PBMCs and IL28B genotype or response to IFN therapy, the biological pathways linking IL28B genetic variants to spontaneous and/or treatment-induced HCV clearance remain unknown. However, recent reports suggest some possible scenarios. Using primary human hepatocytes or chimpanzee, Thomas et al. found that type III but not type I IFNs are primarily induced after HCV infection and

that their degree of induction

is closely correlated with the levels of ISGs.[87] These results strongly suggest that hepatic IFN-λ production may have important roles and could be a principal driver of ISG induction in response to HCV infection. On the other hand, in chronically HCV-infected chimeric mouse model that have the characteristic of immunodeficiency, larger amounts of IFN-λs on HCV-infected human hepatocytes were produced in liver with a favorable IL28B genotype on treatment with IFN-α.[88] However, no significant differences in HCV-RNA reduction related to IL28B variants were observed because of the lack of intrinsic immune cells in the model. In contrast, Zhang et al. and Yoshio et al. reported that a certain subset Akt targets of dendritic cells (DCs) within human PBMCs could recognize HCV and produce large amounts of IFN-λs.[89, 90] The ability of production of IFN-λ3 was superior in subjects with a favorable IL28B genotype.[90] Moreover, IFN-α directly affected DC function and significantly increased IFN-λ production.[89] Based on these findings, it is tempting to speculate that exogenous IFN-α would increase IFN-λ production by DCs and/or HCV-infected hepatocytes during IFN-α therapy, and this P-type ATPase could provide a potential explanation as to why

IL28B genetic variants predict the outcome of IFN-α therapy (Fig. 1). Recently, Olsson et al. performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. They discovered that a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG) was strongly associated with HCV clearance. The ss469415590 polymorphism is located upstream of IL28B and is in high-linkage disequilibrium with rs12979860. The ss469415590 ΔG allele is a frameshift variant that creates a novel gene, designated IFNL4, encoding the type III IFN-λ4 protein, which is fairly similar to IFN-λ3. Interestingly, compared with rs12979860, ss469415590 is more strongly associated with spontaneous and treatment-induced HCV clearance in individuals of African ancestry, whereas it did not improve prediction among Caucasians and Asians.

reported their experience in treating 14 patients with pelvic abscesses successfully using EUS-guided drainage. This report support the results of the other published case series, but additionally demonstrating that successful endoscopic drainage could be achieved without fluoroscopic monitoring.9 This is important because the non-fluoroscopic approach can be used at the bedside if patients are too ill to be transferred to a fluoroscopy suite, such as in the intensive care setting. Given the increasing interest in this field, it is timely to critically assess the role of EUS-guided transenteric drainage and how it fits into the overall management of patients see more with intraabdominal/

pelvic fluid collections and BMS-777607 abscesses. Although EUS-guided drainage is less invasive than surgical drainage with lower costs and shorter hospitalization duration,10 specific criteria must be met and important limitations recognized. Surgical and imaging-guided percutaneous drainage have complementary roles, and depending on the nature and type of collections, may be preferred over EUS-guided endoscopic drainage. The following are commonly accepted criteria for endoscopic drainage in clinical practice. Foremost a patient has to be hemodynamically stable before endoscopy can be performed. To be suitable for endoscopic drainage the fluid collection must have

a mature wall and be adjacent/adherent to the gastrointestinal lumen; otherwise a transenteric puncture is akin to creating a free perforation. The collection Teicoplanin must be within the reach of the endoscope; collections around the esophagus, stomach and duodenum, rectal and distal sigmoid colon are potentially drainable but deeper collections cannot be accessed and hence will not be suitable. In terms of the type of collection, the clinical success rate will be highest if it is a completely liquefied collection because it can then be easily drained out across the transenteric stent; success rates for collections with solid debris are significantly

lower and adjunctive procedures, which will be elaborated upon later, are required. In cases where the patient is hemodynamically unstable, or when the collections are outside the reach of the endoscope or lack a well-defined wall, a percutaneous approach would be needed. When there is peritonism, a surgical approach would be required. Apart from bowel preparation being necessary when performing endoscopic drainage across the lower gastrointestinal (LGI) tract, the technical steps for EUS-guided transenteric drainage are similar whether one uses an upper gastrointestinal (UGI) approach to drain intraabdominal collections or a LGI approach to drain pelvic abscesses. The walled-off fluid collection is visualized using EUS.

reported their experience in treating 14 patients with pelvic abscesses successfully using EUS-guided drainage. This report support the results of the other published case series, but additionally demonstrating that successful endoscopic drainage could be achieved without fluoroscopic monitoring.9 This is important because the non-fluoroscopic approach can be used at the bedside if patients are too ill to be transferred to a fluoroscopy suite, such as in the intensive care setting. Given the increasing interest in this field, it is timely to critically assess the role of EUS-guided transenteric drainage and how it fits into the overall management of patients GSK126 molecular weight with intraabdominal/

pelvic fluid collections and CHIR 99021 abscesses. Although EUS-guided drainage is less invasive than surgical drainage with lower costs and shorter hospitalization duration,10 specific criteria must be met and important limitations recognized. Surgical and imaging-guided percutaneous drainage have complementary roles, and depending on the nature and type of collections, may be preferred over EUS-guided endoscopic drainage. The following are commonly accepted criteria for endoscopic drainage in clinical practice. Foremost a patient has to be hemodynamically stable before endoscopy can be performed. To be suitable for endoscopic drainage the fluid collection must have

a mature wall and be adjacent/adherent to the gastrointestinal lumen; otherwise a transenteric puncture is akin to creating a free perforation. The collection Dichloromethane dehalogenase must be within the reach of the endoscope; collections around the esophagus, stomach and duodenum, rectal and distal sigmoid colon are potentially drainable but deeper collections cannot be accessed and hence will not be suitable. In terms of the type of collection, the clinical success rate will be highest if it is a completely liquefied collection because it can then be easily drained out across the transenteric stent; success rates for collections with solid debris are significantly

lower and adjunctive procedures, which will be elaborated upon later, are required. In cases where the patient is hemodynamically unstable, or when the collections are outside the reach of the endoscope or lack a well-defined wall, a percutaneous approach would be needed. When there is peritonism, a surgical approach would be required. Apart from bowel preparation being necessary when performing endoscopic drainage across the lower gastrointestinal (LGI) tract, the technical steps for EUS-guided transenteric drainage are similar whether one uses an upper gastrointestinal (UGI) approach to drain intraabdominal collections or a LGI approach to drain pelvic abscesses. The walled-off fluid collection is visualized using EUS.

These steps are necessary since signature metabolites will PD-0332991 in vivo not be detected by routine methods for bile acid measurement. With Setchell’s methodology

established, we were ready to screen infants with cholestasis. In 1988 male twins who presented with cholestasis and coagulopathy in the first days of life were referred to us for further evaluation. A similarly affected sibling had died at 4 months of age 3 years previously with what was called “idiopathic neonatal hepatitis / giant cell hepatitis.” Our initial evaluation of the twins strongly suggested a defect in bile acid biosynthesis. Setchell’s lab was able to document that their rate of primary bile acid synthesis was reduced, that cholic acid was absent from blood, and that gallbladder bile contained only trace amounts

of bile acids. Urine served as the main route of excretion, with the excreted compounds in the form of Δ4−3-oxo bile acids. This biochemical picture suggested a defect in bile acid synthesis—specifically, a lack of conversion of Δ4−3-oxo intermediates to 3α-hydroxy-5β products, a reaction catalyzed by cytosolic Δ4−3-oxosteroid 5β-reductase[66] (Fig. http://www.selleckchem.com/products/AZD2281(Olaparib).html 5). The presumed pathophysiology of the hepatocellular and bile ductular injury was directly attributed to inadequate synthesis of primary bile acids (cholic) needed to generate bile acid-dependent bile flow, and accumulation of hepatotoxic Δ4−3-oxo bile acids. P-type ATPase These precursors were shown to act as cholestatic agents by inhibiting canalicular adenosine triphosphate (ATP)-dependent bile acid transport, the rate-limiting step in the overall process of bile acid transport across the hepatocyte.[67] Of interest, electron microscopy of the twins liver biopsies revealed abnormal collapsed bile canaliculi, suggesting that maturation of the canalicular membrane and transport system for bile acid excretion requires a threshold concentration of primary bile acids in early

development.[68] This was consistent with studies of fetal rat liver, in which poorly formed bile canaliculi can be demonstrated by histology and immunocytochemistry.[69, 70] Bile canalicular morphologic maturation in the immediate postnatal period correlates with transition and acceleration of bile acid synthesis. This demonstrates the relationship between the pattern and pace of bile acid synthesis in fetal and neonatal rat liver and bile canalicular development. In the analogy to CAH syndromes, we chose to use cholic acid (3α,7α,12α-trihydroxy-5β-cholanoic acid) as replacement therapy to treat these twins with Δ4−3-oxosteroid 5β-reductase deficiency.

Under conventional hypothermic preservation conditions, however, the biological Pritelivir activities of liver grafts are suppressed to unmeasurable levels and the uptake of therapeutic substances is inhibited. To overcome these limitations, we established a new mouse model of liver transplantation including a machine graft perfusion process and achieved an extracorporeal non-hypothermic

period for evaluation and improvement of the graft viability in this study. We developed a new organ perfusion machine in which an oxygenated perfusion of the liver graft can be performed at a wide range of temperatures. The liver graft was harvested with the diaphragm, and the intra-thoracic IVC was clamped to form a closed perfusion pathway. We

adopted William medium E as the perfusate, and oxygenated it with 100% oxygen. After harvesting, a liver graft was connected to the perfu-sion circuit and a graft perfusion was initiated at 4 degrees C. Thereafter the temperature was raised to 25 degrees C and a sub-normothermic graft perfusion was performed for 60 min. The perfusion speed was at RG7204 research buy 2.5ml/min. After the sub-normo-thermic perfusion, the temperature was lowered again, and the graft was detached and prepared at 4 degrees C. Liver transplantation was performed according to Qian’s method. In this model (n=4), the mean oxygen consumption indicated by the difference of the oxygen partial pressure between the inflow and the outflow perfusate was 74.7 mmHg and the mean carbon dioxide production indicated by the carbon dioxide

partial pressure in the outflow perfusate was 0.0 mmHg at 4 degrees C. During sub-normothermic perfusion at 25 degrees C, the mean oxygen consumption and the mean carbon dioxide production were increased to 290.8 mmHg and 5.6 mmHg respectively. All recipient mice that had undergone liver transplantation Interleukin-3 receptor using liver grafts after sub-normothermic machine perfusion at 25 degrees C for 60 min survived more than 7 days (n=4). In conclusion, we confirmed that metabolic activities of liver grafts were kept at substantial levels and evaluable during sub-normothermic machine perfusion, and succeeded in liver transplantation after sub-normothermic machine perfusion preservation. Disclosures: The following people have nothing to disclose: Masato Fujiyoshi, Akinobu Take-tomi Background: We showed previously that preparative hepatic X-irradiation (HIR) before hepatocyte transplantation (HT), followed by mitotic stimulation with triiodothyronine (T3) permits hepatic repopulation. Aim: To circumvent the cardiac side effects of T3, we sought a substitute for repopulating the liver of apolipoprotein-deficient (ApoE-/-) hypercholesterol-emic mice. We tested the hypothesis that transplanting wild-type hepatocytes in HIR-pretreated ApoE-/- mice, followed by administration of GC-1 (a thyroid hormone receptor-b (TR-b) selective agonist), should ameliorate hypercholesterolemia.

Adequate specimen for histological assessment was obtained in 87 patients (93.5%). The sensitivity, specificity, and accuracy in the diagnosis of SMT by EUS-FNA were 91%, 100%, and 94%, respectively. Finally, 51 patients underwent surgery and surgical diagnoses were GIST in 44, leiomyoma in 5, check details schwannoma in 1, and metastatic cancer in 1. Of the 42 patients with surgical diagnosis of GIST, weighted kappa coefficients between FNA and surgical specimens in

modified Fletcher risk classification was 0.92. No procedure-related complication was observed. Conclusion: EUS-FNA using a 19-gauge needle was a safe and reliable procedure to obtain the histopathological diagnosis. It is also useful to assess the risk classification of GIST preoperatively.

Key Word(s): 1. EUS-FNA; 2. GIST Presenting Author: IK MARIADI Additional Authors: IW DARYA, IDN WIBAWA, N PURWADI, IGA SURYADARMA Corresponding Author: IK MARIADI Affiliations: Department of Internal Medicine, Sanglah General Hospital/ Udayana University School of Medicine Denpasar, Indonesia Introduction: Screening populations using endoscopy is impractical and GSK-3 inhibitor expensive. We need a noninvasive method to choose the patient that really need endoscopy. We evaluate the accuracyof gastrin-17 as a tool of screening patientsfor endoscopy. Method: Endoscopy finding wasclassified in 2 category, severe and mild/normal, severe if we found ulcer or tumor in gastric and mild if we found normal, superficial and erosive gastritis. Fasting serum gastrin-17 was determined by standard immunoassays. Receiving operating characteristic (ROC) analysis was used to determine the Fenbendazole best cut-off for gastrin-17 serum test in severe and mild/normal endoscopic feature.

Results: Seventy seven patients underwent endoscopy. Seventy one patients with normal/mild finding and 6 patients with severe finding. Base on nonparametric test with MannWhitney test, we found significant mean different of gastrin-17 between mild/normal and severe group (p = 0.025). Diagnostic accuracy of Gastrin-17 on determining severe finding base on ROC procedure, we found AUC 78% (95% CI: 63%-91%), p = 0.025, with sensitivity and sensitivity are 66.7% and 77.5% at value ≥ 21.75 pg/ml. Conclusion: In dyspepsia patient, Gastrin-17 has anacceptable accuracy in determining severe abnormality on endoscopy and value ≥ 21.75 pg/ml is the best cut off value for screening severe endoscopic feature. Keyword(s): 1. Gastrin-17; 2. endoscopy feature Presenting Author: LUBIS MASRUL Additional Authors: ALAMSYAH SIREGAR GONTAR, HAKIM ZAIN LUKMAN Corresponding Author: LUBIS MASRUL Affiliations: Gastroenterology-Hepatology Division Internal Medicine Department – Haji Adam Malik General Hospital Objective: Endoscopy has been used with increasing frequency in the investigation of upper gastrointestinal symptoms.

1D and Supporting Table 2). We confirmed these results via real-time qRT-PCR and found that coculture

with HMs for 24 hours or for 5 days increased the expression of known NF-κB–regulated genes, including Il6, Saa3, Cxcl5, Cxcl14, Serpinb2, Ch25h, and Mmp13 (Fig. 2A,C). Surprisingly, HMs did not induce classical HSC activation markers such as Col1a1, Col1a2, or Acta2 messenger RNA (mRNA) and did not change α-smooth muscle actin (α-SMA) protein levels in HSCs (Fig. 2C). We confirmed that all NF-κB–dependent genes, including Timp1, were suppressed in the presence of adenoviral IκB superrepressor (Fig. 2A) or by short-term treatment with IKK inhibitor Bay 11-7085 at very low nontoxic concentrations (Supporting Fig. 3). NF-κB activation was further confirmed via Torin 1 nmr p65 immunohistochemistry (Fig. 2D) and immunoblot (Fig. 2E) demonstrating p65 translocation, p65-S536 phosphorylation, and IκBα degradation in HSCs treated with conditioned media from HMs but not after treatment with control media. Similar observations were made in an NF-κB reporter assay, in which coculture with HMs induced a >15-fold increase in NF-κB–driven luciferase activity (Fig. 2F). Based on these results, we focused on the NF-κB pathway in subsequent analyses of mechanisms by which HMs affect HSCs and fibrogenesis. Next, we determined whether HMs alter NF-κB–dependent

gene expression in HSCs in the fibrotic liver by employing a depletion approach. Resveratrol For this purpose, we analyzed gene expression in fluorescence-activated Bafilomycin A1 solubility dmso cell sorting (FACS) ultrapure HSCs isolates that were immediately lysed after isolation and thus provide a “snapshot” of HSC gene expression in the fibrotic liver. NF-κB–dependent gene expression was highly up-regulated in HSCs activated in vivo compared with quiescent HSCs (Fig. 2G). Macrophage depletion by repeated liposomal clodronate injection efficiently reduced F4/80-positive and CD11b- and F4/80-double positive macrophages and ameliorated liver fibrosis following BDL and CCl4 treatment (Supporting

Fig. 4). Notably, macrophage depletion strongly suppressed the expression of the NF-κB–dependent genes that were up-regulated by HMs in our coculture system (Fig. 2G). We further excluded that liposomal clodronate directly affects NF-κB via NF-κB reporter assay and or cell death in cultured HSCs (Fig. 2H,I). Next, we investigated mechanisms through which HMs induce NF-κB activation in HSCs. First, we tested the contribution of interleukin (IL)−1 and TNF to HM-induced NF-κB in HSCs based on their known potent activation of NF-κB, the presence of the IL-1 receptor in the NF-κB network identified by IPA analysis (Fig. 1C), and up-regulated M1 markers inducible nitric oxide synthase and Cox2 in HMs from BDL mice (Supporting Fig. 1C). HMs induced NF-κB to the same degree as rmIL-1β, and to a higher degree than rmTNFα (Fig. 3A).

34 This has led to the adoption of endoscopic surveillance programs in many centers, but the actual benefit of surveillance in terms of cost and survival is still uncertain; it remains a controversial issue.35 The prognosis of established early esophageal adenocarcinoma is dependent on depth of invasion, which in turn determines the risk of lymph node metastasis. Nigro et al. showed that lesions confined to the mucosa had a 7% risk of

lymphatic click here metastasis, whereas 80% of those invading into muscularis propria had spread to lymph nodes.36 This study, as with other early studies of esophageal adenocarcinoma, was small and involved only 37 patients. Since then, larger studies have shown that tumors of the mucosa and the superficial 500 µm (SM1) of the submucosa provide negligible risk of lymph node metastasis. Westerterp and colleagues demonstrated lymph node metastasis in only 1/79 mucosal and SM1 adenocarcinomas, while Stein et al. reported no lymphatic spread in 53 similar cases.37,38 Early squamous cell carcinoma of the esophagus has been much more extensively studied, in part, due to the routine use of endoscopic ablation in Japan. Patients with early squamous cell carcinoma, no lymph node metastasis on computed tomography scan and no evidence of a second primary cancer have been shown to have a similar survival rate as the general population following endoscopic therapy.39 Mucosal and superficial

submucosal squamous cell cancers check details have an excellent prognosis due to low risk of lymph node metastasis. Tajima et al. reported on 240 patients after surgical resection of squamous cell cancer and showed that none of the mucosal or SM1 tumors had metastasized to lymph nodes.40 Stein and colleagues found a higher

rate of lymphatic spread of 7.7%, but this was based on just 26 mucosal/SM1 patients.38 Minimally invasive squamous cell esophageal cancer can be cured endoscopically; early detection is therefore crucial. In this context, the use of high-resolution video-endoscopy with adjuncts, such as chromoendoscopy and narrow-band imaging, are useful technologies. Although the cure rate is high, surveillance after endoscopic therapy is necessary due a significant risk of local MRIP recurrence.41 Data on endoscopic treatment of early esophageal adenocarcinoma are limited; therefore, evidence-based treatment recommendations are not yet available. Although the worldwide incidence of gastric cancer is slowly declining, it is still the fourth most common malignancy and the second most frequent cause of cancer death. Five-year survival is relatively good in Japan at 40–60%, compared to about 20% in Western countries. Over 50% of gastric cancers diagnosed in Japan are early lesions, and this may explain the overall better survival.30,42 Gastrectomy with regional lymph node dissection was formerly the only available curative treatment for early gastric cancer.

[57] Furthermore, as stated by Raddant and Russo,[3] “The inflammatory cascade can GSK458 be triggered by CGRP actions on dural mast cells and satellite glial cells of the trigeminal ganglion. The peripheral CGRP-containing neurons (in the trigeminal ganglion and elsewhere) are polymodal nociceptors that innervate essentially all peripheral tissues and send primary afferent input to the dorsal horn, trigeminal nucleus caudalis, or nucleus of the solitary tract (which, in turn, project to the brainstem, amygdala, hypothalamus, and thalamic nuclei).[48] CGRP-containing neurons in the trigeminal ganglion project to the trigeminal

nucleus caudalis and C1-C2, where CGRP also acts post-junctionally on these second-order neurons to transmit pain signals from the brainstem to the thalamus.[58, 59] The clinical correlation of CGRP actions

at the level of the trigeminal nucleus caudalis is relevant as well. The brainstem has a key role in the pathophysiology selleck chemicals llc of migraine.[60, 61] Brainstem stimulation causes activation of the trigeminovascular system, resulting in peripheral CGRP release and neurogenic inflammation (described earlier).[62, 63] Furthermore, activation of the brainstem is associated with altered perception termed allodynia (a condition in which nonpainful stimulation is perceived as painful) as well as with the development of second- and third-order neuronal sensitization.[64, 65] Accordingly, if we understand migraine as the combined result of altered perception of stimuli that are usually not painful, as well as the activation of TCL a feed-forward neurovascular dilator mechanism in the first (ophthalmic) division of the trigeminal nerve, we realize that CGRP is involved in the pathophysiology of migraine both centrally and peripherally.[66] CGRP and its receptors are widely distributed across other parts of the CNS as well, in areas that are relevant to pain and in areas that may not be, such as the cerebellum.[67, 68] The function of CGRP in these areas is not well understood. Studies have suggested that CGRP

is expressed in areas that could explain migraine-related photophobia.[69] In a model of transgenic mice, light-aversive behavior was greatly enhanced by intracerebroventricular injection of CGRP and blocked by coadministration of the CGRP-RA olcegepant.[70] Finally, CGRP seems to be important in determining neuronal plasticity and synapse formation. This is either due to its direct actions on neurons or its indirect actions on the glia via its modulatory actions.71-73 In summary, CGRP and its receptors are largely expressed in neurons and glia, both peripherally and centrally. As discussed later, this broad expression has relevance for drug development. Pain improvement can be achieved by blocking CGRP peripherally, centrally, or both, and brain penetration may not be essential for the analgesic properties of CGRP antagonists.