Type 4 cyclic nucleotide phosphodiesterases (PDE4) are a family of low km 3',5'-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterases including at least 20 isozymes encoded by four genes (PDE4A, PDE4B, PDE4C, and PDE4D) in mammals. Each PDE4 gene plays a special, nonredundant role in the control of cell function even though the four subfamilies share the highly conserved catalytic domain and upstream conserved region (UCR) 1 and UCR2 motifs of the regulatory domain. By their wide tissue distribution as well as differential expression and regulation among various cell types, PDE4s are viewed as critical regulators of intracellular cAMP levels, cAMP signaling, and signal compartmentalization. By increasing cAMP levels, PDE4 inhibitors show a broad spectrum of anti-inflammatory effects in almost all inflammatory cells. Many PDE4 inhibitors have been evaluated in clinical trials for various inflammatory conditions. Developed inhibitors, including the recently approved and marketed roflumilast, have considerable efficacy, but they also have adverse effects such as nausea and emesis which limit their dosing and subsequently their immunomodulatory activity. Thus, the development of PDE4 inhibitors with improved therapeutic indexes has been a major focus of pharmaceutical research for the treatment of chronic inflammatory diseases. Recent PDE4 gene knockout studies strongly suggest that PDE4 inhibitors with PDE4B selectivity may retain the anti-inflammatory effects while limiting side effects. Development of PDE4 inhibitors with different delivery routes, such as topical application and inhalation, is also a promising approach for the treatment of pulmonary inflammatory conditions and dermatitis. This review includes a brief overview of the domain structure and function of PDE4 isozymes, the role of PDE4s in inflammatory cell responses, and the potential therapeutic utility of PDE4 inhibitors in inflammatory diseases.

The formation and deposition of β-amyloid (Aβ) plaques are the earliest pathological changes in Alzheimer's disease (AD). Molecular imaging of Aβ plaques could serve as a surrogate marker in early diagnosis and neuropathogenesis studies of AD. Several radionuclide labeled ligands have recently been developed for noninvasive visualization of Aβ plaques in the brains of AD patients using single photon emission computed tomography or positron emission tomography (PET). There has been rapid progress in the field of imaging for plaque pathology. AV-45 was the first plaque imaging agent to enter multi-center, investigational new drug clinical trials in the US, and has now been studied in dozens of trials with more than 1,000 subjects ranging from cognitively normal individuals to those with AD dementia. "Imaging to autopsy" phase III studies further confirmed and validated the specific imaging signal correlated to the plaque burden in living subjects. With these promising and confirmed characteristics of AV-45, the Alzheimer's Disease Neuroimaging Initiative (ADNI) under common consensus decided on AV-45 as the emerging standard PET imaging agent for evaluating the progression of plaque pathology in patients with AD or mild cognition impairment, and even healthy controls. With the wide availability of AV-45 for plaque imaging, the ultimate goal of the ADNI is global clinical trials for disease detection and progression. This review presents recent experience with Aβ-targeting radiotracers at Chang Gung University and Chang Gung Memorial Hospital.

In recent years, there has been increasing interest by reconstructive surgeons in improving the aesthetic and functional outcomes of donor sites. As the success rate of free tissue transfers has exceeded more than 95% in most microsurgical centers, more emphasis can be shifted to the donor site. However, morbidities of donor sites can occur not only in free tissue transfers, but in locoregional flaps as well. In reconstructive procedures, the main principle is to mobilize normal tissue and utilize it to reconstruct an area of defect. The donor site, of course has no pathology, but is a previously healthy area. Therefore, it is of paramount importance to not only minimize postoperative complications at recipient sites, but also pay attention to donor sites. Just as in organ transplantation where efforts are made to ensure the safety and a good outcome for a donor patient, outcomes should be improved and morbidity reduced at donor sites in reconstructive surgery.

Background: Varicella-zoster virus (VZV) is the etiologic agent of two diseases, varicella (chicken pox) and zoster (shingles). Varicella is a self- limited infection, while zoster is mainly a disease of adults. The present study was conducted to isolate VZV from clinically diagnosed children using cell cultures and compare the activity of liquorice powder extract, an alternative herbal antiviral agent, with acyclovir and interferon alpha 2a (IFN-α2a) against the isolated virus. Methods: Forty-eight VZV specimens, 26 from vesicular aspirates and 22 from vesicular swabs, from children clinically diagnosed with varicella were isolated on the Vero cell line. Isolates were propagated and identified with specific antiserum using indirect immunofluorescence and immunodot blotting assays. The growth kinetics of the viral isolates was studied. The antiviral activity of liquorice powder extract, acyclovir (ACV) and IFN-α2a was evaluated against the isolated virus. Results: VZV was successfully isolated in 4 of the 48 specimens, all from vesicular aspirates. The growth kinetics of the viral isolates was time dependent. The inhibitory activity of liquorice powder extract (containing 125 μg/ml glycyrrhizin) when compared to ACV (250 μg/ml) and IFN-α2a is the lowest. Conclusions: VZV isolates were successfully isolated and propagated using Vero cells. Isolates were identified using indirect immunofluorescent and immunodot blotting techniques. Growth kinetics of the isolates revealed an increase in the viral infectivity titer relative to time. Glycyrrhizin in the crude form has low antiviral activity against VZV compared with acyclovir and interferon.

Background: To investigate the effectiveness of histological examination of ulcer margins (HEUM) in detecting Helicobacter pylori (H. pylori) infection in patients with non-bleeding gastric ulcers (GUs). Methods: A retrospective study included 284 patients with GU undergoing concomitant HEUM and rapid urease test (RUT) to detect H. pylori infection between January 2005 and December 2006. The slides were reviewed by an experienced pathologist (revised HEUM) in the 52 patients with inconsistent results on the initial HEUM and RUT. H. pylori infection was defined as a postive RUT and/or revised HEUM. Detection rates of H. pylori infection for HEUM and RUT were calculated accordingly. In patients with H. pylori infection, several parameters including ulcer characteristics and pathological findings were compared between patients with negative and positive (revised) HEUM. Results: A total of 164 (57.7%) patients had positive results of H. pylori infection. The overall detection rates of H. pylori infection on the initial HEUM, revised HEUM and RUT were 78.0% (128/164), 89.0% (146/164), and 94.5% (155/164), respectively. For antrum ulcers, the respective detection rates were 81.0% (85/105), 92.4% (97/105), and 93.3% (98/105), for angulus ulcers, 78.6% (22/28), 85.7% (24/28), and 100% (28/28), and for proximal stomach ulcers, 61.9% (13/21), 81.0% (17/21), and 90.4% (19/21). In patients with H. pylori infection, gastric malignancy was more frequently observed in patients with false negative than true positive HEUMs. Conclusions: HEUM might be not sensitive enough for diagnosing H. pylori in patients with GU. It was especially insensitive when the ulcers were in the proximal stomach, the ulcers were malignant, or the slides were interpreted by pathologists in a rotating manner.

Background: To investigate the role of radiotherapy (RT) for upper urinary tract urothelial cell carcinoma (UTUC) after surgery. Methods: Between July 1997 and February 2007, 40 patients who had undergone radical surgery and RT were selected. Twenty patients received RT as adjuvant treatment for advanced disease (PORT). The remainder received RT as salvage treatment (SART). The prescription dose of RT ranged from 32 to 66.6 Gy (median: 50 Gy). Cisplatin-based chemotherapy was given to 34 patients. The median follow-up was 61 months (22 – 93 months). Results: At the time of analysis, 10 patients were alive, but two of them had tumor recurrence. Twenty-four patients died from disease recurrence, two died from chemotherapy-related complications, and two from non-cancer comorbidities. Two patients were lost to follow-up but one of them had tumor recurrence. The 3-year overall survival (OS) was 45% for the PORT group, and 16% for the SART group (p = 0.03). The 3-year progression-free survival (PFS) was 41% for the PORT group, and 12% for the SART group (p = 0.02). A prescription dose < 50 Gy (p = 0.02) was another poor prognostic factor. The 3-year OS was 38% for a prescription dose ≥ 50 Gy, and 18% for < 50 Gy (p = 0.06). The 3-year PFS improved from 7% to 41% if the prescribed dose was ≥ 50 Gy (p < 0.05). Conclusion: According to our analysis, RT combined with chemotherapy is effective in the postoperative treatment of advanced disease and salvage treatment for recurrent UTUC. The prescription dose should be ≥ 50 Gy.

Background: Intraocular pressure (IOP) measurements are affected by the central cornea thickness (CCT). The conventional method for CCT measurement is ultrasonic pachymetry. However, noncontact procedures lower the risk of infection and corneal damage. In this study, we compared the CCT measured by Orbscan II, SP3000P, and ultrasonic pachymetry in patients with glaucoma or glaucoma suspect. Methods: The CCT of 208 eyes (46 eyes with glaucoma suspect, 42 with primary angle-closure glaucoma, and 120 with primary open-angle glaucoma) was measured using Orbscan II, SP3000P, and ultrasonic pachymetry. We compared the linear correlation of the CCT between each mode. Results: The mean CCT measured by Orbscan II (563.63 ± 35.867 μm) was larger than with the other two devices. There were significant linear correlations between measurements with ultrasonic pachymetry and Orbscan II (Pearson correlation coefficient (r) = 0.793, p < 0.001), ultrasonic pachymetry and SP3000P (r = 0.890, p < 0.001), and Orbscan II and SP3000P (r = 0.803, p < 0.001). We divided the participants into 3 groups on the basis of the CCT measured with ultrasonic pachymetry: ≤ 500 μm, > 500 μm to ≤ 578 μm, and > 578 μm. There was no significant linear correlation between ultrasonic pachymetry and Orbscan II in the thin group. But, in the intermediate and thick CCT groups, there were significant linear correlations between each of the three devices. Conclusion: We showed good linear correlations of CCT measurements between each of 3 devices, especially in the intermediate and thickest CCTs. These results will be helpful in predicting the relationship between IOP and CCT for the diagnosis and screening of glaucoma; even we used optic systems.

Background: Pathology of the long head of the biceps tendon (LHB) is commonly associated with rotator cuff tears (RCTs). Superior labral anterior-posterior (SLAP) lesions can also occur with RCTs. The purpose of this study was to include SLAP lesions as part of LHB pathology in surgical cases of RCT and define the role of SLAP lesions in RCTs. Methods: We retrospectively evaluated clinical data from 176 cases of complete RCT undergoing surgery. During surgery, the LHB was arthroscopically examined. A modified 6-type classification was used to describe the LHB pathology in these cases: tendinitis, subluxation, dislocation, partial tear, complete rupture and SLAP lesions. The relationship of LHB pathology to different characteristics of RCTs was statistically analyzed. Results: Of RCT cases, 33% had Type 1 (tendinitis), 11% had Type 2 (subluxation), 9% had Type 3 (dislocation), 16% had Type 4 (partial tear), 7% had Type 5 (complete rupture) and 6% had Type 6 (SLAP) lesions. The remaining 18% of cases had no obvious LHB pathology. LHB pathology were associated with RCTs of a long duration (> 3 months), large area (> 5 cm2), and multiple or subscapularis tendon involvement. Seventy four percent of patients with affected shoulders underwent simultaneous surgery for both LHB pathology and RCTs. Conclusion: Most patient with RCTs with chronic, massive, and multiple or subscapularis tendon involvement also had LHB injury. SLAP lesions, which we classified as a subgroup of LHB pathology, should be identified during rotator cuff surgery and treated appropriately.

Background: This study aimed to present experience in treating patients with posterior fossa epidural hematoma (PFEDH) and to discuss the risk factors, clinical features, and outcome in PFEDH patients with acute clinical deterioration (ACD). Methods: Twenty-seven patients with PFEDH initially treated conservatively were evaluated. A comparison was made between patients with and without ACD during hospitalization. Results: Eight of the 27 patients subsequently experienced ACD. Local traumatic findings, loss of consciousness due to injury, headache, and vomiting were the four most common clinical features of the 27 cases. Seven of the 8 patients with ACD had good recoveries and 1 died. Eighteen of the 19 patients without ACD had good recoveries, while 1 remained moderately disabled. Stepwise logistic regression demonstrated that the adjusted risk of ACD during hospitalization for patients with vomiting and an occipital fracture across the transverse sinus on computed tomography (CT) had odds ratios of 12.6 (95% confidence interval = 1.03-152.37, p = 0.047) and 8.8 (95% CI = 1.02-75.95, p = 0.048), respectively, compared with those without ACD. Conclusion: This study demonstrated that an occipital fracture across the transverse sinus on CT and vomiting on presentation are risk factors for ACD during hospitalization. In this study, PFEDH patients including those with ACD had good outcomes. Further studies are necessary to clarify the clinical course and risk factors for the clinical deterioration of PFEDH patients and to establish a treatment strategy.

The left superior laryngeal artery was observed arising from the external carotid artery instead of the superior thyroid artery in the cadaver of an approximately 70 year-old Asian man. In addition, on the same side, the superior thyroid artery arose from the common carotid artery 2 cm before the bifurcation instead of its usual origin from the external carotid artery. From the external carotid artery, the lingual and facial arteries arose from the common linguofacial trunk. The nerves in the carotid triangle were normal in course. No variations were observed on the right side carotid system. The multiple variations in this case have not been previously described. The embryogenesis of this combination of variations is not clear, but the anatomic consequences may have important clinical implications. As angiography has gained popularity in diagnostic approaches in recent years, it is essential to be aware of these variations so that they are not overlooked in differential diagnoses.

Hepatoid differentiation in pancreatic carcinoma is a rare phenomenon. It occurs either as a pure form or as a component with other subtypes. Herein, we report a 52-year-old man with an ampullary large cell neuroendocrine carcinoma presenting with obstructive jaundice for 2 months. A 0.5-cm nodule was found in the pancreatic head. Morphologically, the nodule was composed of exclusively hepatocytic tumor cells and sinusoids with dysplastic cytology and capsular invasion. The patient did not have a hepatic mass or ectopic normal liver tissue. This is the first reported case of ampullary large cell neuroendocrine carcinoma coinciding with a pancreatic hepatoid microcarcinoma. The clinicopathological features of pancreatic hepatoid carcinomas and their histogenesis are discussed.