bluuebunny/crossref_metadata_2025 huggingface dataset:
A Rapid Activated Protein C Sensitivity Test as a Diagnostic Marker for a Suspected Venous Thromboembolism in Pregnancy and Puerperium
Authors: Sugimura Motoi , Ohashi Ryota , Suzuki Kazunao , Itoh Hiroaki , Sugihara Kazuhiro , Kanayama Naohiro
Published: August 2011

Objective: The purpose of the study was to examine whether changes in response to activated protein C (APC) can be a diagnostic marker of venous thromboembolism (VTE) during pregnancy and puerperium. Methods: The normalized APC sensitivity ratio (sr) was examined in arbitrarily selected healthy Japanese pregnant females and compared with those in non-pregnant females and patients with VTE at the onset before anticoagulation in pregnancy and puerperium using an endogenous thrombin potential-based assay with a computer-assisted calibrated automated thrombography. Results:Sensitivity to APC in patients with VTE at onset was reduced in comparison to that in late pregnancy period and puerperium (p < 0.01, Student’s t test). The odds ratio for VTE was 31.9 with statistical significance in pregnant females with suspected clinical symptoms and APC-sr (≧5), although the odds ratio for VTE was not significant with D-dimer (≧5). Conclusion: These data suggest that an APC sensitivity test can be a possible surrogate diagnostic marker of suspected VTE during pregnancy and puerperium.
Fetal Scalp Cyst or Small Meningocele: Differential Diagnosis with Three-Dimensional Ultrasound
Authors: Sepulveda Waldo , Wong Amy E. , Sepulveda Sergio , Corral Edgardo
Published: August 2011

Background: Prenatal differential diagnosis of fetal scalp cystic masses is challenging and mainly includes small meningoceles and epidermal cysts. Case: A second-trimester anatomy scan revealed an extracranial cystic mass measuring 17 × 12 × 10 mm in the fetal occipital region. Three-dimensional datasets were obtained transabdominally and off-line analysis revealed a connection between the cyst and the subarachnoid space through a 5-mm skull defect. The diagnosis of a small meningocele was further confirmed by magnetic resonance imaging in the infant. Conclusion: Prenatal three-dimensional ultrasound can be a useful adjunct in the prenatal differentiation between small meningoceles and epidermal cysts.
Characteristics and Outcome and the Omphalocele Circumference/Abdominal Circumference Ratio in Prenatally Diagnosed Fetal Omphalocele
Authors: Kleinrouweler C.E. , Kuijper C.F. , van Zalen-Sprock M.M. , Mathijssen I.B. , Bilardo C.M. , Pajkrt E.
Published: August 2011

Objective: To evaluate the outcome of fetuses with prenatally diagnosed omphalocele and to investigate the predictive value of the omphalocele circumference/abdominal circumference (OC/AC) ratio – a measure for the relative size of the omphalocele. Materials and Methods: This study includes all fetuses prenatally diagnosed with omphalocele at our centre between 1995 and 2007. Medical records and footage of ultrasound examinations were reviewed. Omphalocele was classified in four groups: isolated, chromosomal, syndromic, and multiple anomalies. Results: Eighty-eight cases were identified: 21 (24%) were isolated and 67 had additional structural anomalies. Of the 44 fetuses (50%) with chromosomal anomalies, 2 had omphalocele as a solitary finding. Fifty-three pregnancies (60%) were terminated because of the size of the lesion or associated structural or chromosomal anomalies. Twenty-one cases resulted in a live birth, of which 17 were vaginal deliveries (81%, all uncomplicated) including 3 cases of giant omphalocele (≧5 cm). The OC/AC ratio was found predictive for herniation of the liver, respiratory insufficiency and type of surgical reconstruction. Currently, 12/88 fetuses (14%) are alive and well, including 2 infants with multiple anomalies. Conclusion: Identification of omphalocele should arouse suspicion of genetic abnormalities, even in cases that appear isolated. The OC/AC ratio may influence counselling regarding the postnatal course.
Ultrasound Diagnosis, Management and Prognosis in a Consecutive Series of 27 Cases of Fetal Hydrops following Maternal Parvovirus B19 Infection
Authors: Chauvet Agathe , Dewilde Anny , Thomas Dominique , Joriot Sylvie , Vaast Pascal , Houfflin-Debarge Véronique , Subtil Damien
Published: August 2011

Introduction: Fetal hydrops caused by anemia from parvovirus B19 infection (FH-B19) is rare. Doppler measurement of the middle cerebral artery peak systolic velocity (PSV-MCA) improves its prenatal diagnosis, but its frequency and prognosis are still poorly known. Despite improved survival due to in utero transfusions, the possibility of late neurological sequelae makes prognosis uncertain. Objectives: To assess the frequency, management and prognosis of a consecutive series of FH-B19 observed over a 15-year period. Methods: Retrospective study of 27 cases of FH-B19, that is, 3/100,000 births, 24 of them discovered during routine second-trimester ultrasound. All but 1 case (96.2%) had at least four of the six ultrasound signs that Saltzman et al. [Obstet Gynecol 1989;74:106–111] suggested as indicators of anemia. Of the fetuses tested, 80% had a PSV-MCA >1.5 MoM, also indicative of anemia. Of the 19 fetuses treated by exchange transfusions, 11 were liveborn compared with 2 of the 6 not so treated (57.8 vs. 33.3%, NS). The survival rate was higher during the second half of the study period (23.1 vs. 71.4%, p < 0.02) for less severe anemia (p < 0.03) and for repeated transfusions (p = 0.03). In our series, 1 case of prenatal cerebral atrophy was identified on screening. All 13 liveborn children appeared healthy at the age of 1 year. Conclusion: In cases of fetal hydrops, Saltzman et al.’s ultrasound criteria and PSV-MCA measurement made it possible to determine the likelihood that anemia is the cause of the hydrops and to measure its intensity. Use of these techniques allowed us to choose the most appropriate treatment (transfusion or not, depending on the degree of anemia), and survival improved notably in our series.
Specific Tear IgE in Patients with Moderate-to-Severe Autumnal Allergic Conjunctivitis
Authors: Mimura Tatsuya , Usui Tomohiko , Mori Mikiro , Funatsu Hideharu , Noma Hidetaka , Amano Shiro
Published: August 2011

Background: Recently, a new commercial test for specific IgE based on immunochromatography (Immfast Check J1®) has been developed. We previously reported on the use of this kit for tear fluid samples during spring. In this study, we compared the level of specific IgE in tear fluid among patients with seasonal allergic conjunctivitis during spring or autumn and control subjects. Methods: A nonrandomized, cross-sectional study was conducted in patients with moderate-to-severe allergic conjunctivitis occurring in spring (n = 56, spring group) or autumn (n = 52, autumn group), as well as in age- and sex-matched healthy control subjects (n = 50, control group). Levels of specific IgE for cedar pollen, cat epithelium and Dermatophagoides pteronyssinus were measured in tear fluid with the Immfast Check J1. Results: Specific IgE scores for cedar pollen and D. pteronyssinus were significantly higher in the spring and autumn groups than in the control group (p < 0.0001). In the autumn group, the highest detection rate for a specific allergen was 96.2% for D. pteronyssinus, followed by cedar pollen (86.5%) and cat epithelium (25.5%). In the spring group, the highest detection rate was 98.3% for cedar pollen, followed by D. pteronyssinus (51.7%) and cat epithelium (19.0%). Conclusions: These results suggest that both house dust mite allergen and outdoor allergens such as cedar pollen can be causes of allergic conjunctivitis during both spring and autumn in Japan. The Immfast Check J1 provides rapid measurement of specific IgE in tear fluid, which allows easy diagnosis of allergic conjunctivitis in an outpatient setting.
Feasibility of Vesicoamniotic Shunt Insertion in an Inanimate Model: Comparison of Fetoscopic and Ultrasound-Guided Techniques
Authors: Humphrey R.J. , Grieci T. , Schmidt J. , Gagnon R. , Han V. , Bütter A.
Published: August 2011

Objectives: To determine the feasibility of fetoscopic vesicoamniotic shunt insertion (F-VASI) in an inanimate model and to compare F-VASI to ultrasound (US)-guided VASI (US-VASI) with respect to accuracy of shunt placement and overall success rate. Methods: An inanimate second-trimester fetus with a replaceable bladder balloon was suspended in a pressurized water tank and localized with US. Fetal position was randomized, the operator was blinded and a 5-Fr Harrison Shunt® decompressed the bladder in both groups. Thirty shunt insertions were performed per group. Results: Procedure time was longer for F-VASI (15.0 vs. 2.8 min, p < 0.05), although it decreased with practice. F-VASI and US-VASI were similar for adequate depth of insertion (27/30 vs. 27/30, p = 1.0), placement within 1 cm of midline (27/30 vs. 25/30, p = 0.42), bladder puncture (28/30 vs. 28/30, p = 1.0), and overall success rate (27/30 vs. 23/30, p = 0.3). Conclusions: F-VASI is feasible in an inanimate model. Overall success rate was similar between the groups, although procedure time was longer for F-VASI. Further study is required to determine whether shunt migration is decreased with F-VASI.
Ethical Issues on Pregnancy Termination: Impact of New Imaging Modalities
Authors: Gorincour Guillaume , Tassy Sébastien , Siméoni Umberto , Le Coz Pierre
Published: August 2011

Objective: To explicate the ontological statuses of both the fetus and neonate as a basis for clinical ethical judgments about the obligations of both physicians and pregnant women to protect the life and health of both the fetus and the neonate. Methods: Despite drastic changes in perinatology, there is still a legal separation between fetuses and neonates. Neonatal status remains specific because of the prohibition of ‘transgressing human life’. Nevertheless, the concept of a ‘prenatal human being’ recently emerged. While new technologies blur the fetus/neonate borderline, why is it still legal in many European countries to terminate a fetal life in the late stages of pregnancy? One might even support the idea that what is authorized before birth should also be after, thereby ‘fetalizing’ neonates. Results: The ‘personalistic’ approach is against this ‘fetalization’, considering that terminating a neonate life is ‘transgressive’. The ‘utilitarian’ model considers we cannot decide what is good for someone else, which justifies terminating the life of neonates who are not persons yet. A phenomenological view supports the ontological difference on our perceptions, differing whether we observe ultrasound fetal images or real neonatal pictures. Conclusion: This does not mean the weight of fetal images should be underestimated.
Nitric Oxide: A Promising Methodological Approach in Airway Diseases
Authors: Sahin G. , Klimek L. , Mullol J. , Hörmann K. , Walther L.E. , Pfaar O.
Published: August 2011

Nitric oxide (NO) is a potent biological mediator, and has a regulatory role in a wide variety of cellular and tissue functions. In the upper and lower airways, NO has been suggested to be involved in different functions with regulatory, protective, defensive or damaging effects. It is obvious that NO plays an important role in host defense, and is liberated in the nose and the paranasal sinuses. This review aims to highlight some aspects of the origin and function of NO in airway diseases, such as allergic rhinitis, chronic rhinosinusitis with and without nasal polyps, primary ciliary dyskinesia, and cystic fibrosis. In conclusion, NO measurement may be a promising noninvasive diagnostic marker for airway pathologies.
Treatment of Traumatized Victims of War and Torture: A Randomized Controlled Comparison of Narrative Exposure Therapy and Stress Inoculation Training
Authors: Hensel-Dittmann D. , Schauer M. , Ruf M. , Catani C. , Odenwald M. , Elbert T. , Neuner F.
Published: August 2011

Background: The aim of the present randomized controlled trial was to compare the outcome of 2 active treatments for posttraumatic stress disorder (PTSD) as a consequence of war and torture: narrative exposure therapy (NET) and stress inoculation training (SIT). Methods: Twenty-eight PTSD patients who had experienced war and torture, most of them asylum seekers, received 10 treatment sessions of either NET or SIT at the Outpatient Clinic for Refugees, University of Konstanz, Germany. Posttests were carried out 4 weeks after treatment, and follow-up tests were performed 6 months and 1 year after treatment. The main outcome measure was the PTSD severity score according to the Clinician-Administered PTSD Scale (CAPS) at each time point. Results: A significant reduction in PTSD severity was found for NET, but not for SIT. A symptom reduction in the NET group occurred between pretest and the 6-month follow-up examination, the effect size being d = 1.42 (for SIT: d = 0.12), and between pretest and the 1-year follow-up, the effect size being d = 1.59 (for SIT: d = 0.19). The rates and scores of major depression and other comorbid disorders did not decrease significantly over time in either of the 2 treatment groups. Conclusions: The results indicate that exposure treatments like NET lead to a significant PTSD symptom reduction even in severely traumatized refugees and asylum seekers.
TGFBR3 Polymorphisms and Its Haplotypes Associated with Chronic Hepatitis B Virus Infection and Age of Hepatocellular Carcinoma Occurrence
Authors: Kim Jeong-Hyun , Yu Su Jong , Park Byung-Lae , Cheong Hyun Sub , Pasaje Charisse Flerida A. , Bae Joon Seol , Lee Hyo-Suk , Shin Hyoung Doo , Kim Yoon Jun
Published: August 2011

Objective: Hepatocellular carcinoma (HCC) is one of the most common cancers and is mainly caused by viral infections including hepatitis B virus (HBV). Recently, the decreased expression level of the transforming growth factor, beta receptor III (TGFBR3) gene, has been implicated in HCC and other human cancers. This study investigated whether TGFBR3 polymorphisms might be associated with HBV clearance and HCC occurrence. Methods: This study identified 27 single nucleotide polymorphisms (SNPs) in the exon, promoter, and exon-intron boundary regions of TGFBR3 by resequencing in 24 individuals. Then, 9 SNPs in the promoter and exons of the gene were genotyped from 1,065 Koreans composed of 637 chronic carriers (CC) and 428 spontaneously recovered (SR) subjects. Results: Two SNPs, rs1805113 (Phe676Phe) in exon 13 and rs1805117 in 3′-UTR (p = 0.009 and p = 0.008, respectively) were significantly associated with HBV clearance. In addition, Cox relative hazards analyses revealed that haplotype BL2_ht2 showed a significant association with the age of HCC occurrence among chronic HBV patients (relative hazard = 1.38; p = 0.007). Conclusion: Our findings suggest that TGFBR3 polymorphisms and its haplotypes might be associated with HBV clearance and age of HCC occurrence.
Signaling Pathway and Molecular-Targeted Therapy for Hepatocellular Carcinoma
Authors: Kudo Masatoshi
Published: August 2011

In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar®) was approved in Japan for ‘unresectable hepatocellular carcinoma (HCC)’, and was the first molecular-targeted agent for use in HCC. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has now been approved worldwide. Phase III clinical trials of other molecular-targeted agents comparing them with sorafenib as first-line treatment agents are now ongoing. Those agents target the vascular endothelial growth factor, platelet-derived growth factor receptors, as well as target the epidermal growth factor receptor, insulin-like growth factor receptor and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways. Finally, current status and future perspective will also be discussed.
Molecularly Targeted Therapies for Hepatocellular Carcinoma: Sorafenib as a Stepping Stone
Authors: Kim Hwi Young , Park Joong-Won
Published: August 2011

Since sorafenib, a multikinase inhibitor targeting angiogenesis of hepatocellular carcinoma (HCC), demonstrated survival benefits in recent clinical trials, it has changed the treatment paradigm and become the standard first-line treatment for patients with advanced HCC. However, disease stabilization with sorafenib lasts a few months, possibly due to the development of resistance, and thus the survival advantage was modest, even in patients with preserved liver function. Furthermore, there is currently no biomarker for monitoring the response or resistance to sorafenib. Currently, various kinds of molecularly targeted agents have been developed and are being evaluated in clinical trials. There are several steps required to improve the outcome from sorafenib therapy. First, a reliable predictive and prognostic biomarker is urgently needed. Second, a compelling indication of sorafenib treatment for HCC needs more clinical studies and consensus. Third, the actual benefits of sorafenib to patients with advanced liver dysfunction should be clarified and a more effective strategy for targeted therapy needs to be developed, for example, using a combination of targeted agents acting on different pathways or different levels of a key pathway. Finally, sorafenib could be used with other treatment modalities, such as local ablation or transarterial chemoembolization, to synergize efficacy. Based on the successful introduction of sorafenib, future studies should focus on plans to further improve the outcome of HCC patients by overcoming resistance and maximizing the efficacy of molecularly targeted therapy.
mTOR Inhibitor for the Treatment of Hepatocellular Carcinoma
Authors: Kudo Masatoshi
Published: August 2011

Mammalian target of rapamycin (mTOR) plays a central role in the regulation of cellular growth, proliferation, and survival via a cytoplasmic serine/threonine kinase. mTOR also works as a nutrition sensor to monitor cellular metabolism. mTOR is located downstream in the PI3K/Akt pathway, in which Akt and the tuberous sclerosis complex (TSC) 1/2 are involved, to form a signal transduction pathway. New anticancer agents that target mTOR in the PI3K/Akt pathway of the signal transduction pathways involved in cell proliferation control have recently been developed and are already commercially available. A phase III clinical trial of mTOR inhibitor for hepatocellular carcinoma (HCC) is now ongoing worldwide to expand indications. RAD001 is a signal-transduction inhibitor (STI) that targets mTOR (more specifically, mTORC1). mTORC1 signaling is intricately regulated by mitogens, growth factors, energy, and nutrients. mTORC1 is a regulator essential for general protein synthesis, located downstream of the PI3K/AKT/mTOR pathway, which is dysregulated in most human cancers. Inhibiting mTOR with molecules, such as RAD001, generates additive effects that accompany upstream and downstream target inhibition; alternatively, upstream receptor inhibition is compensated for by inhibiting the downstream pathway, even if some resistance develops against receptor inhibition regardless of initial or acquired resistance. In conclusion, RAD001 is a potential targeted agent for HCC and therefore final results of a phase III study are awaited.
Future Treatment Option for Hepatocellular Carcinoma: A Focus on Brivanib
Authors: Kudo Masatoshi
Published: August 2011

Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is particularly prevalent in the Asia-Pacific region. Guidelines on the treatment of HCC in Japan come from both consensus-based and evidence-based treatment algorithms. However, patients with extensive liver damage and/or more advanced disease (major vascular invasion and/or extrahepatic spread) are currently ineligible for any treatment. Recent knowledge of hepatocarcinogenesis has led to the targeting of new pathways, particularly the angiogenic pathway, with a specific focus on the vascular endothelial growth factor receptor (VEGFR). Apparently the most studied systemic antiangiogenic agent for HCC is sorafenib. An updated version of the aforementioned treatment algorithms recommends sorafenib therapy for advanced HCC patients with Child-Pugh A liver function and extrahepatic spread or major vascular invasion. Moreover, sorafenib is recommended for use in HCC patients who are refractory or intolerant to transarterial chemoembolization (TACE) with well-preserved liver function (Child-Pugh A). However, one of the unresolved issues is anti-VEGF resistance. It is speculated that novel antiangiogenic agents that combine inhibition of other pathways such as fibroblast growth factor receptor signaling in addition to VEGFR signaling might provide a potential mechanism to overcome anti-VEGF resistance in HCC. Brivanib inhibits both VEGF and fibroblast growth factor receptor signaling. To further investigate the benefits of brivanib for advanced HCC, a broad-spectrum, global, phase III development plan, the Brivanib studies in HCC patients at RISK (BRISK) clinical program, has been initiated. Clinical benefits seen with brivanib in the first-line setting, and following the failure of sorafenib therapy, highlight the potential to improve the clinical course of patients with advanced HCC, and this agent may provide a novel therapeutic option for the growing population of patients for whom no other treatment choice exists.
Oral Branched-Chain Amino Acid Granules Reduce the Incidence of Hepatocellular Carcinoma and Improve Event-Free Survival in Patients with Liver Cirrhosis
Authors: Hayaishi Sosuke , Chung Hobyung , Kudo Masatoshi , Ishikawa Emi , Takita Masahiro , Ueda Taisuke , Kitai Satoshi , Inoue Tatsuo , Yada Norihisa , Hagiwara Satoru , Minami Yasunori , Ueshima Kazuomi
Published: August 2011

Background: It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis. Methods: We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for ≧6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis. Results: The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216–0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336–1.017, p = 0.0575). Conclusions: Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis.
Management of Patients with Hepatocellular Carcinoma and Extrahepatic Metastasis
Authors: Lee Hyo-Suk
Published: August 2011

Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) has recently been paradoxically increasing due to increased survival with effective locoregional therapies. The intrahepatic stage of the tumor is important for determining the risk of an extrahepatic lesion. Almost all patients with intrahepatic stage T3–4, with or without EHM, die of progressive intrahepatic HCC but not due to EHM; thus, the majority of patients with HCC and EHM need to undergo concurrent treatment for intrahepatic HCC. There is no convincing evidence, to date, that systemic chemotherapy improves overall survival. Sorafenib is the first systemic agent that has demonstrated a significant survival benefit in patients with advanced HCC; however, the modest improvement of 3 months is far from satisfactory. Therefore, most hepatologists still rely on the conventional multidisciplinary approach to treat patients with EHM. The concept of the multidisciplinary treatment is the combination of locoregional therapies for both the intrahepatic HCC and symptomatic EHM when confined to a single organ. Targeted therapy may be considered for patients with advanced intrahepatic HCC and multiple EHM, however the potential efficacy of this approach requires confirmation. The outcome of ongoing clinical trials of the multidisciplinary approach, combining conventional locoregional therapy and targeted systemic therapy, is pending.
Management of Hepatocellular Carcinoma in Japan: Consensus-Based Clinical Practice Guidelines Proposed by the Japan Society of Hepatology (JSH) 2010 Updated Version
Authors: Kudo Masatoshi , Izumi Namiki , Kokudo Norihiro , Matsui Osamu , Sakamoto Michiie , Nakashima Osamu , Kojiro Masamichi , Makuuchi Masatoshi ,   for the HCC Expert Panel of Japan Society of Hepatology
Published: August 2011

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death not only in Japan but also worldwide. Clinical practice guidelines for HCC were first published in 2001 by the European Society of Study of the Liver (EASL) followed by the American Association for the Study of Liver Disease (AASLD) published in 2005 and updated in 2010. However, these guidelines have proven to be somewhat unsuitable for Japanese patients. In 2005, supported by the Japanese Ministry of Health, Labour and Welfare, evidence-based clinical practice guidelines for HCC were compiled in Japan. In 2009, a revised version of evidence-based guidelines was published. Based on both ‘evidence-based’ guidelines and the consensus of an expert panel on HCC, the Japan Society of Hepatology (JSH) published the Consensus-Based Clinical Practice Manual in 2007 and updated in 2010. In this article, the 2010 updated version of this manual, especially issues on prevention, surveillance, pathology, diagnosis, staging, and treatment algorithm are summarized.
Does the Heterogeneity of Chronic Fatigue Syndrome Moderate the Response to Cognitive Behaviour Therapy? An Exploratory Study
Authors: Cella Matteo , Chalder Trudie , White Peter D.
Published: August 2011

Background: Chronic fatigue syndrome (CFS) is a heterogeneous condition. A few studies have shown that some independent factors predict outcomes after cognitive behaviour therapy (CBT). Two recent systematic reviews suggest that heterogeneity may moderate treatment outcomes. However, no study has explored whether subgroups of CFS predict response to treatment. Methods: We used both latent class analysis (LCA) and latent class regression (LCR) to clarify the relationship between subgroups of CFS patients (n = 236), diagnosed using the Oxford diagnostic criteria, and the response to CBT. We measured symptoms, demographics, mood, and cognitive and behavioural responses to illness to define subgroups. Results: We found 5 latent classes by LCA, which did not differ in the direction of their response to CBT, with all classes showing improvement. In contrast, an exploratory LCR identified 4 latent classes, 1 of which predicted a poor response to CBT, whereas the other 3 predicted a good outcome, accounting for more than 70% of the patients. The negative outcome class was defined by weight fluctuations and physical shakiness, anxiety, pain and being focused on symptoms. Conclusions: CBT should be offered to all classes of patients with CFS, when defined by these measures. It may be possible to predict a minority group with a negative outcome, but this exploratory work needs replication.
Alexithymia and Tissue Inflammation
Authors: Honkalampi Kirsi , Lehto Soili M. , Koivumaa-Honkanen Heli , Hintikka Jukka , Niskanen Leo , Valkonen-Korhonen Minna , Viinamäki Heimo
Published: August 2011

Background: Altered immune responses are seen in depression, and recent data suggest that similar changes could also be observable in alexithymia. We examined whether the inflammatory markers high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 are independently related to alexithymia or its factors in a population-based sample. Methods: This study formed a clinical part of the Kuopio Depression (KUDEP) general population study focusing on the mental health of a general population of adults aged 25–64 years (n = 308). Alexithymia was measured using the Toronto Alexithymia Scale (TAS-20), and depressive symptoms were assessed using the Beck Depression Inventory (BDI-21). Results: The levels of IL-6 (in picograms per milliliter) and hs-CRP (in milligrams per liter) were significantly higher in alexithymic than in nonalexithymic subjects (IL-6 effect size, ES: 0.50; hs-CRP ES: 0.27). The BDI scores, hs-CRP and IL-6 explained 33.5% of the variation in TAS scores in the whole study population. According to logistic regression analysis, hs-CRP but not IL-6 increased the likelihood of belonging to the alexithymic group. This observation remained unaltered after additional adjustments for chronic inflammation-related disorders, the use of inflammation-modulating medications and depressive symptoms. Conclusions: Our findings suggest that the association between hs-CRP and alexithymia resembles that observed in depressed patients. It is, however, independent of depressive symptoms. These findings widen our view on the stress-alexithymia concept.
Neurotrophin-3 Gene-Modified Schwann Cells Promote TrkC Gene-Modified Mesenchymal Stem Cells to Differentiate into Neuron-Like Cells in Poly(Lactic-Acid-Co-Glycolic Acid) Multiple-Channel Conduit
Authors: Zhang Yan-qing , He Liu-min , Xing Bin , Zeng Xiang , Zeng Chen-guang , Zhang Wei , Quan Da-ping , Zeng Yuan-shan
Published: August 2011

Rapid progress in the field of nerve tissue engineering has opened up the way for new therapeutic strategies for spinal cord injury (SCI). Bone marrow-derived mesenchymal stem cells (MSCs) could be differentiated into neural lineages, which can be used as a potential cell source for nerve repair. Schwann cells (SCs) have been reported to support structural and functional recovery of SCI. In this study, we co-cultured neurotrophin-3 (NT-3) gene-modified SCs and NT-3 receptor tyrosine protein kinase C (TrkC) gene-modified MSCs in a three-dimensional porous poly(lactic-acid-co-glycolic acid) (PLGA) conduit with multiple channels in vitro for 14 days. Our results showed that more than 50% of the grafted MSCs were MAP2- and β-III-tubulin-positive cells, and the MSCs expressed a high level of β-III-tubulin detected by Western blotting, indicating a high rate of neuronal differentiation. Furthermore, immunostaining of PSD95 revealed the formation of a synapse-like structure, which was confirmed under electron microscopy. In conclusion, co-culture of NT-3 gene-modified SCs and TrkC gene-modified MSCs in the PLGA multiple-channeled conduit can promote MSCs’ differentiation into neuron-like cells with synaptogenesis potential. Our study provides a biological basis for future application of this artificial MSCs/SCs/PLGA complex in the SCI treatment.
Immunofluorescent Triple-Staining Technique to Identify Sensory Nerve Endings in Human Thumb Ligaments
Authors: Lee Julia , Ladd Amy , Hagert Elisabet
Published: August 2011

Ligament innervation purportedly plays a critical role in stability, proprioception and pathology of joints with minimal bony constraints. The human thumb carpometacarpal (CMC) joint is such a joint: with a complex saddle configuration and wide circumduction, its constraint is primarily ligamentous and it is prone to osteoarthritis. CMC reconstruction is the most commonly performed arthritis surgery in the upper extremity. Little, however, is known about CMC ligament innervation. We describe a novel triple-staining immunofluorescence technique using the markers for low-affinity neurotrophin receptor p75, the pan-neuronal marker protein gene product (PGP) 9.5 and 4′,6′-diamidino-2-phenylindole (DAPI) to simultaneously detect and differentiate between specific sensory nerve endings: the Pacini corpuscles, the Ruffini endings and nerve fascicles. Five primary CMC ligaments (dorsal radial, dorsal central, posterior oblique, anterior oblique and ulnar collateral ligaments) were harvested from 10 fresh-frozen human cadaver hands. Following paraffin sectioning, each ligament was stained using a triple-stain technique and imaged with fluorescence microscopy. Multidimensional acquisition permitted simultaneous capture of images at different wavelengths. Pacini corpuscles were distinguished by their distinct p75 immunoreactive capsules, and Ruffini endings by their overlapping p75 and PGP9.5 immunoreactive dendritic nerve endings. Simultaneous use of PGP9.5, p75 and DAPI immunofluorescence to analyze innervation patterns in human ligaments provides descriptive analysis of staining patterns and receptor structure as well as clues as to the proprioceptive function of CMC ligaments and the joint as a whole. Our novel findings of CMC ligament innervation augment the study of normal and pathological joint mechanics in this joint so prone to osteoarthritis.
Estrogen and Its Receptor Enhance Mechanobiological Effects in Compressed Bone Mesenchymal Stem Cells
Authors: Zhang Min , Chen Fa-Ming , Wang An-Hui , Chen Yong-Jin , Lv Xin , Wu Shun , Zhao Rui-Ni
Published: August 2011

Mechanical stimulation and estrogen have been proven to be two important factors in promoting mesenchymal stem cell activity, which is closely associated with bone formation, mass maintenance and remodeling. However, the superposition effects of mechanical stimulation and estrogen on stem cells remain unknown. It is also unclear if the estrogen receptor (ER) plays only a key role in estrogen signaling or if it is also involved in the mechanotransduction of stem cells. To investigate the role of estrogen and its receptors in the mechanobiological effects in bone mesenchymal stem cells (BMSCs), isolated mesenchymal stem cells from bone marrow were exposed to mechanical pressure under additional estrogen treatment or ER blockade. Cell proliferation was examined using an MTT assay and alkaline phosphatase (ALP) activity was determined by a modified enzyme kinetic method. Alignment of the cytoskeleton was observed by Coomassie brilliant blue staining and F-actin fluorescent staining. Cellular ultrastructure was observed under transmission electron microscope. Expression of ERα was investigated using Western blot analysis. Results indicated that mechanical pressure promoted cell proliferation, ALP activity, ERα expression and F-actin stress fiber formation. Overall, this effect was enhanced by the addition of estrogen and inhibited by ER blockade. We concluded that pressure stimulated proliferation and differentiation capability via F-actin transduction in BMSCs. The effects were enhanced by the addition of estrogen, and the ER plays an important role in regulating mechanobiological effects and the mechanotransduction processes of BMSCs.
Kellner’s Emotional Inhibition Scale: A Clinimetric Approach to Alexithymia Research
Authors: Grandi Silvana , Sirri Laura , Wise Thomas N. , Tossani Eliana , Fava Giovanni A.
Published: August 2011

Background: Emotional inhibition has been an enduring concept in the psychosomatic literature explaining the onset and course of medical disorders. Currently the personality style of alexithymia is a focus of this dimension in psychosomatic theory, while actual conscious emotional inhibition, which may overlap with alexithymia, has received less attention. In the early 80s Robert Kellner developed the Emotional Inhibition Scale (EIS), a self-rating scale for emotional inhibition based on clinimetric principles. In this study we explored whether the EIS differentiated a sample of cardiac recipients from normal controls, as well as the associations between the EIS and 2 measures of alexithymia, i.e. the Toronto Alexithymia Scale-20 (TAS-20) and the Diagnostic Criteria for Psychosomatic Research (DCPR). We also examined whether the EIS and the TAS-20 were differently related to depressive symptoms measured by the Symptom Questionnaire (SQ). Methods: Ninety-five heart-transplanted patients and a sample of normal controls, matched for sociodemographic variables, were administered the EIS (total score and 4 subscales concerning ‘verbal inhibition’, ‘timidity’, ‘disguise of feelings’, and ‘self-control’), the TAS-20, the SQ, and the Structured Interview according to the DCPR for alexithymia. Results: Cardiac recipients did not display significant differences compared to normal controls in observer (DCPR) and self-rated (TAS-20) measures of alexithymia. There were, however, significant differences in EIS with regard to ‘disguise of feelings’. In both groups the EIS ‘verbal inhibition’ and ‘timidity’ subscales were positively associated with the TAS-20, while the EIS ‘disguise of feelings’ and ‘self-control’ subscales were independent of alexithymia. Depressive symptoms were more related to TAS-20 than EIS total scores. Conclusions: Our results suggest that emotional inhibition and alexithymia are distinct phenomena even though they may share certain features. The EIS appears to be relatively independent of depressed mood and will be useful in assessing the individual’s conscious management of affect in future psychosomatic research.
Evidence from the Agonadal Juvenile Male Rhesus Monkey (Macaca mulatta) for the View that the Action of Neurokinin B to Trigger Gonadotropin-Releasing Hormone Release Is Upstream from the Kisspeptin Receptor
Authors: Ramaswamy Suresh , Seminara Stephanie B. , Plant Tony M.
Published: August 2011

Human genetics have revealed that kisspeptin signaling and neurokinin B (NKB) signaling are both required for robust pulsatile gonadotropin-releasing hormone (GnRH) release, and therefore for puberty and maintenance of adult gonadal function. How these two peptides interact to affect GnRH pulse generation remains a mystery. To address the hierarchy of the NKB and kisspeptin signaling pathways that are essential for GnRH release, two experiments were conducted using agonadal, juvenile male monkeys. Pituitary responsiveness to GnRH was first heightened by a pulsatile GnRH infusion to use the in situ pituitary as a bioassay for GnRH release. In the first experiment (n = 3), the kisspeptin receptor (KISS1R) was desensitized by a continuous 99-hour i.v. infusion of kisspeptin-10 (100 µg/h). During the last 4 h of continuous kisspeptin-10 infusion, desensitization of KISS1R was confirmed by failure of an i.v. bolus of kisspeptin-10 to elicit GnRH release. Desensitization of KISS1R was associated with a markedly blunted GnRH response to senktide. The response to senktide was progressively restored during the 72 h following termination of continuous kisspeptin-10. An analogous design was employed in the second experiment (n = 2) to desensitize the NKB receptor (neurokinin 3 receptor, NK3R) by administration of a continuous 48-hour i.v. infusion of senktide (200 µg/h). While a bolus of senktide during the last 3 h of continuous senktide administration failed to elicit GnRH release, thus confirming desensitization of NK3R, the ability of kisspeptin to stimulate GnRH was unimpaired. The foregoing findings support the view that NKB stimulation of GnRH release is upstream from KISS1R.
Analysis of Hearing Preservation and Facial Nerve Function for Patients Undergoing Vestibular Schwannoma Surgery: The Middle Cranial Fossa Approach versus the Retrosigmoid Approach – Personal Experience and Literature Review
Authors: Rabelo de Freitas Marcos , Russo Alessandra , Sequino Giuliano , Piccirillo Enrico , Sanna Mario
Published: August 2011

Objective: To compare hearing preservation and facial nerve function outcomes in patients undergoing vestibular schwannoma surgery performed using either the middle cranial fossa approach (MCFA) or the retrosigmoid approach (RSA). Materials and Methods: A review of the medical records of patients diagnosed with vestibular schwannoma who underwent surgical tumor removal in a single reference center via the MCFA or the RSA between January 1988 and December 2008 was conducted. Results: During this period, 90 patients underwent surgery via the MCFA while 86 patients received surgical treatment via the RSA. Of the patients subjected to the MCFA, 80.7% were characterized by a House-Brackmann (HB) grade I or II outcome, whereas 96.5% of patients undergoing the RSA were characterized by a HB grade I or II outcome (p = 0.001). This difference appeared only for extrameatal tumors when we compared size-matched tumors (58.3% MCFA vs. 98% RSA; p = 0.0006). There was no statistically significant difference in the hearing outcomes upon consideration of hearing preservation as characterized by the modified Sanna classification system involving classes A and B (18.9% MCFA vs. 10.6% RSA; p = 0.122). Conclusion: No statistically significant difference in hearing preservation was identified when comparing tumors operated upon via the MCFA versus the RSA. However, our results indicate that a higher risk of facial nerve function impairment exists if the surgery is performed via the MCFA under circumstances where the tumor extends to the cerebellopontine angle.
Interaural Stacked Auditory Brainstem Response Measures for Detecting Small Unilateral Acoustic Tumors
Authors: Don Manuel , Kwong Betty , Tanaka Chiemi
Published: August 2011

The Stacked auditory brainstem response (SABR) was developed and investigated as a screening tool for small (≤1 cm) unilateral acoustic tumors (vestibular schwannomas) that were missed by standard clinical auditory brainstem response (ABR) measures [Don et al.: Am J Otol 1997;18:608–621; Audiol Neurotol 2005;10:274–290]. While the SABR measure provided much greater sensitivity than the standard ABR measures for small tumor detection, we believed that the large intersubject variability of the SABR measure compromised both the sensitivity and specificity of the measure. However, as we demonstrate in this paper, the variability between ears of a given individual is small. Thus, we introduced an interaural SABR (ISABR) amplitude difference measure to improve the sensitivity and specificity of the SABR amplitude measure to detect small unilateral acoustic tumors. Its main advantages are two-fold. First, it is somewhat immune to variables that affect the absolute SABR amplitudes because it is a relative measure. Second, it is better at assessing tumor patients with very large and non-tumor patients with very small absolute SABR amplitudes. We believe that the ISABR is a useful addition to ABR measures aimed at detecting the presence of unilateral acoustic tumors.
An Evaluation of Intraoperative Renal Support during Liver Transplantation: A Matched Cohort Study
Authors: Parmar Ambica , Bigam David , Meeberg Glenda , Cave Dominic , Townsend Derek R. , Gibney R.T. Noel , Bagshaw Sean M.
Published: August 2011

Background: Intraoperative continuous renal replacement therapy (CRRT) has been utilized during liver transplantation (LT). Our objective was to assess intraoperative CRRT for metabolic control, postoperative complications and outcomes. Methods: Retrospective matched cohort study. Cases were LT patients receiving intraoperative CRRT. Controls were matched for demographics and Model for End-Stage Liver Disease (MELD) score. Data were extracted on physiology, course and outcomes. Results: 72 patients were included. Despite effort to match by MELD, cases had higher scores (35.4 vs. 29.9, p = 0.01) compared to controls. Preoperatively, cases received more vasopressors (p = 0.006), and more RRT (94.4 vs. 25.7%, p < 0.0001). There was no difference in complications (p = 0.35) or ICU re-admission rate (p = 0.29). Cases were more likely to require postoperative RRT (p < 0.0001). There was no difference in hospital mortality (p = 0.61). Conclusions: LT patients selected for intraoperative CRRT more commonly have hemodynamic instability and preoperative acute kidney injury requiring RRT. Despite higher illness severity for cases, there were no differences in complications or mortality.
Exercise Training Restores Hypertension-Induced Changes in the Elastic Tissue of the Thoracic Aorta
Authors: Jordão Maria Tereza , Ladd Fernando V.L. , Coppi Antonio Augusto , Chopard Renato P. , Michelini Lisete C.
Published: August 2011

Background/Aims: Pharmacological antihypertensive therapies decrease both wall hypertrophy and collagen, but are unable to diminish the elastic content in the thoracic aorta. We investigated the effects of exercise training on aortic structure and function. Methods: Spontaneously hypertensive rats (SHR) and normotensive rats (WKY), submitted to low-intensity training (T) or kept sedentary (S), were subjected to haemodynamic analyses. The thoracic aorta was processed for real-time PCR, light (morphometric/stereological evaluations) and electron microscopy. Results: SHRS versus WKYS exhibited a higher heart rate, pressure and pulse pressure, increased α-actin, elastin and collagen mRNA expression, augmented wall volume and cross-sectional area (marked elastin/collagen content). In the SHR, training reduced pressure and heart rate, with slight reduction in pulse pressure. SHRT aortas exhibited small morphometric changes, reduced α-actin, elastin and collagen mRNA expression, normalization of increased elastic content, reduction in collagen/connective tissue and a decrease in smooth muscle cell volume (p < 0.05 for all comparisons). SHRT aortas showed improved circumferential orientation of smooth muscle cells and prevention of rupture/duplication of internal elastic lamina. No effects were observed in trained WKY aortas. Conclusions: Training effectively corrects elastic, collagen and smooth muscle content in SHR aortas. These changes, by reducing aortic pulsatility, facilitate a buffering function and reduce the cardiovascular risk.
Alteration of Pulmonary Artery Integrin Levels in Chronic Hypoxia and Monocrotaline-Induced Pulmonary Hypertension
Authors: Umesh Anita , Paudel Omkar , Cao Yuan-Ning , Myers Allen C. , Sham James S.K.
Published: August 2011

Background: Pulmonary hypertension is associated with vascular remodeling and increased extracellular matrix (ECM) deposition. While the contribution of ECM in vascular remodeling is well documented, the roles played by their receptors, integrins, in pulmonary hypertension have received little attention. Here we characterized the changes of integrin expression in endothelium-denuded pulmonary arteries (PAs) and aorta of chronic hypoxia as well as monocrotaline-treated rats. Methods and Results: Immunoblot showed increased α1-, α8- and αv-integrins, and decreased α5-integrin levels in PAs of both models. β1- and β3-integrins were reduced in PAs of chronic hypoxia and monocrotaline-treated rats, respectively. Integrin expression in aorta was minimally affected. Differential expression of α1- and α5-integrins induced by chronic hypoxia was further examined. Immunostaining showed that they were expressed on the surface of PA smooth muscle cells (PASMCs), and their distribution was unaltered by chronic hypoxia. Phosphorylation of focal adhesion kinase was augmented in PAs of chronic hypoxia rats, and in chronic hypoxia PASMCs cultured on the α1-ligand collagen IV. Moreover, α1-integrin binding hexapeptide GRGDTP elicited an enhanced Ca2+ response, whereas the response to α5-integrin binding peptide GRGDNP was reduced in CH-PASMCs. Conclusion: Integrins in PASMCs are differentially regulated in pulmonary hypertension, and the dynamic integrin-ECM interactions may contribute to the vascular remodeling accompanying disease progression.