bluuebunny/crossref_metadata_2025 huggingface dataset:
A Review of Treatments for Iliotibial Band Syndrome in the Athletic Population
Authors: Beals Corey , Flanigan David
Published: October 2013

Iliotibial band syndrome (ITBS) is a common injury in runners and other long distance athletes with the best management options not clearly established. This review outlines both the conservative and surgical options for the treatment of iliotibial band syndrome in the athletic population. Ten studies met the inclusion criteria by focusing on the athletic population in their discussion of the treatment for iliotibial band syndrome, both conservative and surgical. Conservative management consisting of a combination of rest (2–6 weeks), stretching, pain management, and modification of running habits produced a 44% complete cure rate, with return to sport at 8 weeks and a 91.7% cure rate with return to sport at 6 months after injury. Surgical therapy, often only used for refractory cases, consisted of excision or release of the pathologic distal portion of the iliotibial band or bursectomy. Those studies focusing on the excision or release of the pathologic distal portion of the iliotibial band showed a 100% return to sport rate at both 7 weeks and 3 months after injury. Despite many options for both surgical and conservative treatment, there has yet to be consensus on one standard of care. Certain treatments, both conservative and surgical, in our review are shown to be more effective than others; however, further research is needed to delineate the true pathophysiology of iliotibial band syndrome in athletes, as well as the optimal treatment regimen.
A Comparison of Synonymous Codon Usage Bias Patterns in DNA and RNA Virus Genomes: Quantifying the Relative Importance of Mutational Pressure and Natural Selection
Authors: Chen Youhua
Published: October 2013

Codon usage bias patterns have been broadly explored for many viruses. However, the relative importance of mutation pressure and natural selection is still under debate. In the present study, I tried to resolve controversial issues on determining the principal factors of codon usage patterns for DNA and RNA viruses, respectively, by examining over 38000 ORFs. By utilizing variation partitioning technique, the results showed that 27% and 21% of total variation could be attributed to mutational pressure, while 5% and 6% of total variation could be explained by natural selection for DNA and RNA viruses, respectively, in codon usage patterns. Furthermore, the combined effect of mutational pressure and natural selection on influencing codon usage patterns of viruses is substantial (explaining 10% and 8% of total variation of codon usage patterns). With respect to GC variation, GC content is always negatively and significantly correlated with aromaticity. Interestingly, the signs for the significant correlations between GC, gene lengths, and hydrophobicity are completely opposite between DNA and RNA viruses, being positive for DNA viruses while being negative for RNA viruses. At last, GC12 versus G3s plot suggests that natural selection is more important than mutational pressure on influencing the GC content in the first and second codon positions.
Patterns of Pelvic Radiotherapy in Patients with Stage II/III Rectal Cancer
Authors: Fitzgerald Timothy L. , Zervos Emmanuel , Wong Jan H.
Published: October 2013

High-level evidence supports adjuvant radiotherapy for rectal cancer. We examined the influence of sociodemographic factors on patterns of adjuvant radiotherapy for resected Stage II/III rectal cancer.Methods. Patients undergoing surgical resection for stage II/III rectal cancer were identified in SEER registry.Results. A total of 21,683 patients were identified. Majority of patients were male (58.8%), white (83%), and with stage III (54.9%) and received radiotherapy (66%). On univariate analysis, male gender, stage III, younger age, year of diagnosis, and higher socioeconomic status (SES) were associated with radiotherapy. Radiotherapy was delivered in 84.4% of patients<50; however, only 32.8% of those are>80 years. Logistic regression demonstrated a significant increase in the use of radiotherapy in younger patients who are<50 (OR, 10.3), with stage III (OR, 1.21), males (OR, 1.18), and with higher SES.Conclusions. There is a failure to conform to standard adjuvant radiotherapy in one-third of patients, and this is associated with older age, stage II, area-level of socioeconomic deprivation, and female sex.
Comparison of Adaptive Information Security Approaches
Authors: Evesti Antti , Ovaska Eila
Published: October 2013

Dynamically changing environments and threat landscapes require adaptive information security. Adaptive information security makes it possible to change and modify security mechanisms at runtime. Hence, all security decisions are not enforced at design-time. This paper builds a framework to compare security adaptation approaches. The framework contains three viewpoints, that is, adaptation, security, and lifecycle. Furthermore, the paper describes five security adaptation approaches and compares them by means of the framework. The comparison reveals that the existing security adaptation approaches widely cover the information gathering. However, the compared approaches do not describe how to decide a method to perform a security adaptation. Similarly, means how to provide input knowledge for the security adaptation is not covered. Hence, these research areas have to be covered in the future. The achieved results are applicable for software developers when selecting a security adaptation approach and for researchers when considering future research items.
Antioxidant Activity and Volatile and Phenolic Profiles of Essential Oil and Different Extracts of Wild Mint (Mentha longifolia) from the Pakistani Flora
Authors: Iqbal Tahseen , Hussain Abdullah Ijaz , Chatha Shahzad Ali Shahid , Naqvi Syed Ali Raza , Bokhari Tanveer Hussain
Published: October 2013

The antioxidant activity and free radical scavenging capacity of the essential oil and three different extracts of wildly grownMentha longifolia(M. longifolia) were studied. The essential oil fromM. longifoliaaerial parts was isolated by hydrodistillation technique using Clevenger-type apparatus. The extracts were prepared with three solvents of different polarity (n-hexane, dichloromethane, and methanol) using Soxhlet extractor. Maximum extract yield was obtained with methanol (12.6 g/100 g) while the minimum with dichloromethane (3.50 g/100 g). The essential oil content was found to be 1.07 g/100 g. A total of 19 constituents were identified in theM. longifoliaoil using GC/MS. The main components detected were piperitenone oxide, piperitenone, germacrene D, borneol, andβ-caryophyllene. The total phenolics (TP) and total flavonoids (TF) contents of the methanol extract ofM. longifoliawere found to be significantly higher than dichloromethane and hexane extracts. The dichloromethane and methanol extracts exhibited excellent antioxidant activity as assessed by 2,2′-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging ability, bleachingβ-carotene, and inhibition of linoleic acid peroxidation assays. The essential oil and hexane extract showed comparatively weaker antioxidant and free radical scavenging activities. The results of the study have validated the medicinal and antioxidant potential ofM. longifoliaessential oil and extracts.
Validation of Simultaneous Volumetric and HPLC Methods for the Determination of Pridinol Mesylate in Raw Material
Authors: Simionato Laura D. , Ferello Leonardo , Stamer Sebastián , Zubata Patricia D. , Segall Adriana I.
Published: October 2013

Simple, sensitive, and economical simultaneous volumetric and HPLC methods for the determination of pridinol mesylate in raw material have been developed. The volumetric method is based on the reaction of pridinol with sodium lauryl sulphate in diluted sulphuric acid. Dimethyl yellow was used as indicator to detect the end point of the titration in aqueous/organic layer. The HPLC method for the determination of pridinol mesylate employs a reverse phase C18 column at ambient temperature with a mobile phase consisting of acetonitrile: 0.05 M potassium dihydrogen phosphate, pH adjusted to 5.0 (1 : 2, v/v). The flow rate was 0.8 mL/min. Quantitation was achieved with UV detection at 258 nm based on peak area. Both methods were found to be suitable for the quality control of pridinol mesylate in raw material.
Hepatitis Delta Virus: A Peculiar Virus
Authors: Alves Carolina , Branco Cristina , Cunha Celso
Published: October 2013

The hepatitis delta virus (HDV) is distributed worldwide and related to the most severe form of viral hepatitis. HDV is a satellite RNA virus dependent on hepatitis B surface antigens to assemble its envelope and thus form new virions and propagate infection. HDV has a small 1.7 Kb genome making it the smallest known human virus. This deceivingly simple virus has unique biological features and many aspects of its life cycle remain elusive. The present review endeavors to gather the available information on HDV epidemiology and clinical features as well as HDV biology.
High Resolution Software Defined Radar System for Target Detection
Authors: Costanzo S. , Spadafora F. , Borgia A. , Moreno H. O. , Costanzo A. , Di Massa G.
Published: October 2013

The Universal Software Radio Peripheral USRP NI2920, a software defined transceiver so far mainly used in Software Defined Radio applications, is adopted in this work to design a high resolution L-Band Software Defined Radar system. The enhanced available bandwidth, due to the Gigabit Ethernet interface, is exploited to obtain a higher slant-range resolution with respect to the existing Software Defined Radar implementations. A specific LabVIEW application, performing radar operations, is discussed, and successful validations are presented to demonstrate the accurate target detection capability of the proposed software radar architecture. In particular, outdoor and indoor test are performed by adopting a metal plate as reference structure located at different distances from the designed radar system, and results obtained from the measured echo are successfully processed to accurately reveal the correct target position, with the predicted slant-range resolution equal to 6 m.
A Unique Case of Penile Necrotizing Fasciitis Secondary to Spontaneous Corpus Cavernosal Abscess
Authors: Dempster N. J. , Maitra N. U. , McAuley L. , Brown M. , Hendry D.
Published: October 2013

Corpus cavernosal abscess and necrotizing fasciitis occur rarely, and precipitating factors can usually be elicited with careful history and examination. Whilst both conditions share common risk factors such as diabetes mellitus, this is the first reported case of penile necrotizing fasciitis secondary to spontaneous corpus cavernosal abscess in an otherwise healthy patient. A 32-year-old man presented with 4-day history of swollen, painful penis, with ultrasound confirming corpus cavernosal abscess. Biopsies were taken and the cavity aspirated, but, despite intravenous antibiotics, he developed penile necrotizing fasciitis necessitating open cavernostomy and debridement. The overlying skin defect healed by secondary intention, but the patient experienced persistent postoperative erectile dysfunction, so he was referred for penile prosthesis insertion.
Soy Saponins Meditate the Progression of Colon Cancer in Rats by Inhibiting the Activity ofβ-Glucuronidase and the Number of Aberrant Crypt Foci but Not Cyclooxygenase-2 Activity
Authors: Guo Yu-Wei , Chen Yue-Hwa , Chiu Wan-Chun , Liao Hsiang , Lin Shyh-Hsiang
Published: October 2013

Objective. The effect of extracted crude soybean saponins on preneoplastic lesions, aberrant crypt foci (ACF), and the related mechanism were investigated.Research Methods and Procedures. Rats were assigned into five groups according to different doses of extracted crude soybean saponins and received 1,2-dimethylhydrazine (DMH) injection in week 5. In week 15, all rats were sacrificed. The number of ACFs, the cyclooxygenase-2 (COX-2) protein expression, the level of prostaglandins E2 (PGE2), and the activity ofβ-glucuronidase were examined.Results. Results revealed that the consumption of extracted crude soybean saponins decreased the number of ACFs and the activity ofβ-glucuronidase in rats, while the expression of COX-2 protein and PGE2 level were not affected.Conclusions. Soybean saponins were effective in inhibiting colon cancer by downregulating the activity ofβ-glucuronidase in colonic mucosa but not the COX-2 protein expression and PGE2 level.
A Rare Cause of Stroke in Young Adults: Occlusion of the Middle Cerebral Artery by a Meningioma Postpartum
Authors: Mathis Stéphane , Bataille Benoît , Boucebci Samy , Jeantet Marion , Ciron Jonathan , Vandamme Laurène , Neau Jean-Philippe
Published: October 2013

Meningioma is the most common nonglial intracranial primary tumor. It is a slowly growing tumor and presents clinically by causing seizures along with neurological or neuropsychological deficit. However, acute presentation of meningioma is possible. We are reporting a case of cerebral infarction due to a sphenoid wing meningothelial meningioma (with progesterone receptor positivity) leading to an occlusion of the middle cerebral artery (MCA) in a 30-year-old right-handed woman (1 month after childbirth). After surgery, no new neurological event occurred, and she recovered most of her neurological functions. Strokes due to meningioma are a highly rare clinical occurrence but should be given serious consideration, particularly in young patients.
Ionotropic Glutamate Receptors and Voltage-Gated Ca2+Channels in Long-Term Potentiation of Spinal Dorsal Horn Synapses and Pain Hypersensitivity
Authors: Youn Dong-ho , Gerber Gábor , Sather William A.
Published: October 2013

Over the last twenty years of research on cellular mechanisms of pain hypersensitivity, long-term potentiation (LTP) of synaptic transmission in the spinal cord dorsal horn (DH) has emerged as an important contributor to pain pathology. Mechanisms that underlie LTP of spinal DH neurons include changes in the numbers, activity, and properties of ionotropic glutamate receptors (AMPA and NMDA receptors) and of voltage-gated Ca2+channels. Here, we review the roles and mechanisms of these channels in the induction and expression of spinal DH LTP, and we present this within the framework of the anatomical organization and synaptic circuitry of the spinal DH. Moreover, we compare synaptic plasticity in the spinal DH with classical LTP described for hippocampal synapses.
Paraneoplastic Autoimmunity Associated with Testicular Myeloid Sarcoma and Chronic Myelomonocytic Leukemia
Authors: Craig Jeffrey W. , Lin Richard J.
Published: October 2013

Myeloid sarcomas are rare extramedullary solid tumors composed of immature myeloid cells. The clinical presentations of these malignant neoplasms are highly variable, ranging from asymptomatic to localized mass effect. Here, we report an unusual case of myeloid sarcoma of the testis found in association with chronic myelomonocytic leukemia where the presenting symptoms were autoimmune pericarditis and migratory arthralgias and myalgias that preceded testicular enlargement by nearly three months. Treatment with both radical orchiectomy and leukemia-directed chemotherapy led to immediate reductions in symptom severity, suggesting that these early symptoms were paraneoplastic in origin. Review of the literature identified the association between hematological malignancies, including chronic myelomonocytic leukemia, and paraneoplastic autoimmune phenomena with features similar to polymyalgia rheumatica and rheumatoid arthritis. Importantly, rheumatologic symptoms related to these disease entities may be easily dismissed as vague or unrelated complaints or treated as purely rheumatologic conditions, thus delaying the formal diagnoses. Clinicians must recognize the common association between possible paraneoplastic rheumatologic symptoms and hematologic malignancies such as chronic myelomonocytic leukemia.
Decomposed Sliding Mode Control of the Drive with Interior Permanent Magnet Synchronous Motor and Flexible Coupling
Authors: Vittek Jan , Ryvkin Sergey
Published: October 2013

A decomposed sliding mode control of the drive with an interior permanent magnet synchronous motor and flexible coupling is presented. Decomposition exploits principles of vector control to divide motor into channel for control of magnetic flux and channel for control of torque separately. Sliding mode control principles are exploited to keep demanded value of magnetic flux and to control load angle in the presence of vibration modes and external disturbances. To obtain continues voltage as a control variable a smoothing integrator follows signum function in both channels. As a modification the switching governed by signum function is replaced by the high gain including rearrangement of the control system block diagram. The simulations indicate that the control system yields the desired robustness and further investigations are recommended.
Rehabilitation of Children with Hemiparesis: A Pilot Study on the Use of Virtual Reality
Authors: Olivieri Ivana , Chiappedi Matteo , Meriggi Paolo , Mazzola Marcella , Grandi Attilia , Angelini Lucia
Published: October 2013

Background. A wide range of treatments have been used to improve upper arm motor performances in children with congenital hemiplegia. Recent findings are suggesting that virtual reality based intervention could be a promising tool also in pediatric rehabilitation.Methods. Six patients with congenital hemiplegia (age: 4–16 years) were recruited among those treated in the Child Neuropsychiatry and Rehabilitation Unit of the IRCCS “Santa Maria Nascente” (Milan, Italy), for a preliminary investigation about using nonimmersive virtual reality for upper limb rehabilitation. Ten sessions using VRRS system (Khymeia, Padova, Italy) were weekly administered as a part of the rehabilitative treatment. Melbourne Assessment of Unilateral Limb Movement, Ashworth Scale, and Arm’s PROM were selected as main outcome measures. At the end of treatment, participants filled in an ad hoc satisfaction questionnaire.Results. All subjects completed the proposed treatment, and they also gave a positive judgment regarding this rehabilitative method. Melbourne score increased in all patients.Conclusion. Our findings seem to support the evidence that VR treatment could be a promising and engaging tool for pediatric rehabilitation. However, the limited size of the population and the small number of sessions require further investigations and RCTs to confirm our positive results.
Increasing Affinity of Interferon-γReceptor 1 to Interferon-γby Computer-Aided Design
Authors: Mikulecký Pavel , Černý Jiří , Biedermannová Lada , Petroková Hana , Kuchař Milan , Vondrášek Jiří , Malý Petr , Šebo Peter , Schneider Bohdan
Published: October 2013

We describe a computer-based protocol to design protein mutations increasing binding affinity between ligand and its receptor. The method was applied to mutate interferon-γreceptor 1 (IFN-γ-Rx) to increase its affinity to natural ligand IFN-γ, protein important for innate immunity. We analyzed all four available crystal structures of the IFN-γ-Rx/IFN-γcomplex to identify 40 receptor residues forming the interface with IFN-γ. For these 40 residues, we performed computational mutation analysis by substituting each of the interface receptor residues by the remaining standard amino acids. The corresponding changes of the free energy were calculated by a protocol consisting of FoldX and molecular dynamics calculations. Based on the computed changes of the free energy and on sequence conservation criteria obtained by the analysis of 32 receptor sequences from 19 different species, we selected 14 receptor variants predicted to increase the receptor affinity to IFN-γ. These variants were expressed as recombinant proteins inEscherichia coli, and their affinities to IFN-γwere determined experimentally by surface plasmon resonance (SPR). The SPR measurements showed that the simple computational protocol succeeded in finding two receptor variants with affinity to IFN-γincreased about fivefold compared to the wild-type receptor.
A Flexible Blue Light‐Emitting Diode Based on ZnO Nanowire/Polyaniline Heterojunctions
Authors: Liu Y. Y. , Wang X. Y. , Cao Y. , Chen X. D. , Xie S. F. , Zheng X. J. , Zeng H. D.
Published: October 2013

An organic/inorganic light‐emitting diode (LED) consisting of n‐type vertically aligned ZnO nanowires (NWs) and p‐type proton acid doped polyaniline (PANi) is reported. The device was fabricated on flexible indium‐tin‐oxide (ITO) coated polyethylene terephthalate (PET) substrate. A broad blue light emission band ranging from 390 nm to 450 nm was observed in the electroluminescence (EL) spectra of the device, which was related to the interface recombination of electrons in the conduction band of ZnO NWs and holes in the polaron level of PANi. The turn‐on voltage of the device is ~3.5 V, lower than most of ZnO NWs based LED devices. In combination with the easy fabrication, flexibility, low power consumption, and mechanical robustness, this novel device is very promising in the application of blue LEDs.
Site-Specific Determinants of Cutaneous Melanoma: A Case–Case Comparison of Patients with Tumors Arising on the Head or Trunk
Authors: Kvaskoff Marina , Pandeya Nirmala , Green Adèle C. , Perry Susan , Baxter Catherine , Davis Marcia B. , Mortimore Rohan , Westacott Lorraine , Wood Dominic , Triscott Joe , Williamson Richard , Whiteman David C.
Published: October 2013

Background: Cutaneous melanomas have been hypothesized to arise through different pathways according to phenotype, body site, and sun exposure. To further test this hypothesis, we explored associations between phenotype and melanoma at different sites using a case–case comparative approach.

Methods: Melanoma patients (n = 762) aged 18 to 79 years and diagnosed from 2007 to 2010 were ascertained from pathology laboratories in Brisbane, Australia. Patients reported phenotypic information and a dermatologist counted melanocytic nevi and solar keratoses. We compared data for patients with trunk melanoma (n = 541, the reference group), head/neck melanoma (n = 122), or lentigo maligna melanoma (LMM) of the head/neck (n = 69). ORs and 95% confidence intervals were calculated using classical or polytomous logistic regression models.

Results: Compared with trunk melanoma patients, those with head/neck melanoma were significantly less likely to have high nevus counts (≥135: OR = 0.27; Ptrend = 0.0004). Associations between category of nevus count and LMM head/neck were weaker and significantly different (≥135: OR = 1.09; Ptrend = 0.69; Phomogeneity = 0.02). Patients with head/neck melanoma were more likely than those with truncal melanoma to have high solar keratosis counts (≥7: OR = 1.78, Ptrend = 0.04). Again, associations with LMM head/neck were weaker, albeit not significantly different (≥7: OR = 1.61; Ptrend = 0.42; Phomogeneity = 0.86).

Conclusion: Trunk melanomas are more strongly associated with nevus counts than head/neck melanomas, but are less strongly associated with number of solar keratoses, a marker of chronic sun exposure.

Impact: These findings underscore the notion that melanomas on the trunk typically arise through a causal pathway associated with nevus propensity, whereas melanomas on the head/neck arise through a pathway associated with cumulative sun exposure. Cancer Epidemiol Biomarkers Prev; 22(12); 2222–31. ©2013 AACR.
Weekly nab-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial
Authors: Gonzalez-Angulo Ana M. , Meric-Bernstam Funda , Chawla Sant , Falchook Gerald , Hong David , Akcakanat Argun , Chen Huiqin , Naing Aung , Fu Siqing , Wheler Jennifer , Moulder Stacy , Helgason Thorunn , Li Shaoyi , Elias Ileana , Desai Neil , Kurzrock Razelle
Published: October 2013

Purpose: This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies.

Experimental Design: nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m2. Additional doses were 56.25, 100, 150, and 125 mg/m2.

Results: Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m2 [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m2 (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m2. Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration–time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m2, except for a relatively low AUC at 125 mg/m2. nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1.

Conclusions: The clinical dose of single-agent nab-rapamycin was established at 100 mg/m2 weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies. Clin Cancer Res; 19(19); 5474–84. ©2013 AACR.
The Cell-Cycle Regulator CDK4: An Emerging Therapeutic Target in Melanoma
Authors: Sheppard Karen E. , McArthur Grant A.
Published: October 2013

The recent clinical success of targeted therapies in melanoma directed at the oncogene BRAF validates the concept of targeting oncogenes. The p16-cyclin D-CDK4/6-retinoblastoma protein pathway (CDK4 pathway) is dysregulated in 90% of melanomas, and is, therefore, an obvious therapeutic target for this disease. The main outcome of CDK4 activation is the phosphorylation and, thus, inhibition of the retinoblastoma protein leading to G1–S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. In preclinical studies, the response to CDK4 inhibition correlates with genomic changes that increase CDK4 activity, most notably where the tumor suppressor CDKN2A (p16INK4A) is deleted. A central question is whether melanomas with activating events in the CDK4 pathway have become “addicted” to this signaling pathway, in which case inhibition of CDK4 would not simply induce cell-cycle arrest but induce cell death and tumor regression. Recently, a number of selective CDK4/6 inhibitors have entered clinical trials, and these compounds are showing great promise in that they are well tolerated and show clinical benefit. This review discusses the CDK4 pathway, its dysregulation in melanoma, the consequences of CDK4 pathway inhibition, and potential novel combinational strategies for the treatment of melanoma. Clin Cancer Res; 19(19); 5320–8. ©2013 AACR.
The Intersection of Immune-Directed and Molecularly Targeted Therapy in Advanced Melanoma: Where We Have Been, Are, and Will Be
Authors: Sullivan Ryan J. , LoRusso Patricia M. , Flaherty Keith T.
Published: October 2013

In three years, four drugs have gained regulatory approval for the treatment of metastatic and unresectable melanoma, with at least seven other drugs having recently completed, currently in, or soon to be in phase III clinical testing. This amazing achievement has been made following a remarkable increase of knowledge in molecular biology and immunology that led to the identification of high-valued therapeutic targets and the clinical development of agents that effectively engage and inhibit these targets. The discovery of either effective molecularly targeted therapies or immunotherapies would have led to dramatic improvements to the standard-of-care treatment of melanoma. However, through parallel efforts that have showcased the efficacy of small-molecule BRAF and MAP–ERK kinase (MEK) inhibitors, as well as the immune checkpoint inhibitors, namely ipilimumab and the anti-PD1/PDL1 antibodies (lambrolizumab, nivolumab, MPDL3280), an opportunity exists to transform the treatment of melanoma specifically and cancer generally by exploring rational combinations of molecularly targeted therapies, immunotherapies, and molecular targeted therapies with immunotherapies. This overview presents the historical context to this therapeutic revolution, reviews the benefits and limitations of current therapies, and provides a look ahead at where the field is headed. Clin Cancer Res; 19(19); 5283–91. ©2013 AACR.
Trials of Antidiabetic Drugs in Amyotrophic Lateral Sclerosis: Proceed with Caution?
Authors: Jawaid Ali , Paganoni Sabrina , Hauser Cecile , Schulz Paul E.
Published: October 2013

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited therapeutic options. Clinical trials of several drugs shown to be effective in the superoxide dismutase (SOD1) model of ALS have shown no or negative effects when tested in humans. Here we discuss the role of pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, which failed to show efficacy in a recently published phase II clinical trial of ALS patients. The antioxidant and anti-inflammatory properties of pioglitazone make it an attractive therapeutic candidate for neurodegenerative disorders. However, its antidiabetic and antidyslipidemic effects might be detrimental, as emerging evidence suggests that some features of the metabolic syndrome may be protective in ALS. A number of clinical studies show that dyslipidemia, high body mass index, and possibly diabetes mellitus type 2 are associated with better clinical outcomes in ALS. This is further corroborated by studies on transgenic animal models and immortalized neuronal cell lines. Finally, the intricate interplay between glucose/lipid metabolism and susceptibility to oxidative damage in neurons warrants a judicious approach in further trials of antidiabetic drugs in ALS.
Evaluation of the Internal Structure of Normal and Pathological Guinea Pig Cochleae Using Optical Coherence Tomography
Authors: Kakigi Akinobu , Takubo Yuya , Egami Naoya , Kashio Akinori , Ushio Munetaka , Sakamoto Takashi , Yamashita Shinji , Yamasoba Tatsuya
Published: October 2013

Optical coherence tomography (OCT) makes it possible to visualize the internal structures of several organs, such as the eye, in vivo. Although visualization of the internal structures of the inner ear has been used to try and identify certain pathological conditions, attempts have failed mainly due to the thick bony capsule surrounding this end organ. After decalcifying the bony wall of the cochlea with ethylenediamine tetraacetic acid, we could clearly visualize its internal structures by using OCT. We identified endolymphatic hydrops, strial atrophy and damage to the organ of Corti, evident as a distention of Reissner's membrane, thinning of the lateral wall and flattening of the organ of Corti, respectively. When specimens embedded in paraffin, sliced and stained with hematoxylin and eosin (HE) were examined under a light microscope, the OCT images of normal and pathological cochleae were virtually identical with those of the HE specimens, except that the HE specimens exhibited several artifacts unrecognized in OCT images, which were considered to be induced during the preparation process. Since OCT enables one to obtain arbitrary plane images by manipulating the slice axis of the specimens and avoids any misinterpretation due to artifacts induced during histological preparation, our technique would be useful for examining cochlear pathologies without or prior to histological evaluations.
Changes in Central Aortic Pressure, Endothelial Function and Biomarkers in Hypertensive African-Americans with the Cardiometabolic Syndrome: Comparison of Amlodipine/Olmesartan versus Hydrochlorothiazide/Losartan
Authors: Khan Bobby V. , Merchant Nadya , Rahman Syed T. , Ahmad Mushtaq , Parrott Janice M. , Umar Kanwal , Johnson Julie , Ferdinand Keith C.
Published: October 2013

Sixty-six self-identified African-American subjects with stage 1 and 2 hypertension and characteristics of the cardiometabolic syndrome were treated with amlodipine/olmesartan (A/O) versus losartan/hydrochlorothiazide (L/H) for 20 weeks in an open-label, active comparator fashion. Subjects not meeting a blood pressure (BP) value of <125/75 mm Hg on either regimen at week 14 were placed on additional or alternative therapy. After 20 weeks of therapy, systolic BP was reduced by 34.6 ± 4.2 mm Hg in the A/O group and by 27.0 ± 4.1 mm Hg in the L/H group (p = 0.012 A/O vs. L/H). Diastolic BP was reduced by 16.9 ± 2.0 mm Hg in the A/O group and by 12.3 ± 2.0 mm Hg in the L/H group (p = 0.022 A/O vs. L/H). There was a substantial increase in endothelial function of 44 and 103% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H). Central aorta augmentation pressure was significantly reduced by 42% with the A/O treatment, and a smaller, significant reduction of 28% was observed with the L/H treatment (p = 0.034 A/O vs. L/H). There was a reduction in sIL-6 levels of 20 and 33%, a reduction in serum leptin levels of 22 and 40%, and an increase in serum adiponectin of 19 and 46% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H for each biomarker). Treatment with A/O after 14 weeks reduced pulse wave velocity by 22% (p = 0.011 time comparison), whereas L/H treatment had no significant effect. Our findings suggest that, in addition to effective BP reduction, A/O differentially regulates markers of inflammation and obesity, thereby potentially providing greater vascular protection.
Malignant Hemispheric Cerebral Infarction Associated with Idiopathic Systemic Capillary Leak Syndrome
Authors: Miyata Kei , Mikami Takeshi , Mikuni Nobuhiro , Aisaka Wakiko , Irifune Hideto , Narimatsu Eichi
Published: October 2013

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare condition that is characterized by unexplained episodic capillary hyperpermeability due to a shift of fluid and protein from the intravascular to the interstitial space. This results in diffuse general swelling, fetal hypovolemic shock, hypoalbuminemia, and hemoconcentration. Although ISCLS rarely induces cerebral infarction, we experienced a patient who deteriorated and was comatose as a result of massive cerebral infarction associated with ISCLS. In this case, severe hypotensive shock, general edema, hemiparesis, and aphasia appeared after serious antecedent gastrointestinal symptoms. Progressive life-threatening ischemic cerebral edema required decompressive hemicraniectomy. The patient experienced another episode of severe hypotension and limb edema that resulted in multiple extremity compartment syndrome. Treatment entailed forearm and calf fasciotomies. Cerebral edema in the ischemic brain progresses rapidly in patients suffering from ISCLS. Strict control of fluid volume resuscitation and aggressive diuretic therapy may be needed during the post-leak phase of fluid remobilization.
Persistent enhanced platelet activation in patients with acute myocardial infarction and coronary microvascular obstruction: clinical implications
Authors: Aurigemma Cristina , Scalone Giancarla , Tomai Fabrizio , Altamura Luca , Persio Giovanni De , Stazi Alessandra , Crea Filippo , Lanza Gaetano A.
Published: October 2013

About 30% of patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing recanalisation of the infarct-related coronary artery do not achieve valid myocardial reperfusion (no-reflow phenomenon or coronary microvascular obstruction [MVO]). The mechanisms of MVO are incompletely understood. In this study we investigated the role platelet activation in the pathogenesis of coronary MVO in STEMI patients. We enrolled 48 STEMI patients (age 56.2 ± 11 years; 31 men), treated by primary percutaneous coronary intervention (PCI) followed by double anti-platelet treatment, and 20 control patients with stable coronary artery disease (CAD) on single antiplatelet treatment (age 57.5 ± 6 years, 12 men). STEMI patients were divided into two groups: 35 patients with complete myocardial reperfusion (MR) and 13 patients with coronary MVO despite successful PCI. Platelet activation was assessed on admission and at one-month follow-up by measuring platelet receptor expression and monocyteplatelet aggregates (MPAs). Platelet receptor expression, platelet receptor conformational change for fibrinogen binding availability and MPA formation were increased in STEMI patients with MVO compared to both STEMI patients with MR and stable CAD patients, both on admission and at one-month follow-up (p<0.05 for all). Among STEMI patients, platelet activation is greater in those who display coronary MVO, compared to those with MR, after successful PCI, both on admission and one month after STEMI, suggesting that enhanced platelet activation might be involved in the pathogenesis of MVO. The persistence of enhanced platelet activation despite double classical anti-platelet therapy suggests that new anti-platelet strategies should be considered in patients with coronary MVO.
Circulating CD45+/CD3+ lymphocyte-derived microparticles map lipid-rich atherosclerotic plaques in familial hypercholesterolaemia patients
Authors: Suades Rosa , Padró Teresa , Alonso Rodrigo , López-Miranda José , Mata Pedro , Badimon Lina
Published: October 2013

Circulating microparticles (cMPs) seem to play important roles in vascular function. Beyond markers of activated cells, cMPs may have potential paracrine functions and influence atherosclerosis. Here, our objective was to characterise a) the abundance and phenotype of cMPs in stable statin-treated heterozygous familial hypercholesterolaemia (FH) patients exposed to life-long hypercholesterolaemia and b) the principal phenotype associated to lipid-rich atherosclerotic plaques in hFHpatients with significant atherosclerotic plaque burden. An age/gender/ treatment-matched group of adult-onset non-FH hypercholesterolaemic patients (n=37/group) was comparatively analysed. cMPs were characterised by flow cytometry using annexin-V and cell surface-specific antibodies. Our study shows that LLT-FH patients had higher overall cMP-numbers (p<0.005) than LLT-non-FH patients. Endothelial cellshed cMPs were also significantly higher in FH (p<0.0005). Within the leukocyte-derived cMP-subpopulations, FH-patients had significantly higher lymphocyte- and monocyte-derived cMP-numbers as well as cMPs carrying leukocyte-activation markers. Normalisation of cMPs by LDL levels did not affect cMP number or phenotype, indicating that the proinflammatory effect was derived from chronic vascular damage. Levels of AV+-total, CD45+-pan-leukocyte and CD45+/CD3+-lymphocyte-derived cMPs were significantly higher in FH-patients with subclinical lipid-rich atherosclerotic plaques than fibrous plaques. Levels of CD45+/CD3+-lymphocyte-MPs above 20,000/ml could differentiate between FH-patients with lipidic or non-lipidic plaques (area under the ROC curve of 0.803, 95%CI: 0.641–0.965, p=0.008). In summary, in this snapshot cross-sectional study cMP concentration and phenotype in FH differed markedly from non-FH hypercholesterolaemia. Patients with life-long high LDL exposure have higher endothelial activation and higher proinflammatory profile, even under current state-of-the-art LLT. cMPs carrying lymphocyte-epitopes appear as markers of lipid-rich atherosclerotic plaques in FH.
Intralesional Abciximab and Thrombus Aspiration in Patients With Large Anterior Myocardial Infarction
Authors: Stone Gregg W. , Witzenbichler Bernhard , Godlewski Jacek , Dambrink Jan-Henk E. , Ochala Andrzej , Chowdhary Saqib , El-Omar Magdi , Neunteufl Thomas , Metzger David Christopher , Dizon Jose M. , Wolff Steven D. , Brener Sorin J. , Mehran Roxana , Maehara Akiko , Gibson C. Michael
Published: October 2013

Background—

Whether intralesional abciximab administration and thrombus aspiration confer clinical benefits to patients undergoing primary percutaneous coronary intervention for ST-segment–elevation myocardial infarction is controversial.

Methods and Results—

A total of 452 patients with ST-segment–elevation myocardial infarction caused by proximal or mid left anterior descending artery occlusion undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation were randomized in a 2×2 factorial design to bolus abciximab delivered locally at the infarct lesion site versus no abciximab and to manual thrombus aspiration versus no aspiration. Treatment with intralesional abciximab, thrombus aspiration, or both therapies compared with no active therapy before stent implantation resulted in lower 1-year rates of death (4.5% versus 10.4%;
P
=0.03), severe heart failure (4.2% versus 10.3%;
P
=0.02), and stent thrombosis (0.9% versus 3.8%;
P
=0.046). Between 30 days and 1 year of follow-up, treatment with intralesional abciximab compared with no abciximab was associated with a lower rate of death (1.4% versus 4.9%;
P
=0.04) and composite major adverse ischemic events (3.3% versus 7.8%;
P
=0.04), with nonsignificantly different overall 1-year rates of mortality, composite ischemic events, and heart failure–related events. Thrombus aspiration compared with no aspiration was associated with lower rates of new-onset severe heart failure between 30 days and 1 year (0.9% versus 4.5%;
P
=0.02) and of rehospitalization for heart failure from randomization to 1 year (0.9% versus 5.4%;
P
=0.0008), with nonsignificantly different rates of mortality.

Conclusions—

Intralesional abciximab and thrombus aspiration may have long-term benefits in patients with anterior ST-segment–elevation myocardial infarction presenting early after symptom onset and undergoing primary percutaneous coronary intervention with bivalirudin anticoagulation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00976521.
Long-Term Evolution and Prognostic Stratification of Biopsy-Proven Active Myocarditis
Authors: Anzini Marco , Merlo Marco , Sabbadini Gastone , Barbati Giulia , Finocchiaro Gherardo , Pinamonti Bruno , Salvi Alessandro , Perkan Andrea , Di Lenarda Andrea , Bussani Rossana , Bartunek Jozef , Sinagra Gianfranco
Published: October 2013

Background—

Active myocarditis is characterized by large heterogeneity of clinical presentation and evolution. This study describes the characteristics and the long-term evolution of a large sample of patients with biopsy-proven active myocarditis, looking for accessible and valid early predictors of long-term prognosis.

Methods and Results—

From 1981 to 2009, 82 patients with biopsy-proven active myocarditis were consecutively enrolled and followed-up for 147±107 months. All patients underwent clinical and echocardiographic evaluation at baseline and at 6 months. At this time, improvement/normality of left ventricular ejection fraction (LVEF), defined as a LVEF increase > 20 percentage points or presence of LVEF≥50%, was assessed. At baseline, left ventricular dysfunction (LVEF<50%) and left atrium enlargement were independently associated with long-term heart transplantation–free survival, regardless of the clinical pattern of disease onset. At 6 months, improvement/normality of LVEF was observed in 53% of patients. Persistence of New York Heart Association III to IV classes, left atrium enlargement, and improvement/normality of LVEF at 6 months emerged as independent predictors of long-term outcome. Notably, the short-term reevaluation showed a significant incremental prognostic value in comparison with the baseline evaluation (baseline model versus 6 months model: area under the curve 0.79 versus 0.90,
P
=0.03).

Conclusions—

Baseline left ventricular function is a marker for prognosis regardless of the clinical pattern of disease onset, and its reassessment at 6 months appears useful for assessing longer-term outcome.
Migraine and Hemorrhagic Stroke
Authors: Sacco Simona , Ornello Raffaele , Ripa Patrizia , Pistoia Francesca , Carolei Antonio
Published: October 2013

Background and Purpose—

Several studies have assessed the possible increased risk of hemorrhagic stroke in migraineurs, drawing differing conclusions. No meta-analysis on the topic has been published to date.

Methods—

Multiple electronic databases (MEDLINE, EMBASE, Science Citation Index, and the Cochrane Library) were systematically searched up to March 2013 for studies dealing with migraine and hemorrhagic stroke. We selected case–control and cohort studies with a clear definition of the diagnostic criteria for migraine and hemorrhagic stroke, using an adjusted model or a matching procedure that could control for potential confounders, and reporting effect estimates with 95% confidence intervals (CIs) or enough data to allow calculation of those numbers. Adjusted odds ratios and hazard ratios were used to estimate effect size.

Results—

Of 11 264 records, we identified 8 studies (4 case–control and 4 cohort studies) involving a total of 1600 hemorrhagic strokes, which were included in the meta-analysis. The overall pooled adjusted effect estimate of hemorrhagic stroke in subjects with any migraine versus control subjects was 1.48 (95% CI, 1.16–1.88;
P
=0.002), with moderate statistical heterogeneity (I
2
=54.7%;
P
value for Q test=0.031). The risk of hemorrhagic stroke in subjects with migraine with aura (1.62; 95% CI, 0.87–3.03;
P
=0.129) was not significant. Compared with control subjects, the risk of hemorrhagic stroke was greater in females with any migraine (1.55; 95% CI, 1.16–2.07;
P
=0.003) and in female migraineurs aged less than 45 years (1.57; 95% CI, 1.10–2.24;
P
=0.012).

Conclusions—

Available studies suggest that subjects with migraine have an increased risk of hemorrhagic stroke. Further studies are needed to address the hemorrhagic stroke risk according to migraine type, age, sex, and hemorrhagic stroke type.
Raffaele Pettazzoni from the Perspective of the Anglophone Academy
Authors: Rennie Bryan
Published: October 2013

Abstract

There should be no need to emphasize the significance of Raffaele Pettazzoni (1883–1959) to historians of religions. However, there are only two books by Pettazzoni available in the English language: the monographThe All-knowing God(1956; original:L’onniscienza di Dio, 1955) and an anthology ofEssays on the History of Religions(1954), which is “a collection of sundry writings on various subjects connected with the History of Religions, which have been already published on different occasions in Italian and foreign periodicals” (Pettazzoni 1954).2 Added to this is a tiny collection of articles in English (in fact, the American Theological Libraries Association database references only three). This seems to constitute a serious neglect of such a productive scholar, who has been called an “exemplary historian of religions.” This paper will attempt to assess the reception of the work of Raffaele Pettazzoni in the Anglophone Academy, to question the adequacy and accuracy of that reception, and to indicate what might be learned from it.
Etymological Follies
Authors: Lee John A.L.
Published: October 2013

Abstract

Three smaller lexicons of NT Greek have recently appeared, all introducing etymological material of various kinds. This paper examines the execution and sources in each lexicon and points out serious problems arising from dependence on obsolete works as well as other weaknesses. In conclusion the value of including etymologies in NT lexicons is assessed and the future direction considered.
1 Corinthians 2:14
Authors: Lambrecht Jan
Published: October 2013

Abstract

Can we accept the translation of the second half of 1 Cor 2:14 as proposed by L.B. Dingeldein: (The “psychic” man) is unable to know “that he is pneumatically examined”? An analysis of the preceding and following context of the verse indicates that the traditional causal version is to be preferred: (The “psychic” man) cannot know them (= the things of God’s spirit), “because they are spiritually discerned.”