Median Arcuate Ligament Syndrome

Is the Prevalence of Estimated Pelvic Congestion Higher than Examined? A Retrospective Study of Consecutive Abdominopelvic Computed Tomography Analyses

Background: Chronic Pelvic Pain (CPP) is a common complaint in women, and is the key factor in the diagnosis of Pelvic Congestion Syndrome (PCS).

Introduction: Consecutive abdominal and pelvic Computed Tomography (CT) scans in adult female patients not diagnosed with PCS and collected over a period of 3 years were evaluated retrospectively to determine the prevalence of underestimated Pelvic Congestion (PC).

Methods: 500 consecutive abdominal and pelvic CT scans collected from female patients aged 18-80 years were retrospectively analyzed for the presence of PC.

Results: 90 of the CT scans examined showed the presence of PC (18%). These patients were divided into two groups: Group I had 52 scans with unilateral PC, while Group II had 38 scans with the bilateral enlarged Ovarian Vein (OV). Left and right OV diameters were measured as 7.14±2.15 and 5.56±1.87 mm, respectively. Co-occurrence of additional vascular anomalies, such as nutcracker- type compression of the left renal vein, and May Thurner, was significantly higher in Group I than Group II (p<0.001). The diameter of the OV remained wide irrespective of age in Group I, but showed a decrease with increasing age in Group II. The most common complaint was abdominal pain; these patients required an average of six referrals to two different clinics (primarily general surgery and internal medicine) before being diagnosed with PC.

Conclusion: The diagnosis of PCS remains to be an important problem for patients because of insufficient perception of physicians. PCS should be considered in female patients with complaints of chronic abdominal and pelvic pain and CT may be a valuable examination tool for diagnosis.

Anticoagulation after Iliofemoral Vein Stenting - Old Versus New

In recent years, there has been an increasing interest in endovascular iliofemoral vein stenting to prevent/ alleviate symptoms related to proximal venous outflow obstruction. Maintaining long-term stent patency is one of the main challenges, and risk factors for the development of re-thrombosis are not well understood. Published data on the safety and efficacy of the procedure predominantly come from cohort studies mainly focusing on mechanical aspects relating to stent placement and flow. Aetiology of thrombus formation and thrombotic tendencies of patients due to underlying medical conditions are not captured well or linked to clinical outcomes, and the impact of choice and length of antithrombotic therapy have not been specifically investigated. Here, we review different procedure-related factors and patient characteristics that might increase the risk of re-thrombosis and the utility of antithrombotic treatment options currently available.

Lentiviral Vectors: A Versatile Tool to Fight Cancer

Over the years, there has been an exponential increase in the number of gene therapy approaches that are under investigation for the treatment of cancer. This can be attributed to our growing understanding of the molecular mechanisms that contribute to the onset and maintenance of cancer as well as to the development of gene delivery vectors. In this review, we will focus on the use of lentiviral vectors (LVs) in immuno gene therapy of cancer, as these efficacious gene delivery vehicles have come to the forefront because of their many attractive features. LVs have been successfully applied to generate potent dendritic cellbased anti-cancer vaccines and to deliver cancer-specific receptors to T-cells. Moreover, LVs are under investigation for the modulation of cancer cells. We will describe various strategies of this ‘genuine’ cancer gene therapy, amongst which transfer of suicide genes, modulation of pro- and anti-apoptotic molecules, strategies to optimize chemo- and radiotherapy, expression of molecules that affect angiogenesis or affect the immunogenicity of tumor cells. These will be discussed in view of our current knowledge of tumor immunology. Finally we will discuss some important issues and future directions to push the field forward.

The Role of NPY and Ghrelin in Anorexia Nervosa

Complex mechanisms have evolved that control feeding and energy homeostasis in mammals. Centrally, particularly in the hypothalamus, numerous neurotransmitters have been identified that regulate appetite and energy homeostasis. On the other hand, hormones released from the gut signal states of hunger and satiety to the brain. From the large number of players involved in this interplay, peptides from the neuropeptide Y (NPY) family are unique, with the predominantly neuronally expressed NPY being one of the most strongly stimulating agents for food intake while its two other closely related family members peptide YY (PYY) and pancreatic polypeptide (PP) released from the gut induce satiety. Another major player in this circuitry is ghrelin, which is released from the stomach and is the only known hormone that signals hunger to the brain. It is doing this by stimulating hypothalamic NPY production and release, subsequently leading to increased appetite and feeding behaviour. Deregulation of these processes can lead to either the development of obesity or the other extreme, anorexia. The aim of this review is to summarize the recent literature on NPY and ghrelin and its involvement in anorexia nervosa.

Immunotherapy for Malignant Melanoma Robert

Treatment of metastatic melanoma is a challenge for clinicians as most agents have failed to demonstrate improved survival in phase III trials. Despite the immunogenicity of this tumor entity, different immunological interventions including cytokine therapy, vaccination, biochemotherapy or allogeneic hematopoietic cell transplantation did not lead to a satisfactory response. However, continuous investigation on the immune mediated rejection of melanoma cells has led to the development of effective antibodies blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4), a critical negative regulator of the antitumor T-cell response. Based on data from rodent models, the anti-CTLA-4 antibody ipilimumab was developed into clinical studies where it had encouraging activity in advanced melanoma with unusual response patterns. As in most immunostimulatory therapies, acute toxicities were severe and clearly mechanism-related. Although some patients developed signs of autoimmunity, the toxicities were overall manageable and mostly reversible.

This review summarizes different immunotherapeutical approaches against melanoma that have been applied in the past and focuses on CTLA-4 blockade with respect to its mechanism, clinical effectiveness and immunological side effects.

Gene Therapy and Targeted Toxins for Glioma

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of 15-18 months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenograft, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in preclinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.

Steroid Resistance in Severe Asthma: Current Mechanisms and Future Treatment

The disproportionate cost of treating asthmatic patients who do not respond to conventional anti-inflammatory therapies makes delineation of the mechanism for glucocorticoid resistance an important field of asthma research. Unbiased cluster analysis indicates that asthma is a syndrome with a number of distinct phenotypes and 5-10% of asthmatics fall into this category of relative glucocorticoid insensitivity. This sub-population is itself divided into smaller subsets which have different underlying mechanisms for this relative glucocorticoid resistance ranging from an inherited genetic basis to specific kinase signalling pathways triggered by exposure to environmental stressors such as cigarette smoking or infection. Whilst the underlying mechanisms are becoming better understood there remains a lack of effective novel therapies. However it is clear that relative glucocorticoid insensitive patients who are smokers should be encouraged to quit, thereby reducing their oxidant load. Novel treatments will consist of either developing new anti-inflammatory treatments targeting pathways aberrantly activated in these patients or of suppressing signalling pathways that attenuate glucocorticoid receptor function and thereby restoring glucocorticoid sensitivity. It will be important to uncover non-invasive biomarkers for aberrant pathway activation and for discerning which components of glucocorticoid receptor activation are abnormal if future treatments are to be tailored to address these specific issues. Conventional combination therapies will continue to be used in the near future but additional add-on treatments using drugs directed against aberrantly expressed inflammatory pathways or mediators along with an inhaledglucocorticoid are likely to prove the most effective new therapies in the future.

Tachykinin Receptors as Therapeutic Targets in Stress-Related Disorders

The first report demonstrating the therapeutic efficacy of an orally applied neurokinin-1 (NK1) receptor antagonist in depression was published 10 years ago. Although there were difficulties to reproduce this particular finding, a huge amount of data has been published since this time, supporting the potential therapeutic value of various tachykinin ligands as promising novel tools for the management of stress-related disorders including anxiety disorders, schizophrenia and depression. The present review summarizes evidence derived from anatomical, neurochemical, pharmacological and behavioral studies demonstrating the localization of tachykinin neuropeptides including substance P (SP), neurokinin A, neurokinin B and their receptors (NK1, NK2, NK3) in brain areas known to be implicated in stress-mechanisms, mood/anxiety regulation and emotion-processing; their role as neurotransmitters and/or neuromodulators within these structures and their interactions with other neurotransmitter systems including dopamine, noradrenaline and serotonin (5- hydroxytryptamine, 5-HT). Finally, there is clear functional evidence from animal and human studies that interference with tachykinin transmission can modulate emotional behavior. Based on these findings and on evidence of upregulated tachykinin transmission in individuals suffering from stress-related disorders, several diverse tachykinin receptor antagonists, as well as compounds with combined antagonist profile have been developed and are currently under clinical investigation revealing evidence for anxiolytic, antidepressant and antipsychotic efficacy, seemingly characterized by a low side effect profile. However, substantial work remains to be done to clarify the precise mechanism of action of these compounds, as well as the potential of combining them with established and experimental therapies in order to boost efficacy.

Dengue: Recent Advances in Biology and Current Status of Translational Research

Dengue is a very rapidly growing public health problem being currently faced by ∼40% of the global population living in more than a hundred tropical and sub-tropical countries. It is a viral disease, caused by four types of dengue viruses, transmitted by mosquitoes, to an estimated 50 million people each year. Vector control methods to contain transmission have not been successful and there is currently no useful diagnostic test, drug or vaccine to combat dengue disease. However, as a result of the heightened awareness of its magnitude and its potential to spread beyond the tropical world, dengue has begun to emerge out of the list of neglected diseases in recent years. New interest in this disease has drawn scientists from multiple disciplines into the dengue arena. This has resulted in novel insights into several aspects of dengue virus biology and identified potential drug targets. Several tetravalent vaccines are being developed. Newer animal models that mirror some of the salient features of dengue disease are becoming available to investigate the mechanism of pathogenesis and to aid in drug and vaccine discovery efforts. The realization that therapeutic and prophylactic intervention can be cost-effective has resulted in vigorous industry-driven translational initiatives to develop drugs and vaccines. Dengue research is at a critical juncture and the implementation of existing knowledge supplemented by a better understanding of pathogenesis promises to make a tangible impact in the combat against dengue in the coming years.

The Importance of Steroidomics in the Study of Neurodegenerative Disease and Ageing

In this mini review, the importance of experimental steroidomics in the study of neurodegenerative disease and aging is discussed. Attention is focused on just one class of lipid which is based on the cyclopentanoperhydrophenanthrene ring system. Experimental methods for steroidomic analysis are reviewed, and the potential to use these methods to diagnose disease and to gain a better understanding of neurodegenerative disorders is examined.

Current Status of Pharmacological Thrombolytic Therapy and Mechanical Thrombectomy for the Treatment of Acute Deep Venous Thrombosis

Deep venous thrombosis (DVT) is a highly prevalent clinical problem associated with significant mortality and morbidity. In the United States alone, it is estimated that DVT affects approximately 50 per 100,000 people per year. This results in > 600,000 inpatient and outpatient treatments per year and accounts for approximately 100,000 deaths from thromboembolic complications. Post-thrombotic syndrome (PTS) is associated with serious long-term physical, social and economic sequelae for patients. In this article, we attempt to perform a contemporary review of the literature pertaining to the use of thrombolytic therapy and endovascular thrombectomy in the treatment of acute DVT.

Antigenic Peptide Vaccination: Provoking Immune Response and Clinical Benefit for Cancer

Recent immunotherapy depends largely on understanding of the molecular interactions between T cell receptors (TCR) on cytotoxic T lymphocytes (CTL) and peptide/MHC class I complexes on tumor cells. Many tumor antigens identified by cDNA library expression cloning methods, especially from malignant melanoma, have greatly contributed to clarifying such mechanisms and led to peptide vaccination trials, mainly for patients with melanoma. Although the objective tumor regression rate mediated by peptide vaccination is still low compared to adoptive cell transfer therapy, antigenic peptide vaccination can cause a constant objective response generally evaluated as stable disease or decreased serum levels of tumor markers. In addition, recent trials in the adjuvant setting showed some suppressive effects against recurrence. Therefore, peptide vaccination still has potential for clinical benefits in patients with various cancers. For further improvement of peptide vaccination, we considered that (i) novel antigenic peptides, (ii) effective adjuvants, (iii) more sensitive immunological monitoring and (iv) drugs up-regulating HLA class I molecules might be important.

Inhibition of RNA Virus Infections with Peptide-Conjugated Morpholino Oligomers

RNA virus infections cause immense human disease burdens globally, and few effective antiviral drugs are available for their treatment. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are nuclease resistant and water-soluble single-stranded-DNA-analogues that can enter cells readily and act as steric-blocking antisense agents through stable duplex formation with complementary RNA. Recently there have been a number of publications documenting sequence-specific and dose-dependent inhibition of non-retroviral RNA virus infections by PPMO in both cell culture and murine experimental systems. PPMO have suppressed viral titers by several orders of magnitude in cell cultures, and have reduced viral replication in and/or increased survivorship of mice experimentally infected with poliovirus, coxsackievirus B3, dengue virus, West Nile virus, Venezuelan Equine encephalitis virus, respiratory syncytial virus, Ebola virus and influenza A virus. Along with evaluating PPMO efficacy and toxicity, these studies also explored PPMO mechanism of action, pharmacologic properties and the generation and characterization of resistant virus. Effective PPMO target sites in viral RNA have included regions of highly conserved sequence thought to be important in the pre-initiation or initiation of translation, or in long-range RNA-RNA interactions involved in viral RNA synthesis. These studies provide guidance for the design of steric-blocking antisense agents against RNA viruses, insights into viral molecular biology and novel strategies for the development of antiviral therapeutics. The purpose of this review is to summarize notable findings from the reports documenting antiviral activity by PPMO, with a focus on the specific regions of viral RNA that provided the most effective targets for PPMO-based inhibition of viral replication.

Dendritic Cell Immunotherapy for Acute Inflammatory Diseases

Acute inflammation and the innate immune response to tissue trauma mark a critical pathophysiological challenge within the clinical course of severely injured and critically ill patients. Among the most potent cellular components of the innate host defense system are dendritic cells (DC). This highly effective network of antigen-presenting cells (APC) carries the ability to initiate and amplify diverse immune responses in respect of an appropriate activation signal. Upon activation, DCs direct the immune response towards developing either a Th1 or Th2 response, thus determining the outcome of the inflammatory or infectious stimulus. Advances in the understanding of DC immunobiology have provided new concepts in the treatment of various inflammatory diseases. With gene therapy constantly evolving new methods of celltargeted manipulation of gene expression, DCs have proven to be an exciting new tool in functionally modulating the immune response. In this review we summarize the pivotal functions of DCs and highlight their promising potency of representing an effective immunotherapeutic tool in the treatment of acute inflammation.

Gene Therapy and Targeted Toxins for Glioma

The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted, this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors.

Experimental Onco-Immunology Revisited

The search for the cause of cancer has led to five successive theories involving viruses, oncogenes, tumor suppressor genes, somatic mutation cascade and inflammation. The latter, without discarding the former theories, is now the prevailing paradigm recognizing that neoplastic cells require participation of the microenvironment for tumor progression. Inflammatory reactions are dependent on an overabundance of immune responses which are both in favor and against tumor development. This homeostatic immunological behavior has led to the concept of tumor immunoediting in an attempt to elucidate why tumors grow. This review is a non-exhaustive description of the different experimental highlights which have led to our present knowledge of cancer. During its 47 years of existence, our laboratory has contributed extensively to the experimental development of onco-immunology, so that our results are described within the background of international discoveries. As for cancer therapy, the many attempts made, both at the experimental and clinical levels, have been mainly frustrating and yet, as oncologists, we are always ready to try again.

Immunotherapy and Cancer Vaccines in the Management of Breast Cancer

Besides the traditional therapeutic options, treatment with antibodies specific for the receptor tyrosine kinase HER-2/neu has been established as a standard therapy in the clinical management of advanced breast cancer. Ongoing clinical studies focus on the improvement of application protocols in order to minimize side effects and evaluate the potential therapeutic benefit of anti-HER-2/neu antibodies in combination with conventional chemotherapy. Various similar strategies to target other tumour-associated antigens or proangiogenic factors with inhibitory antibodies are currently investigated in promising preclinical and clinical trials. In addition, research efforts are made to develop procedures to generate tumour-specific cellular immune responses in breast cancer patients. Therapeutic vaccination is, however, still at an early stage of development, despite encouraging results of animal studies. We summarise and discuss vaccination strategies with tumour-specific proteins or peptides, pulsed dendritic cells, and modified tumour cells as well as antibody-based therapeutic concepts to target HER-2/neu, EGF receptor, MUC-1, uPA/uPAR, and VEGF.

Melanoma Immunotherapy: Past, Present, and Future

The incidence of cancer and its related morbidity and mortality remain on the increase in both developing and developed countries. Cancer remains a huge burden on the health and social welfare sectors worldwide and its prevention and cure remain two golden goals that science strives to achieve. Among the treatment options for cancer that have emerged in the past 100 years, cancer vaccine immunotherapy seems to present a promising and relatively safer approach as compared to chemotherapy and radiotherapy. The identification of different tumour antigens in the last fifteen years using a variety of techniques, together with the molecular cloning of cytotoxic T lymphocytes (CTLs)- and tumour infiltrating lymphocytes (TILs)-defined tumour antigens allowed more refining of the cancer vaccines that are currently used in different clinical trials. In a proportion of treated patients, some of these vaccines have resulted in partial or complete tumour regression, while they have increased the disease-free survival rate in others. These outcomes are more evident now in patients suffering from melanoma. This review provides an update on melanoma vaccine immunotherapy. Different cancer antigens are reviewed with a detailed description of the melanoma antigens discovered so far. The review also summarises clinical trials and individual clinical cases in which some of the old and current methods to vaccinate against or treat melanoma were used. These include vaccines made of autologous or allogenic melanoma tumour cells, melanoma peptides, recombinant bacterial or viral vectors, or dendritic cells.

Gamma-Glutamyl Transferase and Male Reproductive Hormone Levels in Men with Type 2 Diabetes: A Cross-Sectional Study

Introduction: Although Gamma-Glutamyl Transferase (GGT) has been implicated in metabolic disorders, its association with male reproductive hormones in type 2 diabetes mellitus (T2DM) remains unclear.

Methods: In this cross-sectional study, 971 men with T2DM were recruited from Shandong Provincial Hospital. Serum GGT levels were measured as the primary exposure variable, while male reproductive hormones—including total testosterone (TT), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin (SHBG)—served as outcome variables. Multivariable linear regression, threshold effect models, and subgroup analyses were used to assess associations, adjusting for age, BMI, glycemic control, and other confounders.

Results: The mean age of participants was 56.37 ± 12.49 years. After full adjustment, men in the highest GGT tertile exhibited a 0.44 ng/mL reduction in TT levels compared to the lowest tertile (P < 0.01). A nonlinear relationship was identified, with a saturation effect at GGT = 118 IU/L. Below this threshold, each 10-IU/L increase in GGT corresponded to a 0.13 ng/mL decrease in TT (95% CI: −0.21 to −0.05). Unadjusted inverse associations with SHBG (β=-14.87, 95%CI:-26.47 to -3.28) and LH (β=-1.34, 95%CI:-2.14 to -0.54) became nonsignificant after adjustment (P>0.05). No FSH associations were detected.

Discussion: Our findings reveal a novel dose-dependent relationship between GGT and testosterone in T2DM, with effects plateauing beyond 118 IU/L. This threshold may reflect the point where oxidative stress overwhelms gonadal compensatory mechanisms.

Conclusion: The nonlinear relationship suggests GGT may help identify androgen deficiency risk, though SHBG/LH links appear confounder-dependent. Monitoring GGT could aid T2DM male health management.