Discovery Category Highlights

Fibromyalgia, Autism, and Opioid Addiction as Natural and Induced Disorders of the Endogenous Opioid Hormonal System

Abstract: Introduction: Because of their circulation through the blood, the multiplicity of receptor sites, and the diversity of functions, opioids may most accurately be designated as a hormone. Opioids modulate the intensity of pain. In mammals, the opioid system has been modified to modulate social interactions as well (Panksepp and Watt, 2011). Methods: Over 10,000 patient encounters were observed on a neuropsychoanalytic addiction medicine service. Cold pressor times (CPT) were recorded before and after stimulation of the opioid system with low-dose naltrexone (LDN) for patients after opioid detoxification and for fibromyalgia patients. Results: Patients maintained on opioids relate autistically. The cold, unrelated nature of their human interactions was reversed by detoxification from opioids. Fibromyalgia patients have difficulty participating in human relationships, as if they lack an ability to respond interpersonally, as do post-detoxification patients. LDN improved pain tolerance as shown by a significant increase on CPT for post detoxification patients from 16 seconds to 55 seconds and in fibromyalgia patients from 21 seconds to 42 seconds, and improved relatedness. The correlation of opioid prescribing increasing over time and autism prevalence increasing over time is highly significant. Conclusions: 1. Opioid-maintained patients relate autistically. 2. Autism is a hyperopioidergic disorder. 3. Fibromylagia is a hypoopioidergic disorder. 4. Low opioid tone caused by opioid maintenance or fibromyalgia can usually be reversed with low-dose naltrexone. 5. The increase in the incidence of autism may have been caused by the increase in use of opioids for analgesia during childbirth. ... Read more

Recent Advances in the Treatment of Hepatitis C

Abstract: Hepatitis C virus (HCV) therapeutics is amidst a revolution. With the recent approval of sofosbuvir (Sovaldi) and simeprevir (Olysio), clinicians and patients started to recognize that for the first time in the history, hepatitis C can be cured in a majority of patients without interferon. These new regimens are safe, and have excellent efficacy and minimal adverse events. Sofosbuvir, a nucleotide analogue (NS5B polymerase inhibitor), is a potent drug with excellent tolerability and pan-genotypic activity with a high barrier to resistance. Simeprevir, a second-generation protease inhibitor which inhibits the initial cleavage of the HCV poly-protein by the NS3/4A protease. Simeprevir has been evaluated in clinical trials in combination with interferon and ribavirin based therapy and also in the COSMO trial in combination with sofosbuvir. More directly acting antiviral therapy drugs are in the pipeline with several drugs being expected to be approved by the FDA in late 2014. Although these drugs have excellent efficacy, they are more costly. The price of these drugs limits treatments of many patients in the world especially in countries with limited economic resources. However, with the availability of a variety of excellent directly acting antivirals (DAAs) in the near future, hopefully many patients would be able to afford the treatment. The future in HCV therapy will focus on special groups of patients who were excluded from initial HCV clinical trials such as post-liver transplant HCV recurrence, patients with HCV/HIV co-infection, and patients with advanced cirrhosis. ... Read more

Advances in Pathogenesis and Treatment of ANCA-associated Vasculitis

Abstract: Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA) are sensitive and specific markers for their associated diseases, granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) and microscopic polyangiitis (MPA), respectively. Clinical observations suggest but do not prove that ANCA are involved in the pathogenesis of GPA and MPA. In vivo and in vitro experimental data strongly suggest if not prove that MPO-ANCA underlie the pathological lesions seen in MPO-ANCA associated MPA. This is less clear for PR3-ANCA associated GPA in which, besides small-vessel vasculitis, granulomatous inflammation is apparent. Here, cellular immunity appears to play an additional role. Insight into the pathogenetic events involved in these diseases has resulted in new ways of treatment that target the specific pathways that underlie the development of the lesions. ... Read more

HBsAg-negative Hepatitis B Virus Infection and Hepatocellular Carcinoma

Abstract: Hepatitis B virus (HBV) is the major causative agent of chronic hepatitis, hepatic decompensation, liver cirrhosis, and hepatocellular carcinoma (HCC). HBV-related serum markers are widely used in clinical diagnosis and prognosis for HBV infection. Among them, the HBV surface antigen (HBsAg) was once regarded as the sole marker for infection. The serum levels of HBsAg, along with HBV DNA levels, are the most important predictors of the risk of developing HCC. Higher levels of HBsAg are usually connected with a higher risk and lower levels of HBsAg are usually connected with a lower risk. However, negative results for serum HBsAg tests do not always represent a clearance or inactivating status of HBV viruses. HCC could still develop in the absence of detectable HBsAg in serum. This situation is called occult hepatitis B virus infection (OBI). OBI is characterized by the presence of HBV viral genome in the patient's liver but no virus surface antigen (HBsAg) detected in serum by commonly used immunoassays. Although there may not be much difference in the extent of HBV genome replication in OBI (HBsAg negative) and the overt HBV infections (HBsAg positive), the duration of HBV replication and its pathological consequences last much longer in OBI than in overt infections. This paper provides a comprehensive review on the reasons behind OBI, the clinical impact of OBI on the development of HCC, and the urgency for implementing new methodological techniques for detecting OBI. ... Read more

The Value of Contrast-Enhanced Ultrasound (CEUS) in Detecting Minute Renal Cell Carcinoma

Abstract: Objectives: To investigate the value of contrast-enhanced ultrasound (CEUS) in the detection of minute renal cell carcinoma (MRCC) compared to conventional ultrasound (US) and contrast-enhanced computed tomography (CECT). Methods: Thirty-eight consecutive patients with 38 histopathologically proven MRCCs (≦15 mm) were enrolled in our study. CEUS and CECT were available in 38 and 24 patients, respectively. The features of CEUS were evaluated and compared to conventional ultrasound (US) and CECT. Results: Ten (26.3%) tumors could not be detected by conventional US, while all tumors were detected by CEUS. The features of tumor border, blood flow, and echogenicity had significant difference between conventional US and CEUS (p=0.000, p=0.003, and p=0.012, respectively). The score of visibility of tumors by CEUS was significant higher than that of conventional US. The sensitivity, specificity, and accuracy of conventional US and CEUS in evaluating tumor necrosis were 42.9%, 50%, and 47.4% vs. 85.7%, 95.8%, and 92.1%, respectively. The enhancement features of MRCC including tumor vascularization, homogeneity, and border had no significant difference between CEUS and CECT (all p>0.05). On CEUS, synchronous-in (89.5%), hypervascular (84.2%), and fast-out (71.1%) were the most commonly observed enhancement characteristics for MRCC. Conclusion: CEUS performs better in detecting MRCC than conventional US, and it has the same capabilities in reflecting the enhanced features of MRCC as CECT. ... Read more

Doxorubicin Encapsulated in Micelles Enhances Radiosensitivity in Doxorubicin-resistant Tumor Cells

Abstract: To evaluate the efficacy of doxorubicin (DOX) loaded micelles in enhancing DOX radiosensitivity in DOX-resistant K562 tumor cells (K562/DOX cells), DOX loaded polyethylene glycol-polycaprolactone (PEG-PCL) copolymer micelles and pluronic 105 (P105) micelles, and composite micelles composed of PEG-PCL and P105 were prepared. By using MTT assay, soft agar cloning assays, confocal laser scanning microscopy, and flow cytometry analyses to evaluate the radiosensitivity of each compound, DOX loaded micelles were found to increase the radiosensitivity of K562/DOX cells, as revealed by a marked cellular uptake and its sustained, slower release than free DOX. The micelles encapsulating DOX significantly enhanced its cytotoxicity in K562/DOX cells. Combined treatment with the encapsulation of DOX in micelles and radiotherapy therefore warrants investigation in clinical trials as a potential anticancer strategy with increased efficacy and reduced side effects. ... Read more

State-Of-The-Art Human Gene Therapy: Part II. Gene Therapy Strategies and Clinical Applications

Abstract: In Part I of this Review (Wang and Gao, 2014), we introduced recent advances in gene delivery technologies and explained how they have powered some of the current human gene therapy applications. In Part II, we expand the discussion on gene therapy applications, focusing on some of the most exciting clinical uses. To help readers to grasp the essence and to better organize the diverse applications, we categorize them under four gene therapy strategies: (1) gene replacement therapy for monogenic diseases, (2) gene addition for complex disorders and infectious diseases, (3) gene expression alteration targeting RNA, and (4) gene editing to introduce targeted changes in host genome. Human gene therapy started with the simple idea that replacing a faulty gene with a functional copy can cure a disease. It has been a long and bumpy road to finally translate this seemingly straightforward concept into reality. As many disease mechanisms unraveled, gene therapists have employed a gene addition strategy backed by a deep knowledge of what goes wrong in diseases and how to harness host cellular machinery to battle against diseases. Breakthroughs in other biotechnologies, such as RNA interference and genome editing by chimeric nucleases, have the potential to be integrated into gene therapy. Although clinical trials utilizing these new technologies are currently sparse, these innovations are expected to greatly broaden the scope of gene therapy in the near future. ... Read more

Advances in the Etiology and Mechanisms of Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is an insulin-dependent form of diabetes resulting from the autoimmune destruction of pancreatic beta cells. The past few decades have seen tremendous progress in our understanding of the molecular basis of the disease, with the identification of susceptibility genes and autoantigens, the demonstration of several abnormalities affecting various cell types and functions, and the development of improved assays to detect and monitor autoimmunity and beta cell function. New findings about the disease pathology and pathogenesis are emerging from extensive studies of organ donors with T1D promoted by the JDRF nPOD (Network for the Pancreatic Organ Donor with Diabetes). Furthermore, the establishment of extensive collaborative projects including longitudinal follow-up studies in relatives and clinical trials are setting the stage for a greater understanding of the role of environmental factors, the natural history of the disease, and the discovery of novel biomarkers for improved prediction, which will positively impact future clinical trials. Recent studies have highlighted the chronicity of islet autoimmunity and the persistence of some beta cell function for years after diagnosis, which could be exploited to expand therapeutic options and the time window during which a clinical benefit can be achieved. ... Read more

Recent Advances in the Treatment of Sarcomas in Gynecology

Abstract: Uterine sarcomas are a heterologous group of rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognoses. Management of uterine sarcomas including leiomyosarcoma and endometrial stromal sarcoma are reviewed here, with additional discussions regarding high-grade undifferentiated sarcoma and adenosarcoma. Uterine carcinosarcomas are currently staged and treated similar to high-grade epithelial endometrial carcinomas, thus will not be discussed in this review. Gemcitabine/docetaxel with adriamycin holds promise for the treatment of leiomyosarcoma, but currently, limited advancements have been made in discovering targeted therapies to these tumors. Continued translational research in both medical oncology and gynecologic oncology is necessary to forward the development of novel and targeted therapeutic agents in the treatment of sarcoma. Enrollment of these patients in clinical trials is encouraged, and will allow for the development of safer and more effective therapies. ... Read more

Current siRNA Targets in the Prevention and Treatment of Intimal Hyperplasia

Abstract: Intimal hyperplasia (IH) is the leading cause of late vein and prosthetic bypass graft failure. Injury at the time of graft implantation leading to the activation of endothelial cells and dedifferentiation of vascular smooth muscle cells to a synthetic phenotype are known causes of IH. Prior attempts to develop therapy to mitigate these cellular changes to prevent IH and graft failure have failed. Small interfering RNA (siRNA) mediated targeted gene silencing is a promising tool to prevent IH. Several studies have been performed in this direction to target genes that are involved in IH. In this review we discuss siRNA targets that are being investigated for prevention and treatment of IH. ... Read more

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