Egg-sharing in return for subsidized fertility treatment: a possible solution for therapeutic cloning?

Sir, We read with great interest the recent advances in therapeuticcloning made by Hwang et al. (2005), in which the efficiencyof therapeutic cloning for the derivation of embryonic stemcells was dramatically improved. Previously, only one in 200attempts were successful, now the success rate stands     

Is methoxydine a new rapid acting antidepressant for the treatment of depression in alcoholics?

Methoxydine is a dissociative anaesthetic belonging to the arylcyclohexylamine class. This substance shows pharmacodynamic similarities with ketamine, a medication with demonstrated rapid-acting antidepressant effects. Like ketamine, results of binding assays have shown that methoxydine is an uncompetitive antagonist of NMDA receptor approximately as potent as ketamine, but less potent than PCP. Furthermore, unlike ketamine, it acts as a dopamine, serotonin, and noradrenaline reuptake inhibitor as well as an agonist at sigma-1, sigma-2, and opioid receptors. The hypothesis is that methoxydine can produce rapid antidepressant effects in depressed patients with high risk of suicide, including depressed alcoholics.     

Outpatient psychotherapy for mothers – a new treatment

Summary The perinatal period and new motherhood entail a multitude of physiologic and psychosocial changes and are also associated with an increased risk of mental illness. Nevertheless, many mothers with an acute postpartum mental illness reject hospitalization to avoid being separated from their children even when treatment is urgently needed. A new psychotherapeutic outpatient treatment program adapted to the special needs of mothers and offering a substitute to inpatient treatment is presented. Empirical results indicate that this treatment is an effective alternative to hospitalization. Received March, 2002; accepted November 14, 2002 Published online January 17, 2003 Correspondence: Dr. med. Anette Kersting, Department of Psychiatry, University of Muenster, Albert-Schweitzer-Str.11, D-48129 Muenster, Germany; e-mail: a.kersting@uni-muenster.de     

Is HMGB1 a new indirect marker for revealing fibrosis in chronic hepatitis and a new therapeutic target in treatment?

In chronic hepatitis B virus (HBV) infection, inflammation-associated cytokines including proinflammatory cytokines are involved in the development and progression of liver fibrosis. The liver is a source of many cytokines that may influence liver function. High-mobility group box 1 (HMGB1) was identified as an inflammatory cytokine. HMGB1 is present in nuclei of all mammalian cells and is released both through active secretion from various cells and by passive release from necrotic cells. Here we explore the relationship between HMGB1 plasma levels and liver fibrosis. HMGB1 serum levels, HBV-DNA, and ALT values were significantly higher in patients with chronic HBV than in controls. In addition, HMGB1 serum levels were significantly higher in patients with low fibrosis (fibrosis score 1-2) compared to those with high fibrosis (fibrosis score 3-4). In the present study, we have shown that HMGB1 is a noninvasive, repeatable, and convenient marker for distinguishing advanced fibrosis from low fibrosis in chronic HBV patients. We believe that the inhibition of HMGB1 may reduce inflammation, apoptosis, and fibrosis, and may stop the progression of chronic liver disease. Furthermore, we are of the opinion that fibrotic progression in chronic liver patients may be prevented by the inhibition of HMGB1, and that this substance can be a new means of following chronic HBV treatment.     

Genetic selection? A study of individual variation in the enzymes of folate metabolism

Background  

Genetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity.     

Bone-cartilage crosstalk: A conversation for understanding the pathogenesis and new treatment strategy of osteoarthritis北大核心

BACKGROUND: Osteoarthritis, a degenerative joint disease, is not only a result from the breakdown of joint cartilage and underlying bone, but also an imbalance of bone remodeling and crosstalk among tissues in the joints. OBJECTIVE: To review the effect of bone-cartilage crosstalk in the progression of osteoarthritis and its new treatment strategy. METHODS: A computer-based search of PubMed and CNKI databases was performed for relevant literatures about the relationship between the progress of osteoarthritis and the bone-cartilage crosstalk published from 2007 to 2017. The keywords were “cartilage, interaction, osteoarthritis, pathogenesis, cytokines, signaling pathway” in English and Chinese, respectively. The relationship between the progress of osteoarthritis and the bone-cartilage crosstalk was summarized in views of cytokines, signaling pathway, and new treatment strategy. RESULTS AND CONCLUSION: Totally 169 articles were retrieved, and finally 54 eligible papers were enrolled based on the inclusion and exclusion criteria. There is a close physical association between subchondral bone and cartilage, and the bone-cartilage interface is a functioning synergistic unit. Increased vascularization, micro-crack formation and abnormal bone remodeling may accelerate the molecules transporting from cartilage to bone in osteoarthritis. Therefore, the bone-cartilage crosstalk plays a pivotal role in the occurrence and development of osteoarthritis. © 2017, Journal of Clinical Rehabilitative Tissue Engineering Research. All rights reserved.     

Primary hyperoxaluria type III—a model for studying perturbations in glyoxylate metabolism

Perturbations in glyoxylate metabolism lead to the accumulation of oxalate and give rise to primary hyperoxalurias, recessive disorders characterized by kidney stone disease. Loss-of-function mutations in HOGA1 (formerly DHDPSL) are responsible for primary hyperoxaluria type III. HOGA1 is a mitochondrial 4-hydroxy-2-oxoglutarate aldolase catalyzing the fourth step in the hydroxyproline pathway. We investigated hydroxyproline metabolites in the urine of patients with primary hyperoxaluria type III using gas chromatography?Cmass spectroscopy. Significant increases in concentrations of 4-hydroxy-2-oxoglutarate and its precursor and derivative 4-hydroxyglutamate and 2,4-dihydroxyglutarate, respectively, were found in all patients as compared to carriers of the corresponding mutations or healthy controls. Despite a functional block in the conversion of hydroxyproline to glyoxylate??the immediate precursor of oxalate??the production of oxalate increases. To explain this apparent contradiction, we propose a model of glyoxylate compartmentalization in which cellular glyoxylate is normally prevented from contact with the cytosol where it can be oxidized to oxalate. We propose that HOGA1 deficiency results in the accumulation of 4-hydroxy-2-oxoglutarate in the mitochondria and its transport into the cytosol where it is converted to glyoxylate by a different cytosolic aldolase. In human hepatocyte cell lines, we detected a cytosolic 4-hydroxy-2-oxoglutarate aldolase activity not due to HOGA1. These studies provide a diagnostic tool for primary hyperoxaluria type III and shed light on glyoxylate metabolism and the pathogenesis of primary hyperoxalurias.     

The use of oncolytic vaccinia viruses in the treatment of cancer: a new role for an old ally?

The use of genetically engineered, tumor-targeting viruses as oncolytic agents has recently emerged as a promising new area for the development of novel cancer therapies. The first viruses to enter the clinic, such as ONYX-015 (an oncolytic adenovirus), provided evidence both for the safety and for the anti-tumor potential of this approach. The results of these early trials have also allowed investigators to examine the limitations of these viruses and to develop potentially far more effective approaches. In this review the development of such next generation viruses, in particular the potential use of strains of vaccinia virus, will be discussed. Vaccinia has an enormous history of use in humans and possesses many of the features felt to be beneficial for the creation of a successful virotherapy agent. It causes no known disease in humans, yet is capable of infecting almost all cell types with a subsequent rapid and lytic infection, which subsequently induces a vigorous local CTL immune response at the site of infection. Vaccinia also displays natural tumor tropism, and several approaches have been used to further limit viral replication to tumor cells and to optimize the immune response induced at the site of the tumor. Finally, the large cloning capacity of vaccinia allows for the addition of multiple foreign genes into the viral genome. This has been exploited to increase the bystander effect of the virus by immune modulation or by expression of pro-drug converting enzymes as well as to incorporate safety controls and reporters for in vivo molecular imaging. Initial clinical trials with these viruses further highlights their potential as the next generation of oncolytic agents and as highly effective future cancer therapies.     

Is there a role for palmitoylethanolamide in the treatment of depression?

Depression is a common brain disorder affecting about 350 million people worldwide. Although the pharmacological treatment currently available can produce benefits in the majority of cases, residual depressive symptoms, cognitive deficits, functional impairment, and increase in frequency of relapses are frequently present in unipolar and bipolar depressed patients correctly treated. In the last years, numerous evidences have demonstrated the involvement of endocannabinoid system in the pathophysiology of mood disorders. Considering the recent findings about the antidepressant effect of palmitoylethanolamide in animal model, we have hypothesized the potential antidepressant effect of this fatty acid amide in unipolar and bipolar depressed patients.     

Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

Tolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T‐cell response while leaving other, protective, T‐cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat‐shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat‐shock proteins could be used as surrogate autoantigens.     

Tungiasis: a neglected epidermal parasitic skin disease of marginalized populations—a call for global science and policy

Tungiasis (sand flea disease) is an ectoparasitic skin disease caused by the female sand flea/jigger flea (Tunga penetrans). As poverty is the major driving force of the disease, it can be called as a poverty-associated plague. It is one of the emerging neglected diseases in Latin America, Caribbean, sub-Saharan Africa, and India. The aim of the present scrutiny was to assess the public health impact of tungiasis, associated risk factors, and emerging opportunities to prevent and control tungiasis. Searches of PubMed, Google Scholar, and online search engines (Google, AOL, and Yahoo) using keywords “parasitic skin disease,” “tungiasis,” “sand flea,” “ tungiasis-associated risk factors,” “tungiasis prevention and control,” and their synonyms were used as a source of references. Searches were made without time limitations. Of 167 potential articles identified by these criteria, 51 appropriate were selected for review. Tungiasis is widespread in the resource-constrained settings of low-income economies. In the tropics, it is highly prevalent among the impoverished populations, but the associated risk factors are often poorly identified and remain uncontrolled. Though it is a self-limiting disease with considerable morbidity, the parasite may cause subsequent secondary morbidity through life-threatening complications and infections like cellulitis, tetanus, and death. However, the direct and indirect sociocultural, economic, and health impact of tungiasis is often undervalued and misunderstood. A systematic assessment on disease burden is still dearth and deficient. Over the decades, tungiasis has been largely neglected by the scientific community, policy makers, and healthcare stakeholders. In the endemic regions, even tungiasis is not listed for the disease control priorities in the regional, national, and international agenda. The majority of the epidermal parasitic skin diseases particularly tungiasis needs a sustainable global scientific research and control policy. This urges intensive efforts to develop a road map that delivers a clear vision towards zero new infection by designing low-cost prevention and control strategies. Besides, there is an urgency to develop culturally appropriate communication techniques and workable collaboration on a global scale by bringing all the stakeholders of endemic countries.     

Is there today a place for corticosteroids in the treatment of scleroderma?

In systemic sclerosis (SSc), the use of corticosteroids (CS) is controversial due to their association with scleroderma renal crisis (SRC). However, patients with very early and early disease, characterised by main inflammatory component, may benefit from CS therapy.The aim of this review is to discuss pros and cons of CS treatment in SSc, providing current evidence about the use of CS in SSc. Moreover, we discuss also the underlying pathogenetic mechanisms that may be the background for the potential harms and efficacy of CS in SSc.     

Analysis of the course and treatment of toxocariasis in children—a long-term observation

Toxocariasis is a helminthozoonotic disease caused by ascarid larvae of Toxocara genus: Toxocara canis and Toxocara cati. In the reported study, the clinical course of toxocariasis and administered therapy were evaluated in 103 children. The majority of the children (68.9%) were from the rural environment, with a prevalence of boys (62.1%). At diagnosis of infection, 36 (35%) children reported recurrent abdominal pain, 19 (18.4%) headache, 6 (5.8%) loss of appetite, 2 subfebrile conditions, and 2 arthralgia, Moreover, 23 (22.3%) children demonstrated symptoms of atopic diseases; in 30 (29.1%) children, moderate enlargement of lymphatic nodes was noted. In five children (4.9%), ophthalmic examination revealed unilateral changes in the eye: in two cases retinitis; in one case fibrotic lesions in the vitreous body, complicated 1 year from diagnosis by retinal detachment; and in other children parafoveal lesions and cataract. Only two children with ocular changes at diagnosis reported visual disorders. In 64.3% of children, eosinophilia was observed. A covert form of the disease was diagnosed in 95.1% of the children and an ocular form in 4.9%. In all the children, antiparasitic treatment was implemented, repeated several times in some of them. After therapy, the mean titer of specific antibodies, the number of children with abdominal pains and enlarged lymphatic nodes were decreased, while headaches maintained at unchanged levels. In approximately one fourth of the children with negative results of antibodies after the therapy, the symptoms of the disease were still reported. Evaluation of the efficacy of treatment is not easy due to non-characteristic symptoms and low kinetics of specific anti Toxocara IgG decrease; however, high IgG titers suggest non-effective treatment of concomitant infection requiring subsequent therapy. Due to risk of ocular form, which may develop in any stage of the disease, irrespectively of specific antibodies concentrations, it seems justified to implement antiparasitic treatment in all children infected with T. canis.     

Which treatment for whom for ADHD? Moderators of treatment response in the MTA

Using receiver operating characteristics, the authors examined outcome predictors (variables associated with outcome regardless of treatment) and moderators (variables identifying subgroups with differential treatment effectiveness) in the Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (ADHD; MTA). Treatment response was determined using parent- and teacher-reported ADHD and oppositional defiant symptoms, with levels near or within the normal range indicating excellent response. Among 9 baseline child and family characteristics, none predicted but 3 moderated treatment response. In medication management and combined treatments, parental depressive symptoms and severity of child ADHD were associated with decreased rates of excellent response; when these 2 characteristics were present, below-average child IQ was an additional moderator. No predictors or moderators emerged for behavioral and community comparison treatments. The authors discuss conceptual and clinical implications of research on treatment moderators.     

Streptozotocin induced diabetes in minipig: a case report of a possible model for type 1 diabetes?

Studies on the pathogenic process in type 1 diabetes are often performed in animal models. Low-dose administration of streptozotocin has been used to induce diabetes with pathological alterations similar to human type 1 diabetes in the animals. Rodent models are frequently used but there is a need of developing new models including larger animals. In this study we wanted to investigate to what extent a minipig was sensitive to low-dose streptozotocin for induction of diabetes with features of human Type I diabetes. A female G?ttingen minipig received two low-doses (40 mg/kg) of streptozotocin with an 11-day interval. Serum was analysed for the presence of the enzyme glutamic acid decarboxylase, isoform 65, (GAD65) and autoantibodies against glutamic acid decarboxylase, isoform 65 (GAD65A), isoform 67 (GAD67A), insulinoma antigen 2 (IA-2) and insulin (IAA). Pancreas tissue was fixated in formaldehyde and was sent for pathoanatomical examination. The minipig became hyperglycaemic after the second injection of streptozotocin. The pathoanatomical examination showed atrophy of the beta-cell population, depletion of insulin with preserved glucagon content. There was no sign of insulitis. Both GAD65 and GAD65A were detected while GAD67A and IAA were absent. It is concluded that chronic diabetes developed after low-dose streptozotocin injection in a female minipig with the characteristics of the end stage of type 1 diabetes. This pilot study suggests that minipigs show promise as a model to induce diabetes by injections of low-dose streptozotocin.