Gene transfer approaches for gynecological diseases.

Gene transfer presents a potentially useful approach for the treatment of diseases refractory to conventional therapies. Various preclinical and clinical strategies have been explored for treatment of gynecological diseases. Given the direst need for novel treatments, much of the work has been performed with gynecological cancers and ovarian cancer in particular. Although the safety of many approaches has been demonstrated in early phase clinical trials, efficacy has been mostly limited so far. Major challenges include improving gene transfer vectors for enhanced and selective delivery and achieving effective penetration and spread within advanced and complex tumor masses. This review will focus on current and developmental gene transfer applications for gynecological diseases.     

Quo vadis haemapheresis. Current developments in haemapheresis.

The techniques of haemapheresis originated in the development of centrifugal devices separating cells from plasma and later on plasma from cells. Subsequently membrane filtration was developed allowing for plasma-cell separation. The unspecificity of therapeutic plasma exchange led to the development of secondary plasma separation technologies being specific, semi-selective or selective such as adsorption, filtration or precipitation. In contrast on-line differential separation of cells is still under development. Whereas erythrocytapheresis, granulocytapheresis, lymphocytapheresis and stem cell apheresis are technically advanced, monocytapheresis may need further improvement. Also, indications such as erythrocytapheresis for the treatment of polycythaemia vera or photopheresis though being clinically effective and of considerable importance for an appropriate disease control are to some extent under debate as being either too costly or without sufficient understanding of the mechanism. Other forms of cell therapy are under development. Rheohaemapheresis as the most advanced technology of extracorporeal haemorheotherapy is a rapidly developing approach contributing to the treatment of microcirculatory diseases and tissue repair. Whereas the control of a considerable number of (auto-) antibody mediated diseases is beyond discussion, the indication of apheresis therapy for immune complex mediated diseases is quite often still under debate. Detoxification for artificial liver support advanced considerably during the last years, whereas conclusions on the efficacy of septicaemia treatment are debatable indeed. LDL-apheresis initiated in 1981 as immune apheresis is well established since 24 years, other semi-selective or unspecific procedures, allowing for the elimination of LDL-cholesterol among other plasma components are also being used. Correspondingly Lp(a) apheresis is available as a specific, highly efficient elimination procedure superior to techniques which also eliminate Lp(a). Quality control systems, more economical technologies as for instance by increasing automation, influencing the over-interpretation of evidence based medicine especially in patients with rare diseases without treatment alternative, more insight into the need of controlled clinical trials or alternatively improved diagnostic procedures are among others tools ways to expand the application of haemapheresis so far applied in cardiology, dermatology, haematology, immunology, nephrology, neurology, ophthalmology, otology, paediatrics, rheumatology, surgery and transfusion medicine.     

Moving toward genome-editing therapies for cardiovascular diseases

The rapid invention of genome-editing technologies over the past decade, which has already been transformative for biomedical research, has raised the tantalizing prospect of an entirely new therapeutic modality. Whereas the treatment of chronic cardiovascular diseases has heretofore entailed the use of chronic therapies that typically must be taken repeatedly and frequently for the remainder of the lifetime, genome editing will enable the development of “one-and-done” therapies with durable effects. This Review summarizes the variety of available genome-editing approaches, including nuclease editing, base editing, epigenome editing, and prime editing; illustrates how these various approaches could be implemented as novel therapies for cardiovascular diseases; and outlines a path from technology development to preclinical studies to clinical trials. Although this Review focuses on PCSK9 as an instructive example of the various genome-editing approaches under active investigation, the lessons learned will be broadly applicable to the treatment of a variety of diseases.     

First experience with a ready-for-use rheohemapheresis system.

Rheohemapheresis is increasingly being used for the improvement of microcirculation in numerous diseases. The method is based on the constant-flow separation of plasma by a cell separator and the secondary filtration of plasma through a hollow-fiber membrane. A new CE-marked system has recently been launched for an improved continuous flow blood separator (dideco Excel Pro) that contains a connection kit between the cell separator and a secondary filter and software which includes differential filtration as a standard protocol. The new system was used in our center using ethylenevinylalcohol secondary filters (Evaflux LA4 or LA5). 99 procedures were completed in 47 patients. A median of 2.7 (1.6-4.2) 1 of plasma were processed via the secondary filter in 109 (41-218) min. The values in peripheral blood before and after the treatment were total protein 6.7 (5.8-8.9)/ 5.3 (4.4-6.7) g/dl, fibrinogen 215 (118-480)/110 (37-275) mg/dl and cholesterol 200 (134-254)/92 (69 149) mg/dl. A median platelet loss of 30% in the peripheral blood of the patients was observed partly by platelet content of the separated plasma of 30 g/l after 500 ml of treatment and 10 g/l after 2,500 ml. Major side effects in the patients were not observed. The new differential filtration system already fulfills the demands of a ready-to-use CE-marked rheohemapheresis system but improvements in the details of the treatment protocol are still required and under way.     

Future of tissue engineering in rheumatic diseases

Chronic inflammation during rheumatoid arthritis and degenerative processes during osteoarthritis eventually result in joint destruction. Anti-inflammatory therapies facilitate the inhibition or delay of progressing joint cartilage and bone loss, but do not regenerate these tissues. Surgical procedures are quite unsatisfactory in long-term evaluation and often lead to endoprothetic joint replacement. Present tissue engineering technologies offer new strategies for the treatment of cartilage and bone defects. Here, beyond implantation of cell suspensions, biomaterials combined with tissue-specific cells or mesenchymal stem cells are clinically applied. This review focuses on state-of-the-art and future in situ mesenchymal stem cell-based tissue engineering approaches for joint repair in patients with rheumatic diseases.     

Gene, stem cell, and future therapies for orphan diseases

There are an estimated 7,000 "orphan diseases," but treatments are currently available for only about 5% of them. Recent progress in the advanced platforms of gene therapy, stem cell therapy, gene modification, and gene correction offers possibilities for new therapies and cures for rare diseases. Many rare diseases are genetic in origin, and gene therapy is being successfully applied to treat them. Human stem cell therapy, apart from bone marrow transplants, is still experimental. Genetic modification of stem cells can make stem cell-based products more effective. Autologous induced pluripotent stem (iPS) cells, when combined with new classes of artificial nucleases, have great potential in the ex vivo repair of specific mutated DNA sequences (zinc-finger proteins and transactivator-like effector nucleases). Patient-specific iPS cells can be corrected and transplanted back into the patient. Stem cells secrete paracrine factors that could become new therapeutic tools in the treatment of orphan diseases. Gene therapy and stem cell therapy with DNA repair are promising approaches to the treatment of rare, intractable diseases.     

Clinical efficacy of haemorheological treatment using plasma exchange, selective adsorption and membrane differential filtration in maculopathy, retinal vein occlusion and uveal effusion syndrome

The aim of the study was to test the clinical efficacy of haemorheological treatment with extracorporeal techniques in ocular diseases. We treated patients suffering from maculopathies of different origin: age-related (AMD, n = 17), uveitis-associated (n = 14) and myopia-associated maculopathy (n = 5). We also treated patients with uveal effusion syndrome (n = 3) and central retinal vein occlusion (n = 4) resistant to haemodilution or steroid therapy. The treatment consisted of plasma exchange, selective adsorption with a tryptophan-polyvinylalcohol adsorber and membrane differential filtration. Maculopathy patients underwent two treatments while the other patients received between 1 and 7 treatments. Pulsatile ocular blood flow was measured in 10 patients before and after therapy. The main parameter for evaluating clinical outcome was the change in visual acuity. Severe side-effects did not occur. The rheological parameters including plasma viscosity, whole blood viscosity and erythrocyte aggregation were statistically significantly lowered. Of 36 patients suffering from maculopathy, 25 showed an improvement of at least 1 line of visual acuity after therapy, 7/17 patients in AMD, 6/14 in uveitis and 0/5 in myopia improved 3 lines or more. All patients suffering from retinal vein occlusion improved at least 1 line and two showed an improvement of 3 lines or more. In uveal effusion syndrome, an improvement of 3 lines or more was reached in all patients. Plasma exchange, selective adsorption and membrane differential filtration are effective rheological treatment approaches to improving visual acuity in patients suffering from maculopathy except myopia-associated maculopathy. Efficacy in patients suffering from central retinal vein occlusion and uveal effusion syndrome was proven, even when the patients were resistant to previous haemodilution or steroid therapy. We conclude that a rheological approach should be considered before invasive methods such as laser coagulation, radiation therapy or surgery are applied.     

Therapeutic apheresis application using membrane plasma fractionation technology: present scope and limitations.

Membrane technologies have been applied for therapeutic apheresis, such as plasma separation and plasma fractionation. Membrane used for plasma fractionation has a microporous structure with pore sizes in the range of 0.01-0.04 microm. A membrane plasma fractionator is utilized for the second filter in the double filtration plasmapheresis (DFPP) system and is applied for treatment of various diseases.This article summarizes the present scope and limitation of membrane plasma fractionation.     

From the Editors

Dear colleagues,Interstitial therapies have been introduced in the spectrum of minimally invasive cancer treatments for a decade, meanwhile a standardization has been introduced in the field of image-guided tumor ablation. This is an important criterion for facilitating effective ideas and for performing appropriate comparisons between treatments with different technologies. Tumor ablation and interstitial therapies are defined as a direct application of chemical or thermal therapies to a specific focal tumor in an attempt to achieve eradication or substantial tumor destruction. Via the term “direct” these therapies are defined as a “direct” differentiation from those therapies which are applied orally or via an intravascular approach.In this issue on “Interstitial Therapies” different technologies are presented which are based on well-known groups of different authors who have presented their experience in image-guided interstitial therapies for the treatment of lung, liver, and head and neck neoplasms. Although at present there are many technologies under investigation, the present issue aims at showing that image-guided tumor ablation has become an integrated part in modern oncology, opening the field of interventional oncology for the future.We do wish to inspire the reader to get involved in this field of interstitial therapies, which is, in fact, one of the most fascinating, exciting and rapidly growing ones.Thomas J. VoglNahum Goldberg     

The current state of extracorporeal haemorheotherapy: from haemodilution via cascadefiltration to rheohaemapheresis.

Rheological therapy aims at an improvement of organ perfusion however, it has to be stressed that the tonus of the blood vessels also plays an important role for both the blood distribution and the rheology in the micro- and the macrocirculation. Conventional rheotherapy consists of attempts to influence nutrition and life style, to apply drugs such as purin derivatives, vasodilatating or defibrinising substances and hypervolaemic (using infusion therapy), hypovolaemic, e.g., blood letting, erythrocytapheresis and – the most widely distributed – isovolaemic haemodilution. With the introduction of centrifugal devices, and approximately 10 years later with the introduction of hollow fibre and flat sheet membrane techniques, a considerable increase of therapeutical efficacy was achieved. These technologies were successfully applied for the treatment of cellular and plasmatic hyperviscosity syndromes. The treatment of less severe diseases of the micro- and macrocirculation, vessel stenosis, vessel wall sclerosis, malformation of the blood vessel architecture, pathological clinical–chemical blood parameters and maldistribution have hardly been taken into consideration. Our group at Köln investigated different plasma differential separation techniques and demonstrated, that adsorption as well as filtration could be applied. These different techniques being 6–10 times more effective as conventional haemodilution techniques have in common high molecular weight proteins determining the viscosity of plasma and thus whole blood viscosity is removed, however differences among the different elimination techniques do exist. The rheological and clinical importance of such differences has to be determined. Applying filtration techniques for both primary and secondary separations, the concept of Rheohaemapheresis was developed. A corresponding quality program was also introduced into our clinical routine. Rheohaemapheresis is supported from the currently introduced concept of the synergetic consideration of the microcirculation. Age related macular degeneration, so far without generally accepted therapy, is a most advanced indication based on several pilot studies and a prospective, randomised controlled trial. Other diseases of the microcirculation have also successfully been treated.     

Ig-Therasorb immunoadsorption for selective removal of human immunoglobulins in diseases associated with pathogenic antibodies of all classes and IgG subclasses, immune complexes, and fragments of immunoglobulins.

Therasorb immunoadsorption (IA), by selectively eliminating pathogenic substances from the circulation, allows for successful therapy of previously insufficiently treatable diseases. Molecules (specific polyclonal sheep antibodies) coupled to a matrix (Sepharose CL 4B) selectively bind plasma components in extracorporeal circulation. This procedure has been established in the treatment of various diseases. Examples are familial hypercholesterolemia (LDL-Therasorb) and selected autoimmune diseases (Ig-Therasorb). Ig-Therasorb IA has been performed in a variety of clinical indications, primarily in the treatment of autoimmune diseases. In most cases, Ig-Therasorb IA has been applied in patients who have failed to respond to conventional therapy with a high rate of clinical improvement. In defined groups of patients with autoimmune diseases and alloantibodies, immunoadsorption can now be considered an established therapeutic means. The fast and efficient removal of immunoglobulins obviously exceeds the efficiency of conventional plasma exchange by far. Autoimmune diseases could be induced by balanced and nonbalanced immunity. The importance of autoantibodies remains unclear, but the efficacy of Ig-Therasorb IA suggests a key role for them. In addition to the established indications for removal of immunoglobulins, there may be a number of promising new indications.     

Management of the extracorporeal shock wave lithotripsy patient.

Over 2 million Americans experience kidney and urinary stone disease each year. Early treatments resulted in high mortality and morbidity rates. With the advent of extracorporeal shock wave lithotripsy less than 20 years ago, treatment for this disease has become far safer with more rapid recovery and fewer complications. The selection of patients eligible for extracorporeal shock wave lithotripsy is dependent on the location and size of the stones and the overall health of the patient. This article discusses the different treatment modalities used for stone disease and the different methods currently available for extracorporeal shock wave lithotripsy. Preprocedure preparation of the patient and postoperative care for this population is reviewed in detail.     

Basic clinical study of an easy and effective leukocytapheresis by the use of nonwoven polyester filter.

Leukocytapheresis (LCAP) is widely used for the treatment of immunological diseases. We studied a new treatment of LCAP using a nonwoven polyester filter. In a basic study, 30-70% of the lymphocytes were adsorbed. Also, 30-68% of the lymphocyte subsets were removed. This method was applied to 2 patients with corticosteroid-resistant active ulcerative colitis. Erosion, edema, bleeding, ulcer formation, and stenosis of the colon were almost completely repaired after 6 LCAP treatments. LCAP using a nonwoven polyester filter will be a very useful treatment for immunological diseases and extracorporeal immunomodulation.     

Molecular profiling of tissue samples using laser capture microdissection

The management of cancer and other genetically based diseases is far from optimal in even our most advanced medical centers. There is still uncertainty regarding how diseases will progress in certain patients, toxicity that must be tolerated with imprecise treatment regimens and significant potential for treatment failure. As our understanding of the complexity of these diseases has increased, it has become clear that we must move toward precisely tailored approaches to treating each individual patient. To that end, a major goal of current medical research is the rapid identification of the specific molecular alterations in each patient's disease. This will enable the design of optimal diagnosis, prognosis and treatment, significantly improving survival. This review describes one important approach to the genetic analysis of disease--molecular profiling--and the tenets and technologies necessary for its success.     

DNA arrays as diagnostic tools in human healthcare

The sequencing of the entire human genome was completed in June 2000. The sequence, however, is only a starting point and gene-function is now of major interest. All this information shows that gene-based diagnostics can be helpful for treatment targeting and patient surveillance. High volume gene expression assays can optimize pharmaceutical therapies by targeting genome-based treatments to specific patient populations and providing methods to study genes involved with cancer growth patterns and tumor suppression. Molecular biology, so far, has elucidated many of the genetic mechanisms underlying heritable metabolic diseases, so that appropriate diagnostic assays will revolutionize molecular diagnostics in medicine and pharmaceuticals. One of the most promising new technologies designed to analyze large amounts of genomic information rapidly is the DNA chip.     

The potential of cell-based therapy in lung diseases

Introduction: Many lung diseases have high morbidity and mortality rates and there are no cures or treatments apart from mechanical ventilation or transplantation. Cell-based therapies are currently an area of intense research, and many groups are working to translate successful in vitro results into treatments that are safe for patients.

Areas covered: This review discusses several types of stem and progenitor cells that have been proven likely candidates for cell therapies, as well as their applications so far in specific acute and chronic lung diseases, focusing on their mechanisms of action and how best they can be directed toward clinical aims.

Expert opinion: The research on cell therapies for the lung, particularly regarding mesenchymal stem cells (MSCs), is promising, but there is still much uncertainty surrounding the mechanisms of MSC action and the factors relevant to clinical applications such as the optimal timing of dosage. Future studies will focus on the microenvironment of the stem cells, including the role of microRNAs and extracellular vesicles.     

Membrane plasmapheresis in the United States: a review over the last 20 years.

Plasmapheresis is a general term involving extracorporeal plasma separation by centrifugation or primary membrane plasma separator (MPS). Further plasma processing can be accomplished by the use of secondary membrane plasma fractionation (PF), as in double filtration plasmapheresis, also called cascade filtration, low-density lipoprotein pheresis, thermofiltration, and cryofiltration apheresis. Otherwise, the separated plasma is replaced by colloid solution as in plasma exchange (PE). PE is used, unselectively, to treat patients with immunological, neurological, hematological, renal, and metabolic disorders. Secondary PF may be a more selective alternative. In general, the primary MPS and secondary PF are safe, effective, and biocompatible. The advantages of the primary MPS include its simplicity to use with blood pumps and no observed white blood cell or platelet loss, compared with centrifugation. The disadvantages are lack of versatility, the need to monitor transmembrane pressure to prevent hemolysis, and possible biocompatibility issues such as use of polyvinyl alcohol membranes. The advantages of secondary PF, compared with PE, include selective removal of macromolecules according to molecular weight and filter pore size. No deficiency syndromes or sepsis are observed, nor is replacement solution required. More than 1 plasma volume may be processed, and it is less expensive than PE. Cryofiltration apheresis, using the cryoglobulin filter, selectively removes cryoproteins and is a specific treatment for cryoprecipitate-induced diseases. The disadvantages of PF include biocompatibility, especially with concomitant ACE inhibitor use, and membrane plugging. An important disadvantage is that most PFs are investigational in the United States. This article reviews the availability, safety, efficacy, and biocompatibility of primary MPSs and secondary PF in the United States.     

Double filtration plasmapheresis in critical care.

Many kinds of technologies have been introduced and successfully developed for therapeutic apheresis. Furthermore, several kinds of these technologies have also been applied in critical care. Double filtration plasmapheresis (DFPP), however, is rarely applied in this field in comparison with other treatments such as continuous hemofiltration, continuous hemodiafiltration, single filtration plasmapheresis, and plasma adsorption therapies. In this paper, the characteristics of the DFPP treatments for critical care are summarized. During the DFPP treatments, the patient's blood volume (BV) often decreases with time due to albumin loss induced by inadequate albumin infusion in a supplementation fluid. We examined the change of BV by a continuous hematocrit monitor, Crit-Line, during an in vivo study for 9 patients. As a result, albumin loss fairly occurred in DFPP treatments. The decrease of patient BV was induced by an oncotic pressure drop due to albumin loss and often resulted in a blood pressure drop. This is a serious problem for DFPP in critical care. We should avoid inadequate albumin infusion if the patient is suffering from these adverse effects. In order to determine the optimal concentration C(S) and volume V(S) values of a supplemented albumin solution, we introduced a variable blood volume model for albumin transport in DFPP.     

Surgical management of patients with primary brain tumors

OBJECTIVES: To provide an overview of the diagnostic work-up, intraoperative technologies, postoperative treatment options, and investigational new therapies in patients with malignant brain tumors. DATA SOURCES: Published textbooks and articles and other reference materials. CONCLUSION: Recent improvements in diagnostic and surgical equipment have influenced outcomes and overall quality of life for patients with central nervous system tumors. The ability to more accurately target and more safely remove brain tumors has enhanced the postoperative period and decreased hospital stays. However, malignant neoplasms continue to be refractory to current treatments, necessitating innovative surgical approaches at the time of initial diagnosis and at tumor recurrence. IMPLICATIONS FOR NURSING PRACTICE: Nurses with an understanding of current diagnostic and surgical treatment modalities for brain tumors are able to provide accurate patient education and comprehensive care, enhancing the overall hospital and outpatient experience.     

Use of traditional,complementary and alternative medicine in nine countries: A cross-sectional multinational survey

ObjectivesTraditional, complementary, and alternative medicine (TC&AM) play an exceptional role in health care around the world as many patients has sought a holistic approach.SettingIn this study, a multinational survey was developed and administered to obtain experience, attitude, and promotion information with regard to the international use of TC&AM among nine countries: Germany, United States, Japan, China, Malaysia, Vietnam, Russia, Kazakhstan, and United Arab Emirates (UAE). The survey was administered via online to members of SurveyMonkey Audience, a proprietary panel of respondents who were recruited from a diverse population worldwide.ResultsA total of 1071 participants has completed the survey. The participants were in favor of the treatments and therapies as well as expressed positive attitudes and also have used herbal medicine treatment more than acupuncture therapy and also used the modalities to promote metabolism rather than treating musculoskeletal diseases. Moreover, participants mentioned that TC&AM should be applied for treating and managing infectious diseases, such as COVID-19. Additionally, participants recommended using Facebook channel to promote its treatments and therapies.ConclusionBased on the results, this study provides initial insights on TC&AM that may influence the non-users globally and perhaps inspire a need for further research including more countries in different continents.