Folinic acid administration following MTX as prophylaxis for GVHD in allogeneic HSCT centres in Australia and New Zealand

The use of MTX for GVHD prophylaxis may be associated with significant toxicity, including hepatotoxicity, graft failure and mucositis. Folinic acid may be involved in the amelioration of MTX toxicity. There is, however, no consensus regarding its use. A survey was conducted in Australian and New Zealand transplant centres (n=22) regarding the use of folinic acid following MTX in the transplant setting. Of 18 participating transplant centres, 12 (66%) used folinic acid following MTX--8 (44%) routinely and 4 (22%) only in the presence of significant mucositis. Those centres that did not use routine dosing of folinic acid post transplant chose not to do so on the grounds that they believed that it was not efficacious or may increase the risk of GVHD. Grading of mucositis was inconsistently done. There is wide variation in the use of folinic acid following HSCT. Folinic acid is infrequently used in the adult transplant setting or is used after mucositis is already apparent, practices that appear to run counter to available clinical evidence and to pharmacological data. Further research is required to conclusively determine whether folinic acid has any benefit in the post-BMT setting.     

Randomized controlled trial of pilocarpine hydrochloride for the moderation of oral mucositis during autologous blood stem cell transplantation

Pilocarpine hydrochloride has been reported to increase salivation and decrease oral mucositis in patients receiving head and neck radiotherapy, but there is only one report of its use in a cancer chemotherapy patient population. This prospective, double-blinded, randomized, placebo-controlled trial was undertaken to determine the efficacy of pilocarpine for the moderation of oral mucositis during autologous blood stem cell transplantation. Subjects were randomized to receive a 5 mg tablet of pilocarpine, or a placebo, during and following chemotherapy. Subjects were seen every other day and evaluated for gingival, oral, and oropharyngeal mucositis; nutrition; oral hygiene; eating; speaking; sleeping; pain at rest and/or with swallowing; and mouth dryness. We recorded the mean and highest scores and duration of problems, along with white blood cell counts and differentials, and the use of systemic narcotics for oral mucosal pain. We enrolled and randomized 36 subjects, and there were no statistically or clinically significant differences for the primary outcome of severity of mucositis and no clinically significant differences in any of the other outcome measures. Pilocarpine has no benefit for the moderation of the incidence, severity, or duration of mucositis in patients receiving autologous blood stem cell transplantation.     

Cryotherapy in the prevention of oral mucositis in patients receiving low-dose methotrexate following myeloablative allogeneic stem cell transplantation: a prospective randomized study of the Gruppo Italiano Trapianto di Midollo Osseo nurses group

Severe oral mucositis is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (AHSCT). Cryotherapy, that is, the application of ice chips on the mucosa of the oral cavity during the administration of antineoplastic agents, may reduce the incidence and severity of chemotherapy-related oral mucositis. In this multicenter randomized study, we addressed whether cryotherapy during MTX administration is effective in the prevention of severe oral mucositis in patients undergoing myeloablative AHSCT. One hundred and thirty patients undergoing myeloablative AHSCT and MTX-containing GVHD prophylaxis were enrolled and randomized to receive or not receive cryotherapy during MTX administration. The incidence of severe (grade 3-4) oral mucositis, the primary end point of the study, was comparable in patients receiving or not cryotherapy. Moreover, no difference was observed in the incidence of oral mucositis grade 2-4 and the duration of oral mucositis grade 3-4 or 2-4, or in the kinetics of mucositis over time. In univariate and multivariate analysis, severe oral mucositis correlated with TBI in the conditioning regimen and lack of folinic acid rescue following MTX administration. Thus, cryotherapy during MTX administration does not reduce severe oral mucositis in patients undergoing myeloablative allogeneic HSCT. Future studies will assess cryotherapy before allogeneic HSCT.     

Capnocytophaga bacteremia in a patient with Hodgkin's disease following bone marrow transplantation: case report and review.

Capnocytophaga is a gram-negative, capnophilic, facultatively anaerobic bacillus that normally inhabits the oral cavity. We report the case of a patient who developed capnocytophaga bacteremia following autologous bone marrow transplantation for Hodgkin's disease, and we review other reported cases of capnocytophaga bacteremia in immunocompromised patients. In our case infection followed pretransplantation conditioning and was associated with severe oral mucositis and neutropenia. Antibiotic therapy resulted in clinical resolution of infection. Capnocytophaga bacteremia should be included in the differential diagnosis of febrile neutropenia in immunocompromised patients (e.g., those undergoing bone marrow transplantation) especially in the presence of mucositis and gingival bleeding.     

Diagnosis and management of choledocholithiasis in the golden age of imaging,endoscopy and laparoscopy

Biliary lithiasis is an endemic condition in both Western and Eastern countries, in some studies affecting 20% of the general population. In up to 20% of cases, gallbladder stones are associated with common bile duct stones(CBDS), which are asymptomatic in up to one half of cases. Despite the wide variety of examinations and techniques available nowadays, two main open issues remain without a clear answer: how to cost-effectively diagnose CBDS and, when they are finally found, how to deal with them. CBDS diagnosis and management has radically changed over the last 30 years, following the dramatic diffusion of imaging, including endoscopic ultrasound(EUS) and magnetic resonance cholangiography(MRC), endoscopy and laparoscopy. Since accuracy, invasiveness, potential therapeutic use and costeffectiveness of imaging techniques used to identifyCBDS increase together in a parallel way, the concept of "risk of carrying CBDS" has become pivotal to identifying the most appropriate management of a specific patient in order to avoid the risk of "under-studying" by poor diagnostic work up or "over-studying" by excessively invasive examinations. The risk of carrying CBDS is deduced by symptoms, liver/pancreas serology and ultrasound. "Low risk" patients do not require further examination before laparoscopic cholecystectomy. Two main "philosophical approaches" face each other for patients with an "intermediate to high risk" of carrying CBDS: on one hand, the "laparoscopy-first" approach, which mainly relies on intraoperative cholangiography for diagnosis and laparoscopic common bile duct exploration for treatment, and, on the other hand, the "endoscopy-first" attitude, variously referring to MRC, EUS and/or endoscopic retrograde cholangiography for diagnosis and endoscopic sphincterotomy for management. Concerning CBDS diagnosis, intraoperative cholangiography, EUS and MRC are reported to have similar results. Regarding management, the recent literature seems to show better short and long term outcome of surgery in terms of retained stones and need for further procedures. Nevertheless, open surgery is invasive, whereas the laparoscopic common bile duct clearance is time consuming, technically demanding and involves dedicated instruments. Thus, although no consensus has been achieved and CBDS management seems more conditioned by the availability of instrumentation, personnel and skills than cost-effectiveness, endoscopic treatment is largely preferred worldwide.     

Keratinocyte growth factor is effective in the prevention of intestinal mucositis in patients with hematological malignancies treated with high-dose chemotherapy and autologous hematopoietic SCT: a video-capsule endoscopy study

Oral and/or intestinal mucositis is a severe complication of hematopoietic SCT. Keratinocyte growth factor (KGF) has proven activity in the prevention of oral mucositis. We examined the efficacy of KGF in the prevention of intestinal mucositis. From January 2006 until December 2007, 35 consecutive patients underwent autologous SCT (auto-SCT) in our institution. A total of 15 consecutive patients who underwent auto-SCT from March 2007 to December 2007 received KGF for the prevention of mucositis and were included in the study group A, whereas 20 consecutive patients treated from January 2006 to March 2007, were included in the historical control group B. Oral and intestinal mucositis were significantly less severe in group A (P=0.002 and P<0.001, respectively). These results were confirmed with the use of video-capsule endoscopy. Patients in group A had a significantly lower incidence of neutropenic fever (P=0.026). Severe intestinal mucositis was significantly associated with a higher incidence of documented infections too (P=0.019). KGF is effective in the prevention of intestinal mucositis in patients undergoing auto-SCT. Patients with severe intestinal mucositis run a higher risk to develop infections.Bone Marrow Transplantation (2008) 42, 337-343; doi:10.1038/bmt.2008.168; published online 16 June 2008.     

Severe mucositis is associated with reduced survival after autologous stem cell transplantation for lymphoid malignancies

Mucositis is a known complication of autologous stem cell transplantation (ASCT). This study retrospectively reviewed 191 patients with lymphoid malignancies undergoing ASCT following a uniform mobilising regimen of etoposide (VP-16)/granulocyte colony-stimulating factor and a uniform high-dose preparative regimen of busulfan/cyclophosphamide/VP-16. Eighty-seven patients experienced severe mucositis (modified Oral Mucositis Assessment Scale > or =1). Patient characteristics compared between mucositis groups were balanced according to disease status, prior exposure to radiation therapy, time from radiation therapy and actual body weight. Log-rank analysis revealed that severe mucositis was associated with inferior overall survival (P = 0.002). A 12-month landmark analysis showed this difference in survival occurred within 1 year post-transplant. Multivariate analysis of all-cause mortality showed lower pretransplant albumin and severe mucositis to be significant risk factors. Multivariate analysis for relapse mortality revealed severe mucositis to be a risk factor (P = 0.047), while lower pretransplant albumin was significant for non-relapse mortality (NRM; P = 0.009). Kaplan-Meier estimates of survival based on relapse and NRM were significantly worse for patients with severe mucositis. Reduced pretransplant forced expiratory volume in 1 s (FEV(1)) and carbon monoxide (CO) diffusing capacity (DLCO) were also associated with severe mucositis. Our data suggest that studies of new treatment strategies for mucositis should include relapse and survival endpoints and that pretransplant factors, such as FEV(1) and DLCO may be useful to risk-stratify patients entered onto such trials.     

Multivariate analysis of factors influencing oral mucositis in allogeneic hematopoietic stem cell transplantation

Little information is available regarding the effect of oral intervention on the outcome of hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the incidence of oral mucositis after allogeneic HSCT with or without oral intervention among 96 consecutive patients in our hospital between January 1988 and March 2006. We combined two oral intervention strategies: cryotherapy and oral health care. The former was applied beginning in 2003 for patients being treated with melphalan, and the latter, which was the study's main strategy, was applied to all HSCT recipients beginning in 2004. Oral mucositis was evaluated according to NCI CTCAE v3.0. The incidence of oral mucositis was 30.9% (17/55) in reduced-intensity stem cell transplantation (RIST), which was significantly lower than the 90.2% (37/41) in conventional stem cell transplantation (CST; P < 0.001). Among these 96 patients, severe oral mucositis was observed in 19 (46.3%) CST cases and in 6 (10.9%) RIST cases (P < 0.001). The occurrence of oral mucositis apparently decreased after oral health care instructions were given. Multiple logistic analysis revealed that the conditioning regimen and oral health care were independent risk factors for the incidence of oral mucositis. The cryotherapy did not exert enough potency to prevent oral mucositis in patients who had undergone CST or RIST. We concluded that oral health care improved tissue damage due to an overall upgrade in oral hygiene during chemotherapy.     

The Prospective Oral Mucositis Audit: relationship of severe oral mucositis with clinical and medical resource use outcomes in patients receiving high-dose melphalan or BEAM-conditioning chemotherapy and autologous SCT

The Prospective Oral Mucositis Audit was an observational study in 197 patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) undergoing, respectively, high-dose melphalan or BEAM chemotherapy and autologous SCT at 25 European centres. We evaluated the relationship between severe oral mucositis (SOM; WHO Oral Toxicity Scale grade 3-4) and local and systemic clinical sequelae and medical resource use. SOM occurred in 44% of patients. The duration of SOM (mean 5.3 days) correlated with time to neutrophil engraftment. The following parameters increased gradiently with maximum grade of oral mucositis: duration of pain score >or=4, opioid use, dysphagia score >or=4, total parenteral nutrition (TPN) use, incidence and/or duration of fever and infection, and duration of antibiotic use. SOM increased the duration of TPN use by 2.7 days (P<0.001), opioids by 4.6 days (P<0.001), and antibiotics by 2.4 days (P=0.045). SOM prolonged hospital stay by 2.3 days (P=0.013) in MM patients, but not in NHL patients (who tended to have a longer hospital stay). In conclusion, this analysis of prospectively collected observational data provides important insight into the scope and impact of SOM in the European transplant setting.     

Efficacy and safety of acupuncture and moxibustion combined with the external application of traditional Chinese medicine in the treatment of primary liver cancer: A protocol for systematic review and meta-analysis

Background:Primary liver cancer (PLC) is one of the most common malignant tumors in the world, and its incidence and fatality rate are increasing year by year. Due to the large population base in China, the aging population is severely affected by environmental pollution, eating habits, and unhealthy lifestyles. And many other influences have caused the number of new PLC cases and deaths in China to rank first in the world. Acupuncture combined with external application of Chinese medicine to treat PLC is currently one of the commonly used treatments in China. However, this combined treatment still lacks evidence-based medicine support. Therefore, this systematic review and meta-analysis aims to evaluate the efficacy and safety of acupuncture combined with external application of traditional Chinese medicine in the treatment of PLC.Method:We will search PubMed, Web of Science, GCBI, Embase, OVID, AMED, Cochrane Library, CNKI, VIP, CBM, and Wanfang databases. As of September 15, 2021, there are no restrictions on search language, publication time, and publication status. We will use the following medical keywords to search, including: “acupuncture”, “external application of traditional Chinese medicine”, and “primary liver cancer”. At the same time, we will manually search all reference lists from relevant systematic reviews to find other eligible studies. We will use the random effects model in REVMAN v5.3 for meta-analysis. The study for acupuncture combined with Chinese herbal medicine in the treatment of PLC was a randomized controlled study. Two researchers will independently review the research selection, data extraction, and research quality assessments. Finally, we will observe the outcome measures.Results:This study will provide evidence-based guidance for the treatment of PLC with acupuncture and the external application of traditional Chinese medicine and offers new ideas and methods for the treatment of PLC.     

The Role of Mesh Implants in Surgical Treatment of Parastomal Hernia

A parastomal hernia is a common complication following stoma surgery. Due to the large number of hernial relapses and other complications, such as infections, adhesion to the intestines, or the formation of adhesions, the treatment of hernias is still a surgical challenge. The current standard for the preventive and causal treatment of parastomal hernias is to perform a procedure with the use of a mesh implant. Researchers are currently focusing on the analysis of many relevant options, including the type of mesh (synthetic, composite, or biological), the available surgical techniques (Sugarbaker’s, “keyhole”, or “sandwich”), the surgical approach used (open or laparoscopic), and the implant position (onlay, sublay, or intraperitoneal onlay mesh). Current surface modification methods and combinations of different materials are actively explored areas for the creation of biocompatible mesh implants with different properties on the visceral and parietal peritoneal side. It has been shown that placing the implant in the sublay and intraperitoneal onlay mesh positions and the use of a specially developed implant with a 3D structure are associated with a lower frequency of recurrences. It has been shown that the prophylactic use of a mesh during stoma formation significantly reduces the incidence of parastomal hernias and is becoming a standard method in medical practice.     

Human immunodeficiency virus and nodular regenerative hyperplasia of liver:A systematic review简

AIM: To investigate the diagnosis, pathogenesis, natural history, and management of nodular regenerative hyperplasia (NRH) in patients with human immunodeficiency virus (HIV).METHODS: We performed a systematic review of the medical literature regarding NRH in patients with HIV. Inclusion criteria include reports with biopsy proven NRH. We studied the clinical features of NRH, in particular, related to its presenting manifestation and laboratory values. Combinations of the following keywords were implemented: “nodular regenerative hyperplasia”, “human immunodeficiency virus”, “noncirrhotic portal hypertension”, “idiopathic portal hypertension”, “cryptogenic liver disease”, “highly active antiretroviral therapy” and “didanosine”. The bibliographies of these studies were subsequently searched for any additional relevant publications.RESULTS: The clinical presentation of patients with NRH varies from patients being completely asymptomatic to the development of portal hypertension – namely esophageal variceal bleeding and ascites. Liver associated enzymes are generally normal and synthetic function well preserved. There is a strong association between the occurrence of NRH and the use of antiviral therapies such as didanosine. The management of NRH revolves around treating the manifestations of portal hypertension. The prognosis of NRH is generally good since liver function is preserved. A high index of suspicion is required to make a identify NRH.CONCLUSION: The appropriate management of HIV-infected persons with suspected NRH is yet to be outlined. However, NRH is a clinically subtle condition that is difficult to diagnose, and it is important to be able to manage it according to the best available evidence.     

Treatment for Malignant Struma Ovarii in the Eyes of Thyroid Surgeons: A Case Report and Study of Chinese Cases Reported in the Literature

Malignant struma ovarii (MSO) is a rare malignant ovarian germ cell tumor that has been scarcely reported by thyroid surgeons focusing on treatment. There are no golden standards for its treatment. There has not been any Chinese case included in the English language literatures. This is the first study by collecting all Chinese cases with clinical information. We emphasize on using I¹³¹ therapy after operation.Presented is a case of struma ovarii with malignant histologic features who underwent definitive initial surgery of reproductive system tumors and a total thyroidectomy combined with thyroid-stimulating hormone (TSH)-suppressive therapy following treatment with I¹³¹. Furthermore, a Chinese full-text database literature search for cases of MSO was performed, and advisable clinical data were collected following our treatment advice.Clinical data from 34 additional cases were compiled. As Chinese genetic background and environment are different from those of Western countries, our clinical data closely mirror theirs in some aspects. In addition, we provide a rare gene mutation type of MSO by the case from our department.Integrating literatures with the experience of thyroid surgeons, we recommend “multidisciplinary joint treatment” for MSO, namely traditional radical initial surgery of ovarian cancer and a total thyroidectomy combined with TSH-suppressive therapy following treatment with I¹³¹ for those who do not desire preservation of fertility.     

The Role of Laparoscopic Surgery in the Management of Children and Adolescents With Inflammatory Bowel Disease

Although laparoscopic surgery is readily used in the management of inflammatory bowel disease (IBD) in adults, its role in the surgical treatment of IBD in the pediatric population is not well established. The aim of this narrative review was to analyze the published evidence comparing laparoscopic and open resection in the management of children and adolescents with IBD.The Pubmed and Embase databases were searched using the terms “inflammatory bowel disease,” “children,” “adolescents,” “laparoscopic,” and “colectomy.”The review identified 10 appropriate studies. Even though laparoscopic surgery generally resulted in longer operating times (between a mean of 40 and 140 min), benefits included reduced postoperative pain (mean duration of opiate use 3 vs 6 days) and reduced length of stay (median length of stay 5–8 vs 10.5–19 days) compared with open surgery. Postoperative complication rates were similar following both approaches.Due to the limited available data and the small sample size of the published series, definite recommendations are not able to be drawn. Nevertheless, current evidence indicates that laparoscopic colorectal resection is safe and feasible in the management of IBD in the paediatric population, with reductions in postoperative pain and length of hospital stay achievable.     

Chinese Herbal Medicine-induced Liver Injury

The widespread use of Chinese herbal medicine (CHM) and the associated adverse reactions has attracted the attention of researchers and physicians. Reports have shown that several types of CHM can cause liver injury, with increasing numbers of cases reported every year. The difficulty in characterizing CHM-induced liver injury stems from clinical manifestations, diagnosis and pathogenesis. The clinical manifestations are varied, but gastrointestinal symptoms are the majority. The Council for International Organizations of Medical Sciences scale is currently the most commonly used method for assessing causality in cases of medicine-induced liver injury with excellent sensitivity, specificity and predictive validity. However, the pathogenesis of CHM-induced liver injury is not well understood. The classic view encompasses a contribution from “toxic metabolites” that either elicit an immune response or directly affect cellular biochemical processes or functions. In addition, poor quality and inappropriate clinical use of CHMs contribute to safety concerns. To ensure the safe use of CHMs and decrease the number of hepatotoxic cases, clinicians, researchers and pharmaceutical companies should share responsibility by regulating clinical use, strengthening basic toxicology research and establishing a strict quality control system.     

The diagnosis and treatment of the no-reflow phenomenon in patients with myocardial infarction undergoing percutaneous coronary intervention

OBJECTIVE

To review the diagnosis and treatment available for myocardial infarction patients having no-reflow in the setting of percutaneous coronary intervention (PCI).

DATA SOURCES

Data for the present review were obtained from searches in PubMed (1997 to 2007) using the following key terms: “acute myocardial infarction”, “no-reflow phenomenon”, “myocardial contrast echocardiography”, “coronary angiography” and “cardioprotection devices”.

STUDY SELECTION

Mainly original articles and critical reviews written by major research pioneers in interventional cardiology were selected.

RESULTS

Despite a fully patent coronary artery post-PCI for myocardial infarction, patients may experience inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction. This phenomenon is defined as no-reflow and is a growing problem in the field of interventional cardiology. Although voluminous clinical trial data are available, the exact mechanisms involved and which treatment should be administered as first-line therapy are currently unknown. The different techniques used to diagnose no-reflow also have their pros and cons; myocardial contrast echocardiography and coronary angiography are the most reliable techniques. In cases when no-reflow was successfully reversed, patient recovery was associated with favourable left ventricular remodelling and increased left ventricular ejection fraction, even in the absence of significant improvement in regional contractile function.

CONCLUSION

Based on the trials in the literature, myocardial contrast echocardiography is the gold standard for the diagnosis of no-reflow. If no-reflow occurs following PCI, treatment with intracoronary adenosine or verapamil should be administered, because this form of therapy is inexpensive and safe, improves flow in the target vessel and may reduce infarct size.     

Target inference from collections of genomic intervals

Finding regions of the genome that are significantly recurrent in noisy data are a common but difficult problem in present day computational biology. Cores of recurrent events (CORE) is a computational approach to solving this problem that is based on a formalized notion by which “core” intervals explain the observed data, where the number of cores is the “depth” of the explanation. Given that formalization, we implement CORE as a combinatorial optimization procedure with depth chosen from considerations of statistical significance. An important feature of CORE is its ability to explain data with cores of widely varying lengths. We examine the performance of this system with synthetic data, and then provide two demonstrations of its utility with actual data. Applying CORE to a collection of DNA copy number profiles from single cells of a given tumor, we determine tumor population phylogeny and find the features that separate subpopulations. Applying CORE to comparative genomic hybridization data from a large set of tumor samples, we define regions of recurrent copy number aberration in breast cancer.Large collections of intervals are a common form of data generated by high-throughput genomics. For example, DNA copy number analysis yields intervals of the genome corresponding to gains or losses of DNA segments. Likewise, chromatin structure is often reported as intervals of the genome. In such cases a common goal is inference of contiguous genomic target regions, which under certain model assumptions, generates the observed patterns in the data. Such target regions are termed “cores” in the following text. The typical evidence for such cores is the presence of “recurrent” observations, suitably defined.The following two examples illustrate how cores arise in a specific genomic setting. In the case of nucleosome positioning problems, the input interval set consists of DNA fragments obtained by micrococcal nuclease digestion. For an appropriate digestion regime, fragments protected by nucleosomes will dominate the set. Cores derived from these input data will correspond to nucleosome positions. As a second example, consider copy number analysis performed on a collection of individual DNAs. In this case, each interval in the input represents an observed region of copy number variation observed in a person. We can ask, “What are the common genomic copy number polymorphisms?” Rare variants, spurious segments created by observation and data processing, and the blurring of interval boundaries by noise in the observation protocol make an otherwise easy problem quite difficult. Cores will then represent genomic regions where copy number variation recurs in the population with a frequency unexpected by chance events.We sought a solution that admits cores with a wide range of lengths, as is appropriate for data comprised of intervals with a wide range of lengths. We also sought to avoid explicit probability models in favor of more general set-theoretic and combinatorial methods, to which specific probabilistic assumptions could be added. We use the term “cores of recurrent events” (CORE) for our method. Central to CORE is the notion of explanatory power. A core is a proposed interval that “explains” an observed interval event by assigning a measure of geometric association between the two. The task is to find a set of cores that jointly provide an optimized explanation of the observed events. We show that certain association measures are more favorable than others with regard to algorithmic complexity. Next, we show how to subject the collection of cores to statistical tests for significance, so that a minimum number of justified cores, the “depth” of the solution, can be set. This approach is described and illustrated with synthetic data. We then demonstrate two applications with actual data sets: one that facilitates phylogenetic analysis and feature extraction for tumor subpopulations from single-cell copy number profiles and another that identifies regions of recurrent copy number aberration in breast cancer made from a large collection of profiles of tumor samples.     

Bed load transport by submerged jets

Some similarities are presented between the bed load transport of noncohesive grains in long rivers and at a local, jet-induced scour. Experiments are described in which a submerged two-dimensional slot nozzle, inclined downward, eroded a deep sand bed. The rate of erosion at the very beginning of a scour was evaluated and compared with river data by use of the idea of “stream-power.” Empirical relationships for the two cases are similar, although the geometry of the boundaries is quite different.     

Vaccination against Borna Disease: Overview,Vaccine Virus Characterization and Investigation of Live and Inactivated Vaccines

(1) Background: Vaccination of horses and sheep against Borna disease (BD) was common in endemic areas of Germany in the 20th century but was abandoned in the early 1990s. The recent occurrence of fatal cases of human encephalitis due to Borna disease virus 1 (BoDV-1) has rekindled the interest in vaccination. (2) Methods: The full genomes of the BD live vaccine viruses “Dessau” and “Giessen” were sequenced and analyzed for the first time. All vaccination experiments followed a proof-of-concept approach. Dose-titration infection experiments were performed in rabbits, based on both cell culture- and brain-derived viruses at various doses. Inactivated vaccines against BD were produced from concentrated cell culture supernatants and investigated in rabbits and horses. The BoDV-1 live vaccine “Dessau” was administered to horses and antibody profiles were determined. (3) Results: The BD live vaccine viruses “Dessau” and “Giessen” belong to clusters 3 and 4 of BoDV-1. Whereas the “Giessen” virus does not differ substantially from field viruses, the “Dessau” virus shows striking differences in the M gene and the N-terminal part of the G gene. Rabbits infected with high doses of cell-cultured virus developed neutralizing antibodies and were protected from disease, whereas rabbits infected with low doses of cell-cultured virus, or with brain-derived virus did not. Inactivated vaccines were administered to rabbits and horses, following pre-defined vaccination schemes consisting of three vaccine doses of either adjuvanted or nonadjuvanted inactivated virus. Their immunogenicity and protective efficacy were compared to the BD live vaccine “Dessau”. Seventy per cent of horses vaccinated with the BD live vaccine “Dessau” developed neutralizing antibodies after vaccination. (4) Conclusion: Despite a complex evasion of immunological responses by bornaviruses, some vaccination approaches can protect against clinical disease. For optimal effectiveness, vaccines should be administered at high doses, following vaccination schemes consisting of three vaccine doses as basic immunization. Further investigations are necessary in order to investigate and improve protection against infection and to avoid side effects.     

Utility of tolcapone in fluctuating Parkinson’s disease

Fluctuating Parkinson’s disease (PD) represents a clinical management challenge. The primary utility of levodopa in patients with PD is moderated by the “wearing off” phenomena seen with long-term use. COMT inhibitors slow down the rapid metabolism of levodopa, resulting in a more-sustained response to dopaminergic therapy. Tolcapone is a selective, reversible catechol-O-methyltransferase (COMT) inhibitor, shown to have both peripheral and central effects. In clinical trials, tolcapone has been shown to reduce “off” time, increase “on” time, improve patient and clinician assessments of disease severity, and improve patient quality of life. In a SWITCH study, tolcapone was associated with greater duration of “on” time than remaining on entacapone. Adverse effects of tolcapone are related to the class, with the exception of rare cases of hepatotoxicity. Tolcapone has been recently reintroduced on the European market and recent guidance from the US Food and Drug Administration has reduced the hepatic monitoring requirements for patients initiating tolcapone therapy. With proper monitoring, tolcapone is an effective, well-tolerated drug useful in the management of patients with fluctuating PD.