Reflux from the continent ileostomy reservoir

The reflux from the continent ileostomy reservoir was studied with radiologic and pressure recording techniques in ten patients. The contrast used was poly-iodine-styrene with a density of 0.8 to 1.1 gm/cm3. Reflux into the afferent loop was demonstrated in all patients at a filling volume of approximately 30 percent of the maximal volume capacity of the reservoir. The magnitude of reflux increased with the increasing volume of the reservoir contents and a rise in reservoir pressure. The reflux could temporarily be influenced by antiperistaltic or isoperistaltic motor activity in the afferent loop. Although no adverse effects were seen from the amount of reflux demonstrated in the present investigation, the finding of increasing reflux with increased fullness and intraluminal pressure of the reservoir would indicate that the reservoir should be emptied at regular intervals and before high pressures are built up.     

Neurotrophic factor intervention restores auditory function in deafened animals

A primary cause of deafness is damage of receptor cells in the inner ear. Clinically, it has been demonstrated that effective functionality can be provided by electrical stimulation of the auditory nerve, thus bypassing damaged receptor cells. However, subsequent to sensory cell loss there is a secondary degeneration of the afferent nerve fibers, resulting in reduced effectiveness of such cochlear prostheses. The effects of neurotrophic factors were tested in a guinea pig cochlear prosthesis model. After chemical deafening to mimic the clinical situation, the neurotrophic factors brain-derived neurotrophic factor and an analogue of ciliary neurotrophic factor were infused directly into the cochlea of the inner ear for 26 days by using an osmotic pump system. An electrode introduced into the cochlea was used to elicit auditory responses just as in patients implanted with cochlear prostheses. Intervention with brain-derived neurotrophic factor and the ciliary neurotrophic factor analogue not only increased the survival of auditory spiral ganglion neurons, but significantly enhanced the functional responsiveness of the auditory system as measured by using electrically evoked auditory brainstem responses. This demonstration that neurotrophin intervention enhances threshold sensitivity within the auditory system will have great clinical importance for the treatment of deaf patients with cochlear prostheses. The findings have direct implications for the enhancement of responsiveness in deafferented peripheral nerves.     

Preservation of Red Blood Cells: Studies of Erythrocyte Adenine Nucleotides Using Luminescence Analysis

The levels of ATP and total adenine nucleotides (ATP + ADP + AMP) were determined by firefly luciferase assay in red blood cells during storage for 5 weeks at 4 degrees C. With few exceptions, no significant differences in nucleotide levels were found between whole blood stored in CPD-adenine and various preparations of red blood cells in CPD-adenine or CPD with saline-adenine-glucose (SAG) as additive. The levels of ATP and total adenine nucleotides during storage are discussed in relation to glucose levels, extracellular pH and shelf life of the red blood cells.     

Cocaine use in Europe - a multi-centre study. Methodology and prevalence estimates

An increase in the use of cocaine and crack in several parts of Europe has raised the question whether this trend is similar to that of the USA in the 1980s. However, research in the field of cocaine use in Europe has been only sporadic. Therefore, a European multi-centre and multi-modal project was designed to study specific aspects of cocaine and crack use in Europe, in order to develop guidelines for public health strategies. Data on prevalence rates were analysed for the general population and for specific subgroups. Despite large differences between countries in the prevalence of cocaine use in the general population, most countries show an increase in the last few years. The highest rate with a lifetime prevalence of 5.2% was found for the United Kingdom, although with a plateau effect around the year 2000. With regard to specific subgroups, three groups seem to show a higher prevalence than the general population: (1) youth, especially in the party scene; (2) socially marginalized groups, such as homeless and prostitutes or those found in open drug scenes; (3) opiate-dependent patients in maintenance treatment who additionally use cocaine. Specific strategies need to be developed to address problematic cocaine use in these subgroups.     

Management of patients with community-acquired pneumonia treated in hospital in Sweden

To investigate the management of patients with community-acquired pneumonia (CAP) treated in hospital in Sweden, a multicentre retrospective cohort study was performed with medical record review of 982 patients (mean age 63 y) at 17 departments of infectious diseases at hospitals in Sweden. Information on antimicrobial therapy, demographic characteristics, comorbid conditions, physical examination findings, and laboratory and microbiological test results were recorded. Outcome measures were in-hospital mortality and length of hospital stay (LOS). Cultures were obtained from blood in 80% and from sputum in 22% of the patients. A microbiological aetiology was determined for 23% of the patients, with Streptococcus pneumoniae as the dominating agent (9%). The initial antibiotic treatment was mostly given intravenously (78%). Penicillin (50%) or a cephalosporin (30%) was the most common choice. Both of these drugs were usually given as a single agent. The overall mortality was 3.5% and the mean LOS was 6.4 d. Thus, the outcome was favourable despite the empirical antibiotic treatment having a narrow spectrum compared with the broader approach recommended in most recent guidelines on the management of CAP. These findings suggest that a majority of patients who are hospitalized with moderately severe pneumonia can be treated initially with penicillin alone.     

Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis

One hallmark of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is infiltration of leukocytes into the CNS, where chemokines and their receptors play a major mediatory role. CX3CR1 is a chemokine receptor involved in leukocyte adhesion and migration and hence a mediator of immune defense reactions. The role of CX3CR1 in MS and EAE pathogenesis however remains to be fully assessed. Here, we demonstrate CX3CR1 mRNA expression on inflammatory cells within active plaque areas in MS brain autopsies. To test whether blocking CNS infiltration of peripheral leukocytes expressing CX3CR1 would be a suitable treatment strategy for MS, we developed a selective, high-affinity inhibitor of CX3CR1 (AZD8797). The compound is active outside the CNS and AZD8797 treatment in Dark Agouti rats with myelin oligodendrocyte glycoprotein-induced EAE resulted in reduced paralysis, CNS pathology, and incidence of relapses. The compound is effective when starting treatment before onset, as well as after the acute phase. This treatment strategy is mechanistically similar to, but more restricted than, current very late antigen-4–directed approaches that have significant side effects. We suggest that blocking CX3CR1 on leukocytes outside the CNS could be an alternative approach to treat MS.Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and degenerative disease of the central nervous system (CNS). It was already discovered in the early 1900s that a similar disease could be induced in different animal species by injection of spinal cord extracts or myelin-derived proteins (1–3). This group of animal models for MS, called experimental autoimmune encephalomyelitis (EAE), has provided an experimental platform for building an extensive understanding of the pathology of MS, as well as discovering strategies for intervention of the disease. A typical feature of the pathogenesis in both MS and EAE is the infiltration of leukocytes from the blood stream into the CNS (3). Leukocyte adhesion and extravasation includes several well defined steps and various adhesion molecules, chemokines and their receptors are important mediators for this process. In line with this, the recently developed therapeutic drugs natalizumab and fingolimod, which broadly target leukocyte migration to the brain, exhibit efficacy in EAE models (4, 5), and they are now established therapies in MS (6).Natalizumab, blocking the interaction between very late antigen-4 (VLA-4) and CD106 (VCAM-1), is an effective treatment both on clinical endpoints and MRI biomarkers (7). Fingolimod, the first oral drug for relapsing remitting MS (RRMS), acts on S1P receptors preventing lymphocytes from moving out of lymphoid tissue (8). Natalizumab is only approved as a second-line monotherapy in RRMS or in patients with very active disease, because it carries increased risk of developing the often fatal progressive multifocal leukoencephalopathy (7, 9). Treatment with fingolimod is associated with side effects such as signs of immune suppression, including increased frequency of infections (8).Considering the pronounced presence of inflammatory cells in the brain of MS patients, the significant correlation between inflammation and axonal injury (10) and the efficiency of treatments that broadly block infiltration of immune cells, a similar but more restricted therapeutic approach is appealing. Chemokines are synthesized and released at sites of inflammation, where they act on specific receptors expressed by immune cells to mediate directed cell migration in synergy with adhesion molecules, such as VLA-4, from the blood stream and into the sites of inflammation. CX3CR1 is a unique member of the chemokine receptor family (11) and binds with high affinity to its ligand CX3CL1 [fractalkine (FKN)]. FKN is produced in a membrane bound form but can also be released following proteolytic cleavage, making it important for mediating both adhesion and migration of CX3CR1-expressing cells. In contrast to VLA-4, which is broadly expressed on most leukocytes except neutrophils (7, 12), the expression of CX3CR1 is restricted to subpopulations of monocytes, T lymphocytes, and natural killer (NK) cells (13–16). We have previously demonstrated intense accumulation of CX3CR1-expressing microglia/macrophages within inflammatory foci in the spinal cord of Dark Agouti (DA) rats with EAE induced by myelin oligodendrocyte glycoprotein (MOG) (17) and formed the hypothesis that CX3CR1 would be an attractive therapeutic target for treating MS.To test the hypothesis, we have developed a selective, high-affinity small-molecule inhibitor of CX3CR1 (AZD8797) (18). This molecule has the potential to be administered as an oral drug in humans. However, because of the decrease in potency to rat CX3CR1 and a modest oral bioavailability in rats (39%), we have chosen continuous s.c. dosing for the proof-of-concept studies in rats. The MOG_1-125–induced EAE model in DA rats was used, because it exhibits pathology very similar to MS with infiltration of inflammatory cells, demyelination, and axonal degeneration in the CNS, as well as a relapsing remitting disease course (19, 20). To further mimic the human treatment situation, we have not only treated rats before the onset of paralysis but also initiated treatment during ongoing disease. We present efficacy (reduced paralysis) versus exposure data, analysis of CNS pathology, and measurements of functional inhibition of CX3CR1. These data, in combination with an analysis for CX3CR1 expression within MS brain autopsy samples, clearly demonstrate the potential of CX3CR1 inhibition as an alternative and unique approach for treating MS.     

Item Response Model Adaptation for Analyzing Data from Different Versions of Parkinson’s Disease Rating Scales

Pharmaceutical Research - Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering drugs into the abdominal cavity as an aerosol under high pressure. It is...     

Outcome and determinants of failure to complete primary R-CHOP treatment for reasons other than non-response among patients with diffuse large B-cell lymphoma

Patients with diffuse large B-cell lymphoma (DLBCL) who fail to complete planned treatment with R-CHOP due to toxicity are sparsely described. We investigated the extent of failure to complete treatment (six cycles or more, or three cycles + RT for patients with stage I disease) with R-CHOP for reasons unrelated to non-response, the determinants of such failure and the outcome among these patients. Three thousand one hundred and forty nine adult DLBCL patients who started primary treatment with R-CHOP were identified through the Swedish lymphoma register 2007-2014. Of these, 147 (5%) stopped prematurely after 1-3 cycles of R-CHOP for reasons unrelated to non-response, 168 (5%) after 4-5 cycles and 2639 patients (84%) completed planned treatment. Additionally, 195 (6%) patients did not complete treatment due to non-response or death before treatment end. In a multivariable logistic regression model, age > 75 years, poor performance status, extranodal disease and Charlson Comorbidity Index ≥1 were significantly associated with failure to complete planned R-CHOP treatment for other reasons than non-response. Non-completion of treatment strongly correlated with survival. Five-year overall survival for patients who received 1-3 cycles was 26% (95% CI: 19%-33%), 49% (95% CI: 41%-57%) for 4-5 cycles and 76% (74%-77%) for patients who completed treatment. Failure to complete planned R-CHOP treatment is an important clinical issue associated with inferior survival. Old age and poor performance status most strongly predict such failure. These results indicate a need for improved treatment tailoring for patients with certain baseline demographics to improve tolerability and chance for treatment completion.