Intravenous immunoglobulin in drug and device refractory patients with the symptoms of gastroparesis-an open-label study.

BACKGROUND: Gastroparesis is a complex clinical entity; many aspects of which remain unknown. Although most patients have idiopathic, diabetic, or postsurgical gastroparesis, many are thought to have measurable neuromuscular abnormalities. Immunotherapy has recently been utilized to treat suspected autoimmune gastrointestinal dysmotility. METHODS: Fourteen patients with symptoms of gastroparesis (Gp) who were refractory to drug/device were selected from 443 Gp patients from 2013 to 2015 who were treated at the University of Louisville motility center. All patients underwent a structural and psychiatric evaluation along with detailed psychological and behavioral examination to rule out eating disorders. We performed detailed neuromuscular evaluation and all 14 patients received at least 12 weeks of intravenous immunoglobulin (400 mg/kg infusion weekly). Response was defined subjectively (symptomatic improvement) using standardized IDIOM score system. KEY RESULTS: All 14 patients had serological evidence and/or tissue evidence of immunological abnormality. Post-IVIG therapy, there was a significant improvement in symptoms scores for nausea, vomiting, early satiety, and abdominal pain. CONCLUSIONS AND INFERENCES: Although limited by the absence of placebo group, the data illustrate the role of autoimmunity and neuromuscular evaluation in patients with gastroparesis and support the utility of a diagnostic trial of immunotherapy in an effort to improve therapeutic outcomes for such patients.

Tides in the Last Interglacial: insights from notch geometry and palaeo tidal models in Bonaire, Netherland Antilles.

The study of past sea levels relies largely on the interpretation of sea-level indicators. Palaeo tidal notches are considered as one of the most precise sea-level indicators as their formation is closely tied to the local tidal range. We present geometric measurements of modern and palaeo (Marine Isotope Stage (MIS) 5e) tidal notches on Bonaire (southern Caribbean Sea) and results from two tidal simulations, using the present-day bathymetry and a palaeo-bathymetry. We use these two tools to investigate changes in the tidal range since MIS 5e. Our models show that the tidal range changes most significantly in shallow areas, whereas both, notch geometry and models results, suggest that steeper continental shelves, such as the ones bordering the island of Bonaire, are less affected to changes in tidal range in conditions of MIS 5e sea levels. We use our data and results to discuss the importance of considering changes in tidal range while reconstructing MIS 5e sea level histories, and we remark that it is possible to use hydrodynamic modelling and notch geometry as first-order proxies to assess whether, in a particular area, tidal range might have been different in MIS 5e with respect to today.

[Pulmonary manifestations of Langerhans cell histiocytosis]. / Manifestations pulmonaires de l'histiocytose langerhansienne.

Pulmonary Langerhans cell histiocytosis is a rare diffuse cystic interstitial pneumonia of unknown etiology that occurs selectively in young smokers of both genders. The multicenter studies conducted by the reference center have better defined the short and medium terms natural history of the disease and the clinical management of patients. A substantial proportion of patients experience a dramatic decline in their lung function soon after diagnosis. Importantly, smoking cessation is associated with a decreased risk of subsequent deterioration. Cladribine, a purine analogue, chemotherapy may dramatically improve lung function in patients with progressive pulmonary Langerhans cell histiocytosis, but this treatment should be used only in the setting of clinical research. Specific pulmonary hypertension therapies (anti-endothelin receptors, inhibitors of phosphodiesterases) may be used with caution in specialized centres for patients with severe pulmonary hypertension, and seem to be well tolerated. The recent identification of the V600E mutation of the BRAF oncogene in approximately half of the Langerhans cell histiocytosis lesions, including pulmonary granulomas, represents an important step forward in the understanding of the pathogenesis of Langerhans cell histiocytosis. Potentially it opens the way to targeted therapies.

Inverse PPARß/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.

Besides its established functions in intermediary metabolism and developmental processes, the nuclear receptor peroxisome proliferator-activated receptor ß/δ (PPARß/δ) has a less defined role in tumorigenesis. In the present study, we have identified a function for PPARß/δ in cancer cell invasion. We show that two structurally divergent inhibitory ligands for PPARß/δ, the inverse agonists ST247 and DG172, strongly inhibit the serum- and transforming growth factor ß (TGFß)-induced invasion of MDA-MB-231 human breast cancer cells into a three-dimensional matrigel matrix. To elucidate the molecular basis of this finding, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) and microarray analyses, which identified the gene encoding angiopoietin-like 4 (ANGPTL4) as the major transcriptional PPARß/δ target in MDA-MB-231 cells, previously implicated in TGFß-mediated tumor progression and metastatic dissemination. We show that the induction of ANGPTL4 by TGFß and other oncogenic signals is strongly repressed by ST247 and DG172 in a PPARß/δ-dependent fashion, resulting in the inhibition of ANGPTL4 secretion. This effect is attributable to these ligands' ability to induce a dominant transcriptional repressor complex at the site of transcription initiation that blocks preinitiation complex formation through an histone deacetylase-independent, non-canonical mechanism. Repression of ANGPTL4 transcription by inverse PPARß/δ agonists is functionally linked to the inhibition of cancer cell invasion into a three-dimensional matrix, as (i) invasion of MDA-MB-231 cells is critically dependent on ANGPTL4 expression, (ii) recombinant ANGPTL4 stimulates invasion, and (iii) reverses the inhibitory effect of ST247 and DG172. These findings indicate that a PPARß/δ-ANGPTL4 pathway is involved in the regulation of tumor cell invasion and that its pharmacological manipulation by inverse PPARß/δ agonists is feasible.

Pneumococcal infections: association with asthma and COPD.

Pneumococci are responsible for lower respiratory tract infections (bronchitis and pneumonia) and invasive infections (bacteremia and meningitis). Pneumococcal vaccination is recommended for adults at high risk of pneumococcal infection. Asthma is not currently considered as an indication for pneumococcal vaccination and this vaccination is indicated only in case of respiratory insufficiency. Indeed, asthma is not usually considered as a risk factor for pneumococcal infection and pneumococcal polysaccharide vaccine does not decrease mortality in patients presenting with COPD. According to several recent epidemiological studies, asthma is associated with a doubled risk of pneumonia and invasive infections. This epidemiological association is supported by biological data suggesting increased susceptibility to pneumococcal infection in asthmatic patients. Pneumococci are responsible for 10 to 15% of acute exacerbations and onset of often-severe pneumonia in patients presenting with COPD. The recent availability of pneumococcal conjugate vaccines could be interesting for these patients, but their clinical and cost effectiveness will have to be demonstrated before they can be recommended for these conditions.

Cake shrinkage during freeze drying: a combined experimental and theoretical study.

The aim of this study is to investigate, by experimental studies and theoretical analysis, the phenomenon of cake shrinkage during the lyophilization process and to investigate the effect of shelf temperature during primary drying and secondary drying on the degree of cake shrinkage. Freeze-drying experiments were performed using 5% w/v sucrose where the drying protocols were altered in order to produce differing product temperature profiles. Resistance data during freeze drying were evaluated by the Manometric Temperature Measurement (MTM) method. Theoretical simulation of the freeze-drying process was performed using the Passage Freeze-Drying software. The difference between the glass transition temperature and the product temperature (Tg-T) obtained from the theoretical analysis was calculated and used for correlation with experimental shrinkage data. The Brunauer, Emmeth, Teller (BET) Specific Surface Area (SSA) Analysis was used as a method to quantify the degree of shrinkage. Samples were also analyzed for pore volume by mercury porosimetry. The SSA analysis on the freeze-dried samples showed an increase in SSA when samples were freeze dried at a lower shelf temperature during primary drying and at a slower ramp rate during secondary drying. The trend in surface area values was consistent with that obtained for pore size values. However, differences obtained among the various samples are small and cake diameter measurements showed that there was approximately 17% shrinkage even in the sample freeze dried at temperatures well below the Tg' and Tg. Variations in process and product temperature only accounted for an additional 2%-3% shrinkage. Resistance data obtained at various primary drying shelf temperatures showed a good correlation with surface area. The Tg-T behavior of the freeze-dried samples showed that a slow ramp rate of 0.1 degrees C/min during secondary drying maintains a product well below the Tg at all times and a higher ramp rate gives negative values of Tg-T. The obtained data suggest that conditions of secondary drying do impact shrinkage, and it is important to maintain a sample well below the collapse temperature during primary drying and below the Tg at all times during secondary drying; however, drying conditions are a second order effect. It seems that, in the case of a sample like sucrose, nearly 17% shrinkage will occur no matter what the product temperature history.

High dose chemotherapy and autologous hematopoietic stem cell transplantation for rheumatoid arthritis: a review.

A new treatment approach, involving intense immunosuppression and autologous hematopoietic stem cell transplantation (SCT), has emerged in recent years for the treatment of severe, refractory rheumatic autoimmune diseases including rheumatoid arthritis (RA). The rationale of this strategy is based on the concept of immunoablation by intense immunosuppression with subsequent regeneration of naïve T lymphocytes derived from reinfused hematopoietic progenitor cells. Patients with a therapy-refractory, progressively erosive disease who are at risk of functional disability and early mortality are considered eligible for treatment with autologous SCT. The goal is long-term improvement of disease activity and quality of life. However, when offering SCT to RA patients these benefits should be balanced against toxicities and treatment-related mortality. In several patients with intractable RA, long-term remissions were observed with this strategy, but failures have been reported as well. Only small numbers of RA patients have been treated thus far. Although different treatment protocols have been used, high dose chemotherapy as a means to achieve immunoablation has been invariably used in all studies. In this review we discuss background, clinical results, protocols, and future prospects of high dose chemotherapy and autologous SCT for RA.

A high-density genetic map of Sorghum bicolor (L.) Moench based on 2926 AFLP, RFLP and SSR markers.

Using AFLP technology and a recombinant inbred line population derived from the sorghum cross of BTx623 x IS3620C, a high-density genetic map of the sorghum genome was constructed. The 1713 cM map encompassed 2926 loci distributed on ten linkage groups; 2454 of those loci are AFLP products generated from either the EcoRI/MseI or PstI/MseI enzyme combinations. Among the non-AFLP markers, 136 are SSRs previously mapped in sorghum, and 203 are cDNA and genomic clones from rice, barley, oat, and maize. This latter group of markers has been mapped in various grass species and, as such, can serve as reference markers in comparative mapping. Of the nearly 3000 markers mapped, 692 comprised a LOD >3.0 framework map on which the remaining markers were placed with lower resolution (LOD <3.0). By comparing the map positions of the common grass markers in all sorghum maps reported to date, it was determined that these reference markers were essentially collinear in all published maps. Some clustering of the EcoRI/MseI AFLP markers was observed, possibly in centromeric regions. In general, however, the AFLP markers filled most of the gaps left by the RFLP/SSR markers demonstrating that AFLP technology is effective in providing excellent genome coverage. A web site, http://SorghumGenome.tamu.edu, has been created to provide all the necessary information to facilitate the use of this map and the 2590 PCR-based markers. Finally, we discuss how the information contained in this map is being integrated into a sorghum physical map for map-based gene isolation, comparative genome analysis, and as a source of sequence-ready clones for genome sequencing projects.

Methamphetamine abuse: issues for special populations.

Methamphetamine (MA) abuse has been a problem in the western United States for decades. However, recently the incidence of MA abuse has risen to epidemic levels in some regions and among particular subgroups of the population. Recognizing the need to develop effective treatments for MA dependence, the Center for Substance Abuse Treatment (CSAT) established a multisite Methamphetamine Treatment Program (MTP) that compares the Matrix Model treatment program for MA to the treatments as usual at seven community-based clinics in California, Montana and Hawaii. Examination of the clients receiving services though this project provides an opportunity to explore particular issues of diverse special populations who are impacted by the problem of MA dependence. These groups include rural Americans, Native Americans, Hawaiians, gay and bisexual males and drug court participants. Specifically, this article examines cultural, geographic and situational barriers to accessing and completing treatment and presents strategies that have been used to overcome these barriers.

Conducting trials in community settings: the provider perspective.

Providers and their treatment programs are the focus of efforts to translate research into practice. In the best of partnerships, they are more than the recipients of research efforts, because they are actively involved in developing and evaluating healthy links between practice and research . This article reports on experiences in a multisite methamphetamine treatment trial funded in October of 1998 by the Center for Substance Abuse Treatment. The goal of the trial is to generate knowledge about how a comprehensive treatment protocol developed by the Matrix Center in Los Angeles can be effectively transferred to the community drug treatment system. The Matrix model provides a three-times-per-week outpatient treatment experience that combines behavioral, educational, and 12-Step counseling techniques. When complete, the study will compare outcomes of the 16-week Matrix program with the usual treatment offered by the programs at the eight participating sites. The UCLA Drug Abuse Research Center and the Matrix Institute on Addictions coordinate the trial. This article describes factors that have fostered or hindered the development of this partnership. These factors can be divided into three temporal phases, although the circumstances presented may occur at any time during the research process. The first set of factors affecting the development of a healthy research-to-practice relationship exists prior to the establishment of that relationship. A second set of circumstances occurs at the initiation of the collaborative enterprise, and the third set of factors is more involved in the development and maintenance of ongoing productive collaboration between researchers and providers.

Methamphetamine and cocaine users: differences in characteristics and treatment retention.

The use of methamphetamine and cocaine have both produced significant public health problems during the past two decades. Although these powerful psychostimulants have many common acute and chronic effects, there are some important differences in who uses these drugs and the consequences of their use. This article reports on two large cohorts of treatment-seeking cocaine and methamphetamine users who entered treatment at the same facility over the same four-year period of time. Patterns of use differed significantly. Cocaine users have more episodic use patterns, spend more money on purchasing their drugs, and use alcohol more heavily. Methamphetamine users include a higher proportion of women, more frequently use on a daily basis, use marijuana more often, and experience more severe medical and psychiatric consequences. Despite the differences in the stimulant drug effects and consequences, the treatment response to a multicomponent, outpatient program is very similar.

The matrix model of outpatient stimulant abuse treatment: history and description.

The Matrix model was originally developed in response to the cocaine epidemic of the 1980s. The program consists of relapse prevention groups, education groups, social support groups, individual counseling, and urine and breath testing delivered in a structured manner over a 16-week period. The treatment is a directive, nonconfrontational approach which focuses on current issues and behavior change. Several evaluations of the model have supported its usefulness and efficacy with methamphetamine (MA) users. Methamphetamine users appear to respond to treatment similarly to cocaine users and many continue to show improvements at follow-up.

A high-throughput AFLP-based method for constructing integrated genetic and physical maps: progress toward a sorghum genome map.

Sorghum is an important target for plant genomic mapping because of its adaptation to harsh environments, diverse germplasm collection, and value for comparing the genomes of grass species such as corn and rice. The construction of an integrated genetic and physical map of the sorghum genome (750 Mbp) is a primary goal of our sorghum genome project. To help accomplish this task, we have developed a new high-throughput PCR-based method for building BAC contigs and locating BAC clones on the sorghum genetic map. This task involved pooling 24,576 sorghum BAC clones ( approximately 4x genome equivalents) in six different matrices to create 184 pools of BAC DNA. DNA fragments from each pool were amplified using amplified fragment length polymorphism (AFLP) technology, resolved on a LI-COR dual-dye DNA sequencing system, and analyzed using Bionumerics software. On average, each set of AFLP primers amplified 28 single-copy DNA markers that were useful for identifying overlapping BAC clones. Data from 32 different AFLP primer combinations identified approximately 2400 BACs and ordered approximately 700 BAC contigs. Analysis of a sorghum RIL mapping population using the same primer pairs located approximately 200 of the BAC contigs on the sorghum genetic map. Restriction endonuclease fingerprinting of the entire collection of sorghum BAC clones was applied to test and extend the contigs constructed using this PCR-based methodology. Analysis of the fingerprint data allowed for the identification of 3366 contigs each containing an average of 5 BACs. BACs in approximately 65% of the contigs aligned by AFLP analysis had sufficient overlap to be confirmed by DNA fingerprint analysis. In addition, 30% of the overlapping BACs aligned by AFLP analysis provided information for merging contigs and singletons that could not be joined using fingerprint data alone. Thus, the combination of fingerprinting and AFLP-based contig assembly and mapping provides a reliable, high-throughput method for building an integrated genetic and physical map of the sorghum genome.

Substance abuse treatment for "hazardous users": an early intervention.

A six-session cognitive behavioral protocol has been developed for substance abusers who meet the description "hazardous users." This category includes individuals evidencing mild to moderate use of alcohol or other drugs, whose lifestyles are minimally disrupted, or who are displaying signs of problem use or abuse, but are unwilling to enter intensive treatment. The treatment model is nonconfrontational and is designed to motivate the individual to recognize the problems associated with his or her substance use and initiate treatment-seeking behavior. The intervention may be particularly useful in situations where employees have tested positive for substances but deny having a problem, where friends or family members report help is needed but the individual denies any problem, or where an alcohol or other drug problem is clearly evidenced but the individual doesn't acknowledge a problem. A positive outcome is indicated by the client taking action which is consistent with an increased awareness of the problem as conceptualized by Prochaska and DiClemente (1982). This model is an alternative to the traditional confrontational models of "breaking through denial." The philosophies employed by William Miller and associates and by the Matrix treatment models form the basis of the intervention.

An intensive outpatient approach for cocaine abuse treatment. The Matrix model.

The Matrix model of outpatient treatment was developed during the 1980s in response to an overwhelming demand for cocaine abuse treatment services. The model was constructed using components based upon empirically supported findings from the substance abuse research field. Over the course of development, data were collected on the treatment model and the model was modified based upon empirical evaluation. A pilot study comparing the Matrix outpatient model with an inpatient hospital treatment program produced preliminary support for the clinical utility of the model. An open trial comparing publicly and privately funded patients demonstrated that patients with fewer resources were more difficult to engage and retain in this model of outpatient treatment. In a controlled trial, a clear positive relationship was documented between duration and amount of treatment involvement in the Matrix model and positive outcome at 1 year. Due to a variety of methodological issues, the study was not able to answer definitively the question of clinical efficacy. In all of these studies, patients treated with the Matrix model demonstrated statistically significant reductions in drug and alcohol use and improvements in psychological indicators. This body of work, along with the public acceptance the model has received in the treatment community, support the usefulness of this intensive outpatient approach for cocaine abuse. Further research is underway to provide additional controlled information on the value of this treatment approach.

History of sexual assault and the treatment of substance abuse disorders.

A treatment outcome study of adult patients treated for substance abuse disorders was conducted in which 80% of the participants were successfully contacted for follow-up six months post discharge. Analyses focused on baseline and outcome comparisons of patients with histories of sexual assault and patients with no history of sexual assault. The prevalence of assault in the sample was 15%. Baseline measures indicated that patients in the assaulted group were more likely to have a history of suicide planning and demonstrated greater psychiatric symptom severity as measured by the Brief Symptom Inventory. Outcome measures indicated that treatment was effective for both groups in psychiatric symptom reduction and in reduction of alcohol and other drug use. Results are discussed in terms of specific treatment needs for substance abuse patients with sexual assault histories.

Addiction treatment in the mid-1990s.

The rapid and dramatic changes now transforming the American healthcare system are also being felt in the addiction treatment field. How this change will be manifested in the structure, content and financing of substance abuse treatment over the next three to five years is described in the following article.

The Matrix model of outpatient stimulant abuse treatment: evidence of efficacy.

The current study examined the effectiveness of Matrix outpatient stimulant treatment. We associated 146 subjects' in-treatment abstinence data, treatment lengths, and weekly treatment activities to their 6-month abstinence outcomes as part of an interim analysis of a NIDA treatment demonstration project. Results indicated that the pretreatment subject characteristics of ethnicity and drug of choice significantly associated with treatment outcome using Matrix model treatment. Findings also demonstrated a treatment dose/abstinence response such that those who received longer Matrix treatment episodes demonstrated better abstinence outcomes. Further, in-treatment abstinence status and treatment length significantly associated with drug use status at follow-up. This set of findings provides evidence for the value of Matrix treatment and allows for these outcome data to be compared with reports on recent psychosocial treatments for stimulant dependence. This study also provides direction for evaluating longer term effectiveness for these types of drug treatments.

Neurobehavioral treatment for cocaine dependency: a preliminary evaluation.

The treatment of cocaine dependency in the 1980s has required the use of a broad range of strategies. Although there are some promising approaches for treating certain aspects of the cocaine withdrawal syndrome, there is no empirical evidence that provides a clear direction to the future development of a comprehensive treatment approach. The neurobehavioral model is an initial attempt to structure information, support, and encouragement across a series of stages that are experienced by cocaine abusers as they progress through the first 6 months of their recovery. This model attempts to sequence strategies in a way that will correspond to an expected timetable of problem emergence during recovery from cocaine dependency. Individual sessions with trained therapists are used extensively to move clients through the recovery process. Relapse prevention techniques have been used extensively within a relapse prevention group format and in a standardized relapse analysis procedure. This model has been standardized into a manual that allows for replication and evaluation. Current research efforts are under way to assess the usefulness of this model as an independent treatment approach and as a framework for evaluating other potentially useful cocaine dependency treatment strategies.