Current and emerging therapeutic options for the management of functional dyspepsia.

Introduction: Functional Dyspepsia (FD), defined as chronic symptoms originating from the gastroduodenal region in absence of readily identifiable organic disease, is one of the most common gastrointestinal disorders. FD is divided into two subgroups: Post-Prandial Distress Syndrome (PDS) or meal-related FD, characterized by postprandial fullness and early satiation, and Epigastric Pain Syndrome (EPS) or meal-unrelated FD, characterized by epigastric pain and burning.Areas covered: This review summarizes the existing and off-label therapeutic options for FD.Expert opinion: The identification of mechanisms, the Rome IV classification, the reduction of PDS/EPS overlap and pictograms for symptom identification allow a better diagnosis and a more targeted treatment choice. Acotiamide, a first-in-class prokinetic agent available only in Japan and India, is the only agent of proven efficacy for FD, but clinicians use acid-suppressive therapy, prokinetics, neuromodulators and herbal therapies for treating FD symptoms. New emerging targets are duodenal low-grade inflammation with eosinophils and duodenal or other modified luminal microbiota.

Validation of the Leuven Postprandial Distress Scale, a questionnaire for symptom assessment in the functional dyspepsia/postprandial distress syndrome.

BACKGROUND: A validated patient-reported outcome instrument is lacking for the functional dyspepsia/postprandial distress syndrome. AIM: To validate the Leuven Postprandial Distress Scale (LPDS). METHODS: The LPDS diary, comprising eight symptoms with verbal descriptors rated for severity (0-4), was derived from focus groups and cognitive debriefing. It was used in a 2-week run-in, 8-week double-blind placebo-controlled trial of itopride 100 mg t.d.s. Results in 60 patients, with concealed treatment allocation, were used to analyse LPDS content validity, consistency, reliability and responsiveness. Patients also filled out Patient Assessment of Gastrointestinal Symptoms (PAGI-SYM), Nepean Dyspepsia Index, overall treatment evaluation and overall symptom severity questionnaires. Construct validity was evaluated by known-group analyses and by correlating LPDS with these additional questionnaires. Minimum Clinically Important Difference was determined from threshold changes in anchor questionnaires. RESULTS: Symptom patterns and factor analysis identified three cardinal symptoms of postprandial distress syndrome (early satiation, postprandial fullness, upper abdominal bloating), whose mean intensities generate weekly LPDS scores. Known-groups analysis showed large-effect-size differences in LPDS scores (Cohen's d = 2.16). Strong correlations (r > 0.57) between LPDS scores and relevant anchors at baseline indicate good convergent validity. Internal consistency of LPDS was good (α > 0.85) with high inter-item correlations (0.67-0.76), and test-retest reliability (r = 0.85). Changes in LPDS scores were highly convergent with changes in overall treatment evaluation, overall symptom severity and PAGI-SYM (r > 0.52). minimum clinically important difference analysis generated thresholds of 0.4-0.6. CONCLUSIONS: The Leuven Postprandial Distress Scale, which is supported by the European Medicines Agency, is a sensitive and reliable patient-reported outcome instrument to assess symptoms in the functional dyspepsia/postprandial distress syndrome.

Functional dyspepsia: outcome of focus groups for the development of a questionnaire for symptom assessment in patients suffering from postprandial distress syndrome (PDS).

BACKGROUND: To date, no patient reported outcomes (PRO) instrument is available for evaluation of treatment efficacy in functional dyspepsia (FD)/postprandial distress syndrome (PDS). The aim of our study was to perform focus group interviews for the development of a new questionnaire for assessing symptom pattern and severity in PDS. METHODS: Random ambulatory patients diagnosed with FD/PDS based on Rome III criteria and no predominant gastro-esophageal reflux disease (GERD) symptoms were invited to participate. Focus group sessions were organized where patients reported and discussed their symptoms, facilitated by an experienced physician. After reaching saturation of identified symptom items, questions for a pilot PRO instrument were drafted and evaluated in cognitive interviews for relevance, clarity, and consistency. KEY RESULTS: Of 225 screened patients, 26 patients were diagnosed with PDS without overlapping GERD as single final diagnosis. Fifteen of these (87% female, 48 ± 3.2 years) participated in one of three focus groups. All (100%) confirmed experiencing symptoms that were triggered or aggravated by ingestion of a meal, corresponding to early satiation (100%), and postprandial fullness (100%). In addition reported gastroduodenal symptoms were nausea (40%, postprandial in all, interprandial in 20%), upper abdominal bloating (33%), excessive belching (27%), and vomiting (13%). Epigastric pain and burning were present in respectively 20% and 13%. Non-gastroduodenal symptoms that patients reported included heartburn (33%, but mostly sporadic), weight loss (93%, on average 5.0 ± 1.7 kg), and fatigue (67%). Questions evaluating these symptoms were validated in 15 cognitive interviews. CONCLUSIONS & INFERENCES: This focus group study confirms symptoms corresponding to postprandial fullness and early satiation as the key items for developing a PRO for PDS.

The use of pictograms improves symptom evaluation by patients with functional dyspepsia.

BACKGROUND: No validated patient-reported outcome (PRO) measure exists for functional dyspepsia (FD) assessment. Verbal descriptions of different upper abdominal symptoms may be poorly distinguishable to patients. AIM: To investigate whether understanding of FD symptoms is enhanced by pictograms symbolising the nature of the symptoms, besides verbal descriptors. METHODS: Consecutive FD patients were randomised to fill out a questionnaire assessing nineupper gastrointestinal symptoms (post-prandial fullness, early satiation, epigastric pain, epigastric burning, bloating centred in the upper abdomen, nausea, vomiting, heartburn, regurgitation) with or without accompanying pictograms. Symptoms were rated for frequency and severity (0-5), and patients also identified the most bothersome symptom. Subsequently, in-depth history was taken by an expert clinician, who filled out the same symptom ratings. Concordance between patient and clinician ratings was quantified using chi-square and kappa statistics. RESULTS: Content validity of pictograms was first confirmed by 15 FD patients. Next, 76 patients (52 women, age 42.2 ± 1.9) were randomised to questionnaires with or without pictograms. The concordance with clinician's assessment as gold standard rose from 36 without to 48% for questions with pictograms (P < 0.0001). Considering the Rome III subdivision, benefit in concordance with pictograms was present for post-prandial distress, epigastric pain syndrome and reflux symptoms. Kappa statistics confirmed these gains (weighted kappa values for concordance of symptom frequency ratings rose from 0.214 to 0.446 with pictograms), and also showed better concordance of the most bothersome symptom with pictograms. CONCLUSION: Pictograms accompanying verbal descriptors significantly improve concordance of functional dyspepsia symptom ratings by patients with evaluation by their physicians.

Functional dyspepsia: still a serious challenge for medical practitioners and new drug investigators? A Belgian, French, German and Hungarian opinion.

The diagnosis of Functional Dyspepsia is based on the identification of long term specific symptoms and the absence of organic lesions. Many pathophysiological mechanisms are intricate and, at least, partially responsible for the syndrome. Widely accepted technical procedures for the identification of these mechanisms are missing. The final etiopathology is not yet established. The relationship between symptoms and putative mechanisms is unclear. At the moment of the prescription, the physician faces a real therapeutic gap. Moreover, Functional Dyspepsia is an evolving area of study and knowledge has to be updated regularly. As a result, consultations for Functional Dyspepsia are usually very challenging and patients look desperately for medical support. It is likely that this disease is both under-diagnosed and under-treated. Classifying patients into symptomatic subgroups is a promising approach proposed by Rome III. It is assumed that these subgroups are based on different pathophysiological mechanisms, and may allow for more specific therapeutic approaches. However the assessment of the symptomatic profiles of patients is time-consuming. It is also a risky process, because the Rome III subgroups have yet to be validated. There are currently no translations of the definitions in the different European languages. Interviews of the patients are biased by cultural, educational and subjective factors. Identification of suitable subjects for clinical trials is uneasy for the same reasons and can explain several recent Research and Development (R&D) failures. Therefore, there is a need for an updated, step by step approach, a real diagnostic algorithm of the consultation including the use of simple, clear, universal and cross-cultural validated tools, as word-figure questionnaires, designed to establish the symptomatic profiles of the patients.

A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia.

Impaired gastric accommodation, hypersensitivity to distension and delayed gastric emptying are major pathophysiological mechanisms in functional dyspepsia (FD). Acotiamide (Z-338) was well-tolerated in healthy volunteers. To determine the effect of three doses of Acotiamide on major pathophysiological mechanisms, symptoms, quality of life (QOL) and safety in functional dyspeptics. A phase IIa, randomized, double-blind, placebo-controlled study (14, 21 and 28 days, respectively, for run-in, study drug administration and follow-up). Gastric accommodation, sensitivity to distension and gastric emptying were assessed by barostat and (13)C breath test, symptoms by daily diary cards and QOL by SF-36. A total of 71 patients were enrolled (62 evaluable). There was no effect on gastric emptying and sensitivity to distension. 300 mg was better than placebo for meal accommodation (P = 0.024). 100 mg was better than placebo at week 2 for upper abdominal bloating (P = 0.001) and overall symptom score (P = 0.022), and at week 3 for bloating (P = 0.008) and heartburn (P = 0.041). 100 mg was also better than placebo for QOL (physical function) (P = 0.003). Acotiamide was safe and well-tolerated in patients with FD. The involved mechanism could at least in part depend on an effect on meal-induced accommodation. 100 mg Acotiamide exhibited the potential to improve FD symptoms and QOL. Further studies are indicated.

Investigation of physiologic leukopenia in Belgian Tervuren dogs.

BACKGROUND: Physiologic leukopenia in Tervuren dogs was reported in North America with a higher frequency in aged Tervurens. If not recognized, physiologic leukopenia can provoke unnecessary clinical investigations. HYPOTHESIS: The primary objective was to compare Tervurens and control dogs in Belgium with respect to the numbers of dogs with physiologic leukopenia. The secondary objectives were to compare Tervurens with control dogs and age classes within Tervurens and controls for parameters related to physiologic leukopenia. ANIMALS: Tervurens (n = 94) and control dogs (n = 48, maximum of 5 dogs per breed and 5 mixed breed dogs) were entered into the study. Dogs were 1-11 years old and healthy on routine physical examination. Dogs had no history of disease or drug administration in the previous 2 months. METHODS: Hematologic analyses were performed by an automated device within 30 hours of sampling. Blood smears were evaluated for cellular morphologic anomalies. RESULTS: Only 1 of the 94 Tervuren dogs had physiologic leukopenia (1.06%; 95% confidence interval, 0.05-5.22). Furthermore, the white blood cell (WBC) count in Tervuren dogs (median, 10.00 x 109/L; range, 5.90-20.80) was not significantly different (P = .55) from that of control dogs (median, 9.75 x 109/L; range, 5.20-20.90). The WBC count decreased significantly (P < .001) with age in Tervuren dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Physiologic leukopenia is uncommon in the Belgian Tervuren dog. Differences with earlier data published in North America might be due to genetic or environmental differences.

[Hereditary neuropathy with liability to pressure palsy presenting with an acute inflammatory demyelinating polyneuropathy]. / Polyradiculonévrite aiguë inflammatoire révélant une neuropathie héréditaire avec hypersensibilité à la pression.

INTRODUCTION: Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant peripheral neuropathy characterized by compressive focal neuropathies and an underlying sensorimotor demyelinative polyneuropathy. It is usually caused by a 1.5 Mb deletion of the PMP22 gene (17p11.2). CASE REPORT: We describe the case of a 31 year-old woman who presented with acute demyelinative peripheral polyneuropathy affecting the four limbs and elevated cerebrospinal fluid protein content a few days after a viral illness. Acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barré syndrome) was suspected. However, electrophysiologic examination suggested HNPP and subsequent genetic testing was confirmatory. CONCLUSION: This case demonstrates that HNPP can present in an acute manner, mimicking AIDP.

Online health networks.

Healthcare networks function as a structural synergy serving the various healthcare actors, including the patient, who is the beneficiary. Medically speaking, they meet the need of healthcare professionals for targeted information sharing with regard to the medical record. Economically speaking, they may represent an added value and/or a diminution of costs, thus contributing to quality of care. The adoption of the same standards for all concerned servers is an absolute prerequisite if multidisciplinary applications are to be generated, as well as related services of an informational and educational nature.

Setting up a common architecture for EPR in primary care: the Belgian experience.

A couple of years ago, the Belgian Federal Ministry of Health decided to back the development of a basic conceptual model for Electronic Patient Record (EPR) in primary care. Using consensus and modeling relational techniques, a working group of experts and experienced practitioners identified 7 key structuring concepts: Health Care Element, Health Approach, Contact, Subcontact, Service, Health Agent, Period. This model could roughly be seen as a restrictive sub-model of the current CEN proposal (prENV 13940) or as a first step to assess this CEN pre-Norm in Belgium. The conceptual model is already used in teaching activities and in a Belgian software labeling process.

Flemish population data and sequence structure of the hypervariable tetranucleotide repeat locus D12S1090.

The allele frequency and sequence structure of the STR locus D12S1090 were investigated in 598 Flemish individuals. The locus shows a complex organisation with repetitions of GATA interrupted by TA and other tetra- and pentanucleotide blocks. No deviation from Hardy-Weinberg equilibrium was observed. The extensive polymorphism makes it a powerful tool for identity as well as paternity testing and even permits differentiation of closely related populations, such as Flemish and Germans. D12S1090 seems to be one of the most informative STRs, however, as seen in other highly variable STRs, the observed mutation frequency of 5.1 x 10(-3), is relatively high. of STR loci is typing highly polymorphic STRs such as ACTBP2 [3]. We thus investigated the tetranucleotide (GATA) repeat locus D12S1090 (GDB accession number GDB:376560, also known as GATA5A09) in a population sample from Flanders, the Dutch speaking part of Belgium. Although this STR is considered to be highly polymorphic [4], compared with other STRs, it has only scarcely been studied.

Histopathological features of X-linked Charcot-Marie-Tooth disease in 8 patients from 6 families with different connexin32 mutations.

There is still confusion as to whether X-linked Charcot-Marie-Tooth disease (CMTX) is primarily an axonal disorder or is primarily demyelinating. Eight symptomatic patients, 7 males and 1 female, from 6 families with identified connexin32 mutations underwent a superficial peroneal nerve biopsy. Quantitative and ultrastructural studies were performed, and histopathological lesions in these 8 patients proved to be quite homogeneous. The myelinated fiber count was within normal values or only moderately decreased. In 7 cases, the distribution of myelinated fibers was unimodal due to a loss of large fibers, coexisting with numerous clusters of small regenerating fibers. At ultrastructural level, these clusters were often surrounded by flattened Schwann cell processes giving an aspect of "pseudo-onion bulb" formation. There was no "naked axon" (ie, demyelinated axon), and real "onion bulb" formations composed of flattened Schwann cell processes surrounding an isolated myelinated fiber were discrete and not numerous. Macrophages laden with myelin debris were scarce or absent in the endoneurium. Several fibers appeared discretely hypomyelinated and the calculated g-ratio was scarcely higher than the mean control value. Lesions of unmyelinated fibers were absent in 7 cases and mild in one. Given that the primary defect concerns connexin32, we think that the histopathological features observed in our patients correspond to primary hypomyelination rather than to ongoing demyelination. The associated axonal degeneration might be secondary to defective axon-Schwann cell interactions.

Variations in primer sequences are the origin of allele drop-out at loci D13S317 and CD4.

STRs have become almost the exclusive tool of genetic scientists in forensic typing work. Consequently, large numbers of samples are genotyped and the detection of rare abnormalities is to be expected. We found rare losses of alleles, also known as drop-out, at the two STR loci D13S317 and CD4. Drop-out at D13S317 was accidentally found in typing of suspects in a murder case and three other examples of drop-out were found at locus CD4 during paternity testing. The lost alleles reappeared when alternative PCR primer pairs were used. Sequences of lost alleles were characterised at the molecular level after cloning. Variations were found in the primer sequences and these are believed to prevent amplification or to reduce amplification yield and to be the origin of the allele drop-out.

Polymorphic short tandem repeats for diagnosis of the Charcot-Marie-Tooth 1A duplication.

BACKGROUND: A 1.5-Mb microduplication containing the gene for peripheral myelin protein 22 (PMP22) on chromosome 17p11.2-12 is responsible for 75% of cases of the demyelinating form of Charcot-Marie-Tooth disease (CMT1A). Methods for molecular diagnosis of CMT1A use Southern blot and/or amplification by PCR of polymorphic poly(AC) repeats (microsatellites) located within the duplicated region, or the detection of junction fragments specific for the duplication. Difficulties with both strategies have led us to develop a new diagnostic strategy with highly polymorphic short tandem repeats (STRs) located inside the CMT1A duplicated region. METHODS: We tested 10 STRs located within the duplication for polymorphic behavior. Three STRs were selected and used to test a set of 130 unrelated CMT1A patients and were compared with nonduplicated controls. The study was then extended to a larger population of patients. Alleles of interest were sequenced. A manual protocol using polyacrylamide electrophoresis and silver staining and an automated capillary electrophoresis protocol to separate fluorescently labeled alleles were validated. RESULTS: We identified three new STRs covering 0.55 Mb in the center of the CMT1A duplication. One marker, 4A, is located inside the PMP22 gene. The two others, 9A and 9B, more telomerically positioned, have the highest observed heterozygosity reported to date for CMT1A markers: 0.80 for 9A, and 0.79 for 9B. Tetra- and pentanucleotide repeats offered clear amplification, accurate sizing, and easy quantification of intensities. CONCLUSIONS: Combined use of the three STRs allows robust diagnosis with almost complete informativeness. In our routine diagnosis for CMT1A, they have replaced the use of other polymorphic markers, either in a manual adaptation or combined with fluorescence labeling and allele sizing on a DNA sequencer.

mRNA 5'-leader trans-splicing in the chordates.

We report the discovery of mRNA 5'-leader trans-splicing (SL trans-splicing) in the chordates. In the ascidian protochordate Ciona intestinalis, the mRNAs of at least seven genes undergo trans-splicing of a 16-nucleotide 5'-leader apparently derived from a 46-nucleotide RNA that shares features with previously characterized splice donor SL RNAs. SL trans-splicing was known previously to occur in several protist and metazoan phyla, however, this is the first report of SL trans-splicing within the deuterostome division of the metazoa. SL trans-splicing is not known to occur in the vertebrates. However, because ascidians are primitive chordates related to vertebrate ancestors, our findings raise the possibility of ancestral SL trans-splicing in the vertebrate lineage.

Mild recurrent neuropathy in CMT1B with a novel nonsense mutation in the extracellular domain of the MPZ gene.

Clinical, electrophysiological, and neuropathological features are reported associated with a novel heterozygote point mutation in the extracellular domain of the MPZ gene, where a transversion at codon 71 in exon 3 leads to a codon stop: Glu71stop (ie GAA-->TAA). A 36 year old woman developed a mild recurrent neuropathy after intensive manual work. The motor nerve conduction velocities were slow without conduction blocks and the nerve biopsy showed signs of demyelination-remyelination, axonal loss, and regular uncompacted myelin lamellae. She inherited the mutation from her father who displayed the same mutation with a normal phenotype. This nonsense mutation may cause a dosage difference of normal P0, and is probably underrepresented in the current mutation data bases. This report further extends the phenotype of MPZ mutations and also emphasises that mild phenotype of CMT1B may be more frequent than has been appreciated.

Analysis of eight STR loci in two Hungarian populations.

A multiplex reaction for the eight STR loci D3S1358, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820 was used to generate allele frequency databases for two Hungarian population samples, Caucasians from the Budapest area and Romanies from Baranya county. During the analysis two intermediate-sized alleles and a sequence variant allele were observed at the D7S820 locus. All three types of allelic variants were found to have modifications in the same block of a (T)9 stretch located within the 3' flanking region of each allele, which may indicate a possible higher mutation rate of this (T)9 block. For the loci D3S 1358 and D7S820 the Romany population database showed departures from Hardy-Weinberg equilibrium. The forensic efficiency values for the Romany population were slightly different from those found in the Hungarian Caucasian population. Comparing the allele frequency values by G-statistic, calculating the F(ST) indices and with the pair-wise comparisons of interpopulation variance, the two Hungarian populations could be distinguished using data from the eight STR loci.