Systematic review: probiotics in the management of lower gastrointestinal symptoms - an updated evidence-based international consensus.

BACKGROUND: In 2013, a systematic review and Delphi consensus reported that specific probiotics can benefit adult patients with irritable bowel syndrome (IBS) and other gastrointestinal (GI) problems. AIM: To update the consensus with new evidence. METHODS: A systematic review identified randomised, placebo-controlled trials published between January 2012 and June 2017. Evidence was graded, previously developed statements were reassessed by an 8-expert panel, and agreement was reached via Delphi consensus. RESULTS: A total of 70 studies were included (IBS, 34; diarrhoea associated with antibiotics, 13; diarrhoea associated with Helicobacter pylori eradication therapy, 7; other conditions, 16). Of 15 studies that examined global IBS symptoms as a primary endpoint, 8 reported significant benefits of probiotics vs placebo. Consensus statements with 100% agreement and "high" evidence level indicated that specific probiotics help reduce overall symptom burden and abdominal pain in some patients with IBS and duration/intensity of diarrhoea in patients prescribed antibiotics or H. pylori eradication therapy, and have favourable safety. Statements with 70%-100% agreement and "moderate" evidence indicated that, in some patients with IBS, specific probiotics help reduce bloating/distension and improve bowel movement frequency/consistency. CONCLUSIONS: This updated review indicates that specific probiotics are beneficial in certain lower GI problems, although many of the new publications did not report benefits of probiotics, possibly due to inclusion of new, less efficacious preparations. Specific probiotics can relieve lower GI symptoms in IBS, prevent diarrhoea associated with antibiotics and H. pylori eradication therapy, and show favourable safety. This study will help clinicians recommend/prescribe probiotics for specific symptoms.

Altered functional brain network connectivity and glutamate system function in transgenic mice expressing truncated Disrupted-in-Schizophrenia 1.

Considerable evidence implicates DISC1 as a susceptibility gene for multiple psychiatric diseases. DISC1 has been intensively studied at the molecular, cellular and behavioral level, but its role in regulating brain connectivity and brain network function remains unknown. Here, we utilize a set of complementary approaches to assess the functional brain network abnormalities present in mice expressing a truncated Disc1 gene (Disc1tr Hemi mice). Disc1tr Hemi mice exhibited hypometabolism in the prefrontal cortex (PFC) and reticular thalamus along with a reorganization of functional brain network connectivity that included compromised hippocampal-PFC connectivity. Altered hippocampal-PFC connectivity in Disc1tr Hemi mice was confirmed by electrophysiological analysis, with Disc1tr Hemi mice showing a reduced probability of presynaptic neurotransmitter release in the monosynaptic glutamatergic hippocampal CA1-PFC projection. Glutamate system dysfunction in Disc1tr Hemi mice was further supported by the attenuated cerebral metabolic response to the NMDA receptor (NMDAR) antagonist ketamine and decreased hippocampal expression of NMDAR subunits 2A and 2B in these animals. These data show that the Disc1 truncation in Disc1tr Hemi mice induces a range of translationally relevant endophenotypes underpinned by glutamate system dysfunction and altered brain connectivity.

Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice -- an evidence-based international guide.

BACKGROUND: Evidence suggests that the gut microbiota play an important role in gastrointestinal problems. AIM: To give clinicians a practical reference guide on the role of specified probiotics in managing particular lower gastrointestinal symptoms/problems by means of a systematic review-based consensus. METHODS: Systematic literature searching identified randomised, placebo-controlled trials in adults; evidence for each symptom/problem was graded and statements developed (consensus process; 10-member panel). As results cannot be generalised between different probiotics, individual probiotics were identified for each statement. RESULTS: Thirty seven studies were included; mostly on irritable bowel syndrome [IBS; 19 studies; treatment responder rates: 18-80% (specific probiotics), 5-50% (placebo)] or antibiotic-associated diarrhoea (AAD; 10 studies). Statements with 100% agreement and 'high' evidence levels indicated that: (i) specific probiotics help reduce overall symptom burden and abdominal pain in some IBS patients; (ii) in patients receiving antibiotics/Helicobacter pylori eradication therapy, specified probiotics are helpful as adjuvants to prevent/reduce the duration/intensity of AAD; (iii) probiotics have favourable safety in patients in primary care. Items with 70-100% agreement and 'moderate' evidence were: (i) specific probiotics help relieve overall symptom burden in some patients with diarrhoea-predominant IBS, and reduce bloating/distension and improve bowel movement frequency/consistency in some IBS patients and (ii) with some probiotics, improved symptoms have led to improvement in quality of life. CONCLUSIONS: Specified probiotics can provide benefit in IBS and antibiotic-associated diarrhoea; relatively few studies in other indications suggested benefits warranting further research. This study provides practical guidance on which probiotic to select for a specific problem.

Gastro-oesophageal reflux symptoms, oesophagitis and Barrett's oesophagus in the general population: the Loiano-Monghidoro study.

OBJECTIVE: Existing endoscopy-based data on gastro-oesophageal reflux disease (GORD) in the general population are scarce. This study aimed to evaluate typical symptoms and complications of GORD, and their associated risk factors, in a representative sample of the Italian population. METHODS: 1533 adults from two Italian villages were approached to undergo symptom assessment using a validated questionnaire and upper gastrointestinal endoscopy. Data were obtained from 1033 individuals (67.4% response rate). RESULTS: The prevalence of reflux symptoms was 44.3%; 23.7% of the population experienced such symptoms on at least 2 days per week (frequent symptoms). The prevalence rates of oesophagitis and Barrett's oesophagus in the population were 11.8% and 1.3%, respectively. Both frequent (relative risk (RR) 2.6; 95% confidence interval (CI) 1.7 to 3.9) and infrequent (RR 1.9; 95% CI 1.2 to 3.0) reflux symptoms were associated with the presence of oesophagitis. No reflux symptoms were reported by 32.8% of individuals with oesophagitis and 46.2% of those with Barrett's oesophagus. Hiatus hernia was associated with frequent reflux symptoms and oesophagitis, and was present in 76.9% of those with Barrett's oesophagus. We found no association between body mass index and reflux symptoms or oesophagitis. CONCLUSIONS: GORD is common in Italy, but the prevalence of Barrett's oesophagus in the community is lower than has been reported in selected populations. Both frequent and infrequent reflux symptoms are associated with an increased risk of oesophagitis. Individuals with oesophagitis and Barrett's oesophagus often have no reflux symptoms.

Modelling prefrontal cortex deficits in schizophrenia: implications for treatment.

Current treatments of schizophrenia are compromised by their inability to treat all symptoms of the disease and their side-effects. Whilst existing antipsychotic drugs are effective against positive symptoms, they have negligible efficacy against the prefrontal cortex (PFC)-associated cognitive deficits and negative symptoms. New models that reproduce core pathophysiological features of schizophrenia are more likely to have improved predictive validity in identifying new treatments. We have developed a NMDA receptor antagonist model that reproduces core PFC deficits of schizophrenia and discuss this in relation to pathophysiology and treatments. Subchronic and chronic intermittent PCP (2.6 mg/kg i.p.) was administered to rats. PFC activity was assessed by 2-deoxyglucose imaging, parvalbumin and Kv3.1 mRNA expression, and the attentional set-shifting test (ASST) of executive function. Affymetrix gene array technology was employed to examine gene expression profile patterns. PCP treatment reduced glucose utilization in the PFC (hypofrontality). This was accompanied by a reduction in markers of GABAergic interneurones (parvalbumin and Kv3.1 mRNA expression) and deficits in the extradimensional shift dimension of the ASST. Consistent with their clinical profile, the hypofrontality was not reversed by clozapine or haloperidol. Transcriptional analysis revealed patterns of change consistent with current neurobiological theories of schizophrenia. This model mirrors core neurobiological deficits of schizophrenia; hypofrontality, altered markers of GABAergic interneurone activity and deficits in executive function. As such it is likely to be a valuable translational model for understanding the neurobiological mechanisms underlying hypofrontality and for identifying and validating novel drug targets that may restore PFC deficits in schizophrenia.

Use of relaxation time as a marker for arterial distensibility.

Arterial stiffening is associated with a number of known cardiovascular risk factors, including advancing age, increased systolic blood pressure (SBP), diabetes, hypertension, heart failure, myocardial infarction, and obesity. Many methodologies, both invasive and noninvasive, have been applied to the assessment of the stiffening of large elastic arteries in vivo, but there is no economically and/or universally accepted means of screening patients for atherosclerosis. From preliminary studies, a novel parameter, arterial relaxation time, has been identified as a potential indicator for inferring the elasticity of arteries. Preliminary measurements of arterial relaxation time of six normotensive subjects are significantly less than measurements of four hypertensive subjects.

Expression of a homeobox gene (SIX5) in borderline ovarian tumours.

AIMS: To assess the expression of SIX5 (a homeobox gene) mRNA in surface coelomic epithelium, endocervical epithelium, Fallopian tube epithelium, and benign, borderline, and malignant epithelial ovarian tumours. METHODS: 10 normal premenopausal ovaries, 10 normal Fallopian tubes, 10 normal cervices, 10 normal postmenopausal ovaries, 10 benign epithelial ovarian tumours, 10 malignant epithelial ovarian tumours, and 40 borderline epithelial ovarian tumours were studied retrospectively. The tissues had been fixed in formalin and embedded in paraffin wax. The tumours had previously been typed into mucinous, serous, or mixed tumours and assigned to the borderline category according to the FIGO/WHO criteria. Expression was assessed by in situ binding of SIX5 specific sense and antisense riboprobes. Hybridization of the riboprobes was detected using a standard immunohistochemical technique and the results correlated with expression in the normal epithelium of the endocervix, Fallopian tube, surface coelomic epithelium, and ovarian tumours. RESULTS: Expression of SIX5 mRNA was demonstrated in normal Fallopian tube epithelium and normal endocervical epithelium. SIX5 mRNA was not detected in normal ovarian epithelial tissue at any of the times studied during the menstrual cycle. Expression of SIX5 was not shown in benign epithelial ovarian tumours or in any of the malignant epithelial ovarian tumours. In 31 of 37 borderline epithelial ovarian tumours (84%), SIX5 expression was found in the epithelial cells. CONCLUSIONS: SIX5 expression is present in the normal epithelium throughout most of the female reproductive tract, suggesting it may have a role in maintaining epithelial differentiation in these tissues. SIX5 expression appears to be restricted to borderline epithelial ovarian tumours and may be a marker of epithelial differentiation in these tumours; thus borderline ovarian tumours may not be part of a continuum of disease between benign and malignant epithelial ovarian tumours. Further investigation of expression of SIX5 may clarify the molecular processes that promote differentiation of the ovarian surface epithelium.

Structure, mapping and expression of the human gene encoding the homeodomain protein, SIX2.

Vertebrate genes with sequence similarity to the Drosophila homeobox gene, sine oculis (so), constitute the SIX family. There is notable expression of members of this family in anterior neural structures, and several SIX genes have been shown to play roles in vertebrate and insect development, or have been implicated in maintenance of the differentiated state of tissues. Mutations in three of these genes in man (SIX5, SIX6 and SIX3) are associated with severe phenotypes, and therefore, the cloning of other human genes from this family is of interest. We have cloned and characterised the gene that encodes human SIX2, elucidated its gene structure and conducted expression studies in a range of tissues. SIX2 is widely expressed in the late first-trimester fetus, but has a limited range of expression sites in the adult. The expression pattern of SIX2 and its localisation to chromosome 2p15-p16 will be of use in assessing its candidacy in human developmental disorders.

Functional analysis of the homeodomain protein SIX5.

SIX5 (previously known as myotonic dystrophy associated homeodomain protein - DMAHP ) is a member of the SIX [ sine oculis homeobox (Drosophila ) homologue ] gene family which encodes proteins containing a SIX domain adjacent to a homeo-domain. To investigate the DNA binding specificities of these two domains in SIX5, they were expressed as GST fusion proteins, both separately and together. Affinity purified recombinant proteins and cell lysates from bacteria expressing the recombinant proteins were used in gel retardation assays with double stranded oligonucleotides representing putative DNA binding sites. The putative sites included two in the promoter region of DMPK (dystrophia myotonica protein kinase ) and the previously characterised murine Six4 DNA binding site in the Na(+)/K(+) ATPase alpha 1 subunit gene ( ATP1A1 ) regulatory element (ARE). None of the recombinant proteins showed any affinity for the two putative sites in DMPK. However, the two recombinant proteins containing the homeodomain both formed at least one specific complex with the ARE. The recombinant protein containing both domains formed a second specific complex with the ARE, assumed to be a dimer complex. Finally, a whole genome PCR-based screen was used to identify genomic DNA sequences to which SIX5 binds, as an initial stage in the identification of genes regulated by SIX5.

Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells.

We previously demonstrated that lysis of tumor cells that express Hsp70, the highly stress-inducible member of the HSP70 family, on their plasma membrane is mediated by natural killer (NK) cells. Here, we studied the effects of different proteins of the HSP70 family in combination with interleukin 2 (IL-2) on the proliferation and cytotoxic activity of human NK cells in vitro. Proliferation of NK cells was significantly enhanced by human recombinant Hsp70 (rHsp70) and to a lesser extent by rHsp70homC, the recombinant C-terminal peptide-binding domain derived from Hsp70hom, but not by the constitutive Hsc70 or DnaK, the Escherichia coli analogue of human Hsp70. Even rHsp70 protein alone moderately enhances proliferation and cytolytic activity of NK cells, thus indicating that the stimulatory effect is not strictly dependent on IL-2. NK cells stimulated with rHsp70 protein also exhibit an increased secretion of interferon gamma (IFN-gamma). The phenotypic characterization of NK cells with specificity for Hsp70-expressing tumor cells revealed a CD16dim/CD56bright and increased CD57 and CD94 expression. The cytolytic activity of NK cells also was significantly reduced when a CD94-specific antibody or rHsp70 was added directly before the cytotoxicity assay, whereas other antibodies directed against CD57 and major histocompatibility complex class I molecules or Hsp70 proteins, including Hsc70 and DnaK, did not affect the NK-mediated killing. However, long-term incubation of NK cells with rHsp70 protein enhances not only the proliferative but also the cytolytic response against Hsp70-expressing tumor cells. Our results indicate that the C-terminal domain of Hsp70 protein affects not only the proliferative but also the cytolytic activity of a phenotypically distinct NK cell population with specificity for Hsp70-expressing tumor cells. 1999 International Society for Experimental Hematology.

Characterization of the expression of DMPK and SIX5 in the human eye and implications for pathogenesis in myotonic dystrophy.

The pathogenic mechanisms underlying myotonic dystrophy (DM), which results from a (CTG) n repeat expansion mutation in the 3'-untranslated region (3'-UTR) of the myotonic dystrophy protein kinase gene ( DMPK ), remain obscure. The multisystemic nature and variable expressivity of the symptoms are unlikely to be explained by a defect in this gene alone. However, the location of the DM-associated (CTG) n repeat in the promoter region of SIX5, immediately downstream of DMPK, implicates it as a second candidate with a pathological role in DM. We hypothesize that dysfunction of SIX5, which is homologous to the Drosophila eye development gene sine oculis ( so ), is primarily responsible for the ophthalmic features of DM. We report an expression pattern for SIX5 in the normal adult eye that matches the sites of the ocular pathology in DM. SIX5 transcripts were detected in the adult corneal epithelium and endothelium, lens epithelium, ciliary body epithelia, cellular layers of the retina and the sclera. SIX5 expression was not detected in fetal eyes. We also report a restricted but partially overlapping expression pattern for DMPK transcripts and DMPK protein in normal fetal and adult eyes. DMPK transcripts were detected in fetal eyes and in adult conjunctival and corneal epithelia, uvea, cellular layers of the retina, optic nerve and in the sclera. DMPK protein was detected in the adult retina, conjunctival and ciliary body epithelia and in the smooth muscle of the ciliary body, pupillary sphincter and uveal blood vessels. We propose that the expression patterns of these two genes indicate their relative contribution to the ophthalmological dysfunction seen in DM. Furthermore, the expression of SIX5 and not DMPK in the adult lens implicates a role for SIX5 dysfunction in the development of adult onset cataracts, the most frequently occurring eye phenotype in DM.

A randomized comparison of dilatation alone versus dilatation plus laser in patients receiving chemotherapy and external beam radiation for esophageal carcinoma.

Most patients with carcinoma of the esophagus have advanced disease at presentation. Since cure is usually not possible, the goal of treatment is the palliation of dysphagia. Palliative modalities include bougies, balloons, stents, tumor probe, laser, surgery, chemotherapy, and radiation. In recent years, combined chemotherapy and radiation has shown promising results. However, the relief of dysphagia is slow and frequently incomplete. We compared the effectiveness of dilatation alone versus dilatation plus Nd-YAG laser therapy for the relief of dysphagia while assessing the role of chemotherapy and radiation as an adjunct to surgery. Fifteen patients with squamous cell carcinoma of esophagus who were deemed fit for intensive chemotherapy and radiation were randomized to receive either dilatation alone (N = 7) or dilatation plus laser (N = 8); the end-point for initial success was the passage of a 45 French Savary dilator, and the relief of dysphagia. At entry, 13 of these 15 patients were judged potentially resectable. However, after chemotherapy and radiation, only 3 of 13 (20%) patients could be offered surgery; the remainder were considered too poor a surgical risk. Follow-up was for 30 months, or until death. Further dilatations were performed as needed for relief of dysphagia. No difference was observed between the laser plus dilatation and the dilatation alone group with respect to the degree of dysphagia, weight record, quality of life index (Karnofsky score), or mortality rate. Our results indicate that in patients undergoing chemotherapy and radiation for esophageal carcinoma, dilatation alone provides adequate palliation of dysphagia, and in these patients, chemotherapy and radiation is a poor adjunct to surgical treatment.

Psychosocial functioning of homeless children.

OBJECTIVE: To investigate the psychosocial characteristics of homeless children and their parents. METHOD: Homeless families were assessed within 2 weeks of admission to seven hostels and were compared with a group of housed families matched for socioeconomic status. Measures included a semistructured interview, the General Health Questionnaire (GHQ), the interview Schedule for Social Interaction, the Child Behavior Checklist (CBCL), the Communication domain of the Vineland Adaptive Behavior Scales, and height and weight percentiles. The sample consisted of 113 homeless families (249 children aged 2 through 16 years) and 29 comparison families (83 children). RESULTS: Homeless families primarily consisted of single mothers and an average of two children, who had become homeless because of domestic violence (56%) or violence from neighbors (29%). Homeless mothers reported high rates of previous abuse (45%) and current psychiatric morbidity (49% caseness on the GHQ) and poor social support networks compared with housed controls. Homeless children were more likely to have histories of abuse, living in care, and being on the at-risk child protection register and less likely to have attended school or a preschool/day-care center since admission to the hostel. They also had delayed communication and higher CBCL scores. Maternal GHQ scores best predicted CBCL caseness. CONCLUSIONS: Homeless mothers and children have high rates of psychosocial morbidity, which are related to multiple risk factors and chronic adversities. Their complex needs should be best met by specialized and coordinated health, social, and educational services.

Assessing the need for challenging behaviour services in an English health district.

The aim of the present study was to assess the health care needs for people with learning difficulties who display challenging behaviour in a newly established health district. Ninety-eight clients were studied, using Disability Assessment Schedule (DAS), Aberrant Behaviour Checklist (ABC) and The Psychopathology Inventory for Mentally Retarded Adults (PIMRA). The results showed that a large proportion of them were mobile, continent and able to feed themselves. Almost half had no problems in communication but less than half were sociable. On the whole, they did not have adequate skills. A large proportion of them did not present severe challenging behaviour and did not suffer from psychiatric illnesses, apart from inappropriate adjustment disorder. Correlation coefficients showed that there were relationships between challenging behaviours and some of clients' disabilities and inappropriate adjustment disorder.

A preliminary study on the prevalence of challenging behaviours.

The purpose of this study was to estimate the prevalence of challenging behaviour among subjects with learning disabilities in an English health district. Subjects' disabilities included incontinence, lack of communication skills, and need of assistance with domestic activities, feeding, washing, and dressing. Some also had physical impairments. The most common behaviours were hyperactivity and irritability and the most common psychiatric disorders included severe anxiety, affective disorder, and adjustment disorder.

A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.

Myotonic dystrophy (DM) is associated with a (CTG)n trinucleotide repeat expansion in the 3'-untranslated region of a protein kinase-encoding gene, DMPK, which maps to chromosome 19q13.3. Characterisation of the expression of this gene in patient tissues has thus far generated conflicting data on alterations in the steady state levels of DMPK mRNA, and on the final DMPK protein levels in the presence of the expansion. The DM region of chromosome 19 is gene rich, and it is possible that the repeat expansion may lead to dysfunction of a number of transcription units in the vicinity, perhaps as a consequence of chromatin disruption. We have searched for genes associated with a CpG island at the 3' end of DMPK. Sequencing of this region shows that the island extends over 3.5 kb and is interrupted by the (CTG)n repeat. Comparison of genomic sequences downstream (centromeric) of the repeat in human and mouse identified regions of significant homology. These correspond to exons of a gene predicted to encode a homeodomain protein. RT-PCR analysis shows that this gene, which we have called DM locus-associated homeodomain protein (DMAHP), is expressed in a number of human tissues, including skeletal muscle, heart and brain.

Prospective randomized comparison of polyvinyl bougies and through-the-scope balloons for dilation of peptic strictures of the esophagus.

We prospectively compared the efficacy of polyvinyl bougies (Savary type) passed over a guide wire and through-the-scope balloons for the dilation of peptic esophageal strictures in a randomized study. Thirty-four patients, 17 in each treatment arm, were studied. At entry, dysphagia was assessed according to a six-point scale (0, unable to swallow; 5, normal). The end-point for dilation was to size 45F or 15 mm. Discomfort during the procedure was graded on a four-point scale (0, no discomfort; 1, mild; 2, moderate; 3, severe discomfort). Follow-up visits were at 1 week, 1 month, 3 months, and every 3 months thereafter for 2 years. At the 1-week visit, the size of esophageal lumen was measured by 8-, 10-, and 12-mm pills. Both devices effectively relieved dysphagia. By life-table analysis, stricture recurrence during the first year of follow-up was similar in both groups, but during the second year, the risk of recurrence was significantly lower in patients whose strictures were dilated with balloons. Other advantages of balloons included the need for fewer treatment sessions to achieve the defined end-diameter for dilation (1.1 + 0.1 versus 1.7 + 0.2, p < .05), and less procedural discomfort (p < .05). The differences in luminal size after dilation, measured by the barium pill test, were not significant. Ability to pass the 12-mm pill and absence of dysphagia were correlated. Our results indicate that both devices are effective in relieving dysphagia, but balloons may have a long-term advantage.

Clinical applications of nuclear medicine in gastroenterology.

Nuclear medicine (NM) has traditionally been a non-nursing field. This specialty has grown rapidly and continues to expand. Most nurses have had very limited exposure to nuclear medicine, except in the area of patient preparation for the nuclear medicine department. Because this specialty has had significant advances that require patient monitoring in many diagnostic and therapeutic procedures, nurses will benefit by learning more about this field and by equipping themselves to care for pre- and postprocedural patients. This article is an overview of the nuclear medicine process and its most common clinical applications in the GI field as they relate to nursing practice.