Nutrient-specific modulation of gastric mechanosensitivity in patients with functional dyspepsia

Intraduodenal lipid infusion induces symptoms and increases sensitivity to gastric distension in patients with functional dyspepsia. To test whether these effects are specific for lipid, we compared the effects of intraduodenal infusions of either lipid or glucose on symptoms and gastric sensory and motor responses to gastric distension. Eighteen dyspeptic patients and nine controls were studied. The stomach was distended with a flaccid bag during isocaloric infusions (1 kcal/ml) of saline and either 10% Intralipid (nine patients) or 26.7% glucose (nine patients) into the duodenum. Dyspeptic symptoms and sensory thresholds for epigastric fullness and discomfort were assessed. Gastric pressure profiles during distensions were similar during lipid and glucose infusions in patients and controls, but both were significantly lower than during saline infusion. Lower volumes were required to induce fullness and discomfort in the patients compared with the controls. In the controls, the threshold volumes required to induce fullness and discomfort were greater during infusion of lipid and glucose than during saline infusion, but in the patients, the threshold volumes were increased during glucose infusion but further reduced during lipid infusion. Moreover, in the patients, nausea was more common during lipid than glucose infusion and did not occur during saline. The controls did not experience any symptoms during any infusion. In conclusion, intraduodenal lipid but not glucose sensitizes the stomach to distension in patients with functional dyspepsia but not in controls.     

Musculoskeletal pain in older adults at the end-of-life: a systematic search and critical review of the literature with priorities for future research

Background

Pain is an important issue in end of life care. Although musculoskeletal pain is common in older adults, it is rarely associated with the cause of death and may be overlooked as death approaches. Hence a major target for improving quality of life may be being missed.

Methods

The aim of this study was to systematically search and critically review the literature on musculoskeletal pain at the end of life. Amed, Cinahl, Internurse, Medline, Psych Info, Web of Knowledge and Cochrane review databases were searched for relevant research up to September 2012. The search strategy combined key words expanding the terms ‘palliative’ for population, ‘musculoskeletal’ for exposure, and ‘pain’ for outcome. Predefined inclusion and exclusion criteria were applied.

Results

Five relevant papers and one letter to the editor were found, including case studies and epidemiological research. Current evidence suggests musculoskeletal pain is common in older adults at the end of life and that it can have a substantial impact on individual experience. No information about community based treatment of musculoskeletal pain at the end of life was found.

Conclusion

Priorities for future research include high quality epidemiological studies to establish the prevalence, natural history, impact, assessment, patient priorities and outcomes associated with musculoskeletal pain in the end of life period, and intervention research that provides an evidence base for treatment.

     

Effect of stool size and consistency on defecation.

The ability of subjects to expel from the rectum objects simulating stools of different characteristics was assessed in paired studies carried out in a total of 58 normal subjects and 25 young women with severe constipation. Our results showed that a lower percentage of normal subjects and a lower percentage of constipated patients were able to pass a 1.8 cm incompressible sphere compared with a 50 ml deformable balloon, although constipated patients found it more difficult than normal subjects to expel both types of simulated stool. It was also more difficult for normal subjects to pass a soft compressible silicon rubber simulated stool than a stool made up of a similar volume of incompressible 1 cm wooden spheres contained in a cylindrical latex envelope, but both objects were much easier to pass than the same number of 1 cm spheres placed loose within the rectum. When normal subjects were instructed to expel single incompressible spheres of different sizes placed in the rectal ampulla, the intrarectal pressure and the time needed to pass these objects varied inversely with their diameter. These results suggest that more effort is required to expel stools from the rectum if they are small and hard than if they are large and soft.     

Adaptation of hydrogen analysis to measure stomach to caecum transit time in the rat

Excreted hydrogen analysis was used to measure stomach to caecum transit time of the head of a test meal in 120 rats fed by gavage. Results were compared with the distribution of a labelled test meal in the gastrointestinal tract of rats killed at different time intervals after gavage. Values for stomach to caecum transit were compatible with the distribution of labelled meals in 91% of animals, although in the remainder the hydrogen concentration had not risen even though food residues were in the caecum when the animals were killed. The technique gave reproducible results; the coefficients of variation for four studies carried out in each of six animals varied between 4 and 14%. A meal consisting of homogenised baked beans had a significantly shorter stomach to caecum transit time (88.1 +/- 4.5 min; mean +/- SE; n = 21; p less than 0.001) than an equivalent volume of Complan/lactulose (180.9 +/- 8.7 min; n = 13). This technique was used to investigate the effect of ileal infusion of a fat emulsion (20% Intralipid) via a chronically implanted intestinal cannula on the stomach to caecum transit time of a bean meal, in a series of paired studies carried out in six rats. Stomach to caecum transit time was significantly delayed during ileal infusion of 20% Intralipid compared with the control infusion of an isotonic saline solution (218.3 +/- 21 min v 106.7 +/- 33 min Intralipid v saline; n = 6; p less than 0.001).     

Use of anorectal manometry during rectal infusion of saline to investigate sphincter function in incontinent patients

Anal and rectal pressures and external sphincter electromyogram were recorded continuously during rectal infusion of 1.5 L saline in 18 normal subjects and 37 patients who complained of diarrhea and fecal incontinence. All subjects exhibited a pattern of regular fluctuations in anorectal pressure and electromyogram. All except 1 of the normal subjects were able to retain 1500 ml saline without leakage, and their pressure record comprised simultaneous rectal contractions, internal sphincter relaxations, and external sphincter contractions. None of the incontinent patients were able to retain 1500 ml saline without leakages, and leakages always coincided with the peaks of rectal pressure. Two manometric patterns were observed. Fifty-nine percent of incontinent patients exhibited a pattern of contractions of similar profile occurring throughout the anorectum. This finding was associated with low basal sphincter pressures, an easily inhibited anal sphincter tone, an obtuse anorectal angle, and a funnel-shaped configuration to the anal canal. These results suggested that, in this group, the internal sphincter was weak and easily inhibited so that the whole anorectum behaved as one fluid-filled compartment recording contractions of the external sphincter. The remaining 41% of incontinent patients exhibited a normal pattern of anorectal pressure fluctuations and had normal maximum basal pressures, although maximum squeeze pressures, rectoanal inhibitory reflex, and anorectal angles were abnormal. Peak rectal pressures were abnormally high in this group during saline infusion, suggesting that abnormally strong rectal contractions may play a role in the incontinence in this group.     

Sentinel-Lymph-Node-Mapping beim Adenokarzinom des Kolons verbessert nicht die Genauigkeit des Tumorstagings

ZusammenfassungZiel: In dieser Studie sollten die Wirksamkeit von Sentinel-Lymph-Node-Mapping bei Patienten mit intraperitonealem Kolonkarzinom bestimmt und ein Algorithmus zur Vorhersage eines möglichen Überlebensvorteils unter Verwendung Sentinel-Node-Mapping und Lymphknoten-Ultrauntersuchungstechniken favorisierender Best-Case-Einschätzungen entwickelt werden.Methodik: 41 Patienten mit intraperitonealem Kolonkarzinom, die sich einer Kolektomie mit kurativer Zielsetzung unterzogen, wurden prospektiv untersucht. Nach Mobilisation von Kolon und Mesenterium wurden 1–2 ml des Farbstoffs Isosulfanblau subserös um den Tumor herum injiziert. Die ersten blaugefärbten Lymphknoten wurden als Sentinel Nodes (Wächterknoten) identifiziert. Weitere Knoten wurden vom Pathologen routinemäßig durch manuelle Präparation des Mesenteriums erkannt. Alle Knoten wurden routinemäßig durch histologische Untersuchung mittels Hämatoxylin-Eosin-Färbung aufgearbeitet. Um einen Algorithmus zur Vorhersage des möglichen Überlebensvorteils durch Sentinel-Node-Mapping und Lymphknoten-Ultrauntersuchungstechniken zu entwickeln, wurden Annahmen auf der Basis von Literaturdaten postuliert. Jede Tendenz war auf den Erfolg der Techniken gerichtet.Ergebnisse: Drei von 41 Patienten (7%) wurde keine Farbe injiziert, und sie wurden von der weiteren Analyse ausgeschlossen. Das Krankheitsstadium der übrigen 38 Patienten verteilte sich wie folgt: Stadium I: n = 10 (26%); Stadium II: n = 15 (39%); Stadium III: n = 11 (29%); Stadium IV: n = 2 (5%). Mindestens ein Sentinel Node wurde bei 30 von 38 Patienten (79%) identifiziert. Die mittlere Anzahl erkannter Wächterknoten lag bei zwei (Streuung ein bis drei). Die mittlere insgesamt gewonnene Anzahl an Lymphknoten betrug 14 (Streuung sieben bis 45). Bei 26 von 38 Patienten (68%) waren alle Knoten negativ. Sentinel Nodes und Nonsentinel Nodes waren bei zwei von 38 Patienten (5%) positiv. Bei einem von 38 Patienten (3%) waren Sentinel Nodes die einzigen positiven Lymphknoten. Bei neun von 38 Patienten (24%) waren Sentinel Nodes negativ und Nonsentinel Nodes positiv. Folglich wäre Sentinel-Node-Mapping nur für 3% möglicherweise von Nutzen gewesen, versagte aber in 24% der Patienten unserer Untersuchung bei der genauen Erkennung von Lymphknotenmetastasen. Um einen Algorithmus zur Berechnung des Überlebensvorteils zu entwickeln, trafen wir folgende Annahmen: Kombination des Krankheitsstadiums I und II (0,5); Anteil des Materials, bei dem durch Anwendung histologischer Untersuchung mittels Hämatoxylin-Eosin-Färbung das Stadium zu niedrig eingestuft worden war und das bei differenzierterer Analyse verborgene positive Knoten enthalten könnte (0,15); Anteil von okkulten positiven Knoten, die durch Sentinel-Node-Mapping entdeckt wurden (0,9); sowie Überlebensvorteil durch Chemotherapie (0,33). Somit läge der Anteil der Patienten, die von Sentinel-Lymph-Node-Mapping und Lymphknoten-Ultrauntersuchungstechniken profitierten, bei 0,02 (2%).Schlussfolgerungen: Sentinel-Node-Mapping mit Isosulfanblau-Färbung und Routineaufarbeitung entnommener Knoten verbessert die Genauigkeit des Stagings bei Patienten mit intraperitonealem Kolonkarzinom nicht. Sogar bei Anwendung von Best-Case-Annahmen ist der Prozentsatz von Patienten, die möglicherweise vom Sentinel-Lymph-Node-Mapping profitieren könnten, klein.Übersetzter Nachdruck aus Diseases of the Colon & Rectum 2005;48:80–5. DOI 10.1007/s10350-0795-5     

Influence of acid-pepsin secretion on gastric emptying of solids in humans: studies with cimetidine.

The commonly accepted model for gastric emptying suggests that the 'antral mill' is responsible for the triturition and subsequent emptying of solid food from the stomach. Little is known about the contribution to solid emptying made by other digestive mechanisms such as acid-pepsin secretion. We have investigated the effect of inhibiting gastic secretion on the rate at which a solid test meal emptied from the stomach. Using a radiolabelled beefburger, we performed paired gammacamera studies on consecutive days in 10 fasted, healthy volunteers to compare gastric emptying of the test meal with and without oral cimetidine (400 mg 1 hour before the test, 800 mg at the start of the meal). Inhibition of acid-pepsin secretion by cimetidine was associated with an appreciable delay in the rate of emptying of the burger from the stomach (T50 cimetidine 187 (16) min (mean (SEM); T50 no cimetidine 146 (15) min; p less than 0.01, paired t test). This delay was related to a change in the slope of the emptying profile and was not associated with a prolonged lag phase. These results may be explained by the relative achlorhydria and reduced pepsin activity induced by cimetidine impairing the breakdown of solid food into particles small enough to leave the stomach.     

Role of the proximal and distal stomach in mixed solid and liquid meal emptying.

The role of the proximal and distal stomach in the emptying of solids and liquids from the stomach remains unclear. We have used a dual isotope technique to quantify proximal and distal stomach emptying of a solid (100 g of 99mTc labelled liver/ground beef) liquid (either 200 ml of normal saline (eight subjects) or 25% dextrose (seven subjects) labelled with 113mIn-diethylenetriaminepenta-acetic acid) mixed meal. A manometric catheter simultaneously measured antral, pyloric, and duodenal motor activity. The liquid component dispersed rapidly throughout the stomach and emptied after a minimal lag period. The emptying of the 25% dextrose was delayed compared with the saline. This delay was associated with increased retention of the liquid in the distal stomach, a significant increase in localised phasic pyloric contractions, and a suppression of antral contractions. The solid component initially resided wholly within a proximal stomach reservoir area. Solids then redistributed from proximal to distal stomach during the emptying of liquid from the stomach. Dextrose delayed gastric emptying of solids compared with saline by increasing the solid lag period and retention in the proximal stomach. There was no significant difference between saline and dextrose meals in the distal stomach retention of solid or in the linear rate of emptying after the lag period. We conclude that, contrary to general opinion, the proximal stomach plays an important role in the control of gastric emptying of solids while the distal stomach is important in the emptying of nutrient liquids.     

Distinct neural ensemble response statistics are associated with recognition and discrimination of natural sound textures

The perception of sound textures, a class of natural sounds defined by statistical sound structure such as fire, wind, and rain, has been proposed to arise through the integration of time-averaged summary statistics. Where and how the auditory system might encode these summary statistics to create internal representations of these stationary sounds, however, is unknown. Here, using natural textures and synthetic variants with reduced statistics, we show that summary statistics modulate the correlations between frequency organized neuron ensembles in the awake rabbit inferior colliculus (IC). These neural ensemble correlation statistics capture high-order sound structure and allow for accurate neural decoding in a single trial recognition task with evidence accumulation times approaching 1 s. In contrast, the average activity across the neural ensemble (neural spectrum) provides a fast (tens of milliseconds) and salient signal that contributes primarily to texture discrimination. Intriguingly, perceptual studies in human listeners reveal analogous trends: the sound spectrum is integrated quickly and serves as a salient discrimination cue while high-order sound statistics are integrated slowly and contribute substantially more toward recognition. The findings suggest statistical sound cues such as the sound spectrum and correlation structure are represented by distinct response statistics in auditory midbrain ensembles, and that these neural response statistics may have dissociable roles and time scales for the recognition and discrimination of natural sounds.

What makes a sound natural, and what are the neural codes that support recognition and discrimination of real-world natural sounds? Although it is known that the early auditory system decomposes sounds along fundamental acoustic dimensions such as intensity and frequency, the higher-level neural computations that mediate natural sound recognition are poorly understood. This general lack of understanding is in part attributed to the structural complexity of natural sounds, which is difficult to study with traditional auditory test stimuli, such as tones, noise, or modulated sequences. Such stimuli can reveal details of the neural representation for relatively low-level acoustic cues, yet they don’t capture the rich and diverse statistical structure of natural sounds. Thus, they cannot reveal many of the computations associated with higher-level sound properties that facilitate auditory tasks such as natural sound recognition or discrimination. A class of stationary natural sounds termed textures, such as the random sounds emanating from a running stream, a crowded restaurant, or a chorus of birds, have been proposed as alternative natural stimuli which allow for manipulating high-level acoustic structure (1). Texture sounds are composed of spatially and temporally distributed acoustic elements that are collectively perceived as a single source and are defined by their statistical features. Identification of these natural sounds has been proposed to be mediated through the integration of time-averaged summary statistics, which account for high-level structures such as the sparsity and time-frequency correlation structure found in many natural sounds (1–3). Using a generative model of the auditory system to measure summary statistics from natural texture sounds, it is possible to synthesize highly realistic synthetic auditory textures (1). This suggests that high-order statistical cues are perceptually salient and that the brain might extract these statistical features to build internal representations of sounds.Although neural activity throughout the auditory pathway is sensitive to a variety of statistical cues such as the sound contrast, modulation power spectrum, and correlation structure (4–12), how sound summary statistics contribute toward basic auditory tasks such as recognition and discrimination of sounds is poorly understood. Furthermore, it is unclear where along the auditory pathway summary statistics are represented and how they are reflected in neural activity. The inferior colliculus (IC) is one candidate midlevel structure for representing such summary statistics. As the principal midbrain auditory nucleus, the IC receives highly convergent brainstem inputs with varied sound selectivities. Neurons in the IC are selective over most of the perceptually relevant range of sound modulations and neural activity is strongly driven by multiple high-order sound statistics (4–7, 10). In previous work, we showed the correlation statistics of natural sounds are highly informative about stimulus identity and they appear to be represented in the correlation statistics of auditory midbrain neuron ensembles (4). Correlations between neurons have also been proposed as mechanisms for pitch identification (13) and sound localization (14). This broadly supports the hypotheses that high-order sound statistics are reflected in the response statistics of neural ensembles and that these neural response statistics could potentially subserve basic auditory tasks.Here using natural and synthetic texture sounds, we test the hypothesis that statistical structure in natural texture sounds modulates the response statistics of neural ensembles in the IC of unanesthetized rabbits, and that distinct neural response statistics have the potential to contribute toward sound recognition and discrimination behaviors. By comparing the performance of neural decoders with human texture perception, we find that place rate representation of sounds (neural spectrum) accumulates evidence about the sounds on relatively fast time scales (tens of milliseconds) exhibiting decoding trends that mirror those seen for human texture discrimination. High-order statistical sound cues, by comparison, are reflected in the correlation statistics of neural ensembles, which require substantially longer evidence accumulation times (>500 ms) and follow trends that mirror those measured for human texture recognition. Collectively, the findings suggest that spectrum cues and accompanying place rate representation (neural spectrum) may contribute surprisingly little toward the recognition of auditory textures. Instead, high-order statistical sound structure is reflected in the distributed patterns of correlated activity across IC neural ensembles and such neural response structure has the potential to contribute toward the recognition of natural auditory textures.     

Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi

Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants can be extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance.