From Ischochymia to Gastroparesis: Proposed Mechanisms and Preferred Management of Dyspepsia Over the Centuries

Dyspeptic symptoms are common with most patients suffering functional disorders that remain a therapeutic challenge for medical practitioners. Within the last three decades, gastric infection, altered motility, and hypersensitivity have gained and lost traction in explaining the development of functional dyspepsia. Considering these shifts, the aim of this review was to analyze changing understanding of and approaches to dyspepsia over a longer time period. Monographs, textbooks, and articles published during the last three centuries show that our understanding of normal gastric function has improved dramatically. With increased insight came new ideas about disease mechanisms, diagnostic options, and treatments. Despite shifts over time, the importance of functional abnormalities was recognized early on and explained in the context of societal influences and stressors, anxieties, and biological influences, thus resembling the contemporary biopsychosocial model of illness. Symptoms were often attributed to changes in secretion, motility, and sensation or perception with technological innovation often influencing proposed mechanisms and treatments. Many of the principles or even agents applied more than a century ago are still part of today’s approach. This includes acid suppression, antiemetics, analgesics, and even non-pharmacologic therapies, such as gastric decompression or electrical stimulation of the stomach. This historical information does not only help us understand how we arrived at our current state of knowledge and standards of care, it also demonstrates that enthusiastic adoption of various competing explanatory models and the resulting treatments often did not survive the test of time. In view of the benign prognosis of dyspepsia, the data may function as a call for caution to avoid the potential harm of overly aggressive approaches or treatments with a high likelihood of adverse effects.     

Sodium channel blockers alter slow-wave frequency of the rat stomach in vivo.

Treatment with sodium-channel-blocking agents is accompanied by a high incidence of gastrointestinal side effects. We therefore studied the influence of two sodium channel blockers, mexiletine and flecanaide, on gastric and jejunal myoelectrical activity of unanesthetized rats. Bipolar electrodes were implanted chronically on the serosal surface of the antrum or the jejunum of male rats (weight: 250-350 g). Electrical activity was recorded on a Polygraph starting on day 5 after the operation After 1 h of baseline recordings, either vehicle or an active drug was given randomly. Recordings were continued for 4 h after drug administration. Vehicle did not induce changes in slow-wave frequency. In contrast, gastric slow-wave activity significantly decreased after the administration of both mexiletine and flecanaide. Jejunal myoelectrical activity was only slightly affected by sodium channel blockade. The disruption of gastric myoelectrical activity may contribute to the side effects observed during chronic treatment with class I antiarrhythmic drugs.     

Fundoplication for gastroesophageal reflux disease: regional variability and factors predicting operative approach

We have recently shown that the majority of patients undergoing fundoplication in the United States are women. Based on these findings, we hypothesized that nonbiological factors contribute to the decisions on surgical reflux therapy. Using State Inpatient Databases of the Agency for Healthcare Research and Quality, we extracted annual fundoplication rates, sex distribution, age cohorts, racial background, and insurance coverage. To account for potential differences in state populations, the results were normalized and correlated with Census data, adult obesity rates, median income, poverty rates, and physician workforce within the state. Fundoplication rates varied fivefold between states, ranging from 4.1 ± 0.1 per 100 000 in New Jersey to 21.8 ± 0.4 per 100 000 in Oregon. Higher poverty rates and a higher fraction of Caucasians within a state independently predicted higher fundoplication rates. While the majority of operations were performed laparoscopically, surgical approaches also differed between states with rates of laparoscopic ranging from 52.3 ± 1.8% in Oklahoma to 87.4 ± 1.7% in Hawaii. A lower number of pediatric and Medicaid‐insured patient and a higher fraction of privately insured patients best predicted higher rates of laparoscopic surgery. Our study shows significant regional variation in surgical reflux management, which cannot be explained by differences in disease mechanisms. Insurance coverage and racial background influenced the likelihood of surgery, suggesting a role of financial incentives.     

Pain without nociception?

We describe a young woman with complete cervical spinal cord transsection, who developed significant abdominal pain, triggered by gastric distension and deep abdominal palpation. On the basis of the nature of her spinal cord injury, her brain-gut axis was limited to vagal pathways. Studies in mammalian models of human visceral sensation consistently showed that the subdiaphragmatic vagus contains a homogeneous population of afferents that are activated by low-intensity stimuli, which are generally believed to be important in regulating autonomic function and perhaps contributing to visceral sensory experiences triggered by such low-intensity stimuli (e.g. fullness, nausea), but not pain, although many fibers encode stimuli well into the noxious range. In contrast, spinal afferent pathways include fibers with high-activation thresholds that are thought to represent specialized nociceptors. This illustrative case argues against an exclusive role of specialized nociceptive pathways in visceral pain, but supports a concept of intensity coding with the composite of vagal and spinal input contributing to conscious perception and pain.     

Surface antigen expression by bovine alveolar macrophages: functional correlation and influence of interferons in vivo and in vitro

Alveolar macrophages (AM) procured by bronchoalveolar lavage of healthy calves were tested for the expression of two antigens defined by monoclonal antibodies. One of these, H34A, detects a MHC type II (Ia)-antigen; the other, B18A, a heterodimer of unknown function. No single AM-activity could be ascribed solely to the subpopulations defined by the presence or absence of these two surface antigens. The expression of both antigens could be modulated by in vitro treatment of the AM with recombinant E. coli-derived bovine interferon-gamma (rBoIFN-gamma), but not by interferon-alpha 1 (rBoIFN-alpha 1). Enhanced Ia-expression was detectable within 3 h of exposure to rBoIFN-gamma and reached a maximum by 24-48 h. Expression of the Ia-antigen required continual presence of bioactive IFN. However, cells that reverted from the Ia+ to the Ia- state did not become refractory to reinduction, and induction was possible even after several days (at least 96 h) in culture, despite the in vitro maturation and modulation of the AM that occurred. Treatment of calves with rBoIFN-gamma also resulted in increased numbers of Ia(H34A)+ cells, but in a decline of B18A+ cells. In contrast to the in vitro findings, rBoIFN-alpha 1 appeared to have some modulatory effect in vivo. The latter effect may be indirect rather than direct as for rBoIFN-gamma. As previously shown for rBoIFN-alpha 1, in vitro treatment of the AM with rBoIFN-gamma "activated" the AM as judged by enhanced cytotoxicity, enhanced accessory cell activity in mitogen-driven lymphocyte-proliferation, enhanced IgG Fc- and C3b-receptor expression and content of some enzymes. The fact that the two IFNs have very similar effects on cell functions, but differ markedly in their Ia-inducing immunoregulatory activity, supports the notion that the Ia-antigen expression may be irrelevant as a surface marker for macrophage activation, and may rather be a marker for a certain functional stage of the macrophage. Moreover, the acquisition of this stage appears to be, at least in the AM, a reversible event.     

Production and properties of Staphylococcus aureus (strain Newman D2C) with uniform clumping factor activity.

The most active CF+ $\text{Staphylococcus aureus}$ (strain Newman D₂C) cells were recovered during the exponential through the early resting phases of the growth cycle. Fermentation conditions are described for preparation of large quantities of those cells on BHI. Extractions with 70 per cent ethanol produced sterile particles with intact CF activity. Subsequent ethanol and acetone drying steps completed procedures for production of uniformly active, stable CF+ particles.Congo red stained the killed staphylococci without affecting CF activity, and the stained particles enhanced visualization of the agglutination end-points. Tris buffers (50 mM, pH 7.3) were excellent diluents for CF reagents, but only if freshly prepared or sterilized before storage.     

Neonatal colon insult alters growth factor expression and TRPA1 responses in adult mice

Inflammation or pain during neonatal development can result in long-term structural and functional alterations of nociceptive pathways, ultimately altering pain perception in adulthood. We have developed a mouse model of neonatal colon irritation (NCI) to investigate the plasticity of pain processing within the viscerosensory system. Mouse pups received an intracolonic administration of 2% mustard oil (MO) on postnatal days 8 and 10. Distal colons were processed at subsequent timepoints for myeloperoxidase (MPO) activity and growth factor expression. Adult mice were assessed for visceral hypersensitivity by measuring the visceromotor response during colorectal distension. Dorsal root ganglion (DRG) neurons from adult mice were retrogradely labeled from the distal colon and calcium imaging was used to measure transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) responses to acute application of capsaicin and MO, respectively. Despite the absence of inflammation (as indicated by MPO activity), neonatal exposure to intracolonic MO transiently maintained a higher expression level of growth factor messenger RNA (mRNA). Adult NCI mice displayed significant visceral hypersensitivity, as well as increased sensitivity to mechanical stimulation of the hindpaw, compared to control mice. The percentage of TRPA1-expressing colon afferents was significantly increased in NCI mice, however they displayed no increase in the percentage of TRPV1-immunopositive or capsaicin-sensitive colon DRG neurons. These results suggest that early neonatal colon injury results in a long-lasting visceral hypersensitivity, possibly driven by an early increase in growth factor expression and maintained by permanent changes in TRPA1 function.