Prostaglandin stimulation of gastrointestinal transit in post-operative ileus rats

The prostaglandins PGF_2α, PGE₂ and 16,16-dimethyl PGE₂, when administered intravenously, orally, subcutaneously or intraduodenally to laparotomized rats, decreased gastric emptying, small intestinal transit and colonic transit as compared to unoperated controls. All three prostaglandins increased colonic transit above that found with unoperated controls. This activity was independent of small intestinal fluid accumulation (i.e., enteropooling) since ligating the ileal-cecal junction had no effect on colonic transit. Small intestinal transit was increased, but not normalized, by PGE₂ and 16,16-dimethyl PGE₂. 16,16-Dimethyl PGE₂ completely restored gastric emptying when given intravenously to laparotomized rats at doses greater than 5.0 μg/kg. This effect on gastric emptying lasted approximately 4 hrs. Thus, 16,16-dimethyl PGE₂, when given intravenously, normalized gastric emptying, significantly increased small intestinal transit, and made the colon hypermotile. Prostaglandins may be beneficial in the treatment of post-operative ileus and other conditions of sluggish gastrointestinal propulsion.     

Differences in intragastric pH in diabetic vs. idiopathic gastroparesis: relation to degree of gastric retention

Evidence suggests that distinct mechanisms underlie diabetic and idiopathic gastroparesis. Differences in gastric acid in gastroparesis of different etiologies and varying degrees of gastric stasis are uninvestigated. We tested the hypotheses that 1) gastric pH profiles show differential alteration in diabetic vs. idiopathic gastroparesis and 2) abnormal pH profiles relate to the severity of gastric stasis. Sixty-four healthy control subjects and 44 gastroparesis patients (20 diabetic, 24 idiopathic) swallowed wireless transmitting capsules and then consumed (99m)Tc-sulfur colloid-labeled meals for gastric scintigraphy. Gastric pH from the capsule was recorded every 5 s. Basal pH was higher in diabetic (3.64 +/- 0.41) vs. control subjects (1.90 +/- 0.18) and idiopathic subjects (2.41 +/- 0.42; P < 0.05). Meals evoked initial pH increases that were greater in diabetic (4.98 +/- 0.32) than idiopathic patients (3.89 +/- 0.39; P = 0.03) but not control subjects (4.48 +/- 0.14). pH nadirs prior to gastric capsule evacuation were higher in diabetic patients (1.50 +/- 0.23) than control subjects (0.58 +/- 0.11; P = 0.003). Four-hour gastric retention was similar in diabetic (18.3 +/- 0.5%) and idiopathic (19.4 +/- 0.5%) patients but higher than control subjects (2.2 +/- 0.5%; P < 0.001). Compared with control subjects, those with moderate-severe stasis (>20% retention at 4 h) had higher basal (3.91 +/- 0.55) and nadir pH (2.23 +/- 0.42) values (P < 0.05). In subgroup analyses, both diabetic and idiopathic patients with moderate-severe gastroparesis exhibited increased pH parameters vs. those with mild gastroparesis. In conclusion, diabetic patients with gastroparesis exhibit reduced gastric acid, an effect more pronounced in those with severely delayed gastric emptying. Idiopathic gastroparetic subjects exhibit nearly normal acid profiles, although those with severely delayed emptying show reduced acid vs. those with mild delays. Thus both etiology and degree of gastric stasis determine gastric acidity in gastroparesis.     

Association of Proteinuria Threshold in Pre-Eclampsia with Maternal and Perinatal Outcomes: A Nested Case Control Cohort of High Risk Women

Objectives

To evaluate occurrence of adverse maternal and perinatal outcomes with different thresholds of proteinuria (300-499mg and ≥500mg/24 hours) in pre-eclamptic women, comparing outcomes against women with chronic and gestational hypertension.

Design

Secondary analysis of the Vitamins in Pre-Eclampsia Trial.

Setting

25 UK hospitals in ten geographical areas.

Population

946 women with pre-existing risk factors for pre-eclampsia.

Methods

Women with pre-eclampsia and proteinuria 300-499mg/24h (PE300, referent group, n=60) or proteinuria ≥500 mg/24h (PE500, n=161) were compared with two groups of non-proteinuric women with chronic hypertension (CHT, n=615) or gestational hypertension (GH, n=110).

Main Outcome Measures

Maternal: progression to severe hypertension. Perinatal: small for gestational age (SGA) <5^th centile, gestation at delivery.

Results

Severe hypertension occurred more frequently in PE500 (35%) and PE300 (27%) than CHT (5.9%; P≤0.01) and GH (10%; p≤0.001). Gestation at delivery was earlier in PE500 (33.2w) than PE300 (37.3w; P≤0.001), and later in CHT (38.3w; P≤0.05) and GH (39.1w; P≤0.001). SGA infants were more frequent in PE300 (32%) than in CHT (13.3%; P≤0.001) and GH (16.5%; P≤0.05). Women in PE500 were more likely to have a caesarean section than PE300 (78% vs. 48%; P≤0.001), and to receive magnesium sulphate (17% vs. 1.7%, P≤0.05).

Conclusion

Women with PE300 have complication rates above those of women managed as out-patients (GH and CHT), meriting closer surveillance and confirming 300 mg/d as an appropriate threshold for determining in-patient management. Adverse perinatal outcomes are higher still in women with PE500.     

Pramlintide, an amylin analog, selectively delays gastric emptying: potential role of vagal inhibition

The amylin analog pramlintide delays gastric emptying in type I diabetics. The effects of multiple doses of pramlintide and the mechanism of action in non-amylin-deficient humans are unknown. We investigated the effects of pramlintide on gastrointestinal and colonic transit and on the plasma pancreatic polypeptide response to the meal in a parallel-group dose-response study with subjects randomized to placebo, or 30 or 60 microg (tid, sc) of pramlintide. Pramlintide delayed gastric emptying [half-time (t(1/2)): 112 min (SE 8.7 min), 169 min (SE 12 min), or 177 min (SE 25 min) after placebo or 30- or 60-microg pramlintide treatment, respectively; P = 0.033]. Pramlintide did not significantly affect small bowel or colonic transit. Pancreatic polypeptide concentrations in the first postprandial hour were lower with pramlintide than with placebo (P<0.01 for drug effect). An inverse correlation was observed between mean pancreatic polypeptide concentrations in the first postprandial hour and gastric emptying t(1/2) [Spearman correlation coefficient (R(s)) = 0.48; P = 0.044]. Pramlintide at 30 and 60 microg delays gastric emptying in healthy humans without affecting small bowel or colonic transit. Vagal inhibition is a potential mechanism of the effects of pramlintide on gastric emptying.     

The water load test: observations from healthy controls and patients with functional dyspepsia

Gastric sensation and accommodation are studied by barostat, but this is invasive. The drink test is noninvasive and may provide similar information. We evaluated relationships between drink test, gastric function, symptoms, and psychiatric distress. Controls (73) and functional dyspeptics (FD) (92) were studied using a 5-min water load test (WL5), gastric emptying, and electrogastrography (EGG). Symptoms, quality of life, and psychiatric distress were measured using standardized measures. Controls underwent test-retest of WL5 and comparison of WL5 with 100 ml/min water-based drink test (WL100) or nutrient drink. Controls, FD, and gastroparetics estimated drinking capacity before WL5 using a visual analog scale. WL5 correlated with WL100 (r = 0.7929) but not nutrient drink test (r = 0.1995). WL5 was significantly less in FD than controls, and abnormal WL5 was seen in 46%. In FD, volume to fullness inversely correlated with symptom severity (r =-0.29; P = 0.0154) and WL5 produced more symptoms, particularly nausea. Gastric function was not different between FD with normal or abnormal WL5. Symptoms and psychiatric distress were similar between normal and abnormal WL5 groups, but the abnormal group had significantly poorer quality of life. Controls and gastroparetics had good correlation of estimated and ingested volumes, but FD did not. Versus FD with normal WL5 capacity, FD with impaired drinking capacity have normal gastric function and similar symptoms but poorer quality of life. FD are less able to predict drinking capacity. These data suggest that WL5 identifies FD with intact gastric function but abnormal visceral perception.     

Disturbed gastric motility and pancreatic hormone release in diabetes mellitus.

BACKGROUND AND AIMS: The influence of glucose metabolism and postprandial release of glucagon on gastric emptying in diabetes mellitus is still unclear. The aim of this study was to assess the relationship between glucose, insulin and glucagon and alterations of gastric motility in symptomatic diabetic subjects with delayed gastric emptying. METHODS: Scintigraphy for solids and liquids, 13C-acetate breath test, electrogastrography and antral manometry were assessed in 20 symptomatic subjects with diabetes mellitus type II and in 20 healthy controls. Simultaneously, serum glucose, glucagon and insulin levels were determined during the functional studies. RESULTS: Postprandial increase in antral motility and myoelectrical activity were seen in controls, but were missing in the group with diabetes mellitus. Moreover, in the fasting state the dominant frequency instability coefficient observed in healthy individuals and in subjects with diabetes of short (<5 years) duration was significantly reduced in subjects with longer duration of diabetes while the postprandial increase in dominant frequency instability coefficient was missing in all diabetics. Following the standard test meal, serum glucose and plasma glucagon in the diabetics increased to a significantly higher degree when compared to controls. CONCLUSIONS: Symptomatic subjects with delayed gastric emptying present abnormal patterns of gastric motor and electrical activity. Higher than normal postprandial plasma levels of glucagon may, at least in part, be responsible for disturbed gastric motility in non-insulin-dependent diabetic subjects.     

Birth Weight,Growth and Feeding Pattern in Early Infancy Predict Overweight/Obesity Status at Two Years of Age: A Birth Cohort Study of Chinese Infants

Objectives

To investigate the early determinants of overweight and obesity status at age two years.

Methods

A total of 1098 healthy neonates (563 boys and 535 girls) were involved in this community-based prospective study in China. Data on body weight and length were collected at birth, the 3^rd and 24^th month. A self-administered questionnaire was used to collect data on social demography and feeding patterns of children, etc. Three multivariable logistic regression models were employed to make various comparisons of weight status, i.e., model 1 (obesity vs. non-obesity), model 2 (combined overweight and obesity vs. normal weight, and model 3 (obesity, overweight and normal weight).

Results

Prevalences of overweight/obesity (95^th >BMI ≥85^th p and BMI ≥95^th p, referring to WHO BMI standards) at 2 years of age are 15.8%/11.2% for boys and 12.9%/9.0% for girls, respectively. Being born with macrosomia (OR: 1.80–1.88), relatively greater BMI increment in the first 3 months (OR: 1.15–1.16) and bottle emptying by encouragement at age two (OR: 1.30–1.57) were found in all three models to be significant risk factors for higher BMI status at 2 years. Pre-pregnancy maternal BMI (OR: 1.09–1.12), paternal BMI (OR: 1.06), and mixed breastfeeding (OR: 1.54–1.57) or formula feeding (OR: 1.90–1.93) in the first month were identified as significant in models 2 and 3. Child-initiated bottle emptying at age two was observed to increase the risk of obesity by 1.31 times but only in model 1.

Conclusion

Fetal and early postnatal growth and feeding pattern appear to have significant impacts on early childhood overweight and obesity status independent of parental BMI. Policy-based and multidisciplinary approaches to promote breastfeeding and enhancement of feeding skills of care takers may be promising intervention strategies.     

Prevalence of Dental Caries and Fissure Sealants in a Portuguese Sample of Adolescents

Introduction

The aims of this study were to assess the prevalence of dental caries and the DMFT index, as well as the distribution pattern of pit and fissure sealants on permanent teeth in a Portuguese sample of adolescents, and to assess whether the existing usage of sealants and socio-demographic factors are correlated to caries prevalence on the examined sample.

Materials and Methods

A cross-sectional study was designed with a sample of 447 adolescents aged 12 to 18 years old, attending a public school in Sátão, Portugal. A self-administered questionnaire with questions about oral health behaviours and socio-economic status was answered by adolescents in the classroom. Clinical examination of oral health status and assessment of fissure sealants were accomplished by only one trained member of the research team.

Results

We obtained a DMFT index of 3.32 (2.92), which indicates a moderate level of prevalence of dental caries. When considering a DMFT = 0, we found significant statistical differences between the parents´ level of education (≤ 4^th grade = 26.3 vs 5^th–12^th grade = 18.8 vs <12^th grade = 43.3, p = 0.001), gender (male = 27.3 vs female = 19.6, p = 0.04), age (≤15 years = 27.1 vs <15 years = 18.5, p = 0.02), presence of fissure sealants (yes = 30.6 vs no = 13.5, p = 0.001) and experience of dental pain (no = 25.4 vs yes = 16.8, p = 0.02). When analyzing the prevalence of fissure sealants, we verified that 58.8% of adolescents had at least one fissure sealant applied. Significant statistical differences were found when analyzing the presence of fissure sealants related with parents´educational level (<9^th grade, OR = 1.56 CI95% = 1.05–2.54), gender (female, OR = 1.86 CI95% = 1.19–2.98), experience of dental pain (yes, OR = 0.62 CI95% = 0.39–0.97) and presence of dental caries (yes, OR = 0.35 CI95% = 0.19–0.65).

Conclusions

The moderate level of caries prevalence reveals the need of improvement of primary prevention interventions among Portuguese adolescents. The establishment of a more targeted preventive program with better and more effective oral health education is essential, having into account socio-demographic aspects.     

Severe Obesity and Cardiometabolic Risk in Children: Comparison from Two International Classification Systems

Objectives

There is no agreed-upon definition for severe obesity (Sev-OB) in children. We compared estimates of Sev-OB as defined by different cut-points of body mass index (BMI) from the Centers for Disease Control and Prevention (CDC) or the World Health Organization (WHO) curves and the ability of each set of cut-points to screen for the presence of cardiometabolic risk factors.

Research Design and Methods

Cross-sectional, multicenter study involving 3,340 overweight/obese young subjects. Sev-OB was defined as BMI ≥99^th percentile or ≥1.2 times the 95^th percentile of the CDC or the WHO curves. High blood pressure, hypertriglyceridemia, low High Density Lipoprotein -cholesterol and impaired fasting glucose were considered as cardiometabolic risk factors.

Results

The estimated prevalence of Sev-OB varied widely between the two reference systems. Either using the cut-point ≥99^th percentile or ≥1.2 times the 95^th percentile, less children were defined as Sev-OB by CDC than WHO (46.8 vs. 89.5%, and 63.3 vs. 80.4%, respectively p<0.001). The CDC 99^th percentile had lower sensitivity (58.5 vs 94.2), higher specificity (57.6 vs 12.3) and higher positive predictive value (34.4 vs 28.9) than WHO in identifying obese children with ≥2 cardiometabolic risk factors. These differences were mitigated using the 1.2 times the 95^th percentile (sensitivity 73.9 vs. 88.1; specificity 40.7 vs. 22.5; positive predictive value 32.1 vs. 30.1). Substantial agreement between growth curves was found using the 1.2 times the 95^th percentile, in particular in children ≤10 years.

Conclusions

Estimates of Sev-OB and cardiometabolic risk as defined by different cut-points of BMI are influenced from the reference systems used. The 1.2 times the 95^th percentile of BMI of either CDC or WHO standard has a discriminatory advantage over the 99^th percentile for identifying severely obese children at increased cardiometabolic risk, particularly under 10 years of age.     

Therapeutic potential of synchronized gastric electrical stimulation for gastroparesis: enhanced gastric motility in dogs

The aim of this study was to determine the effects and mechanism of synchronized gastric electrical stimulation (SGES) on gastric contractions and gastric emptying. The first experiment was designed to study the effects of SGES on antral contractions in four randomized sessions. Sessions 1 (control) and 2 (atropine) were performed in the fasting state, composed of three 30-min periods (baseline, stimulation, and recovery). Sessions 3 (control) and 4 (SGES performed during 2nd 20-min period) were performed in the fed state, consisting of two 20-min periods; glucagon was injected after the first 20-min recording. The second experiment was designed to study the effect of SGES on gastric emptying and consisted of two sessions (control and SGES). SGES was delivered with train duration of 0.5-0.8s, pulse frequency of 40 Hz, width of 2 ms, and amplitude of 4 mA. We found that 1) SGES induced gastric antral contractions in the fasting state. The motility index was 1.3 +/- 0.5 at baseline and 6.1 +/- 0.7 (P = 0.001) during SGES. This excitatory effect was completely blocked by atropine. 2) SGES enhanced postprandial antral contractions impaired by glucagon. 3) SGES significantly accelerated glucagon-induced delayed gastric emptying. Gastric emptying was 25.5 +/- 11.3% without SGES and 38.3 +/- 10.7% with SGES (P = 0.006 vs. control). This novel method of SGES induces gastric antral contractions in the fasting state, enhances glucagon-induced antral hypomotility in the fed state, and accelerates glucagon-induced delayed gastric emptying. The effect of SGES on antral contractions is mediated via the cholinergic pathway.     

Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation

The C57BLKS/J db/db mouse develops hyperglycemia and has delayed gastric emptying that is improved with tegaserod, a partial 5-HT4 agonist. Our aims here were to determine regional gastric contractility alterations in C57BLKS/J db/db mice and to determine the effects of serotonin and tegaserod. The contractile effects of bethanechol, serotonin, and tegaserod in fundic, antral, and pyloric circular muscle were compared in C57BLKS/J db/db mice and normal littermates. The effects of tetrodotoxin, atropine, and 5-HT receptor antagonists were studied. Contractions in response to bethanechol were decreased in the fundus, similar in the antrum, but increased in the pylorus in diabetic mice compared with controls. Serotonin and, to a lesser extent, tegaserod caused contractions that were more pronounced in the fundus than in the antrum and pylorus in both diabetic and normal mice. Serotonin-induced contractions were partially inhibited by atropine, the 5-HT4 antagonist GR113808, and the 5-HT2 antagonist cinanseron but not tetrodotoxin. Regional gastric contractility alterations are present in this diabetic gastroparesis mouse model. Fundic contractility was decreased, but pyloric contractility was increased in the pylorus to cholinergic stimulation in diabetic mice. Serotonin's contractile effect is mediated, in part, through muscarinic, 5-HT2, and 5-HT4 receptors. This study suggests that fundic hypomotility and pyloric hypercontractility, rather than antral hypomotility, play important roles for the gastric dysmotility that occurs in diabetes.     

Neuronal anomalies and normal muscle morphology at the hypomotile ileocecocolonic region of patients affected by idiopathic chronic constipation.

Patients suffering from idiopathic slow-transit chronic constipation have a delayed colonic transit referable to a decrease or loss of propagating contractions. Myogenic and/or neural mechanisms have been implicated in the pathophysiology of this dysfunction and neuronal abnormalities have been described at the ascending, descending and sigmoid colon. The morphology and motile behaviour of the ileocecocolonic region, which in healthy subjects regulates cecum filling and emptying, have never been investigated in such disease. Therefore, we endoscopically ascertained whether a motility impairment was present at these junctional areas and neither spontaneous nor provoked occlusive contractions were found at the cecocolonic junction. Light and electron microscope examination of the entire colon revealed apparently normal features of neurons, smooth muscle cells and interstitial cells of Cajal, while immunohistochemistry and quantitative analysis demonstrated neuronal anomalies at the junctional areas. These anomalies consisted of low total neuron density and significantly few VIP-immunoreactive neurons at the two enteric plexuses, significantly few NOS-immunoreactive neurons at the myenteric plexus and significantly more NOS-immunoreactive neurons at the submucous plexus. These findings exclude a myopathy and demonstrate the existence of a neuropathy. In particular, the presence at the ileocecocolonic region of few VIP- and NO-producing neurons suggests that there might be a reduced VIP and NO production which may result in a compromised relaxation and/or onset of propagating contractions, slowing down bolus transit. The presence at the proximal colon of such an abnormality might explain why left colectomy and/or cecorectal anastomosis are unsuccessful in patients with this disease.     

Determination of gastric emptying in nonobese diabetic mice

Animal studies on diabetic gastroparesis are limited by inability to follow gastric emptying changes in the same mouse. The study aim was to validate a nonlethal gastric emptying method in nonobese diabetic (NOD) LtJ mice, a model of type 1 diabetes, and study sequential changes with age and early diabetic status. The reliability and responsiveness of a [(13)C]octanoic acid breath test in NOD LtJ mice was tested, and the test was used to measure solid gastric emptying in NOD LtJ mice and nonobese diabetes resistant (NOR) LtJ mice. The (13)C breath test produced results similar to postmortem recovery of a meal. Bethanechol accelerated gastric emptying [control: 92 +/- 9 min; bethanechol: 53 +/- 3 min, mean half emptying time (T(1/2)) +/- SE], and atropine slowed gastric emptying (control: 92 +/- 9 min; atropine: 184 +/- 31 min, mean T(1/2) +/- SE). Normal gastric emptying (T(1/2)) in nondiabetic NOD LtJ mice (8-12 wk) was 91 +/- 2 min. Aging had differing effects on gastric emptying in NOD LtJ and NOR LtJ mice. Onset of diabetes was accompanied by accelerated gastric emptying during weeks 1-2 of diabetes. Gastric emptying returned to normal by weeks 3-5 with no delay. The [(13)C]octanoic acid breath test accurately measures gastric emptying in NOD LtJ mice, is useful to study the time course of changes in gastric emptying in diabetic NOD LtJ mice, and is able to detect acceleration in gastric emptying early in diabetes. Opposing changes in gastric emptying between NOD LtJ and NOR LtJ mice suggest that NOR LtJ mice are not good controls for the study of gastric emptying in NOD LtJ mice.     

Inhibitory effect of sildenafil on gastrointestinal smooth muscle: role of NO-cGMP transduction pathway

Nitric oxide (NO) is an important neurotransmitter in the gut and has been demonstrated to be a key physiological mediator of non-adrenergic non-cholinergic (NANC) relaxation of gastrointestinal smooth muscle. In the present study the effect of PDE 5 inhibitor sildenafil on the gastrointestinal function (gastric emptying and intestinal transit) has been demonstrated in mice. Sildenafil (0.5-2 mg/kg, po) did not alter the percent gastric emptying however, in higher doses (5, 10 and 30 mg/kg, po) it inhibited the gastric emptying. On acute administration (0.5-5 mg/kg, po) it did not alter the intestinal transit but in higher doses (10 and 30 mg/kg, p.o.) delayed the intestinal transit. Further, the inhibitory effect of sildenafil was significantly blocked by L-NAME (10 mg/kg, ip), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor. These findings suggest the participation of NO-cGMP transduction pathway in the inhibitory effect of sildenafil (higher doses) on the gastrointestinal smooth muscles and its potential application in patients with nutcracker oesophagus, hypertensive lower oesophageal sphincter (LOS), achalsia and diabetic gastroparesis or colitis where there is a loss of nNOS.     

Synchronized gastric electrical stimulation improves delayed gastric emptying in nonobese mice with diabetic gastroparesis.

The aim of this study was to investigate the effect and mechanism of synchronized gastric electrical stimulation (SGES) on gastric emptying in nonobese mice with diabetic gastroparesis (DB-GP). Eight control mice and 48 nonobese diabetic (NOD) mice with two pairs of gastric electrodes were used in this study. The study included seven groups in a randomized order [control, diabetes (DB), DB-GP, DB + SGES, DB-GP + SGES, DB-GP + Atropine, and DB-GP + SGES + Atropine groups]. In the control, DB, DB-GP, and DB-GP + Atropine groups, gastric emptying was measured in BLAB/cJ mice (control group) or NOD mice with a duration of diabetes of 0-7 days (DB group) or 28-35 days (DB-GP or DB-GP + Atropine group). In the DB + SGES, DB-GP + SGES, and DB-GP + SGES + Atropine groups, the experiment was the same as the corresponding DB, DB-GP, and DB-GP + Atropine groups except that SGES was applied during the experiment. SGES was applied via the proximal pair of electrodes and synchronized with the intrinsic gastric slow waves. The following results were obtained: 1) gastric emptying was delayed in NOD mice with a duration of diabetes of 28-35 days; 2) SGES was able to significantly increase gastric emptying in both diabetic mice and diabetic gastroparetic mice; and 3) the excitatory effect of SGES was completely blocked by atropine. SGES accelerates gastric emptying in NOD mice with diabetic gastroparesis. The effect of SGES on gastric emptying is mediated via the cholinergic pathway. These findings suggest that SGES may have a therapeutic potential for treating patients with diabetic gastroparesis.     

Increased T Regulatory Cells Are Associated with Adverse Clinical Features and Predict Progression in Multiple Myeloma

Background

Regulatory T (Treg) cells play an important role in the maintenance of immune system homeostasis. Multiple myeloma (MM) is a plasma cell disorder frequently associated with impaired immune cell numbers and functions.

Methods

We analyzed Treg cells in peripheral blood (n = 207) and bone marrow (n = 202) of pre-malignant and malignant MM patients using flow cytometry. Treg cells and their subsets from MM patients and healthy volunteers were functionally evaluated for their suppressive property. A cohort of 25 patients was analyzed for lymphocytes, CD4 T cells and Treg cells before and after treatment with cyclophosphamide, thalidomide plus dexamethasone (CTD).

Results

We found elevated frequencies of Treg cells in newly diagnosed (P<0.01) and relapsed MM patients (P<0.0001) compared to healthy volunteers. Also, Treg subsets including naïve (P = 0.015) and activated (P = 0.036) Treg cells were significantly increased in MM patients compared to healthy volunteers. Functional studies showed that Treg cells and their subsets from both MM and healthy volunteers were similar in their inhibitory function. Significantly increased frequencies of Treg cells were found in MM patients with adverse clinical features such as hypercalcemia (>10 mg/dL), decreased normal plasma cell (≤5%) count and IgA myeloma subtype. We also showed that MM patients with ≥5% of Treg cells had inferior time to progression (TTP) (13 months vs. median not reached; P = 0.013). Furthermore, we demonstrated the prognostic value of Treg cells in prediction of TTP by Cox regression analysis (P = 0.045). CTD treatment significantly reduced frequencies of CD4 T cells (P = 0.001) and Treg cells (P = 0.018) but not Treg cells/CD4 T cells ratio compared to pre-treatment.

Conclusions

Our study showed immune deregulation in MM patients which is evidenced by elevated level of functionally active Treg cells and patients with increased Treg cells have higher risk of progression.     

Diabetes and the stomach.

Abnormalities in the function of the stomach in patients with long-standing diabetes mellitus, usually insulin-dependent, may provide difficult management problems. There is a reduced frequency of peptic ulcer disease in diabetics. Gastric atrophy, often with parietal cell antibodies, is common and the frequency of pernicious anemia with its expected intrinsic factor antibodies is increased. Gastric analysis results have been conflicting but generally suggest that long-standing diabetics have lower acid levels than normals, possibly secondary to vagal neuropathy. Gastric atony occurring in a small but significant number of patients with longstanding insulin-dependent diabetes, usually with a clinically apparent peripheral neuropathy, has been associated with upper abdominal discomfort, vomiting, and a clinical picture of gastric outlet obstruction. Various degrees of subclinical delays in gastric emptying are probably present in many asymptomatic patients and, indeed, are underemphasized contributors to poor control of blood sugar levels. Studies utilizing radioactive-labeled physiological meals have demonstrated abnormalities in the gastric emptying of solids, in particular, and sometimes liquids in the latter stages of the disease. Metoclopramide, a dopamine antagonist, which stimulates upper gastrointestinal smooth musculature, results in accelerated gastric emptying; clinical trials have shown that it is capable of alleviating symptoms related to diabetic gastroparesis and with its recent approval and release in this country, it promises improved management of this entity. Another agent, domperidone, a selective peripheral dopamine antagonist with no appreciable side effects, is in this country an investigational drug which has shown clinical efficacy in Europe in improving gastric stasis syndromes.     

Ghrelin Does Not Influence Gastric Emptying in Obese Subjects

Objective: To evaluate the relationship between fasting plasma concentrations of ghrelin and gastric emptying in obese individuals compared with lean subjects. Research Methods and Procedures: We included 20 obese patients (9 men and 11 women, BMI > 30 kg/m²) and 16 nonobese control subjects (7 men and 9 women, BMI ≤ 25 kg/m²). Gastric emptying of solids (egg sandwich labeled with radionuclide) was measured at 120 minutes with (99m)Tc‐single photon emission computed tomography imaging. Ghrelin and leptin were analyzed by radioimmunoassay and ELISA methods, respectively. Results: The gastric half‐emptying time was similar in obese men and women (67.8 ± 14.79 vs. 66.6 ± 13.56 minutes) but significantly shorter (p < 0.001) than in the control population (men: 88.09 ± 11.72 minutes; women: 97.25 ± 10.31 minutes). Ghrelin levels were significantly lower in obese subjects (131.37 ± 47.67 vs. 306.3 ± 45.52 pg/mL; p < 0.0001 in men and 162.13 ± 32.95 vs. 272.8 ± 47.77 pg/mL; p < 0.0001 in women). A negative correlation between gastric emptying and fasting ghrelin levels was observed only in lean subjects (y = ?0.2391x + 157.9; R² = 0.95). Also, in the lean group, ghrelin was the only significant independent determinant of gastric emptying, explaining 98% of the variance (adjusted R²) in a multiple regression analysis. Discussion: This report shows that, in humans, gastric emptying is faster in obese subjects than in lean controls and that, whereas ghrelin is the best determinant of gastric kinetics in healthy controls, this action is lost in obesity.     

Inhibitory effects and mechanisms of intestinal electrical stimulation on gastric tone, antral contractions, pyloric tone, and gastric emptying in dogs

The aim of this study was to investigate the effects and mechanisms of intestinal electrical stimulation (IES) on gastric tone, antral and pyloric contractions, and gastric emptying in dogs. Female hound dogs were equipped with a duodenal or gastric cannula, and one pair of serosal electrodes was implanted in the small intestine. The study consisted of five different experiments. Liquid gastric emptying was assessed by collection of chyme from the duodenal cannula in a number of sessions with and without IES and with and without N-nitro-l-arginine (l-NNA). Postprandial antral and pyloric contractions were measured with and without IES and in the absence and presence of l-NNA or phentolamine by placement of a manometric catheter into the antrum and pylorus via the duodenal cannula. Gastric tone was assessed by measurement of gastric volume at a constant pressure. Gastric emptying was substantially and significantly delayed by IES or l-NNA compared with the control session. IES-induced delay of gastric emptying became normal with addition of l-NNA. IES reduced gastric tone, which was blocked by l-NNA. IES also inhibited antral contractions (frequency and amplitude), and this inhibitory effect was not blocked by l-NNA but was blocked by phentolamine. IES alone did not affect pyloric tone or resistance, but IES + l-NNA decreased pyloric tone. In conclusion, IES reduces gastric tone via the nitrergic pathway, inhibits antral contractions via the adrenergic pathway, does not affect pyloric tone, and delays liquid gastric emptying. IES-induced delay of gastric emptying is attributed to its inhibitory effects on gastric motility.