Measurement of Small Intestinal Permeability Markers, Lactulose, and Mannitol in Serum (Results in Celiac Disease)

To date, tests of small intestinal passivepermeability have involved the ingestion of testmolecules whose permeation is assessed indirectly bymeasuring their urinary recovery. Excretion ratios ofmarker molecules (e.g., lactulose-to-mannitolexcretion ratio, LMER) are useful clinically.Measurement of permeability markers in serum wouldimprove the convenience of the tests. Our aim was toassess small intestinal permeability in celiac patients using serumlactulose and mannitol levels with calculation oflactulose to mannitol serum ratios (LMSR) and to comparethe results with the standard methods using urinary recoveries. Twenty-four newly diagnosed celiacsand 10 control subjects were studied; 10 celiacs wererestudied while established on a gluten-free diet. Testsubjects and patients ingested 10 g lactulose and 2.5 g mannitol in 50 ml water. In 10untreated celiacs and the controls, blood was taken from0 to 120 min and all urine was collected for 6 hr. Theremaining 14 untreated and the 10 treated celiacs had a single serum sample taken 60 min afteringestion of the test solution. At 1 hr after ingestion,the mean mannitol level in normals (0.156 mmol/liter)was significantly higher than in untreated celiacs (0.06 mmol/liter). The 1-hr mean serumlactulose level in normals (0.125 mol/liter) wassignificantly lower than in untreated celiacs (0.56mol/liter). The median 1-hr LMSR in untreatedceliacs was 0.42 compared with 0.039 in normals and 0.08 intreated celiacs. There was a significant correlationbetween LMSR and LMER. Permeability testing using serummeasurements of lactulose and mannitol gave comparable results in celiac patients to the tests usingurinary recovery of the permeability markers and mayprove to be more convenient, especially in pediatricpatients.     

Majority of Gliadin-Specific T-Cell Clones from Celiac Small Intestinal Mucosa Produce Interferon-γ and Interleukin-4

An abnormal mucosal cell-mediated immune response plays a fundamental role in the pathogenesis of celiac disease. To characterize locally infiltrating T cells, gliadin-specific T-cell clones were isolated from two treated celiac patients. Mucosal biopsies were cultured in vitro for 24 hr with a peptic-tryptic digest (PT) of gliadin. T-cell clones (TCC) were then isolated by limiting dilution. The production of interferon- (IFN-) and interleukin-4 (IL-4) was evaluated by ELISA in culture supernatants obtained after a short incubation with anti-CD3 and PMA, or with antigen. Twenty-two TCC were specific for gliadin and/or PT. All were CD3⁺, CD4⁺, CD8⁺, TCR ⁺. In one such clone the PT-specific response was inhibited by an anti-DQ, but not by an anti-DR antibody. Of the five gliadin-specific TCC examined, four produced IL-4 and high levels of IFN-; the remaining one initially produced only IL-4, but subsequently also IFN-. All clones obtained from the celiac mucosa, including the gliadin-specific ones, produced high levels of IFN-, in most cases with IL-4. This cytokine profile could explain most of the immunological features of the celiac mucosa.     

Pancreatic insufficiency in celiac disease is not dependent on nutritional status

To determine the relationship between pancreatic secretory capacity and nutritional status in celiac patients, we studied 52 patients with celiac disease (24 males, 28 females; age range 6–36 months) and 30 healthy control subjects (14 males, 16 females; age range 6–42 months). A secretin-cerulein test was performed on all patients, and levels of serum albumin and plasma fibronectin were assayed. In addition, weight/height ratios were calculated in the celiacs, who were then divided into three groups on this basis, as follows: celiacs with weight/height ratio3rd percentile; those with weight/height ratio between the 4th and 10th percentiles; and those with weight/height ratio>10th percentile. There was no significant difference in the duodenal output of chymotrypsin, phospholipase and lipase between these groups. When the total celiac group was compared to control subjects, only lipase levels were significantly lower (P<0.009). However, subnormal values in one or more pancreatic enzymes were observed in 15/52 celiacs (29%). A residual enzyme activity<10% of normal secretory capacity, was also found in 4/52 patients. There was no correlation between the output of the various pancreatic enzymes and levels of albumin, fibronectin, and weight/height ratios in the patients. Furthermore, there was no difference in weight/height ratio and levels of albumin and fibronectin between the celiac subjects with pancreatic deficiency and those with normal pancreatic function. We conclude that a mild/moderate pancreatic insufficiency is quite frequent in celiacs, but that it may be completely independent of nutritional status; further studies are therefore required to shed light on its pathogenesis.     

Intraepithelial leukocytes of the intestinal mucosa in normal man and in Whipple's disease

Intraepithelial lymphocytes (IEL) of the intestinal mucosa of normal man and of patients with Whipple's disease were studied by light microscopy of 1-m-thick sections, and by electron microscopy of thin sections. IEL in normal human intestine tend to be elongated in outline, have few cytoplasmic organelles, have compact nuclei, and are unattached to epithelial cells. IEL in Whipple's disease are more likely to be activated in appearance, ie, to be larger and to contain more cytoplasmic organelles than IEL of normal intestine. The number of IEL/100 intestinal epithelial cells is similar in normal man and in patients with Whipple's disease. Other intraepithelial (IE) cells found in normal intestine include eosinophils and mast cells, and we note for the first time the presence of IE macrophages. There are no globule leukocytes in the intestine of normal man or of patients with Whipple's disease. Other IE cells found in the intestine in Whipple's disease include eosinophils, polymorphonuclear (PMN) leukocytes, and macrophages in untreated disease and intraepithelial macrophages in treated disease. These IE cells may be involved in the acute and chronic immune responses of the intestine.Supported by Merit Review Funding from Veterans Administration Central Office, Washington, D.C.     

Presence of Two Signaling TGF-β Receptors in Human Pancreatic Cancer Correlates with Advanced Tumor Stage

Transforming growth factor- (TGF-)signal transduction is mediated via specific cellsurface signaling TGF- receptors, most notably thetype I ALK5 (TR-I_ALK5)and the type II(TR-II). We evaluated TR-I_ALK5 andTR-II expression in 41 human pancreatic cancertissue samples and correlated these findings withclinical data of the patients. Northern blot analysisindicated that, in comparison with the normal pancreas,pancreatic adenocarcinomas exhibited 8.0-fold and4.5-fold increases (P < 0.01), respectively, in mRNAlevels encoding TR-I_ALK5 andTR-II. In situ hybridization showed that both TR-I_ALK5 mRNAwere highly expressed in the majority of pancreaticcancer cells. Immunohistochemical analysis ofTR-I_ALK5 and TR-II revealedpositive immunostaining in 73% and 56% of the tumors, respectively. Both receptorswere concomitantly present in 54% of the pancreaticcancer samples. The presence ofTR-I_ALK5 or TR-II and theconcomitant presence of TR-I_ALK5 and TR-II in the cancer cells was associatedwith advanced tumor stage (P < 0.01). These findingsshow that in many human pancreatic cancers, increasedlevels of the two signaling TRs are present. The presence of the signaling TRs inadvanced tumor stages indicates a role in diseaseprogression.     

Der Patient als Keimquelle in der Intensivpflegestation

Zusammenfassung 133 Patienten einer Intensivpflegestation, die bei der Aufnahme keine Symptome bakterieller Infektion zeigten und noch keine Antibiotika erhalten hatten, wurden nach dem Zufallsprinzip zwei Gruppen zugeordnet. Eine Gruppe (+Pat.) erhielt eine Antibiotikaprophylaxe mit Penicillinen oder Cephalosporinen, die zweite Gruppe (–Pat.) erhielt keine Antibiotika. Staph. aureus war bei –Pat. im Trachealsekret und in der Umgebung der häufigste potentiell pathogene Keim. Staph. aureus war im Trachealsekret und in der Umgebung der –Pat. signifikant häufiger als bei +Pat.. Klebsiella spp. standen im Trachealsekret und in der Umgebung von +Pat. an erster Stelle. Sie waren im Trachealsekret von +Pat. signifikant häufiger als bei –Pat.. In der ersten Woche des Stationsaufenthaltes traten bei +Pat. starke Veränderungen in der Keimflora der Trachealsekrete auf: die Besiedelung mit gramnegativen Keimen stieg auf fast 100% an, gleichzeitig ging die Frequenz von Staph. aureus zurück. In den Abklatschuntersuchungen aus der Patientenumgebung traten gramnegative Stäbchen bei +Pat. in signifikant höheren Koloniezahlen auf als bei –Pat.. Die paarweisen Vergleiche von Bakterienstämmen aus den Trachealsekreten und aus der Patientenumgebung ergaben, daß +Pat. gramnegative Keime und –Pat. Staph. aureus signifikant häufiger an die Umgebung abgaben. Auf die Kontamination der Patientenumgebung mit Staph. aureus wirkte sich der Faktor der trachealen Intubation nicht aus. Gramnegative Keime waren im Trachealsekret von intubierten Patienten signifikant häufiger als bei nicht intubierten. Derselbe Trend zeigte sich auch in der Patientenumgebung. Die Antibiotikaprophylaxe konnte, wie die klinischen Ergebnisse der Studie zeigten, die Patienten nicht im erwarteten Ausmaß vor Infektionen schützen. Patienten, insbesondere tracheal-intubierte, die Antibiotika erhalten, sind als Streuquellen für hochresistente gramnegative Keime anzusehen.

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The patient as a source of bacteria in intensive care units: Influence of antibiotics and tracheal intubation

Summary 133 patients in an intensive care unit, who prior to admission had not shown any signs of bacterial infection and had not received antibiotic treatment, were assigned to two groups at random. One group received antibiotic prophylaxis with penicillins or cephalosporins (+Pat.), the other group did not receive antibiotics (–Pat.). Staph. aureus was the most frequent facultative pathogen in tracheal secretions and in the environment of –Pat.. This organism was significantly more frequent in –Pat. than in +Pat. in both the tracheal secretions and the enviroment. Klebsiella spp. outnumbered all other species in +Pat.. They were significantly more frequent in tracheal secretions of +Pat. than of –Pat.. In the first week of hospitalisation marked changes were seen in bacterial flora of tracheal secretions of +Pat.. Colonization with gramnegative bacteria rose to nearly 100%, the frequency of Staph. aureus diminishing at the same time. Monitoring by contact cultures revealed that gramnegative rods were significantly more numerous in the environment of +Pat. than of –Pat.. Matching bacterial strains cultured from tracheal secretions and from the environment of the patients proved that +Pat. spread significantly higher numbers of their gramnegative bacteria into the environment. The same is true of –Pat. for Staph. aureus. Intubation had no noticeable effect on the degree of contamination of the surroundings with Staph. aureus. Gramnegative rods were significantly more frequent in tracheal secretions of patients with intubation than in patients without. The same trend was observed for environmental contamination. As the clinical results of this study have shown, antibiotic prophylaxis does not protect patients from infections to the extent expected. Patients, and particularly intubated patients, receiving antibiotic treatment have to be considered as sources of highly resistant gramnegative organisms.

     

Compound heterozygosity for a β∘-thalassemia (frameshift codons 38/39; -C) and a nondeletional swiss type of HPFH (A→C at NT -110, Gγ) in a Czechoslovakian family

Summary We have analyzed the levels and composition of the fetal hemoglobin (Hb F) in several members of a Czechoslovakian family with a heterozygosity for a newly discovered -thalassemia (codons 38/39; -C), or for a newly detected nondeletional hereditary persistence of fetal hemoglobin (a form of Swiss-HPFH with an AC mutation at nucleotide –100 5 to the Cap site of G), or with a compound heterozygosity for these two conditions. The Hb F level in the -thalassemia heterozygotes averaged 0.3% with low G values ( 28%) and relatively high AT values ( 50%), that in the two Swiss-HPFH heterozygotes averaged 0.8% with 95% G, while that of the compound heterozygote was 3.1% with 95% G. The low Hb F levels were determined with a recently published cation exchange high-performance liquid chromatography (HPLC) procedure that is accurate at the 0.1%–0.2% Hb F level [3]. This method, together with a reversed-phase HPLC procedure, made it possible to detect this unusual type of nondeletional G-HPFH and provided the data indicating that the increased Hb F in the compound heterozygote was derived mainly from the chromosome with the HPFH determinant.This study was supported in part by USPHS Research Grant HLB-41544     

Improved parameters of lactose maldigestion using lactulose

Lactulose is a disaccharide derived from lactose. There has been recent rekindling of interest in the possible benefits of pro- and prebiotics: mainly, lactic acid-producing bacteria and lactulose for the lower intestine. Since lactose maldigestion is a common genetic trait, we undertook this study to delineate similar effects between these two disaccharides. Nine healthy lactose maldigesting subjects underwent two separate periods of three weeks adaptation, first with 10 g twice daily lactulose and then 1.5 g twice daily lactose (in milk). Adaptation was defined by reduced breath Hydrogen (BH₂) and symptoms after 50 g lactose challenges. In six subjects fecal -galactosidase was measured. All subjects consumed some lactose daily. In the first period, eight subjects improved symptoms and reduced BH₂ significantly, while in the second period they did not. Fecal -galactosidase significantly increased after lactulose. This study supports the notion that lactulose and lactose may have similar clinical effects.     

Effect of α-methylnorepinephrine,an α2-adrenergic agonist,on jejunal absorption in neurally intact conscious dog

Although ₂-adrenergic agonists stimulate absorption in the mammalian small and large intestinein vitro, the possibility of central neural effects have confounded interpretation ofin vivo studies. Our aim was to assess the effects of intravenous administration of -methylnorepinephrine (MNE), and ₂-adrenergic agonist that does not cross the blood-brain barrier, on net jejunal absorption of water and electrolytes in the neurally intact, conscious dog. Absorption from a 30-cm proximal jejunal segment was studied using a triple-lumen perfusion technique in seven dogs. A warmed, isosmolar, balanced electrolyte solution containing [¹⁴C]polyethylene glycol was infused at 5 ml/min. Net jejunal fluxes of water and electrolytes were determined before, during, and after a 1.5-hr infusion of MNE (900 nmol/kg/hr). MNE increased net jejunal water absorption (from 12.9±1.8 to 22.5±1.5 l/cm/min,P<0.05). Peripheral ₂-adrenergic receptors mediate a net proabsorptive response in the neurally intact canine jejunumin vivo independent of direct central neural effects.Parts of this work were published as an abstract inGastroenterology (100:A689, 1991). Supported in part by the United States Surgical Corporation, a grant provided by Harry S. Tan, and USPHS NIH grant DK39337 (M.G.S.).     

Macrophages enhance binding of beta-VLDL and cholesterol ester accumulation in cultured aortic smooth muscle cells

Summary The effect of macrophages on the uptake of -very low-density lipoprotein (-VLDL) by smooth muscle cells (SMC) expressing different morphological phenotypes was examined in culture. The SMC were grown alone and in co-culture with macrophages for four days, then incubated with different concentrations of¹²⁵I--VLDL for 3 h at 4°C or with 75 ug/ml -VLDL for 24h at 37°C. The binding of -VLDL to SMC at 4°C was enhanced in the presence of macrophages irrespective of the phenotype expressed by SMC. This occurred through modification of the lipoprotein, since binding of re-isolated macrophage-conditioned -VLDL to SMC was 12.5 times that of fresh -VLDL. This modified form of -VLDL competed with fresh -VLDL for binding to SMC. Binding was inhibited in the presence of probucol, suggesting that an oxidative mechanism may be involved.The presence of macrophages also enhanced the accumulation of -VLDL-derived cholesterol in SMC. While most of this is a consequence of the enhanced binding, macrophages may also act directly on SMC to increase cholesterol accumulation, since the activity of acid cholesterol ester hydrolase and neutral cholesterol ester hydrolase in SMC was reduced in the presence of macrophages.     

Estrogen receptor beta (ERβ) is expressed in brain astrocytic tumors and declines with dedifferentiation of the neoplasm

Purpose Estrogen receptor (ER) is the second identified receptor mediating the effects of estrogen on target tissues. The role of ER in cancer pathobiology is largely unknown, because specific antibodies have not been available until recently. Initial studies have shown that ER expression declines in breast, ovarian, prostatic, and colon carcinomas. Tamoxifen, a synthetic anti-estrogen compound that is a mixed agonist/antagonist of estrogen receptor (ER) and a pure antagonist of ER, has moderate beneficial effects in human astrocytic neoplasms. However, most published studies agree that glial tumors do not express ER. The purpose of this study was to explore the expression of ER in astrocytic neoplasms.Methods ER expression was monitored immunohistochemically in 56 cases of astrocytomas of all grades (grade I–IV) and in adjacent non-neoplastic brain tissue.Results Moderate or strong nuclear immunopositivity was obtained in non-neoplastic astrocytes and in low-grade astrocytomas, whereas the majority of high-grade tumors were immunonegative or displayed weak immunoreactivity. The progressive decline in ER expression paralleled the increase in tumor grade.Conclusions In as much as ER is possibly the only ER expressed in astrocytes, its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.     

Prospective and randomized study of the antihypertensive effect and tolerability of three antihypertensive agents,losartan, amlodipine,and lisinopril,in hypertensive patients

We prospectively evaluated the antihypertensive effect and tolerability of three different antihypertensive agents, losartan (angiotensin II receptor blocker), amlodipine (calcium channel blocker), and lisinopril (angiotensin-coverting enzyme inhibitor), in patients with mild-to-moderate hypertension. After a 2-week washout period, 121 patients were randomly allocated to three different groups for 12 weeks. Medications were titrated upward as necessary to achieve the goal office-recorded sitting diastolic blood pressure (SiDBP) (defined as SiDBP 90mmHg or SiDBP 900mmHg but with a 10mmHg drop from baseline). Efficacy and tolerability were assessed after 4, 8, and 12 weeks of therapy with each regimen. At 12 weeks, significant differences in SiDBP compared with data of baseline were noted in all three groups (P 0.001 in all comparisons). Similarly, significant differences in the sitting systolic blood pressure compared with baseline data were also seen for all three groups (P 0.001 in all comparisons). The number of patients reaching goal SiDBP were comparable for the three groups: 25 patients (62.5%) in the losartan group, 27 patients (67.5%) in the amlodipine group, and 22 patients (59.5%) in the lisinopril group (not significant). Amlodipine produced a more pronounced reduction in SiDBP than the other two medications, although without statistical significance. Patients receiving lisinopril showed a high incidence of coughing (31.7%). Low leg edema was noted only in the amlodipine group (7.5%). Compared with the amlodipine and lisinopril groups, the losartan group seemed to have relatively fewer episodes (7.5%), and fewer patients (three cases) experienced adverse effects. In conclusion, this study demonstrates that losartan has the same antihypertensive effect, but has superior tolerability compared with the other two drugs. Coughing was a common side effect of lisinopril therapy in our population.     

Renal proteinases and kidney hypertrophy in experimental diabetes

Summary IDDM is associated with an increase in kidney size, which is due to cellular hypertrophy and progressive matrix accumulation within the glomerulus and throughout the tubulointerstitium. The present study addressed the potential role of cysteine and metalloproteinases in renal hypertrophy of short-term diabetes. Three weeks after induction of streptozotocin diabetes in rats, intraglomerular gelatinase activity (streptozotocin: 23±4 vs control: 44±3 mU/g DNA) and cathepsin L + B activity (streptozotocin: 6.7±0.8 vs control: 9.3±0.7 U/g DNA) were significantly decreased. Insulin treatment completely prevented the decline in glomerular proteinase activity (gelatinase: 37±6 mU/g DNA; cathepsin L + B: 9.6±0.9 U/g DNA). In isolated proximal tubules a similar pattern of enzyme activity could be observed. Three weeks of diabetes caused a significant decline in cathepsin L + B activity (streptozotocin: 28±2 vs control: 37±3 U/g DNA). Insulin treatment again prevented the decline in these tubular proteinase activities. In parallel, kidney weight increased by 22% and glomerular protein/DNA ratio rose by 17% in untreated diabetic rats. Diabetic rats receiving insulin displayed a normal glomerular protein/DNA ratio and the kidney weight was increased by only 5%. These results show that renal hypertrophy of early diabetes is closely associated with a decline in both glomerular and tubular proteinase activity. Adequate insulin substitution prevented renal hypertrophy and the reduction in proteinase activity.Abbreviations AMC 7-Amino-4-methyl coumarin - EDTA ethylene diamine tetra-acetic acid - PMSF phenylmethylsulfonyl fluoride - TGF- transforming growth factor- - TIMP tissue inhibitor of metalloproteinases - GFR glomerular filtration rate - IDDM insulin-dependent diabetes mellitus     

Hypertrophic osteoarthropathy: Endothelium and platelet function

Summary Hypertrophic osteoarthropathy (HOA) is characterized by finger clubbing, periostosis and arthritis. The pathogenesis of hypertrophic osteoarthropathy is still uncertain. Earlier studies have been focused on the potential role of platelet and endothelium in the pathogenesis of HOA.The aim of this study was to evaluate the circulating levels of endothelin-1 (ET-1), -thromboglobulin (-TG) and platelet-derived growth factor (PDGF) in 21 HOA patients.The circulating levels of ET-1, -TG were significantly higher in HOA patients vs healthy controls, but not vs controls with lung diseases. On the contrary, PDGF was significantly higher in HOA patients vs healthy controls and vs subjects with lung diseases.These findings suggest that endothelium/platelet unit may play a role in the pathogenesis of HOA, and PDGF could induce the changes observed in HOA.     

Untersuchungen mit Phytoagglutininen bei Inzuchthühnern

Zusammenfassung Es wurde in einem Inzuchtstamm von rebhuhnfarbigen Italienern durch drei Generationen der Hi-Faktor mit sechs selbst hergestellten Phytoagglutininen untersucht. Das Vorhandensein des Hi-Antigens konnte bestätigt werden. Seine natürliche Nachweisbarkeit beschränkte sich auf weibliche Tiere. Das vorliegende Gen HI, das dominant vererbt wird, konnte bei beiden Geschlechtern und allen Altersstufen bei Vorhandensein des weiblichen Geschlechtshormons (Östrogen) nachgewiesen werden.

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Summary The Hi-factor was studied with six self-produced phytoagglutinins in an inbred strain of partridge coloured Italiens through three generations. The presence of Hi-antigen could be confirmed. It can only be demonstrated in female animals. The HI gen, which is inherited in a dominant manner, could be demonstrated in both sexes and at all ages in the presence of female sex hormone (estrogen).

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Die Arbeiten wurden mit Mitteln der Deutschen Forschungsgemeinschaft durchgeführt.     

The Ovarian Androgen-Producing Cells: A 2001 Perspective

The androgen-producing cells in the postnatal mammalian ovary are located in the interstitial compartment of the ovary. The most important types of androgen-producing interstitial cells are the cells in the theca interna and the cells of the secondary interstitial glands. There has been some confusion in recent years regarding the terminology used to describe the ovarian androgen-producing cells, namely that theca-interstitial cells are somehow different from theca cells. In fact, these are the same cells. The name theca-interstitial was used by Erickson et al. [1] to describe the theca cells as one of the four androgen-producing cell types in the interstitial compartment of the ovary along with primary interstitial cells which are present only during embryonic development, secondary interstitial gland cells, and steroidogenic cells located in the hilar region of the ovary. For the sake of clarity and according to current convention, the term theca cell will be used throughout this review to refer to cells in the theca interna of the ovarian follicle.     

Acid rereflux: a review,emphasizing detection by impedance,manometry, and scintigraphy,and the impact on acid clearing pathophysiology as well as interpreting the pH record

Acid clearing, the interval while intraesophageal pH is <4 after a traditional acid reflux event (RE), is a potential blind spot during pH monitoring, when reflux of acidified gastric contents may occur undetected by the pH probe. This is termed acid rereflux. Acid rereflux comprised 61% (169/262) of acid REs in recumbent postprandial patients with severe GERD in two reports using simultaneous pH monitoring and manometry as well as multichannel intraluminal impedance (MII) in one, and scintigraphy in the other. Acid rereflux events often recurred with short intervals between them. The pH probe alone was insufficient to detect most acid rereflux REs, since expanding pH criteria for an acid RE (>1 unit fall while pH < 4) detected only 35% of acid rereflux REs. When a variety of patients and study conditions was examined, simultaneous manometry–pH monitoring found more frequent acid rereflux in the following situations: (1) patients with vs those without esophagitis; (2) recumbent vs upright posture, and (3) postprandial vs preprandial. Of pathophysiologic importance, acid rereflux in the blind spot is the most common cause of prolonged daytime acid REs in GERD patients. Of clinical importance, the 24-hr pH parameter % acid exposure should be relied upon most in interpreting the 24-hr pH record, because those parameters that relate to RE frequency may be inaccurate due to acid rereflux REs that are not counted. Furthermore, identifying as many REs as possible gives a more reliable indication of the severity of antireflux barrier incompetence, as well as more REs to correlate with patients symptoms that should improve sensitivity of the symptom index. Ambulatory simultaneous pH monitoring and MII will allow these and other roles for acid rereflux to be assessed during the patients normal day.     

Efficacy and Tolerability of the Long-Acting Somatostatin Analog Lanreotide in Acromegaly. A 12-Month Multicenter Study of 58 Acromegalic Patients

Objective: To determine the effects of the new somatostatin analogue, lanreotide, in its prolonged released form (PR), in patients with acromegaly.Design: Prospective open multicenter non comparative study.Setting: Thirty-three university-affiliated medical centers.Patients: One hundred sixteen acromegalic patients with active disease, of whom 58 patients complied with the protocol and completed the 12-month period treatment.Intervention: Lanreotide PR treatment was started at a dose of 30 mg intramuscularly every 14 days. If integrated mean plasma GH levels were not below 5 g/L and/or IGF-I levels were not normalized after one month of treatment, injections were given every 10 days. The duration of the study was 12 months.Results: After one month of treatment mean plasma GH and IGF-I levels had fallen from 10.7 ± 11.1 g/L (mean ± SD; range, 2.6 – 74.8 g/L; median, 7 g/L) and 718 ± 270 g/L (range 338 – 1440 g/L; median, 645 g/L), respectively, to 7.8 ± 10.1 g/L and 575 ± 252 g/L, respectively. Thirty patients (22%) had plasma GH levels below 2.5 g/L, and 8 patients (16%) had age-adjusted normal plasma IGF-I levels. At the sixth month of treatment mean plasma GH levels of 2.5 g/L or less, and normal plasma IGF-I levels were observed in 33%, and 33% of patients, respectively. At the twelvth month of treatment, these percentages were 41%, and 41%, respectively. The interval between two injections was shortened (one injection every 10 days) in 8 of the 58 patients (13%) at the second month of treatment, and at the end of the study, 70% of patients required 3 injections per month. The most frequent adverse event elicited by enquiry was transient diarrhea (76% of patients), followed by abdominal pain (62%) and pain at the injection site (59%). Based on the analysis of a subgroup of 46 patients who had at least a measurement of fecal fat content after day 0 of the study, a non significant increase (from 4.2 ± 3.4 to 5.1 ± 4.3 g/24h, p = 0.3) in mean steatorrhea was observed during treatment. Before treatment, steatorrhea was present in 9 (19%) patients. During the study, 15 additional patients (32%) developed persistent steatorrhea, and there was a transient increase in fecal fat content above 6 g/24 h in another 11 patients. After exclusion of the 7 patients (12%) with gallstones at enrolment, new gallstones were diagnosed in 6 out of 50 patients (12%) during the study.Conclusion: Two or three monthly injections of lanreotide PR decreased GH concentration to less than 2.5 g/L and normalized IGF-I levels in 41% of patients treated during 12 months. The good tolerability of this treatment, and the reduction in the frequency of injections, plus the sustained drug serum concentrations, confirm the usefulness of this new somatostatin analog formulation.     

The Physical Conditions of Different Organs Are Reflected Specifically in the Pressure Pulse Spectrum of the Peripheral Artery

We try to solve the hemodynamic inverse problem of the internal organs in terms of the peripheral pressure pulse spectrum analysis. Side-branch organs are approximated as resonators with own natural frequencies. They are depicted not as ordinary reflection sites but as antennas that receive energy from the main artery and undergo forced oscillations with selective frequencies. Every organ also reacts back to the main artery as a secondary small heart source that generated harmonic forces with maximum amplitude near its own natural frequency. The whole arterial system is in a steady distributed oscillatory state that is the superposition result of encountering the forces generated by the heart and many internal organs. A frequency matching theory of the organ and the main artery is proposed. The Fourier components of the pressure pulse in the arterial system are related to the matching conditions of different organs. In vivo studies in kidney and spleen of rats are provided.     

Effects of ischemia, preconditioning, and adenosine deaminase inhibition on interstitial adenosine levels and infarct size

In order to examine the relationship between local adenosine concentrations before, during, and after ischemia and the extent of ischemic myocardial damage, measurements of interstitial fluid (ISF) nucleosides were made using microdialysis probes implanted in the ischemic region of isoflurane anesthetized Micropigs undergoing 60 coronary artery occlusion (CAO) and 3h of reperfusion (REP). Nucleoside concentrations in the dialysate collected from the microdialysis probes were used as an index of ISF levels. Dialysate nucleoside concentrations (ADO, inosine and hypoxanthine), myocardial infarct size, and myocardial blood flow (MBF) were determined in control animals (n=6), animals preconditioned with a single 10 cycle of CAO and REP (PC, n=6), and those treated with the adenosine deaminase inhibitor pentostatin (n=6, 0.2 mg/Kg IV 30 prior to CAO). The brief PC occlusion resulted in a transient but significant increase in dialysate ADO (6.7±1.8 M vs. 0.67±0.1 M at baseline). Pentostatin administration had no significant effect on either dialysate nucleosides or MBF at baseline. During the 60 CAO, dialystate ADO increased in control animals. In PC animals, however, dialysate ADO during CAO was lower than control. Pretreatment with pentostatin resulted in a six-fold augmentation in dialysate ADO during the 60 min CAO when compared to the control values (110.62±30.2 M vs. 16.31±2.1 M at 60 min of ischemia). Pentostatin also resulted in a significant reduction in the accumulation of inosine and hypoxanthine, indicating inhibition of adenosine deaminase activity. There were no significant differences in MBF between groups at any time point. Following 3 h REP, infarct size was 35.4±5.5%, 8.1±1.5% and 8.3±1.8% of the region at control, PC, and pentostatin groups, respectively. These data suggest that marked increase in ISF ADO during CAO, may be as effective in reducing INF as a modest increase in ISF ADO prior to prolonged CAO.Supported in part by NIH grant R01 HL32043