Comorbidity in acute pancreatitis relates to organ failure but not to local complications.

OBJECTIVE: Organ failure and local complications contribute to morbidity and mortality in acute pancreatitis. Comorbidity is known to be related to organ failure. The impact of comorbidity on local complications has not yet been delineated. Moreover, it is not clear if the outcome of first-attacks and acute-on-chronic episodes, respectively, differs from outcome in all episodes. METHODS: Consecutive cases of confirmed acute pancreatitis in a four-year period were reviewed. Charlson comorbidity index (CCI), complications (organ failure and local complications), disease severity (according to the revised Atlanta Classification), need for intensive care, and mortality were derived from the charts. RESULTS: A total of 391 episodes of acute pancreatitis were included. Patients with organ failure were significantly older (P< 0.001) und had a higher CCI (P< 0.001) than patients without organ failure. Patients with and without local complications did not significantly differ in age or CCI. The complication rate of the entire cohort (n = 391; 47.1 %) was comparable with the complication rate of first-attacks (n = 269; 46.8 %) and acute-on-chronic episodes (n = 68; 47.1 %). The majority of the twelve deceased patients had been old and/or chronically ill. Six of these patients had an advanced malignant disease. CONCLUSIONS: Comorbidity and age clearly are contributors to organ failure and mortality. Local complications occur independently of age and concomitant diseases. The overall complication rate is not significantly influenced by preceding inflammation of the pancreas. To further improve care in patients with acute pancreatitis special attention should be given to old and multi-morbid patients.

Intranasal application of the melanocortin 4 receptor agonist MSH/ACTH(4-10) in humans causes lipolysis in white adipose tissue.

OBJECTIVE: The melanocortin system has a highly significant role in the hypothalamic regulation of body weight and energy expenditure. In animals, intracerebroventricular infusion of melanocortin receptor 4 (MCR-4) agonists increases basal metabolic rate through activation of the sympathetic nervous system and subsequently reduces food intake. In humans, direct access of MCR-4 agonists to the central nervous system can be achieved by a transnasal route, which leads to weight loss with chronic administration. In the present study, we aimed at investigating the effects of intranasally administered MC4-R agonist MSH/ACTH(4-10) on lipolysis and sympathetic nervous system activity in healthy humans. DESIGN: Healthy normal weight, male volunteers (n=10) received either 10 mg MSH/ACTH(4-10) or placebo intranasally in a double-blinded randomized crossover design. Interstitial glycerol release was assessed by microdialysis in abdominal white adipose tissue (WAT) and in skeletal muscle (SM) of the forearm. Local blood flow, systemic blood pressure, heart rate and muscle sympathetic nerve activity (MSNA) within the superficial peroneal nerve were recorded at rest and after nitroprusside infusion. RESULTS: At 45 min after MSH/ACTH(4-10) administration WAT glycerol concentrations increased by 53.4±19.3% compared with baseline conditions (P<0.05) and remained significantly higher throughout the experiment when compared with placebo (P<0.05) while local glycerol release in SM was not significantly affected. Resting MSNA was not altered by MSH/ACTH(4-10) administration; however, sympathoexcitation by intravenous nitroprusside was markedly elevated (MSH/ACTH(4-10) 569±69% increase to baseline; placebo: 315±64%; P<0.01). CONCLUSION: Intranasally administered MCR-4 agonist MSH/ACTH 4-10 increases both subcutaneous WAT lipolysis and MSNA, which suggests a direct central nervous peptide effect in humans on key factors of human energy metabolism.

MIS approach for diverticula of the esophagus.

PURPOSE: diverticula of the esophagus represent a rare pathological entity. Distinct classifications of the disease imply different surgical concepts. Surgery should be reserved for symptomatic patients only. Minimally invasive surgery (MIS) for treatment of esophageal diverticula encompasses rigid and flexible intraluminal endoscopy, thoracoscopy and laparoscopy. We here give an overview on the pathogenesis of esophageal diverticula, the minimally invasive surgical techniques for treatment and the recent literature. Additionally, we present our own experience with MIS for midthoracic diverticula. METHODS: we analyzed the cases of patients who underwent MIS for midthoracic diverticula with regard to preoperative symptoms, perioperative and follow-up data. RESULTS: three patients (two female, one male, age 79, 78 and 59 years) received thoracoscopic surgery for midthoracic diverticula. All patients reported of dysphagia and regurgitation. In two patients pH-investigation showed pathological reflux but manometry was normal in all patients. Operating time was 205, 135 and 141 minutes. We performed intraoperative intraluminal endoscopy in all patients. There were no intraoperative complications and although no surgical complications occured postoperatively one patient developed pneumonia which advanced to sepsis and lethal multi organ failure. Upon follow-up the two patients did not have recurrent diverticula or a recurrence of previous symptoms. CONCLUSIONS: surgery for diverticular disease of the esophagus has been associated with high rates of morbidity and mortality. Despite the lethal non-surgical complication we encountered, with regard to recent publications minimally invasive apporaches to treat patients with symptomatic esophageal diverticula entail lower rates of complications with better long term results in comparison to open surgery.

Synthesis of kininogen and degradation of bradykinin by PC12 cells.

1. In this study, the abilities of PC12 cells to synthesize and degrade kinins were investigated. Kinin formation was assessed as kinin and kininogen content of cells and supernatants in serum-free incubations by use of a bradykinin-specific radioimmunoassay. Expression of kininogen mRNA was demonstrated by reverse-transcriptase PCR. Kinin degradation pathways of intact PC12 cells were characterized by identification of the kinin fragments generated from tritiated bradykinin either in the absence or presence of the angiotensin I-converting enzyme inhibitor ramiprilat. 2. Kinin immunoreactivity in the supernatant of PC12 cell cultures accumulated in a time-dependent fashion during incubations in serum-free media. This effect was solely due to de novo synthesis and release of kininogen (35 pg bradykinin h-1 mg-1 protein) since it could be suppressed by cycloheximide. Continuous synthesis of kininogen was a specific property of PC12 cells, as it was not observed in cultured macro- or microvascular endothelial cells. PC12 cells contained only minor amounts of stored kininogen. The rate of kininogen synthesis was not affected by ramiprilat, bacterial lipopolysaccharide, nerve growth factor or dexamethasone, but was stimulated 1.4 fold when cells were pretreated for 1 day with 1 microM desoxycorticosterone. 3. By use of cDNA probes specific for kininogen subtype mRNAs, expression of low-molecular-weight kininogen and T-kininogen in PC12 cells was confirmed. Expression of high molecular weight kininogen mRNA was also shown, though only at the lowest limit of detection of the assay. 4. Degradation of tritiated bradykinin by PC12 cells occurred with a half-life of 48 min resulting in the main fragments [1-7]- and [1-5]-bradykinin. The degradation rate of bradykinin decreased to 15% in the presence of ramiprilat (250 nM). Apart from angiotensin I-converting enzyme direct cleavage of bradykinin to [1-7]- and [1-5]-bradykinin still occurred under this condition as a result of additional kininase activities. 5. Along with previous findings of B2-receptor-mediated catecholamine release, these results now confirm the hypothesis that a cellular kinin system is expressed in PC12 cells. The presence of such a system may reflect a role of kinins as local neuromodulatory mediators in the peripheral sympathetic system.

Intravascular and interstitial degradation of bradykinin in isolated perfused rat heart.

1. Bradykinin (BK) has been shown to exert cardioprotective effects which are potentiated by inhibitors of angiotensin I-converting enzyme (ACE). In order to clarify the significance of ACE within the whole spectrum of myocardial kininases we investigated BK degradation in the isolated rat heart. 2. Tritiated BK (3H-BK) or unlabelled BK was either repeatedly perfused through the heart, or applied as an intracoronary bolus allowing determination of its elution kinetics. BK metabolites were analysed by HPLC. Kininases were identified by ramiprilat, phosphoramidon, diprotin A and 2-mercaptoethanol or apstatin as specific inhibitors of ACE, neutral endopeptidase 24.11 (NEP), dipeptidylaminopeptidase IV and aminopeptidase P (APP), respectively. 3. In sequential perfusion passages, 3H-BK concentrations in the perfusate decreased by 39% during each passage. Ramiprilat reduced the rate of 3H-BK breakdown by 54% and nearly abolished [1-5]-BK generation. The ramiprilat-resistant kininase activity was for the most part inhibited by the selective APP inhibitor apstatin (IC50 0.9 microM). BK cleavage by APP yielded the intermediate product [2-9]-BK, which was rapidly metabolized to [4-9]-BK by dipeptidylaminopeptidase IV. 4. After bolus injection of 3H-BK, 10% of the applied radioactivity were protractedly eluted, indicating the distribution of this fraction into the myocardial interstitium. In samples of such interstitial perfusate fractions, 3H-BK was extensively (by 92%) degraded, essentially by ACE and APP. The ramiprilat- and mercaptoethanol-resistant fraction of interstitial kininase activity amounted to 14%, about half of which could be attributed to NEP. Only the product of NEP, [1-7]-BK, was continuously generated during the presence of 3H-BK in the interstitium. 5. ACE and APP are located at the endothelium and represent the predominant kininases of rat myocardium. Both enzymes form a metabolic barrier for the extravasated fraction of BK. Thus, only interstitial, but not intravascular concentrations of BK are increased by kininase inhibitors to the extent that a significant potentiation of BK effects could be explained. NEP contributes less than 5% to the total kininase activity, but is the only enzyme which is exclusively present in the interstitial space.

Clinical trial: cyclophosphamide pulse therapy - a promising therapeutic alternative in refractory Crohn's disease.

BACKGROUND: In severe steroid-refractory Crohn's disease (CD), established therapies fail in a relevant proportion of patients. Recent pilot studies indicated the efficacy of cyclophosphamide pulse therapy in these patients. AIM: To provide further and substantial evidence for the rationale to apply cyclophosphamide pulse therapy as therapeutic option in severe courses of CD. METHODS: Fifteen patients with steroid-refractory (n = 13) or steroid-dependent (n = 2) CD received 2-6 (median 3) monthly pulses of 750 mg cyclophosphamide in an open-label fashion. Eleven patients were on concomitant immunosuppression (azathioprine/mercaptopurine n = 9; methotrexate n = 2). RESULTS: Thirteen of 15 patients (87%) had a clinical response (CDAI decrease >100). Ten patients (67%) went into remission (CDAI <150) after 8 weeks. Steroid-free remission was achieved in eight patients (54%). Two patients (13%) failed to respond. Median CDAI decreased from 420 (245-550) to 100 (26-538) at week 8. Remission lasted 16 months (median, range 4-40). In three patients, arthritis, erythema nodosum and episcleritis completely resolved. Cyclophosphamide pulse therapy administration was well tolerated in all subjects. CONCLUSIONS: Cyclophosphamide pulse therapy is safe and highly effective for induction and maintenance of remission in steroid-refractory/-dependent CD. There is a strong need for additional experience to improve the setting of the encouraging cyclophosphamide treatment in CD.

In vivo effects of corticotropin-releasing hormone on femoral adipose tissue metabolism in women.

OBJECTIVE: To investigate whether i.v. injected corticotropin-releasing hormone (CRH) (1 microg/kg) has a direct effect on adipose tissue metabolism in humans. DESIGN: Double-blinded, placebo-controlled, crossover study. SUBJECTS: Twelve healthy normal weight female volunteers (age 20-37 years, body mass index: 22.75+/-1.33 kg/m(2)) MEASUREMENTS: Assessment of local generation of glycerol, and glucose in adipose tissue by microdialysis. Measurement of adipose tissue and skin blood flow by laser Doppler flowmetry. RESULTS: Injection of CRH acutely increases interstitial concentrations of glycerol (19.0+/-5.4%, P<0.05) and glucose (13.5+/-5.8%, P<0.05) reaching peak levels after 15 min. Plasma glycerol increases in parallel (Delta=16.7+/-5.9% after 15 min (P<0.05)), whereas plasma glucose remains unaffected. Changes in tissue blood flow do not explain interstitial metabolite alterations. Initial CRH effects on adipose tissue metabolism are short lasting and disappear after 15 min. CONCLUSIONS: The importance of CRH on human energy metabolism is underlined by the present in vivo study demonstrating peptidergic effects on lipolysis and glucose homeostasis in human subcutaneous adipose tissue.

Laser-Doppler flowmetry reveals rapid perfusion changes in adipose tissue of lean and obese females.

The present study aimed to evaluate adipose tissue blood flow (ATBF) by means of laser-Doppler flowmetry (LDF) in humans. Lower body negative pressure (LBNP) and straining known to affect epidermal blood flow through the autonomic nervous system were performed in 11 lean and 11 obese female volunteers. ATBF changes were compared between both groups and also discriminated from skin blood flow (SBF) responses of the immediate vicinity. Additionally, LDF measurements were compared with flow measurements using (133)xenon washout in 10 lean subjects during whole body cooling. LDF estimations of SBF and ATBF showed a positive correlation to (133)Xe during cooling. SBF and ATBF were reduced to the same extent in both lean and obese subjects during LBNP. Straining induced divergent changes in SBF and ATBF: initially SBF decreased while ATBF increased, but toward the end of straining SBF increased above baseline and ATBF returned down to baseline level. Those changes were similar in both weight groups. Interestingly, only in obese subjects, both LBNP and straining were followed by ATBF augmentation, while SBF levels remained stable. In conclusion, LDF compares with (133)Xe washout in monitoring ATBF during tonic perfusion changes. Its strength, however, lies in the detection of rapid flow alterations within the subcutaneous tissue, allowing the evaluation of reflex responses of the subcutaneous microcirculation. Interestingly, those rapid changes in SBF and ATBF can be both concordant and discordant. With regard to ATBF, vasoconstrictor components of the reflex responses were similar in lean and obese subjects, whereas vasodilatory responses were more pronounced in obese volunteers.