Physical laws of cholesterol gallstone fragmentation

Efficient fragmentation is the most important prerequisite for successful treatment of gallstones by extracorporeally induced shock waves. No data are available on the amount of energy necessary for stone disintegration and on the threshold energy below which no further fragmentation occurs. We therefore performed an in vitro investigation on human cholesterol gallstones to elucidate physical laws governing shock-wave lithotripsy. First, the focal pressure of the lithotripter was measured to calculate the energy traversing a stone. Second, 96 gallstones from 16 gall bladders were analysed with respect to physicochemical composition, radiological features and ultrasound before fragmentation was performed. Energy for stone disintegration was constant within each stone family but varied between 4.6 J mL^?1 and 36.8 J mL^?1 in different families. This energy correlated linearly with stone volume. None of the radiological and physicochemical factors revealed a clear-cut correlation of the different energies necessary for similar stone disintegration. The threshold energy differed between 0.26 mJ and 1.04 mJ per pulse. In conclusion, stone volume was the best parameter predicting stone fragmentation. However, in cholesterol stones with a similar composition the required energy per volume varies considerably together with the threshold energy. Radiological and ultrasound parameters appear to be of minor importance in explaining these differences.     

Inadequate Erythropoietin Response to Anaemia in HIV Patients: Relationship to Serum Levels of Tumour Necrosis Factor-Alpha, Interleukin-6 and Their Soluble receptors

Severe anaemia is a frequent complication in advanced HIV infection. In our study we investigated the interaction between cytokine network, HIV infection and erythropoietin (Epo) response with increasing anaemia levels. No correlations could be established between circulating tumour necrosis factor (TNF)-alpha and any of the examined parameters. However, a negative correlation was found between haemoglobin values and soluble TNF receptor levels (sTNF-R-I: r  = −0.54; P  < 0.001; sTNF-R II: r  = −0.47; P  < 0.001) as well as interleukin-6 levels ( r  = −0.29; P  < 0.001). In contrast, no significant increase in log[Epo], counterbalancing haemoglobin decline and paralleling the rise in sTNF receptors, was found. In patients classified as stage III, according to the Centers for Disease Control (CDC) classification, the erythropoietin response was significantly more impaired than in patients from CDC groups I and II ( P  < 0.001). The results of this study suggest that similar to its action in vitro , activation of the TNF/TNF-R system may impair erythropoietin production in HIV-associated anaemia. Due to the brief half-life of TNF-α, this activation is particularly reflected by elevations of soluble TNF receptor levels.     

Effect of oral pancreatic enzyme administration on digestive function in healthy subjects: comparison between two enzyme preparations

Background : Intraduodenal proteases exert a negative feedback on pancreatic secretion.
Aim : To investigate the effect of two pancreatic enzyme preparations (enteric-coated tablets, and capsules with enteric-coated microtablets) on postprandial pancreatic and bile acid secretion, gastroduodenal motility and release of gastrin and pancreatic polypeptide in healthy humans.
Methods : Twenty healthy males were studied on two different days one week apart. After an overnight fast a nine-lumen motility tube was positioned with the distal tip at the Treitz angle. On each study day, 30 min after an interdigestive migrating motor complex-phase III, a semi-liquid test meal was given either alone ( n =20) or with enzymes (3 tablets ( n =10) or 2 capsules with microtablets ( n =10); 40000 U lipase and 2000 proteases) in a randomized order, and the study continued over 2 h. Motility was continuously recorded with four ports in the antrum and three in the duodenum, using a low-compliance pneumohydraulic perfusion system. Secretion of human-specific pancreatic elastase and bile acids was measured by a standard duodenal intubation perfusion technique. Plasma concentrations of gastrin and pancreatic polypeptide were measured by specific radioimmunoassays.
Results : Postprandial pancreatic secretion was significantly reduced by administration of microtablets (median 82 mg/2 h vs. 70 mg/2 h, P <0.02) but not by tablets (median 59 mg/2 h vs. 58 mg/2 h, N.S.). No changes were observed in bile acid secretion, antroduodenal motility or release of gastrin and pancreatic polypeptide.
Conclusions : Oral administration of pancreatic enzymes at normal therapeutic doses significantly inhibits postprandial pancreatic secretion in healthy humans, when capsules with enteric-coated microtablets are given. Exogenous pancreatic enzymes have no significant effect on bile acid secretion, gastroduodenal motility and hormone release.     

Correlation of transient elastography with APRI and FIB‐4 in a cohort of patients with congenital bleeding disorders and HCV or HIV/HCV coinfection

Summary. Patients with inherited bleeding disorders frequently suffer from chronic hepatitis C virus (HCV) mono‐ or human immunodeficiency virus (HIV)/HCV coinfection. Non‐invasive markers for liver fibrosis are warranted for these patients. We tested a large cohort of haemophilic patients with HCV mono‐ or HIV/HCV coinfection for correlation of transient elastography (TE) with two simple surrogate markers of liver fibrosis and for differences in fibrosis stages according to these markers. We prospectively enrolled HCV‐positive patients with congenital bleeding disorders with or without HIV coinfection. Liver function tests and platelet counts were determined and TE was performed. Aspartate aminotransferase‐to‐platelet ratio index (APRI) and a simple index called FIB‐4 were calculated and results were correlated with TE. A total number of 174 patients were included (23% HCV, 36% HIV/HCV coinfected, 33% with cleared HCV and 8% with ongoing HIV but cleared HCV). TE correlated significantly with APRI and FIB‐4 (r = 0.60; P < 0.001 and r = 0.54; P < 0.001 respectively). This correlation was pronounced in patients with ongoing HCV infection (r = 0.67; P < 0.001 and r = 0.60; P < 0.001). Prediction of advanced fibrosis resulted in concordance rates >80% with combinations of TE plus APRI and APRI plus FIB‐4. HIV/HCV coinfected patients did not present with advanced fibrosis stages when compared with HCV‐monoinfected patients. Combinations of two non‐invasive markers may significantly reduce the number of liver biopsies in patients with bleeding disorders and advanced liver fibrosis. Furthermore, our data support previous studies that observed a favourable outcome in patients with HIV/HCV and a preserved immune function in times of highly active antiretroviral therapy.     

Endoscopic management of bile duct stones

The surgical risk of common duct exploration for the treatment of biliary calculi is considerably higher than that of cholecystectomy. Therefore, introduction of endoscopic sphincterotomy in 1974 was a major advance. It has become the therapy of choice in cholecystectomized patients or in those with an increased operative risk. Endoscopic sphincterotomy has a mortality rate of around 1% and a morbidity rate of 7%. These figures compare favourably with open surgery, especially in old patients. The procedure fails in about 10% of all patients referred for endoscopic removal of their calculi. However, several techniques have been described or are currently under evaluation to overcome these failures: intracorporeal or extracorporeal lithotripsy, long-term stenting of the bile duct, or direct application of solvents. Long-term follow-up studies show that between 2% and 20% of successfully managed patients may develop recurrent stones, mainly caused by bile stasis and infection. Patients with a functioning gall-bladder and no concomitant gall-bladder stones probably do not require cholecystectomy after successful endoscopic treatment of their choledochal stones. While endoscopic stone removal has replaced surgery in the elderly frail patients it has no major advantages in the young and fit patients, especially when the gall-bladder is still in situ.     

Independent cycles of exocrine pancreatic secretion, hormones and gastroduodenal motility in healthy fasting humans: reassessment of a complex partnership

Background: interdigestive pancreatic secretion cycles in close association with the phases of the migrating motor complex (MMC) and release of regulatory hormones. The extrinsically denervated pancreas exhibits an intrinsic cyclic rhythm. We hypothesized that this intrinsic rhythm is normally present in the intact human pancreas. Methods: 19 healthy males (age range 26–35 years) were studied after 12 h fasting. A manometry catheter was positioned with four pressure ports in the antrum and three in the duodenum, and motility was recorded for a complete MMC cycle or 5 h. Duodenal aspirates were sampled at 15-min intervals, and immediately analysed for amylase, lipase and chymotrypsin activities; enzyme outputs were calculated by standard marker perfusion techniques. Plasma levels of pancreatic polypeptide (PP) and motilin were also determined (RIA) at 15-min intervals. Results: output of amylase, lipase and chymotrypsin occurred in parallel. All phase III motility fronts were accompanied by a pancreatic secretory peak. However, in 12 subjects at least one secretory peak was observed without the concomitant occurrence of phase III. A total of 16 out of 51 secretory peaks identified across all subjects were independent (31%). These phase III-independent peaks of pancreatic secretion occurred in subjects with a longer MMC cycle (160 ± 19 min vs 102 ± 13 min, P < 0.05). Phase III-associated and -independent peaks had a similar magnitude (amylase output: 21.6 ± 3.9 kU h⁻¹ vs 21.1 ± 2.8 kU h⁻¹, respectively). Irrespective of MMC phases, antral but not duodenal motor activity was closely correlated with fluctuations of pancreatic secretion (P < 0.05). Cycling of PP and motilin were also closely coordinated with pancreatic enzymes, with a particularly tight link between endocrine and exocrine secretion from the pancreas. Conclusions: peaks of pancreatic secretion invariably occur when a phase III motor activity occurs, but additional secretory peaks occur without a concomitant phase III. Interdigestive phasic pancreatic secretion is tightly coordinated with PP and motilin release as well as with antral motor activity. An intrinsic rhythm of the pancreas distinct from other cyclic activity may be present in healthy humans, expressed as peaks of pancreatic secretion independent of a motor phase III.     

Physical laws of cholesterol gallstone fragmentation

Efficient fragmentation is the most important prerequisite for successful treatment of gallstones by extracorporeally induced shock waves. No data are available on the amount of energy necessary for stone disintegration and on the threshold energy below which no further fragmentation occurs. We therefore performed an in vitro investigation on human cholesterol gallstones to elucidate physical laws governing shock-wave lithotripsy. First, the focal pressure of the lithotripter was measured to calculate the energy traversing a stone. Second, 96 gallstones from 16 gall bladders were analysed with respect to physicochemical composition, radiological features and ultrasound before fragmentation was performed. Energy for stone disintegration was constant within each stone family but varied between 4.6 J mL⁻¹ and 36.8 J mL⁻¹ in different families. This energy correlated linearly with stone volume. None of the radiological and physicochemical factors revealed a clear-cut correlation of the different energies necessary for similar stone disintegration. The threshold energy differed between 0.26 mJ and 1.04 mJ per pulse. In conclusion, stone volume was the best parameter predicting stone fragmentation. However, in cholesterol stones with a similar composition the required energy per volume varies considerably together with the threshold energy. Radiological and ultrasound parameters appear to be of minor importance in explaining these differences.     

The IL-1 system in HIV infection: peripheral concentrations of IL-1β, IL-1 receptor antagonist and soluble IL-1 receptor type II

The proinflammatory cytokine IL-1β is thought to be involved in ongoing HIV disease. Furthermore, its naturally occurring inhibitors soluble IL-1 receptor type II (sIL-1RII) and IL-1 receptor antagonist (IL-1Ra) may play a pivotal role in regulating its biological action. To investigate the involvement of the IL-1 system we determined serum levels of IL-1β, IL-1Ra and sIL-1RII in 90 HIV⁺ patients. The obtained values were compared with markers of disease progression such as CD⁺ count, 5′-neopterin, β₂-microglobulin and soluble tumour necrosis factor receptors (sTNF-R) p55 and p75 and then compared with C-reactive protein (CRP), granulocyte count, lL-6 and TNF-α. While IL-1Ra concentrations increased significantly with progressive CDC disease stages, sIL-1RII and IL-1β were not altered in our cohort. IL-1Ra showed statistical relation to decreasing CD4⁺ lymphocytes and increasing 5′-neopterin, β₂-microglobulin, sTNF-R p55, sTNF-R p75. Furthermore, IL-1Ra correlated positively with serum IL-6, TNF-α, CRP and granulocytes. In contrast, sIL-1RII and IL-1β tended to show an inverse correlation or showed no significant relationship to all these parameters. Il-1β was measurable only in a limited number of samples. IL-1Ra showed a clear relationship to acute inflammatory events as well as to the different disease stages. Our data suggest a dissociation between IL-1Ra and sIL-1RII serum levels which may indicate that the two IL-1 binding proteins have different pathophysiological roles in HIV infection.