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The first example of 16-membered aminomethylphosphines with pyridyl substituents on the phosphorus atom was synthesized as an RSSR isomer by covalent self-assembly in the system 1,3-bis[(pyridin-2-yl)phosphino]propane-formaldehyde-isopropylamine. [ABSTRACT FROM AUTHOR]

Novel 1,9-diaza-3,7,11,15-tetraphosphacyclohexadecanes with alkyl, arylalkyl, or heteroarylalkyl substituents at the endocyclic nitrogen atoms were synthesized by condensation of 1,3-bis(phenylphosphino)propane, formaldehyde, and primary amines. The reactions are stereoselective and result in the isomer with the RSSR configuration of the phosphorus atoms as the major product. The 16-membered tetrakis(phosphine) ligands form stable neutral tetranuclear complexes with gold(I). In these complexes, the 16-membered cyclic ligands retain their free-state conformations and the configuration of the chiral phosphorus atoms. [ABSTRACT FROM AUTHOR]

The first representative of the specific RSSR isomer of 14-membered tetrakisphosphine has been obtained instead of the RRRR/SSSS isomer predicted according to the empirical rule formulated recently. The geometry of the obtained 14-P4N2 is preorganized for the dicopper complex formation with the unique coordination mode in the row of P4N2 corands. [ABSTRACT FROM AUTHOR]

Extended application of allogeneic stem cell transplantation (alloSCT) is expected to increase the frequency of JC polyomavirus (JCPyV)-related progressive multifocal leukoencephalopathy (PML). The aim of this study was to assess frequency, risk factors and course of JCPyV reactivation in allografted hematology patients. This retrospective study included consecutive adult patients, treated with alloSCT between January 2008 and December 2011. Quantitative JCPyV-PCR analysis was performed on whole blood DNA samples, originally drawn for cytomegalovirus detection since transplant date. The study included 164 patients diagnosed with hematological malignancies. Patients received reduced-intensity conditioning (n=74) or myeloablative conditioning (n=90), followed by alloSCT. Twenty patients developed transient and 20 had persistent JCPyV reactivation. Two of the patients with persistent reactivation showed a gradual increase in JCPyV levels, preceding PML development by 96 and 127 days. Cessation of immunosuppression resulted in complete resolution of neurological symptoms in one patient, while the other died of PML. Seventy percent of the 'persistently reactivating' patients died. Multivariate analysis confirmed age to be the only significant predictive factor for JCPyV reactivation. In conclusion, JCPyV reactivation occurs in a quarter of allografted patients. Preemptive detection of JCPyV reactivation in high-risk subjects and early discontinuation of immunosuppressive therapy may prevent development of lethal PML. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 615–624 Background Alverine citrate and simeticone combination has been used for almost 20 years in irritable bowel syndrome (IBS), but supportive scientific evidence of efficacy was limited. Aim To evaluate the efficacy of alverine citrate and simeticone combination in patients with IBS-related abdominal pain/discomfort. Methods A total of 412 IBS patients meeting ROME III criteria were included in this double-blind randomized placebo-controlled study if their abdominal pain/discomfort intensity was at least 60 mm on a 0–100 mm visual analogue scale (VAS) during a 2-week run-in treatment-free period. Patients were randomly assigned through the use of Interactive Voice Response System to receive either alverine citrate 60 mg with simeticone 300 mg three times daily or matching placebo for 4 weeks. Results The full analysis set included 409 patients (71.4% female: mean age: 46.2 ± 13.9 years). At week 4, alverine citrate and simeticone group had lower VAS scores of abdominal pain/discomfort (median: 40 mm vs. 50 mm, P = 0.047) and higher responder rate (46.8% vs. 34.3%, OR = 1.3; P = 0.01) as compared with placebo group. Patient receiving alverine citrate and simeticone reported greater global symptom improvement compared with those receiving placebo ( P = 0.0001). Reported adverse events were similar in both groups. Conclusion Alverine citrate/simeticone combination was significantly more effective than placebo in relieving abdominal pain/discomfort in patients with IBS. [ABSTRACT FROM AUTHOR]

Full characterization of single ultrashort laser pulses, as needed for attosecond metrology and spectroscopy, requires precise measurement of the offset between the electric field and pulse envelope, or carrier–envelope phase (CEP). Until now, all CEP measurements have been made by averaging over a large number of phase-stabilized laser pulses. Here, we demonstrate the first single-shot CEP measurement of intense few-cycle laser pulses. We focus a laser pulse on a gas target and detect photoelectrons emitted in opposing directions (‘left–right’) parallel to the polarization of the laser. By comparing the left–right asymmetries of photoelectrons at different energies, we mapped the CEP of consecutive non-phase-stabilized pulses on a parametric plot. This new evaluation method enables us to determine the CEP without phase ambiguity at unprecedented measurement precision. Future investigation of phase-dependent phenomena with CEP tagging at a much lower phase jitter than accessible at present with phase-stabilized lasers is now possible. [ABSTRACT FROM AUTHOR]

The article discusses a study on the role of proteases as signalling molecules regulating cell functions by cleaving protease-activated receptors (PARs) in irritable bowel syndrome (IBS). IBS is described as a chronic gastrointestinal disorder whose characteristics include abdominal pain. bloating and altered defecation. It describes mechanisms in the generation of IBS symptoms that are mediated by PAR. It concludes that the role of proteases and PARs in the development of IBS symptoms needs further investigations.

The effects of small amounts of energy delivered at times before the peak intensity of ultrahigh-intensity ultrafast-laser pulses have been a major obstacle to the goal of studying the interaction of ultraintense light with solids for more than two decades now. We describe implementation of a practical double-plasma-mirror pulse cleaner, built into a f=10 m null telescope and added as a standard beamline feature of a 100 TW laser system for ultraintense laser-matter interaction. Our measurements allow us to infer a pulse-height contrast of 5×1011—the highest contrast generated to date—while preserving ∼50% of the laser intensity and maintaining excellent focusability of the delivered beam. We present a complete optical characterization, comparing empirical results and numerical modeling of a double-plasma-mirror system. [ABSTRACT FROM AUTHOR]

Cases: We present 2 cases of traumatic testicular dislocation associated with a pelvic ring injury after a motorcycle collision. Case 1 describes bilateral testicular dislocation discovered intraoperatively. Urology was consulted, and the testicles were manually reduced under general anesthesia. Case 2 describes unilateral testicular dislocation discovered at the 1-month follow-up after pelvic ring fixation. Concern for infarction prompted urology to take the patient for surgical reduction. Both cases resolved uneventfully without genitourinary complaints at the follow-up. Conclusions: Testicular dislocation is rare but should be considered in the setting of pelvic injury due to a motorcycle collision. Detection warrants urgent urologic consultation. [ABSTRACT FROM AUTHOR]

A response from T. Wittmann and colleagues to a letter to the editor about their article on the use of alverine citrate, simeticone in the treatment of Rome III irritable bowel syndrome, in a previous issue is presented.

Background: Impaired gastric emptying has previously been detected by ultrasonography in cirrhotic patients, and the role of the type of meal has also been discussed. While these earlier studies dealt with the distal part of the stomach, the aim of our study was to examine the effects of three different types of meal on the proximal stomach in cirrhotic patients. Methods: The proximal stomach was examined by ultrasonography in 15 healthy volunteers and in 21 alcoholic cirrhotic patients. The subjects received a liquid meal with a low calorie content and two different semisolid test meals with a low calorie content or high calorie and fat contents. The proximal gastric size was assessed by ultrasonography in a sagittal area and a frontal diameter. On the basis of assessment of the autonomic nervous function, the cirrhotic patients were divided into two groups: autonomic neuropathy positive and autonomic neuropathy negative. Results: The postcibal gastric size immediately after ingestion of the liquid test meal was significantly lower in the cirrhotic patients than in the healthy controls. In the healthy volunteers, the measures of the proximal gastric size were significantly higher than in either group of cirrhotic patients at t[sub 0] , and at 10, 20 or 30 min after ingestion of a semisolid test meal with low calorie and fat contents. The proximal gastric sizes in the three groups of investigated subjects did not differ when the meal with high fat and calorie contents was tested. When the liquid meal was administered, the proximal gastric size was significantly lower in the cirrhotic patients with autonomic neuropathy. A significant intragroup difference was not observed when the semisolid meals were tested. Conclusions: This study reveals an impairment of the proximal stomach in alcoholic cirrhotic patients. The low calorie liquid meal distinguishes between the two groups of cirrhotic patients and healthy controls. [ABSTRACT FROM AUTHOR]

Abstract. Comparative study of solid and liquid phase ablation on the same sample by time-resolved investigations is presented in this paper. Polyethylene-glycol (PEG) 1000 having relatively low melting point (35 Celsius) was used in our experiments. By varying the sample temperature in the 20-80 Celsius range we could study the ablation mechanism in both solid and liquid (below and above the melting point) state of matter. An ArF excimer laser (lambda = 193 nm, FWHM = 20 ns) was used for ablation at 1.95 J/cm[sup 2] fluence. Ablation processes were observed by transmission fast photographic arrangement. It was demonstrated that plasma development and expansion (primer ablation, in 0-50 ns time range), formation and propagation parameters of shock wave and contact front did not depend on sample temperature and state of matter. The secondary material ejection (between 1-100 micro s) showed a strong temperature dependence. Material ejection in the case of solid target occurred in the form of dense material cloud, and in the form of splashing for liquid (molten) sample. The ejection velocity of splashed jets depended on the sample temperature, significantly. This can be due to the change of molten PEG 1000 viscosity. [ABSTRACT FROM AUTHOR]

Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhoea. In this study, our aim was to characterise the cellular pathomechanism of bile-induced diarrhoea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na/H exchanger (NHE) and Cl/HCO exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhoea, compared to control patients. Acute treatment of colonic crypts with 0.3 mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca elevation. We also showed that chenodeoxycholate induced Ca release from the endoplasmic reticulum and extracellular Ca influx contributing to the Ca elevation. Importantly, our results suggest that the chenodeoxycholate-induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca elevation. We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote the development of diarrhoea. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article which proposed a calculation formula to predict the response to ciclosporin treatment for severe ulcerative colitis.

Background Some of the most important questions relating to the use of biological therapy in inflammatory bowel diseases concern the duration of maintenance therapy. Aim To assess the disease course and frequency of relapse of Crohn's disease ( CD) following discontinuation of biological therapy, and to determine predictive factors for relapse. Methods One hundred twenty-one CD patients who had achieved clinical remission following 1 year of biological therapy and for whom biological therapy was then discontinued participated in this prospective observational study. Eighty-seven CD patients had received infliximab and 34 adalimumab. The definition of relapse was an increase of >100 points in CDAI to at least a CDAI of 150 points. Results Biological therapy was restarted within 1 year of treatment cessation in 45% of patients. Logistic regression analysis revealed that previous biological therapy ( P = 0.011) and dose intensification during the 1-year course of biological therapy ( P = 0.024) were associated with the need for and the time to the restarting of biological therapy. Smoking was observed to have an effect that was not statistically significant ( P = 0.053). Conclusions Biological therapy was restarted a median of 6 months after discontinuation in almost half of Crohn's disease patients in who had been in clinical remission following 1 year of biological therapy. These results suggest that, in the event of the presence of certain predictive factors, biological therapy should probably be continued for more than 1 year by most patients. [ABSTRACT FROM AUTHOR]

Although the pathogenesis of cervical inlet patch (CIP) is not fully understood, most authors consider it as a congenital abnormality, whereas others surmise it to be related to gastroesophageal reflux disease (GERD). We aimed to evaluate esophageal function and the prevalence of GERD and Barrett's esophagus in patients with CIP. GERD is defined by the presence of erosive esophagitis or an abnormal pH monitoring. Seventy-one consecutive patients with endoscopic and histological evidence of CIP were prospectively evaluated. Esophageal symptom analysis, 24-hour simultaneous biliary reflux and double-channel pH-monitoring, and esophageal manometry were carried out in 65/71 (92%) patients and in 25 matched controls. Six patients were not suitable for testing and were, therefore, excluded. The histological evaluation of the heterotopic islands showed cardia and/or oxyntic mucosa in 64/65 (98%) patients and specialized intestinal metaplasia (SIM) in one patient (2%). The cardia and/or oxyntic mucosa was accompanied by focally appearing pancreatic acinar metaplasia and pancreatic ductal metaplasia in 7/64 (11%) and in 1/64 (2%), superficial mucous glands in 6/64 (9%), and SIM in 2/64 (3%) cases. In total, SIM was present in three patients (5%), and one of them had low-grade dysplasia. At the gastroesophageal junction, 28 (43%) patients had columnar metaplasia, including nine (14%) patients with SIM. Erosive esophagitis was present in 37 (57%) cases. Thirty-two patients (49%) had abnormal acid reflux in the distal and 25 (38%) in the proximal esophagus. Abnormal biliary reflux was present in 25 (38%) cases. On the basis of endoscopic and pH studies, GERD was established in 44/65 (68%) patients. Typical reflux symptoms were common (33/65, 51%). The combined 24-hour biliary and double-channel pH-monitoring detected significantly more significant acidic reflux at both measurement points and significantly longer bile exposure time in the distal esophagus in patients with CIP. Acid secretion in the CIP was detected in three (5%) cases. Esophageal manometry revealed decreased LES pressure and prolonged relaxation with decreased peristaltic wave amplitude, and an increased number of simultaneous contractions in the esophageal body. The detailed evaluation of the esophageal morphology and function in subjects with CIP showed a high prevalence of GERD and Barrett's esophagus. Further studies are needed to evaluate whether combined acidic and biliary reflux is able to promote similar histomorphological changes in the CIP, as it is shown distally in patients with Barrett's esophagus. [ABSTRACT FROM AUTHOR]

SUMMARY Specialized intestinal metaplasia (SIM) is considered as a premalignant condition of the esophagus, but other types of esophageal metaplasia are commonly neglected. A standardized histopathological analysis was focused not only on SIM but also on the presence of metaplastic processes typical of additional glands. A morphological study using standardized histopathological tests was carried out between 2004 and 2007, with biopsies taken from esophageal mucosa of 826 consecutive patients. Mean age and male : female ratio of patients were 55.6 ± 14.7 and 1.1 : 1, respectively. Only 4.1% ( n= 34) of all cases proved to have SIM. The remainder of the cases ( n= 615; 74.4%) contained cardiac-fundic mucosa without SIM. Some samples exhibited superficial mucous glands, pancreatic acinar metaplasia (PAM), and ciliated metaplasia accounting for 24% ( n= 198), 14.9% ( n= 123), and 0.2% ( n= 2), respectively. SIM was colocalized with superficial mucous glands (103/198 superficial mucous gland cases; P < 0.001). Low-grade dysplasia ( n= 51; 6.2%) and high-grade dysplasia ( n= 9; 1.1%) were found mainly in SIM (37/51; 9/9; P= 0.071) with male preponderance (3 : 1 at low-grade and 2 : 1 at high-grade dysplasia). PAM was found mainly in cases without dysplasia (103 of 123 pancreatic metaplasias; P < 0.001). SIM alone in the esophagus is rare, and its frequent association with cardiac mucosa-type metaplasia testifies to transition of mucinous-goblet cell through pseudogoblet cells. PAM rather indicates absence of dysplasia, but superficial mucous glands predicts that SIM follows dysplasia. [ABSTRACT FROM AUTHOR]

Background Activation of proteinase-activated receptor-4 (PAR-4) from the colonic lumen has an antinociceptive effect to colorectal distension (CRD) in mice in basal conditions. We aimed to determine the functional localization of the responsible receptors and to test their role in two different hyperalgesia models. Methods Mice received PAR-4 activating peptide (PAR-4-AP, AYPGKF-NH2) or vehicle intraperitoneally (IP), and abdominal EMG response to CRD was measured. The next group received PAR-4-AP intracolonically (IC) with or without 2,4,6-triaminopyrimidine, a chemical tight junction blocker, before CRD. The SCID mice were used to test the role of lymphocytes in the antihyperalgesic effect. The effects of PAR-4-AP and PAR-4-antagonist (P4pal-10) were evaluated in water avoidance stress (WAS) model and low grade 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis. Spinal Fos protein expression was visualized by immunohistochemistry. Key Results The antinociceptive effect of PAR-4-AP disappeared when was administrered IP, or with the blockade of colonic epithelial tight junctions, suggesting that PAR-4-AP needs to reach directly the nerve terminals in the colon. The CRD-induced spinal Fos overexpression was reduced by 43% by PAR-4-AP. The PAR-4-AP was antihyperalgesic in both hyperalgesia models and in mice with impaired lymphocytes. The PAR-4-antagonist significantly increased the TNBS, but not the WAS-induced colonic hyperalgesia. Conclusions & Inferences The antinociceptive effect of PAR-4-AP depends on its penetration to the colonic mucosa. The PAR-4 activation is endogenously involved as a feedback loop to attenuate inflammatory colonic hyperalgesia to CRD. [ABSTRACT FROM AUTHOR]

Abstract: The high cost of infliximab inhibits the regular retreatment of all patients in Hungary with Crohn''s disease (CD) after beneficial induction therapy. This study is set out to evaluate the medium-term efficacy of induction therapy with infliximab without retreatment in CD patients with chronic activity and/or fistulae refractory to conventional therapy. Methods: A retrospective 1-year review was undertaken of all CD patients with successfully induced remission or fistula closure with 3 infusions of infliximab. Infliximab was administered in a dose of 5 mg/kg 3 times, in weeks 0, 2 and 6. Clinical remission was defined as symptom resolution and an estimated Crohn''s Disease Activity Index (CDAI) <150 and complete fistula closure. We evaluated the clinical response, the estimated CDAI, the number of draining fistulae, the dosages of steroid and immunosuppressive drugs at 6 and 12 months after the last infusion, and the needs for hospitalization and surgical intervention during this period. Breslow (Generalized Wilcoxon) test was used as the statistical method. Results: The data of the 50 patients (19 luminal, 31 fistulizing disease; average age 29. 3 [13–59] years, disease localization: 23 colon, 13 ileum, 13 ileocolon, 1 duodenum) were suitable for analysis. Infliximab induction therapy without retreatment resulted in a beneficial effect lasting for at least 1 year in 22 of the 50 patients (44%). 11 of the 19 patients (57.9%) with luminal disease remained in steroid-free complete remission, while the fistulae persisted closed in only 11 of the 31 patients (35.5%) (p <0.05). Conclusion: Infliximab induction therapy alone may result in sustained remission mainly in patients with luminal disease. These results suggest the need for maintenance therapy with infliximab after successful therapy induction in patients with fistulae, while luminal CD patients could possibly participate in regular retreatment only if needed. If these data are confirmed, this modification of the therapeutic procedure could well increase the cost-effectiveness of infliximab. [Copyright &y& Elsevier]

OBJECTIVES: Diarrhoea-predominant irritable bowel syndrome (IBS-D) is characterised by elevated colonic lumenal serine protease activity. The aims of this study were (1) to investigate the origin of this elevated serine protease activity, (2) to evaluate if it may be sufficient to trigger alterations in colonic paracellular permeability (CPP) and sensitivity, and (3) to examine the role of the proteinase-activated receptor-2 (PAR-2) activation and signalling cascade in this process. PATIENTS AND METHODS: Faecal enzymatic activities were assayed in healthy subjects and patients with IBS, ulcerative colitis and acute infectious diarrhoea. Following mucosal exposure to supernatants from control subjects and IBS-D patients, electromyographic response to colorectal balloon distension was recorded in wild-type and PAR-2-/- mice, and CPP was evaluated on colonic strips in Ussing chambers. Zonula occludens-1 (ZO-1) and phosphorylated myosin light chain were detected by immunohistochemistry. RESULTS: The threefold increase in faecal serine protease activity seen in IBS-D patients compared with constipation-predominant IBS (IBS-C) or infectious diarrhoea is of neither epithelial nor inflammatory cell origin, nor is it coupled with antiprotease activity of endogenous origin. Mucosal application of faecal supernatants from IBS-D patients in mice evoked allodynia and increased CPP by 92%, both of which effects were prevented by serine protease inhibitors and dependent on PAR-2 expression. In mice, colonic exposure to supernatants from IBS-D patients resulted in a rapid increase in the phosphorylation of myosin light chain and delayed redistribution of ZO-1 in colonocytes. CONCLUSIONS: Elevated colonic lumenal serine protease activity of IBS-D patients evokes a PAR-2-mediated colonic epithelial barrier dysfunction and subsequent allodynia in mice, suggesting a novel organic background in the pathogenesis of IBS. [ABSTRACT FROM AUTHOR]

Neonatal maternal separation induces visceral hyperalgesia before and after stress in male rats. This study compares the effects on sensitivity to rectal distension in adult male and female rats, using two protocols of deprivation. Between postnatal days 1 and 14, maternal deprivation was performed for 2 h per day according to a protocol of type M (removal of all pups from home cage) or type P (separation of half of littermates). Visceral sensitivity was assessed at 12 weeks of age by the number of abdominal contractions induced by rectal distension before and after restraint stress. Calcitonin gene-related peptide (CGRP) was identified in the rectal wall by immunohistochemistry. In basal conditions, both separation protocols induced hyperalgesia, that was greater after type M than type P, and in females than in males for type P separation. Acute restraint stress induced hyperalgesia in control females only, and this effect was similarly enhanced by both type P and M separation. No difference was found between controls and deprived rats in rectal CGRP immunoreactivity which was greater in females and increased after rectal distension. These results indicate that long-term visceral hyperalgesia depends upon the type of maternal deprivation and that females are more sensitive than males. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 48-year old man, who was admitted with a history of dysphagia, nausea and fever. It mentions that abdominal ultrasound revealed hepatosplenomegaly, while histological examination of the biopsy, showed lymphocytic esophagitis with positive T-cells in the mucosa. Moreover, it notes that aciclovir therapy was started and lasted for two months, then after one month the esophagitis resolved completely.

A letter to the editor is presented in response to article regarding the Crohn's disease by AWG Waugh and colleagues in the 2011 issue.

A letter to the editor on outcomes of pregnancy in women with inflammatory bowel disease (IBD)is presented.

A letter to the editor is presented in response to an article on the biological therapy of ulcerative colitis , which was published in a previous issue of this journal.

The article presents a case study of a 79-year-old man who has a history of weakness and black stool. It states the gastric penetration of epicardial pacemaker implanted after cardiar surgery. It discusses the several complications of temporary pacing leads such as infections, arrhythmias, and perforation.

A letter to the editor is presented in response to an article on safety profile and long-term applicability of Infliximab in inflammatory bowel disease by Y. Zabana and colleagues.

A letter to the editor is presented in response to the article "The association of diet with onset and relapse in patients with inflammatory bowel disease." by C. E. G. M. Spooren and colleagues.