Cardiac resynchronization therapy: a breakthrough in heart failure management.

Heart failure is now considered an epidemic. In patients with heart failure, electrical and mechanical dyssynchrony, evident primarily as prolongation of the QRS-complex on the surface electrocardiogram, is associated with detrimental effects on the cardiovascular system at several levels. In the past 10 years, studies have demonstrated that by stimulating both cardiac ventricles simultaneously, or almost simultaneously [cardiac resynchronization therapy (CRT)], the adverse effects of dyssynchrony can be overcome. Here, we provide a comprehensive overview of different aspects of CRT including the rationale behind and evidence for efficacy of the therapy. Issues with regard to gender effects and patient follow-up as well as a number of unresolved concerns will also be discussed.

Simulation-based design study for the passive shielding of the COSINUS dark matter experiment.

The COSINUS (Cryogenic Observatory for SIgnatures seen in Next-generation Underground Searches) experiment aims at the detection of dark matter-induced recoils in sodium iodide (NaI) crystals operated as scintillating cryogenic calorimeters. The detection of both scintillation light and phonons allows performing an event-by-event signal to background discrimination, thus enhancing the sensitivity of the experiment. The choice of using NaI crystals is motivated by the goal of probing the long-standing DAMA/LIBRA results using the same target material. The construction of the experimental facility is foreseen to start by 2021 at the INFN Gran Sasso National Laboratory (LNGS) in Italy. It consists of a cryostat housing the target crystals shielded from the external radioactivity by a water tank acting, at the same time, as an active veto against cosmic ray-induced events. Taking into account both environmental radioactivity and intrinsic contamination of materials used for cryostat, shielding and infrastructure, we performed a careful background budget estimation. The goal is to evaluate the number of events that could mimic or interfere with signal detection while optimising the geometry of the experimental setup. In this paper we present the results of the detailed Monte Carlo simulations we performed, together with the final design of the setup that minimises the residual amount of background particles reaching the detector volume.

Geant4-based electromagnetic background model for the CRESST dark matter experiment.

The CRESST (Cryogenic Rare Event Search with Superconducting Thermometers) dark matter search experiment aims for the detection of dark matter particles via elastic scattering off nuclei in CaWO 4 crystals. To understand the CRESST electromagnetic background due to the bulk contamination in the employed materials, a model based on Monte Carlo simulations was developed using the Geant4 simulation toolkit. The results of the simulation are applied to the TUM40 detector module of CRESST-II phase 2. We are able to explain up to ( 68 ± 16 ) % of the electromagnetic background in the energy range between 1 and 40 keV .

p53 splice acceptor site mutation and increased HsRAD51 protein expression in Bloom's syndrome GM1492 fibroblasts.

GM1492 human diploid skin fibroblasts derived from a patient with Bloom's syndrome (BS), lack detectable p53 mRNA and protein as shown by Northern and Western blotting, and express an increased RecA-like activity. Here we demonstrate that the p53 gene is grossly intact in GM1492 cells according to Southern blotting. DNA sequencing did not reveal any mutations in the promoter region of p53. A highly sensitive RT-PCR produced a p53 cDNA fragment that was shorter than expected. DNA sequence analysis of p53 cDNA showed that exon 6 was missing, explaining the shorter PCR product. Furthermore, sequencing of genomic DNA revealed a base substitution at the nucleotide preceding the AG splice acceptor site of intron 5. The omission of exon 6 creates a frameshift at the junction of exons 5 and 7, and a premature stop codon in exon 7. The aberrant transcript is predicted to encode a truncated p53 protein containing 189 amino acid residues. Moreover, Western blotting demonstrated elevated HsRAD51 protein levels in GM1492 cells. The lack of sufficient levels of wild-type p53 and increased levels of HsRad51 protein may contribute to the elevated RecA-like activity in the GM1492 fibroblasts.

Sucralfate versus placebo in treatment of non-ulcer dyspepsia.

One hundred fifty-one patients with non-ulcer dyspepsia, defined as chronic epigastric pain without concomitant symptoms of the irritable bowel syndrome and with no evidence of any organic disease other than macroscopic or microscopic gastritis/duodenitis seen at endoscopy on entry into the trial, were randomly assigned to treatment for four weeks with sucralfate or a placebo, 1 g three times a day one-half hour before meals, according to a double-blind model. Seventy-nine patients received sucralfate and 72 patients received a placebo. According to patients' subjective assessment of their symptoms at four weeks, 61 patients (77 percent) in the sucralfate group and 40 patients (56 percent) in the placebo group had become symptom-free or showed improvement, whereas the condition of 18 (23 percent) in the former group compared with 32 (44 percent) in the latter group remained unchanged or deteriorated. The difference between the groups was significant (p less than 0.01). The best response to sucralfate treatment (84 percent or more symptom-free or improved) was achieved in patients with mild or moderate symptoms and without macroscopic or microscopic inflammation of their gastric mucosa--a typical patient with non-ulcer dyspepsia. Our results indicate that sucralfate is significantly more effective than placebo in the treatment of non-ulcer dyspepsia.

Immunochemical detection of human liver cytochrome P450 forms related to phenobarbital-inducible forms in the mouse.

Polyclonal antibodies generated to four distinct mouse liver phenobarbital-inducible cytochrome P450 isoforms were used to analyse related forms in human liver. N-terminal sequence analysis and biochemical properties of the P450s used as antigens suggest that they belong to P450 subfamilies IIB (P450PBI), IA (P450PBII), IIC (P450PBIII) and IIA (P450Coh). In immunoblot analysis, anti-P450PBII detected a single protein presumed to be P450IA2 in all the human livers tested. No proteins corresponding with P450IA1 could be detected. Anti-PBIII and anti-P450Coh antibodies each detected one band (54 and 48 kDa, respectively) in the liver samples. No bands were revealed by anti-P450PBI antibody. Protein dot-immunobinding analysis showed that P450s immunodetectable by anti-P450PBII, anti-P450PBIII and anti-P450Coh antibodies are expressed in human liver (range 9 to 69 pmol P450/mg protein). In immunoinhibition experiments the activity of 7-ethoxyresorutin O-deethylase (EROD) was blocked up to 90% by the anti-P450PBII antibody. Aryl hydrocarbon hydroxylase (AHH) was inhibited only by anti-P450PBIII, and coumarin 7-hydroxylase (COH) only by anti-P450Coh antibody. Testosterone hydroxylations in positions 6 beta, 7 alpha, 15 alpha and 16 alpha were not affected significantly by any of the antibodies. These data suggest that the human liver P450IA2 is responsible for most of the elevated EROD activity, P450s in the IIC subfamily for constitutive AHH and P450s in the IIA subfamily for all of COH activity.

Adsorption of bile acids by sucralfate, antacids, and cholestyramine in vitro.

Sucralfate, one of the newer drugs shown to be effective in the treatment of peptic ulcer and esophagitis; cholestyramine, a known bile acid binder; and commercial antacid preparations of pure aluminum hydroxide, pure magnesium hydroxide, and a combination of aluminum hydroxide, magnesium hydroxide, and magnesium carbonate were tested in vitro for bile acid-binding capacity. Cholestyramine was found to be the most effective bile acid binder, with more than 90% of bile acids adsorbed at all of the pH values studied. Sucralfate proved efficacious at pH 4, 6, and 8, adsorbing about 50% of the bile acids, but its binding capacity decreased at pH 2. Pure aluminum hydroxide was the most effective of the various antacid preparations; it adsorbed about 90% of bile acids at pH 2, although this percentage was significantly reduced at pH 6 and 8. Sucralfate was significantly more effective as a bile acid absorbent at pH 4 than either the magnesium hydroxide or aluminum-magnesium hydroxide plus magnesium carbonate antacids, as effective as the aluminum hydroxide antacid, and significantly less effective than cholestyramine.

Staplers in palliative bypass surgery for unresectable pancreatic cancer.

To assess the role of stapling devices and routine gastroenterostomy in palliative bypass surgery, the hospital records of 150 consecutive patients with unresectable, histologically proven pancreatic adenocarcinoma requiring palliative bypass procedure were reviewed. During recent years staplers have gained increasing acceptance for construction of palliative anastomoses. Mortality and morbidity were lower after stapled anastomoses. The use of staplers for construction of double bypass reduced the operation time by 45 min (p less than 0.001). After initial biliary diversion 6% of the patients required later reoperation for gastric outlet obstruction. Routine gastroenterostomy made reoperation unnecessary. Delayed gastric emptying occurred, however, in 10% and significant upper gastrointestinal bleeding in 7% of the patients after prophylactic gastroenterostomy. We conclude that stapling devices are safe and practical in palliative bypass surgery and they significantly reduce operation time if more than one bypass is required. The relatively high incidence of delayed gastric emptying, and significant upper gastrointestinal bleeding after prophylactic gastroenterostomy and the infrequent occurrence of gastric outlet obstruction after initial biliary bypass together with the low mortality after reoperation, suggest that gastroenterostomy should be performed on a selective basis only.

A method for studying the mutagenicity of some gaseous compounds in Salmonella typhimurium.

A dynamic flow-through exposure system was designed for mutagenicity studies of gaseous compounds in Salmonella. Salmonella typhimurium strain TA100 was the primary tester strain. The dose ranges were 0.5-20% of vinyl chloride, ethene, propene, and 1,3-butadiene, 1-200 ppm of ethylene oxide, 0.5-20 ppm of nitrogen dioxide, and 0.1-3.5 ppm of ozone. The gas flow rate was 250, 500, or 1,000 ml/min, and the exposure time was 6 or 7 hours. Of the tested gases, vinyl chloride, ethylene oxide, and nitrogen dioxide were mutagenic. Ethene, propene, and 1,3-butadiene were not mutagenic in this system. Ozone is bacteriotoxic, and no mutagenic effect could be demonstrated in the nontoxic dose range. The exposure system was considered suitable for studies on gaseous chemicals.

Photochemical formation of mutagenic compounds from alkenes and ozone or nitrogen dioxide.

In order to investigate the possible formation of mutagenic compounds from alkenes emitted in ambient air, laboratory experiments were performed with Salmonella typhimurium strain TA100 in a small-scale flow-through exposure system. The reaction time for mixtures of alkenes with ozone or nitrogen dioxide was 40 minutes, and the exposure time for bacteria was 6 hours. Ozone gave rise to a small mutagenic effect in combination with 1,3-butadiene or vinyl chloride, with and without ultraviolet (UV) irradiation, but not in combination with ethene or propene. Nitrogen dioxide gave rise to a mutagenic effect in combination with propene, 1,3-butadiene, or vinyl chloride, but only after UV irradiation. The mutagenic activity was highest with butadiene and seemed to be dose-related to the concentration of nitrogen dioxide. Nitrogen dioxide with ethene did not produce a mutagenic effect. A mixture of ethene, propene, and butadiene, tested with ozone or nitrogen dioxide with UV irradiation, did not potentiate each other's mutagenic effect.

Superselective intra-arterial chemotherapy with mitomycin C in liver and gallbladder cancer.

This phase 2 study was undertaken to evaluate the feasibility and efficiency of superselective intra-arterial chemotherapy with mitomycin C (SIAC) in patients with liver and gallbladder cancer and compare them to hepatic artery ligation (HAL) and regional chemotherapy with 5-fluorouracil (5-FU). Survival time was related to the percent hepatic replacement (PHR) of the tumour (P less than 0.01) in all patients. SIAC had no advantage over HAL +/- 5-FU as chemotherapy regimen for unresectable liver cancer. The overall response rate of SIAC was 42% (15/36), 27% (3/11) for primary liver cancer, 40% (8/20) for hepatic metastases from colorectal cancer and 60% (3/5) for carcinoma of the gallbladder. The patients who responded to SIAC survived significantly longer (P less than 0.005). The survival rate for responders at 1 year was 68% and for non-responders 26%. Chemotherapy toxicity after SIAC occurred in 16 (44%) patients requiring cessation of therapy in 6 (16%) patients. We conclude that the results of this phase 2 clinical trial were not encouraging. There is an urgent need for reliable means of predicting tumour response to chemotherapy and for a more careful patient selection.

Tissue distribution of two NMDA receptor antagonists, [3H]CGS 19755 and [3H]MK-801, after intrathecal injection in mice.

The tissue distribution of [3H]cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (NK-801) was investigated after a single IT injection into lumbar spinal cord of mice. The level of radioactivity was analyzed in the lumbar, thoracic, and cervical spinal cord, brainstem, frontal cortex, liver, lungs, kidneys, stomach, intestine, spleen, heart, and blood from 5 min up to 6 h after injection. Within the CNS, [3H]CGS 19755 redistributed slowly from the site of injection toward the brainstem and cortex, peaking in the cortex 3-4 h after IT injection. At no time, however, did the relative level per gram of tissue in the frontal cortex exceed 10% of the relative level in the lumbar region of the spinal cord. The highest peripheral level of [3H]CGS 19755 was found in the kidneys. [3H]MK-801 redistributed rapidly from the spinal cord injection site to the peripheral organs. The highest peripheral levels of [3H]MK-801 were found in the lungs and liver, where the radioactivity peaked at 10 and 30-60 min, respectively, after injection. The relative levels of [3H]CGS 19755 were consistently higher in CNS tissues (except for the first 15 min in the frontal cortex) and blood than the corresponding levels of [3H]MK-801. The opposite relationship was true in the liver, lungs, kidneys, stomach, intestine, spleen, and heart. The effect on the response latency in the hot-plate test was quantified in the same animals immediately prior to sacrifice for the distribution study.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrasound compared with computed tomography and pancreatic arteriography in the detection of endocrine tumours of the pancreas.

We have evaluated ultrasound, computed tomography and arteriographic findings in 15 patients with 17 endocrine pancreatic tumours having a mean diameter of 2.3 cm (range 1-7 cm). All patients under-went computed tomography, and all but one ultrasound and arteriography. Ultrasound was the initial investigation in 11 patients, and identified 10 of the 16 tumours present in 14 patients. Two tumours were found at ultrasound reexamination after having been identified by other radiological methods. Computed tomography revealed 8 out of 17 tumours, while arteriography identified 8 out of 16 tumours. Computed tomography was the initial investigation in 4 patients, and identified one tumour. In only 4 patients were tumours not detected by any of the imaging methods. The sensitivities of ultrasound, computed tomography and arteriography in the detection of pancreatic tumours were 62.5% (95% confidence interval 50.4-74.6%), 47.1% (95% confidence interval 35.0-59.2%), and 50.0% (95% confidence interval 37.5-62.5%), respectively. Ultrasound was thus more accurate than computed tomography or arteriography in detecting endocrine pancreatic tumours, and should be the initial radiological investigation.

Results of pancreatoduodenectomy for carcinoma of the head of the pancreas.

Seventy-eight patients underwent either pancreatoduodenectomy (88%) or total pancreatectomy (12%) for carcinoma of the head of the pancreas. The operative mortality decreased from 27% in 1968-1977 to 3% in 1978-1987. There was no operative mortality during the last 5-year period 1983-1987. Mortality (9% vs 7%) and morbidity (57% vs 42%) were similar in patients aged greater than or equal to 70 and less than 70 years. The pylorus-preserving technique did not increase mortality or operative blood loss, but it did reduce the operative time about by one hour (p less than 0.05). The actuarial 5-year survival for periampullary cancer was 40 +/- 9%, but none of the patients with pancreatic adenocarcinoma survived for 5 years (p less than 0.001). The long-term survival for radical resection was 33 +/- 8%, whereas no patient who underwent palliative resection survived for 3 years (p less than 0.001). The actuarial 5-year survival rates for patients greater than or equal to 70 and less than 70 years of age were 18 +/- 12% and 31 +/- 12% (p greater than 0.2), respectively. It is concluded that age as such is not a limiting factor for pancreatoduodenectomy. It can be performed with acceptable mortality and morbidity rates even on patients over 70 years of age. The long-term prognosis is nevertheless related to tumor histology and radicality of resection. The recent decline in operative mortality is mostly due to the resections being performed by the same group of surgeons. The best biopsy, and also palliation, is radical removal of the suspicious mass, providing that this can be performed with minimal risk.