Smoking cessation in patients with respiratory diseases: a high priority, integral component of therapy.

Smoking cessation is the one of the most important ways to improve the prognosis of patients with respiratory disease. The Task Force on guidelines for smoking cessation in patients with respiratory diseases was convened to provide evidence-based recommendations on smoking cessation interventions in respiratory patients. Based on the currently available evidence and the consensus of an expert panel, the following key recommendations were made. 1) Patients with respiratory disease have a greater and more urgent need to stop smoking than the average smoker, so respiratory physicians must take a proactive and continuing role with all smokers in motivating them to stop and in providing treatment to aid smoking cessation. 2) Smoking cessation treatment should be integrated into the management of the patient's respiratory condition. 3) Therapies should include pharmacological treatment (i.e. nicotine replacement therapy, bupropion or varenicline) combined with behavioural support. 4) Respiratory physicians should receive training to ensure that they have the knowledge, attitudes and skills necessary to deliver these interventions or to refer to an appropriate specialist. 5) Although the cost of implementing these recommendations will partly be offset by a reduction in attendance for exacerbations, etc., a budget should be established to enable implementation. Research is needed to establish optimum treatment strategies specifically for respiratory patients.

Efficacy and safety of short course (5-day) moxifloxacin vs 7-day ceftriaxone in the treatment of acute exacerbations of chronic bronchitis (AECB).

The aim of this multicenter, open, randomized study was to compare the efficacy and tolerability of a 5-day treatment course with oral moxifloxacin (MXF) vs a 7-day course with i.m. ceftriaxone (CRO) in 476 patients with acute exacerbations of chronic bronchitis (AECB), and to conduct a cost minimization analysis of the two treatments from the perspectives of both the Italian National Health Service (INHS) and society. The study was conducted in Italy. Clinical success rates at test-of-cure in the 423 patients of the PP (Per Protocol) population (primary efficacy parameter) were 90.6% and 89.0% for MXF and CRO, respectively. Statistical non-inferiority of MXF vs CRO was confirmed. Similar results were found between study drugs on the secondary efficacy parameters, including success at end-of-treatment (95.3% for MXF vs 92.9% for CRO), success at test-of-cure in bacteriologically-positive patients (94.1% vs 90.7%) and eradication/presumed eradication rates (91.7% vs 93.3%). ITT (Intention-to-Treat) analysis confirmed these data. There was a low incidence of adverse events (10.8% vs 9.1%). During a 6-month follow-up period, relapse rates were lower for MXF vs CRO (23.3% vs 28.3%; p > .05). Compared with CRO, MXF was associated with cost savings per patient ranging from Euro226.57 (INHS perspective) to Euro448.23 (societal perspective), with lower hospitalization rate the major variable contributing to reduced costs. MXF appears to be an ideal candidate for AECB treatment.

[Cost of ICU in Italy. Results from an empirical study on a sample of 12 hospitals]. / Il costo del reparto di terapia intensiva in Italia. Risultati da un'indagine empirica su un campione di 12 centri.

BACKGROUND: The Italian hospital payment system based on DRG doesn t properly include Intensive Care Units (ICU) costs. Since great emphasis has been recently given to rationing health care resources, assessing ICU costs seems to be dramatically relevant. Aim of the study was to assess the average yearly cost and the cost per diem of a sample of Italian multispecialistic ICU wards. METHODS: In September 1995, a questionnaire concerning data on variable and fixed cost was sent to 25 Italian ICU wards, 11 NHS hospital-based (Northern Italy: 5; Central Italy: 4; Southern Italy: 2) and 14 school of medicine-based (Northern Italy: 7; Central Italy: 5; Southern Italy: 2). Variable cost data included: disposable, drugs, blood and blood-derived products, physical tests, chemical and microbiological routines, instrumental diagnostic procedures and physiotherapy. Concerning fixed costs, data on personnel and equipment were requested. In addition, some hospital overheads data (utilities; power; heating; maintenance; cleaning; laundry; accounting; waste disposal; cafeteria) were collected. RESULTS: On the basis of the 12 questionnaires returned (Northern Italy: 9; Central Italy: 3; Southern Italy: 0), the yearly cost of an ICU ward is Liras 4,580,032,000 (range 2,739,277,000-7,704,292,000), whereas the average cost per diem is Liras 1,802,000 (range 1,234,000-3,179,000). Cost of personnel is about 61% of the above mentioned costs. CONCLUSIONS: Despite the lack of questionnaires from Southern Italy and the unavailability of some data concerning both the cost of equipment and the overheads, the remarkable average cost values obtained could support further research.

The effects of a mechanical thrombolytic device on normal canine vein valves.

PURPOSE: To determine if the Arrow-Trerotola Percutaneous Thrombolytic Device (PTD) causes damage to normal vein valves. MATERIALS AND METHODS: Ten lateral saphenous veins in five dogs were studied with descending venography with use of a wedge balloon catheter positioned above 48 valves (demonstrating 51 valves) before and after five antegrade passes each with an over-the-wire (0.025-inch), 6.5-F, 9-mm-diameter PTD. Vein diameters were 3.2-11.4 mm (mean, 5.9 mm). Contrast matter was injected at incremental rates from 3 to 15 mL/min during continuous pressure monitoring. Imaging was performed with digital subtraction angiography at a rate of 1 frame/sec. The time to valve reflux was determined by noting the frame at which reflux was first seen through the valve. The time to reflux and pressure required to reflux were compared before and after the PTD passes. All vessels were explanted and evaluated histologically for presence or absence of endothelial loss, thrombus formation, inflammation, or valve degeneration. Four veins in two animals were studied with venography to determine the variability of the venographic method. These veins thrombosed during venography and therefore served as positive pathologic controls. In two animals, one vein was studied with venography and one was not studied to provide pathologic controls. RESULTS: With use of two physiologic tests of valve function, 77% of valves had minimal or no damage as assessed by valve competency and 80% had minimal or no damage as demonstrated by the change in the pressures the valve can withstand before reflux. Twenty-six of 51 valves (51%) had no difference or later reflux after PTD use. Thirteen (26%) refluxed 1 second earlier after PTD use and 12 (23%) refluxed > or =2 seconds earlier (six at 2, four at 3, and two at 4). Four of the six valves with more than a 2-second difference in reflux times were in valves with diameters less than 4.2 mm. All these vessels were smaller than 7 mm in diameter. Twenty-one of 48 valve levels (44%) had no difference or sustained higher pressures before reflux after PTD use. Seventeen (36%) had a pressure drop of <10 mm Hg; five (10%) had drops of 12-24 mm Hg; and five (10%) had drops of more than 40 mm Hg. There was a significant difference in endothelial loss, thrombus formation, and inflammation between experimental veins, the veins with thrombus, the venography controls, and the normal vein controls. There was significant difference only in terms of inflammation when the experimental group was compared to the thrombosis group. CONCLUSION: The antegrade use of the PTD across normal canine vein valves does not cause physiologically significant damage in valves 7 mm or larger in diameter in this animal model.

Preclinical in vivo testing of the Arrow-Trerotola percutaneous thrombolytic device for venous thrombosis.

PURPOSE: To test the safety and efficacy of using the Arrow-Trerotola percutaneous thrombolytic device (PTD) for treating deep vein thrombosis (DVT) in an animal model. MATERIALS AND METHODS: An established canine model of iliocaval subacute thrombosis was used. Thrombosis was caused by balloon occlusion of the infrarenal inferior vena cava (IVC) for 7 (n = 12), 10 (n = 1), or 17 (n = 1) days. Treatment was performed with use of an 8-F, over-the-wire (0.035-inch) PTD with a 15-mm-diameter basket. The procedure was performed without IVC filtration. Two acute procedures were performed and 12 procedures were intended as survival procedures with 30-day follow-up. Pulmonary arteriography, blood gases, and pulmonary artery pressure measurement were performed before and after the procedure, and at follow-up. The animals were killed after the follow-up procedure and their IVC, iliac veins, and lungs were removed and examined histologically. Heparin was used intraprocedurally but thrombolytic agents were not used. Low-molecular-weight heparin was given daily after the procedure. RESULTS: Thrombolysis was completely (12 of 13) or partially (one of 13) successful in all animals in the 7- and 10-day groups, but was unsuccessful in the animal in the 17-day group (n = 1). Variable amounts of segmental and subsegmental pulmonary emboli were found in all animals with small increases in pulmonary artery pressure. Two animals died within 6 days of the procedure, possibly due to pulmonary emboli. At 30-day follow-up, IVC patency was preserved in 80% (eight of 10) of animals, but significant caval narrowing due to intimal hyperplasia was noted at follow-up. All pulmonary emboli had resolved angiographically at follow-up, but evidence of recanalized or resolving pulmonary thromboemboli was found in seven of the 12 surviving animals. No acute vascular injury (eg, perforation) occurred. CONCLUSION: The modified PTD used in this study is effective in treating subacute (<7 days old) venous thrombosis, but temporary filtration will probably be necessary to keep pulmonary emboli to a minimum during the procedure. The 30-day patency is encouraging. The results in this animal model indicate that the Arrow-Trerotola PTD may be useful in the percutaneous treatment of DVT in humans.

Modified use of the arrow-trerotola percutaneous thrombolytic device for the treatment of thrombosed hemodialysis access grafts.

PURPOSE: To assess the safety and efficacy of using the Arrow-Trerotola percutaneous thrombolytic device (PTD) as the sole means of mechanical thrombolysis in hemodialysis access grafts, including in situ treatment of the arterial plug. PATIENTS AND METHODS: Fifty consecutive patients (22 women, 28 men; mean age, 58 years; mean graft age, 29 months), in whom mechanical thrombolysis of a thrombosed hemodialysis access graft using the PTD was planned, were included in the study. In all patients, the PTD was used to treat the arterial plug in situ at the arterial anastomosis, instead of using a Fogarty catheter to reposition the plug, as indicated in the PTD product labeling. Prospective data collection included demographic information, technical details of the procedure, immediate outcomes, and complications. Patients were followed for 3 months using definitions and data forms that were identical to those used in the original clinical trial of the PTD. A sample of procedures drawn from the PTD clinical trial database (n = 54) served as control. RESULTS: Immediate technical patency was 100%. Complications included arterial embolization (6% versus 2% control; P = NS; all successfully treated with backbleeding); venous rupture (6% versus 2% control; P = NS); and sepsis (n = 1), probably due to occult graft infection. Adjunctive therapy with an Adherent Clot catheter was needed in two procedures (4%). Three month patency using life-table analysis was 42% (versus 39% control; P = NS). The number of subsequent interventions (surgical/percutaneous) to the arterial limb of the graft did not differ from the PTD trial, and no native arterial stenoses were detected during the follow-up period. CONCLUSIONS: The PTD is safe and effective when used as the sole means of mechanical thrombolysis of hemodialysis grafts. Treating the arterial plug in situ with the PTD eliminates the need for a Fogarty or Adherent Clot catheter in 96% of procedures. A slight increase in arterial embolic complications was observed but these were easily treated with backbleeding.

Hereditary desmoid disease in a family with a germline Alu I repeat mutation of the APC gene.

Two families with autosomal dominantly inherited desmoid tumors have recently been shown to have germline mutations at the 3' end of the APC gene. We subsequently identified an Amish family with autosomal dominantly inherited desmoid tumors. Genetic analysis performed on one family member, a 47-year-old man with multiple desmoid tumors and no colon polyps, revealed a protein truncating mutation in the middle of the APC gene. The truncating mutation is the result of a 337-bp insertion of an Alu I sequence into codon 1526 of the APC gene. The presence of a poly(A) tail at the 3' end of the insertion suggests that the Alu I sequence was inserted by a retrotranspositional event. Germline insertions of Alu I sequences have occasionally been reported to cause other genetic diseases including type I neurofibromatosis, hereditary site-specific breast cancer (BRCA2), and hemophilia B. However, this is the first report of a germline mutation of the APC gene resulting from an Alu I insertion.

Use of cardiac troponin T rapid assay in the diagnosis of a myocardial injury secondary to electrical cardioversion.

BACKGROUND AND HYPOTHESIS: This study was carried out to determine whether cardiac troponin T test in rapid assay gives positive results in patients previously submitted to cardioversion or electrical defibrillation. METHODS: Forty patients with supraventricular tachyarrhythmias lasting no more than 2 days were treated with electrical cardioversion. The total creatine phosphokinase (CPK)-MB isoenzyme and troponin T in rapid assay were measured at baseline and at 6, 12, and 24 h thereafter. RESULTS: Total CPK baseline levels were normal in all cases; within 4 h, the serum CPK levels increased by 98%, at 6 h by 111.5%, at 12 h by 168%, and at 24 h by 225% (p > 0.01). The CPK-MB isoenzyme showed no percentage increase of total CPK higher than 5%, measured at 6, 12, and 24 h after the shock, independent of the number of attempts of cardioversion. The troponin T test was also negative in all cases at baseline and at 6, 12, and 24 h after cardioversion. CONCLUSION: We conclude that the absence of elevations in CPK-MB levels and cardiac troponin T levels matched clinical and electrocardiographic results showing absence of myocardial damage after electrical cardioversion.

Medication self-administration: an outcome-oriented, consumer-driven program.

The ability to understand medication and consistently follow a prescribed medical regimen varies among the general population. The Department of Nursing at Mohawk Valley Psychiatric Center developed a medication self-administration program to help consumers gain knowledge and/or improve their ability to participate in medication and symptoms management. Results have demonstrated that consumers can learn at least one more piece of information about their illness and/or medication despite their level of cognitive functioning, can learn to self-administer medications with minimal supervision before leaving the hospital, and can make an easier transition into the community setting.

Reducing high-risk interventions for managing aggression in psychiatric settings.

Seclusion and restraints have traditionally been major interventions for controlling patient aggression. The implementation of less restrictive measures may or may not be an option in managing individual cases of psychiatric emergencies. Improvement in patients, knowledge of alternatives and the need to reduce the use of restraints have led to the development of new tools to enhance prevention of high-risk interventions. At one institution, an anger management assessment tool and "Triangle of Choices" have assisted patients in identifying and managing feelings of frustration and anger. Since their inception 1 year ago, the implementation of documented alternatives to restraints has increased, and use of most restrictive measures has decreased.

Intermediate forms of glycoconjugates are present in the envelope of herpes simplex virions during their transport along the exocytic pathway.

In cells infected with herpes simplex virus 1, intracellular virions in transit along the exocytic pathway carry glycoconjugates that react, in fracture-label technique, with helix pomatia lectin. This lectin is specific for unsubstituted N-acetylgalactosamine, an intermediate sugar added in O-linkage to ser/thr residues in cis-Golgi and then substituted with galactose and sialic acid in the trans-Golgi. Virions in the perinuclear space do not react with helix pomatia lectin. In intracellular transport vesicles and vacules, close to the Golgi complex, virions are positively labeled by helix pomatia lectin and variably labeled by wheat germ agglutinin, a lectin specific for fully mature glycoconjugates. Extracellular virions react only with wheat germ agglutinin. The detection of glycoconjugates at intermediate steps of maturation, coupled with previous results that virions in the perinuclear space carry high mannose oligosaccharides (Torrisi et al., J. Virol. 66, 554-561, 1992), favor the view that maturation of herpes simplex virion envelope proceeds in a stepwise manner along the exocytic pathway. Should transit of virions involve a deenvelopment of enveloped virions followed by reenvelopment of naked nucleocapsids, our results rule out reenvelopment at trans- or post-Golgi compartments and could be consistent with reenvelopment occurring earlier in the exocytic pathway, most likely at the cis-Golgi.

Immunotoxins to the HER-2 oncogene product: functional and ultrastructural analysis of their cytotoxic activity.

Two immunotoxins were prepared using monoclonal antibodies (mAb) directed towards two distinct epitopes of the gp185HER-2 extracellular domain, and the type I ribosome inactivating protein (RIP) plant toxin saporin 6. Cell protein synthesis inhibition assay reveals that the immunotoxins display a potent and specific cytotoxicity that is characterized by a slow rate, since the time required to inhibit incorporation of radiolabeled leucine completely ranges from 36 h to 60 h depending on the target cell line and the immunotoxin. Because this feature may hamper the immunotherapeutic use of these conjugates we analysed this further by studying the early phases of internalization of immunotoxins by immunoelectron microscopy. The results of this study have demonstrated that the distribution pattern of the immunotoxins and of the unconjugated mAb over the cell surface overlaps. Similarly the mAb and immunotoxins are internalized into the cell by two different pathways: via clathrin-coated pits or via smaller uncoated pits and vesicles. A higher degree of internalization is achieved when the two immunotoxins are used in combination. Unlike the slow kinetics of cell intoxication the process of immunotoxin endocytosis is characterized by a rapid rate of internalization (above 40% at 5 min in the SK-BR-3 cell line). Although these findings provide no clue to explain the mechanisms of the slow rate of cytotoxicity of the two immunotoxins their rapid internalization indicates that these reagents can be exploited in immunotherapeutic approaches to gp185HER-2-expressing malignancies.

The herpes simplex virus UL20 protein compensates for the differential disruption of exocytosis of virions and viral membrane glycoproteins associated with fragmentation of the Golgi apparatus.

The Golgi apparatus is fragmented and dispersed in Vero cells but not in human 143TK- cells infected with wild-type herpes simplex virus 1. Moreover, a recombinant virus lacking the gene encoding the membrane protein UL20 (UL20- virus) accumulates in the space between the inner and outer nuclear membranes of Vero cells but is exported and spreads from cell to cell in 143TK- cell cultures. Here we report that in Vero cells infected with UL20- virus, the virion envelope glycoproteins were of the immature type, whereas the viral glycoproteins associated with cell membranes were fully processed up to the addition of sialic acid, a trans-Golgi function. Moreover, the amounts of viral glycoproteins accumulating in the plasma membranes were considerably smaller than those detected on the surface of Vero cells infected with wild-type virus. In contrast, the amounts of viral glycoproteins present on the plasma membranes of 143TK- cells infected with wild-type or UL20- virus were nearly identical. We conclude that (i) in Vero cells infected with UL20- virus the block in the export of virions is at the entry into the exocytic pathway, and a second block in the exocytosis of viral glycoproteins associated with cytoplasmic membranes is due to an impairment of transport beyond Golgi fragments containing trans-Golgi enzymes and not to a failure of the Golgi oligosaccharide-processing functions; (ii) these defects are manifested in cells in which the Golgi apparatus is fragmented; and (iii) the UL20 protein compensates for these defects by enabling transport to and from the fragmented Golgi apparatus.

Nerve growth factor regulates the subcellular localization of the nerve growth factor-inducible protein PC4 in PC12 cells.

The immediate early gene (IEG) PC4, which encodes a protein related to gamma interferon, is activated at the onset of the neuronal differentiation induced by nerve growth factor (NGF) in PC12 cells. With an antibody raised to a bacterial beta gal-PC4 fusion protein, the PC4 protein is detected as an immunoreactive molecular species of 49 kDa, whose synthesis is rapidly induced by NGF in parallel with the induction of its mRNA. Immunofluorescence, electron microscopy and subfractionation studies indicate that the PC4 immunoreactivity is localized in the cytoplasm of PC12 cells, where it is increased transiently by NGF within 3 hr of treatment. In addition, the PC4 immunoreactivity presents an NGF-dependent pattern of intracellular localization. In fact, within 3 hr after addition of NGF, PC4 is also significantly expressed on the inner face of the plasma membrane, to which it is physically associated. After longer NGF treatment, PC4 disappears from the plasma membrane and appears in the nucleus, with reduced cytoplasmic expression. Localization in the nucleus is reversed by removal of NGF and closely parallels changes in the state of differentiation of the cell. The existence within the PC4 protein of a consensus sequence for the addition of myristic acid and of a putative sequence for the nuclear localization suggests possible mechanisms for the NGF-dependent redistribution. For an NGF-inducible IEG product, such growth factor-dependent localization of PC4 is a novel type of regulation in the pathways from the NGF receptor to the adjacent membrane proteins and to the nucleus.

Fragmentation and dispersal of Golgi proteins and redistribution of glycoproteins and glycolipids processed through the Golgi apparatus after infection with herpes simplex virus 1.

In Vero monkey cells and HEp-2 human epidermoid carcinoma cells infected with herpes simplex virus 1 the proteins beta-COP, galactosyltransferase, and alpha-mannosidase II associated with the Golgi apparatus appear to be associated with numerous smaller structures dispersed throughout the cytoplasm. Concomitantly, the intracytoplasmic ligands of lectins normally associated wholly (Helix pomatia or Ricinus communis agglutinin) or in part (wheat germ agglutinin) with the Golgi apparatus increased in amount and became dispersed. This phenomenon was seen in some of the baby hamster kidney cells analyzed but not in others and not in the human 143TK- cells. The fragmentation and dispersal of the Golgi apparatus was a late event in the reproductive cycle coinciding with virion assembly, processing of viral glycoproteins, and exocytosis from infected cells. The fragmentation of the Golgi apparatus is morphologically different from that seen with brefeldin A and may reflect disequilibration between the anterograde and retrograde Golgi transport caused by the huge influx of viral glycoproteins contained in virions and membranes flowing through the exocytic pathway.

Surface distribution and internalization of erbB-2 proteins.

We report the localization over the cell surface and the early steps of antibody-induced internalization of the product of the erbB-2 proto-oncogene, structurally related to the epidermal growth factor receptor (EGFR). We show that erbB-2/p 185 is mostly excluded from endocytic pits on the cell surface. Incubation at 37 degrees C with an anti-erbB-2/p185 monoclonal antibody induces the rapid entry of the protein into the cell. Similar internalization is shown by a chimeric molecule EGFR/erbB-2 in response to EGF. Both the timing and the pathway of internalization followed by the erbB-2/p185 appear totally similar to those described for the EGFR. At variance with the normal erbB-2/p185, two mutant activated erbB-2 proteins are frequently localized within endocytic pits of the cell surface, indicating that mutations in the transmembrane regions may determine constitutive internalization of the protein.

Herpes simplex virus envelopment and maturation studied by fracture label.

Herpes simplex virus envelopment and maturation were investigated by thin-section fracture label. The distribution of glycoproteins B and D was analyzed by labeling with antibodies; the precursor and mature forms of the glycoproteins were differentiated by labeling with the lectins concanavalin A (ConA) and wheat germ agglutinin (WGA), respectively. We report that the two glycoproteins were readily detected in the intracellular virion, whether located between the inner and outer nuclear membranes or within cytoplasmic membrane-bound vesicles and in the inner and outer nuclear membranes themselves. The enveloped virion between the inner and outer nuclear membranes labeled with ConA but not with WGA. During the transit to the extracellular space the reactivity of the virion membranes with ConA decreased and that with WGA ensued. The results document that herpes simplex viruses acquire at the inner nuclear membrane an envelope carrying the immature forms of the glycoproteins and that during the transit to the extracellular space the envelope glycoproteins become of the fully processed type.