NEbivolol inhibition of coronary artery smooth muscle cell proliferation after percutaneous coronary artery intervention. Results of the NESCIO Study, a randomized, double blind trial.

OBJECTIVES: This study compared the efficacy of metoprolol and nebivolol in reducing the frequency of in-stent restenosis (ISR) after a percutaneous coronary intervention (PCI). BACKGROUND: ISR results from excessive neointimal proliferation. Nebivolol inhibits proliferation of human coronary endothelial and smooth muscle cells in vitro. Its efficacy has not been studied in clinical trials. MATERIAL AND METHODS: In a single-centre double-blind study, 79 subjects with de novo lesions were randomly assigned to receive either nebivolol (n=37) or metoprolol (n=42) 3 to 7 days before elective PCI with bare metal stents. The study medication was continued for 6 months. Nebivolol was administered at 5 mg/day for 3 weeks, then at 10 mg/day. Metoprolol was administered at 100 mg/day. The endpoints were the difference in fractional flow reserve (deltaFFR) between values immediately after PCI and those at 6 months and ISR during the 6 months following PCI The study was powered to detect a deltaFFR of 6% with 30 subjects per treatment group. RESULTS: Among subjects who underwent angiography at 6 months, mean deltaFFR was--0.08 for the nebivolol group (n=25) and -0.12 in the metoprolol group (n=26; p = 0.367). ISR occurred in 11 subjects (26.2%) on metoprolol and in 3 (8.1%) on nebivolol during treatment, and in 7 subjects on metoprolol and in 3 on nebivolol at 6 months (p = 0.014) CONCLUSION: There was a non-significant trend toward less decline in detaFFR at 6 months with nebivolol. Nebivolol should be investigated further in larger trials. Nebivolol significantly reduced the frequency of ISR as compared to metoprolol.

Demonstration of vasoproliferative activity from mammalian retina.

Vasoproliferative activity has been demonstrated in extracts of retinas from human, bovine, and feline sources. These retinal extracts are capable of stimulating (a) proliferation and thymidine uptake of bovine vascular endothelial cells in culture and (b) neovascularization on the chick chorioallantoic membrane. Extracts of skeletal muscle, cardiac muscle, and liver lack similar stimulatory activity. The activity is nondialyzable, stable at 56 degrees C, and inactivated at 100 degrees C. Retinal extracts stimulate the proliferation of corneal fibroblasts but have no effect on the proliferation of vascular smooth muscle cells. Indirect evidence suggests the liberation of a vasoproliferative factor from retina in several ocular disorders. The data in this report represent the first direct demonstration of vasoproliferative activity from mammalian retina.

[Lower incidence of type 2 diabetes mellitus with changes in lifestyle: clues from World War II]. / Lagere incidentie van diabetes mellitus type 2 bij verandering van leefstijl: aanwijzingen uit de Tweede Wereldoorlog.

OBJECTIVE: To investigate the relation between diabetes and food consumption on a population level. DESIGN: Retrospective, descriptive. METHOD: Data were collected from the archives of the Public Health Service of Amsterdam and the diabetes aftercare outpatient clinic ('Diabetes Nazorg') in Utrecht, the Netherlands, to determine the incidence of diabetes between 1940 and 1950. The number of outpatient visits for newly-diagnosed diabetes in Amsterdam and Utrecht were used to investigate whether the incidence of diabetes decreased during World War II, when food was scarce. RESULTS: Between 1940 and 1945 there was a considerable decrease in the incidence of diabetes in the Netherlands. The number of outpatient consultations at the Public Health Service of Amsterdam for newly-diagnosed diabetes declined from 140 in 1940 (18% of the total number of consultations) to only 3 in 1940 (2%). This figure rose to 112 (21%) in 1949. CONCLUSION: The marked decrease in the number of new cases of diabetes during the last years ofWorld War II supports the hypothesis that shortage of food induced a decrease in the incidence of type 2 diabetes in The Netherlands.

Correlation of fibrosis and transforming growth factor-beta type 2 levels in the eye.

Approximately 1 out of every 10 eyes undergoing surgery for retinal detachment develops excessive intraocular fibrosis that can lead to traction retinal detachment and ultimate blindness. This disease process has been termed proliferative vitreoretinopathy (PVR). The ability to monitor and grade this fibrotic response accurately within the eye as well as the ability to aspirate vitreous cavity fluid bathing the fibrotic tissue makes this an ideal setting in which to investigate the development of fibrosis. Although laboratory studies have recently shown that transforming growth factor-beta (TGF-beta) can enhance fibrosis, little clinical evidence is yet available correlating the level of this or other growth factors with the degree of fibrosis in a clinical setting. We have found that vitreous aspirates from eyes with intraocular fibrosis associated with PVR have more than three times the amount of TGF-beta (1,200 +/- 300 pM [SEM]) found in eyes with uncomplicated retinal detachments without intraocular fibrosis (360 +/- 91 pM [SEM]). Using an in vitro assay, 84-100% of the TGF-beta activity could be blocked with specific antibodies against TGF-beta 2, whereas only 10-21% could be blocked by specific antibodies against TGF-beta 1. TGF-beta 1 was used in an animal model of traction retinal detachment. Since beta 1 and beta 2 have essentially identical biologic effects and only human beta 1 was available in quantities required, beta 1 was chosen for these in vivo studies. The injection of TGF-beta1 plus fibronectin (FN) but not TGF-beta1 alone into the vitreous cavity of rabbits resulted in the increased formation of intraocular fibrosis and traction retinal detachments as compared to control eyes. In previous studies, intravitreal FN levels were also found to be elevated in eyes with intraocular fibrosis.

The organic preservation of fossil arthropods: an experimental study.

Modern arthropod cuticles consist of chitin fibres in a protein matrix, but those of fossil arthropods with an organic exoskeleton, particularly older than Tertiary, contain a dominant aliphatic component. This apparent contradiction was examined by subjecting modern cockroach, scorpion and shrimp cuticle to artificial maturation (350 degrees C/700 bars/24 h) following various chemical treatments, and analysing the products with pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). Analysis of artificially matured untreated cuticle yielded moieties related to phenols and alkylated substituents, pyridines, pyrroles and possibly indenes (derived from chitin). n-Alkyl amides, C16 and C18 fatty acids and alkane/alk-1-ene homologues ranging from C9 to C19 were also generated, the last indicating the presence of an n-alkyl component, similar in composition to that encountered in fossil arthropods. Similar pyrolysates were obtained from matured pure C16 and C18 fatty acids. Py-GC/MS of cuticles matured after lipid extraction and hydrolysis did not yield any aliphatic polymer. This provides direct experimental evidence that lipids incorporated from the cuticle were the source of aliphatic polymer. This process of in situ polymerization appears to account for most of the fossil record of terrestrial arthropods as well as marine arthropods that lacked a biomineralized exoskeleton.

Magnification--a new look at a long-known optical property of dentin.

Light propagation in human dentin exhibits a strong directional dependence featuring the long-known optical magnification property. We hypothesized that this anisotropic effect is caused by multiple scattering at the dentin tubules, and not by fiberoptic effects, as had been previously assumed. We performed measurements of the transmitted intensity from dentin disks and compared them with Monte Carlo simulations of light propagation in dentin, considering the scattering by the tissue's microstructure. We found that the optical anisotropy of dentin can be fully explained with this model. We concluded that the magnification property of dentin is due to multiple scattering by the dental microstructure.

Impairment of cerebrovascular reactivity in long-term type 1 diabetes.

The early preclinical detection of cerebrovascular complications in individuals with diabetes is one of the goals of care described in the St. Vincent Declaration. In accordance with this goal, the aim of the present work was to investigate whether altered cerebral microvascular function in patients suffering from type 1 diabetes can be detected with a transcranial Doppler probe after the administration of acetazolamide. A total of 72 type 1 diabetic patients and 40 healthy control subjects entered the study. Patients were divided into two groups: those with long-term diabetes (disease duration of >10 years, n = 37) and those with short-term diabetes (disease duration of < or =10 years, n = 35). Mean blood-flow velocity in the middle cerebral artery (MCAV) was measured at rest and at 5, 10, 15, and 20 min after intravenous administration of 1 g acetazolamide with a transcranial Doppler probe and expressed as the percentage change from the pretest measurement. The percentage increase in MCAV (cerebrovascular reactivity) was calculated at each time point and compared between the groups. Cerebrovascular reserve capacity (CRC), expressed as the maximal percentage increase of the MCAV, was compared between the groups. Additionally, a reproducibility study of CRC was performed in 10 patients, using intraclass correlations. Cerebrovascular reactivity in the long-term diabetes group was lower (means +/- SD: 5 min, 23.4 +/- 15.4%; 10 min, 28.8 +/- 17.0%; 15 min, 30.0 +/- 15.6%; 20 min, 24.2 +/- 17.8%) than that of the control subjects (5 min, 43.5 +/- 23.9%; 10 min, 55.3 +/- 24.0%; 15 min, 56.7 +/- 23.8%; 20 min, 54.8 +/- 25.9%) and the short-term diabetic patients (5 min, 43.6 +/- 25.9%; 10 min, 52.2 +/- 27.7%; 15 min, 55.3 +/- 32.2%; 20 min, 45.8 +/- 35.8%). CRC was lower in the long-term diabetes group than in the control group or the short-term diabetes group. Impairment of cerebrovascular reactivity was associated with retino- and nephropathy and increased levels of fibrinogen. In contrast, CRC was independent from actual glucose, insulin, glycosylated hemoglobin, von Willebrand factor antigen, and alpha-2 macroglobulin levels. Transcranial Doppler measurements of the changes in MCAV after stimulation with acetazolamide can detect altered cerebral microvascular function in patients with diabetes. Cerebrovascular reactivity and reserve capacity are reduced in patients with long-term diabetes. Further prospective studies should delineate the clinical significance of our results.

Randomized, double-blind study comparing saruplase with streptokinase therapy in acute myocardial infarction: the COMPASS Equivalence Trial. Comparison Trial of Saruplase and Streptokinase (COMASS) Investigators.

OBJECTIVES: This study sought to demonstrate the equivalence of saruplase and streptokinase in terms of 30-day mortality. BACKGROUND: The use of thrombolytic agents in the treatment of acute myocardial infarction is well established and has been shown to substantially reduce post-myocardial infarction mortality. METHODS: Three thousand eighty-nine patients with symptoms compatible with those of acute myocardial infarction for < 6 h entered the study at a total of 104 centers and were randomized to receive streptokinase (1.5-MU infusion over 60 min) or saruplase (20-mg bolus and 60-mg infusion over 60 min). In the saruplase group, a bolus of heparin (5,000 IU) was administered before saruplase, and a corresponding blinded double-dummy placebo bolus was administered before streptokinase. All patients received intravenous heparin infusions for > or = 24 h starting 30 min after the end of the thrombolytic infusions; the infusions were titrated to maintain an activated partial thromboplastin time at 1.5 to 2.5 times that of normal. RESULTS: Death of any cause up to 30 days after randomization occurred in 88 (5.7%) of 1,542 patients randomized to receive saruplase and 104 (6.7%) of 1,547 patients randomized to receive streptokinase (odds ratio 0.84, p < 0.01 for equivalence). Hemorrhagic strokes occurred more often in patients receiving saruplase (0.9% vs. 0.3%), whereas thromboembolic strokes were more prevalent in the streptokinase-treated patients (0.5% vs. 1.0%). The rate of bleeding was similar in the two treatment groups (10.4% vs. 10.9%). Hypotension and cardiogenic shock occurred less frequently in the saruplase group. Reinfarction rates were similar. CONCLUSIONS: Saruplase is a clinically safe and effective thrombolytic medication. This profile ranks saruplase favorably among the currently available thrombolytic agents.

Anecortave acetate for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE: Anecortave acetate is a novel angiostatic cortisene being evaluated clinically for treatment of exudative age-related macular degeneration (ARMD). A randomized, placebo-controlled, efficacy and safety dose duration study of anecortave acetate for depot suspension (3 mg, 15 mg, 30 mg) in this patient population was completed in June 2003. As part of this trial, 128 patients with subfoveal choroidal neovascularization (CNV) secondary to ARMD were enrolled and treated for up to 2 years by 18 clinical sites in the United States and European Union. METHODS: Study patients were evaluated clinically with detailed ophthalmic examinations, general physical examinations, assessments of best-corrected logMAR visual acuity, and angiographic evaluations. The Digital Angiography Reading Center (New York City, NY) assessed lesion eligibility while the clinical investigators assessed overall patient eligibility prior to treatment. As part of this study, study medication was delivered as a posterior juxtascleral depot using a specially designed curved cannula at 6-month intervals if in the masked investigator's opinion the patient's lesion could benefit from additional treatment. RESULTS: The 2-year efficacy results of this placebo-controlled study demonstrated that RETAANE 15 mg (anecortave acetate for depot suspension) was statistically superior to placebo for stabilization of vision (<3 logMAR line change from baseline) and for inhibition of neovascular lesion growth. There were no serious treatment-related safety issues associated with either the study medication or the procedure for administration. CONCLUSIONS: Anecortave acetate 15 mg for depot suspension is clinically efficacious compared to placebo for treatment of subfoveal exudative ARMD lesions when administered at 6-month intervals as a posterior juxtascleral depot.

[Continuous subcutaneous insulin infusion is sometimes a good choice in case of poorly regulated diabetes mellitus type I]. / Continue subcutane insuline-infusie soms goede optie bij slecht gereguleerde diabetes mellitus type I.

Continuous subcutaneous insulin infusion (CSII) was initiated in 3 patients with diabetes mellitus type I who experienced difficulties with their glucose regulation: a woman aged 26 years and two men aged 56 and 41 years. 2 patients responded very well, while the third, the youngest man, did not benefit. Although interest in CSII has been growing in recent years, considerable uncertainty exists about which patients will benefit from it. In most studies, patients have attained a lower HbA,, and fewer blood glucose fluctuations. Recently, the advantages of CSII have been confirmed in 2 large studies in patients with diabetes mellitus type I. Motivated patients in poor glycaemic control seem to benefit most from CSII. Some questions remain, especially whether these advantages can be confirmed in studies comparing CSII with injection regimens using the new long-acting insulin analogues. Motivated patients in poor control and those with an unpredictable daily life, needing a flexible mode of therapy, should not be denied a trial of CSII.

ACS, myocardial bridging, Tako-tsubo syndrome and mitral regurgitation.

Isolated systolic compression of the mid portion of the left anterior descending artery (LAD) by a bridge of overlying cardiac muscle is an infrequent but well-recognised angiographic anomaly that is often considered harmless. The long-term prognosis appears to be excellent, but occasional reports of patients with angina pectoris, myocardial infarction and sudden death indicate that this is not always true. The prevalence of the anomaly in the normal population is unknown, but the incidence is low and ischaemic events are rare. Tako-tsubo-like left ventricular dysfunction syndrome (TTS) is characterised by ischaemia, anterior ST-segment elevation, no significant coronary artery disease and reversible ampulla-like left ventricular ballooning in postmenopausal females after emotional or physical stress. Dynamic left ventricular outflow tract (LVOT) obstruction is a rare but potentially fatal complication of acute anterior wall infarction. We present a patient with an acute coronary syndrome (ACS) with ST-segment elevation in the anterior leads, transient TTS and transient LVOT obstruction with systolic anterior motion (SAM) of the mitral valve and severe mitral regurgitation. This is the first report of myocardial bridging associated with TTS, and the first report of TTS associated with dynamic LVOT obstruction with SAM and mitral regurgitation.

Regional implementation of the NWC guideline on ST-elevation myocardial infarction: Report from the Task Force Prehospital Triage Zuidoost Brabant (PHT ZoB).

BACKGROUND: The NVVC guideline on ST-elevation myocardial infarction forms the basis for the regional prehospital triage (PHT) project in Zuidoost Brabant. In this project diagnosis and treatment strategies are determined in the ambulance. AIM: To summarise quality assessment and clinical results after one year. METHODS: We evaluated the protocol and patient record form, the patient's call, assignment of tasks, diagnosis, treatment, time intervals, information to hospitals, cooperation and data transmission. Time delays were compared with time delays in a regional dry run before the start of the project and with time delays reported in the literature. RESULTS: Patients still wait over one hour before seeking medical attention. The GP received the majority (65%) of patient calls. In half of all cases (51%), GPs call the ambulance centre only after they have seen the patient. When the patient calls the ambulance centre (35%), information to the GP is either prompt or absent. In 77% of calls to 112 it remains unclear whether the GP was informed at all. The treatment strategy was correct in 97% of cases. Time between symptoms and call decreased in comparison with our local preliminary investigation. Quality assessment after one year shows protocol deviations that are either logical procedural improvements or correctable flaws with no substantial negative influence. CONCLUSION: Short-term clinical results are good, but structured follow-up is needed to reduce mortality in the long term, especially after thrombolysis. A guideline is a snapshot of a dynamic process. The PHT project allows rapid adaptations to be made to new paradigms.

The role of psychiatrists in the medical school admissions process.

Psychiatrists function in various ways in the admissions process of medical schools. They serve on admissions committees, act as consultants, and provide expertise in evaluating applicants known to be at psychological risk. The authors discuss the pros and cons of broadening admissions criteria; the assessment of the diagnosis, functioning, and prognosis of an applicant; the supportive services necessary for students screened into medical school; and the avoidance of homogenization of medical students. They conclude that the participation of psychiatrists is critical to the efficient operation of the admissions process and the medical school itself.

The psychodynamic formulation: its purpose, structure, and clinical application.

The authors present a brief written psychodynamic formulation that focuses on central conflicts, anticipates transferences and resistances, and helps guide all psychiatric treatments. After placing the presenting problem in the context of the patient's life and identifying nondynamic determinants of the psychopathology, the formulation explains the development of central conflicts and their repetitive effect on the patient's behavior. It concludes by describing how these conflicts will be manifested in treatment. Three sample formulations and their application are presented to illustrate the value of this clinical tool.

Comparison of saruplase and alteplase in acute myocardial infarction. SESAM Study Group. The Study in Europe with Saruplase and Alteplase in Myocardial Infarction.

Four hundred seventy-three patients with acute myocardial infarction (AMI) were treated with either saruplase (80 mg/hour, n = 236) or alteplase (100 mg every 3 hours, n = 237). Comedication included heparin and acetylsalicylic acid. Angiography was performed at 45 and 60 minutes after the start of thrombolytic therapy. When flow was insufficient, angiography was repeated at 90 minutes. Coronary angioplasty was then performed if Thrombolysis In Myocardial Infarction (TIMI) trial 0 to 1 flow was seen. Control angiography was at 24 to 40 hours. Baseline characteristics were similar. Angiography showed comparable and remarkably high early patency rates (TIMI 2 or 3 flow) in both treatment groups: at 45 minutes, 74.6% versus 68.9% (p = 0.22); and at 60 minutes 79.9% versus 75.3% (p = 0.26). Patency rates at 90 minutes before additional interventions were also comparable (79.9% and 81.4%). Angiographic reocclusion rates were not significantly different: 1.2% versus 2.4% (p = 0.68). After rescue angioplasty, angiographic reocclusion rates of 22.0% and 15.0% were observed. Safety data were similar for both groups. Thus, (1) early patency rates were high for saruplase and alteplase treatment, (2) reocclusion rates for both drugs were remarkably low, and (3) complication rates were similar. Thus, saruplase seems to be as safe and effective as alteplase.

Psychotherapeutic approaches to the treatment of anxiety and depressive disorders.

Psychotherapy, both alone and in combination with pharmacotherapy, is one of the most prevalent treatments for depression and anxiety. Research data are sparse, but there is ample evidence that several psychotherapies are effective for acute affective and panic disorders. The best data are for interpersonal and cognitive-behavioral therapies, with only early reports on the more common psychodynamic psychotherapies. There has been less study of more chronic disorders, but once again the suggestion is that appropriate psychotherapy is effective. Treatment should be active and focused on the patient's symptoms and current problems, not on character pathology or developmental psychodynamics.

Surgical management of nonmagnetic intraocular foreign bodies.

Selected nonmagnetic, intraocular foreign bodies can be successfully removed from the posterior segment by a modification of the pars plana vitrectomy technique using foreign-body forceps. Opacities of the ocular media are cleared and the foreign body mobilized using the vitrectomy instrument. The foreign body is extracted, under direct visualization, with forceps. Reflex-free illumination is provided by an intraocular, fiberoptic light source. The globe is supported with a double Flieringa ring to prevent collapse after removal of the formed vitreous. Retinal reattachment surgery can be performed during the same operation if indicated.

Vitrectomy for complications of diabetic retinopathy.

Pars plana vitrectomy was used to treat 134 consecutive eyes with complications resulting from proliferative diabetic retinopathy, including nonabsorbing vitreous hemorrhage, recent traction and rhegmatogenous retinal detachment, progressive fibrovascular proliferation, and early rubeosis iridis with recent vitreous hemorrhage. Vision improved after surgery in 65% of the eyes, was unchanged in 16%, and decreased after surgery in 19%. In 24% of the successful cases, vision of 20/50 or better was achieved. When all posterior cortical vitreous was removed, no preretinal fibrovascular growth occurred after surgery. Nonatrophic epiretinal fibrovascular membranes that were not removed usually underwent centripetal contraction after surgery, causing tangential traction on the adjacent retina. Rubeosis iridis was the most common postoperative complication in otherwise successful cases, and rubeosis underwent regression after scatter retinal photocoagulation in some eyes.

Treatment of dislocated posterior chamber intraocular lenses.

We treated five patients with posterior chamber intraocular lenses that were dislocated into the vitreous cavity. Using a pars plana approach, a vitrectomy was performed, and the intraocular lens was grasped with forceps and repositioned behind the iris with the lens loops in the ciliary sulcus. The loops were sutured to the iris in four cases. Visual acuity returned to 20/25, or better, in each case.

New system of intraocular instruments. I. Guillotine intraocular forceps.

A four-instrument system of 20-gauge, rustproof intraocular forceps can be used in conjunction with pars plana vitrectomy to (1) extract intraocular foreign bodies, (2) manipulate intraocular tissue and a dislocated pseudophakos, and (3) obtain biopsy specimens of vitreous gel and abnormal preretinal and epiretinal membranes. The forceps can also be used as an intraocular needleholder for transvitreal suturing of selected giant retinal tear flaps. These instruments are lightweight and sturdy and use a guillotine action and a new barrel-handle design. To facilitate introduction and use through a pars plana approach, the various jaw faces are angled 135 degrees from the long axis. Prototype models have been used successfully in numerous and varied clinical applications.