Late outcomes after acute pulmonary embolism: rationale and design of FOCUS,a prospective observational multicenter cohort study

Acute pulmonary embolism (PE) is a frequent cause of death and serious disability. The risk of PE-associated mortality and morbidity extends far beyond the acute phase of the disease. In earlier follow-up studies, as many as 30?% of the patients died during a follow-up period of up to 3 years, and up to 50?% of patients continued to complain of dyspnea and/or poor physical performance 6 months to 3 years after the index event. The most feared ‘late sequela’ of PE is chronic thromboembolic pulmonary hypertension (CTEPH), the true incidence of which remains obscure due to the large margin of error in the rates reported by mostly small, single-center studies. Moreover, the functional and hemodynamic changes corresponding to early, possibly reversible stages of CTEPH, have not been systematically investigated. The ongoing Follow-Up after acute pulmonary embolism (FOCUS) study will prospectively enroll and systematically follow, over a 2-year period and with a standardized comprehensive program of clinical, echocardiographic, functional and laboratory testing, a large multicenter prospective cohort of 1000 unselected patients (all-comers) with acute symptomatic PE. FOCUS will possess adequate power to provide answers to relevant remaining questions regarding the patients’ long-term morbidity and mortality, and the temporal pattern of post-PE abnormalities. It will hopefully provide evidence for future guideline recommendations regarding the selection of patients for long-term follow-up after PE, the modalities which this follow-up should include, and the findings that should be interpreted as indicating progressive functional and hemodynamic post-PE impairment, or the development of CTEPH.

     

Magnetic resonance imaging of the distal radial epiphysis: a new criterion of maturity for determining whether the age of 18 has been completed?

To improve the accuracy of forensic age estimation where there is no legal basis for carrying out x-ray examinations, it would be useful to establish non-x-ray imaging techniques. The objective of this study was to provide reference data for the magnetic resonance imaging-based evaluation of the ossification stage of the distal radius. Furthermore, we tested a new criterion of the maturity of the distal radial epiphysis for determining whether an individual has completed the age of 18. We investigated 668 MRI scans of the distal radial epiphysis from 333 female and 335 male subjects ranging in age from 12 to 24. To determine the ossification stage, we used the clavicular ossification staging systems described by Schmeling et al. and Kellinghaus et al. Ossification stage IV as described by Schmeling et al. was divided into two sub-stages, IVa and IVb, depending on whether or not it was possible to identify a triple-banded meta-epiphyseal zone of calcification. All study subjects were able to be assigned to an ossification stage without ambiguity. We present statistics relating to the distribution of ossification stages divided by sex. The age of the youngest female subject assessed as ossification stage IVb was 16.8, the age of the youngest male subject 18.6. The youngest age at which female subjects were assessed as ossification stage V was 22.3; for male subjects it was 23.1. Further independent studies should be carried out to determine whether ossification stage IVb can indeed be used to reliably determine whether a male subject has completed the age of 18.

     

Halothane-induced Dilatation of Intraparenchymal Arterioles in Rat Brain Slices: A Comparison to Sodium Nitroprusside

Background: Halothane is a potent dilator of cerebral arteries. The predominant site of cerebrovascular resistance is thought to be intracerebral arterioles, and the effects of halothane on these vessels were not previously examined. This study compared the effects of halothane with those of the vasodilator and nitric oxide donor, sodium nitroprusside, on intraparenchymal microvessel responsiveness in a brain slice preparation.

Methods: Anesthetized Sprague-Dawley rats underwent thoracotomy and intracardiac perfusion and then were decapitated. Hippocampal brain slices were prepared and placed in a perfusion/recording chamber and superfused with artificial cerebrospinal fluid. An arteriole was located within the brain parenchyma and its diameter was monitored with videomicroscopy before, during, and after various concentrations of halothane or sodium nitroprusside were equilibrated in the perfusate. All vessels were preconstricted with prostaglandin F2alpha before halothane or sodium nitroprusside treatment. An observer blinded to treatment analyzed vessel diameter changes with a computerized videomicrometer.

Results: Baseline microvessel diameter was 18 +/- 2 micro meter in the halothane group (n = 14) and 15 +/- 1 micro meter in the sodium nitroprusside group (n = 15). Prostaglandin F2alpha (0.5 micro Meter) preconstricted vessels by approximately 15% from resting diameter in both groups. Halothane significantly and dose dependently dilated intracerebral microvessels by 54% +/- 6%, 74% +/- 8%, 108% +/- 13%, and 132% +/- 7% (normalized to the preconstricted diameter) at 0.5%, 1.0%, 1.5%, and 2.5% halothane, respectively. This dilatation corresponds to a decrease in a calculated index of cerebrovascular resistance index of up to 117% +/- 2% at 2.5% halothane. Sodium nitroprusside, in concentrations ranging from 10 sup -8 to 10 sup -3 M, also dose dependently dilated these intraparenchymal vessels by 129% +/- 7% at the highest concentration. These alterations in microvessel diameter corresponded to a decrease in the cerebrovascular resistance index of up to 116% +/- 4% for the largest dose.     

Region-specific and Agent-specific Dilation of Intracerebral Microvessels by Volatile Anesthetics in Rat Brain Slices

Background: Volatile anesthetics are potent cerebral vasodilators. Although the predominant site of cerebrovascular resistance is attributed to intracerebral arterioles, no studies have compared the actions of volatile anesthetics on intraparenchymal microvessels. The authors compared the effects of halothane and isoflurane on intracerebral arteriolar responsiveness in hippocampal and neocortical microvessels using a brain slice preparation.

Method: After Institutional Review Board approval, hippocampal or neocortical brain slices were prepared from anesthetized Sprague-Dawley rats and placed in a perfusion-recording chamber, superfused with artificial cerebrospinal fluid. Arteriolar diameters were monitored with videomicroscopy before, during, and after halothane or isoflurane were equilibrated in the perfusate. PGF2 alpha preconstricted vessels before anesthetic administration. A blinded observer using a computerized videomicrometer analyzed diameter changes.

Results: Baseline microvessel diameter and the degree of preconstriction were not different between groups. In the hippocampus, the volatile agents produced similar, concentration-dependent dilation (expressed as percent of preconstricted control +/- SEM) of 68 +/- 6% and 79 +/- 9% (1 MAC) and 120 +/- 3% and 109 +/- 5% (2 MAC) (P < 0.05) during halothane and isoflurane, respectively. In the cerebral cortex, isoflurane caused significantly less vasodilation than did similar MAC levels of halothane (84 +/- 9% vs. 42 +/- 5% dilation at 1 MAC; 121 +/- 4% vs. 83 +/- 5% dilation at 2 MAC halothane vs. isoflurane, respectively).     

Effect of Δ-tetrahydrocannabinol on hypothalamic thermosensitive units

Thermosensitive anterior hypothalamic neurons (pre-optic region) were studied in urethane and chloralose anesthetized cats in an attempt to characterize the hypothermic action of Δ⁹-THC at the neuronal level. One hundred and seventy-eight single neurons were isolated and subjected to thermal challenge, 66 were found to reproducibly alter firing frequency at a significant level (thermosensitivity (T.S.) > 0.75). Twenty-one of these units met the criteria for primary thermodetectors, 34 were heat-sensitive interneurons, and 11 were cold-sensitive interneurons. Administration of Δ⁹-THC (1.0–2.0 mg/kg i.v.) decreased the spontaneous firing and increased the T.S. of the primary thermodetector units. Δ⁹-THC also increased the spontaneous firing frequency as well as the T.S. of heat-sensitive interneurons, while decreasing both the T.S. and spontaneous firing of cold-sensitive interneurons. The decreased spontaneous firing of primary thermodetectors could result from altered facilitory or inhibitory influences converging on these cells. The increased thermosensitivity is consistent with the hypothesis that the pre-optic region modulates cannabinoid-induced hypothermia.     

Incontinentia pigmenti Bloch-Sulzberger Fallbericht

Background. Bloch-Sulzberger syndrome (incontinentia pigmenti) is an x-linked dominant disease, affecting the skin, the central nervous system, the eyes, the teeth and the skeleton with variable expression. Diagnosis is suspected in the presence of typical sequence of skin symptom change during the first weeks of life. Case report. Here, we report on a now two year old girl who first presented with epileptic seizures, severe encephalopathy with distinct necrosis of cerebral medulla and cortex at the age of two days. Thereafter the child developed mental retardation, spastic tetraparesis and microcephaly. There were no distinct skin eruptions. A typical generalised dermatosis appearing with papular and pustular lesions resulting into reticular hyperpigmentation became evident at the age of two years when she suffered from septic lymphadenitis. Diagnosis of incontinentia pigmenti was considered and confirmed by the histologic examination of skin biopsy. Conclusion. This case demonstrates, that if skin changes do not occur during the infant period, diagnosis may be delayed. Since the family history revealed no further affected individuals and the mother had no history of abortions with two living healthy sons, sporadic mutation may have occurred in this child.     

High-resolution CT in the differential diagnosis of consolidative processes (I. Acute processes)

Consolidations are usually result of the replacement of the alveolar air by fluid, cells or tissue but these can also be seen with extensive interstitial processes. These diseases cannot be clearly categorized into the classic classification scheme of airspace and interstitial disease since there are features of both categories seen in the imaging and histologic findings. Because this definition includes wide variety of diseases with overlapping HRCT-findings it is difficult to distinguish among these entities with imaging criteria alone. However, integration of HRCT-findings and clinical findings may enable a narrower differential diagnosis. This review describes the most common types of lung diseases associated with acute appearance of consolidation and discuss the differential diagnosis.     

Infliximab in two patients with juvenile ankylosing spondylitis

Infliximab, a monoclonal chimeric anti-tumor necrosis factor alpha (anti-TNF-) antibody, was tried in two patients suffering from severe refractory juvenile ankylosing spondylarthritis with disease duration of more than 10 years. To assess the response, validated clinical activity parameters were monitored prospectively. In both patients, treatment with infliximab at a dosage of 5 mg/kg body weight already led to considerable improvement with loss of joint pain the day after it was given. Bath Ankylosing Spondylitis Functional Index scores decreased from 5.8 to 0 and 7.2 to 1.0 and the Bath Ankylosing Spondylitis Disease Activity Index from 2.6 to 1.4 and 9.0 to 1.0. In one patient, the response to a single infusion continued for more than 8 months. Because of a recurrence of symptoms in intervals of 2 months, the fourth infusion has now been given to the second patient, resulting in immediate clinical response. No side effects have been noted. Infliximab seems to be a promising agent for treatment of active and refractory juvenile ankylosing spondylitis. Controlled studies and long-term observations are warranted.     

Effects of hypoxia-reoxygenation on microvascular endothelial function in the rat hippocampal slice.

BACKGROUND: Cerebral ischemia and hypoxia may cause injury to both neuronal and vascular tissue. The direct effects of hypoxia on endothelial function in intraparenchymal cerebral arterioles are unknown. Using a modification of the rat brain slice preparation, allowing continuous imaging of these previously inaccessible vessels, microvessel dilation was evaluated before and after a brief hypoxic episode. METHODS: Rat brain slices were superfused with oxygenated artificial cerebrospinal fluid. Hippocampal arterioles were visualized using computerized videomicroscopy, and their diameters (range, 12-27 microm) were measured using image analysis. After preconstriction with prostaglandin F2alpha and controlled pH and carbon dioxide tension, graded concentrations of either acetylcholine (endothelium-dependent vasodilation) or sodium nitroprusside (endothelium-independent vasodilation) were given before and after a 10-min period of hypoxia. RESULTS: Sodium nitroprusside (100 microM) caused similar dilation before and after hypoxia (mean +/- SEM: 9.6 +/- 0.6% vs. 13.0 +/- 0.9%). Acetylcholine (100 microM) caused significantly less dilation (P < 0.05) after hypoxia (mean +/- SEM: 9.3 +/- 1.8% vs. 3.6 +/- 1.2%). The decreased acetylcholine-induced dilation after hypoxia was not reversed by pretreatment with L-arginine (1 mM), the precursor of nitric oxide (mean +/- SEM: 8.8 +/- 1.3% vs. 4.4 +/- 0.7%). CONCLUSIONS: Even brief periods of hypoxia may cause endothelial dysfunction in intraparenchymal cerebral arterioles. This does not seem to be related to a deficiency of the nitric oxide substrate, L-arginine. Endothelial dysfunction and impaired endothelium-dependent dilation of microvessels may decrease oxygen delivery and increase neuronal injury during cerebral hypoxia-reoxygenation.     

Sevoflurane Selectively Increases Coronary Collateral Blood Flow Independent of KATP Channels In Vivo

Background: Volatile anesthetic agents produce coronary vasodilation via activation of adenosine triphosphate-sensitive potassium (KATP) channels. The authors tested the hypothesis that sevoflurane selectively increases coronary collateral blood flow and assessed the role of KATP channel activation in this process.

Methods: Experiments were conducted in dogs 8 weeks after long-term implantation of a left anterior descending coronary artery (LAD) ameroid constrictor to stimulate coronary collateral growth. Dogs were instrumented for measurement of retrograde LAD blood flow (an index of large coronary collateral blood flow) and LAD tissue flow (via radioactive microspheres; an index of small collateral blood flow). Coronary collateral perfusion and normal (left circumflex coronary artery [LCCA]) zone tissue blood flow were determined in four groups of dogs pretreated with intracoronary glyburide (50 [micro sign]g/kg) or vehicle in the presence or absence of sevoflurane (1 minimum alveolar concentration). Dose-response relationships to the KATP channel agonist nicorandil were established in each dog using doses (25, 50, and 100 [micro sign]g/min) previously shown to increase coronary collateral blood flow.

Results: Sevoflurane increased blood flow through large and small collaterals and increased collateral vascular conductance in the presence of glyburide but did not affect LCCA blood flow or conductance. In contrast, nicorandil increased blood flow through small but not large collaterals. Nicorandil also increased LCCA blood flow and conductance, actions that were attenuated by glyburide.