The assessment of the risk of fracture in femora with metastatic lesions: comparing case-specific finite element analyses with predictions by clinical experts.

Previously, we showed that case-specific non-linear finite element (FE) models are better at predicting the load to failure of metastatic femora than experienced clinicians. In this study we improved our FE modelling and increased the number of femora and characteristics of the lesions. We retested the robustness of the FE predictions and assessed why clinicians have difficulty in estimating the load to failure of metastatic femora. A total of 20 femora with and without artificial metastases were mechanically loaded until failure. These experiments were simulated using case-specific FE models. Six clinicians ranked the femora on load to failure and reported their ranking strategies. The experimental load to failure for intact and metastatic femora was well predicted by the FE models (R(2) = 0.90 and R(2) = 0.93, respectively). Ranking metastatic femora on load to failure was well performed by the FE models (τ = 0.87), but not by the clinicians (0.11 < τ < 0.42). Both the FE models and the clinicians allowed for the characteristics of the lesions, but only the FE models incorporated the initial bone strength, which is essential for accurately predicting the risk of fracture. Accurate prediction of the risk of fracture should be made possible for clinicians by further developing FE models.

Influence of an increased intracranial pressure on cerebral and systemic haemodynamics during endoscopic neurosurgery: an animal model.

BACKGROUND: During endoscopic neurosurgery, direct mechanical stimulation of the brain by the endoscope and increased intracranial pressure (ICP) caused by the continuous rinsing can induce potentially lethal haemodynamic reflexes, brain ischaemia, and excessive fluid resorption. METHODS: In a newly presented rat model of endoscopic neurosurgery, stereotactic access to the cerebrospinal fluid was secured and the ICP was increased by controlled infusion until complete suppression of the cerebral perfusion pressure (CPP). The haematocrit (Hct) level was determined before and after the procedure. During the whole procedure, invasive arterial pressure, ICP, and heart rate were continuously recorded and evaluated in a subsequent offline analysis. After the procedure, the animals were allowed to recover and 7 days later they were killed for histological examination. RESULTS: Suppression of the CPP resulted in a severe hypertension combined with tachycardia or mild bradycardia. The Hct decreased from 41 to 35 over the minutes of CPP suppression. After cessation of the infusion, the ICP decreased to 37% of the plateau pressure within 2.5 s. In the first few minutes after restoration of normal ICP, five animals died because of pulmonary oedema. CONCLUSIONS: Upon complete suppression of the CPP, an obvious hypertension developed, often together with tachycardia, but no severe bradycardia. At high ICP levels, we observed an important translocation of irrigation fluid to the vascular space. Fatality was not caused by ischaemia or arrhythmia but due to pulmonary oedema.

Is elongation-induced leaf emergence beneficial for submerged Rumex species?

BACKGROUND AND AIMS: Plant species from various taxa 'escape' from low oxygen conditions associated with submergence by a suite of traits collectively called the low oxygen escape syndrome (LOES). The expression of these traits is associated with costs and benefits. Thus far, remarkably few studies have dealt with the expected benefits of the LOES. METHODS: Young plants were fully submerged at initial depths of 450 mm (deep) or 150-240 mm (shallow). Rumex palustris leaf tips emerged from the shallow flooding within a few days, whereas a slight lowering of shallow flooding was required to expose R. acetosa leaf tips to the atmosphere. Shoot biomass and petiole porosity were measured for all species, and treatments and data from the deep and shallow submergence treatments were compared with non-flooded controls. KEY RESULTS: R. palustris is characterized by submergence-induced enhanced petiole elongation. R. acetosa lacked this growth response. Upon leaf tip emergence, R. palustris increased its biomass, whereas R. acetosa did not. Furthermore, petiole porosity in R. palustris was twice as high as in R. acetosa. CONCLUSIONS: Leaf emergence restores gas exchange between roots and the atmosphere in R. palustris. This occurs to a much lesser extent in R. acetosa and is attributable to its lower petiole porosity and therefore limited internal gas transport. Leaf emergence resulting from fast petiole elongation appears to benefit biomass accumulation if these plants contain sufficient aerenchyma in petioles and roots to facilitate internal gas exchange.

Comparison of long term outcome of patients with rheumatoid arthritis presenting with undifferentiated arthritis or with rheumatoid arthritis: an observational cohort study.

BACKGROUND: The outcome of undifferentiated arthritis (UA) ranges from remission to rheumatoid arthritis (RA) fulfilling the American College of Rheumatology (ACR) classification criteria. OBJECTIVES: To report the outcome of UA after 1 year of follow up and compare the disease course of patients who presented with UA, but evolved into RA within 1 year (UA-RA group), with that of patients who presented with RA fulfilling the ACR criteria (RA-RA group). METHODS: The diagnosis of 330 patients who presented with UA was recorded at 1 year. The UA-RA and RA-RA groups were then followed up for 3 more years. Outcome measurements were radiographic progression, disease activity, and functional capacity. RESULTS: From 330 patients who were diagnosed UA, 91 had evolved into RA at 1 year; 62 patients had presented with RA. No significant differences were detected between the UA-RA and RA-RA groups in median Sharp/van der Heijde score at baseline, radiographic progression rates, disease activity, and functional capacity. However, significantly more disease modifying antirheumatic drugs were prescribed in the RA-RA group. CONCLUSION: The disease outcome of patients who present with UA that evolves into RA within 1 year is the same as that of patients who present with RA as measured by radiographic progression, disease activity, and functional capacity.

Value of Cushing reflex as warning sign for brain ischaemia during neuroendoscopy.

BACKGROUND: During an endoscopic neurosurgical procedure a sudden increase in intracranial pressure may occur at any time. We present a prospective study of haemodynamic changes during such procedures. METHODS: Physiological data were recorded during the whole operative procedure in 17 consecutive patients who underwent an endoscopic neurosurgical procedure under general anaesthesia. Monitoring included invasive blood pressure, intracranial pressure, electrocardiogram, end-expired carbon dioxide, pulse oximetry and heart rate. Pressure and ECG waveforms were recorded at 100 Hz and evaluated in a subsequent offline analysis. RESULTS: In almost every case, the occurrence of hypertension and tachycardia was clearly the result of an increase in intracranial pressure. Also, a Cushing reflex developed in almost every case where the cerebral perfusion pressure dropped below 15 mm Hg. The occurrence of bradycardia was not systematically associated with a low cerebral perfusion pressure. CONCLUSION: In this study, we describe the haemodynamic effects of increased intracranial pressure during endoscopic neurosurgical procedures and their respective sequence of events at high temporal resolution. Although most clinicians rely on the occurrence of bradycardia to diagnose intracranial hypertension during endoscopic neurosurgical procedures, we show that a simultaneous onset of hypertension and tachycardia is a better indicator of impaired brain perfusion. Waiting for a persistent bradycardia to alert the surgeon during endoscopic neurosurgical procedures could allow severe bradycardia or even asystole to develop.

Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis.

OBJECTIVE: To determine the effect of different treatment strategies (early versus delayed) on the radiological progression of joint damage during 4 years. Additionally, to determine the effect of treatment strategy on the association of HLA class II alleles and joint damage. METHODS: Progression of radiographic damage and association of radiographic damage and genetic predisposition were compared in two cohorts, one treated according to the delayed treatment strategy (initial treatment with analgesics), the other treated according to the early treatment strategy (treatment with disease modifying antirheumatic drugs (DMARDs) chloroquine or sulfasalazine). Radiographic damage was measured by the modified Sharp-van der Heijde method. Genetic predisposition was determined by high resolution HLA-DR and DQ typing. RESULTS: A completers-only analysis of 153 patients (originally 206 patients) in a non-randomised design showed less radiographic progression from 0 to 4 years in the early treatment group (median Sharp progression rate 1.3 points/year, n = 75) than in the delayed treatment group (2.5 points/year, n = 78) (p = 0.03). The progression from 1 to 4 years did not differ significantly between the groups. At 4 years, joint destruction in both groups was positively correlated with the presence of the shared epitope. CONCLUSIONS: The beneficial effect of early DMARD treatment on the radiological progression of joint damage is still present at 4 years. However, the rate of joint destruction from 1 to 4 years did not differ between the delayed and early treatment group. Neither the radiographic nor the immunogenetic data suggest that longlasting disease modification has been induced by early treatment.

Cardiovascular changes during endoscopic third ventriculostomy.

During an endoscopic third ventriculostomy (ETV) a sudden increase in intracranial pressure (ICP) may occur at any time. In the literature little attention has been paid to the early detection of such an increase. In particular the occurrence of a 'Cushing reflex' has not been discussed in this context. Therefore, we have now analysed retrospectively the anesthesia charts of 88 patients with obstructive hydrocephalus who had undergone ETV under general anesthesia. Monitoring included invasive blood pressure, electrocardiogram, end-expired carbon dioxide, pulse oximetry and heart rate. These variables were now evaluated before and after the introduction of the endoscope and during and after the occurrence of any change. In 67 patients the procedure had been uneventful. In 6 patients the occurrence of tachycardia and hypertension followed by bradycardia and hypertension was clearly the result of an increase in ICP, which we call a Cushing reflex. In his classical description of this pressure response Cushing reported the occurrence of hypertension, bradycardia and apnoea. However, many investigators have shown that beside systemic hypertension, both tachycardia and bradycardia are essential components of the Cushing reflex. Waiting for a persistent bradycardia to alert the surgeon during ETV can allow a fatal asystole.

The Leiden Early Arthritis Clinic.

In 1993 a special Early Arthritis Clinic (EAC) was established at the Department of Rheumatology of the Leiden University Medical Center in order to detect and treat inflammatory disorders early in the disease state, especially early rheumatoid arthritis. Patients with confirmed arthritis of recent onset (less than 2 years) were included by rheumatologists and trained research nurses. Parameters of first and follow-up visits (3, 6 and 9 months and yearly) that were entered in the EAC-database include the medical history, physical-diagnostic examination, laboratory tests, questionnaires, radiographic joint scores and diagnosis. This database enables us to conduct research on arthritis, with an emphasis on rheumatoid arthritis, in many ways. Physicians and basic scientists have studied cellular immunology and genetic, environmental and clinical risk factors in order to determine the pathophysiologic mechanisms of inflammatory arthritis. The present article is a review on reports published from the EAC. Over the past ten years, these reports have been highly relevant for both daily clinical practice and research. Present and planned future studies, as described in this article, reconfirm the importance of an EAC framework to ensure that research continues on this disease in the Leiden EAC area.

The effect of temperature and protein synthesis on the renaturation of firefly luciferase in intact H9c2 cells.

A mild increase in temperature that does not exert an effect on tolerance development or synthesis of heat shock proteins (Hsps) in control cells can stimulate these processes when applied to cells that have previously been heat shocked. To study the underlying mechanism of this effect, H9c2 cells were stably transfected with the gene encoding firefly luciferase (Luc). Heat-shock-induced inactivation of Luc and its subsequent reactivation is frequently used as a model for cellular protein denaturation and renaturation. Luc reactivation was determined following a damaging heat shock (43 or 44 degrees C for 30 min) in cells that were subsequently exposed to either control temperatures (37 degrees C) or various mild hyperthermic conditions (from 38.5 to 41.5 degrees C for 1 h). To prevent changes in Luc activity consequent to new synthesis of Luc, Luc reactivation was monitored in the presence of cycloheximide, an inhibitor of protein synthesis. The results showed that reactivation of Luc was inhibited when heat-treated cells were post-treated under mild hyperthermic conditions. The observed increase in Hsp synthesis under mild hyperthermic post-heat shock conditions therefore appears to be the result of an increase in the period during which denatured proteins are present. In addition, we studied Luc reactivation in the absence of protein synthesis inhibitors. This condition led to much higher Luc activity. By estimating half-life times of Luc, the contribution of new Luc synthesis in this recovery could be determined, and only partially explained the observed increase in Luc reactivation after heat shock. Thus the synthesis of other proteins must be important for the renaturation of heat-damaged proteins.

[Tuberculosis of the larynx]. / Tuberculose in de larynx.

Laryngeal tuberculosis was diagnosed in two men, a 73-year-old man Dutch by birth and a 40-year-old one Turkish by birth. In the former patient it was probably primary tuberculosis, in the latter secondary (he had lung tuberculosis as well). The clinical picture was highly suggestive of laryngeal carcinoma in both patients. They both recovered with chemotherapy. Laryngeal tuberculosis may mimic laryngeal carcinoma. The diagnosis is based on Ziehl-Neelsen staining, culture and polymerase chain reaction (PCR) on Mycobacterium tuberculosis. Because laryngeal tuberculosis is highly infectious, the patient has to be nursed in isolation and people in his or her environment have to be screened. The response of laryngeal tuberculosis to chemotherapy is good.

Jugular bulb oximetry: review on a cerebral monitoring technique.

Jugular bulb oximetry is the first available continuous monitoring method estimating the adequacy of cerebral perfusion. Despite its major technical as well as methodological shortcomings the information on the oxygen supply to demand balance of the brain seems most valuable. Especially the deleterious consequences of systemic variations (mainly concerning arterial blood pressure and CO2-tension) on the diseased brain are revealed by jugular bulb saturation values. The prevention and/or the early detection of these systemic secondary insults could have important implications as to final neurological outcome. Jugular bulb oximetry could also guide specific intracranial antihypertensive treatment, as it may reveal the pathophysiological mechanisms behind intracranial hypertension with regard to the status of cerebral perfusion (cerebral hyperemia or cerebral hypoperfusion). These insights might increase the efficacy of all treatments available for intracranial hypertension.

In vitro evaluation of the effect of profound haemodilution with hydroxyethyl starch 6%, modified fluid gelatin 4% and dextran 40 10% on coagulation profile measured by thromboelastography.

Synthetic colloids have been implicated as a cause of coagulopathy when administered in large quantities. The effect of profound haemodilution (50%) on coagulation profile was measured in vitro by thromboelastography. Blood samples were taken from 11 ASA grade 1 patients prior to induction of anaesthesia for elective surgery. Each sample was simultaneously tested in four different preparations: undiluted blood (control sample); blood diluted with hydroxyethyl starch 6%; blood diluted with modified fluid gelatin 4%; blood diluted with dextran 40 10%. There was a significant decrease in reaction time in the preparations treated with hydroxyethyl starch 6% and modified fluid gelatin 4%, reflecting activation of initial fibrin formation. A significant increase in clot formation time was noted in the hydroxyethyl starch 6%-treated preparations. There was also a significant decrease in clot formation rate and maximum amplitude in the hydroxyethyl starch 6% group. Clot formation time, clot formation rate and maximum amplitude did not change in the modified fluid gelatin 4% group. Profound haemodilution with dextran 40 10% exerted extreme effects on the measured variables, very often resulting in a straight line on the thromboelastography profile.

Fever attributed to the use of hydroxyurea.

We report on three patients who developed fever after starting treatment with the anti-neoplastic agent, hydroxyurea. Fever occurred within 5 days to 3 weeks after starting treatment. In all cases the causal relationship between fever and use of hydroxyurea was demonstrated by spontaneous recovery after drug withdrawal and was confirmed by recurrence of fever after rechallenge. Other causes were excluded. Fever was accompanied by rash, gastro-intestinal and pulmonary symptoms, and arthralgia. Physicians should be aware of the fact that unexplained fever may be caused by hydroxyurea.

Seat-belt use and relation to neurologic injury in motor vehicle crashes.

The relation between seat-belt use and neurologic injury was examined for the 1,352 patients who had spinal injuries as the result of motor vehicle crashes and were subsequently admitted to the Midwest Regional Spinal Cord Injury Center at Northwestern University between 1971 and 1993. Intact lesions were observed in 44% of patients (Frankel level E), complete lesions in 28% (Frankel A), sensory intact lesions in 8% (Frankel B), motor intact lesions in 5% (Frankel C), and functional motor lesions in 14% (Frankel D). Whereas only 14% of the sample were wearing seat belts, 60% of the belted and 41% of the unbelted vehicle occupants had intact lesions. The odds of surviving a motor vehicle crash with an intact injury were greater for patients who were wearing a lap or shoulder belt (odds = 1.57) for women (odds = 0.63) and for patients whose injury occurred more recently (odds = 1.05). The relation between position in the vehicle and extent of injury was strongest for rear passengers: intact lesions were sustained by 73% of belted and 35% of unbelted rear passengers, whereas complete lesions were sustained by 9% of the belted and 21% of the unbelted rear passengers. In conclusion, seat belts appear to be an effective means of decreasing the extent of neurologic deficit in those sustaining spinal injuries caused by motor vehicle crashes. The results of this study support injury-prevention efforts that emphasize lap- and shoulder-belt use.

Operative closure of patent ductus arteriosus in the neonatal intensive care unit.

Preterm infants undergoing surgical closure of patent ductus arteriosus are usually critically ill and are suffering from many concomitant diseases. The high risk of increased morbidity in transferring them from the neonatal intensive care unit (NICU) to a distant operating room is generally recognized. For this reason we report our experience in 33 premature infants with patent ductus arteriosus who have been operated in the NICU over a six-year period. There were no operative or immediate postoperative deaths and the 30 days hospital mortality was 6%. Based upon these findings we can confirm that operative closure of PDA can be performed safely in the NICU.

Evaluation of the anticoagulant properties of aprotinin in vitro.

The interaction of aprotinin with normal coagulation was studied in blood samples obtained from 10 healthy subjects. Each sample was simultaneously tested in four different preparations: NaCl-treated blood: 0.03 mL 0.9% NaCl in 0.33 mL blood; aprotinin treated blood: 0.33 mL blood+aprotinin in 0.03 mL in aliquots to obtain a final blood concentration of respectively 50 KIU mL-1; 100 KIU mL-1 and 200 KIU mL-1. The coagulation process was analysed by thromboelastography. R-time, reflecting intrinsic coagulation, increased in a dose dependent manner between NaCl-treated and aprotinin-treated blood. These findings suggest a dose dependent impairment of intrinsic coagulation by aprotinin.

Tip-localized calcium entry fluctuates during pollen tube growth.

Studies have been conducted on the dynamics of Ca2+ entry in pollen tubes using ratiometric ion imaging to measure the intracellular gradient and an ion selective vibrating electrode to detect the extracellular influx. A steep tip-focused gradient occurs in all species examined, including Lilium longiflorum, Nicotiana sylvestris, and Tradescantia virginiana. Anlaysis of Lilium pollen tubes loaded with dextran conjugated fura-2 reveals that the gradient derives from Ca2+ entry that is restricted to a small area of plasma membrane at the extreme apex of the tube dome. Since the apical membrane is continually swept to the flanks during tube elongation, either Ca2+ channels are specifically retained at the extreme apex or, as seems more likely, the Ca2+ channels which were active at the tip rapidly inactivate, as new ones are inserted during vesicle fusion. Ratiometric imaging further indicates that the high point of the gradient fluctuates in magnitude from 0.75 to above 3 microM, during measuring intervals of 60 sec, with the elevated points being correlated with an increased rate of tube growth. Independent analysis of the growth at 2- to 3-sec intervals reveals that the rates can fluctuate more than threefold; tubes longer than 700 mu m exhibit oscillations with a period of 23 sec, while tubes shorter than 700 mu m display erratic fluctuations. Inhibition of pollen tube growth caused by mild temperature shock or caffeine (1.5 to 3.0 mM) is correlated with the dissipation of the tip-focused gradient and the Ca2+ influx. Recovery from both treatments is denoted by a global swelling of the pollen tube tip, concomitant with a high transient entry of Ca2+ in the tip. The location of the highest Ca2+ domain within the tip region defines the point from which normal cylindrical elongation will proceed.