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Abundant reserves of metals and oil have spurred large-scale mining developments across northwestern Canada during the past 80 years. Historically, the associated emissions footprint of hazardous metal(loid)s has been difficult to identify, in part, because monitoring records are too short and sparse to have characterized their natural concentrations before mining began. Stratigraphic analysis of lake sediment cores has been employed where concerns of pollution exist to determine pre-disturbance metal(loid) concentrations and quantify the degree of enrichment since mining began. Here, we synthesize the current state of knowledge via systematic re-analysis of temporal variation in sediment metal(loid) concentrations from 51 lakes across four key regions spanning 670 km from bitumen mining in the Alberta Oil Sands Region (AOSR) to gold mining (Giant and Con mines) at Yellowknife in central Northwest Territories. Our compilation includes upland and floodplain lakes at varying distances from the mines to evaluate dispersal of pollution-indicator metal(loid)s from bitumen (vanadium and nickel) and gold mining (arsenic and antimony) via atmospheric and fluvial pathways. Results demonstrate 'severe' enrichment of vanadium and nickel at near-field sites (≤20 km) within the AOSR and 'severe' (near-field; ≤ 40 km) to 'considerable' (far-field; 40-80 km) enrichment of arsenic and antimony due to gold mining at Yellowknife via atmospheric pathways, but no evidence of enrichment of vanadium or nickel via atmospheric or fluvial pathways at the Peace-Athabasca Delta and Slave River Delta. Findings can be used by decision makers to evaluate risks associated with contaminant dispersal by the large-scale mining activities. In addition, we reflect upon methodological approaches to be considered when evaluating paleolimnological data for evidence of anthropogenic contributions to metal(loid) deposition and advocate for proactive inclusion of paleolimnology in the early design stage of environmental contaminant monitoring programs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The properties of conventional materials result from the arrangement of and the interaction between atoms at the nanoscale. Metamaterials have shifted this paradigm by offering property control through structural design at the mesoscale, thus broadening the design space beyond the limits of traditional materials. A family of mechanical metamaterials consisting of soft sheets featuring a patterned array of reconfigurable bistable domes is reported here. The domes in this metamaterial architecture can be reversibly inverted at the local scale to generate programmable multistable shapes and tunable mechanical responses at the global scale. By 3D printing a robotic gripper with energy-storing skin and a structure that can memorize and compute spatially-distributed mechanical signals, it is shown that these metamaterials are an attractive platform for novel mechanologic concepts and open new design opportunities for structures used in robotics, architecture, and biomedical applications., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley‐VCH GmbH.)

Origami enables folding of objects into a variety of shapes in arts, engineering, and biological systems. In contrast to well-known paper-folded objects, the wing of the earwig has an exquisite natural folding system that cannot be sufficiently described by current origami models. Such an unusual biological system displays incompatible folding patterns, remains open by a bistable locking mechanism during flight, and self-folds rapidly without muscular actuation. We show that these notable functionalities arise from the protein-rich joints of the earwig wing, which work as extensional and rotational springs between facets. Inspired by this biological wing, we establish a spring origami model that broadens the folding design space of traditional origami and allows for the fabrication of precisely tunable, four-dimensional-printed objects with programmable bioinspired morphing functionalities., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Soft actuation allows robots to interact safely with humans, other machines, and their surroundings. Full exploitation of the potential of soft actuators has, however, been hindered by the lack of simple manufacturing routes to generate multimaterial parts with intricate shapes and architectures. Here, we report a 3D printing platform for the seamless digital fabrication of pneumatic silicone actuators exhibiting programmable bioinspired architectures and motions. The actuators comprise an elastomeric body whose surface is decorated with reinforcing stripes at a well-defined lead angle. Similar to the fibrous architectures found in muscular hydrostats, the lead angle can be altered to achieve elongation, contraction, or twisting motions. Using a quantitative model based on lamination theory, we establish design principles for the digital fabrication of silicone-based soft actuators whose functional response is programmed within the material's properties and architecture. Exploring such programmability enables 3D printing of a broad range of soft morphing structures.

We review the current status of studies of the coalescence of binary neutron star systems. We begin with a discussion of the formation channels of merging binaries and we discuss the most recent theoretical predictions for merger rates. Next, we turn to the quasi-equilibrium formalisms that are used to study binaries prior to the merger phase and to generate initial data for fully dynamical simulations. The quasi-equilibrium approximation has played a key role in developing our understanding of the physics of binary coalescence and, in particular, of the orbital instability processes that can drive binaries to merger at the end of their lifetimes. We then turn to the numerical techniques used in dynamical simulations, including relativistic formalisms, (magneto-)hydrodynamics, gravitational-wave extraction techniques, and nuclear microphysics treatments. This is followed by a summary of the simulations performed across the field to date, including the most recent results from both fully relativistic and microphysically detailed simulations. Finally, we discuss the likely directions for the field as we transition from the first to the second generation of gravitational-wave interferometers and while supercomputers reach the petascale frontier.

Objective: The aim of this research is to compute a prediction of the future intelligence of every neonate with a meningomyelocele (MMC) on the day of birth to inform the parents. Earlier research revealed that the variables ventricle size, open arch above vertebra lumbar 3, a very small or a very large head can be attended by an IQ below 85 points: the turning point between dependence and independence., Methods: Until now no research has been done combining the values of influencing variables in one equation. Our study used the equation of multiple longitudinal linear regression. For reference, data from the files of 148 neonates born in the years 1960-1980 were compared with those of Dutch children sampled by Verger. The working hypothesis that the IQ level is directly related to congenital deformities of the nervous system needs to be tested. As standard the values of variables at birth, the head circumference and length, the size of the ventricles and the highest open vertebral arch, are to be used., Results: The Wisc-R of the MMC cohort had a mean of 84 points and 55% had an IQ above 85. The correlation computation of the values of all available variables with the values of the measured Wisc-R revealed the significance of the neuroanatomical variables, size of ventricle and level of the highest open vertebral arch and for the anthropomorphic variables Length and Length/Circumference. To establish the relationship between the Wisc-R value and the values of the significant variables an equation with the multiple linear regression method was used. The measured IQ is made dependent on the significant variables size of ventricle, level of highest open arch and quotient Length by Circumference. This equation produces a value called predicted IQ. The predicted IQ was 92%, the same or nearly the same as the measured Wisc-R IQ., Conclusion: This conformity of the measured IQ and the predicted IQ proves the possibility of using these birth data for prediction.

Object: The goal of this study was to evaluate the long-term results of a flow-regulating shunt (Orbis Sigma Valve [OSV] II Smart Valve System; Integra NeuroSciences, Sophia Antipolis, France) in the treatment of hydrocephalus, whether it was a first insertion procedure or surgical revision of another type of shunt, in everyday clinical practice in a multicenter prospective study., Methods: Patients of any age who had hydrocephalus underwent implantation of an OSV II system. The primary end point of the study was defined as any shunt-related surgery. The secondary end point was a mechanical complication (shunt obstruction, overdrainage, catheter misplacement, migration, or disconnection) or infection. The overall 5-year shunt survival rates and survival as it applied to different patient subgroups were assessed. Five hundred fifty-seven patients (48% of whom were adults and 52% of whom were children) were selected for OSV II shunt implantation; 196 patients reached the primary end point. Shunt obstruction occurred in 75 patients (13.5%), overdrainage in 10 patients (1.8%), and infection in 46 patients (8.2%). The probability of having experienced a shunt failure-free interval at 1 year was 71% and at 2 years it was 67%; thereafter the probability remained quite stable in following years (62% at the 5-year follow-up examination). No difference in shunt survival was observed between the overall pediatric (< or = 16 years of age) and adult populations. In the pediatric age group, however, there was a significantly lower rate of shunt survival in children younger than 6 months of age (55% at the 5-year follow-up examination)., Conclusions: In this prospective study the authors demonstrate the effectiveness of flow regulation in the treatment of hydrocephalus both in children and in adults. Flow-regulating shunts limit the incidence of overdrainage and shunt-related complications. The overall 5-year shunt survival rate (62%) compares favorably with rates cited in other recently published series.

Coalescing binary neutron stars (NS) are expected to be an important source of gravitational waves (GW) detectable by laser interferometers. We present here a simple method for determining the compactness ratio M/R of NS based on the observed deviation of the GW energy spectrum from point-mass behavior at the end of inspiral. Our method is based on the properties of quasiequilibrium binary NS sequences and does not require the computation of the full GW signal h(t). Combined with the measurement of the NS masses during inspiral, the determination of M/R will allow very strong constraints to be placed on the equation of state of dense nuclear matter.

Study Design: Prospective cohort study., Objectives: To study the predictive value of magnetic resonance imaging (MRI) findings of thoracolumbar spine fractures concerning the radiologic and clinical outcome., Summary of Background Data: Disagreement about the proper treatment of thoracolumbar spine fractures is caused by insufficiency of conventional imaging techniques. Previous studies have shown that MRI is capable of distinguishing injury to all structures of the fractured spine and thus may help develop schemes with higher predictive power., Methods: A total of 53 patients with 71 fractures were studied with MRI in a prospective fashion. A total of 24 patients with 39 fractures were treated conservatively and 29 patients with 32 fractures were treated operatively after a protocol concerning the treatment options. MRI scans were obtained within 1 week of injury and at the 2-year follow-up. Pain scores were obtained at the 2-year follow-up. Previously described MRI schemes concerning the trauma and post-trauma conditions were used., Results and Conclusions: An unfavorable outcome in the conservative group was related to the progression of kyphosis, which in most cases was predictable with the use of trauma MRI findings concerning the endplate comminution and vertebral body involvement. In the operatively treated group, recurrence of the kyphotic deformity was predictable by the lesion of the posterior longitudinal ligamentary complex together with endplate comminution and vertebral body involvement as seen on trauma MRI. The authors recommend the use of MRI to develop reliable prognostic criteria for these injuries.

Objective: Concerns have been voiced about possible dilation and insufficiency of the neo-aortic valve after the arterial switch operation (ASO)., Aims: To determine growth of the neo-aortic valve and the aortic anastomosis after ASO and the prevalence of insufficiency or stenosis., Patients and Methods: Since 1977, 144 consecutive patients (pts) underwent ASO for transposition of the great arteries (TGA). Median follow-up was 8.65 years (0.1--22.5 years). Simple TGA was present in 97 pts and 47 had TGA with ventricular septal defect (VSD). Detailed echocardiography included measurements of aortic diameter at four levels. The 608 measurements were compared with published normal values., Results: The mean aortic valve z-score was 1.5, without significant change with age (P=0.75). Under 4 months, mean valve z-score was 0.63+/-2.20, between 5 and 12 months 2.56+/-2.30 (P<0.0001). Gradual growth occurs thereafter. The aortic sinus follows an identical growth pattern. The aorta at the anastomosis, is initially smaller than normal (z-score -0.64). After 4 months the z-score is 0.83, followed by continued growth of 0.1 z-score per year. At the last visit, the aortic valve z-score was above 2 in 51 patients, between -2 and 2 in 72 and less than -2 in six patients, none of whom had a flow velocity above 2 m/s. z-score of patients with VSD remained above those without VSD (P<0.0001). Aortic insufficiency was grade 2/4 in three patients, grade 3/4 in one and grade 4/4 in one. No patient developed aortic stenosis., Conclusion: After ASO the neo-aortic valve and sinus are larger than normal, representing the natural size difference in the prenatal situation and influence of associated cardiac malformations. In the first year of life, rapid dilatation of the new aorta is observed, followed by growth towards normalization of the valve and sinus size. Stenosis at the anastomosis was not observed. Aortic dilatation by itself is rarely associated with significant insufficiency.

Background: Although knowledge concerning the impact of acne vulgaris on quality of life has increased in recent years, relatively few studies have assessed the effect of a change in clinical severity on psychosocial state., Objective: Assessment of the effect of a change in clinical acne severity on psychosocial state., Methods: This was investigated by means of questionnaires and clinical assessments by acne patients and dermatologists. Fifty females with mild to moderate facial acne were seen before and after a 9-month treatment with oral contraceptives., Results: The results showed a great variability in psychosocial impairment between individuals. After 9 months, a significant reduction in clinical severity was seen overall which did not relate to the significant improvements in self-esteem, stability of self-esteem and acceptance of appearance., Conclusion: Perceived psychosocial impairment is individually based, is greater in women who subjectively overrate their acne and does not relate to clinical improvement., (Copyright 2001 S. Karger AG, Basel)

Objectives: To determine the homocysteine-lowering effect of different treatment regimens on both fasting and postmethionine-load plasma total homocysteine (tHcy) concentrations., Design: Descriptive study of consecutive hyperhomocysteinaemic subjects per treatment regimen. Homocysteine was measured in the fasting state and 6 h after methionine loading, both before and after 8 weeks of vitamin therapy. Hyperhomocysteinaemia was defined as a fasting tHcy and/or increase in tHcy (postmethionine-load minus fasting tHcy concentration) exceeding the 95th percentile of local controls., Setting: Outpatient clinic of internal medicine of a large non-academic teaching hospital., Subjects: One hundred and seventeen hyperhomocysteinaemic subjects (vascular patients and first-degree relatives)., Interventions: There were four regimens: pyridoxine, 200 mg; folic acid, 5 mg; combination of folic acid 0.5 mg and pyridoxine 100 mg; and folic acid, 0.5 mg daily., Results: All regimens, except pyridoxine 200 mg, significantly reduced fasting tHcy without differences in the percentage reduction (32-38%). All regimens produced a significant reduction in the increase in tHcy and postmethionine-load tHcy. The reduction in postmethionine-load tHcy was smaller for pyridoxine 200 mg than for combination therapy. No differences were found in the percentage reduction (for both increase in tHcy and postmethionine-load tHcy) between folic acid 5 mg and folic acid 0.5 mg., Conclusions: Monotherapy folic acid (0.5 mg daily) is the lowest effective therapy for reducing both fasting and postmethionine-load tHcy concentrations, with the same results as high-dose folic acid (5 mg daily). Pyridoxine has no additional value.

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) may involve the bone marrow in nodular, interstitial, diffuse, or mixed patterns. However, B-cell CLL/SLL associated with large reactive germinal centers (the so-called interfollicular pattern) involving the bone marrow is not reported. We describe 2 examples of B-cell CLL/SLL that subtotally replaced the bone marrow with an interfollicular pattern. In both cases, the neoplasms were composed of small round lymphoid cells; proliferation centers also were present. The neoplasms surrounded large reactive germinal centers that were devoid of peripheral mantle zones. The germinal centers were paratrabecular and nonparatrabecular in case 1 and nonparatrabecular in case 2. Flow cytometry immunophenotypic studies done on bone marrow aspiration samples of both cases showed a uniform population of neoplastic cells positive for pan-B-cell antigens and the CD5 and CD23 antigens. Immunohistochemical studies done on bone marrow biopsy sections supported the flow cytometry results and demonstrated that the germinal centers were negative for BCL-2. B-cell CLL/SLL may rarely involve the bone marrow with an interfollicular pattern. Knowledge of this pattern will prevent confusion with follicle center lymphoma and large cell transformation, both of which initially were considered in the differential diagnosis of these cases.

As part of a nationwide surveillance in The Netherlands during 1994-1997, 53 patients with invasive group A streptococcal (GAS) infections were evaluated for medical history, symptoms, and outcome. Patients' isolates were tested for the production of pyrogenic exotoxins A (SPE-A) and B (SPE-B). Acute-phase sera from all patients and convalescent sera from 12 patients were investigated for the presence of antibodies against SPE-A and SPE-B. Twenty-three patients developed toxic shock-like syndrome and 16 died. Absence of antibodies against SPE-A and/or SPE-B was a risk factor for developing invasive streptococcal disease. Toxic shock and mortality were associated with a lack of anti-SPE-A antibodies (P<.025). Anti-SPE-A antibodies were found in convalescent sera from all patients infected by speA-positive isolates. Virtually all invasive speA-positive streptococci expressed SPE-A protein in vitro. Thus antibodies against SPE-A appeared vital for mediating the outcome of invasive GAS disease in this population.

Exercise training is currently advocated as part of the treatment of patients with cystic fibrosis (CF). However, data are few that document physiologic benefits or changes in patients' perceptions of long-term training programs in children with CF. The aim of this study was to investigate the effects and acceptability of a home cycling program in children with CF. Fourteen patients (9 boys, 5 girls) with CF, mean (SD) age 14.1 (2.0) years, with mild to moderate impairment of lung function (forced expiratory volume in 1 s, mean (SD) 58.3 (16.3)% of predicted) were studied for 1 year. The first half of the study year was used to obtain baseline values at 0 and 6 months. During the second half of the year, a cycle program was carried out 5 times a week, for 20 min each day at a level of work that resulted in a heart rate of 140-160 beats/min. Once a week the cycle program was supervised by a physiotherapist. Measurements were repeated at 12 months. Effects of the exercise program were measured in terms of lung function, nutritional status, growth, muscle strength, exercise performance, perceived competence, and attitude towards the training program. Differences between the changes during the 6-month training period as compared to the 6-month control period were analyzed by multivariate statistics and nonparametric tests. Statistically significant differences (P < 0.05) between the two periods were found with respect to muscle strength of knee extensors and ankle dorsiflexors, and with respect to maximal oxygen consumption per kg body weight as well as per kg fat free mass. All changes were positive. No adverse effects were found. Perceived competence showed significant positive changes in feelings about physical appearance, general self-worth, and Total Perceived Competence Score. Scores concerning perceived acceptability of the program were significantly lower at the end of the training period; however, patients reported that they did want to continue with other sorts of training. We conclude that an exercise training program in the home can produce beneficial effects on oxygen consumption, muscle force, and perceived competence in children with CF. However, acceptability of the program was low, suggesting that long-term adherence would be poor, and hence, other sorts of training need to be identified.

Small-cell variants of Sézary syndrome and mycosis fungoides (MF) have been described. However, in these studies the nuclear area of the small-cell variant of MF (SC-MF) as compared to histological classical MF (CL-MF) was not characterized objectively by quantitative electron microscopy. In a 14-year follow-up period, of a total of 76 patch/plaque stage MF patients seen in the Department of Dermatology of the University Hospital Utrecht, 14 (18%) had an infiltrate composed of atypical lymphocytes characterized by a distinctly smaller cell diameter and smaller, hyperchromatic, deeply indented nuclei as compared to the usual cell type of MF. The aim of the investigation was to confirm this observation objectively using quantitative electron microscopy (morphometry) and to define SC-MF as compared to CL-MF. The study was performed on the 14 patients with SC-MF, and 10 patients with clinical and histological CL-MF and 4 patients with chronic eczema. Electron micrographs of sections obtained from each biopsy were analysed by computer to produce the following data: a nuclear contour index (NCI), the mean nuclear area (MNA), the mean nuclear area of the cells above the 75th percentile (P75NA) and the percentage of cells larger than 30 microm2. The values of MNA differed significantly between patients with SC-MF and those with CL-MF (17.6 vs 23.2 microm2; P = 0.02), as did the values of P75NA (20.7 vs 27.9 microm2; P = 0.01). The NCI of the SC-MF and CL-MF patients were similar. These results are consistent with our observations that SC-MF does indeed exist.

We have compared the location of the ocular tumors in hereditary retinoblastoma in relation to the age of the patients at time of diagnosis. Eighty fundus drawings were analyzed from 59 hereditary patients containing I 59 tumors. At the time of diagnosis, indirect ophthalmoscopy was performed under general anaesthesia in all patients and standard drawings of the retina were made depicting the number and relative location of all tumors. The distance between the center of the tumor and the center of the macula was measured and plotted against the age of the patients at time of diagnosis. The results show that the distance between the center of the tumor and the center of the macula at time of diagnosis increases with age during the first seven months after birth.

The effect of raised intracranial pressure (ICP), due to infantile hydrocephalus, on the process of myelination has been suggested in the literature. In this study 19 hydrocephalic infants were followed-up with anterior fontanelle pressure (AFP) measurement (assessment of ICP), MRI (assessment of the myelination process and the CSF volume), and neurodevelopmental testing (NDT). There was a high correlation (r = 0.80) between the myelination and NDT scores. The size of the CSF volume showed a poor correlation with the mean AFP, the degree of myelination and the NDT scores. There was, however, a significant correlation between the mean AFP and the degree of myelination (r = 0.67) and also between the mean AFP and the NDT scores (r = 0.70). Longer-term follow-up (mean = 27 months) showed a significant correlation between the early progress of myelination and later developmental level (r = 0.78). Most of the children with a severely delayed myelination, preoperatively, showed a recovery of myelination following CSF drainage. It was concluded that: (1) raised ICP is related to developmental outcome, through the process of myelination; (2) the delay in myelination can be (partially) reversible; and (3) CSF volume is of minor importance regarding neurodevelopment.

To assess the role of insulin-like growth factors (IGFs) in growth and transformation of normal (myometrium) and tumorous smooth muscle cell (SMC) tissues, in situ hybridization (ISH) analysis for insulin-like growth factor I and II (IGF-I and IGF-II) mRNAs was combined with detection of IGF peptides, their receptors and IGF binding protein-3 (IGFBP-3). mRNAs for both IGFs were detected in smooth muscle cells in normal, benign and malignant SMC tissues, together with the IGF peptides, both IGF receptors and IGFBP-3. This suggests an autocrine role for both IGFs. Leiomyomas had higher IGF-I peptide levels and higher levels of type I IGF receptors than myometrium, supporting the idea that IGFs play a role in the growth and transformation of these tumours. Low-grade leiomyosarcomas contained more IGF-II mRNAs than myometrium and leiomyoma, fewer type II IGF/mannose 6-phosphate receptors and less IGFBP-3 than myometrium and, in addition, fewer IGF-I mRNAs and type I IGF receptors than leiomyoma. Intermediate- and high-grade leiomyosarcomas had intermediate levels of IGF-II mRNAs and peptide, ranging between those in myometrium and low-grade leiomyosarcomas. Thus, growth and transformation of leiomyosarcomas may be regulated by IGF-II, although more markedly in low-grade than in high-grade leiomyosarcomas. In conclusion, the various categories of SMC tissues are associated with a distinct expression pattern of the IGF system. This suggests that each category of SMC tumours arises as a distinct entity and that there is no progression of transformation in these tissues.

The histopathology of 61 eyes was studied with special attention to the morphology of the retina adjacent to the main tumour. Three retinal types were distinguished. Retina type 1 (RT-1, 28 specimens) contained a single tumour that was sharply demarcated from surrounding normal retina. In retina type 2 (RT-2, 29 specimens) large parts of the retina were affected and the main tumour mass gradually blended with the adjacent pathological retina. Retina type 3 (RT-3, four specimens) was characterised by a retina almost entirely affected by diffuse tumour growth. RT-1 correlated significantly with early enucleation (0-3 years) both in hereditary and non-hereditary cases. RT-2 was seen in eyes enucleated later (2-5 years). The progressing tumour may release growth factors in the intraocular space that stimulate the cells of the adjacent retina and lead to multiple new primary tumours in the adjacent retinal area. RT-3 was only present in non-hereditary cases with late enucleation (at 2-5 years). Hereditary retinoblastoma cases are usually detected early. Therefore in hereditary cases RT-1 is significantly more common than RT-2. In 25 eyes of the 44 patients with unilateral sporadic retinoblastoma, multifocal tumours of the retina were observed. Such cases should not mistakenly be classified as hereditary cases on the basis of the histological pattern of multifocality of the tumour process.

The treatment of choice in progressive hydrocephalus is drainage of cerebrospinal fluid in order to reduce elevated intracranial pressure (ICP). Defining the right moment for surgical intervention, however, in a hydrocephalic infant on the basis of clinical signs alone can be a difficult task. Clinical signs of raised ICP are known to be unreliable and sometimes even misleading. In the present study, the relationship between long-term anterior fontanelle pressure (AFP) measurements and clinical signs was investigated in 37 infants with hydrocephalus. The decision as to whether to operate or not was based on clinical signs alone; AFP values were not taken into account. There was an overall difference between the non-operated group and the preoperative measurements in the operated group, and also between the preoperative and the postoperative measurements in the latter, in regard to both AFP measurements and clinical signs. Almost all preoperative AFP values were increased. The direct correlation (phi) between most individual clinical signs and AFP levels, however, was low (phi = 0.15-0.41). The clinical sign "tense fontanelle" showed the best correlation with the AFP levels (phi = 0.75). Furthermore, using logistic regression analysis, no combination of clinical signs could be found which reliably predicted the AFP. The relationship between the AFP pressure variables and clinical signs was also examined. The pathological A-waves occurred only in the presence of raised (baseline) AFP, a situation in which considerably more frequent B-waves were observed as well. It was concluded that clinical signs of raised ICP in infantile hydrocephalus are not very reliable and AFP monitoring can therefore provide valuable information on intracranial dynamics in patients with dubious neurological manifestations of progressive hydrocephalus.

Study Objective: To estimate age dependent sensitivity and sojourn time in a breast cancer screening programme by different methods., Population and Methods: The study population comprised women participating in the DOM project--the Utrecht screening programme for the early detection of breast cancer. Breast cancer screening prevalence data and incidence rates after a negative screen were used to estimate age specific sensitivity and mean sojourn time by different methods., Main Results: Maximum likelihood estimates of the mean sojourn time varied from one year for women aged 40-49 years to three years for women over the age of 54. Sensitivity was calculated by two different methods. Both pointed to a high sensitivity (around 100%) in the age groups 40-49 and over 55 years. For women aged 50-54, the sensitivity varied from 63% to 100%, depending on the method used and the value of the baseline incidence rate., Conclusions: Different methods of estimating sensitivity pointed at an acceptable level in women over and under 50 years of age. Sojourn time, and thus the tumour growth rate, seemed to be age dependent. This could mean that the until now disappointing screening results in women under 50 years of age are not so much a result of low sensitivity as of a relatively high tumour growth rate in younger women.

In Zimbabwe, ocular squamous cell carcinoma (OSCC) was frequently observed in 5 breeding herds of Simmental cattle, a Bos taurus breed originating from Switzerland. In these herds, initial signs of OSCC were already noticeable in cattle about 3 years old. Gradually, OSCC prevalence increased, and 36 to 53% of cattle over 7 years old had 1 or more tumors. More tumors developed in Simmental cattle with periorbital white skin than in cattle with periorbital pigmented skin. Other breeds of cattle (eg, Friesian) also are partly white-faced and live in Zimbabwe in a comparable environment; yet, OSCC prevalence was lower in those breeds.

Cerebral hemodynamic changes in infants with progressive hydrocephalus have been studied with the transcranial Doppler (TCD) technique. Several authors have referred to the correlation between the hemodynamic changes and increased intracranial pressure (ICP). Despite conflicting conclusions on the value of pulsatility index (PI) and resistance index (RI) measurements for monitoring infantile hydrocephalus, these pulsatility indices are the most commonly used for this purpose. Although clinical signs of raised ICP are highly variable and unreliable in infants, assumptions have been made in most of the studies about the presence of elevated ICP on the basis of the patient's clinical state. Few studies have reported on actual ICP values, however, and a direct relationship between ICP and TCD changes has never been adequately demonstrated. In the present study, this relationship was investigated in long-term simultaneous TCD/ICP measurements, in an attempt to develop a noninvasive method of monitoring the effect of ICP on intracranial hemodynamics. Two groups of data sets were established. Group I consisted of pre- and postoperative (shunt implantation) TCD/ICP measurements. Group II were long-term simultaneous TCD/ICP recordings showing significant ICP variations. In most of the postoperative measurements there was a decrease in the average PI and RI values. The correlation between PI or RI and ICP in the long-term simultaneous recordings, however, was generally poor. The risk of obtaining false positive or false negative PI or RI values in short-term measurements was also demonstrated. It can be concluded from our results, besides the wide range of reference values for the Doppler indices and extracranial influences upon them, that the present Doppler indices are inadequate for monitoring the complex intracranial dynamic responses in patients with raised ICP.

We have tested the therapeutic potency of peritumorally injected low doses of interleukin-2 (IL-2). Seventy tumours of the bovine ocular squamous-cell carcinoma (BOSCC), 1-3 cm in diameter, were treated with 5000, 20,000 or 200,000 U IL-2 from Eurocetus (Chiron) to find the optimal dose for treatment. Injections were given peritumorally on Monday to Friday on 2 consecutive weeks. The size of the tumours was measured before treatment and 1, 3, 4, 9 and 20 months after treatment. After 9 months complete regression was observed in 89% of the tumours treated with 5000 U IL-2, 80% treated with 20,000 U and 67% treated with 200,000 U. After 20 months, there was complete regression of 35%, 31% and 67% of the tumours respectively. The 9- and 20-month results of the 200,000-U treatment are significantly better than those of the 5000-U and 20,000-U treatments taken together. This protocol may be useful to treat advanced inoperable tumours (e.g. of the nasopharynx or skin) of human patients.

Recently, we showed that complement resistance is an important virulence factor of Moraxella (Branhamella) catarrhalis. Our study used a serum bactericidal assay to determine complement resistance in M. catarrhalis. Although the serum bactericidal assay is considered the "gold standard" for determining complement resistance, it is laborious and time-consuming and therefore not well suited for large-scale studies. Using a large number (n = 324) of M. catarrhalis isolates obtained from the sputa of patients with lower respiratory tract infections (n = 200) and young carriers (n = 124), we assessed the value of a simple "culture-and-spot" test as an alternative to the serum bactericidal assay. For both groups of isolates, the degree of concordance between the two tests used was very significant (P < 0.0001). The agreement between the two assays was estimated to be "excellent beyond chance" (as determined by Cohen's kappa test). The culture-and-spot assay is a valuable alternative to the serum bactericidal assay, not only for screening purposes as shown here but also for studying the mechanism of complement resistance in M. catarrhalis at the molecular level.

The aims of the present study were: (i) to identify the association of patterns of congenitally missing teeth with combinations of ectodermal symptoms occurring in patients with oligodontia; and (ii) to propose a diagnostic scheme for the general practitioner. For this study 167 patients with oligodontia, both isolated and as part of a syndrome, and 135 healthy controls were interviewed and documented. Chi-square tests, logistic regression and correspondence analysis were used to evaluate and test differences between the groups and associations between the congenitally missing teeth and ectodermal symptoms. No significant differences were found between the control group and the patients with isolated oligodontia with exception of the skin. It could be concluded from the present study that there were no clear associations between congenitally missing teeth, either individually or patterns, and the ectodermal symptoms or combinations of ectodermal symptoms. However, it could be concluded that if the most stable teeth are missing, or if the number of missing teeth is large the patient should be examined carefully for symptoms of ectodermal dysplasia. Using logistic regression a patient could be classified as having isolated oligodontia or oligodontia as part of a syndrome with a specificity and sensitivity of 88.2%.

A 72-year-old man had posturally induced syncopal episodes, followed by quadriparesis, coma, and death. Neuroimaging studies supported the clinical diagnosis confirmed by neuropathological findings.

Risk factors for breast cancer were compared in 107 women with interval breast cancer (cancers occurring within 2 years after a negative screen) and 258 women with breast cancer detected at 1st screening. All women (aged 40-67) were screened in the DOM project (the Utrecht programme for the early detection of breast cancer). Women with an interval cancer reported more often a history of benign breast disease (OR 4.66, 95% C.I. 2.08-10.41) and an artificial menopause (OR 4.07; 95% C.I. 1.74-9.55) than women with a screen detected cancer. Women with an interval cancer were taller than women with a screen detected cancer; this was seen most clearly in women with an artificial menopause (chi 2 for trend = 5.88; p = 0.02) and to a lesser extent in premenopausal women (chi 2 for trend = 1.70; p = 0.19). Premenopausal women with an interval cancer were heavier than women with a screen detected cancer (chi 2 for trend = 4.66; p = 0.03); whereas natural postmenopausal women with an interval cancer were leaner than women with a screen detected cancer (chi 2 for trend = 1.57; p = 0.21). All analyses were done while correcting for age and selected other risk factors for breast cancer. These results suggest that the epidemiological profile of pre- and post-menopausal women with an interval cancer differs from that of women with a screen detected cancer, which might imply a different natural history of these two types of breast tumours.

For a better definition of diagnostic subgroups of patients with temporomandibular disorders (TMD), clinical orthopedic tests have been developed for the masticatory system, for use together with the commonly used active movement tests and palpation. In the present study, the characteristics and additional diagnostic value of four orthopedic tests--namely, passive opening, the joint play test, compression, and the static pain test--were determined for a patient group, diagnostic subgroups, and a control group. Significant differences among the scores of the tests in the different groups indicated that all six orthopedic tests contributed to the diagnostic process. Because of the close functional relationship of the masticatory system, most information was obtained when patients indicated where pain occurred during the different tests. Logistic regression techniques were used for determination of the relative diagnostic value of each orthopedic test in the diagnostic process. Active movement was the most powerful test for distinguishing the different subgroups. Palpation and passive opening were additionally useful for distinguishing between patients and control subjects and between the subgroups of arthrogenous and myogenous patients. Besides active movement, both compression and the joint play test played a minor role in the distinction of subgroups of arthrogenous patients. It may be concluded that in routine clinical practice, besides history taking and conventional radiography, a functional examination consisting of active movements, passive opening, and palpation provides valuable diagnostic information. In patients with a specific diagnostic problem, one of the other additional tests might be indicated.

In a previous study the expression of the adhesion molecule LFA-1 on tumour cells in patients suffering from multiple myeloma (MM) was correlated with growth of the malignant plasma cells in vivo. Here we describe a novel in vitro flow cytometric adhesion assay (FCAA) which, based on scatter and fluorescence properties, was used to analyse the contribution of the LFA-1/intercellular adhesion molecule-1 (ICAM-1) adhesion pathway in the binding of bone marrow (BM)-derived LFA-1-positive primary tumour cells of patients with MM to interferon-gamma (IFN-gamma)-activated, ICAM-1-positive, human venous umbilical endothelial cells (huVEC) in vitro. To validate the FCAA, cells from different myeloma cell lines were labelled with the fluorescent dye CFDA or stained for CD38 expression, and LFA-1-mediated adhesion to IFN-gamma-activated endothelial cells was quantified. Results obtained with the FCAA were compared with a conventional adhesion assay employing 51Cr-labelled cells. Statistical analysis revealed that both assays gave similar results. This allowed analysis of the contribution of LFA-1 to the adhesive potential of malignant plasma cells in bone marrow mononuclear cells (BMMC) from MM patients to IFN-gamma-activated endothelial cells. The results prove that LFA-1 expressed on bone marrow-derived plasma cells from MM patients can be used for cellular adhesion to ICAM-1 expressed on adherent growing cells, and are suggestive for a role of the LFA-1/ICAM-1 adhesion pathway in the pathophysiology of MM. The FCAA described in this study is a generally applicable assay, allowing analysis of the interaction of distinct subpopulations with in vitro grown adherent cells of different origin.

In children with hydrocephalus, accurate and reproducible estimation of the presence, severity, and course of the condition is of paramount importance for both clinical and scientific purposes. In this study, 30 hydrocephalic patients were assessed with a number of commonly used methods, such as occipitofrontal skull circumference (SC) measurements, Evans ratio (ER), and bicaudate index (BCI), as well as, for comparison, another ratio of linear measurements [ventricle-skull ratio (VSR)] and MR measurements of total intracranial CSF volume. In repeated CSF volume measurements in healthy volunteers, the MR method appeared to be accurate and reproducible. This technique was simpler and easier in application, requiring less interaction than comparable MR techniques described by others. The variation coefficients were within the same range. In increased CSF volumes, our technique can be recommended; in very small CSF volumes, another technique is more adequate. Direct assessment of CSF volume as a measure of hydrocephalus was preferable over derived estimations for scientific purposes and may function as a gold standard against which to evaluate other techniques that are easier to apply clinically. In comparison, SC measurements were poor; CSF volume changes were not reflected in SC changes. VSR was preferable over ER and BCI, because it correlated more closely with CSF volume.

Background: Thrombus regression in heparin-treated, acute deep venous thrombosis of the lower extremity is poorly documented in the literature; different rates of thrombus resolution and recanalization are reported., Methods and Results: In a prospective follow-up study, duplex scanning was used to evaluate the thrombus regression in patients with documented acute femoropopliteal thrombosis. Eighty vein segments in 20 legs of 18 patients were subjected to repeat duplex scans at 1, 3, 6, 12, and 26 weeks after diagnosis; 49 segments showed thrombus at diagnosis. The popliteal vein showed the highest thrombus load at diagnosis, followed in descending order by the superficial femoral, profunda femoris, and common femoral vein segments (p less than 0.001). Thrombus regression was significant (p less than 0.001) in all segments and proceeded at an exponential rate that was equal in the different vein segments of the upper leg. Both thrombus resolution and recanalization appeared to be a function of the initial thrombus load and could not be related to individual vein segments. Recanalization was seen in 23 of 31 initially occluded segments and occurred within the first 6 weeks after diagnosis in 20 of 23 segments. Extension of thrombus despite anticoagulant therapy was observed in 15 vein segments and was not related to the initial thrombosis score (p = 0.1) or individual vein segments (p = 0.23). Thrombus extension in seven patients with prethrombotic conditions was not different (p = 0.9) from the other patients., Conclusions: Duplex scanning is an important noninvasive tool to quantify thrombus regression in acute deep venous thrombosis in detail without unnecessary discomfort to the patient.

A prospective cross-sectional study was performed on hydrocephalic infants and children. MRI was used to assess the state of myelination and to quantify the intracranial cerebrospinal fluid (CSF) volume repeatedly in all children. At the same time, neurodevelopmental testing was performed. A positive correlation was found between the progress of myelination and psychomotor development, but there were no significant correlations between CSF volume and myelination or between CSF volume and psychomotor development. This study provides strong evidence in favour of Flechsig's thesis that myelination expresses the functional maturity of the brain. The interdependency of neuronal maturation and progress of myelination are discussed.

We compared the behavior of a 70% water content hydrogel lens to a 24-hour collagen shield in 11 healthy volunteers. Corneal swelling was measured by means of ultrasound pachymetry. After 24 hours of continuous wear, mean corneal thickness increased 26.4 microns (4%) with the hydrogel lens and 17.9 microns (3%) with the collagen shield, a difference that was not significant at the P less than 0.05 level. Both the hydrogel lens and the corneal shield were well tolerated. Ocular discomfort was slightly greater with the collagen shield. We assume that this is related to the reduction in visual acuity and subsequent loss of binocular vision with the collagen shield. The development of a fully transparent collagen shield would enhance patient compliance and facilitate assessment of the corneal and intraocular status in eye disease.

After birth the human brain is subject to major maturational changes, which are associated with changes in the biochemical composition of the brain and brain metabolism. Magnetic resonance (MR) spectroscopy has special capabilities in the analysis of in vivo metabolism. Volume-selective proton and phosphorus MR spectroscopy of the brain was performed on a 1.5-T magnet in 41 healthy children aged 1 month to 16 years. With advancing age, phosphorus spectra revealed a decrease in the ratios of phosphomonoesters (PMEs) to beta-adenosine triphosphate (ATP) and PMEs to phosphocreatine (PCr) and an increase in the ratios of phosphodiesters to beta-ATP, PCr to beta-ATP, and PCr to inorganic phosphate (Pi). No significant changes were observed in Pi/beta-ATP and pH. No changes occurred after the age of 3 years. Proton spectroscopy revealed an increase in the ratios of N-acetylaspartate (NAA) to choline (Ch) and NAA to creatine (Cr) and a decrease in Ch/Cr with increasing age. The most rapid changes were noted during the first 3 years of life, but changes were still observed at the age of 16 years.

A hospital-based case-control study on the possible relationship between cholecystectomy and colon cancer is described. In all, 569 cases and 1,129 controls were included in the study. Controls were patients who had been admitted either with another malignant disease (lung cancer or breast cancer), or because of benign gastrointestinal diseases. No differences with regard to colon cancer risk were observed between the two control groups. The crude odds ratio (OR) after cholecystectomy for colon cancer was 2.1 [95% CL (confidence limits) = 1.5; 2.9]. No significant difference in risk between males (OR = 2.0; 95% CL = 1.1; 3.6) and females (OR = 2.1; 95% CL = 1.4; 3.2) was found. A significant inverse relationship was found between the relative risk for colon cancer and sublocalization of the colon cancer, the highest relative risk (RR) found proximal in the colon. A decreasing risk with increasing interval between cholecystectomy and date of diagnosis of colon cancer was found. It is hypothesized that the apparent association between cholecystectomy and colon cancer does not reflect a necessary cause-effect relationship, but is rather an epiphenomenon representing a diminished exposure level to other etiologic factors.

We present a clinical study of 43 macrocephalic children with a normal rate of headgrowth. The aims of the study were an evaluation of the usual criteria of macrocephaly and the drafting of a differentiated approach to the investigation of macrocephalics. Firstly, the value of head measurement in evaluating intracranial volume was assessed. As a golden standard for the intracranial volume the volume obtained by means of a CT-scan technique was used. It appeared that only about 30% of the variance of the intracranial volume was determined by the occipito-frontal circumference (OFC). A better estimation of the intracranial volume of the macrocephalic children was obtained by means of the "Utrecht Head Measure", the product of OFC-squared and the head height. Based on length measurements taken from CT-scans, the macrocephalic children were divided into three subgroups: megalencephaly (n = 15), extraventricular obstructive hydrocephalus (n = 5) and communicating hydrocephalus (n = 23). The clinical pictures of the megalencephalic and hydrocephalic children appeared to differ substantially. The megalencephalic subgroup had less neurological symptoms and physical abnormalities and showed a higher intelligence or a more advanced development or both. On the basis of our experience and theoretical considerations guidelines were developed for the assessment of patients with macrocephaly and a normal rate of head growth with a differentiated approach for megalencephalic and hydrocephalic patients.

The present study aims to determine the accuracy and the distribution of the error of probing depth measurements. Duplicate measurements were performed at 1069 sites in 13 subjects. Measurements in shallow pockets (less than or equal to 3 mm) were significantly (p less than 0.001) more reproducible than measurements in deep pockets (greater than 3 mm). The overall standard deviation of the measurements was 0.74 mm. Differences between duplicate measurements were not normally distributed. Differences of 2 mm or more were recorded more frequently than one would expect on basis of the standard deviation and a hypothetical normal distribution. The observed frequency of large differences (greater than or equal to 3 mm) is much higher than the theoretical change as suggested in the literature that such differences may occur as a result of the inaccurate probing measurements. This finding implies consequences for the chance of making false claims that true changes in probing depth and attachment level have occurred over time, if the claims are based on the standard deviation and the wrong assumption that the error of the measurement is normally distributed.

The aim of this study was to determine the influence of the probing depth and the bleeding tendency on the reproducibility of probing depth measurements. Duplicate probing depth and bleeding tendency measurements were performed at 717 interproximal sites in 13 subjects. Analysis indicated that the factor probing depth had a larger effect on the accuracy of probing depth measurements than the factor bleeding tendency.

In 60 patients with hypertension and unilateral renal artery stenosis (URAS) radio-hippuran renograms were performed before and 6 weeks after anatomically adequate percutaneous transluminal angioplasty (PTA). Two characteristics of the renographic curves have been analyzed: the difference in time to peak (DTP) between the affected and contralateral kidneys, which would be expected to be positive in blood flow impairment, and the relative hippuran uptake (RHU) in the second minute by the affected kidney as compared with the total uptake by both kidneys: this would be less than 50% in the case of stenosis. Before PTA, both variables were predominantly abnormal. The DTP did not predict the blood pressure response to PTA. The group of patients with a RHU between 25 and 45% comprised all cured patients and predicted a more favorable response of the blood pressure than a RHU of less than 25% and especially more than 45% which group contained 83% patients whose blood pressure failed to respond after PTA. After PTA the DTP did normalize in the majority of patients, but this was not related to the blood pressure response. The RHU increased in patients in whom it had been low initially, but frequently remained low (less than 45%). The increase of the RHU was significantly higher in patients with a favorable blood pressure response. Pretreatment with captopril did intensify the abnormal curves of hippuran and of DTPA renograms in 6 patients with URAS who did respond favorably to PTA. There was no such deterioration in 2 patients whose blood pressure did not change sufficiently after PTA or in 4 patients without renal artery stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Forty-one dairy cows were fed a low (LCa-13 g/d) and a high (HCa-83.5 g/d) calcium ration in the 8 weeks prior to parturition and the effect on the Ca mobilization rate around parturition was studied. Plasma Ca values were stable in the LCa group around parturition. In the older cows of the HCa group a very slight decrease in the mean plasma Ca was observed: 2.58 mmol/l at 12-36 h ante partum decreased to 2.38 mmol/l at parturition. Hypocalcaemia, which commonly occurs around parturition, did not occur in 40 of the cows. A subclinical hypocalcaemia (1.8 mmol/l) occurred in one cow (parity 10) from the HCa group. To assess the efficiency of Ca mobilization, a severe hypocalcaemia (1.0 mmol/l) with clinical signs was induced by means of Na2EDTA infusion (0.90 mmol/min), starting at 10 h post-partum. The older cows in the LCa group required more Na2EDTA than those in the HCa group. Higher urinary hydroxyproline excretion in the week before parturition in the LCa than in the HCa group suggested a higher bone turnover. Plasma PTH levels around parturition were not significantly different between the groups. The amount of colostrum milked out in the first 10 h post-partum did not influence Ca homeostasis around parturition. The results contradict those of many other experiments in which hypocalcaemia was observed in cows ingesting high levels of Ca. It is concluded that the restricted feed intake prepartum possibly had a favourable effect on Ca homeostasis.

The effects of a number of factors on the concentration of gamma globulins in the serum of newborn calves were studied in 181 calves from six different dairy farms as was also the use of the refractometer test in controlling the ingestion of colostrum. The refractometer test was found to be reliable in controlling the concentration of gamma globulins in the serum of calves up to the sixth day of life. The factors 'time the first colostrum was ingested', 'amount of first colostrum ingested' and the 'concentration of gamma globulins in the colostrum' were found to account for 23.5 per cent of the variations in serum gamma globulin concentration; this became 42.4 per cent when the 'system of administration' and the 'farm-bound factors' were also taken into account. The first colostrum is best ingested when it is offered in a pail or bottle provided with a nipple. Calves of heifers were found to show a lower concentration of gamma globulins in the serum than did calves of older cows.

The present study aims to determine to which extent averages or deepest recordings of repeated duplicates of probing depth measurements may increase the accuracy as compared to repeated single measurements. In total, 1247 sites were recorded in 8 patients with advanced periodontitis. The patients had received initial treatment. Each site was probed 4 times with time intervals of 100 min. The standard deviation of differences between repeated single measurements of 0.97 mm decreased with a factor square root of 2 to 0.69 mm for differences between averages of repeated duplicates of measurements. Differences between the averages and the deepest recordings of repeated duplicates of measurements showed a non-Gaussian distribution. This implies that the type-I error can not be computed on the basis of the standard deviation of the error with the use of parametric statistical analysis. The best estimate for the type-I error is the observed frequency of differences. The type-I error for differences of 3 mm or more between repeated single measurements decreased from 1.5% to 0.9% and 0.2%, when deepest recordings and averages of repeated duplicates of measurements, respectively, were compared.