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PubMed2001

In-vivo analysis of the human planum temporale (PT): does the definition of PT borders influence the results with regard to cerebral asymmetry and correlation with handedness?

The aim of our study was to examine whether the degree of planum temporale (PT) asymmetry and the possible correlation of morphological PT asymmetries with handedness are influenced by the definition of PT borders. For this reason, we applied three different anatomical PT definitions formerly used in the literature. The PT total (with the end of the Sylvian fissure (SF) as its posterior border) was separated into anterior and posterior regions. The border between anterior and posterior PT was set according to the following definitions: at the end of Heschl's gyrus (1st definition); at the start of the ascending SF ramus according to the 'knife-cut' method (2nd definition); and at the bifurcation of the SF (3rd definition). Thirty right-handed healthy men were recruited. MRI data sets analyzed with the software program BRAINS were used for in vivo PT volumetry. The Edinburgh Handedness Inventory (EHI) and the Hand Dominance Test were used to determine the degree of handedness. In summary, we detected that the type and the degree of asymmetry between left and right PT were strongly dependent on the definition used for PT borders: a left>right asymmetry was found in all PT regions, except a right>left asymmetry of the anterior PT according to our 1st PT definition (lateral to Heschl's gyrus) and a symmetry of the posterior PT according to our 3rd PT definition (posterior to SF bifurcation). In addition, a significant correlation was found between the degree of handedness measured by the EHI and the right posterior PT (3rd definition). We conclude that the influence of the definition of PT borders on the investigated variables may explain some of the variances between former investigations on PT asymmetry and handedness. The possible implications of the correlation between handedness and the extension of the right parietal PT are discussed and have to be elucidated by further studies.

Adolescent↗

PubMed2004

Vascular anatomy of the foramen of Vicq d'Azyr: a microsurgical perspective.

INTRODUCTION: The foramen of Vicq d'Azyr, is a triangular-shaped area located rostral to the ventral median fissure of the medulla oblongata. Its importance relies on the fact that it is penetrated by small vessels from the vertebrobasilar axis that nourish vital pontine nuclei and tracts. We described the microvascular anatomy of the perforating vessels of the foramen of Vicq d'Azyr (FVA). MATERIALS AND METHODS: The vertebrobasilar junction arteries and the perforating arteries of the foramen of Vicq d'Azyr were examined using a surgical microscope in 21 formalin-fixed brain stems. RESULTS: The total number of perforating branches found was 286 in the 21 brains, an average of 13.6 perforators per brain, range 7 to 22. They arose as distal branches of 73 main trunks, average of 3.5 per brain, range 2 to 5, originating mainly from the basilar artery in 41 (56.1 %); the left ventral spinal artery in 12 (16.4 %), and the left vertebral artery in 8 (11 %). The average outer diameters of the left and right vertebral arteries were 3.2 mm and 2.9 mm, 4.1 mm for the basilar artery, and 0.6 mm for the right and left ventral spinal arteries. The branching pattern and interesting anatomic variations of the main vessels of the vertebro-basilar junction are also described. DISCUSSION: The vascular anatomy of the infratentorial compartment is highly variable. These variations should be kept in mind to avoid pitfalls during vascular or tumor surgery. In contrast, the entering locations of perforating vessels remain constant, referring to these zones as key areas when planning or doing surgical procedures in this region.

Basilar Artery↗

PubMed1998

Effects of posture on blood flow diversion by hypoxic pulmonary vasoconstriction in dogs.

We used differential excretion of sulphur hexafluoride from the left and right lung to measure blood flow diversion by hypoxic pulmonary vasoconstriction (HPV) in the prone and supine positions in dogs (n = 9). Gas exchange was assessed using the multiple inert gas elimination technique. Blood flow diversion from the hypoxic (3% oxygen) left lung was mean 70.7 (SD 11.2)% in the supine compared with 57.0 (12.1)% in the prone position (P < 0.02). The supine position was associated with increased perfusion to low VA/Q regions (P < 0.05). The increased flow diversion with hypoxia in the supine position was associated with more ventilation to high VA/Q regions (P < 0.05). We conclude that flow diversion by hypoxic pulmonary vasoconstriction is greater in the supine position. This effect could contribute to the variable response in gas exchange with positioning in patients with ARDS.

Animals↗

PubMed1993

Myocardial cytoprotection during percutaneous transluminal coronary angioplasty.

Transluminal coronary angioplasty (PTCA) is a well defined controlled model inducing regional myocardial ischaemia in man. Direct cardiac anti-ischaemic effects of anti-anginal drugs can be assessed by intracoronary injection of small doses which do not affect systemic parameters. Trimetazidine (TMZ) has recently been shown to improve anginal symptoms without modifying haemodynamic variables. A randomized, double-blind, placebo-controlled trial was conducted in 20 patients to study the effects of TMZ on the severity of myocardial ischaemia during PTCA of the left anterior descending coronary artery. Five minutes after a first successful dilation (D0), a control balloon inflation (D1) was performed until onset of ischaemic signs on both the intracoronary (i.c.) and precordial ECG. Two minutes later, patients received either trimetazidine 6 mg or placebo i.c. Another inflation (D2) was performed 5 min after D1. No differences were found between the two groups regarding responses in heart rate, systemic and i.c. pressures during the study. TMZ decreased maximum ST segment shift at D2 as compared to D1 (0.8 +/- 0.1 vs 1.4 +/- 0.3 mV, P = 0.023) and delayed its onset (46 +/- 4 vs 36 +/- 5 s, P = 0.024). TMZ also decreased maximum T wave changes (1.06 +/- 0.24 vs 2.19 +/- 0.3 mV, P = 0.001), and significantly reduced the area under the curve (AUC:mV.s-1) of the i.c. ST segment and T wave changes during balloon inflation (P = 0.002 and P < 0.001 respectively). Placebo had no effect on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗

PubMed2004

Innervation zones of the external anal sphincter in healthy male and female subjects. Preliminary results.

OBJECTIVES: The objective of this work was to investigate the distribution of the innervation zones of the motor units that make up the external anal sphincter (EAS) in healthy males and females. METHODS: A cylindrical probe carrying a circumferential array of 16 electrodes was used to detect the generation, propagation and extinction of individual motor unit action potentials (MUAPs) at 1, 2, and 3 cm depth from the orifice of the anal canal during maximal voluntary contractions of the EAS. Fifteen healthy males and 37 healthy nulliparous females were investigated. RESULTS: IZs could be detected in all males and in 34 out of 37 females. In the males, the IZs are scattered in the right and left hemisphincter at each of the three levels and their distribution is not affected by depth. In the females, the distribution is also concentrated in the right and left hemisphincter at depth 1 cm but is more uniform at depth 2 cm and more concentrated in the dorsal and ventral regions at depth 3 cm. ANOVA shows a statistically significant dependence of the IZ distribution on depth only in females and not in males. CONCLUSIONS: It is concluded that (a) IZs of the EAS can indeed be detected with a circumferential array placed at different depths along the anal canal; (b) large individual variability is observed, and (c) IZs show similar distribution at the three depth levels in males and different distributions in females.

Adult↗

PubMed2001

Localization of deep white matter lymphoma using VARETA: a case study.

Methods have recently been proposed for localization of multiple brain sources of particular EEG frequencies recorded from the scalp, to identify their most probable neuroanatomical generators. This paper reports the accurate localization of a deep white matter lymphoma, using Variable Resolution Electromagnetic Tomography (VARETA). The accuracy of this localization was confirmed by MRI studies. The patient was referred for a quantitative EEG evaluation, two weeks following an automobile accident, with no known loss of consciousness. There was marked excess and asymmetry of frontal slow wave activity, with highly significant hypocoherence. Significant gradient shifts within the left hemisphere were also seen. Visual inspection of the EEG tracings revealed theta paroxysms in left dorsolateral and mesial frontal regions. The MRI revealed a large space-occupying lesion deep within the white matter of the left frontal lobe, with evidence of subependymal spread and significant surrounding vasogenic edema. Localization of the sources of the maximal QEEG abnormalities using VARETA was consistent with the lesion location seen in the MRI images. This case demonstrates that VARETA can achieve highly sensitive and accurate localization of sources of QEEG abnormalities which lie in the deepest brain regions.

Aged↗

PubMed1996

[Dorso-lumbal pain and idiopathic scoliosis in adolescence].

Current knowledge on the association between back pain and idiopathic scoliosis is often contradictory. The presence, localisation and importance of pain was evaluated for a cohort of 426 adolescents with AIS. Patients were recruited from a scoliosis clinic in a pediatric hospital. A questionnaire and an analogue visual scale graduated from 0 (no pain) to 100 (maximal pain) were used in order to verify more precisely, the importance of the association between AIS and back pain. Chisquare, linear regression and Student T-test were used for statistical analysis. 239 patients with right thoracic and left lumbar curves (RTLL) had a prevalence of pain of 54%. The mean of maximum pain intensity was 49 mm +/- 20. No relation was found between the severity of the scoliosis and back pain. The two groups (with and without pain) were comparable. Cobb angles were about the same for the thoracic and lumbar regions, as well as kyphosis and lordosis, weight, height and age. Risser sign, sex, brace and pelvic tilt were the only variables associated with pain (p < 0.0001). Association between AIS and pain is more frequent than generally reported. Pain appears to be more related with pelvic tilt than severity of the scoliosis.

Adolescent↗

PubMed1998

Advances in high-speed, three-dimensional imaging and automated segmentation algorithms for thick and overlapped clusters in cytologic preparations. Application to cervical smears.

OBJECTIVE: To use three-dimensional (3-D) imaging and localized adaptive image analysis to enable automated cervical smear screening systems to efficiently and effectively process thick and overlapped cell clusters currently left unprocessed. STUDY DESIGN: Instrumentation was developed to perform high-speed (50-200 optical sections per second at 256 x 256 resolution), 3-D imaging of thick regions of cervical smears. Normal and abnormal ThinPrep smears were imaged at two levels of resolution to approximate higher-resolution, wide-area imaging. Improved dual-resolution, 3-D image analysis algorithms were developed for segmenting nuclei in these clusters. RESULTS: Despite low contrast, high variability and dense overlaps, the algorithms detected 89% and correctly segmented 76% of nuclei in clusters from normal smears and detected 75% and correctly segmented 45% of nuclei in clusters from abnormal smears in low-resolution images. In high-resolution images they detected 88% and segmented 76% of nuclei from normal specimens and detected 55% and segmented 45% of nuclei from abnormal specimens. At least one nucleus from each cell cluster was correctly segmented. CONCLUSION: Selective application of 3-D imaging and 3-D image analysis to thick and overlapped regions can enable a significant fraction (45-89%) of clustered and embedded cells to be accessed by an automated analysis system. These regions are, for the most part, unprocessable by current two-dimensional methods.

Algorithms↗

PubMed1986

Palindromic sequences are associated with sites of DNA breakage during gene conversion.

Gene conversion is a recombinatorial mechanism which transfers genetic information from a donor into a recipient gene. A case of gene conversion between immunoglobulin VH region genes was analysed and palindromic sequences were found to be located near to the left recombinatorial breakpoint, which also is flanked by a direct repeat sequence. We performed a computer search for palindromes and direct repeats in the published sequences of eucaryotic genes which had been involved in gene conversion. In these sequences, the palindrome with the best or second best quality is located near to a breakpoint of recombination. A correlation of recombination breakpoints with direct repeats was not observed. This suggests that gene conversion is promoted by palindromic sequences.

Animals↗

PubMed2004

Comparison of the effects of dexmedetomidine and esmolol on myocardial oxygen consumption in dogs.

BACKGROUND AND OBJECTIVE: The beta-adrenergic blocker esmolol and the alpha 2-adrenergic agonist dexmedetomidine have the potential to decrease perioperative myocardial ischaemia. The pathophysiological mechanisms involved in these anti-ischaemic properties have not been thoroughly studied. We compared the effects of esmolol and dexmedetomidine on two indices of overall myocardial oxygen demand and on directly measured myocardial oxygen consumption of the left anterior coronary artery territory. METHODS: Eleven mongrel dogs were instrumented to measure aortic and left ventricular pressure, aortic and left anterior coronary artery flow and myocardial wall thickening. Variables related to myocardial oxygen metabolism were also determined. Measurements were performed during four sequential experimental conditions in each dog (Control 1: esmolol; Control 2: dexmedetomidine). RESULTS: Esmolol and dexmedetomidine decreased haemodynamic indices of myocardial oxygen demand to a similar extent: esmolol decreased the rate-pressure product by 16+/-3% and the pressure-work index (PWI) by 16+/-3%, dexmedetomidine decreased the rate-pressure product by 26+/-3% and the PWI by 16+/-7%. However, these similar decreases resulted from different haemodynamic effects of the two study drugs. Dexmedetomidine had a more pronounced bradycardic effect than esmolol (P = 0.01) and increased systolic aortic pressure (SAP) by 15+/-4% while esmolol decreased SAP by 8+/-2% (P < 0.01). dP/dt(max) and regional myocardial area decrease were lower after esmolol than after dexmedetomidine. Neither drug had an effect on myocardial oxygen consumption. CONCLUSIONS: Esmolol and dexmedetomidine decreased two haemodynamic indices of overall myocardial oxygen demand to a similar extent but neither drug decreased directly measured myocardial oxygen consumption in the territory of the left anterior descending artery.

Adrenergic alpha-Agonists↗

PubMed1992

Catheter optimization during contrast ventriculography: a prospective randomized trial.

Although newer contrast mediums have improved hemodynamic stability during left ventriculography, the image quality and hence the diagnostic yield of the procedure is largely determined by the choice of catheter and injection technique. In this study 125 patients were prospectively assigned at random to undergo ventriculography using either of two pigtail catheters, one with a straight shaft throughout its length (straight) and one with a 145-degree bend placed 6.5 cm from the distal end (angled). Injectate composition, flow rate, and volume were held constant for all injections, and baseline clinical and catheterization variables were found to be similar in each group. The angled catheter exhibited a statistically superior ease of insertion (p = 0.038) and took less time to position (p = 0.012), saving a mean of 23 seconds of fluoroscopy time per procedure. It was also associated with superior contour edge definition (p = 0.037) and a trend toward more uniform distribution of contrast medium (p = 0.089). Compared with the straight catheter, the angled catheter was less frequently accompanied by artifactual mitral regurgitation (p = 0.038) but was equally likely to provoke ventricular arrhythmias during injection. These observed differences may be explained in part by the tendency for angled catheters to more frequently localize in the central as opposed to the inferoposterior region of the left ventricular cavity (mean distance from center = 0.53 vs 1.10 cm, respectively; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1984

Relationship of specific coronary lesions and regional left ventricular dysfunction to prognosis in survivors of sudden cardiac death.

We prospectively evaluated the relationship of specific coronary arterial and left ventricular segments to subsequent clinical outcome in 80 persons who were survivors of sudden cardiac death and had failed conventional antiarrhythmic therapy. There were 68 men and 12 women with an average age of 51 years who were treated with investigational antiarrhythmic agents, rendered asymptomatic, and followed for 16 +/- 14 (SD) months. At the end of the study 48 patients (60%) were alive and asymptomatic while 32 (40%) had experienced either recurrent syncope (five) or sudden cardiac death (27). The independent relationship of clinical and angiographic variables was performed in a univariate fashion using a Kaplan-Meier survival analysis and then multivariate logistic analysis was used to simultaneously consider all clinical and arteriographic variables. The results reconfirmed the importance of ejection fraction and left ventricular filling pressure on outcome. However, coronary arterial and left ventricular segmental analyses provided additional predictive power. Specifically, the survival outcome was found to be inversely related to the degree of proximal left anterior coronary (LAD) arterial narrowing: at 1 year 90% of patients with minimal LAD narrowing were alive/asymptomatic in contrast with 70% who had partial and 40% who had complete proximal LAD obstruction (p less than 0.005). Analysis of the posterobasal left ventricular segment wall motion demonstrated that 100% of patients with minimal dysfunction were alive/asymptomatic at 1 year, whereas only 52% of patients with severe dysfunction were alive (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1993

Biologic properties of a CH2 domain-deleted recombinant immunoglobulin.

Monoclonal antibody (MAb) B72.3 reacts with TAG-72, a high-molecular-weight mucin expressed on several types of human carcinoma, and is currently being used in clinical trials for the diagnosis and therapy of human carcinoma. An expression construct containing cDNA encoding an immunoglobulin (Ig) heavy chain, with the variable region of murine MAb B72.3 and a human Ig constant region with a deletion of the CH2 domain, was generated. Immunoglobulin from the transfectoma with the highest expression of the TAG-72 immunoreactive antibody was designated MAb chimeric (c) B72.3 delta CH2. The pharmacokinetics of serum clearance of iodine-labeled MAbs cB72.3 delta CH2 and the intact cB72.3 were compared in athymic mice. By 24 hr, less than 1% of the cB72.3 delta CH2 was left in the plasma, while 36% of the cB72.3 still remained. The T1/2 alpha values of the cB72.3 delta CH2 and cB72.3 MAbs were 1.7 and 2.4 hr, respectively. The T1/2 beta values were 7.8 hr for the domain-deleted cMAb and 48.9 hr for cB72.3. Biodistribution studies in athymic mice bearing LS-174T xenografts showed a reduction in the percentage of injected dose per gram in tumor with 131I-cB72.3 delta CH2; however, the 131I-cB72.3 delta CH2 both localized to tumors faster and cleared from the blood faster than the 125I-cB72.3 MAb. Only trace amounts of the 131I-cB72.3 delta CH2 were detected in normal tissues, including kidney. The faster clearance rate, more rapid tumor targeting and lack of metabolic uptake in normal tissues demonstrated with the iodine-labeled CH2 domain-deleted cMAb may be an advantage for certain clinical protocols.

Animals↗

PubMed1987

Meningocerebral hemangiomatosis resembling Sturge-Weber disease in a horse.

A 3-year-old horse presented with intermittent generalized seizures of 2-month duration. During interictal periods, the horse appeared normal and a cause for the seizures could not be identified. Necropsy revealed opacity of the leptomeninges, covering most of one cerebral hemisphere along with thinning and collapse of the cortex in the ipsilateral pyriform lobe. Histopathology demonstrated leptomeningeal vascular proliferation and meningothelial hyperplasia. Prominent tortuous vessels of the gyri and sulci extended into some regions of the subjacent cortex, where there was neuronal loss, ectopia, and disorganization. Clusters of prominent arterioles were found in the sclerotic choroid plexus of the lateral and fourth ventricles. Milder vascular lesions were present in the leptomeninges of the ventral brain stem, right cerebrum, spinal cord, and in the eye. The left trigeminal nerve was distorted by swollen fasicles containing onion bulb-like structures. Most bulbs contained central axons surrounded by myelin sheaths of variable thickness. Electron microscopy demonstrated concentrically arranged cells with continuous basal laminae and rare pinocytotic vesicles. S-100 immunohistochemistry showed strong positive staining in these cells. This is an unusual combination of lesions to which analogies can be drawn with the human neuroectodermal dysplasias, specifically Sturge-Weber disease. The relationship of the neuropathy to the leptomeningeal hemangiomatosis is unclear, but a compound anomaly in embryological development resulting in dysplasia and neoplasia may be involved.

Angiomatosis↗

PubMed1990

Preservation of P300 event-related potential topographic asymmetries in schizophrenia with use of either linked-ear or nose reference sites.

Previous studies of the auditory P300 event-related potential (ERP) from our laboratory have reported a left- greater than right-sided attenuation in medicated chronic schizophrenics compared with normal controls. A possible confound in these studies has been the use of the linked-ear reference (LER), which has been criticized on the grounds that it might either induce or suppress topographic asymmetries. To test the effects of LER on P300 asymmetries in schizophrenia, we recorded ERPs with both LER and a nose reference (NR) in a group of 20 chronic medicated schizophrenics and in group of 20 age-matched normal controls. We here report: (1) confirmation of our previous P300 findings of left temporal scalp region deficit using both LER and NR with a 28-electrode montage; this feature was prominent in the wave form associated with the target stimulus, without the use of the wave form subtractions of our previous studies; (2) no statistically significant topographic differences between the LER and NR for either the schizophrenic or normal subjects; and (3) better performance of the LER in differentiating schizophrenics versus normal controls, due to lower wave form variability. We conclude that the LER is preferable for studies using subject groups and methodology similar to the present study.

Adult↗

PubMed2005

Longitudinal volumetric MRI study in first- and multiple-episode male schizophrenia patients.

In this longitudinal study we compared brain volume changes in first- and multiple-episode patients with schizophrenia to normal aging changes observed in healthy control subjects scanned at comparable times. Two to four years after an initial examination including MRI volumetry, we followed up 21 first episode patients, 17 patients after multiple episodes of schizophrenia, and 20 healthy controls. Volumetric measurements of left and right hemispheres, total brain volume, lateral ventricles, hippocampus and amygdala as well as a clinical evaluation were performed. Patients with schizophrenia showed significant ventricular enlargement and volume reduction of the hippocampus-amygdala complex compared with healthy control subjects both at baseline and follow-up. While there were no differences between patients and controls with respect to mean annual volume changes in the measured regions, patients with schizophrenia showed higher between-subject variability in ventricular volume change. These data are consistent with cross-sectional studies demonstrating ventricular enlargement and hippocampal volume deficits in schizophrenia. However, we were not able to demonstrate a difference in the rate of volume changes over time that distinguished patients with schizophrenia from healthy controls for any of the brain structures measured. Drawbacks of the study are that the follow-up was done after a relatively short interval and that there was a difference in time to follow-up and age between patients and controls. Our results do not support the hypothesis that schizophrenia leads to progressive volume reduction in these areas, although there may be a subset of patients with morphologically visible disease progression.

Adult↗

PubMed1984

Regional left ventricular systolic function in patients with segmental early relaxation and normal coronary arteries.

The purpose of the study was to determine whether regional differences of left ventricular systolic function exist in patients with normal coronary arteries who manifest segmental early relaxation. The presence or absence of segmental early relaxation was determined angiographically in 16 patients with normal coronary arteries who underwent diagnostic cardiac catheterization because of chest pain. Seven patients had early relaxation localized to the left ventricular anterior wall and nine patients had no evidence of segmental early relaxation. Regional function was assessed from ventriculograms obtained in the right anterior oblique projection using the area method to calculate the regional fractional area of shortening. The fractional area of shortening of the anterolateral region was greater in patients with than in those without segmental early relaxation (69 +/- 4 versus 55 +/- 11%; p less than 0.01). In addition, in patients with segmental early relaxation, this variable exceeded the fractional area of shortening of the diaphragmatic region (69 +/- 4 versus 53 +/- 9%; p less than 0.01). There was no difference in the fractional area of shortening between these two regions in patients who did not manifest segmental early relaxation. These results suggest that regional differences in systolic function are present in patients with but not in those without segmental early relaxation. Augmented regional systolic function was observed in patients with segmental early relaxation and was limited to regions that manifested early relaxation.

Adult↗

PubMed2001

Interictal 99mTc-HMPAO SPECT in temporal lobe epilepsy: relation to clinical variables.

PURPOSE: Factors affecting blood flow observed by interictal single-photon emission computed tomography (SPECT) images in temporal lobe epilepsy (TLE) have not been systematically studied or consistently demonstrated. We evaluated interictal SPECT results with respect to many clinical variables in a large population of TLE patients, all of whom underwent temporal lobectomy. METHODS: Interictal 99mTc-HMPAO SPECT scans from 61 TLE patients were obtained before an anterior temporal lobectomy. SPECT was analyzed using a region of interest analysis (ROI) in the cerebellum, anterior temporal lobe, lateral temporal lobe, mesial temporal lobe, whole temporal lobe, and inferior frontal lobe. Asymmetry indices (AIs) were calculated. Correlative analysis of AIs and clinical variables was performed. RESULTS: The AIs from TLE patients differed significantly from those of controls in the anterior temporal (p < 0.01), lateral temporal (p < 0.001), and whole temporal (p < 0.01) regions. No consistent overall correlation between the AIs and clinical variables existed. In right TLE (RTLE) only, AIs in the lateral and whole temporal lobe were positively correlated with age of onset (r = 0.470, p < 0.05; r = 0.548, p < 0.01, respectively). Similarly, in RTLE only, duration of epilepsy was negatively correlated with the anterior (r = -0.395, p < 0.05) and mesial (r = -0.45, p < 0.05) temporal lobe AI. No correlations were found between clinical variables and AIs in left TLE (LTLE) patients. CONCLUSIONS: Significant correlation of age at onset and duration of epilepsy with AIs in RTLE but not LTLE suggests physiologic processes may be determined in part by laterality of TLE. Clinical applications are problematic.

Adult↗