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Memory functions and rCBF (99m)Tc-HMPAO SPET: developing diagnostics in Alzheimer's disease.

Alzheimer's disease (AD) is a primary degenerative disease of the brain. The prevalence increases with age, with devastating consequences for the individual and society. The aim of this study was to evaluate whether patients with early AD show an altered regional cerebral blood flow (rCBF) compared with control persons. Furthermore, we aimed to investigate the correlation between rCBF in sublobar volumes of the brain and performance on memory tests. Memory tests were chosen to evaluate episodic and semantic memory. Fourteen patients (aged 75.2+/-8.8 years) with early AD and 15 control persons (aged 71.4+/-3.2 years) were included. rCBF measurements with single-photon emission tomography (SPET) using technetium-99m hexamethylpropylene amine oxime (HMPAO) were performed. The rCBF (99m)Tc-HMPAO SPET images were spatially transformed to fit a brain atlas and normalised for differences in rCBF (Computerised Brain Atlas software). Cortical and subcortical volumes of interest (VOIs) were analysed and compared. Compared with the controls, AD patients showed a significantly lower rCBF ratio in temporoparietal regions, including the left hippocampus. The diagnostic sensitivity and specificity for AD were high in temporoparietal regions. AD patients had significantly reduced performance on semantic and, in particular, episodic memory tests compared with age-matched normative data, and their performance on several episodic tests correlated with rCBF ratios in parietal and temporal regions, including the left hippocampus. The correlation between rCBF ratio and level of episodic memory performance suggests that abnormalities in rCBF pattern underlie impaired episodic memory functioning in AD.

Aged↗

Prostaglandin D2-sensitive, sleep-promoting zone defined in the ventral surface of the rostral basal forebrain.

The site of action for the sleep-promoting effect of prostaglandin (PG) D2 was extensively examined in the brain of adult male rats (n = 231). PGD2 was administered at 100 pmol/0.2 microliter per min for 6 hr (2300-0500 hr) through chronically implanted microdialysis probes or infusion cannulae. Among the administrations of PDG2 by dialysis probes (n = 176), only those (n = 8) to a ventro-rostral part of the basal forebrain by the probes implanted on the midline consistently increased slow-wave sleep (SWS), by 51 +/- 6 min (mean +/- SEM) above the baseline value (111 +/- 11 min). Since this area is separated by a cleft into right and left regions, the results were interpreted to mean that, through this cleft, PGD2 diffused in the subarachnoid space over the adjacent ventral surface, where it had the effect of promoting sleep. When PGD2 was directly infused into the subarachnoid space (n = 55), extraordinary increases exceeding 90 min were consistently attained for the SWS at sites located between 0.5 and 2 mm rostral to the bregma and between 0 and 1.2 mm lateral to the midline defined according to the stereotaxic coordinates adopted from the brain atlas of Paxinos and Watson [Paxinos, G. & Watson, C. (1986) The Rat Brain in Stereotaxic Coordinates (Academic, San Diego)]. Thus, we demarcated a "PGD2-sensitive, sleep-promoting zone" within this region in the ventral surface of the rostral basal forebrain. During the bilateral infusion of PGD2 into the subarachnoid space of this zone, the hourly mean SWS level of the nocturnal animals (n = 6) in the night reached the maximum at the second hour of the infusion period; this maximum hourly SWS level, corresponding to the daytime level of the same animals, lasted until the end of PGD2 infusion.

Animals↗

Atlantooccipital junction: standards for measurement in normal children.

This study describes a simple method for measuring the distance between the occiput and atlas when a distraction-dislocation injury is suspected in a child. Measurements were made at five evenly spaced locations along the atlantooccipital joint on cross-table lateral skull radiographs in 100 normal children. These data were compared with similar measurements in eight patients with proved atlantooccipital dislocation. The mean normal measurement fell between 1.96-2.63 mm for all five points. For boys or girls aged 1-15 years, the normal distance should not exceed 5 mm at any point in the joint. The likelihood that any normal child will have a measurement greater than or equal to 4.5 mm at any point is between 0.4-5.85% (expected false-positive rate).

Adolescent↗

Construction and accuracy assessment of an efferocytosis-related prognostic model for ovarian cancer: A diagnostic accuracy study.

The study aimed to investigate the prognostic significance of efferocytosis-related genes in ovarian cancer (OC) with regard to cancer development, progression, invasion, and metastasis. OC cohorts were assembled from bioinformatics repositories. Utilizing consensus clustering analysis, distinct clusters were delineated based on the intersection of OC-related genes and efferocytosis-related genes. A prognostic signature specific to efferocytosis in OC was developed using data from The Cancer Genome Atlas, validated against the gene expression omnibus database, and subjected to independent prognostic analysis. Subsequently, a nomogram model was formulated. Moreover, investigations encompassed the immune microenvironment, immunotherapy, mutation profiling, drug sensitivity assessments, drug prediction models, and molecular docking analyses. Finally, quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were employed to ascertain the mRNA expression levels of key genes. Five key genes, FCGBP, BTN3A3, WDR91, SLC25A45, and BTNL3, were identified as significantly associated with OC. Both datasets and qRT-PCR demonstrated elevated expression levels of FCGBP and WDR91 in OC. Notably, AFLATOXIN B1 exhibited strong binding affinity to SLC25A45, ciclopirox to BTN3A3, and irinotecan to WDR91. The risk score, age, and stage were identified as independent prognostic factors, with the nomogram displaying efficacy in predicting OC patient survival. Variations in the immune cell infiltration profiles, including naive B cells, and expression levels of 6 immune checkpoint genes, such as CTLA4, were notable. High tumor mutation burden scores were associated with improved survival outcomes. Additionally, significant differences in the IC50 values of 123 anticancer drugs were observed between the 2 risk groups. This findings of this study highlight the efficacy of the efferocytosis-associated risk model in predicting the survival outcomes of OC patients, thus providing a novel reference for prognostic prediction in OC patients.

Humans↗

Reproducibility and repeatability of 99Tcm-HMPAO rCBF SPET in normal subjects at rest using brain atlas matching.

The aim of this study was to assess regional cerebral blood flow (rCBF) in normal subjects at rest using 99Tcm-HMPAO single photon emission tomography (SPET). Analysis of reproducibility and repeatability was performed both before and after normalization of flow data. Six healthy volunteers were examined, three times each, according to a routine rCBF protocol. A computerized brain atlas was used to evaluate flow data in eight selected regions. The overall reproducibility of rCBF was evaluated from two scans performed at an average interval of 3 months. Repeatability was evaluated from two scans, 3 h apart and without re-injection of 99Tcm-HMPAO. For the normalized (relative) flow data, the reproducibility was +/- 1.3% and the repeatability +/- 2.2% (i.e. methodological errors dominate). For the non-normalized flow data, the corresponding values were +/- 14.8% and +/- 5.9%. rCBF SPET with 99Tcm-HMPAO is highly reproducible provided that the flow data are normalized. The variation in flow between individuals at one point in time and 3 months later was less than +/- 5% for all brain regions.

Adult↗

Dusting off old books: comments on classic gynecologic pathology books of yesteryear.

Selected outstanding books from the older literature on gynecological pathology are reviewed with emphasis on drawing attention to the abundant helpful information and outstanding illustrations that are worthy of review by present-day pathologists. The first three works are Cancer of the Uterus, Myomata of the Uterus, and Adenomyoma of the Uterus by Thomas S. Cullen. The senior author of the second book is Howard A. Kelly even though he did not have any role in the preparation of the text; he was given senior authorship by Dr. Cullen as a token of appreciation to his mentor. The next book, Fibroids and Allied Tumors by Cuthbert Lockyer, is particularly noteworthy for the quality of the numerous color illustrations. The final book on the uterus is The Cervix Uteri and Its Diseases by C. Frederic Fluhmann. It provides detailed coverage of the normal and pathologic aspects of the cervix, including the endocervical clefts (glands) and their abnormalities. The next three books are on the ovary: Ovarian Tumors by Samuel H. Geist, Atlas of Ovarian Tumors by Gemma Barzilai, and Endocrine Pathology of the Ovary by John McLean Morris and Robert E. Scully. The first is notable for the quality of the coverage of clinical and gross aspects of ovarian tumors and the second for the quality of the description of the microscopic features. The third book expanded the range of functioning ovarian tumors by showing that this could be a feature of tumors not usually considered hormonally active and also discussed in detail the endocrine function of non-neoplastic lesions. The final two books cover general gynecological pathology: Manual of Obstetrical and Gynaecological Pathology by John H. Teacher and Gynecological and Obstetrical Pathology by Emil Novak. Both have particularly outstanding coverage of normal histology and non-neoplastic lesions.

Female↗

Evaluating the role of magnetic resonance imaging scans in the surgical management of acoustic neuromas.

OBJECTIVE: To assess the reliability of magnetic resonance imaging (MRI) in predicting the size and position of an acoustic neuroma, with particular reference to the intracanalicular portion. STUDY DESIGN: Prospective study comparing the position of the tumor in the internal auditory canal on fast spin-echo MRI with the actual position measured intraoperatively. METHODS: The study was performed in a tertiary referral neurotology center, encompassing both the public and private health care systems. Fifteen consecutive patients admitted for acoustic neuroma removal via the translabyrinthine approach were studied. The main outcome measure was tumor position in the internal auditory canal expressed in millimeters, accurate to the nearest 0.5 mm. RESULTS: The fast spin-echo MRI was accurate within an error of 1 mm in predicting the lateral extent of the tumor in the internal auditory canal. CONCLUSION: Fast spin-echo MRI can accurately predict the lateral extent of an acoustic neuroma and allow accurate planning of the surgical approach.

Adult↗

The biology of bone maturation and ageing.

The only indicator of development that is available from birth to maturity is skeletal age. This short review discusses how standard bone ages have been developed from assessment of radiographs, and describes the advantages and disadvantages of the 'atlas' approach as developed by Greulich and Pyle, and the bone by bone approach, as developed by Tanner. As the standards currently available are based mainly on historical series of radiographs from particular populations, it is stressed that national standards should be established and updated regularly if bone ages are to be used to assess development. The question of the clinical relevance of using bone age assessments of the hand and wrist to determine the state maturation of the whole skeleton and particularly, the growth potential is also discussed. It is concluded that, despite the difficulties of assessing bone age, and the assumptions on which the various methods are based, determination of skeletal development is clinically relevant in that it provides the only means of assessing rates of maturational change throughout the growing period.

Age Determination by Skeleton↗

Analysis of the molecular mechanism underlying di(2-ethylhexyl) phthalate-induced bladder carcinogenesis via network toxicology and molecular docking approaches: An observational study.

This study aims to investigate the toxicity of di(2-ethylhexyl) phthalate (DEHP) and the potential molecular mechanisms of DEHP-induced bladder cancer (BLCA) using network toxicology and molecular docking strategies. The toxicity of DEHP was assessed using Prox-II software, and potential targets for DEHP-induced BLCA were identified by integrating data from ChEMBL database, Search Tool for Interactions of Chemicals, SwissTargetPrediction, GeneCards, Therapeutic Target Database, Online Mendelian Inheritance in Man, and The Cancer Genome Atlas. STRING database and Cytoscape were employed to construct target networks and determine core targets. The expression levels of core targets were analyzed using R. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on potential and core targets. Molecular docking was carried out using CB-Dock 2 to verify the interactions between DEHP and core targets. A total of 105 potential targets related to DEHP-induced BLCA were identified, from which 7 core targets were selected: cyclin-dependent kinase 1, interleukin 6, cyclin-dependent kinase 2, cyclin B1, Erb-B2 receptor tyrosine kinase 2, cyclin B2, and B-cell lymphoma 2. IL-6 and B-cell lymphoma 2 showed downregulated expression in tumor tissues, while cyclin-dependent kinase 1, cyclin-dependent kinase 2, cyclin B1, Erb-B2 receptor tyrosine kinase 2, and cyclin B2 were upregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these targets were enriched in cell signaling and cancer-related pathways. Molecular docking confirmed that DEHP interacts with these core targets. DEHP may promote the development of BLCA by interacting with key proteins and signaling pathways. This study provides a theoretical basis for understanding the molecular mechanisms of DEHP-induced BLCA and offers references for future prevention and treatment strategies.

Diethylhexyl Phthalate↗

Regional size differences in four commonly used cephalometric atlases: the Ann Arbor, Cleveland (Bolton), London (UK), and Philadelphia atlases compared.

OBJECTIVE: To explore regional influence on size in roentgenocephalometric atlases. DESIGN: Comparisons of the size of 10 linear distances in four atlases from geographically different regions, i.e. Ann Arbor Michigan, Cleveland Ohio, Philadelphia Pennsylvania and London, UK. DISTANCES COMPARED: anterior cranial base length (S-N), posterior cranial base length (S-Ba), total face height (N-Me), upper face height (N-ANS), lower face height (ANS-Me), mandibular diagonal (Ar-Gn), corpus length (Go-Pg), ramus height (Ar-Go), maxillary length (SNP-SNA), posterior face height (S-Go). RESULTS: Correction for enlargement appeared to be a necessity before distances could be compared. After correction for enlargement, the anterior cranial base was longest in Ann Arbor, lower face height smallest in Cleveland (Bolton standards) and the maxilla was shortest in Philadelphia. CONCLUSION: Regional size variance in cephalometric data cannot be ignored.

Adolescent↗

The accessory atlantoaxial ligament.

OBJECTIVE: The stability of the joints connecting the cranium to the upper cervical spine is of vital importance. The ligaments of this region, for the most part, have been thoroughly investigated, with the exception of the accessory atlantoaxial ligament. METHODS: Ten cadaveric specimens were examined to observe the anatomy of this ligament. RESULTS: This ligament was found in all specimens, and in each, it not only connected the atlas to the axis but also continued cephalically to the occipital bone. The approximate dimensions of this structure were 3 cm x 5 mm. Functionally, this ligament became maximally taut with a rotation of the head of 5 to 8 degrees. Laxity was observed with cervical extension, and maximal tautness was seen at 5 to 10 degrees of cervical flexion. CONCLUSION: The accessory atlantoaxial ligament seems to participate in craniocervical stability and perhaps should be renamed the accessory alar ligament or accessory atlantoaxialoccipital ligament; both of these terms better denote its anatomic characteristics. Perhaps in the future, better magnetic resonance imaging techniques and machines will be able to identify this structure so as to appreciate its integrity after upper cervical spine trauma.

Aged↗

Verification of the Schaltenbrand and Wahren stereotactic atlas.

The Schaltenbrand and Wahren stereotactic atlas was critically re-examined focusing on the technical quality and the consistency of the horizontal, sagittal and frontal microscopic cut series. From each series, both an isotropic contour and a solid volume model represented by a 256 matrix with an edge length of 6.4 cm were created using 3D-interpolation. Reslicing of the solid volumes in corresponding orthogonal planes enabled thorough direct comparison of the three series. In a 3D-navigation system prototype, the contour models can be matched to MRI and CT series. Different procedures for rigid matching including landmark matching were implemented. As regards the verification criteria, the frontal Schaltenbrand and Wahren series yielded the most comprehensible results whereas in the horizontal and sagittal series artifacts appear more pronounced.

Brain Mapping↗

A template for spatial normalisation of MR images of the rat brain.

In this paper, we describe the preparation of a rat template intended for use together with SPM to enable spatial normalisation of individual rat brains. The template was created from T2-weighted images of the brains of five adult female Sprague-Dawley rats. A large number of anatomical landmarks were manually identified in each of these image volumes and recorded in the appurtenant image space. The same landmarks were defined in the space of the commonly used atlas by Paxinos and Watson. For each individual volume the affine transformation that best (in a least square sense) matched the two sets of points was estimated. These transforms were used to resample the individual volumes into the "Paxinos space", and a template was created from the average of these. Hence, a rat brain spatially normalised to this template will facilitate reporting results in co-ordinates directly corresponding to the Paxinos co-ordinate system. The usage of the template is exemplified with a functional magnetic resonance imaging (fMRI) study of the somatosensory cortex of the rat. The template image volumes together with the necessary modifications to the SPM software code can be downloaded from http://mr.imaging-ks.nu/expmr.htm.

Afferent Pathways↗

A cross validation study of deep brain stimulation targeting: from experts to atlas-based, segmentation-based and automatic registration algorithms.

Validation of image registration algorithms is a difficult task and open-ended problem, usually application-dependent. In this paper, we focus on deep brain stimulation (DBS) targeting for the treatment of movement disorders like Parkinson's disease and essential tremor. DBS involves implantation of an electrode deep inside the brain to electrically stimulate specific areas shutting down the disease's symptoms. The subthalamic nucleus (STN) has turned out to be the optimal target for this kind of surgery. Unfortunately, the STN is in general not clearly distinguishable in common medical imaging modalities. Usual techniques to infer its location are the use of anatomical atlases and visible surrounding landmarks. Surgeons have to adjust the electrode intraoperatively using electrophysiological recordings and macrostimulation tests. We constructed a ground truth derived from specific patients whose STNs are clearly visible on magnetic resonance (MR) T2-weighted images. A patient is chosen as atlas both for the right and left sides. Then, by registering each patient with the atlas using different methods, several estimations of the STN location are obtained. Two studies are driven using our proposed validation scheme. First, a comparison between different atlas-based and nonrigid registration algorithms with a evaluation of their performance and usability to locate the STN automatically. Second, a study of which visible surrounding structures influence the STN location. The two studies are cross validated between them and against expert's variability. Using this scheme, we evaluated the expert's ability against the estimation error provided by the tested algorithms and we demonstrated that automatic STN targeting is possible and as accurate as the expert-driven techniques currently used. We also show which structures have to be taken into account to accurately estimate the STN location.

Algorithms↗

Within-arm somatotopy in human motor areas determined by positron emission tomography imaging of cerebral blood flow.

Within-arm somatotopy was identified in multiple motor areas of six normal human subjects who performed a visuomotor tracking task during positron emission tomography (PET) measurement of relative cerebral blood flow (relCBF). A randomly moving target, presented on a computer monitor, was continuously followed with the index finger (movement at the metacarpophalangeal joint), thumb, fist (movement at the wrist), forearm (movement at the elbow), elbow (movement at the shoulder), and eyes alone (control task) during sequential imaging. Segmental limb movements were associated with relCBF responses in the contralateral motor, supplementary motor, cingulate, and parietal cortex, and in the ipsilateral cerebellum. Localization of responses after stereotaxic transformation into Talairach atlas space, as well as within-subject analysis without anatomic deformations, demonstrated an overlapping somatotopic distribution in the motor cortex, with thumb responses most ventrolateral and shoulder responses most dorsomedial. Proximal limb movements induced relCBF responses of greater magnitude than distal movements. Somatotopy was also identified in the supplementary motor area, with index finger responses dorsal and anterior to shoulder responses. An additional set of somatotopic responses were located in the cingulate cortex, also with finger responses anterior to shoulder responses. Somatotopy was not identified in the anterior cerebellum. The distribution of relCBF responses is concordant with electrophysiologic studies in nonhuman primates that demonstrate a fractured somatotopy on a fine scale and a general somatotopic scheme of the limb on a large scale in multiple discrete motor areas.

Adult↗

Mapping of central D2 dopamine receptors in man using [11C]raclopride: PET with anatomic standardization technique.

D2 dopamine receptors are of interest in the pathophysiology of schizophrenia. For group comparisons of neuroreceptor distribution measured by PET on a pixel-by-pixel basis, an anatomic standardization technique is required. The aim of the present study is to build a database of normal D2 dopamine receptor distribution using [11C]raclopride and an anatomic standardization technique. In each subject, two PET measurements were performed with rapid bolus injection and with continuous infusion of [11C]raclopride. The radioactivity of the PET images were integrated in the time interval. Integrated images were normalized by the radioactivity of the cerebellum, providing a measure of the binding potential (BP) in each pixel. Each PET image was transformed into a standard brain anatomy using a Computerized Brain Atlas system. From the standardized PET images, the sample mean and the SD of the BP were calculated in each pixel. On the anatomically standardized average images for the both rapid bolus injection and continuous infusion, high BP was observed in the putamen and the caudate nucleus, whereas low BP was observed in the cerebral cortices. The BP for the thalamus and the substantia nigra were slightly higher than those for the cerebral cortices. This regional distribution is in good agreement with the distribution of D2 dopamine receptors known from in vitro studies. The anatomic standardization technique permits to build a database of the normal D2 dopamine receptor distribution in the living human brain. This technique can be applied for group comparisons on a pixel-by-pixel basis.

Adult↗

Three-dimensional probabilistic atlas of the human orbitofrontal sulci in standardized stereotaxic space.

A quantitative analysis of the variability of human orbitofrontal anatomical landmarks is required if one is to describe properly the location of functional or structural changes within this brain region. The present study investigated the orbitofrontal sulci in 100 normal adult human cerebral hemispheres using magnetic resonance images that were transformed into the standardized proportional stereotaxic space most commonly used, that of Talairach and Tournoux (1988). Four orbitofrontal sulci were identified and marked on each hemisphere: the olfactory, the medial, the lateral, and the transverse orbital sulci. Probability maps were then constructed for each sulcus. These maps provide a statistical description of the variability of the location of each orbitofrontal sulcus within the three-dimensional coordinate system of Talairach and Tournoux (1988). These probability maps may be directly compared with any image transformed into the same standardized space, providing a valuable tool for identifying and describing the location of functional or structural changes in the orbitofrontal region of the human brain.

Adult↗

Role of PLZF in melanoma progression.

The promyelocytic leukemia zinc finger (PLZF) protein has been described as a transcriptional repressor of homeobox (HOX)-containing genes during embryogenesis. As we previously demonstrated a functional link between overexpression of HOXB7 and melanoma progression, we investigated the lack of PLZF as the possible cause of HOXB7 constitutive activation in these neoplastic cells. Accordingly, we found PLZF expression in melanocytes, but not in melanoma cells, a pattern inversely related to that of HOXB7. PLZF retroviral gene transduction was then performed in a panel of melanoma cell lines, and tumorigenicity was compared with that of empty vector-transduced control cell lines. Evaluation of in vitro migration, invasion and adhesion indicated that PLZF gene transduction induced a less malignant phenotype, as confirmed through in vivo studies performed in athymic nude mice. This reduced tumorigenicity was not coupled with HOXB7 repression. In order to find more about the molecular targets of PLZF, the gene expression profiles of PLZF- and empty vector-transduced A375 melanoma cells were analysed by Atlas Cancer macroarray. Among several genes modulated by PLZF enforced expression, of particular interest were integrin alphavbeta3, osteonectin/SPARC and matrix metalloprotease-9 that were downmodulated, and the tyrosinase-related protein-1 that was upregulated in all the analysed samples. This profile confirms the reduced tumorigenic phenotype with reversion to a more differentiated, melanocyte like, pattern, thus suggesting a suppressor role for PLZF in solid tumors. Moreover, these results indicate that PLZF and HOXB7 are functionally independent and that their coupled deregulation may account for most of the alterations described in melanomas.

Animals↗