The progressive course of neurological symptoms in anterior choroidal artery infarcts.

BACKGROUND: Infarctions of the anterior choroidal artery affect multiple anatomical structures, leading to a wide spectrum of neurological deficits with frequent symptom fluctuation or progression. AIMS: To assess etiological mechanisms, frequency, and predictors of symptom progression, as well as its impact on prognosis. METHODS: Anterior choroidal artery infarct patients were prospectively identified via predefined infarct locations with ischemic lesions ≥1·5 cm vertical diameter in cerebral imaging. Definition of neurological progression was ≥2 National Institutes of Health Stroke Scale points in motor function or ≥4 in total National Institutes of Health Stroke Scale. Stroke etiology was determined according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. We assessed demographical data, risk factors, and acute phase parameters in order to find predictors of neurological progression. RESULTS: Thirty patients fulfilled the inclusion criteria. Eighteen patients (60%) had neurological progression during days 1-3. Despite similar stroke severity at admission (median National Institutes of Health Stroke Scale in progressive infarcts 4·5 versus 4; P = 0·72), patients with progression had more severe deficits at day 3 (median National Institutes of Health Stroke Scale 9 vs. 3·5; P = 0·04) and worse three-month outcome. Only 31% of patients with progression scored <2 in the modified Rankin Scale compared with 89% without progression (P = 0·01) after three-months. No statistically significant differences regarding possible predictors of progression were found. Magnetic resonance imaging findings and etiological assessment suggest overlapping mechanisms of small and large vessel disease. CONCLUSIONS: Neurological deterioration is frequent in anterior choroidal artery infarcts and is associated with worse outcome. While mechanisms of small and large vessel disease seem to overlap in anterior choroidal artery infarction, we were not able to identify predictors of neurological progression.

Barnacle bonding: morphology of attachment of Xenobalanus globicipitis to its host Tursiops truncatus.

Xenobalanus globicipitis, a unique type of small pseudo-stalked barnacle occurs on the appendages of cetaceans, including the common bottlenose dolphin Tursiops truncatus. In this study, we examined attachment structures of X. globicipitis and modifications to the skin of T. truncatus in areas of attachment compared to skin nearby an attachment site. Barnacles and their six calcareous footplates were measured for their length and width. There was a positive correlation of barnacle width and length to footplate width and length. The thickness of the stratum corneum increased significantly in areas of attachment compared to skin nearby a footplate. The mitotic stratum germinativum at the base of the dermal papillae did not change significantly in areas of attachment compared to skin nearby a footplate. The stratum germinativum lining the lateral walls of the dermal papillae was significantly thicker in areas of skin nearby a footplate compared to in areas of attachment. Skin of T. truncatus nearby a footplate, displayed dermal papillae extending from the dermis and pointing roughly perpendicular to the epidermal stratum corneum. At sites of X. globicipitis attachment, the dermal papillae were forced to extend laterally, parallel to the stratum corneum, and the dermal papillae length to width ratio at an attachment site was significantly higher than on skin near an attachment site. Our results show that attachment of X. globicipitis through production of footplates organized into calcareous rings, leads to a thickened stratum corneum of the epidermis, a thinner lateral mitotic stratum germinativum and displaced structures of the upper dermis. These resulting modifications to the epidermis and dermis of the host may add to securing barnacle attachment to its host.

Sea urchin tube feet are photosensory organs that express a rhabdomeric-like opsin and PAX6.

All echinoderms have unique hydraulic structures called tube feet, known for their roles in light sensitivity, respiration, chemoreception and locomotion. In the green sea urchin, the most distal portion of these tube feet contain five ossicles arranged as a light collector with its concave surface facing towards the ambient light. These ossicles are perforated and lined with pigment cells that express a PAX6 protein that is universally involved in the development of eyes and sensory organs in other bilaterians. Polymerase chain reaction (PCR)-based sequencing and real time quantitative PCR (qPCR) also demonstrate the presence and differential expression of a rhabdomeric-like opsin within these tube feet. Morphologically, nerves that could serve to transmit information to the test innervate the tube feet, and the differential expression of opsin transcripts in the tube feet is inversely, and significantly, related to the amount of light that tube feet are exposed to depending on their location on the test. The expression of these genes, the differential expression of opsin based on light exposure and the unique morphological features at the distal portion of the tube foot strongly support the hypothesis that in addition to previously identified functional roles of tube feet they are also photosensory organs that detect and respond to changes in the underwater light field.

Differences in cerebral activation during perception of optokinetic computer stimuli and video clips of living animals: an fMRI study.

AIMS: There is behavioral evidence of increased spontaneous recruitment of visual attention to ancestral evolved categories, such as animals, compared with expertise-derived categories, such as a computer. In order to investigate the association between visual perception and spontaneous visual attention, a study was performed to determine if brain activation whilst viewing moving animals was increased compared with optokinetic computer stimuli. METHODS: Functional MRI was performed in 12 healthy volunteers using a standard block-design paradigm, consisting of three consecutive experiments. Subjects viewed the following images: Experiment one--optokinetic computer stimuli alternating with static computer stimuli; Experiment two--moving animals alternating with non-moving animals; Experiment three--moving animals alternating with optokinetic computer stimuli. RESULTS: Moving animals evoked motion-dependent activation bilaterally in the middle and superior temporal gyri, right inferior temporal gyrus, left occipital gyrus, right supramarginal gyrus, and left straight gyrus. Integrated object-and-motion-dependent activation was found bilateral in inferior and middle temporal gyri, right superior temporal gyrus, right superior parietal lobule, left dorsal putamen, and right amygdala. CONCLUSIONS: These results suggest that there is increased cerebral activity in the visuo-attentional network whilst viewing moving animals compared with optokinetic computer stimuli.

Methods for karyotyping and for localization of developmentally relevant genes on the chromosomes of the purple sea urchin, Strongylocentrotus purpuratus.

The purple sea urchin, Strongylocentrotus purpuratus, is the only non-chordate deuterostome model with a fully sequenced genome. Chromosomal localization of individual genes and resulting gene maps are unavailable for this or for any sea urchin. As a result, the purple sea urchin genome has not been mapped onto specific chromosomes and remains inaccessible to genome-wide approaches addressing questions that require positional information for particular genes. Here we describe the first successful methods for karyotyping and localizing specific gene loci on chromosomes of Strongylocentrotus purpuratus and those of the phylogenetically related Strongylocentrotus droebachiensis. Both species have 42 chromosomes in their diploid genomes (n = 21). There are 2 large, 8 medium, and 10 small pairs, plus one putative sex pair. In both species, bindin genes were localized to 2 pair of homologous chromosomes by fluorescent in situ hybridization. Fluorescently labeled bacterial artificial chromosome clones generated from S. purpuratus for the functionally related genes brachyury, foxa, and foxb were localized to different chromosomes. Our protocols provide previously unavailable tools for developing a gene map for the purple sea urchin genome.

A naturally occurring cancer with molecular connectivity to human diseases.

As Jessani et al.,(1) point out development of cell and animal models that accurately depict human tumorigenesis remains a major goal of cancer research. Clam cancer offers significant advantages over traditional models for genotoxic and non-genotoxic preclinical analysis of treatments for human cancers with a similar molecular basis. The naturally occurring clam model closely resembles an outbreeding, human clinical population and provides both in vitro and in vivo alternatives to those generated from inbred mouse strains or by intentional exposure to known tumor viruses. Fly and worm in vivo models for adult human somatic cell cancers do not exist because their adult somatic cells do not divide. Clam cancer is the best characterized, naturally occurring malignancy with a known molecular basis remarkably similar to those observed in several unrelated human cancers where both genotoxic and non-genotoxic strategies can restore the function of wild-type p53. To further emphasize this point of view, we here demonstrate a p53-induced, mitochondrial-directed mechanism for promoting apoptosis in the clam cancer model that is similar to one recently identified in mammals. Discerning the molecular basis for naturally occurring diseases in non-traditional models and correlating these with related molecular mechanisms responsible for human diseases is a virtually unexplored aspect of toxico-proteomics and genomics and related drug discovery.

Genotoxic stress-induced expression of p53 and apoptosis in leukemic clam hemocytes with cytoplasmically sequestered p53.

In nature, the soft shell clam, Mya arenaria, develops a fatal blood cancer in which a highly conserved homologue for wild-type human p53 protein is rendered nonfunctional by cytoplasmic sequestration. In untreated leukemic clam hemocytes, p53 is complexed throughout the cytoplasm with overexpressed variants for both clam homologues (full-length variant, 1,200-fold and truncated variant, 620-fold above normal clam hemocytes) of human mortalin, an Hsp70 family protein. In vitro treatment with etoposide only and in vivo treatment with either etoposide or mitoxantrone induces DNA damage, elevates expression (600-fold) and promotes nuclear translocation of p53, and results in apoptosis of leukemic clam hemocytes. Pretreatment with wheat germ agglutinin followed by etoposide treatment induces DNA damage and elevates p53 expression (893-fold) but does not overcome cytoplasmic sequestration of p53 or induce apoptosis. We show that leukemic clam hemocytes have an intact p53 pathway, and that maintenance of this tumor phenotype requires nuclear absence of p53, resulting from its localization in the cytoplasm of leukemic clam hemocytes. The effects of these topoisomerase II poisons may result as mortalin-based cytoplasmic tethering is overwhelmed by de novo expression of p53 protein after DNA damage induced by genotoxic stress. Soft shell clam leukemia provides excellent in vivo and in vitro models for developing genotoxic and nongenotoxic cancer therapies for reactivating p53 transcription in human and other animal cancers displaying mortalin-based cytoplasmic sequestration of the p53 tumor suppressor, such as colorectal cancers and primary and secondary glioblastomas, though not apparently leukemias or lymphomas.

Mortalin-based cytoplasmic sequestration of p53 in a nonmammalian cancer model.

In nature the soft shell clam Mya arenaria develops a fatal neoplasm that shares molecular similarity with an unrelated group of human cancers. In leukemic clam hemocytes, wild-type p53 and mortalin proteins co-localize in the cytoplasm. A similar phenotype, characterized by cytoplasmic sequestration of wild-type p53 protein, has been observed in several human cancers (undifferentiated neuroblastoma, retinoblastoma, colorectal and hepatocellular carcinomas, and glioblastoma). In some of these cancers p53 is tethered in the cytoplasm by mortalin when the latter protein is overexpressed. Using co-immunoprecipitation we have demonstrated that mortalin and p53 proteins are complexed in the cytoplasm of leukemic clam hemocytes (and not in normal hemocytes). In addition, treatment of leukemic clam hemocytes with MKT-077, a cationic inhibitor of mortalin, disrupts the interaction of mortalin and p53 proteins, resulting in translocation of some p53 to the nucleus. Based on these data, we introduce leukemic clam hemocytes as novel and easily accessible, in vivo and in vitro models for human cancers displaying a similar mortalin-based phenotype. Treatment of these models with novel chemotherapeutics may help reveal the molecular mechanism(s) involved in inactivating p53 by this form of cytoplasmic sequestration.

Prognosis of patients after hemicraniectomy in malignant middle cerebral artery infarction.

BACKGROUND AND PURPOSE: There are unsatisfactory therapeutic options for treatment of large infarctions of the middle cerebral artery with secondary development of life threatening brain edema. In most cases, post-ischemic brain edema can not be adequately treated by conservative means. However, several studies have shown that operative procedures such as decompressive hemicraniectomy can decrease mortality. Apart from mortality, the morbidity and quality of life are major features with which to estimate therapeutic benefit. The aim of this study was to acquire follow-up data on quality of life and outcome in patients treated with hemicraniectomy after stroke. METHODS: Eighteen patients were treated with decompressive hemicraniectomy after life threatening middle cerebral artery infarction between July 1997 and April 2000 in our clinic. Six patients (33 %) died within the first six months after the procedure. All twelve surviving patients were seen in a follow-up examination 7 to 26 months after the stroke and tested using the Rankin-Scale, Barthel Index (BI), Aachener Life Quality Inventory (ALQI) and Zung Self-Rating Depression Scale. RESULTS: Survivors with a mean age of 40.7 +/- 16.5 years were significantly younger than non-survivors with a mean age of 64.5 +/- 9.2 years (p = 0.006). Mean Barthel-Index of surviving patients was 61.1 +/- 26.1 points, mean Rankin-Scale 3.3 +/- 1.2 points. Two patients were able to return to work. Patients younger than 45 years (n = 7) had a significantly better outcome (BI 75.7 +/- 20.7) than patients over 45 years (n = 5) (BI 42.0 +/- 22.7 points, p = 0.026). Among five patients with an infarction of the left hemisphere, four had a slight to moderate Broca aphasia and one patient a global aphasia. Quality of life assessment by ALQI showed moderate disability (58.0 +/- 22.7 of 107 points) with no significant difference between left- and right-hemispheric infarctions. Using the Zung Self-Rating Depression Scale six patients were ranked as slightly depressive, one patient as moderately depressive and five patients as not depressive. Eleven out of twelve survivors, as well as their relatives, approved of the decision to have the operation. CONCLUSIONS: The study provides evidence that hemicraniectomy as treatment of severe space occupying ischemic brain edema saves lives and results in good quality of life in a high proportion of patients, especially in the young. This conclusion is restricted by the lack of a control group, which was deemed unethical in studying a potentially life saving therapy.