Endothelial injury following experimental subarachnoid hemorrhage in rats: Effects on brain blood flow

Background: The leading cause of death and disability in patients suffering from aneurysmal subarachnoid hemorrhage (SAH) is cerebral vasospasm, a persistent, progressive, and often irreversible constriction of cerebral arteries. A wide array of pathological changes occur in cerebral arteries following SAH, with endothelial injury being the earliest and most consistent one. Since intact endothelium modulates many reflexes that influence vascular tone, damage to them may represent a significant contributor to cerebral vasospasm. Methods: Changes in local cerebellar blood flow (LCBF) and pathological alterations in major cerebral arteries were studied and compared in rats at various time intervals following SAH. SAH induced by the subarachnoid injection of 0.3 ml of whole blood. Sham rats received a subarachnoid injection of 0.3 ml of isotonic saline. Results: Except for an immediate but transient decrease, LCBF remained unchanged over a 3 day period following saline injection. Likewise, there were no pathological alterations in cerebral arteries of saline-injected rats. In contrast, the subarachnoid injection of whole blood produced significant changes in both LCBF and cerebral arteries. Within 30 minutes postblood injection, LCBF became significantly decreased and remained so for 4 hours. However, within 24 hours, LCBF had returned to control levels where it remained for 3 days. Endothelial injury was observed in the basilar and middle cerebral arteries from 30 minutes through 4 hours, the same periods in which LCBF was significantly reduced. Within 24 hours, the time period in which LCBF had rebounded to control ranges, cerebral arteries showed no evidence of endothelial damage and resembled control cells. Conclusion: The results indicate a direct correlation between changes in LCBF and the structural integrity of endothelial cells in the early stages following SAH. The lack of chronically depressed LCBF (after 1 day) may be related to the quick structural repair of endothelium. © 1994 Wiley-Liss, Inc.     

The child as a projectile

Unintentional injury is the leading cause of death in children under the age of fourteen. The majority of these injuries/deaths occur when the child becomes airborne during an accident. The most common mechanisms by which children become airborne are motor vehicle collisions, bicycling accidents, and falls. A head injury is seen in a significant number of children in this setting. This includes injury to the scalp, skull, coverings of the brain, or the brain itself. These injuries are the most common cause of death in children resulting from unintentional injury. Other typical injuries include external bruises and abrasions, extremity fractures, and bruising or bleeding of internal organs. We propose to name this constellation of injuries the projectile child syndrome. This refers to those injuries occurring in infants and children as a result of becoming airborne during the events of an accident. The pattern of injuries seen as related to the anatomy of the child is stressed. A review of the impact to society and guidelines for prevention are presented. Anat. Rec. (New Anat.) 253:167–175, 1998. © 1998 Wiley-Liss, Inc.     

Why neurons die: Cell death in the nervous system

It is likely that humans are born with all of the nerve cells (neurons) that will serve them throughout life. For all practical purposes, when our neurons die, they are lost forever. During nervous system development, about one-and-a-half times the adult number of neurons are created. These “extra” neurons are then destroyed or commit suicide. This process of programmed cell death occurs through a series of events termed apoptosis and is an appropriate and essential event during brain development. Later in life, inappropriate neuronal cell death may result from pathological causes such as traumatic injury, environmental toxins, cardiovascular disorders, infectious agents, or genetic diseases. In some cases, the death occurs through apoptosis. In other cases, cell death is random, irreversible, and uncontrollable; to distinguish it from the controlled, planned cell death of apoptosis, we call this necrotic cell death. Understanding the difference between apoptotic and necrotic cell death is essential for designing therapies which will prevent or limit inappropriate cell death in the nervous system. Anat. Rec. (New Anat.): 253:79–90, 1998. © 1998 Wiley-Liss, Inc.     

New face of an old enzyme: Alkaline phosphatase may contribute to human tissue aging by inducing tissue hardening and calcification

Tissue nonspecific alkaline phosphatase (AP) plays a well-known role in bone mineralization. This role was first suggested by a human AP deficiency disease, hypophosphatasia. Further studies with AP gene knockout mice have also suggested a role for AP in mineralization. However, AP is also expressed in other human tissues besides bone and cartilage, and this raises a question as to whether AP may also play a role in pathological mineralization such as dystrophic and vascular calcification. In vitro studies carried out in our laboratory indicate that a variety of cell types stably expressing membrane-bound AP can affect extracellular mineralization regardless of the tissue from which the cell lines originated (e.g. fibroblasts, vascular endothelial cells, or renal epithelial cells). This AP-mediated extracellular mineralization is both substrate/dependent and culture environment/dependent and may be consistent with a putative role for AP in pathological mineralization in tissues other than bone and cartilage. In this regard, it is interesting to note that high levels of AP are observed in vascular endothelia of small arterioles in brain and heart. It is probable that expression of AP in small arterioles of brain and heart may also contribute to the vascular hardening and calcification observed in humans. This in turn could be related to vascular aging, vascular disease, and the resultant weakening of and/or rupture of vessel walls. Anat Rec. (New Anat.): 253:91–94, 1998. © 1998 Wiley-Liss, Inc.     

Learning deficits after experimental subarachnoid hemorrhage in rats

About 50% of subarachnoid hemorrhage (SAH) survivors have cognitive or neurobehavioral dysfunction. The mechanisms are not known. This study characterized behavioral deficits in a rat SAH model, and correlated these changes with histological alterations. SAH was induced by injection of 0.3 ml blood into the prechiasmatic cistern. Cognitive and memory changes were investigated in the Morris water maze. Neuronal cell death was evaluated by fluoro-jade and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Vasospasm was assessed on cross-sections of middle and anterior cerebral arteries. Microthromboemboli were quantified by fibrinogen staining. Escape latency and swimming distance were significantly increased in rats with SAH as compared to controls (P<0.05–0.001). SAH rats tended to do poorly on accuracy in spatial and working memory tests. SAH rats had a significantly higher number of fluoro-jade and TUNEL positive neurons in CA1 and CA3 of the hippocampus, cerebral cortex and Purkinje cells in the cerebellum (P<0.05–0.001). The number of microthromboemboli in the cortex and cerebellum were significantly higher after SAH than in controls (P<0.05–0.001). Cognitive deficits were induced by SAH in rats. There was a significant increase in apoptotic neurons in all regions of brain examined. However, cell death in the hippocampus was not sufficient to cause the neurobehavioral deficits observed in the Morris water maze. This suggests that other factors such as dysfunction of neurotransmission or plasticity in hippocampal pathways might contribute to the impairments.     

Curcumin attenuates vascular inflammation and cerebral vasospasm after subarachnoid hemorrhage in mice

Cerebral vasospasm is a major cause of death and disability after subarachnoid hemorrhage (SAH); however, clinical therapies to limit the development of cerebral vasospasm are lacking. Although the causative factors underlying the development of cerebral vasospasm are poorly understood, oxidative stress contributes to disease progression. In the present study, curcumin (150 or 300 mg/kg) protected against the development of cerebral vasospasm and limited secondary cerebral infarction after SAH in mice. The protective effect of curcumin was associated with a significant attenuation of inflammatory gene expression and lipid peroxidation within the cerebral cortex and the middle cerebral artery. Despite the ability of curcumin to limit the development of cerebral vasospasm and secondary infarction, behavioral outcome was not improved, indicating a dissociation between cerebral vasospasm and neurologic outcome. Together, these data indicate a novel role for curcumin as a possible adjunct therapy after SAH, both to prevent the development of cerebral vasospasm and to reduce oxidative brain injury after secondary infarction.     

Potentials of magnesium treatment in subarachnoid haemorrhage.

Subarachnoid hemorrhage from a ruptured aneurysm is a subset of stroke. The young age (median 55 years) and poor outcome (50% of patients die; 30% of survivors remain dependent) explain why in the population the loss of productive life years from aneurysmal subarachnoid hemorrhage (SAH) is as large as that from brain infarcts, the most common type of stroke. Ischemia plays an important role in the pathophysiological process after SAH. A period of global cerebral ischemia firstly occurs in the acute phase, immediately after rupture of the aneurysm, due to acute vasoconstriction and elevated intracranial pressure, which leads to a drop in perfusion pressure. This is quite distinct from the secondly, delayed cerebral ischemia (DCI), which is focal or multi-focal. DCI usually occurs between 4 and 10 days after the initial bleeding, has a gradual onset and is multi-focal, and is an important cause of death and dependency after SAH. The interval between the bleeding and the onset of ischemia provides an opportunity for preventive treatment. Magnesium is readily available, inexpensive and has a well-established clinical profile in obstetrical and cardiovascular practice. It is beneficial in the treatment of eclampsia, a disease with a pathophysiology comparable to DCI after subarachnoid hemorrhage. Neuroprotective mechanisms of magnesium include inhibition of the release of excitatory amino-acids and blockade of the NMDA-glutamate receptor. Magnesium is also a non-competitive antagonist of voltage dependent calcium channels, has cerebrovascular dilatory activity and is an important co-factor of cellular ATPases, including the Na/K-ATPase. Magnesium can reverse delayed cerebral vasospasm and reduces the extent of acute ischemic cerebral lesions after experimental subarachnoid hemorrhage in rats. In this article we discuss the neuroprotective potency of magnesium in SAH by describing the pathophysiology of ischaemia after SAH and the many ways magnesium may interfere with this.     

Blood supply of the tensor fasciae latae muscle

The tensor fasciae latae (TFL) muscle has been successfully harvested as a myocutaneous flap in reconstructive surgery. Reports on the vascular supply of this muscle, however, are incomplete or inconclusive. Therefore the arterial pattern was examined by dissection in 100 injected human cadaveric specimens. It was observed that whereas 67 muscles were supplied exclusively by a single vessel derived from the ascending branch of the lateral circumflex femoral (LCF) artery, 13 were supplied by a secondary vessel derived from the same branch, while 20 muscles were supplied by two vessels, the larger one arising as before and the smaller from the descending branch of the LCF. Our observations reveal that although the majority of TFL muscles are clinically Type I (one vascular pedicle) according to the classification of Mathes and Nahai (1981), 20% are actually Type II (major and minor vascular pedicles). Clin. Anat. 11:236–238, 1998. © 1998 Wiley-Liss, Inc.     

N-tert-butyl-α-phenylnitrone reduces the number of microinfarctions in the rabbit brain cortex

Dementia due to cerebral ischemic lesions is relatively common in the elderly. Since many of these lesions are probably caused by emboli, studying emboli-induced cerebral lesions in rabbits should, hopefully, provide information that is useful when searching for a means of preventing and treating vascular dementia in humans. Using magnetic resonance imaging we have found that N-tert-butyl-α-phenyl-nitrone (a free radical scavenger) reduced the number of emboli-induced cerebral microinfarctions in the rabbit cortex but did not have any impact on the number of infarctions found in the subcortical structures. The results suggest that significant amount of free radicals are produced in the ischemic foci located in the cortex, but not in the ischemic foci located in the subcortical structures. This finding may be of importance when considering treatments for cerebral ischemia in humans. Received: 20 January 1998 / Accepted: 7 October 1998     

Autopsy approach to stroke

Love S
(2011) Histopathology 58 , 333ndash;351
Autopsy approach to stroke Stroke is a major cause of morbidity and mortality but the brain and other relevant tissues are often examined only cursorily when stroke patients come to autopsy. The pathological findings and clinical implications vary according to the type of stroke and its location and cause. Large ischaemic strokes are usually associated with atherosclerosis of extracranial or major intracranial arteries but can be caused by dissection. Most small cerebral infarcts are caused by arteriosclerosis or, in the elderly, cerebral amyloid angiopathy (CAA). However, vasculitides and coagulopathies can cause a range of different patterns of ischaemic (and, occasionally, haemorrhagic) stroke. Global brain ischaemia, caused by severe hypotension or raised intracranial pressure, produces damage that is accentuated in certain regions and neuronal populations and may be confused with hypoglycaemic injury. The main cause of subarachnoid haemorrhage is a ruptured berry aneurysm but CAA, arteriovenous malformations and infective aneurysms are occasionally responsible. These can also cause parenchymal brain haemorrhage, although this most often complicates hypertensive small vessel disease. Sometimes the haemorrhage arises from a neoplasm. Performing an adequate autopsy in stroke requires proper preparation, awareness of the likely pathological processes, familiarity with intracranial vascular anatomy, careful gross examination and dissection, and appropriate use of histology.     

Wade RS. 1998. Medical mummies: The history of the Burns collection. Anat Rec (New Anat) 253:158–161.

Wade RS. 1998. Medical Mummies: The History of the Burns Collection. Anat Rec (New Anat) 253:158–161. In the Historical Note “Medical Mummies: The History of the Burns Collection” by Ronald S. Wade, which appeared in our December 1998 issue [Anatomical Record (New Anat) 253, 158–161, 1998], credit should have been attributed to Mark Teske, R.B.P. for his expert photographic work. The author and editors apologize for this unintended omission. Mark H. Paalman Managing Editor, The New Anatomist © 1999 Wiley‐Liss, Inc.     

A role for DNA-dependent activator of interferon regulatory factor in the recognition of herpes simplex virus type 1 by glial cells

Background

Subarachnoid haemorrhage (SAH) elicits rapid pathological changes in the structure and function of parenchymal vessels (≤ 100 μm). The role of neutrophils in these changes has not been determined. This study investigates the role of neutrophils in early microvascular changes after SAH

Method

Rats were either untreated, treated with vinblastine or anti-polymorphonuclear (PMN) serum, which depletes neutrophils, or treated with pyrrolidine dithiocarbamate (PDTC), which limits neutrophil activity. SAH was induced by endovascular perforation. Neutrophil infiltration and the integrity of vascular endothelium and basement membrane were assessed immunohistochemically. Vascular collagenase activity was assessed by in situ zymography.

Results

Vinblastine and anti-PMN serum reduced post-SAH accumulation of neutrophils in cerebral vessels and in brain parenchyma. PDTC increased the neutrophil accumulation in cerebral vessels and decreased accumulation in brain parenchyma. In addition, each of the three agents decreased vascular collagenase activity and post-SAH loss of vascular endothelial and basement membrane immunostaining.

Conclusions

Our results implicate neutrophils in early microvascular injury after SAH and indicate that treatments which reduce neutrophil activity can be beneficial in limiting microvascular injury and increasing survival after SAH.     

Branching Pattern of the Cerebral Arterial Tree

Quantitative data on branching patterns of the human cerebral arterial tree are lacking in the 1.0–0.1 mm radius range. We aimed to collect quantitative data in this range, and to study if the cerebral artery tree complies with the principle of minimal work (Law of Murray). To enable easy quantification of branching patterns a semi-automatic method was employed to measure 1,294 bifurcations and 2,031 segments on 7 T-MRI scans of two corrosion casts embedded in a gel. Additionally, to measure segments with a radius smaller than 0.1 mm, 9.4 T-MRI was used on a small cast section to characterize 1,147 bifurcations and 1,150 segments. Besides MRI, traditional methods were employed. Seven hundred thirty-three bifurcations were manually measured on a corrosion cast and 1,808 bifurcations and 1,799 segment lengths were manually measured on a fresh dissected cerebral arterial tree. Data showed a large variation in branching pattern parameters (asymmetry-ratio, area-ratio, length-radius-ratio, tapering). Part of the variation may be explained by the variation in measurement techniques, number of measurements and location of measurement in the vascular tree. This study confirms that the cerebral arterial tree complies with the principle of minimum work. These data are essential in the future development of more accurate mathematical blood flow models. Anat Rec, 302:1434–1446, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.     

Exploring development and disease through germ-line genetic engineering in the mouse

New developments in mouse genetics have transformed the field of genetics from a reactive to a proactive science. Current technologies in transgenesis, chromosome engineering, and saturation mutagenesis are introduced. These approaches permit the creation of new mutations and consequent mutant phenotypes that facilitate both the understanding of functions of existing genes and the search for previously unidentifed genes affecting important phenotypes in all mammals. Anat. Rec. (New Anat.) 253:19–23, 1998. © 1998 Wiley-Liss, Inc.     

Infrequent genetic alterations of the PTEN gene in Japanese patients with sporadic prostate cancer

Prostate cancer is a major cause of cancer death among elderly men in America, Europe, and Japan. However, the molecular mechanism of carcinogenesis is not yet well characterized. Frequent loss of heterozygosity (LOH) on chromosome 10q was reported in prostate cancer, and a candidate tumor suppressor gene, PTEN, was isolated on chromosome band 10q23.3. To investigate the genetic alterations of PTEN, we examined 45 primary prostate cancer specimens. LOH at the PTEN locus was observed in two (11.1%) of 18 tumors. However, no mutations were observed in any of the primary prostate cancers. These data suggest that mutation of the PTEN gene does not play a major role in prostate carcinogenesis of Japanese patients. Received: February 6, 1998 / Accepted: July, 3, 1998     

Morphological changes of cerebral arteries in a canine double hemorrhage model

Cerebral vasospasm is a major cause of morbidity and mortality in patients suffering from subarachnoid hemorrhage (SAH). Despite numerous studies, the pathogenesis of this deadly disorder is not clearly understood. Alterations in endothelial cells are a distinct morphological feature of cerebral vasospasm and some recent studies suggest that apoptosis might play a role in the cells' death. The goal of the present study is to examine the time course of apoptosis in endothelial cells of spastic cerebral arteries following experimental subarachnoid hemorrhage. Fifteen dogs were used in the present study. Twelve of them were divided into three groups (four per group) and subjected to a double-hemorrhage method of SAH. Following SAH, groups were sacrificed respectively on days 3, 5, and 7. Three dogs served as controls without blood injection. The basilar arteries were studied with the transmission electron microscopy and with angiography. Angiographic vasospasm began on day 3 and peaked on day 7. In morphologic studies, control dogs did not demonstrate apoptotic-like changes in endothelial cells of the basilar arteries. Beginning with day 3, apoptotic-like changes were noted in endothelial cells and consisted of condensation of peripheral nuclear chromatin, blebbing of the cell membrane, and condensation of the cytoplasm. Such changes progressed with time and were maximally developed by day 7. This is the first study that demonstrates the time course of apoptotic-like changes in the endothelial cells in the vasospastic basilar artery. Apoptosis might play an important role in the pathogenesis of vasospasm.     

Anatomy education in a changing medical curriculum

How we educate students in the first two years of medical school is changing at many institutions. Effective medical education should be viewed as a continuum, integration of the basic sciences and clinical medicine should occur throughout the curriculum, and self-directed, life-long learning should be emphasized. Curricular revision may be appropriate if these fundamental concepts are absent. The principles of three curricular models are discussed: traditional, problem-based, and systems-oriented. The ideal curriculum may draw from each of these: A truly integrated curriculum. However, the curricular model chosen must meet the needs of the institution and its students. As anatomists we should not shy away from this process of change. With progressive educational approaches, we can be leaders in this climate of curricular reform. Anatomy courses are laboratory based and the laboratory is an outstanding small group, faculty/student interactive opportunity. However, we must show flexibility and innovation in our educational approaches whatever the curricular design being proposed. Anat. Rec. (New Anat.) 253:28–31, 1998. © 1998 Wiley-Liss, Inc.     

Internal Ophthalmic Arteries Within the Brain‐Base Arterial System in Guinea Pig

In situ vascular specimens of the arterial circle were collected from 15 adult guinea pigs, both male and female. After specimen preparation, the vessels were filled with synthetic latex and subjected to analysis. Similar as in the case of other rodents, vertebral arteries were merged into basilar artery, further dividing into two short terminal branches. Distally, the terminal branches extend into caudal cerebral arteries. Rostral part of the arterial circle of brain is supplied with blood from maxillary arteries via external and internal ophthalmic arteries connected by a short anastomosis. This type of vascularity may probably be considered a functional analogy to the internal carotid arteries observed in other species. Rostral and caudal parts of the arterial circle of brain are connected by exceptionally long caudal communicating arteries. In author's opinion, the disputable contribution of internal carotid artery and the exceptional contribution of internal ophthalmic arteries in the cerebral blood supply in guinea pigs as compared to other rodents, warrants further research on the subject. Anat Rec, 301:887–891, 2018. © 2017 Wiley Periodicals, Inc.