Biomedical subjects

J Towfighi

Publications and source records attributed to J Towfighi.

At least 19 recordsLinked to original sources

PubMed2001

Experimental stroke in the female diabetic, db/db, mouse.

Diabetic hyperglycemia increases brain damage after cerebral ischemia in animals and humans, although the underlying mechanisms remain unclear. Gender-linked differences in ischemic tolerance have been described but have not been studied in the context of diabetes. In the current study, we used a model of unilateral common carotid artery ligation, combined with systemic hypoxia, to study the effects of diabetes and gender on hypoxic-ischemic (HI) brain damage in the genetic model of Type II diabetes, the db/db, mouse. Male and female, control and db/db, mice were subjected to right common carotid artery ligation followed by varying periods of hypoxia (8% oxygen/92% nitrogen) to assess mortality, infarct volume, and tissue damage by light microscopic techniques. End-ischemic regional cerebral blood flow (CBF) was determined using [14C] iodoantipyrine autoradiography. Glycolytic and high energy phosphate compounds were measured in blood and brain by enzymatic and fluorometric techniques. Gender and diabetes had significant effects on mortality from HI and extent of brain damage in the survivors. Female mice were more resistant than their male counterparts, such that the severity (mortality and infarction size) in the male diabetics > female diabetics - male controls > female controls. Endischemic CBF and depletion of cerebral high energy reserves were comparable among all groups. Surprisingly, female diabetic mice were more hyperglycemic and demonstrated a greater prolonged lactacidosis than the males; however, they were more resistant to damage. The results suggest a unique pathophysiology of hypoxia-ischemia in the female diabetic brain.

Animals↗

PubMed2001

Effect of extreme hypercapnia on hypoxic-ischemic brain damage in the immature rat.

To ascertain the effect of extreme hypercapnia on perinatal hypoxic-ischemic brain damage, 7-d-postnatal rats were exposed to unilateral common carotid artery occlusion followed by hypoxia with 8% oxygen combined with 3, 12, or 15% carbon dioxide (CO2) for 2 h at 37 degrees C. Survivors underwent neuropathologic examination at 30 d of postnatal age, and their brains were characterized as follows: 0 = normal; 1 = mild atrophy; 2 = moderate atrophy; 3 = cystic infarct with external dimensions <3 mm; and 4 = cystic infarct with external dimensions >3 mm. The width of the cerebral hemisphere ipsilateral to the carotid artery occlusion also was determined on a posterior coronal section and compared with that of the contralateral hemisphere to ascertain the severity of cerebral atrophy/cavitation. CO2 tensions averaged 5.08, 11.1, and 13.2 kPa in the 3, 12, and 15% CO2-exposed animals, respectively, during hypoxia-ischemia (HI). Neuropathologic results showed that immature rats exposed to 3 and 12% CO2 had similar severities of brain damage. In contrast, rat pups exposed to HI combined with 15% CO2 were significantly more brain damaged than littermates exposed to 3% CO2. Specifically, eight of 14 animals exposed to 15% CO2 showed cystic infarcts (grades 3 and 4), whereas none of 14 littermates exposed to 3% CO2 developed cystic infarcts (p < 0.01). Analyses of coronal width ratios at each CO2 exposure provided results comparable with those of the gross neuropathology scores. Cerebral blood flow (CBF), measured at 90 min of HI, was lowest in those immature rats exposed to 15% CO2 compared with control (p = 0.04), with higher values in those rat pups exposed to 3 and 12% CO2. The findings indicate that 7-d-postnatal rats exposed to HI with superimposed 12% CO2 are neither less nor more brain damaged than littermates exposed to 3% CO(2) (normocapnia). In contrast, animals exposed to 15% CO2 are the most brain damaged of the three groups. Presumably, extreme hypercapnia produces more severe cardiovascular depression than is seen in animals subjected to lesser degrees of hypercapnia; the cardiovascular depression, in turn, leads to greater cerebral ischemia and ultimate brain damage.

Animals↗

PubMed2001

Primitive neuroectodermal tumor of cerebrum with adipose tissue.

Primitive neuroectodermal tumors (PNETs) of the central nervous system are uncommon embryonal neoplasms, rarely occurring in adults. Differentiation into specific mesenchymal tissues, such as cartilage, bone, skeletal muscle, smooth muscle, or adipose tissue, is rare. We report a case of a 51-year-old woman with a PNET of cerebrum that showed extensive mature adipose tissue differentiation. This is the second case, to our knowledge, of PNET of cerebrum with adipose tissue elements that has been described.

Adipose Tissue↗

PubMed2000

Increased plasma beta-hydroxybutyrate, preserved cerebral energy metabolism, and amelioration of brain damage during neonatal hypoxia ischemia with dexamethasone pretreatment.

Dexamethasone (DEX) pretreatment has been shown to be neuroprotective in a neonatal rat model of hypoxia ischemia (HI). The exact mechanism of this neuroprotection is still unknown. This study used 31P nuclear magnetic resonance spectroscopy to monitor energy metabolism during a 3-h episode of HI in 7-d-old rat pups in one of two groups. The first group was pretreated with 0.1 mL saline (i.p.) and the second group was treated with 0.1 mL of 0.1mg/kg DEX (i.p.) 22 h before HI. Animals pretreated with DEX had elevated nucleoside triphosphate and phosphocreatine levels during HI when compared with controls. Saline-treated animals had significant decreases in nucleoside triphosphate and phosphocreatine and increases in inorganic phosphate over this same period. 31P nuclear magnetic resonance data unequivocally demonstrate preservation of energy metabolism during HI in neonatal rats pretreated with DEX. Animals pretreated with DEX had little or no brain damage following 3 h of HI when compared with matched controls, which experienced severe neuronal loss and cortical infarction. These same pretreated animals had an increase in blood beta-hydroxybutyrate levels before ischemia, suggesting an increase in ketone bodies, which is the neonate's primary energy source. Elevation of ketone bodies appears to be one of the mechanisms by which DEX pretreatment provides neuroprotection during HI in the neonatal rat.

3-Hydroxybutyric Acid↗

PubMed1999

Effect of seizures on cerebral hypoxic-ischemic lesions in immature rats.

The present investigation was designed to study the effect of chemically induced seizures on cerebral hypoxic-ischemic (HI) damage in immature animals. Accordingly, cerebral HI was produced in 7-day postnatal (p7) rats and p13 rats by combined unilateral common carotid artery ligation and hypoxia with 8% oxygen. Seizures were induced chemically by the subcutaneous injection of kainic acid (KA) or inhalation of flurothyl vapor. Three types of experiments were conducted in each age group and for each convulsant. In some animals (group 1), seizures were produced at 24 h and again at 6 h prior to HI. In groups 2 and 3, seizures were induced 2 h or 24 h post HI, respectively. The results indicate that in group 1 animals, the first seizure significantly reduced duration of the second seizure challenge 18 h later at both p7 and p13 (p=0.001). Histologic examination of brains of animals in group 1 subjected to seizures prior to HI and their HI-only controls showed that seizures prior to HI conferred protection against cerebral damage. This effect was significant for flurothyl seizures in p13 rats for all cerebral regions, especially hippocampal CA1 (p=0.0004), and in p7 rats for hippocampus (p=0.04) and particularly cerebral cortex (p=0.007). For KA seizures, the protective effect was only significant in p13 rats and was limited to hippocampal CA regions and subiculum (p=0.0009). Histologic assessment of cerebral lesions of p7 and p13 rats in the other two groups showed no significant difference between the animals subjected to seizures 2 h or 24 h post HI and their HI-only controls (p>0.05). In conclusion, the results of the present study provide no evidence that seizures in early postnatal development aggravate pre-existing cerebral HI damage. They do suggest that seizures prior to HI or prior to a second seizure confer tolerance to both conditions.

Animals↗

PubMed1999

Rat model of perinatal hypoxic-ischemic brain damage.

To gain insights into the pathogenesis and management of perinatal hypoxic-ischemic brain damage, the authors have used an immature rat model which they developed many years ago. The model entails ligation of one common carotid artery followed thereafter by systemic hypoxia. The insult produces permanent hypoxic-ischemic brain damage limited to the cerebral hemisphere ipsilateral to the carotid artery occlusion. The mini-review describes recently accomplished research pertaining to the use of the immature rat model, specifically, investigations involving energy metabolism, glucose transporter proteins, free radical injury, and seizures superimposed upon cerebral hypoxia-ischemia. Future research will focus on molecular mechanisms of neuronal injury with a continuing focus on therapeutic strategies to prevent or minimize hypoxic-ischemic brain damage.

Animals↗

PubMed1999

Localized hypertrophic neuropathy: magnetic resonance imaging findings and long-term follow-up.

Four patients with painless, progressive focal neurological deficits that localized to peripheral nerve or plexus were eventually found to have the relatively rare condition of localized hypertrophic neuropathy or intraneural perineurioma. Magnetic resonance imaging (MRI) was an excellent tool for aiding in the precise localization of the lesion, if specifically tailored with regard to imaging planes and specific MRI sequences. Fat-saturated T2-weighted and fat-saturated T1-weighted postgadolinium images provided the best visualization, particularly with a high-field magnet and phase array body coil. Two patients stabilized following resection of the lesion and sural nerve grafting, and 1 had partial improvement in a proximal muscle following neurolysis.

Adolescent↗

PubMed1999

Experimental models of hypothermic circulatory arrest.

This article reviews information obtained from experimental models of hypothermic circulatory arrest, which models have been developed in our and other laboratories over the past several years. The described experiments clearly demonstrate an ability to produce and completely reverse hypothermic circulatory arrest in newborn and developing animals, allowing for a comprehensive evaluation of those physiological variables and therapeutic interventions that would potentially reduce or accentuate ischemic brain damage. Further experiments will allow for a determination of whether or not specific modalities of therapy will reverse secondary systemic complications, thereby allowing for more complete recoverability and ultimately reduced brain damage.

Animals↗

PubMed1999

Optic nerve enlargement in Krabbe's disease.

We report imaging and gross pathologic findings from two cases of Krabbe disease in which there was marked enlargement of the intracranial optic nerves. Numerous globoid cells were observed in the optic nerves at autopsy in one case. Krabbe disease should be included in the differential diagnosis of children with enlargement of the optic nerves.

Diagnosis, Differential↗

PubMed1998

Temporal evolution of neuronal changes in cerebral hypoxia-ischemia in developing rats: a quantitative light microscopic study.

Studies in adult animal models of transient cerebral hypoxia-ischemia (HI) and ischemia suggest that morphologic evidence of neuronal death in some regions such as striatum appears early, while in other regions such as cerebral cortex and CA1 region of hippocampus it is delayed for few days and is referred to as delayed neuronal death (DND). Moreover, in some regions such as CA2/CA3 early 'reactive' neuronal changes occur that are potentially reversible. The aim of this study was to determine whether such changes may also occur in the developing brain. To that end, unilateral cerebral HI was produced in postnatal rats of 13, 21, and 30 days (p13, p21, p30) by right common carotid artery ligation and hypoxemia (breathing 8% O2), and their brains were examined at 24 h, 36 h, 72 h, and 96 h of recovery. The results suggest that: (i) DND is present in developing brain, but its regional distribution varies with animals' age. In cerebral cortex, it is more pronounced in p30 rats than in younger animals. In hippocampus, comparison of lesions of similar severity at different age groups shows a more pronounced DND in CA2/CA3 region of p13 rats than in older animals, but no significant differences exist in the degree of DND in CA1 neurons among different age groups. (ii) 'Reactive' neuronal changes characterized by reduction in Nissl staining and acidophilia of neuronal perikaryon with minimal nuclear abnormality are present at 24 h of recovery. These changes in some regions, such as in CA1 and cortex, progress to neuronal death, while in other regions such as in CA2/CA3 are potentially reversible. (iii) Recovery of reactive neurons in CA2/CA3 region is age dependent in that there is significant recovery in the older age groups, but not in p13 rats. The pathogenetic mechanisms of the reactive neuronal changes, the chain of events leading to DND or neuronal recovery, and the influence of age in these processes remain to be elucidated.

Animals↗

PubMed1998

Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates.

It has been reported that immature rats subjected to cerebral hypoxia-ischemia sustain less brain damage if they are previously exposed to systemic hypoxia compared with animals not exposed to prior hypoxia. Accordingly, neuropathologic and metabolic experiments were conducted to confirm and extend the observation that hypoxic preconditioning protects the perinatal brain from subsequent hypoxic-ischemic brain damage. Six-day postnatal rats were subjected to systemic hypoxia with 8% oxygen at 37 degrees C for 2.5 h. Twenty-four hours later, they were exposed to unilateral cerebral hypoxia-ischemia for 2.5 h, produced by unilateral common carotid artery ligation and systemic hypoxia with 8% oxygen. Neuropathologic analysis, conducted at 30 days of postnatal age, indicated a substantial reduction in the severity of brain damage in the preconditioned rats, such that only 6 of 14 such animals exhibited cystic infarction, but all 13 animals without prior preconditioning exhibited infarction (p < 0.001). Measurement of cerebral glycolytic and tricarboxylic acid intermediates and high-energy phosphate reserves at the terminus of and at 4 and 24 h following hypoxia-ischemia showed no differences in the extent of alterations in the preconditioned and nonpreconditioned immature rats. A difference was seen in the restitution of high-energy stores during the first 24 h of recovery from hypoxia-ischemia, with a more optimal preservation of these metabolites in the preconditioned animals, reflecting the less severe ultimate brain damage. Accordingly, the neuroprotection afforded to the preconditioned animals was not the result of any differences in the extent of anaerobic glycolysis, tissue acidosis, or depletion in high-energy reserves during hypoxia-ischemia but rather the result of other mechanisms that improved the metabolic status of the immature brain during the early hours of reperfusion following hypoxia-ischemia.

Aging↗

PubMed1997

Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia: a light microscopic study.

The most frequently used model of neonatal cerebral hypoxia-ischemia consists of a 7-day postnatal rat model with combined common carotid artery ligation and hypoxemia. Neuropathologic studies have shown major differences between this 7-day postnatal rat model and a similar adult model in regard to overall cerebral vulnerability, type and distribution of lesions. It is not clear how and when during animals' development these changes in cerebral vulnerability take place. To determine this we studied groups of rats of 2 to 30 postnatal days. The animals underwent unilateral common carotid artery ligation followed by breathing in 8% oxygen for 30, 60, 90, or 120 min and their brains were examined at 24- or 72-h recovery intervals. Due to resistance of 2-3-day-old rats to develop cerebral hypoxic-ischemic damage, 5% O2 was used instead of 8% O2. The results indicate that: (i) There is an overall increase in severity of cerebral lesions on the side of common carotid artery ligation between 2 and 7 postnatal days. There is also an increase in the frequency of cerebral lesions in developing animals with increasing age. (ii) Hippocampus is remarkably resistant to hypoxic-ischemic insult at 2-3 postnatal days but becomes progressively vulnerable, and by age 13 postnatal days hippocampal vulnerability far exceeds that of cortex. (iii) Cortical lesions change from predominantly columnar cell death to laminar selective neuronal death at age 13 postnatal days. (iv) Also significant changes occur in relative vulnerability of various hippocampal regions during development. During the first 5 postnatal days relative vulnerability of hippocampal regions is similar, but as the animals' development proceeds and hippocampal vulnerability increases lesions tend to involve specific regions while sparing others. By age 13 postnatal days CA1 and lateral CA3 develop increased vulnerability while medial CA3 and fascia dentata become relatively resistant and by 21 postnatal days adult pattern of CA1 selective vulnerability is approached. The underlying mechanisms for these changes in regional vulnerability to cerebral hypoxia-ischemia during development should be sought in complex regional anatomic, functional, and metabolic alterations that take place as brain matures.

Aging↗

PubMed1997

Neuropathology of normothermic circulatory arrest in newborn dogs.

Neuropathologic findings are described, for the first time, in a neonatal dog model of circulatory arrest in normothermic conditions, and the findings are compared to those reported in neonatal dogs with hypothermic circulatory arrest. Total circulatory arrest was produced in 3- to 6-day-old anesthetized, paralyzed and ventilated, normothermic dogs either by asphyxiation or cardioplegia. Duration of circulatory arrest was 8-20 min and 10-40 min in asphyxiated and cardioplegic animals, respectively. The animals were resuscitated and maintained under controlled systemic physiologic conditions until neuropathologic examination after 8 or 24 h of recovery. The results suggest that the minimal durations of circulatory arrest for brain damage to occur following asphyxia or cardioplegia are 10 and 15 min, respectively. Ischemic lesions in both groups consisted of neuronal necrosis and involved mainly the brain stem structures, particularly the reticular nuclei and the spinal cord gray matter. The medulla was more severely involved than midbrain and pons. There was a direct correlation between the length of circulatory arrest and the severity of damage in the medulla (P = 0.001) and overall brain stem damage (P = 0.004) in animals with cardioplegia, but not in animals with asphyxia. These findings are compared to the neuropathologic changes previously described in newborn dogs subjected to hypothermic circulatory arrest, in which ischemic lesions are focused on the cerebral cortex and basal ganglia. It is concluded that hypothermia in this model not only prolongs the period of circulatory arrest that is required to produce brain damage, but also shifts the pattern of regional ischemic vulnerability from caudal to more rostral structures.

Animals↗

PubMed1997

Measuring the accentuation of the brain damage that arises from perinatal cerebral hypoxia-ischemia.

To ascertain the manner in which the severity of perinatal brain damage occurs as a result of hypoxia-ischemia, 7-day postnatal rats were subjected to unilateral common carotid artery ligation followed thereafter by exposure to 8% oxygen for up to 2.5 h. Following the hypoxic-ischemic exposure, the rat pups were reared with their dams until 30 days of postnatal age, at which time their brains underwent pathologic analysis. The severity of brain damage at each of four specific intervals of hypoxia-ischemia was determined and statistically compared by linear polynomial and nonparametric regression procedures. The data indicated that the accentuation of brain damage with increasing duration of hypoxia-ischemia was linear rather than curvilinear.

Animals↗

PubMed1997

The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat.

Neutrophils contribute to ischemic brain injury in adult animals. The role of neutrophils in perinatal hypoxic-ischemic (HI) brain injury is unknown. Allopurinol reduces neutrophil accumulation after tissue ischemia and is protective against HI brain injury. This study was designed to investigate how neutrophils contribute to perinatal hypoxic ischemic brain injury and how neutropenia compared with allopurinol in its neuroprotective effects. A HI insult was produced in the right cerebral hemisphere of 7-d-old rats by right common carotid artery ligation and systemic hypoxia. Half the rats were rendered neutropenic with an anti-neutrophil serum (ANS). At 15 min of recovery from hypoxia, half the neutropenic and nonneutropenic rats received allopurinol (135 mg/kg, s.c.). The protective effect of the four treatment combinations was determined on brain swelling at 42 h of recovery. Neutropenia reduced brain swelling by about 70%, p < 0.01. Allopurinol alone produced similar protection so that the relatively small number of animals studied did not permit assessment of an additive effect. Neutrophil accumulation in cerebral hemispheres was measured by myeloperoxidase (MPO) activity assay and by neutrophil counts in 6-microm sections stained by MPO and ANS immunostaining. MPO activity peaked between 4 and 8 h of recovery in both hemispheres. Hemispheric neutrophil counts peaked at the end of the HI insult and again at 18 h of recovery. Neutrophils were stained within blood vessels and did not infiltrate the injured brain before infarction had occurred. We conclude that neutrophils contribute to HI brain injury in the neonate and that neutrophil depletion before the insult is neuroprotective.

Allopurinol↗

PubMed1996

Cerebrospinal fluid concentrations of glutamate and GABA during perinatal cerebral hypoxia-ischemia and seizures.

Cerebrospinal fluid (CSF) concentrations of glutamate and gamma- aminobutyric acid (GABA), as estimates of levels in the extracellular compartment of brain, were determined in 7-day postnatal rats at the terminus of hypoxia-ischemia and during status epilepticus, induced with bicuculline, at 2 and 24 h of recovery. Hypoxia-ischemia was associated with increased CSF glutamate, which was not increased further during status epilepticus. In contrast, CSF GABA was increased by hypoxia-ischemia as well as by status epilepticus during recovery. CSF glutamate/GABA ratios in rat pups subjected to status epilepticus with or without prior hypoxia-ischemia were lower than control animals during recovery. The lack of any significant increase in glutamate or in the glutamate/GABA ratio during status epilepticus would preclude any neuronal injury from occurring in those immature rats sustaining seizures alone or any accentuation of brain damage in those animals subjected to prior cerebral hypoxia-ischemia.

Animals↗

PubMed1996

Effect of hyperglycemia on ischemic brain damage during hypothermic circulatory arrest in newborn dogs.

The effect of hyperglycemia on ischemic brain damage was investigated in a newborn dog model of hypothermic circulatory arrest. Newborn dogs were anesthetized with halothane, paralyzed, and artificially ventilated to maintain normoxia and acid-base balance. Animals were surface-cooled to 20 degrees C, after which cardiac arrest was effected with i.v. KCl. Before surface cooling, one-half of the dogs (n = 12) received a bolus injection of 50% glucose to increase plasma glucose concentrations to approximately 33 mmol/L (600 mg/dL); control littermates (n = 12) received an equivalent volume of 1 N saline. The dogs remained asystolic for 1.75 h, after which cardiopulmonary resuscitation was accomplished. All animals survived, were allowed to recover from anesthesia at 37 degrees C, and were maintained for 8 h of recovery, at which interval they underwent perfusion-fixation of their brains for pathologic analysis. Histologic grading of brain damage showed no statistically significant difference in the severity of neuronal necrosis within the cerebral cortex or caudate nucleus between hyperglycemic and normoglycemic littermates, with greater brain damage apparent in the amygdaloid nucleus of the hyperglycemic dogs (p < 0.02). Brainstem injury occurred more frequently in the hyperglycemic animals (p < 0.05). Correlation of coefficients analyses revealed a positive correlation between the severity of brain damage and plasma glucose concentration for both the caudate nucleus and amygdaloid nucleus but not for the cerebral cortex. The findings suggest that hyperglycemia superimposed upon hypothermic circulatory arrest in the newborn dog accentuates brain damage only in selected regions of the brain, especially the caudate and amygdaloid nuclei and brainstem, excluding the cerebral cortex.

Amygdala↗

PubMed1996

Ganglion cell-containing tumors of the pituitary gland.

The ganglion cell-containing tumors of the pituitary are rare lesions of undetermined histogenesis and nosology. A review of the literature revealed 42 such tumors, including the 3 cases described below. On the basis of this review, the tumors were divided into two histologic groups, one consisting of both adenomatous and gangliocytic elements (32 cases), and the other of the gangliocytic component only (10 cases). The first group of tumors were more common in females (23 of 32 cases) and were often active endocrinologically (28 of 32 cases), and acromegaly was the most common manifestation (19 cases). The second group was also more common in females (7 of 10 cases) but was less frequently active endocrinologically (3 of 19 cases). We review histologic and immunocytochemical findings in these tumors and discuss their histogenesis. We propose that the term mixed pituitary adenoma-gangliocytoma be used for the first group and gangliocytoma for the second. The two groups should be kept separate until their histogenesis is better understood.

Adolescent↗