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Biomedical subjects

M L Cohen

Publications and source records attributed to M L Cohen.

At least 55 records · Page 3Linked to original sources
PubMed1999

Role of radical surgery for intracranial melanotic neuroectodermal tumor of infancy: case report.

OBJECTIVE AND IMPORTANCE: Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, locally aggressive tumor that arises most commonly from the maxilla or mandible. Infrequently, it originates from the cranial vault, and recent reports have described a favorable outcome after radical surgery. Some lesions are particularly problematic, such as those located along the cranial midline or cranial base and those with significant intracranial extension. Currently, there is no effective adjuvant therapy for MNTI; radiation is precluded by the patients' young age, and chemotherapy trials have not demonstrated long-term efficacy. CLINICAL PRESENTATION: A 2-month-old infant boy presented with a firm, immobile subcutaneous mass behind the right ear. The mass had been present at birth and enlarged with time. INTERVENTION: Initial resective surgery down to the dura resulted in massive tumor recurrence within weeks. Successful management required repeat surgery including excision of the dura and dural venous sinuses. CONCLUSION: This patient's large MNTI of the cranial base was successfully managed by radical surgery. Although MNTI is a rapidly growing tumor that is locally highly invasive, radical surgery may be associated with a favorable outcome and offers the potential for long-term cure.

Humans↗
PubMed1999

Atypical teratoid/rhabdoid tumor of the CNS: cytopathology and immunohistochemistry of insulin-like growth factor-II, insulin-like growth factor receptor type 1, cathepsin D, and Ki-67.

Insulin-like growth factor (IGF)-II is a potent growth factor, normally controlled by a number of other factors, including IGF binding proteins and IGF binding protein proteases. In general, the latter increase the bioavailability of IGF by cleaving IGF binding proteins. Cathepsin D (an IGF binding protein protease) was also implicated in tumor invasion. Although IGF-II was implicated in the pathogeneses of various childhood neoplasms, its significance in the pathogenesis of atypical teratoid/rhabdoid tumor of the central nervous system (ATRT-CNS) was not studied to date. We present clinicopathologic features of two cases of ATRT-CNS. In addition, formalin-fixed, paraffin-embedded tissue sections were stained immunohistochemically for IGF-II, IGF receptor type 1, cathepsin D, and Ki-67. Both tumors demonstrated diffuse strong cytoplasmic positivity for IGF-II, diffuse cytoplasmic and focal membranous positivity for IGF receptor type I, and diffuse cytoplasmic positivity for cathepsin D. The Ki-67 labeling indices were 10.0% and 1.4%. We conclude that ATRT-CNS cells express both IGF-II and IGF receptor type 1, supporting the hypothesis that autocrine/paracrine stimulation of cell growth by IGF-II might be one mechanism involved in ATRT-CNS tumorigenesis. Cathepsin D expressed by the tumor cells might also be involved in both tumor cell invasion and growth. The exact pathogenesis of ATRT-CNS remains to be elucidated.

Adolescent↗
PubMed1999

5-Hydroxytryptamine(1F) receptors do not participate in vasoconstriction: lack of vasoconstriction to LY344864, a selective serotonin(1F) receptor agonist in rabbit saphenous vein.

Recently, several novel approaches to the treatment of migraine have been advanced, including selective 5-hydroxytryptamine (or serotonin) 1B/1D (5-HT(1B/1D)) receptor agonists such as sumatriptan and 5-HT(1F) receptor agonists such as LY344864. Many 5-HT(1B/1D) receptor agonists have been identified based on their ability to produce cerebral vascular contraction, whereas LY344864 was identified as an inhibitor of trigeminal nerve-mediated dural extravasation. In our study, several triptan derivatives were compared with LY344864 for their ability to contract the rabbit saphenous vein, a tissue used in the preclinical identification of sumatriptan-related agonists. Sumatriptan, zolmitriptan, rizatriptan, and naratriptan all contracted the rabbit saphenous vein from baseline tone, whereas LY344864 in concentrations up to 10(-4) M did not contract the rabbit saphenous vein. Furthermore, vascular contractions to sumatriptan were markedly augmented in the presence of prostaglandin F(2alpha) (PGF(2alpha)). However, even in the presence of PGF(2alpha) (3 x 10(-7) M), LY344864 did not contract the rabbit saphenous vein in concentrations well in excess of its 5-HT(1F) receptor affinity (pK(i) = 8.2). Only when concentrations exceeded those likely to activate 5-HT(1B) and 5-HT(1D) receptors (>10(-5) M) did modest contractile responses occur in the presence of PGF(2alpha). Use of these serotonergic agonists revealed a significant correlation between the contractile potency in the rabbit saphenous vein and the affinities of these agonists at 5-HT(1B) and 5-HT(1D) receptors, although contractile agonist potencies were not quantitatively similar to 5-HT(1B) or 5-HT(1D) receptor affinities. In contrast, no significant correlation existed between the contractile potencies of these serotonergic agonists in the rabbit saphenous vein and their affinity at 5-HT(1F) receptors. These data support the contention that activation of 5-HT(1F) receptors will not result in vascular contractile effects.

Animals↗
PubMed1999

5-Hydroxytryptamine(1A) receptor activation enhances norepinephrine release from nerves in the rabbit saphenous vein.

Although serotonergic receptor agonists are known to modulate release of central serotonin, less is known about the ability of serotonin to alter neurotransmission in peripheral adrenergic nerves. The present study used field stimulation (40V, 0.7 ms duration, 1-16 Hz) to contract the rabbit saphenous vein, an effect that was abolished in the presence of tetrodotoxin and prazosin (10(-6) M), consistent with stimulation of neuronal norepinephrine release. Furthermore, the field-stimulated contraction was not altered by the 5-hydroxytryptamine (5-HT)(1B/1D) receptor antagonist GR127935 (10(-6) M), but was markedly inhibited by the 5-HT(1A) receptor antagonist WAY 100635 (10(-6) M). GR127935 (10(-8) M) inhibited contraction to sumatriptan, documenting that the concentration used was sufficient to block 5-HT(1B/1D-like) vascular receptors in this tissue. Likewise, WAY 100635 (10(-6) M) inhibited contraction to the 5-HT(1A) receptor agonists (+/-)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) and LY238729, without altering contraction to norepinephrine or sumatriptan. Furthermore, both 8-OH-DPAT and LY228729 enhanced the contractile response to field stimulation (1. 0-8.0 Hz) and activated norepinephrine release in the absence of field stimulation. Contractile responses of the rabbit saphenous vein to both 5-HT(1A) receptor agonists were markedly inhibited by prazosin and dextrally shifted by WAY 100635, supporting the idea that the 5-HT(1A) receptor agonists were activating presynaptic 5-HT(1A) receptors to enhance norepinephrine release even in the absence of field stimulation. Thus, in the rabbit saphenous vein, 5-HT(1A) but not 5-HT(1B/1D) receptors enhanced neurotransmitter release from adrenergic nerves. These observations suggested that serotonergic nerves or other cell types in the saphenous vein are activated by field stimulation to release serotonin, which in turn activates presynaptic 5-HT(1A) receptors on adrenergic neurons to effect norepinephrine release. To support this hypothesis, serotonin levels were measured in the saphenous vein and were increased after pargyline pretreatment (30 mg/kg s.c.), decreased after dl-p-chlorophenylalanine methyl ester pretreatment (300 mg/kg s.c.), and unaltered after pretreatment with 6-hydroxydopamine hydrobromide (100 mg/kg s.c.). Thus, we provide strong evidence for the 1) presence of serotonin and its direct synthesis independent of adrenergic nerves and 2) a novel excitatory effect of presynaptic 5-HT(1A) receptor activation on adrenergic nerves in a peripheral blood vessel.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Synthesis and structure-activity relationships of potent and orally active 5-HT4 receptor antagonists: indazole and benzimidazolone derivatives.

A series of indole-3-carboxamides, indazole-3-carboxamides, and benzimidazolone-3-carboxamides was synthesized and evaluated for antagonist affinity at the 5-HT4 receptor in the rat esophagus. The endo-3-tropanamine derivatives in the indazole and benzimidazolone series possessed greater 5-HT4 receptor affinity than the corresponding indole analogues. 5-HT4 receptor antagonist affinity was further increased by alkylation at N-1 of the aromatic heterocycle. In a series of 1-isopropylindazole-3-carboxamides, replacement of the bicyclic tropane ring system with the monocyclic piperidine ring system or an acyclic aminoalkylene chain led to potent 5-HT4 receptor antagonists. In particular, those systems in which the basic amine was substituted with groups capable of forming hydrogen bonds showed increased 5-HT4 receptor antagonist activity. While some of these compounds displayed high affinity for other neurotransmitter receptors (in particular, 5-HT3, alpha1, and 5-HT2A receptors), as the conformational flexibility of the amine moiety increased, the selectivity for the 5-HT4 receptor also increased. From this series of compounds, we identified LY353433 (1-(1-methylethyl)-N-[2-[4-[(tricyclo[3.3.1.1(3, 7)]dec-1-ylcarbonyl)amino]-1-piperidinyl]ethyl]-1H-indazole-3- carboxamide) as a potent and selective 5-HT4 receptor antagonist with clinically suitable pharmacodynamics.

Adamantane↗
PubMed1998

Advanced lipid peroxidation end-products in Alexander's disease.

Rosenthal fibers (RF), intra-astrocytic hyaline inclusions, accumulate in various pathological conditions and are the histological hallmark of Alexander's disease. While the major protein components of RF have been identified, the factors accounting for their pathogenesis, accumulation, and insolubility are largely unknown. In this study, we immunohistochemically examined three cases of Alexander's disease using antibodies to a lysine-derived pyrrole modification arising from 4-hydroxy-2-nonenal, a highly cytotoxic reactive aldehyde produced by lipid peroxidation. In all the cases of Alexander's disease examined, strong immunolabeling of RF by the antibodies to 4-hydroxy-2-nonenal pyrrole adducts were noted. By contrast, age-matched control cases showed no immunoreactivity. These results indicate that modification of protein by lipid peroxidation adducts may play an important role in the formation of RF as well as in the pathogenesis of Alexander's disease. Furthermore, taken together with our previous data indicating advanced Maillard reaction end products in RF, it seems that post-translational modification of RF, initiated by oxidative stress, is critical for both the accumulation and the insolubility of RF, and therefore, by inference, in the pathogenesis of Alexander's disease.

Adolescent↗
PubMed1998

Serotonin in migraine: theories, animal models and emerging therapies.

A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.

Animals↗
PubMed1998

Psychophysical evidence for a neuropathic component of chronic neck pain.

Recent studies into the common complaint of chronic neck pain have focused on its anatomical origin, identifying especially the cervical zygapophysial joints. However the pathophysiology of chronic neck pain remains poorly understood. In this psychophysical study, responses to electrocutaneous stimulation in subjects with chronic neck pain were examined. In an ascending method of limits design. electrical stimuli at 100 Hz with variation in current from 0 to 45 mA and in pulse width from 100 to 1000 micros were delivered transcutaneously to two points 2 cm from the midline bilaterally at the levels of C5/6 and C7/T1 in 35 subjects with chronic neck pain and 22 pain-free volunteers. There was a small difference in detection threshold between the two groups: both pain threshold and pain tolerance were significantly lower in the pain group compared with pain free controls. These findings define hyperalgesia psychophysically and, taken together with the absence of tissue damage at the sites of testing. suggest that these painful cervical regions may be examples of secondary hyperalgesia which, in turn, implies central sensitisation of nociceptive pathways. These results are compatible with studies which identify potential anatomical origins of chronic neck pain but provide evidence that central sensitisation may be the relevant mechanism of pain production.

Adult↗
PubMed1998

Resurgent and emergent disease in a changing world.

Emerging infectious diseases pose important public health problems for both the developed and developing world. Many new or previously unrecognized bacterial, fungal, viral, and parasitic diseases have emerged within the past two decades. At the same time, many once-controlled infections have re-emerged or become resistant to antimicrobial therapy. This emergence is the result of changes in society, technology, the environment, and the microbes themselves, and these changes have had often unpredictable consequences. Important factors influencing emergence include changes in human demographics and behaviour, changes in technology and industry, changes in economic development and land use, increasing and rapid international travel and commerce, microbial adaptation and change, and the breakdown of public health measures. Addressing emerging infectious diseases will require international and interdisciplinary partnerships to build an appropriate infrastructure to detect and respond to these often unanticipated threats to health.

Communicable Diseases↗
PubMed1998

An investigation of the possible neurotoxic effects of intrathecal midazolam combined with fentanyl in the rat.

In previous work, midazolam was injected intrathecally and produced reversible, segmental, spinally mediated anti-nociception sufficient for abdominal surgery in a rat model. The neurotoxic effect of midazolam, alone or combined with fentanyl, injected intrathecally repeatedly on 15 occasions over a period of 1 month, was studied in the same model. We sought to establish whether this would produce neurological damage or neurotoxic injury. Histopathological examination of the excised spinal cord and paraspinal tissues was carried out. Thirty Wistar strain rats with nylon catheters chronically implanted in the lumbar subarachnoid space were divided into five groups: group 1 (n = 6) received 40 microL of midazolam 0.1%; group 2 (n = 6) received 40 microL of fentanyl 0.005%; group 3 (n = 6) received 20 microL of midazolam 0.1% plus 20 microL of fentanyl 0.005%; group 4 (n = 6) received 40 microL of lignocaine 2%; group 5 (n = 6) received 40 microL of phenol in water. All substances were injected through the implanted catheters. The neurological recovery of all the animals in the four groups that received intrathecal midazolam alone, fentanyl alone, midazolam plus fentanyl and lignocaine alone was similar and complete. There were no significant differences in the histological changes in the neural tissues of these groups, despite repeated application of the test substances. Group 5 demonstrated the typical neurolytic lesions of phenol when injected intentionally into the subarachnoid space.

Analgesics, Opioid↗
PubMed1998

Neurocytoma presenting with intraparenchymal cerebral hemorrhage.

Neurocytomas are uncommon intracranial neoplasms that have only recently been characterized pathologically. Neurocytomas are histologically benign neoplasms that are often quite large when diagnosed, and previous reports have commonly described presentation with mass effect or cerebrospinal fluid outflow obstruction. We describe the first case of neurocytoma presenting with intraparenchymal cerebral hemorrhage.

Adolescent↗
PubMed1998

Candidate bacterial conditions.

This article provides background information on bacterial diseases and discusses those that are candidates for elimination or eradication. Only one disease, neonatal tetanus, is a strong candidate for elimination. Others, including Haemophilus influenzae b infection, leprosy, diphtheria, pertussis, tuberculosis, meningococcal disease, congenital syphilis, trachoma and syphilis are important causes of morbidity and mortality in industrialized and developing countries. For all these diseases, eradication/elimination is not likely because of the characteristics of the disease and limitations in the interventions.

Adult↗
PubMed1997

Advanced glycation modification of Rosenthal fibers in patients with Alexander disease.

Rosenthal fibers, astrocytic inclusions that accumulate in various neoplastic and non-neoplastic conditions, are a characteristic of Alexander disease, a leukodystrophy of unknown etiology. Given that alphaB crystallin is the major protein component of Rosenthal fibers and that crystallins in the diabetic and aged lens are targets for advanced glycation end product modifications via the Maillard reaction we hypothesized that Rosenthal fibers might contain similar modifications. Using antibodies specific for two products of glycation, pyrraline and pentosidine, we showed labeling of Rosenthal fibers that may account for their insolubility and accumulation. These data suggest that advanced glycation end products may be critical to the pathogenesis of Alexander disease.

Adolescent↗
PubMed1997

5-HT1F receptor agonists inhibit neurogenic dural inflammation in guinea pigs.

The serotonin (5-HT) receptor subtype mediating inhibition of neurogenic dural inflammation in guinea pigs was investigated using a series of serotonin agonists with differing affinities for the 5-HT1B, 5-HT1D and 5-HT1F receptors. When agonist potencies for inhibiting neurogenic inflammation were compared with affinities for these receptor subtypes, a significant positive correlation was seen only with the 5-HT1F receptor. The potency of agonists in inhibiting adenylate cyclase in cells transfected with human 5-HT1F receptor was also highly correlated with their potency in the animal model of migraine. In situ hybridization demonstrated 5-HT1F receptor mRNA in guinea pig trigeminal ganglion neurons. These data suggest that the 5-HT1F receptor is a rational target for migraine therapeutics.

Animals↗
PubMed1997

Amyloid beta-induced neurotoxicity is associated with phospholipase D activation in cultured rat hippocampal cells.

The role of phospholipase D (PLD) in amyloid beta (Abeta)-induced neurotoxicity was studied by comparing the effects of Abeta (1-40) on PLD activity and release of lactate dehydrogenase (LDH) from cultured rat hippocampal cells. PLD activity was determined in [3H]myristic acid-labeled cells by measuring the formation of [3H]phosphatidylethanol in the presence of ethanol (0.5%), and LDH activity in the cell media was measured via colorimetric assay. Abeta (50 microM), aged for 3 days to allow for peptide aggregation, acutely (1 h) stimulated PLD activity. Unaged Abeta (50 microM) had no acute (1 h) effect on PLD activity, but significantly stimulated PLD activity by 87% when incubated with cells for 1-3 days. Abeta (50 microM)-induced PLD activity was closely correlated with Abeta (50 microM)-induced LDH release over a time course of 1-3 days. These data suggest that PLD activation may be involved in Abeta-induced neurotoxicity.

Amyloid beta-Peptides↗