Fibromyalgia in the workplace.
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Cumulative Trauma Disorders↗
Biomedical subjects
M L Cohen
Publications and source records attributed to M L Cohen.
Intestinal lactase: maturational excess expression of mRNA over enzyme protein.
The mechanism of decline of intestinal lactase during mammalian development remains uncertain. Despite a major loss of catalytic activity, lactase mRNA appears to persist at detectable concentrations in adult rats. We quantified lactase activity, total lactase protein, and lactase mRNA in rats aged 7, 11, 15, 18, 22, 30, and 60 days using the 7S ribosomal RNA as the developmental control. The active lactase fraction was 0.81 of total lactase for all age groups except 60-day-old animals, in which it declined to 0.60 (P = 0.004), indicating that conversion of active lactase to inactive species contributed to the lower activity in the adult. Northern blots revealed a single discrete 6.8-kb message at all ages. Although lactase activity and immunoprotein decreased coordinately to a minimum by day 30 (20% of the 7-day value), lactase mRNA doubled to a maximum at day 22 and was maintained at 7-day concentrations even in 60-day adults. The lactase mRNA-to-protein ratio was low at 7 days (0.19) but more than doubled (0.50) by 22 days, achieved a fivefold increase (1.0) by 30 days, and persisted at 0.77 in adults. The relative excess of lactase message during maturation suggests that translational or post-translational events may be paramount in the developmental regulation of lactase gene expression.
Aging↗
Intracranial Wegener's granulomatosis.
We describe an atypical neurologic presentation of Wegener's granulomatosis (WG) with striking meningeal and cerebral involvement, responding to immunosuppressive therapy. WG may cause treatable intracranial complications in the absence of nasal or renal disease and without cerebral angiographic abnormalities, CSF pleocytosis, or a positive assay for antineutrophil cytoplasmic antibodies.
Brain Diseases↗
Abnormal responses to electrocutaneous stimulation in fibromyalgia.
OBJECTIVE: As disturbed nociception may be relevant to the pathogenesis of fibromyalgia, nonnoxious electrocutaneous stimulation was used as a tool to investigate nociceptive status. METHODS: Perception threshold and pain tolerance were studied in the upper limbs of 10 patients with fibromyalgia and 10 healthy volunteers. RESULTS: Perception threshold did not differ between the groups but the marked reduction in pain tolerance found in patients with fibromyalgia was accompanied by spread and persistence of dysesthesiae. CONCLUSION: The upper limbs of patients with fibromyalgia resembled regions of secondary hyperalgesia, which may imply that perturbation of central nociceptive mechanisms is involved in the pathogenesis of this syndrome.
Adolescent↗
Vascular serotonin 5-hydroxytryptamine2 receptor blockade by LY215840: lack of effect upon neointima formation in balloon-injured rat carotid arteries.
5-Hydroxytryptamine (5-HT) is mitogenic for vascular smooth muscle cells, an effect that may result from 5-HT2 receptor activation. After arterial balloon injury, platelet-derived products including 5-HT are delivered to the denuded vessel wall via platelet adhesion/aggregation and degranulation. To assess the role of 5-HT2 receptors in neointima formation, the selective 5-HT2 receptor antagonist LY215840 was infused continuously in rats with osmotic minipumps from 2 days before until 2 weeks after balloon injury to the left common carotid artery, at which time effects upon intimal thickening were examined. Chronic i.v. infusion of LY215840 (25 micrograms/kg/hr) produced a significant, rightward shift (approximately 500-fold) in the 5-HT pressor-response curve in pithed rats determined at 1 hr, 4 days or 16 days after initiation of infusion. Under these conditions, LY215840 had no significant effect upon cross-sectional intimal area determined 2 weeks postballoon injury (0.118 +/- 0.010 vs. 0.114 +/- 0.017 mm2 for vehicle- and LY215840-treated groups, respectively). Furthermore, the cellular density of neointima from LY215840-treated rats was unchanged relative to that of the vehicle group. As a positive control, heparin infusion produced dose-dependent reductions in intimal thickening in this model. At the infusion rate of 0.22 mg/kg/hr, heparin reduced intimal area from a control value of 0.114 +/- 0.015 to 0.025 +/- 0.007 mm2 (P < .05). Thus, extensive blockade of vascular 5-HT2 receptors does not inhibit neointima formation in this model of vascular balloon injury.
Animals↗
DOI and alpha-methylserotonin: comparative vascular and nonvascular smooth muscle effects and central 5-hydroxytryptamine2 receptor affinities.
Both alpha-methylserotonin and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) are agonists at 5-hydroxytryptamine2 (5-HT2) receptors. The present study compared these agonists for their binding affinities at the high- and low-affinity states of the 5-HT2 receptor and for their contractile activities in certain smooth muscle preparations. Both agonists contracted the rat aorta and rat jugular vein, tissues possessing 5-HT2 receptors, and contraction was blocked by ketanserin. However, alpha-methylserotonin produced greater maximal response (80-90% maximum response to serotonin) than DOI. In the rat jugular vein, the calculated dissociation constant of DOI (-log Kb = 7.7) corresponded well with its affinity for [3H]ketanserin- (pKi = 7.5) but not [125I]DOI- (pKi = 8.6) radiolabeled sites. This might suggest that binding to the agonist low-affinity state of the 5-HT2 receptor is more relevant to vascular agonist activity. alpha-Methylserotonin was slightly more potent than serotonin in contracting the rat aorta but not the jugular vein, whereas DOI was more potent in the jugular vein than in the aorta. In the jugular vein but not the aorta, the relative potency of these agents corresponded well with their relative affinities for either the [3H]ketanserin- or the [125I]DOI-labeled 5-HT2 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Amphetamines↗
Cytomegalovirus ventriculoencephalitis in AIDS. A syndrome with distinct clinical and pathologic features.
Cytomegalovirus ventriculoencephalitis is a late and terminal complication of AIDS. Cytomegalovirus retinitis was diagnosed before the onset of encephalitis in all but 1 of the 7 patients in this series. A distinct clinical presentation was observed, with encephalitis often associated with cranial nerve deficits and gaze-directed nystagmus. Examination of CSF demonstrated pleocytosis with elevated protein and hypoglycorrhachia. Increased signal of periventricular white matter was visualized by MRI soon after the development of encephalitis, and progressive ventriculomegaly was detected by serial CT scanning. Cytomegalovirus ventriculoencephalitis developed in some patients while receiving ganciclovir or foscarnet maintenance therapy, and the response to higher doses of these agents was limited in the 2 patients so treated. Death ensued a median of 4 weeks after the onset of neurologic symptoms. Pathologic examination showed extensive necrotizing periventriculitis involving ependymal and subependymal regions with spread to the meninges and adjacent cranial nerve roots. The infection was associated with characteristic CMV inclusion-bearing cells. This entity should be considered in AIDS patients with encephalitis, particularly in the presence of cranial nerve impairment or ascending muscle weakness. With the improvement in survival of patients with AIDS it is expected that this manifestation of CMV infection will become increasingly common.
AIDS-Related Opportunistic Infections↗
Time-dependent improvement in guinea pig tracheal contractility: modification by cyclooxygenase inhibitors.
In vitro guinea pig tracheal contraction to 5-hydroxytryptamine (5-HT) and to KCl increased significantly with time, an effect specific to the trachea because contraction of the rat aorta to KCl changed only modestly with time. The possibility that with time, contractile agonists could release endogenous contractile substances was considered and ruled out. Neither the neurotoxin tetrodotoxin, the muscarinic antagonist atropine, the thromboxane synthase inhibitor (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propanoic acid hydrochloride monohydrate (OKY 046), the leukotriene D4 and E4 antagonists 7-(3-hydroxy-2-prophylphenoxy[2-hydroxypropoxyl]-4- oxo-8-propyl-4H-1-benzopyran-2-carboxylate) (FPL55712) and 4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmythyl )-3-methoxy-N-o-toylsulfonyl benzamide (ICI 204,219), or the lipoxygenase inhibitor N-(3-phenoxycinnamyl)-acetohydroxamic acid (BWA4C) markedly affected the tracheal increase in contraction to KCl over time. The possibility that bronchodilatory substances were released and opposed contractility at early times, but not later was also considered. However, adenosine was not likely to be involved because 8-(p-sulfophenyl)theophylline, an inhibitor of adenosine, did not modify agonist-induced tracheal contractility. Propranolol (10(-6) M) also had no effect on tracheal improvement, suggesting that beta receptor activation of relaxation was not involved. Interestingly, incubation of trachea with the cyclooxygenase inhibitors indomethacin (10(-5) and 10(-6) M) or piroxicam (10(-6) M) increased the initial tracheal contraction to KCl, permitting the trachea to reach maximal force sooner, thereby minimizing the apparent improvement in contractility.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Serotonin-induced contraction in porcine coronary artery: use of ergolines to support vascular 5-hydroxytryptamine2-receptor heterogeneity.
Serotonin-induced contraction in porcine coronary artery was studied in ring segments of coronary artery without endothelium. 5-hydroxytryptamine (5-HT), 5-methoxytryptamine (5-MeOT) and alpha-methyl-5-HT (alpha Me-5-HT) concentration-dependently contracted vessels with similar maximal force. The agonist rank order potency was 5-HT > alpha Me-5-HT > 5-MeOT. Neither prazosin (1 microM) nor tetrodotoxin (0.3 microM) significantly altered 5-HT-induced contraction, ruling out activation of alpha-1 adrenoceptors and sodium channels in the contractile response, respectively. Using 5-MeOT as the prototype agonist, cyanopindolol blocked contraction with an antagonist dissociation constant lower than expected for 5-HT1-receptor blockade and ICS 205-930 (10 microM) did not affect 5-MeOT-induced contraction. Five structurally distinct 5-HT2-receptor antagonists (ketanserin, cisapride, spiperone, MDL11939, ICI169369) blocked 5-HT-induced contraction with antagonist dissociation constants similar to reported 5-HT2-receptor affinities. Two ergoline-based 5-HT2-receptor antagonists, LY53857 and sergolexole, blocked 5-HT-induced contraction with antagonist dissociation constants lower than expected for vascular 5-HT2-receptor blockade. Based on the agonist profile and the fact that ICS 205-930 and cyanopindolol were not potent antagonists, the 5-HT receptor-mediating contraction does not represent either the 5-HT1A/B/C/D, 5-HT3 or 5-HT4 receptor. Rather, based on the affinity of several established 5-HT2-receptor antagonists, a 5-HT2 receptor mediates contraction in porcine coronary artery. However, the low antagonist affinity of the ergolines (i.e., LY53857 and sergolexole) suggests that heterogeneity of 5-HT2 receptors may exist among species.
5-Methoxytryptamine↗
Further evidence that the guinea pig tracheal contractile serotonergic receptor is a 5-hydroxytryptamine2 receptor: use of 5-methyltryptamine and dipropyl-5-carboxamidotryptamine.
The guinea pig tracheal contractile serotonergic receptor shows pharmacological similarity to both 5-hydroxytryptamine2 (5-HT2) and 5-hydroxytryptamine1C (5-HT1C) receptors. The present in vitro study utilizes 5-methyltryptamine (5-MT), a high-affinity 5-HT1C receptor ligand, and dipropyl-5-carboxamidotryptamine (DP-5-CT), a low-affinity 5-HT1C receptor ligand, as tools to probe the role of 5-HT1C vs. 5-HT2 receptors in tracheal contractility. Both tryptamines contracted trachea with lower potency (-log EC50 < 5) than 5-HT (-log EC50 = 6.98). Maximum contraction to both 5-MT and DP-5-CT was only 50 to 80% of the maximum response to 5-HT, suggesting that these compounds were partial agonists relative to 5-HT. Guinea pig tracheal contraction to 5-HT, 5-MT and DP-5-CT was inhibited by 1-(1-naphthyl)piperazine (1-NP, 30 nM). The apparent antagonist dissociation constants (KB) for 1-NP were similar when 5-HT (-log KB, K = 8.70 +/- 0.17) or 5-MT (- log KB = 8.40 +/- 0.12) were used as agonists. Although 1-NP also blocked tracheal contraction to DP-5-CT, solubility limitations with DP-5-CT did not permit calculation of a KB value for 1-NP. Nevertheless, these data indicate that 5-MT and DP-5-CT interact with the same receptor as 5-HT. As antagonists, both 5-MT and DP-5-CT inhibited tracheal contraction to 5-HT, indicating interaction with the same receptor as 5-HT and confirming partial serotonergic agonist activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Apparent cure of rheumatoid arthritis by bone marrow transplantation.
We describe the induction of sustained remissions and possible cure of severe erosive rheumatoid arthritis (RA) by bone marrow transplantation (BMT) in 2 patients. BMT was used to treat severe aplastic anemia which was caused by gold in one case and D-penicillamine in the other. In the 8 and 6 years since the transplants (representing 8 and 4 years since cessation of all immunosuppressive therapy, respectively), the RA in each case has been completely quiescent. Although short term remission of severe RA following BMT has been reported, these are the first cases for which prolonged followup has been available. This experience raises the question of the role of BMT itself as a therapeutic option for patients with uncontrolled destructive synovitis.
Adult↗
Pharmacological characteristics of the newly cloned rat 5-hydroxytryptamine2F receptor.
The rat 5-hydroxytryptamine (5-HT)2F (serotonin2F) receptor is a newly cloned member of the 5-HT2/1C receptor family. The pharmacology of the 5-HT2F receptor was explored using a variety of structurally different compounds in a radioligand binding assay. In addition, the 5-HT2F receptor was shown to stimulate production of inositol 1,4,5-trisphosphate in the transformed cells. Based on the affinities of the compounds tested, their known affinities for certain of the other 5-HT receptors, and the fact that activation of the cloned 5-HT2F receptor stimulates inositol 1,4,5-trisphosphate production, the 5-HT2F receptor was determined to be a novel receptor and a member of the 5-HT2/1C receptor family. In addition, several agonists and partial agonists were evaluated for contractile activity in the rat stomach fundus, and these activities were correlated with their binding affinities at the 5-HT2F receptor. A highly significant correlation was found, providing additional evidence that is consistent with the 5-HT2F receptor being the stomach fundal contractile receptor. [3H]5-HT had high affinity for this receptor both at 37 degrees and at 0 degree (Kd = 7.87 +/- 0.55 and 0.12 +/- 0.02 nM, respectively). The difference in affinity for [3H]5-HT at the two temperatures prompted an investigation of potential temperature-dependent differences in the binding affinities of agonists versus antagonists. Agonists such as 5-HT, 5-methoxytryptamine, etc., showed higher affinity for the 5-HT2F receptor at 0 degree than at 37 degrees, whereas antagonists such as methysergide, 1-naphthylpiperazine, etc., showed no difference in affinity for this receptor at the two different temperatures. Therefore, the affinity of a compound for the 5-HT2F receptor at 37 degrees versus 0 degree was shown to be useful for predicting agonist or antagonist activity. Additionally, information is provided about some of the structural requirements for the affinity of certain tryptamines at the 5-HT2F receptor.
Animals↗
In search of the pathogenesis of refractory cervicobrachial pain syndrome.
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Cumulative Trauma Disorders↗
Epidemiology of drug resistance: implications for a post-antimicrobial era.
In the last several years, the frequency and spectrum of antimicrobial-resistant infections have increased in both the hospital and the community. Certain infections that are essentially untreatable have begun to occur as epidemics both in the developing world and in institutional settings in the United States. The increasing frequency of drug resistance has been attributed to combinations of microbial characteristics, selective pressures of antimicrobial use, and societal and technologic changes that enhance the transmission of drug-resistant organisms. Antimicrobial resistance is resulting in increased morbidity, mortality, and health-care costs. Prevention and control of these infections will require new antimicrobial agents, prudent use of existing agents, new vaccines, and enhanced public health efforts to reduce transmission.
Bacterial Infections↗
Presence of beta- but not alpha-adrenoceptors in the rat jugular vein: autoradiographical evidence.
Previous functional studies with the rat jugular vein have shown alpha-adrenergically mediated contraction was minimal to nonexistent, yet this tissue relaxed in response to norepinephrine via beta 1 and to isoproterenol via beta 2-receptor activation. Unlike the rat jugular vein, the rat aorta markedly contracted to norepinephrine and relaxed to beta-adrenoceptor stimulation. This study qualitatively examined the alpha- and beta-receptor distributions in the rat jugular vein, as compared to the rat aorta, with autoradiographical methods. Cross-sections of blood vessels were labelled with the alpha-receptor ligand, [125I]HEAT ([beta-(4-hydroxy-3-iodophenyl)-ethyl-aminomethyl]-tetralone) and the beta-receptor ligand, [125I]ICYP (iodo-cyanopindolol), and subsequently were opposed to emulsion coated coverslips. Specific binding of both alpha- and beta-receptors was demonstrated in the rat aorta. While specific beta-receptor binding was demonstrated in the rat jugular vein, this tissue showed no detectable alpha-receptors. These autoradiographic studies indicate that the lack of alpha-adrenergically mediated contraction in the rat jugular vein is likely due to a virtual absence of alpha-receptor binding sites, rather than poor functional alpha-receptor coupling.
Animals↗
In search of the pathogenesis of refractory cervicobrachial pain syndrome. A deconstruction of the RSI phenomenon.
OBJECTIVE: To discuss the clinical and social phenomenon of refractory cervicobrachial pain, more popularly known as repetitive strain injury (RSI), from the standpoint of medical knowledge and to present the phenomenon as a problem of chronic musculoskeletal pain in which clinical clues suggest a neuropathic pathogenesis. DATA SOURCES: Published articles from both medical and non-medical literature, primarily since 1980, were integrated with our clinical experience and observations. DATA SYNTHESIS: Three sets of formal responses to the issue--medical, psychiatric and sociological--were identified and analysed with respect to the validity of their conclusions, which formed the conventional wisdom. Clinical observation revealed clues to disturbed nociception in a carefully defined set of subjects with chronic cervicobrachial pain. Theoretical pathophysiological correlations of these led to the formulation of an hypothesis. CONCLUSIONS: We doubt that clinical method and diagnostic logic were rigorously applied to the RSI phenomenon, which helped to produce an unresolved controversy with widespread ramifications. Our hypothesis is that there is a central disturbance of nociception in this syndrome, induced by continual afferent barrage from nociceptors in anatomically relevant sites in the neck and upper limbs. Initial and proposed testing of this hypothesis are discussed.
Cumulative Trauma Disorders↗
Sumatriptan and 5-benzyloxytryptamine: contractility of two 5-HT1D receptor ligands in canine saphenous veins.
Sumatriptan and 5-benzyloxytryptamine are ligands with high affinity for 5-HT1D receptors in the caudate nucleus. Both compounds contracted canine saphenous veins, in vitro. Benzyloxytryptamine was less potent as a contractile agonist than sumatriptan which was less potent than serotonin. In high concentrations (greater than 10(-5) M) serotonin-induced contraction resulted, in part, from activation of alpha-adrenoceptors as determined by blockade of contraction with prazosin (10(-6) M) and idazoxan (10(-6) M). Likewise, benzyloxytryptamine but not sumatriptan also activated contractile alpha-receptors in the canine saphenous vein. Furthermore, benzyloxytryptamine antagonized contraction to sumatriptan in an apparently non-competitive fashion. Thus, benzyloxytryptamine, although possessing some alpha-receptor agonist activity, like sumatriptan, can interact with serotonin receptors in canine saphenous veins. Although effects of sumatriptan and benzyloxytryptamine quantitatively differed in canine saphenous veins, both agents showed similar affinity and agonist efficacy at 5-HT1D receptors in brain. These studies may reflect potential differences between the 5-HT1D receptor in brain and the 5-HT1-like receptor in canine saphenous veins.
Animals↗
Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.
Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
Animals↗