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Dermatomyositis is a heterogeneous idiopathic inflammatory myopathy associated with various cutaneous manifestations and variable presence of myositis, interstitial lung disease, and other visceral organ involvement. An accurate diagnosis of dermatomyositis requires correlating clinical examination findings with serological and histological findings. Familiarity with pathognomonic and common cutaneous manifestations of dermatomyositis, which are highlighted here, can be especially helpful in making an accurate diagnosis. Additionally, evaluating patients for presence of myositis-specific autoantibodies can further support or refute a dermatomyositis diagnosis. When present, myositis-specific autoantibodies can also help guide workups for various dermatomyositis-associated manifestations, as each is associated with relatively distinct clinical characteristics. Evaluating patients for various systemic manifestations often relies on expert opinion recommendations; however, societal guideline statements concerning the evaluation of some manifestations have recently been described. Although malignancy-associated dermatomyositis is a well-accepted subtype, there is limited evidence to support extensive malignancy screening has a favorable benefit-risk ratio in most dermatomyositis patients. However, recent research has uncovered novel associations between dermatomyositis and malignancy, suggesting the possibility of identifying high-risk subsets of dermatomyositis patients in whom malignancy screening may have a high value. Treatment for dermatomyositis has remained largely unchanged over the past several decades. Although many dermatomyositis patients can be effectively treated with current options, either as monotherapy or with combination regimens, there is a need for more targeted and effective DM therapies, in general, and for MDA5(+) dermatomyositis-associated rapidly progressive interstitial lung disease. Fortunately, significant current and emerging research activities evaluating various novel medications for dermatomyositis provide hope for exciting future advances in patients with this intriguing immune-mediated disease.

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer ( R )-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the ( R )-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect. Activation of the tumor suppressor p53 is a promising approach in cancer therapy. Here, the authors discover a series of small molecule dihydroorotate dehydrogenase (DHODH) inhibitors that increase p53 synthesis and reduce tumor growth in synergy with the common mdm2 inhibitor nutlin3.

Cyclooxygenase (COX) is the rate-limiting enzyme in the metabolism of arachidonic acid into prostanoids. Although it is constitutively expressed in brain neurons, the inducible isoform (COX-2) is also upregulated in pathological conditions such as seizures, ischemia or some degenerative diseases. To assess whether COX-2 is regulated after stress, we have used adult male Wistar rats, some of which were immobilized during 6 h. An increase in PGE 2 concentration occurs in brain cortex after 2–6 h of the onset of stress as well as an enhancement of COX-2 protein. Immunohistochemical studies indicate that COX-2 is expressed in the cortex and hippocampus after stress in cells with morphology of neurons. Administration of PDTC (150 mg/kg), an inhibitor of the transcription factor NF- κ B or MK-801 (0.2 mg/kg), an N -methyl- D -aspartate receptor blocker, prevents both stress-induced increase in COX-2 activity and protein levels, suggesting an implication of these factors in the mechanism by which stress induces COX-2 in brain. To assess if COX-2 accounts for the oxidative status seen in brain after stress, a group of animals were i.p. injected with NS-398, a specific COX-2 inhibitor 1 h prior to the onset of stress. NS-398 (5 mg/kg) decreases stress-induced malondialdehyde accumulation in cortex as well as prevents the stress-induced oxidation of glutathione. Finally, NS-398 reduced Ca 2+ -independent inducible nitric oxide synthase (iNOS, NOS-2) activity and lowered the stress-induced accumulation of NO metabolite levels in cortex. These effects of NS-398 seem to be due to the specific inhibition of COX-2, since it has no effect on stress-induced corticosterone release, glutamate release, and NF- κ B activation. These findings are discussed as possible damaging and/or adaptive roles for stress-induced COX-2 in the brain.

To explore the mechanisms by which NO elicits endothelial cell (EC) migration we used murine and bovine aortic ECs in an in vitro wound-healing model. We found that exogenous or endogenous NO stimulated EC migration. Moreover, migration was significantly delayed in ECs derived from endothelial NO synthase-deficient mice compared with WT murine aortic EC. To assess the contribution of matrix metalloproteinase (MMP)-13 to NO-mediated EC migration, we used RNA interference to silence MMP-13 expression in ECs. Migration was delayed in cells in which MMP-13 was silenced. In untreated cells MMP-13 was localized to caveolae, forming a complex with caveolin-1. Stimulation with NO disrupted this complex and significantly increased extracellular MMP-13 abundance, leading to collagen breakdown. Our findings show that MMP-13 is an important effector of NO-activated endothelial migration.

Nitric oxide is a regulatory biological substance and an important intracellular messenger that acts as a specific mediator of various neuropathological disorders. In mammals and invertebrates, nitric oxide is synthesized from L-arginine in the central and peripheral neural structures by the endothelial, neuronal and inducible enzymatic isoforms of nitric oxide synthase. Nitric oxide may affect the function of various neurotransmitter-specific systems, and is involved in neuromodulation, reproductive function, immune response, and regulation of the cerebral blood circulation. This makes nitric oxide the main candidate in brain responses to brain ischemia/hypoxia. The cerebellum has been reported to be the area of the brain that has the highest nitric oxide synthase activity and the highest concentration of glutamate and aspartate. By glutamate receptors and physiological action of nitric oxide, cyclic guanisine-5'-monophosphate may be rapidly increased. The cerebellum significantly differs with respect to ischemia and hypoxia, this response being directly related to the duration and intensity of the injury. The cerebellum could cover the eventual need for nitric oxide during the hypoxia, boosting the nitric oxide synthase activity, but overall ischemia would require de novo protein synthesis, activating the inducible nitric oxide synthase to cope with the new situation. The specific inhibitors of nitric oxide synthesis show neuroprotective effects.

ABSTRACT PURPOSE: We compared the efficacy, predictability, and safety of photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) for the surgical correction of low and moderate myopia. METHODS: A retrospective study was performed to evaluate uncorrected and spectacle-corrected visual acuity, and manifest refraction 1 year after PRK or LASIK. All procedures were done using an automatic microkeratome (Chiron Ophthalmic) and the Nidek EC-5000 excimer laser. RESULTS: PRK was performed in 75 eyes of 45 patients and LASIK in 133 eyes of 77 patients. Mean age for PRK patients was 32.8 years (range, 18 to 52 yr) and LASIK patients was 29.6 years (range, 18 to 49 yr). Mean preoperative spherical equivalent refraction for PRK patients was -3.28 D (range, *1.00 to -6.00 D) and LASDI, -3.86 D (range, -1.00 to -6.00 D). One year after surgery, mean spherical equivalent refraction for Group 1 (baseline, -1.00 to -3.00 D) PRK eyes was -0.18 ± 0.61 D (range, -1.50 to +0.75 D) and for LASIK eyes, -0.08 ± 0.61 D (range, *1.50 to +1.62 D), with no statistically significant difference. For Group 2 eyes (baseline, -3.E5 to -6.00 D), mean spherical equivalent refraction for PRK eyes was -0.44 ± 0.87 D (range, -2.00 to +2.12 D) and for LASDI eyes, -0.09 ± 0.83 D (range, -1.50 to +1.75 D), with no statistically significant difference. The antilogarithm of the mean UCVA (antilogUCVA) in Group 1 for PRK was 0.79 ± 0.21 (20/25) and for LASDI was 0.87 ± 0.19 (20/23), with no statistically significant difference. The antilogUCVA in Group 2 for PRK eyes was 0.70 ± 0.24 (20/28) and for LASDI eyes was 0.83 ± 0.18 (20/24), with a statistically significant difference (0.7 vs. 0.83, P < .005). The percentage of eyes with a postoperative UCVA>20/40 in Group 1 for PRK was 91.5% (38 eyes) and for LASDI was 95% (50 eyes) (no statistically significant differenee), and in Group 2 for PRK eyes, it was 82% (27 eyes) and 97.5% (78 eyes) for LASDI (statistically significant difference, P < .05). CONCLUSION: PRK and LASDI with the Nidek EC-5000 excimer laser are effective and safe for correcting low to moderate myopia, but LASDI eyes showed better results for moderate myopia in terms of uncorrected visual acuity. [J Refract Surg 2000;16:711-715]

Nitric oxide (NO) has been postulated to contribute significantly to analgesic effects of opiates as well as to the development of tolerance and physical dependence to morphine. The present study was undertaken to determine the effect of chronic morphine treatment and abstinence on the expression of neuronal NO synthase (neuronal NOS, nNOS) in several brain regions of mice. Seven days after the implantation of a 75 mg morphine pellet, adult male CD1 mice received a SC dose of 1 mg/kg naloxone. Fifteen minutes after the naloxone injection, brains were removed and nNOS expression was studied by using immunohistochemical methods. Morphine-dependence produced an increase in the number of nNOS-positive cells in the main and accessory olfactory bulb, olfactory nuclei, cerebellum, locus coeruleus, medulla oblongata (nucleus of the solitary tract and prepositus hypoglossal nucleus), and a decrease in nNOS immunoreactivity in hypothalamus. The administration of naloxone to morphine-dependent mice to induce abstinence increased nNOS immunoreactivity in the hypothalamus and locus coeruleus. These results indicate that the chronic treatment with morphine leads to alterations in nNOS expression in important regions implicated in the physical tolerance and dependence to opiates and suggest the use of specific inhibitors of this isoform in these conditions.

Primary care (PC) professionals' knowledge about alcohol use has been identified as one of the barriers PC providers face in their clinic. Both PC professionals' level of training and attitude are crucial in the clinical practice regarding alcohol use. To evaluate the knowledge, attitude, and preventive practices of Spanish PC physicians and nurses towards alcohol use. An observational, descriptive, cross-sectional, multi-center study. Location: PC centers of the Spanish National Health System (NHS). Participants: PC physicians and nurses selected randomly from health care centers, and by sending an e-mail to semFYC and SEMERGEN members. Healthcare providers completed an online survey on knowledge, attitude, and follow-up recommendations for reducing alcohol intake. A descriptive, bivariate, and multivariate statistical analysis was conducted (p<0.05). Participants: 1,760 healthcare providers completed the survey (75.6% [95% CI 73.5-77.6] family physicians; 11.4% [95% CI 9.9-12.9] medical residents; and 12.5% [95% CI 10.9-14.1] nurses), with a mean age of 44.7 (SD 11.24, range: 26-64, 95% CI: 47.2-48.2). Knowledge was higher in family physicians (p<0.001), older professionals (Spearman's r = 0.11, p<0.001), and resident trainers (p<0.001). The PC professional most likely to provide advice for reducing alcohol use was: a nurse (p <0.001), female (p = 0.010), between 46 and 55 years old (p <0.001). PC providers' knowledge and preventive practices regarding alcohol use are scarce, hence specific training strategies to increase their knowledge and improve their attitude and skills with regard to this health problem should be considered a healthcare policy priority.