Pharmacological analysis of cyclooxygenase-1 in inflammation

The enzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. These lipid mediators play important roles in inflammation and pain and in normal physiological functions. While there are abundant data indicating that the inducible isoform, COX-2, is important in inflammation and pain, the constitutively expressed isoform, COX-1, has also been suggested to play a role in inflammatory processes. To address the latter question pharmacologically, we used a highly selective COX-1 inhibitor, SC-560 (COX-1 IC50 = 0.009 microM; COX-2 IC50 = 6.3 microM). SC-560 inhibited COX-1-derived platelet thromboxane B2, gastric PGE2, and dermal PGE2 production, indicating that it was orally active, but did not inhibit COX-2-derived PGs in the lipopolysaccharide-induced rat air pouch. Therapeutic or prophylactic administration of SC-560 in the rat carrageenan footpad model did not affect acute inflammation or hyperalgesia at doses that markedly inhibited in vivo COX-1 activity. By contrast, celecoxib, a selective COX-2 inhibitor, was anti-inflammatory and analgesic in this model. Paradoxically, both SC-560 and celecoxib reduced paw PGs to equivalent levels. Increased levels of PGs were found in the cerebrospinal fluid after carrageenan injection and were markedly reduced by celecoxib, but were not affected by SC-560. These results suggest that, in addition to the role of peripherally produced PGs, there is a critical, centrally mediated neurological component to inflammatory pain that is mediated at least in part by COX-2.     

Reproductive sequelae in female rats after in utero and neonatal exposure to the phytoestrogen genistein

OBJECTIVE: To determine reproductive sequelae in female rats after in utero and lactational dietary exposure to genistein. DESIGN: Experimental animal study. SETTING: University laboratory. ANIMAL(S): Sprague Dawley rats. INTERVENTION(S): Pregnant rats were fed control rat chow or rat chow incorporated with genistein (approximately 50 microg/d) beginning on day 17 of gestation and continuing until the end of lactation (postpartum day 21). Genistein-exposed female pups were divided into two groups on day 21. One group continued to receive a genistein-added diet (G70); the other group was changed to a control diet (Ex-G). At necropsy (days 21 and 70), blood and reproductive tissues were collected. MAIN OUTCOME MEASURE(S): Serum levels of gonadotropins and gonadal steroids and histopathologic examination of the ovaries. RESULT(S): The weight of the ovaries and uterus and serum levels of E2 and progesterone in genistein-exposed rats on day 21 (G21) were significantly reduced compared with control rats. On day 70, serum levels of E2, progesterone, LH, and FSH were similar in all groups. Atretic follicles and secondary interstitial glands were more common in G70 and Ex-G rats compared with control rats. Cystic rete ovarii was observed in some G70 and Ex-G rats. CONCLUSION(S): Our data indicate that in utero and lactational exposure to dietary genistein adversely affects reproductive processes in the adult female rat.     

Equity is out of fashion? An essay on autonomy and health policy in the individualized society

The 67-kDa laminin receptor (67LR) is a nonintegrin cell surface receptor that mediates high-affinity interactions between cells and laminin. Overexpression of this protein in tumor cells has been related to tumor invasion and metastasis. Thus far, only a full-length gene encoding a 37-kDa precursor protein (37LRP) has been isolated. The finding that the cDNA for the 37LRP is virtually identical to a cDNA encoding the ribosomal protein p40 has suggested that 37LRP is actually a component of the translational machinery, with no laminin-binding activity. On the other hand, a peptide of 20 amino acids deduced from the sequence of 37LR/p40 was shown to exhibit high laminin-binding activity. The evolutionary relationship between 23 sequences of 37LRP/p40 proteins was analyzed. This phylogenetic analysis indicated that all of the protein sequences derive from orthologous genes and that the 37LRP is indeed a ribosomal protein that acquired the novel function of laminin receptor during evolution. The evolutionary analysis of the sequence identified as the laminin-binding site in the human protein suggested that the acquisition of the laminin-binding capability is linked to the palindromic sequence LMWWML, which appeared during evolution concomitantly with laminin.     

Association of cocaine and methamphetamine use with giant gastroduodenal ulcers

OBJECTIVES: Giant gastric and duodenal ulcers (>2-3 cm in greatest dimension) are reported to have higher rates of complication and mortality and to be associated with increasing age, renal failure, and use of nonsteroidal antiinflammatory drugs (NSAIDs). This study investigated the outcome and associations of gastric and duodenal ulcers >2.5 cm compared to ulcers of lesser size. METHODS: Records from all patients with gastric and duodenal ulcers >0.5 cm diagnosed by upper endoscopy between January 1994 and September 1995 were studied for evidence of concurrent use of aspirin, NSAIDs, methamphetamine, and cocaine, as well as for transfusion requirements, length of hospital stay, mortality, surgery, rebleeding, Helicobacter pylori infection, and malignancy. RESULTS: A logistic regression analysis of the 220 patients identified revealed that recent methamphetamine and/or cocaine use was significantly predictive of giant ulcer formation (p = 0.0002) with an odds ratio of 9.66. Also significant was younger age (p = 0.026) and aspirin or NSAID use (p = 0.046). H. pylori infection was significant only for giant gastric ulcers (p = 0.031). Ulcer size did not predict mortality, rate of rebleeding, requirement for surgery, transfusion requirements, or length of hospital stay. However, giant gastric ulcers were significantly more likely to be malignant (p = 0.002). CONCLUSIONS: Giant gastric and duodenal ulcers were strongly associated with stimulant abuse. They were also associated with younger age and use of aspirin or NSAIDs. Additionally, giant gastric ulcers were associated with malignancy and H. pylori infection. Ulcer size did not predict rate of complications or outcome.     

Photorefractive keratectomy for astigmatism greater than -2.00 diopters in eyes with low, high, or extreme myopia

PURPOSE: To assess the efficacy of excimer laser photorefractive astigmatic keratectomy (PARK) in correcting astigmatism of more than -2.00 diopters (D) in eyes with low, high, and extreme myopia. SETTING: Pusan National University Hospital, Pusan, Korea. METHODS: Eighty-five patients (110 eyes) whose spherical error ranged from -3.00 to -13.00 D and cylinder ranged from -2.00 to -5.50 D had PARK with a VISX Twenty-Twenty excimer laser; follow-up was 6 months. All cases of myopic astigmatism were treated using the elliptical method and multizone ablation technique. Eyes were divided into 3 groups: low myopia, less than 6.00 D (n = 47); high myopia, from 6.25 to 10.00 D (n = 43); extreme myopia, over 10.25 D (n = 20). Alpins vector analysis was used to calculate the astigmatic change. RESULTS: By vector analysis, the success rate of astigmatic correction was more predictable in the low and high myopia groups than in the extreme myopia group (P < .05). There was little improvement in astigmatism in the extreme myopia group. CONCLUSION: Using PARK to correct astigmatism greater than -2.00 D in eyes with myopia less than -10.00 D tended to result in undercorrection; astigmatic correction in eyes with myopia over 10.25 D was minimal.     

Distinguishing small molecular mass differences of proteins by mass spectrometry

This study was undertaken to determine if acidic or basic fibroblast growth factor (FGF1 or FGF2) or vascular endothelial growth factor (VEGF) alters the radiation response of small bowel after total-body irradiation (TBI). Female C3H mice were treated with various doses of angiogenic growth factor administered intravenously 24 h before or 1 h after TBI. Radiation doses ranged from 7 to 18 Gy. End points measured were the number of crypts in three portions of the small bowel, the frequency of apoptosis of crypt cells at various times after TBI, and the LD50/30 (bone marrow syndrome) and LD50/6 (GI syndrome). Fibroblast growth factors alone, without TBI, decreased the number of crypts per circumference significantly. Among the factors tested, FGF2 caused the greatest decline in baseline crypt number. Despite this decrease in the baseline crypt number, after irradiation the number of surviving crypts was greater in animals treated with growth factor. The greatest radioprotection occurred at intermediate doses of growth factor (6 to 18 pg/mouse). Mice treated with FGF1 and FGF2 had crypt survival curves with a slope that was more shallow than that for saline-treated animals, indicating radiation resistance of crypt stem cells in FGF-treated mice. The LD50/6 was increased by approximately 10% for all treatments with angiogenic growth factors, whether given before or after TBI. Apoptosis of crypt cells was maximum at 4 to 8 h after TBI. The cumulative apoptosis was decreased significantly in animals treated with angiogenic growth factors, and the greatest protection against apoptosis was seen in animals treated with FGF2 prior to TBI. All three angiogenic growth factors tested were radioprotective in small bowel whether given 24 h before or 1 h after irradiation. The mechanism of protection is unlikely to involve proliferation of crypt stem cells, but probably does involve prevention of radiation-induced apoptosis or enhanced repair of DNA damage of crypt cells.     

Medication side effects in anxious patients: negative placebo responses?

Heart sounds produce an incessant noise during lung sounds recordings. This noise severely contaminates the breath sounds signal and interferes in the analysis of lung sounds. In this paper, the use of a wavelet transform domain filtering technique as an adaptive de-noising tool, implemented in lung sounds analysis, is presented. The multiresolution representations of the signal, produced by wavelet transform, are used for signal structure extraction. In addition, the use of hard thresholding in the wavelet transform domain results in a separation of the nonstationary part of the input signal (heart sounds) from the stationary one (lung sounds). Thus, the location of the heart sound noise (1st and 2nd heart sound peaks) is automatically detected, without requiring any noise reference signal. Experimental results have shown that the implementation of this wavelet-based filter in lung sound analysis results in an efficient reduction of the superimposed heart sound noise, producing an almost noise-free output signal. Due to its simplicity and its fast implementation the method can easily be used in clinical medicine.     

Localization of the human phosphotyrosine phosphatase-related genes (h-PRL-1) to chromosome bands 1p35-p34, 17q12-q21, 11q24-q25 and 12q24

The h-PRL-1 gene codes for a new phosphotyrosine phosphatase that may play an important role in the control of basic cellular processes such as cell growth and proliferation. Using the cDNA of the h-PRL-1 gene as a probe, we examined a somatic mouse and hamster x human hybrid panel and found that chromosomes 1, 17 and 11 harbor sequences homologous to h-PRL-1. By in situ hybridization of metaphase spreads, subchromosomal localizations were determined at bands 1p35-p34, 17q12-q21 and 11q24-q25; in addition, a faint signal was detected at 12q24. The chromosomal assignment of the genes homologous to h-PRL-1 will help the investigation of its possible involvement in human diseases involving genetic alteration at these chromosomal regions.     

S100B, a neurotropic protein that modulates neuronal protein phosphorylation, is upregulated during lesion-induced collateral sprouting and reactive synaptogenesis

Using light and electron microscopic immunocytochemistry, we examined the expression of the Ca2+-binding protein S100B in the dentate gyrus of adult rats during lesion-induced sprouting and reactive synaptogenesis. Nine days following unilateral lesioning of the entorhinal cortex, S100B was upregulated in cells primarily in the outer part of the molecular layer of the ipsilateral dentate gyrus. When examined with electron microscopy, numerous astrocytes and synapses containing S100B were identified. These data show that during lesion-induced sprouting and reactive synaptogenesis, S100B is upregulated in astrocytes and can be found in pre- and post-synaptic compartments where it might influence neuronal protein phosphorylation.     

Curcumin–amino acid conjugates: Synthesis,antioxidant and antimutagenic attributes

Curcumin, a natural yellow colourant from turmeric, is insoluble in water. It has been rendered water-soluble by preparation of suitable amino acid derivatives. Several amino acid conjugates of curcumin were synthesised in high yields (45–76%). These curcumin derivatives were soluble in water at 1–10 mg/ml concentrations. Derivatives of curcumin with alkyl-substituted amino acids, such as alanine, valine, serine and cysteine, exhibited smaller IC₅₀ values (∼50%) than did curcumin in antioxidant assays. With respect to antimutagenicity against Salmonella typhimurium TA 98 and TA 1531, the derivatives showed an effect stronger than or, in a few cases, similar to curcumin. These results clearly demonstrated that the conjugation of curcumin at the phenolic position with amino acids, while rendering the molecule water-soluble, led to the improvement of several of its in vitro biological attributes, the effect being more pronounced in the case of specific alkyl-substituted amino acids.