How credible is the science behind cosmetic skin creams?
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Cosmetics↗
Biomedical subjects
R Sinclair
Publications and source records attributed to R Sinclair.
Male pattern androgenetic alopecia.
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Administration, Oral↗
L-Mandelate dehydrogenase from Rhodotorula graminis: cloning, sequencing and kinetic characterization of the recombinant enzyme and its independently expressed flavin domain.
The l-mandelate dehydrogenase (L-MDH) from the yeast Rhodotorula graminis is a mitochondrial flavocytochrome b2 which catalyses the oxidation of mandelate to phenylglyoxylate coupled with the reduction of cytochrome c. We have used the N-terminal sequence of the enzyme to isolate the gene encoding this enzyme using the PCR. Comparison of the genomic sequence with the sequence of cDNA prepared by reverse transcription PCR revealed the presence of 11 introns in the coding region. The predicted amino acid sequence indicates a close relationship with the flavocytochromes b2 from Saccharomyces cerevisiae and Hansenula anomala, with about 40% identity to each. The sequence shows that a key residue for substrate specificity in S. cerevisiae flavocytochrome b2, Leu-230, is replaced by Gly in L-MDH. This substitution is likely to play an important part in determining the different substrate specificities of the two enzymes. We have developed an expression system and purification protocol for recombinant L-MDH. In addition, we have expressed and purified the flavin-containing domain of L-MDH independently of its cytochrome domain. Detailed steady-state and pre-steady-state kinetic investigations of both L-MDH and its independently expressed flavin domain have been carried out. These indicate that L-MDH is efficient with both physiological (cytochrome c, kcat=225 s-1 at 25 degrees C) and artificial (ferricyanide, kcat=550 s-1 at 25 degrees C) electron acceptors. Kinetic isotope effects with [2-2H]mandelate indicate that H-C-2 bond cleavage contributes somewhat to rate-limitation. However, the value of the isotope effect erodes significantly as the catalytic cycle proceeds. Reduction potentials at 25 degrees C were measured as -120 mV for the 2-electron reduction of the flavin and -10 mV for the 1-electron reduction of the haem. The general trends seen in the kinetic studies show marked similarities to those observed previously with the flavocytochrome b2 (L-lactate dehydrogenase) from S. cerevisiae.
Alcohol Oxidoreductases↗
Re-design of Saccharomyces cerevisiae flavocytochrome b2: introduction of L-mandelate dehydrogenase activity.
Flavocytochrome b2 from Saccharomyces cerevisiae is an l-lactate dehydrogenase which exhibits only barely detectable activity levels towards another 2-hydroxyacid, l-mandelate. Using protein engineering methods we have altered the active site of flavocytochrome b2 and successfully introduced substantial mandelate dehydrogenase activity into the enzyme. Changes to Ala-198 and Leu-230 have significant effects on the ability of the enzyme to utilize l-mandelate as a substrate. The double mutation of Ala-198-->Gly and Leu-230-->Ala results in an enzyme with a kcat value (25 degrees C) with L-mandelate of 8.5 s-1, which represents an increase of greater than 400-fold over the wild-type enzyme. Perhaps more significantly, the mutant enzyme has a catalytic efficiency (as judged by kcat/Km values) that is 6-fold higher with l-mandelate than it is with L-lactate. Closer examination of the X-ray structure of S. cerevisiae flavocytochrome b2 led us to conclude that one of the haem propionate groups might interfere with the binding of L-mandelate at the active site of the enzyme. To test this idea, the activity with l-mandelate of the independently expressed flavodehydrogenase domain (FDH), was examined and found to be higher than that seen with the wild-type enzyme. In addition, the double mutation of Ala-198-->Gly and Leu-230-->Ala introduced into FDH produced the greatest mandelate dehydrogenase activity increase, with a kcat value more than 700-fold greater than that seen with the wild-type holoenzyme. In addition, the enzyme efficiency (kcat/Km) of this mutant enzyme was more than 20-fold greater with L-mandelate than with l-lactate. We have therefore succeeded in constructing an enzyme which is now a better mandelate dehydrogenase than a lactate dehydrogenase.
Alcohol Oxidoreductases↗
Effect of a comprehensive quality management process on compliance with protocol in an emergency medical dispatch center.
STUDY OBJECTIVE: Modern emergency medical dispatch provides appropriate resource responses with the use of an emergency medical dispatch priority reference system (EMDPRS). The EMDPRS is a systematic protocol for all aspects of the dispatch process, including interrogating the caller, matching responses with severity, and providing pre-arrival care. We tested the hypothesis that appropriate performance feedback would increase dispatcher compliance with the protocol. METHODS: We examined how emergency medical dispatchers complied with the protocols contained in the Advanced Medical Priority Dispatch System, a commercially available EMDPRS. Six key areas and overall compliance were studied. Dispatchers performed for 2 months without feedback and for a further 2 months with performance feedback. We used statistical methods to compare the dispatchers' compliance with the protocols each month. RESULTS: The mean overall compliance score improved from 76.4%+/-10.2% (mean+/-SD) in the absence of performance feedback to 96.2%+/-4.0% (n=217; P <.001) when performance feedback was provided. Five of 6 key areas showed similar improvements. CONCLUSION: Providing emergency medical dispatchers with regular and objective feedback regarding their performance dramatically improves how rigorously they follow a systematized dispatch protocol.
Emergency Medical Service Communication Systems↗
Hirsutes. I: Diagnosis.
Hirsutes, the coarse, androgen-dependent growth of hair in women, is a common problem faced by doctors. Whether a woman presents to a clinician or not depends on cultural and racial factors. The clinician must differentiate normal biological variation from cases of hirsutes. In the vast majority of cases, androgen excess is only found locally at the level of the hair follicle; that is, the hirsutism is idiopathic. Important causes of androgen excess, such as an ovarian tumour, need to be excluded. Part one describes the causes of hirsutism and how to differentiate them using history, examination and investigation.
Adrenocortical Hyperfunction↗
Hirsutes. II: Treatment.
The treatment of hirsutes includes cosmetic measures, such as bleaching, plucking, electrical epilation and, more recently, laser epilation. Pharmacological therapy consists of anti-androgens and includes the androgen receptor blockers spironolactone and cyproterone acetate. Other drugs reducing androgen expression include oral contraceptives and corticosteroids. A new follicular 5 alpha reductase inhibitor, finasteride, is currently under evaluation, as is the anti-androgen flutamide. Gonadotrophin-releasing hormone agonists reduce androgen expression and show early promise in the treatment of hirsutes.
5-alpha Reductase Inhibitors↗
What is the cost of onychomycosis?
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Antifungal Agents↗
There is something wrong with my nail.
Nail problems are a frequent source of concern to patients and are a relatively common presenting complaint to general practitioners. While tinea unguium and psoriasis are the main causes of nail problems for the majority of patients, there are numerous other causes of nail dystrophies. This article aims to discuss some of the commoner causes of nail dystrophy. In addition it will give GPs an understanding of the anatomy and function of the nail and provide an approach to diagnosis based on morphology. Treatment will be dealt with in a subsequent article.
Humans↗
Treating common nail problems.
This article is a follow up to the article There is something wrong with my nail (AFP, June 1997). Conditions of the nail often pose diagnostic and management problems. The former issues were addressed in the previous article while this article focuses on current management options for this difficult range of conditions.
Humans↗
Practical cryosurgery.
Cryosurgery is a widely used modality for the treatment of superficial cutaneous lesions. It can be used for the treatment of benign, premalignant and malignant skin conditions.
Australia↗
Active site structure in cytochrome c peroxidase and myoglobin mutants: effects of altered hydrogen bonding to the proximal histidine.
The globins and peroxidases, while performing completely different chemistry, share features of the iron heme active site: a protoporphyrin IX prosthetic group is linked to the protein by the proximal histidine residue. X-ray absorption spectroscopy provides a method to determine the local structure of iron heme active sites in proteins. Our previous studies using X-ray absorption spectroscopy revealed a significant difference in the Fe-N epsilon bond length between the peroxidases and the globins [for a review, see Powers, L. (1994) Molecular Electronics and Molecular Electronic Devices, Vol. 3, p 211 CRC Press Inc., Boca Raton, FL]. Globins typically have an Fe-N epsilon distance close to 2.1 A while the Fe-N epsilon distance in the peroxidases is closer to 1.9 A. We have proposed [Sinclair, R., Powers, L., Bumpus, J., Albo, A., & Brock, B. (1992) Biochemistry 31, 4892] that strong hydrogen bonding to the proximal histidine is responsible for the shorter bond length in the peroxidases. Here we use site-specific mutagenesis to eliminate the strong proximal hydrogen bonding in cytochrome c peroxidase and to introduce strong proximal hydrogen bonding in myoglobin. Consistent with our hypothesis, elimination of the Asp235-His175 hydrogen bond in CcP results in elongation of Fe-N epsilon from approximately 1.9 to approximately 2.1 A. Conversely, introduction of a similar strong proximal hydrogen bond in myoglobin shortens Fe-N epsilon from approximately 2.1 to approximately 1.9 A. These results correlate well with other biochemical data.
Aspartic Acid↗
Anomalous moment and anisotropy behavior in Fe3O4 films.
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Journal Article↗
The structure-function relationship and reduction potentials of high oxidation states of myoglobin and peroxidase.
In these studies, we substitute electron-withdrawing (diacetyl) or -donating (diethyl) groups at the 2- and 4-positions of the heme in sperm whale Mb and HRP, and examine the structural and biochemical consequences. X-ray absorption spectroscopy shows that increased electron density at the heme results in an increased iron-pyrrole nitrogen average distance in both HRP and Mb, while decreased electron density results in shorter average distances. In HRP, the proximal ligand is constrained by a H-bonding network, and axial effects are manifested entirely at the distal site. Conversely, in Mb, where the proximal ligand is less constrained, axial effects are seen at the proximal side. In HRP, electron density at the heme iron depends linearly on pK3, a measure of the basicity of the porphyrin pyrrole nitrogens [Yamada, H., Makino, R., & Yamazaki, I. (1975) Arch. Biochem. Biophys. 169, 344-353]. Using diethyl substitution (pK3 = 5.8) and diacetyl substitution (pK3 = 3.3) in HRP and Mb, we measured the one-electron reduction potentials (E(O)') of HRP compounds I and II and ferryl Mb. Compound I showed a decreased E(O)' with increasing electron density at the heme (pK3), similar to E(O)' of ferric HRP. E(O)' of HRP compound II and ferryl Mb showed an opposite dependence. This behavior of E(O)', while initially surprising, can be explained by the apparent net positive charge on the iron porphyrin in each oxidation state of the hemoproteins.
Animals↗
Leukocyte hydrogen peroxide production in a surgical wound in mice. The effects of an amide local anaesthetic.
The oxygen metabolism of polymorphonuclear leukocytes (PMN) is of importance in local tissue repair processes. Amide local anaesthetics are commonly used to relieve surgical wound pain. The cellular effects of local anaesthetics in vivo is poorly described in the literature. However, interactions between amide local anaesthetics and the oxygen metabolism of leukocytes have been reported. To extend that knowledge, this paper investigates the influence of lidocaine treatment on the production of hydrogen peroxide (H2O2) by leukocyte oxygen metabolism. A soft tissue chamber model in the mouse was used, allowing measurements of the H2O2 production spontaneously and after phorbol myristate acetate (PMA) addition, from two different leukocyte pools. Exudate leukocytes were generally more reactive to PMA stimulation in comparison to tissue chamber adherent leukocytes. Topically administered lidocaine significantly influenced the number of leukocytes in the wound exudate at 24 h postoperatively. Exudate leukocytes, topically exposed to lidocaine, showed an enhanced H2O2 production in comparison to leukocytes receiving lidocaine systemically. At 6 days, the viability and the H2O2 production differed significantly between the group receiving topically applied lidocaine in comparison to placebo. We conclude that the wound healing process may be effected by topically applied lidocaine, administered in clinical doses, at least via interference with leukocyte oxygen metabolism.
Anesthetics, Local↗
The radial artery as a bypass graft.
The radial artery is being reintroduced into clinical practice to increase the number of arterial grafts for patients undergoing coronary artery bypass surgery. The radial artery is readily available from one or both forearms and removal is safe in patients who have a normal collateral circulation to the hand. Harvesting the radial artery with the adjacent veins using a minimal touch technique and vasodilators will prevent vasospasm and possibly early occlusion. A concern is that subclinical atheroma is present in many patients. The radial artery can be used as a single graft, anastomosed in a "Y" fashion with the internal mammary artery, or used as a sequential graft. The early mortality and complications are low. There are potential cost savings because the need for an incision in the leg is avoided, so that patients may be discharged early. The early results of radial artery grafting are encouraging. Further follow-up is required to determine the late patency and effects on survival of using the radial artery graft.
Aged↗
Postoperative pain relief by topical lidocaine in the surgical wound of hysterectomized patients.
BACKGROUND: To improve postoperative analgesia, local anesthetics have been administered perioperatively as infiltration or as aerosol in the surgical area. A previous study showed good analgesic effects by topical lidocaine in the wound in minor extraabdominal surgery (herniorraphy), while the same treatment in minor lower laparothomies did not improve postoperative analgesia. The present study investigated the effect of topical wound anesthesia using lidocaine aerosol on postoperative pain following major lower abdominal surgery. METHODS: Postoperative pain and analgesic requirements were studied in a double-blind randomized trial including 30 hysterectomized patients. Patients were randomized to receive single wound treatment either with lidocaine aerosol 500 mg (100 mg/ml; Xylocain aerosol, ASTRA, Sweden) (n = 15) or placebo aerosol (n = 15). Postoperative pain was evaluated by visual analogue scale (VAS). Requirements of opiate analgesics (buprenorphine) after surgery were monitored. RESULTS: Lidocaine aerosol induced a significantly (P < 0.001) better analgesia at rest (VAS) and a significant (P < 0.001) reduction in postoperative requirements of buprenorphine during the first 24 hours after surgery compared to placebo aerosol. Differences between the groups in pain scores (VAS) and buprenorphine requirements during the second postoperative day were not significant. Mean pain scores upon mobilization 24 h after surgery were significantly lower in the group receiving lidocaine aerosol (P < 0.05). The plasma lidocaine concentration 4 h after the administration of lidocaine was well below toxic level and plasma lidocaine was detectable 48 h postoperatively. No drug-related side effects were reported. CONCLUSION: A single dose of lidocaine aerosol topically administered in the surgical wound of hysterectomy patients improved analgesia during the first postoperative day with minimal risk of side effects.
Adult↗