Copper is unlikely to cause contact allergy.
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Copper↗
Biomedical subjects
J English
Publications and source records attributed to J English.
Atenolol facilitates light-induced phase shifts in humans.
During time-zone travel, the endogenous melatonin rhythm is often out of phase with the new local time cues. Since endogenous melatonin could act as an endogenous zeitgeber, when its secretory rhythm is out of phase it may hinder adaptation by natural zeitgebers. It is possible that by temporarily suppressing the production of melatonin, by beta-blockers for example, adaptation may be facilitated. In a double-blind, crossover study eight healthy volunteers (aged 23-30 years) took 100 mg atenolol or placebo at 1900 h on Day (D) 1. Volunteers were then exposed to bright light (approx. 1000 lux) from 0000 to 0400 h during the following night and remained in dim light (<50 lux) or darkness until 1200 h on D3. Salivary melatonin (MT) and urinary 6-sulphatoxymelatonin (aMT6s) were measured every 30-60 min and every 2 h (except when asleep), respectively. Subjective alertness and core body temperature (cBT) were also measured. aMT6s and MT were significantly suppressed under atenolol treatment on the night of D1 only. Atenolol significantly phase delayed the salivary melatonin onset by 1.8+/-0.6 h and 1.28+/-0.35 h compared with the onsets on D1 placebo leg and D2 placebo leg (i.e. onset times before and after light treatment), respectively. There were no detrimental effects on cBT or alertness. Temporary suppression of melatonin by beta-blockers may facilitate adaptation to phase shifts.
Administration, Oral↗
Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee.
PURPOSE: D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. METHODS: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of D-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. RESULTS: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (Cmax) for D-limonene ranged from 10.8+/-6.7 to 20.5+/-11.2 microM. Predominant circulating metabolites were perillic acid (Cmax 20.7+/-13.2 to 71+/-29.3 microM), dihydroperillic acid (Cmax 16.6+/-7.9 to 28.1+/-3.1 microM), limonene-1,2-diol (Cmax 10.1+/-8 to 20.7+/-8.6 microM), uroterpenol (Cmax 14.3+/-1.5 to 45.1+/-1.8 microM), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of D-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. CONCLUSIONS: D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.
Adult↗
Can the number of cigarettes smoked predict high-grade cervical intraepithelial neoplasia among women with mildly abnormal cervical smears?
OBJECTIVE: We investigated whether the number of cigarettes smoked by women who had mildly abnormal cytologic study results could identify those at risk for high-grade dysplasia. STUDY DESIGN: This was a prospective study of all women who were referred for colposcopy with a mildly abnormal cervical smear over a 4-year period. A detailed questionnaire was completed that evaluated sociodemographic characteristics including smoking history. Colposcopy then determined the degree of disease. RESULTS: One hundred seventy-three women were referred with a mildly abnormal cervical smear. There was a significant relationship between the numbers of cigarettes smoked and the risk of high grade disease (P = .007). Once the number of cigarettes smoked daily exceeded 20, the risk of high grade cervical intraepithelial neoplasia was increased fivefold (odds ratio 5.85 [95% confidence interval 1.92 to 17.80]). CONCLUSION: Cigarette smoking is associated with a dose-dependent increased risk of cervical intraepithelial neoplasia grade 2 or 3 among women who have mildly abnormal cervical smears.
Adult↗
Effect of several interventions on the frequency of handwashing among elementary public school children.
BACKGROUND: The purpose of this educational project was to assess the effect of several interventions on the frequency of handwashing among elementary public school children. METHODS: Participants in this project were first-graders and fourth-graders from jurisdictions within a mid-Atlantic metropolitan area. Phase I included a baseline assessment of bathroom cleanliness as well as adequacy of supplies for handwashing in each school. During phase 2, the frequency of handwashing before lunch or after bathroom use was monitored and recorded during a 2-month period. The schools were separated into four groups: a peer education group, a hand wipes and instructional poster group, a combination of the education and hand wipes/poster groups, and a (control) comparison school. RESULTS: Overall, a significant increase occurred in the proportion of handwashing frequency from preintervention to postintervention for each intervention group (wipes: 0.50 vs 0.66, p = 0.03; education only: 0.64 vs 0.72, p = 0.02; and education and wipes: 0.45 vs 0.67, p = 0.03) but not in the control group (0.42 vs 0.46, p = 0.26). When the first 3 weeks and the last 3 weeks after intervention were compared, handwashing frequency remained unchanged in the wipes only group (0.66 vs 0.66, p = 0.96), decreased in the education group (0.77 vs 0.65, p = 0.006), and increased in the education and wipes group (0.58 vs 0.75, p = 0.003), as well as in the control group (0.37 vs 0.52, p = 0.01). CONCLUSION: Education combined with accessible convenient hand hygiene may result in a sustainable increase in the frequency of handwashing among elementary school children.
Child↗
Docetaxel: response in patients who have received at least two prior chemotherapy regimens for metastatic breast cancer.
It is unusual to obtain responses after two different sequential regimens in patients with metastatic breast cancer. In this retrospective analysis, data were examined on 22 patients who had already received two or three different regimens for metastatic breast cancer before being treated with 100 mg/m2 docetaxel (or 75 mg/m2 if clinically warranted). 13 patients received three or more courses and 21 patients were assessable for response. 5 of 21 assessable patients (24%) responded for 3-11 months and a further 6 (29%) stabilised. Toxicity (WHO grade 3 and/or 4), principally neutropenia, stomatitis and fluid retention, occurred in 10 patients. We conclude that docetaxel is an active agent in heavily pretreated patients with metastatic breast cancer, but care should be taken to minimise side-effects in this group of patients.
Adult↗
A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer.
Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3.
Adult↗
Enamel thickness of the posterior dentition: its implications for nonextraction treatment.
This study describes mesial and distal enamel thickness of the permanent posterior mandibular dentition. The sample comprised 98 Caucasian adults (59 males, 39 females) 20 to 35 years old. Bitewing radiographs of the right permanent mandibular premolars and first and second molars were illuminated and transferred to a computer at a fixed magnification via a video camera. Enamel and dentin thicknesses were identified and digitized on the plane representing the maximum mesiodistal diameter of each tooth. The results showed that there were no significant sex differences in either mesial or distal enamel thickness. Enamel on the second molars was significantly thicker (0.3 to 0.4 mm) than enamel on the premolars. Distal enamel was significantly thicker than mesial enamel. There was approximately 10 mm of total enamel on the four teeth combined. Assuming 50% enamel reduction, the premolars and molars should provide 9.8 mm of additional space for realignment of mandibular teeth.
Adolescent↗
Extraocular light exposure does not suppress plasma melatonin in humans.
Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects' eyes were exposed to white light (2250 lux for 30 mins) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 +/- 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects' knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 +/- 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nucleipineal pathway.
Adolescent↗
Effects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism.
This study was undertaken to determine whether the internal clock contributes to the hormone and metabolic responses following food, in an experiment designed to dissociate internal clock effects from other factors. Nine female subjects participated. They lived indoors for 31 days with normal time cues, including the natural light: darkness cycle. For 7 days they retired to bed from 0000 h to 0800 h. They then underwent a 26-h 'constant routine' (CR) starting at 0800 h, being seated awake in dim light with hourly 88 Kcal drinks. They then lived on an imposed 27-h day (18 h of wakefulness, 9 h allowed for sleep), for a total of 27 days. A second 26-h CR, starting at 2200 h, was completed. During each CR salivary melatonin and plasma glucose, triacylglycerol (TAG), non-essential fatty acids (NEFA), insulin, gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured hourly. Melatonin and body temperature data indicated no shift in the endogenous clock during the 27-h imposed schedule. Postprandial NEFA, GIP and GLP-1 showed no consistent effects. Glucose, TAG and insulin increased during the night in the first CR. There was a significant effect of both the endogenous clock and sleep for glucose and TAG, but not for insulin. These findings may be relevant to the known increased risk of cardiovascular disease amongst shift workers.
Adult↗
Reconstitution of mitogen-activated protein kinase phosphorylation cascades in bacteria. Efficient synthesis of active protein kinases.
Mitogen-activated protein (MAP) kinase pathways include a three-kinase cascade terminating in a MAP kinase family member. The middle kinase in the cascade is a MAP/extracellular signal-regulated kinase (ERK) kinase or MEK family member and is highly specific for its MAP kinase target. The first kinase in the cascade, a MEK kinase (MEKK), is characterized by its ability to activate one or more MEK family members. A two-plasmid bacterial expression system was employed to express active forms of the following MEK and MAP kinase family members: ERK1, ERK2, alpha-SAPK, and p38 and their upstream activators, MEK1, -2, -3, and -4. In each kinase module, the upstream activator, a constitutively active mutant of MEK1 or MEKK1, was expressed from a low copy plasmid, while one or two downstream effector kinases were expressed from a high copy plasmid with different antibiotic resistance genes and origins of replication. Consistent with their high activity, ERK1 and ERK2 were doubly phosphorylated on Tyr and Thr, were recognized by an antibody specific to the doubly phosphorylated forms, and were inactivated by either phosphoprotein phosphatase 2A or phosphotyrosine phosphatase type 1. Likewise, activated p38 and alpha-stress-activated protein kinase could also be inactivated by either phosphatase, and alpha-stress-activated protein kinase was recognized by an antibody specific to the doubly phosphorylated forms. These three purified, active MAP kinases have specific activities in the range of 0.6-2.3 micromol/min/mg. Coexpression of protein kinases with their substrates in bacteria is of great value in the preparation of numerous phosphoproteins, heretofore not possible in procaryotic expression systems.
Calcium-Calmodulin-Dependent Protein Kinases↗
Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT--pathologic correlation.
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Aged↗
Modification of postprandial hyperglycemia with insulin lispro improves glucose control in patients with type 2 diabetes.
OBJECTIVE: Insulin lispro is a rapid-acting analog of human insulin that can be used to target the postprandial rise in plasma glucose. We designed an open-label randomized crossover study of type 2 diabetic patients with secondary failure of sulfonylurea therapy to determine whether improvement of postprandial hyperglycemia would affect total daily glucose control. RESEARCH DESIGN AND METHODS: Twenty-five type 2 diabetic patients who were poorly controlled on a maximum dose of sulfonylureas were studied in a university hospital clinical research center. In one arm of the study, patients continued therapy with maximum-dose sulfonylureas. In the other arm, patients used a combination therapy with insulin lispro before meals and sulfonylureas. After 4 months, patients were crossed over to the opposite arm. Fasting plasma glucose (FPG) and 1- and 2-h postprandial glucose (after a standardized meal), HbA1c, total, HDL, and LDL cholesterol, and triglyceride levels were measured at the end of each arm of the study. RESULTS: Insulin lispro in combination with sulfonylurea therapy significantly reduced 2-h postprandial glucose concentrations compared with sulfonylureas alone, from 18.6 to 14.2 mmol/l (P < 0.0001), and incremental postprandial glucose area from 617.8 to 472.9 mmol.min.1-1 (P < 0.0007). FPG levels were decreased from 10.9 to 8.5 mmol/l (P < 0.0001), and HbA1c values were reduced form 9.0 to 7.1% (P < 0.0001). Total cholesterol was significantly decreased in the lispro arm from 5.44 to 5.10 mmol/l (P < 0.02). HDL cholesterol concentrations were increased in the lispro arm from 0.88 to 0.96 mmol/l (P < 0.01). The patients weighed significantly more after lispro therapy than after sulfonylureas alone, but the difference was small in absolute terms (sulfonylurea therapy alone, 90.6 kg; lispro therapy, 93.8 kg; P < 0.0001). Two episodes of hypoglycemia (glucose concentrations, < 2.8 mmol/l) were reported by the patients while using lispro. CONCLUSIONS: Previously, it has not been possible to address the effect of treatment of postprandial hyperglycemia specifically. We have now shown that the treatment of postprandial hyperglycemia with insulin lispro markedly improves overall glucose control and some lipid parameters in patients with type 2 diabetes.
Adult↗
'Natural' light treatment of seasonal affective disorder.
Patients with seasonal affective disorder (SAD) were treated for 1 week either with a daily 1-h morning walk outdoors (natural light) or low-dose artificial light (0.5 h@2800 lux). The latter treatment (given under double-blind conditions) can be considered mainly placebo and did not improve any of the depression self-ratings, whereas natural light exposure improved all self-ratings. According to the Hamilton depression score, 25% remitted after low-dose artificial light and 50% after the walk. Sleep duration or timing were not crucial for the therapeutic response. The morning walk phase-advanced the onset and/or offset of salivary melatonin secretion, but individual clinical improvement could not be correlated with specific phase-shifts. Morning cortisol was decreased. Low-dose artificial light did not modify melatonin or cortisol patterns. This is the first study to provide evidence for the use of outdoor light exposure as a potential alternative or adjuvant to conventional artificial light therapy in SAD.
Adult↗
Chalcone synthase cosuppression phenotypes in petunia flowers: comparison of sense vs. antisense constructs and single-copy vs. complex T-DNA sequences.
Flower pigmentation patterns were scored in 185 sense Chalcone synthase (Chs) transgenotes and 85 antisense Chs transgenotes; upon first flowering, 139 (75%) of sense transgenotes were found to be phenotypically altered, as were 70 (82%) of the antisense transgenotes. The observed patterns document the range of phenotypic variations that occur, as well as confirm and extend the finding that sense Chs constructs produce several types of morphology-based flower pigmentation patterns that antisense Chs constructs do not. Long-term monitoring for epigenetic variations in one population of 44 sense Chs transgenotes showed that 43 (98%) were capable of producing a cosuppression phenotype. The primary determinant of sense-specific patterns of cosuppression of Chs was found to be the repetitiveness and organization pattern of the transgene, not 'position effects' by, or 'readthrough' from, flanking plant DNA sequences. The degree of cosuppression observed in progeny of transgenotes carrying multiple, dispersed copies as compared to that observed with a single copy of the transgene suggests that sense cosuppression of Chs is subject to a transgene dosage effect.
Acyltransferases↗
A pilot study to evaluate paclitaxel (Taxol) as primary medical treatment for patients with inoperable stage III and IV breast carcinoma.
The activity of paclitaxel has been extensively investigated in previously treated patients with metastatic breast carcinoma. We evaluated the activity of paclitaxel as primary medical therapy in patients with stage III and IV breast carcinoma, 6 female patients were recruited with no previous history of surgery, radiotherapy or chemotherapy. Paclitaxel was administered as a 3-h infusion at a dose of 225 mg/m2 repeated every 3 weeks weekly to a maximum of 10 cycles. 2 patients achieved a complete response, one of whom had a normal trucut biopsy of the affected breast 6 months after discontinuation of chemotherapy and radiotherapy and a normal mammogram at 17 months. 3 patients achieved a partial response and one stabilised. The patients received between four and ten cycles of chemotherapy. Paclitaxel at this dose was associated with toxicity including alopecia, stomatitis, nausea and diarrhoea. Moderately severe neutropenia occurred in 4 patients, 2 requiring antibiotics but was of short duration and did not necessitate a dose reduction for subsequent courses. Paclitaxel has shown activity as primary medical therapy in patients with inoperable breast carcinoma at presentation at this dosage and schedule. One patient achieved a complete response and avoided surgery altogether and all 6 patients had their primary tumour downgraded. It may be indicated as a single agent in this context or in combination with other drugs with proven activity in breast carcinoma.
Adult↗
Susceptibility to multiple cutaneous basal cell carcinomas: significant interactions between glutathione S-transferase GSTM1 genotypes, skin type and male gender.
The factors that determine development of single and multiple primary cutaneous basal cell carcinomas (BCCs) are unclear. We describe a case-control study firstly, to examine the influence of allelism at the glutathione S-transferase GSTM1 and GSTT1 and cytochrome P450 CYP2D6 loci on susceptibility to these tumours and, secondly, to identify interactions between genotypes and relevant individual characteristics, such as skin type and gender. Frequency distributions for GSTM1 genotypes in cases and controls were not different, although the frequency of GSTM1 A/B was significantly lower (P = 0.048) in the multiple BCCs than in controls. We found no significant differences in the frequencies of GSTT1 and CYP2D6 genotypes in cases and controls. Interactions between genotypes were studied by comparing multinomial frequency distributions in mutually exclusive groups. These identified no differences between cases and controls for combinations of the putatively high risk GSTM1 null, GSTT1 null, CYP2D6 EM genotypes. Interactions between GSTM1 A/B and the CYP2D6 PM and GSTT1-positive genotypes were also not different. Frequency distributions of GSTM1 A/B with CYP2D6 EM in controls and multiple BCCs were significantly different (P = 0.033). The proportion of males in the multiple BCC group (61.3%) was greater than in controls (47.0%) and single BCC (52.2%), and the frequency of the combination GSTM1 null/male gender was significantly greater in patients with multiple tumours (P = 0.002). Frequency distributions of GSTM1 null/skin type 1 were also significantly different (P = 0.029) and the proportion of subjects who were GSTM1 null with skin type 1 was greater (P = 0.009) in the multiple BCC group. We examined the data for interactions between GSTM1 null/skin type 1/male gender by comparing frequency distributions of these factors in the single and multiple BCC groups. The distributions were almost significantly different (exact P = 0.051). No significant interactions between GSTT1 null or CYP2D6 EM and skin type 1 were identified. Comparisons of frequency distributions of smoking with the GSTM1 null, GSTT1 null and CYP2D6 EM genotypes identified no differences between patients with single and multiple tumours.
Aged↗
Hypogonadotrophic hypogonadism and primary amenorrhoea associated with increased melatonin secretion from a cystic pineal lesion.
A 17-year-old girl presented with primary amenorrhoea and failure to develop secondary sexual characteristics, although her height was above the 90th centile. Endocrine investigations revealed hypogonadotrophic hypogonadism (basal LH and FSH levels < 0.5 U/l; FSH rose to 2.0 U/l and LH to 1.0 U/l after GnRH). ACTH, GH, TSH and PRL secretion were normal. A magnetic resonance scan revealed no abnormality in the pituitary, pituitary stalk or hypothalamus but demonstrated a partly cystic enhancing lesion in the pineal region. Melatonin production (assessed as urinary 6-sulphatoxymelatonin: aMT6s) at baseline was markedly increased: 459-530 ng/kg/24 h compared with aged-matched controls: 136 +/- 69 (P = 0.01). However, melatonin production retained a largely normal rhythm with increased production during the night. Treatment with ethinyloestradiol 100 micrograms daily had no apparent effect on the production of melatonin. Treatment with atenolol, 100 mg daily at 1600 h, was associated with suppression of nocturnal melatonin secretion but a brisk rebound in the morning and a considerably delayed peak excretion time (10.2 h) compared with controls (3.9 h). It is likely the pineal lesion, which may be hyperplasia or possibly even tumour, was responsible for the increased melatonin secretion. These data support the hypothesis that melatonin may have a causal role in hypogonadotrophic hypogonadism.
Adolescent↗