A randomized controlled study to assess patients' understanding of and consenting for clinical trials using two different consent form presentations.

BACKGROUND: Informed consent is the ethical basis for clinical research. The physical appearance of the consent document may influence patients' willingness to carefully read the consent document. We therefore tested the hypothesis that presentation of consent documents in an enhanced format improves patients' attention, understanding and therefore willingness to consent for clinical research. METHODS: Patients being asked to participate in three large clinical trials were randomly assigned to enhanced or routine presentation. The enhanced document was printed on 20-pound, cream-colored bond paper and presented in a blue folio. In contrast, patients assigned to routine presentation were given an otherwise identical stapled set of photocopied pages. The primary outcome was the effect of the enhanced format on the proportion of patients consenting; the major secondary outcome was patient's understanding of the presented procedures and risks. RESULTS: A total of 189 of 251 (75%) patients approached with standard format consenting documents consented for an underlying study, whereas 164 of 248 (66%) approached with enhanced format documents consented; the adjusted odds ratio (95% confidence interval) for consenting (comparing enhanced to standard formats) was 0.64 (0.43, 0.95), P=0.03. About 90% of the patients in each group correctly identified the major study intervention and major associated risk. Neither patients' characteristics nor understanding affected the consenting rate for the presented clinical research. CONCLUSION: Consent forms in an enhanced format (i.e., printed on fine paper and presented in a folio) did not improve patients' understanding or willingness to consent to participate in clinical trials.

A survey of spatial defects in Homo Sapiens Affymetrix GeneChips.

Modern biology has moved from a science of individual measurements to a science where data are collected on an industrial scale. Foremost, among the new tools for biochemistry are chip arrays which, in one operation, measure hundreds of thousands or even millions of DNA sequences or RNA transcripts. While this is impressive, increasingly sophisticated analysis tools have been required to convert gene array data into gene expression levels. Despite the assumption that noise levels are low, since the number of measurements for an individual gene is small, identifying which signals are affected by noise is a priority. High-density oligonucleotide array (HDONAs) from NCBI GEO shows that, even in the best Human GeneChips 1/4 percent of data are affected by spatial noise. Earlier designs are noisier and spatial defects may affect more than 25 percent of probes. BioConductor R code is available as supplementary material which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/TCBB.2008.108 and via http://bioinformatics.essex.ac.uk/users/wlangdon/TCBB-2007-11-0161.tar.gz.

Computational studies of Family A and Family B GPCRs.

A full picture of the similarities between Family A and Family B GPCRs (G-protein coupled receptors) has been frustrated by the lack of clear homology between the respective sequences. Here, we review previous computational studies on GPCR dimerization in which the putative dimerization interfaces have been analysed using entropy, the ET (evolutionary trace) method and related methods. The results derived from multiple sequence alignments of Family A subfamilies have been mapped on to the rhodopsin crystal structure using standard alignments. Similarly, the results for the Family B alignments have been mapped on to the rhodopsin crystal structure using the 'cold-spot' alignment. For both Family A and Family B GPCRs, the sequence analysis indicates that there are functional sites on essentially all transmembrane helices, consistent with the parallel daisy chain model of GPCR oligomerization in which each GPCR makes interactions with a number of neighbouring GPCRs. The results are not too sensitive to the quality of the alignment. Molecular Dynamics simulations of the activation process within a single transmembrane bundle of the rhodopsin and the beta(2)-adrenergic receptor have been reviewed; the key observation, which is consistent with other computational studies, is that there is a translation and bending of helix 6, which contributes to a significant opening out of the intracellular face of the receptor, as shown in the accompanying movies. The simulations required the application of specific experiment-derived harmonic and half-harmonic distance restraints and so the application of such simulations to Family B GPCRs requires considerable care because of the alignment problem. Thus, in order to address the alignment problem, we have exploited the observation that GCR1, a plant GPCR, has homology with Family A, Family B and Family E GPCRs. The resulting alignment for transmembrane helix 3 is presented.

Dimerization of G-protein-coupled receptors.

The evolutionary trace (ET) method, a data mining approach for determining significant levels of amino acid conservation, has been applied to over 700 aligned G-protein-coupled receptor (GPCR) sequences. The method predicted the occurrence of functionally important clusters of residues on the external faces of helices 5 and 6 for each family or subfamily of receptors; similar clusters were observed on helices 2 and 3. The probability that these clusters are not random was determined using Monte Carlo techniques. The cluster on helices 5 and 6 is consistent with both 5,6-contact and 5,6-domain swapped dimer formation; the possible equivalence of these two types of dimer is discussed because this relates to activation by homo- and heterodimers. The observation of a functionally important cluster of residues on helices 2 and 3 is novel, and some possible interpretations are given, including heterodimerization and oligomerization. The application of the evolutionary trace method to 113 aligned G-protein sequences resulted in the identification of two functional sites. One large, well-defined site is clearly identified with adenyl cyclase, beta/gamma and regulator of G-protein signaling (RGS) binding. The other G-protein functional site, which extends from the ras-like domain onto the helical domain, has the correct size and electrostatic properties for GPCR dimer binding. The implications of these results are discussed in terms of the conformational changes required in the G-protein for activation by a receptor dimer. Further, the implications of GPCR dimerization for medicinal chemistry are discussed in the context of these ET results.

Venlafaxine in the treatment of premenstrual dysphoric disorder.

OBJECTIVE: To evaluate the efficacy and safety of venlafaxine, a new-generation antidepressant that selectively inhibits serotonin and norepinephrine reuptake, in the treatment of premenstrual dysphoric disorder (PMDD). METHOD: We conducted a randomized, double-blind, placebo-controlled, parallel-group, flexible-dose trial. After three screening cycles, including a single-blind placebo cycle, 164 women were randomly assigned to double-blind treatment with venlafaxine (50-200 mg/day) or placebo for four menstrual cycles. Primary outcome measures were the total premenstrual symptom scores as assessed by a daily symptom report (DSR) and the Hamilton Rating Scale for Depression. RESULTS: Venlafaxine was significantly more effective than placebo in reducing PMDD symptoms as assessed by DSR scores (P <.001 for last observation carried forward and observed analyses). Sixty percent of venlafaxine versus 35% of placebo subjects improved >50% (P =.003). Forty-three percent of venlafaxine subjects versus 25% of placebo subjects experienced symptom remission, defined as reduction of DSR scores to the postmenstrual level (P =.034). Venlafaxine treatment was significantly better than placebo for all statistically derived DSR factors (mood, function, pain, and physical symptoms). Improvement was relatively swift, with approximately 80% symptom reduction in the first treatment cycle. Mean venlafaxine doses ranged from 50 mg/day in the first treatment cycle to 130 mg/day in the fourth treatment cycle. Adverse events such as nausea, insomnia, and dizziness were mild and transient. CONCLUSIONS: Venlafaxine is significantly more efficacious than placebo for PMDD treatment. Response to treatment can occur in the first treatment cycle, and venlafaxine is well tolerated. Further studies are needed to evaluate the potential of intermittent (luteal phase) dosing for this cyclic disorder and the efficacy of long-term maintenance treatment with venlafaxine.

Red cell distribution width (RDW) changes in pregnancy.

OBJECTIVE: As part of an exercise in establishing normograms of hematological parameters in pregnancy, we studied the red cell distribution width (RDW) in healthy pregnant women. METHODS: A longitudinal study of RDW measurements in 121 pregnant women at 16 and 34 weeks gestation and during labor and at Days 3 and 7 postpartum. All the women had uncomplicated pregnancies, minimum hemoglobin (Hb) of 11.0 g/dl at recruitment and took iron supplements from 16 weeks of gestation and until 7 days after delivery. All subjects went into spontaneous labor, 110 achieving a normal vaginal delivery while the remaining 11 were delivered by cesarean section. Two-way analysis of variance was used to study the changes in RDW between any given gestations to test the variability between and within subjects. RESULTS: RDW increased significantly (P < 0.0001) between 34 weeks of gestation and the onset of labor. No significant changes occurred between 16 and 34 weeks gestation, or during the 7 days postpartum. CONCLUSION: This is the first longitudinal study analyzing the between and within women changes in RDW with progression of pregnancy. The unexpected rise in the RDW during the last 4-6 weeks leading up to the onset of labor suggests increased bone marrow activity. The stimulus is unknown, but as RDW changes are highly significant there may well be a useful indicator of impending parturition.

Expressed concerns of Yemeni adolescents.

This study examined the concerns of adolescents in the Republic of Yemen. A short version of the Mooney Problem Check List was administered to 150 13- to 17-year-old males and females. Results indicated that the major concerns and problems reported by Yemeni adolescents were related to their vocational and educational future, recreational activities, religious matters, and school curriculum and teaching methods. Problems related to social life, family, and health and physical issues were less prominent. Results also showed that though there were similarities in the number of concerns expressed by males and females, males reported more difficulties with their vocational and educational future, marriage and sexual matters, and finances and employment, while females reported more problems with recreational activities, personal relationships, and health.

The use of venlafaxine in the treatment of major depression and major depression associated with anxiety: a dose-response study. Venlafaxine Investigator Study Group.

This 12-week, double-blind, placebo-controlled study evaluated the efficacy and safety of venlafaxine as first-line therapy for the treatment of major depression and major depression associated with anxiety in 384 adult outpatients. Fixed total daily dosages of 75, 150, and 200 mg of venlafaxine were administered in a twice-a-day regimen. Primary efficacy parameters were the Hamilton Rating Scale for Depression (HAM-D) total score, the HAM-D Depressed Mood Item, the Montgomery-Asberg Depression Rating Scale total score, and the Clinical Global Impressions Scale. Overall, a higher percentage of patients responded to venlafaxine than to placebo. Efficacy data indicated a dose-related response, most evident in the onset of clinical improvement; statistically significant improvements in some primary parameters were seen as early as 1 to 2 weeks after initiation of treatment, especially in the 150-and 200-mg/day groups. These dose-related clinical improvements continued through week 12. Venlafaxine-treated patients who had depression associated with anxiety showed significant dose-related improvements compared with placebo-treated patients; improvement was noted by scores on the HAM-D Anxiety-Psychic Item and Anxiety-Somatization Factor. Few clinically significant changes were observed in laboratory values, vital signs, or electrocardiogram tracings. Venlafaxine was generally well tolerated at all dosages. The most common study events included nausea, dizziness, somnolence, insomnia, dry mouth, and asthenia, which are consistent with findings of previous studies. The current study demonstrated that 75 to 200 mg/day of venlafaxine twice daily produced a dose-related improvement in the primary efficacy parameters and in the onset of significant antidepressant effects, which was noted at weeks 1 to 2 with the highest dosage tested (200 mg/day). The study also demonstrated that these dosages of venlafaxine were safe and effective as first-line therapy for major depression and depression associated with anxiety.

Incidence of third-degree perineal tears in labour and outcome after primary repair.

The incidence and outcome of third-degree tears following 16,583 vaginal deliveries were prospectively assessed over a 5.5-year period. Ninety-three deliveries (0.56 per cent) were complicated by a third-degree tear and the patients underwent primary repair. Eighty-one patients were reviewed 3 months postpartum at a colorectal clinic. Third-degree tears were significantly more common in primigravidae and mothers with higher birth-weight babies. They were significantly associated with the use of forceps and were not prevented by episiotomy. Of the 81 patients reviewed, 30 had an abnormal anorectal examination. Six patients (7 per cent) were incontinent of faeces. A further ten (12 per cent) were incontinent of flatus only. The overall incidence of faecal incontinence was 0.04 per cent. An important group of women with significant subclinical sphincter injury was identified. Obstetric trauma causes significant anorectal dysfunction and patients with third-degree tears require assessment by a colorectal specialist.

Contraception for the transitional years of women older than 40 years of age.

PIP: Many women older than 40 years of age require both contraceptive protection and hormonal replacement therapy for climacteric symptoms. Combination therapy is advisable but progestins should be added to estrogen to prevent endometrial hyperplasia, decrease the risk of breast cancer, and prevent bone loss. Since the mid-1970s oral contraceptives (OCs) have been limited to women under 35 years of age because of risks of myocardial infarction and thromboembolic disease. The new low-dose OCs used in the 1980s and 1990s have minimized these risks, however, older women who smoke are advised against using estrogen-containing OCs. Natural estrogens are often preferred to the synthetic estrogenic hormones in hormone-replacement products including conjugated equine estrogens, 17 beta estradiol, estradiol valerate, estrone sulfate, and combinations. New progestational agents, 19-nortestosterone derivatives, include norgestimate, gestodene, and desogestrel. RU-486 has potential applications in abortion, once-a-north treatment to induce menses, postcoital therapy, and in breast cancer. Reversible nonhormonal methods such as rhythm, abstinence and withdrawal are used frequently. Barrier methods (diaphragms, cervical caps, and condoms) and spermicides alone or with barrier methods (e.g., vaginal sponges) are increasingly used by older women. IUDs have enjoyed wide acceptance. Sterilization is a nonreversible method but clips (e.g., Filshie clip) have provided reversibility. Progestin-only contraceptives are supplied as oral tablets, injectable solution, silastic implants, medicated IUDs and vaginal rings. Combination estrogen and progestin contraceptives are available as oral tablets and as vaginal rings. A variety of doses and alternate products are necessary for older women.^ieng

Lipids, cardiovascular disease, and oral contraceptives: a practical perspective.

Figure 9 is an attempt to summate the influences of life-style on lipid parameters. Based on the work of Nikkila, it shows the source of the production of HDL and LDL, the factors that can affect these lipoprotein levels, and where in the cascade of lipoprotein metabolism these factors exert influence. The source of HDL production is the liver and the intestine. At this stage, diet, exercise, hormones, genetics, drugs, and certain disease states can affect HDL levels. Lecithin-cholesterol acyl transferase (LCAT) esterifies HDL-free cholesterol in plasma, and HDL3 is formed that in turn is transformed to HDL2. At the same time, VLDL from the gut and the liver will be converted, under the influence of LPL, to HDL2 and LDL. Thus HDL2 is being formed by the breakdown of VLDL and from the transformation of HDL3 to HDL2. Insulin, exercise, alcohol, fats, drugs, and diet affect lipoprotein lipase and consequently influence levels of LDL and HDL2 indirectly. Progestogens increase and estrogens decrease hepatic endothelial lipase, thus affecting the HDL2 concentration. It is at this point that combination OCs influence HDL2. The balance between estrogen and progestogen in a given contraceptive determines the extent and direction of HDL2 concentration. A separate pathway in the liver also catabolizes HDL2 and HDL3. LDL is generated partly from catabolism of VLDL and is partly secreted from the liver. The removal of LDL is mediated by receptors in both the liver and peripheral tissues. It is here that the Brown-Goldstein theory plays a major role. If LDL receptors are present in an insufficient number or are defective, then the C will accumulate and atherosclerosis may follow. Thus two key enzymes, LCAT and LPL, control the production of HDL2 and LDL, whereas a third enzyme, hepatic endothelial lipase, catabolizes HDL2.

PIP: A practical interpretation of the mass of literature on lipids, lipoproteins, oral contraceptives and cardiovascular disease is presented. 1st it is important to realize that lipoprotein values reported by researchers use ultracentrifugation and electrophoresis methods that make commercial laboratory results meaningless. 2nd, most epidemiological studies cited to claim that oral contraceptives cause cardiovascular disease are based on data from the early 1970s, when women took high dose pills and were not screened for risk factors or smoking. The effect of a combined pill on lipids is a summation of the estrogenic and androgenic, as well as antiestrogenic, and anabolic, effects of the respective steroids it contains. Thus, although levonorgestrel is said to be androgenic, when combined with ethinyl estradiol its effect is balanced, as shown by its anti-acne effects. Lipid changes during oral contraceptive use go through a cycle of enzyme induction that occurs for the 1st 3-6 months, after which many observed changes will return to normal. Possible adverse effects of estrogen- induced high triglycerides must be evaluated by the HDL-C level. It is likely that atherogenic risk factors, such as smoking, alcohol and lack of exercise, far outweigh adverse lipid effects of the pill itself.

The relevance of the pharmacologic properties of a progestational agent to its clinical effects as a combination oral contraceptive.

Levonorgestrel (LNg) is known for its marked progestational/contraceptive activity. As shown in animal experiments, however, high doses of LNg are required to elicit an androgenic response; in contrast, considerably lower doses of LNg are required for antiovulatory (contraceptive) action. Thus, a large dose separation exists between androgenic and contraceptive activity. When LNg is combined with an estrogen, as in the contraceptive formulations, the androgenic response is attenuated or negated. The results of recent clinical trials have demonstrated that the androgenic activity of LNg is not expressed at contraceptive doses, particularly when LNg is combined with ethinyl estradiol (EE), as in the low-dose monophasic/triphasic formulations (monophasic [Nordette]: 150 mcg LNg/30 mcg EE; triphasic [Triphasil/Trinordiol]: six days, 50 mcg LNg/30 mcg EE; five days, 75 mcg LNg/40 mcg EE; ten days, 125 mcg LNg/30 mcg EE). Clinical evidence from several trials confirms that sex hormone-binding globulin levels are increased, plasma androgen levels are decreased, and acne is markedly improved with the use of Triphasil and Nordette, suggesting a non-androgenic profile.

Contraception for the perimenopausal patient.

All the existing data show that combination estrogen/progestogen therapy is mandatory if any replacement therapy is to be given to the woman over age 40. Sufficient evidence has indicated that estrogen alone is inadequate; progestogen must be given to prevent endometrial hyperplasia, lower the risk of breast cancer, and prevent bone loss. In the premenopausal woman, such therapy should also provide contraception. Because of the lack of minimal dose products fulfilling such criteria, many physicians will allow women to continue with their contraceptive if they do not smoke and have no other contraindications. It will remain to be seen if a product close to ideal can be found to fulfill the contraceptive and therapeutic needs of women traversing the most physiologically hazardous period of their lives.

PIP: Epidemiological studies of oral contraceptives pertaining to premenopausal women are briefly reviewed. Therapeutic considerations are noted. The clinical effects of aging and hormone replacement therapy are indicated in terms of metabolism, the endometrium, and bone mass. The pharmacological advantages and consequences of nonhormonal and hormonal contraception are explored. For aging women over 40, there is a need for relief of menopausal symptoms, contraception, and reduction of risks for atherosclerosis, hypertension, coronary heart disease, endometrial carcinoma, breast cancer, and osteoporosis. With the availability and use of low estrogen products, women over 40 can insure tissue support and prevent bone loss as long as the therapy is instituted within 3 years of the last menses. Over-40 women who drink and smoke should not use oral contraceptives. Sterilization does not satisfy longterm hormonal needs, and has other reported menstrual side effects. The dose and duration regimen of hormonal therapy must be carefully considered due to the effects on the endometrium., the coagulation system, the liver, lipids, and bone. Combination estrogen and progestogen is necessary, but consideration must be given to existing levels of endogenous hormones. Lipid patterns may change due to hormone replacement or as a result of aging and contribute to coronary heart disease. Hormone replacement can reverse the atherogenic pattern of increased low density lipoprotein levels and decreased high density lipoprotein levels; a chart gives the effects on lipids and coagulation from various estrogen or estrogen plus progestogen products. For the estrogen-deficient menopausal woman, high estrogen can decrease antithrombin III plasminogen and alpha-antitrypsin antigen levels. Lower dose progestogens are recommended. Studies of dose and effects on bone mass are reviewed and vaginal rings and transdermal steroid patches, triphasic formulations, and new progestational agents such as 19-nortestosterone derivatives are described. Newer low dose formulations are needed for the aging woman, as well as further research on what product best suits the variability of women aged 40-50

Multiple sclerosis associated with sinusitis: case-controlled study in general practice.

In an analysis of general practice records the rate of chronic sinusitis was significantly greater in 92 patients with multiple sclerosis (MS) than in matched controls (p less than 0.0001). MS and chronic sinus infection were also significantly associated in the timing of attacks, in the age at which patients suffered their attacks, and in the seasonal pattern of attacks.

The contraceptive and hormonal requirements of the premenopausal woman: the years from forty to fifty.

There is a growing awareness that many women over 40 require both contraceptive protection and hormonal replacement for the symptoms of the climacteric. These women are still menstruating and the risk of pregnancy remains, overshadowed by the increased life-threatening risk due to childbirth in this age group. The risk of mortality due to the use of oral contraceptives is little increased for the nonsmoking woman in the over 40 years compared with the years under 40. In contrast, women over 40 who smoke are best advised not to use hormonal contraceptives. It is evident from all the existing data that combination therapy is strongly advised if any replacement therapy is to be given a woman. There is considerable evidence suggesting that estrogen alone may be insufficient therapy and progestogen should be added to prevent endometrial hyperplasia, decrease the risk of breast cancer and prevent bone loss. In the premenopausal woman, such therapy should also provide contraception. Many physicians allow women 35 to 45 who do not smoke to continue on an oral contraceptive if there is no contraindication. However, a minimum-dose product has yet to be found close to the ideal of fulfilling both the contraceptive and therapeutic needs of women traversing a physiologically very hazardous period.

Therapeutic considerations in the management of the climacteric. A critical analysis of prevalent treatments.

The natural aging process affects a woman greatly during the climacteric; hormonal patterns, metabolic parameters, reproductive target organs and bone are involved. In every instance one can compare these changes with the effects of hormone-replacement therapy (HRT) on these same parameters. Therapy should reverse the negative trends imposed by the aging process and preserve the status quo. The approach must be holistic, and consideration must be given to the effects of HRT on all the parameters and not just to the uterus as the sole end point. Ideally the smallest amount of hormone should be used that will effectively treat symptoms and favorably affect metabolic parameters, the reproductive target organs and bone. Since recent clinical evidence has emphasized the protective nature of estrogen-plus-progestagen therapy in the prevention of endometrial and breast cancer and of osteoporosis, combination therapy is an essential feature of treatment. The shortfalls in our knowledge of the ideal therapy are undeniable. However, it is crucial to provide hormonal support with the available therapy to the woman suffering from estrogen-deficiency symptoms, particularly in view of the high mortality rates associated with postmenopausal osteoporosis, a preventable disease.

Concepto trifasico y su aplicacion clinica. / Triphasic concept and its clinical application

Se describe el concepto trifasico en el campo de la anticoncepcion por via oral, haciendo una breve resena historica sobre la evolucion de los nuevos esquemas de administracion encaminados a disminuir el contenido esteroide total, desde el inicial metodo monofasico al nuevo metodo trifasico. Se pone enfasis en la exposicion razonada del nuevo anticonceptivo oral trifasico y la demostracion clinica de la inhibicion de la ovulacion, el mantenimiento de la integridad funcional del eje hipofisoovarico y el pronto retorno a la fertilidad, despues que ha cesado el regimen trifasico. Se describen extensos estudios clinicos que refuerzan el concepto de que el metodo trifasico el ultimo adelanto en la tecnologia anticonceptiva, constituye una contribucion importante en este campo

The phasic approach to oral contraception: the triphasic concept and its clinical application.

The phasic approach to oral contraception is described with a historical review of the evolution of new administration regimens aimed at lowering total steroid content from monophasic to biphasic to the new triphasic approach. The phasic regimen designs which support the intended mechanism of action of each of the phasic approaches are discussed. Emphasis is placed on the discussion of the rationale for the new triphasic oral contraceptive and the clinical demonstration of the triphasic's inhibition of ovulation and maintenance of functional integrity of the pituitary-ovarian axis. A new theoretical formula and practical concept are presented that incorporate a progestogen potency factor, and consequently provide a common denominator enabling a comparison of the magnitude of the effects of various oral contraceptive products on pituitary responsiveness. Widespread clinical studies are described which reinforce the suggestion that the triphasic is the state of the art and represents an important contribution to contraceptive technology.

PIP: The phasic approach to oral contraception (OC) is described with a historical review of the evolution of new administration regimens aimed at lowering total steroid content from monophasic to biphasic to the new triphasic approach. The phasic regimen designs which support the intended mechanism of action of each of the phasic approaches are discussed. Emphasis is placed on the discussion of the rationale for the new triphasic OC and the clinical demonstration of the triphasic's inhibition of ovulation and maintenance of functional integrity of the pituitary-ovarian axis. A new theoretical formula and practical concept are presented that incorporate a progestogen potency factor, and consequently provide a common denominator for enabling a comparison of the magnitude of the effects of various OCs on pituitary responsiveness. Widespread clinical studies are described which reinforce the suggestion that the triphasic is the state of the art and represents an important contribution to contraceptive technology.