PTEN mutations and proteus syndrome.
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Diagnostic Errors↗
Biomedical subjects
M J Rosenberg
Publications and source records attributed to M J Rosenberg.
Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations.
We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.
Abnormalities, Multiple↗
Detection of chromosomal aberrations by a whole-genome microsatellite screen.
Chromosomal aberrations are a common cause of multiple anomaly syndromes that include developmental and growth retardation. Current microscopic techniques are useful for the detection of such aberrations but have a limit of resolution that is above the threshold for phenotypic effect. We hypothesized that a genomewide microsatellite screen could detect chromosomal aberrations that were not detected by standard cytogenetic techniques in a portion of these individuals. To test this hypothesis, we performed a genomewide microsatellite screen of patients, by use of a currently available genetic-marker panel that was originally designed for meiotic mapping of Mendelian traits. We genotyped approximately 400 markers on 17 pairs of parents and their children who had normal karyotypes. By using this approach, we detected and confirmed two cases of segmental aneusomy among 11 children with multiple congenital anomalies. These data demonstrate that a genomewide microsatellite scan can be used to detect chromosomal aberrations that are not detected by microscopic techniques.
Abnormalities, Multiple↗
A GNAS1 imprinting defect in pseudohypoparathyroidism type IB.
Pseudohypoparathyroidism type IB (PHPIB) is characterized by renal resistance to parathyroid hormone (PTH) and the absence of other endocrine or physical abnormalities. Familial PHPIB has been mapped to 20q13, near GNAS1, which encodes G(s)alpha, the G protein alpha-subunit required for receptor-stimulated cAMP generation. However, G(s)alpha function is normal in blood cells from PHPIB patients, ruling out mutations within the G(s)alpha coding region. In mice G(s)alpha is expressed only from the maternal allele in renal proximal tubules (the site of PTH action) but is biallelically expressed in most other tissues. Studies in patients with Albright hereditary osteodystrophy suggest a similar G(s)alpha imprinting pattern in humans. Here we identify a region upstream of the G(s)alpha promoter that is normally methylated on the maternal allele and unmethylated on the paternal allele, but that is unmethylated on both alleles in all 13 PHPIB patients studied. Within this region is an alternative promoter and first exon (exon 1A), generating transcripts that are normally expressed only from the paternal allele, but that are biallelically expressed in PHPIB patients. Therefore, PHPIB is associated with a paternal-specific imprinting pattern of the exon 1A region on both alleles, which may lead to decreased G(s)alpha expression in renal proximal tubules. We propose that loss of exon 1A imprinting is the cause of PHPIB.
Alleles↗
Efficacy, cycle control, and side effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations.
Estrogen content represents a tradeoff between cycle control and side effects, but few direct comparisons of 20 and 30/35 micrograms preparations are available. To address this issue, we conducted a randomized, open-label multicenter clinical trial comparing Alesse (20 micrograms ethinyl estradiol [EE]), Mircette (20 micrograms EE), and Ortho Tri-Cyclen (35 micrograms EE) among 463 OC starters or switchers. Bloating, breast tenderness, and nausea were approximately 50% more common in women using 35 micrograms EE as compared to 20 micrograms EE preparations. Cycle control was similar in all products, although during the first two cycles among starters; users of Mircette and Ortho Tri-Cyclen (Tri-Cyclen) exhibited better cycle control than Alesse users. Discontinuation and pregnancy rates were not significantly higher in 35 micrograms EE users.
Adolescent↗
Oral contraceptive discontinuation: a prospective evaluation of frequency and reasons.
OBJECTIVES: Our purpose was to define the frequency and reasons for oral contraceptive discontinuation and subsequent contraceptive behavior. STUDY DESIGN: A nationwide prospective study of 1657 women initiating or switching to the use of a new contraceptive from private practices, clinics, and a health maintenance organization was performed. RESULTS: Six months after a new oral contraceptive prescription, 68% of new starts and 84% of switchers still used oral contraceptives. Of women who discontinued, 46% did so because of side effects, whereas 23% had no continuing need. More than four fifths of women who discontinued oral contraceptives but remained at risk of unintended pregnancy either failed to adopt another method or adopted a less effective method. Fifteen percent of women who discontinued oral contraceptives resumed their use within the 7-month follow-up period. CONCLUSIONS: Counseling should emphasize the possibility of side effects, stressing the fact that most will be transient, and the need to identify a backup method. Follow-up visits should be scheduled for 1 to 2 months after a prescription is written.
Adult↗
Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI.
Glycogen storage disease type VI (GSD6) defines a group of disorders that cause hepatomegaly and hypoglycemia with reduced liver phosphorylase activity. The course of these disorders is generally mild, but definitive diagnosis requires invasive procedures. We analyzed a Mennonite kindred with an autosomal recessive form of GSD6 to determine the molecular defect and develop a non-invasive diagnostic test. Linkage analysis was performed using genetic markers flanking the liver glycogen phosphorylase gene ( PYGL ), which was suspected to be the cause of the disorder on biochemical grounds. Mennonite GSD6 was linked to the PYGL locus with a multipoint LOD score of 4.7. The PYGL gene was analyzed for mutations by sequencing genomic DNA. Sequencing of genomic DNA revealed a splice site abnormality of the intron 13 splice donor. Confirmation of the genomic mutation was performed by sequencing RT-PCR products, which showed heterogeneous PYGL mRNA lacking all or part of exon 13 in affected persons. This study is the first to demonstrate that a mutation in the PYGL gene can cause GSD6. This mutation is estimated to be present on 3% of Mennonite chromosomes and the disease affects 0.1% of that population. Determination of this mutation provides a basis for the development of a simple and non-invasive diagnostic test for the disease and the carrier state in this population and confirms biochemical data showing the importance of this gene in glucose homeostasis.
Base Sequence↗
Do spermicides containing nonoxynol-9 prevent sexually transmitted infections? A meta-analysis.
BACKGROUND AND OBJECTIVES: There are conflicting opinions on whether to recommend spermicides containing nonoxynol-9 for prevention of sexually transmitted diseases, including human immunodeficiency virus (HIV). GOAL: To systematically review and summarize the medical literature on the effect of spermicides containing nonoxynol-9 on prevention of gonorrhea, chlamydial infection, and HIV. STUDY DESIGN: Meta-analysis. Potential articles were identified through computerized literature searches. Articles were included if the design was clinical trial, cohort, case-control, or cross-sectional; original outcome data were presented for gonorrhea, chlamydial infection, or HIV; and spermicides containing nonoxynol-9 were used separately from other barrier methods. Study characteristics including design, population, spermicide dose, and delivery method were abstracted. Relative risks (RR) and 95% confidence intervals (CI) were determined from information published in the study or from study authors. Summary risk estimates were computed for clinical trials. RESULTS: Twelve eligible articles were identified, including six clinical trials and six observational studies. Eleven articles evaluated gonorrhea; each found a reduced risk of infection with spermicide use. Among six clinical trials, the summary RR was 0.62 (95% CI, 0.49-0.78). The five articles evaluating chlamydial infection also found significant reduction among spermicide users, with the four clinical trials having a summary RR of 0.75 (95% CI, 0.62-0.91). The degree of spermicidal protection against gonorrhea and chlamydial infection did not differ materially among studies with different study designs or spermicidal preparations (i.e., sponge, gel, suppository, or film). Three studies evaluated degree of protection according to consistency of use and found stronger protection with more consistent use. The two studies on spermicidal prevention of HIV had contrasting results: An observational study found a significant protective effect (RR = 0.1), whereas a clinical trial found a nonsignificantly increased risk (RR = 1.7). CONCLUSIONS: Nonoxynol-9-containing spermicides have an appreciable protective effect against both gonorrhea and chlamydial infection, and wider use of spermicides might substantially reduce the incidence of these diseases. However, insufficient data exist to judge their effect on HIV transmission, and more research on the effect of nonoxynol-9 on HIV transmission is urgently needed to make evidence-based clinical decisions and public health recommendations in the future.
Chlamydia Infections↗
Latex condom breakage and slippage in a controlled clinical trial.
Although millions of couples rely on male latex condoms to protect against unintended pregnancy and sexually transmitted infections, their use is limited in part by questions about their performance. Rates of condom breakage and slippage, two measures of performance, vary broadly across studies. This variation in part reflects study variability and limitations, including sample size, reliance on subjects' memory, user populations, and products evaluated. In an effort to define condom performance in a group of monogamous couples typical of those using condoms for contraception, we conducted a clinical trial of a single brand of lubricated condoms (Durex Ramses). A total of 4637 attempts to use the condom were evaluated. Six breaks occurred before intercourse (nonclinical breaks), and 10 condoms broke during intercourse or were only noted to have broken upon withdrawal (clinical breaks), resulting in a nonclinical breakage rate of 0.13% (95% confidence interval, 0.05-0.28%), clinical breakage rate of 0.28% (0.15-0.48%), and a total breakage rate of 0.41% (0.25-0.64%). The rate of complete slippage was 0.63% (0.42-0.90%), and total failure (clinical breaks plus complete slips) was 1.04% (0.76-1.37%). These rates are lower than those in other studies with the exception of one, a prospective investigation in a population of female prostitutes. Results indicate that condoms can, in experienced, motivated populations, provide excellent performance and suggest that their efficacy at preventing pregnancy may equal that of the most reliable forms of contraception. Because this study involved a single condom brand, these results may not be generalizable to other brands.
Adult↗
A comparison of "U" and standard techniques for Norplant removal.
OBJECTIVE: To evaluate the "U" technique versus the manufacturer-recommended technique for Norplant removal. METHODS: We conducted a randomized comparison of the manufacturer-recommended method of removal and the "U" technique. The latter involves an incision between and parallel to the third and fourth implants and uses a modified vasectomy clamp to remove the implants by pulling perpendicular to the implant's axis. RESULTS: Twenty-one physicians (three experienced, 18 inexperienced) performed 200 Norplant removals. Inexperienced physicians took significantly less time for removal using the "U" technique than the standard technique (7.9 versus 10.5 minutes), even after controlling for other factors. Experienced physicians also required less time for removal using the "U" technique (3.1 versus 3.7 minutes), but the difference was not statistically significant after controlling for other factors. Both experienced and inexperienced physicians broke implants more frequently using the standard technique, although the difference was significant only for experienced physicians (relative risk 3.6, 95% confidence interval 1.2, 10.8). No differences were noted between the techniques with respect to tissue damage or patient reports of pain during or after removal. CONCLUSIONS: These results suggest that the "U" technique is an improvement over the standard technique, particularly for personnel who are not highly experienced in Norplant removal.
Adult↗
Estrogen-androgen for hormone replacement. A review.
OBJECTIVE: To critically examine the role of androgens as part of postmenopausal hormone replacement therapy. STUDY DESIGN: Examination of original reports and reviews obtained by electronic database searches and supplemented by manual search of bibliographies. RESULTS: As compared to estrogens alone, estrogen-androgen therapy may better protect against osteoporosis and increase libido, energy levels and general sense of well-being. However, estrogen-androgen replacement also reduces the beneficial increases in high-density lipoprotein induced by estrogens alone, although this effect may be offset at least partially by decreases in atherogenic triglycerides. The long-term net effect of estrogen-androgen replacement on cardiovascular disease remains unknown. CONCLUSION: Although the literature includes relatively few clinical trials or well-controlled studies and is further limited by the subjective nature of outcomes, such as sexual and psychological function, the available data suggest that for many postmenopausal women, estrogen-androgen replacement may provide benefits beyond those provided by estrogen-only replacement therapy.
Affective Symptoms↗
The effect of desogestrel, gestodene, and other factors on spotting and bleeding.
Spotting and bleeding are among the most common side effects associated with oral contraceptive (OC) use and their occurrence is a prime determinant of whether a new user will continue to use OCs. Desogestrel and gestodene are two new progestins that were developed in part to minimize the occurrence of these side effects. Assessing the effect of these progestins is difficult, however, in part because their effects may be subtle, requiring a large sample size and possibly being overshadowed by other factors. To address these issues, we analyzed data from two comparative multicenter clinical trials that included 15,421 cycles among 2767 women. One study compared 75 micrograms gestodene + 30 micrograms ethinyl estradiol (EE) with 150 micrograms desogestrel + 30 micrograms EE, the other compared the same gestodene preparation with 150 micrograms desogestrel + 20 micrograms EE. Both studies found a higher risk of spotting or bleeding in all cycles among users of the desogestrel-containing preparation, with the differences ranging between 20% and 70% higher for the first study and 40% and 140% in the second. These differences were statistically significant in four of six cycles in each study and persisted after controlling for consistency and recency of OC use as well as smoking. After pooling the data and controlling for estrogen dose, the desogestrel-containing preparation was significantly associated with more frequent spotting or bleeding in five of six cycles. Smoking and consistency and recency of OC use were also independent predictors of spotting or bleeding.
Adolescent↗
The male polyurethane condom: a review of current knowledge.
Condoms are one of the oldest form of contraceptive and the best recognized form of protection against sexually transmitted diseases. Their use, however, is limited by both behavioral factors and device-related factors, including complaints about decreased sensitivity and sexual enjoyment. To address these limitations, a male condom made of polyurethane was developed. Polyurethane is a strong impermeable material with good heat transfer characteristics that is less susceptible to deterioration during storage than latex. Because little information is available comparing polyurethane and latex condoms in terms of consumer preferences as well as breakage and slippage, we reviewed four pre-marketing studies of polyurethane condoms, one of which included comparison to latex. No significant differences in slippage and breakage rates between latex and polyurethane condoms were reported in the study that included a latex comparator, and other studies of polyurethane condoms alone resulted in rates in the same range as published for latex condoms. Subjectively, consumers expressed significantly greater preference for the polyurethane condom over latex in regard to appearance, lack of smell, likelihood of slippage, comfort, sensitivity, natural look, natural feel, and overall. While additional testing is needed, these preliminary results suggest that the male polyurethane condom reviewed performed at least as well as latex condoms and is preferred by consumers. If preference translates to greater use, the male polyurethane condom may address important barriers that have been linked with inadequate condom use in the past. These results, however, may not be generalizable to other brands of polyurethane condom currently under development.
Condoms↗
Performance of the TCu380A and Cu-Fix IUDs in an international randomized trail.
To compare the clinical performance of the TCu380A, the most widely used copper IUD in the world today, and a new frameless device, the Cu-Fix, we report results from a randomized international two-year clinical trial involving 874 parous women followed for an average of fourteen months. Event rates at the end of two years (per 100 women) for pregnancy were 0.0 for the TCu380A and 1.5 for the Cu-Fix. Termination due to expulsion was significantly less for TCu380A as compared with Cu-Fix users (2.0 and 11.4 per hundred women, respectively); other medical reasons for termination (bleeding/pain, pelvic inflammatory disease (PID), and other) did not differ significantly. PID incidence rates at two years were 1.0 per hundred women for the TCu380A and 1.6 for the Cu-Fix (equivalent to 6.0 and 8.3 per 1,000 woman-years, respectively). The net cumulative continuation rates at two years per hundred women were 78.8 for TCu380A, and 71.9 for the Cu-Fix. Both IUDs provide highly effective protection against pregnancy, but the TCu380A has a lower expulsion rate. The low rate of PID indicates that it is an in-frequent occurrence in appropriately selected candidates.
Adolescent↗
Smoking and cycle control among oral contraceptive users.
OBJECTIVE: Because cigarette smoking has a variety of antiestrogenic actions, we investigated the possibility that smoking may adversely affect spotting and bleeding among women using oral contraceptives. STUDY DESIGN: Three open-label, randomized clinical trials involving 16,506 cycles among 2956 oral contraceptive users were performed. RESULTS: Smokers reported a consistently higher frequency of spotting or bleeding than did nonsmokers. After recency and consistency of oral contraceptive use and progestin component were controlled for, smokers were, on average, 47% more likely to have spotting or bleeding than nonsmokers were over six cycles of oral contraceptive use, with higher levels of smoking associated with a greater frequency of spotting or bleeding. By the sixth cycle women who smoked > or = 16 cigarettes per day were almost three times more likely to have spotting or bleeding than were nonsmokers. CONCLUSION: Cigarette smoking adversely affects cycle control among oral contraceptive users, possibly by increasing estrogen catabolism. Although these findings also raise the possibility that oral contraceptive efficacy may also be impaired in smokers, an immediate concern is that oral contraceptive users who have spotting and bleeding are more likely to discontinue their use, placing them at risk of unintended pregnancy.
Adolescent↗
Risk assessment of polymyositis/dermatomyositis after treatment with injectable bovine collagen implants.
BACKGROUND: Questions have been raised about a possible relation between injectable collagen and polymyositis and dermatomyositis (PM/DM). Predictions of the prevalence of PM/DM have been based on anecdotal estimates of the duration of follow-up for the collagen-treated population. OBJECTIVE: Our purpose was to study the duration of follow-up for a large sample of collagen-treated patients. METHODS: Physicians in North America who purchased collagen implants during fiscal year 1988 were categorized according to collagen practice size; one third were randomly invited to participate in the study. RESULTS: Review of 2622 patient records yielded an average duration of follow-up of 4 years. CONCLUSION: Five-year incidence rates were used to estimate the expected number of cases of PM/DM in the collagen-treated population. Through June 1993 the expected number was 30.2. The number of confirmed cases after treatment was seven, less than one fourth of the number of cases expected for a model of the collagen-treated population, matched for age, sex, and race.
Adolescent↗
Use and misuse of oral contraceptives: risk indicators for poor pill taking and discontinuation.
The contraceptive efficacy of oral contraceptives (OCs) depends on their proper and continued use, particularly with lower estrogen preparations. However, few studies have examined why women miss pills or discontinue OCs, and those that do tend to be small and to focus on adolescents. To address the issues of poor OC compliance and early OC discontinuation, we analyzed OC use in a convenience sample of 6,676 women between the ages of 16 and 30 from Denmark, France, Italy, Portugal, and the United Kingdom. Logistic regression was used to examine the independent effect of each factor. Poor compliance was associated with a lack of established routine for pill-taking (relative risk [RR] = 3.3), failure to read and understand written materials that came with the OC package (RR = 2.2), not receiving adequate information or help about OCs from their health care provider (RR = 1.5), and occurrence of certain side effects, including hirsutism (RR = 2.1), nausea (RR = 1.4), bleeding irregularities (RR = 1.3), and breast tenderness (RR = 1.2). Women who were inconsistent OC users, missing one or more pills per cycle, were almost three times as likely to experience an unintended pregnancy while using OCs than were women who took their OCs consistently. Factors that predicted early discontinuation (women who wished to continue contraceptive protection but discontinued OC use) were primarily side effects, including nausea (RR = 2.1), bleeding (RR = 1.9), breast tenderness (RR = 1.8), mood changes (RR = 1.8), and weight gain (RR = 1.4).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Compliance and oral contraceptives: a review.
Compliance difficulties are more common among oral contraceptive (OC) users than generally appreciated by clinicians, in part because unintended pregnancy is a relatively infrequent consequence and in part because more common manifestations such as spotting and bleeding may not be recognized as resulting from poor compliance. While improving compliance is a shared responsibility of patients, clinicians, and manufacturers, the clinician is the focal point for these efforts. Counseling must be individualized, which requires knowledge of factors that predict compliance and an understanding of the patient's decision-making process as it relates to medications. Most OC compliance research has focused on adolescents, where predictors of poor compliance include multiple sex partners, low evaluation of personal health, degree of concern about pregnancy, and previous abortion. Good compliance has been linked with patient satisfaction with the clinician, the absence of certain side effects, establishing a regular daily routine to take OCs, and reading information distributed with OC packaging.
Contraceptives, Oral↗