Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study.

BACKGROUND: As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses. STUDY DESIGN: A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. RESULTS: The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (Cmax) 918 pg/mL; time to maximum concentration (Tmax) 3.5 h. For E2, the Cmax occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment. CONCLUSION: PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. IMPLICATIONS: While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.

The role of the anterolateral ligament in ACL insufficient and reconstructed knees on rotatory stability: A biomechanical study on human cadavers.

Studies suggest that the anterolateral ligament (ALL) is important for knee stability. The purpose was to clarify ALL's effect on rotatory and anterior-posterior stability in the anterior cruciate ligament (ACL)-insufficient and reconstructed knees and the effect of reconstruction of an insufficient ALL. Eighteen cadaveric knees were included. Stability was tested for intact (+ALL), detached (-ALL) and reconstructed (+ reALL) ALL, with ACL removed (-ACL) and reconstructed (+ACL) in six combinations. All were tested in 0, 30, 60, and 90 °C flexion. Anterior-posterior stability was measured with a rolimeter. Rotation with a torque of 8.85 Nm was measured photographically. The ALL was well defined in 78% of knees. ACL reconstruction had a significant effect on anterior-posterior stability. Detaching the ALL had a significant effect on internal rotatory stability and on anterior-posterior stability in ACL-insufficient knees. Reconstruction of ACL and ALL reestablished knee stability. The appearance of the ALL was not uniform. The ALL was an internal rotational stabilizer. Anatomical ALL reconstruction in combination with ACL reconstruction could reestablish stability. ALL reconstruction might be considered in patients with combined ACL and ALL tears, but the clinical effect should be established in a controlled clinical study.

Nurse-administered propofol sedation for endoscopy: a risk analysis during an implementation phase.

BACKGROUND AND STUDY AIMS: The aim of the present study was to perform a risk analysis during the implementation phase of nurse-administered propofol sedation (NAPS) and to validate our structured training program. PATIENTS AND METHODS: A structured training program was developed both for endoscopists and for endoscopy nurses who were administering propofol sedation. The nurses' program comprised a 6-week course including theoretical and practical training in airway management, and the endoscopists' program consisted of 2.5 h of theory and a short course in practical airway management. In the implementation phase, data from 1822 endoscopic procedures in 1764 patients were prospectively collected. All adverse events related to sedation were recorded (defined as oxygen saturation < 92%, airway handling, assisted ventilation, need for intubation, change in blood pressure > 20 mmHg). RESULTS: 78 cases of hypoxemia were documented in 1764 patients (4.4%), in 56/983 upper endoscopies (5.7%) and 22/754 lower endoscopies (2.9%) (P = 0.007). Assisted ventilation was necessary in 19 cases (1.1%) and anesthesiologic assistance was requested 10 times. Two patients required endotracheal intubation. A change in blood pressure was recorded in 451 patients (26%). Independent risk factors were type of intervention and level of experience of the staff performing the sedation. CONCLUSION: These results were obtained after development of a structured training program both for endoscopists and nurses using propofol for sedation, and can be used as basis for further comparison. NAPS for endoscopic procedures is safe when performed by personnel properly trained in airway handling and sedation with propofol, and has considerable advantages compared with conventional sedation for endoscopy.

Effective treatment of heavy and/or prolonged menstrual bleeding with an oral contraceptive containing estradiol valerate and dienogest: a randomized, double-blind Phase III trial.

BACKGROUND: This double-blind trial investigated the efficacy and safety of estradiol valerate/dienogest (E(2)V/DNG) for the treatment of heavy menstrual bleeding without recognizable organic pathology. METHODS: Otherwise healthy women with idiopathic heavy, prolonged or frequent menstrual bleeding, confirmed during a 90-day run-in phase, were randomized (2:1) according to a permuted-block, computer-generated schedule to E(2)V/DNG or placebo for 196 days at 34 centres in Europe and Australia. The primary efficacy end-point was the proportion of women with a 'complete' response (i.e. a return to 'menstrual normality') during a 90-day efficacy phase. Secondary end-points included changes in measured menstrual blood loss (MBL) and iron metabolism parameters. RESULTS: The intention-to-treat population comprised 231 women. The E(2)V/DNG response rate was much higher than with placebo (P < 0.0001). The mean reduction in MBL volume in E(2)V/DNG recipients was 69.4% (median 79.2%) versus 5.8% (median 7.4%) in placebo recipients. The between-treatment difference in MBL volume was 373 ml in favour of E(2)V/DNG (95% confidence interval 490, 255 ml; P < 0.0001). Significant improvements in iron metabolism parameters were observed with E(2)V/DNG but not placebo. Overall, 14 women (9.7%) treated with E(2)V/DNG and 5 (6.2%) treated with placebo prematurely discontinued treatment because of adverse events, headache being the most prevalent. Serious adverse events occurred in both the E(2)V/DNG and placebo groups (each n = 2). CONCLUSIONS: E(2)V/DNG is an effective treatment in women with heavy and/or prolonged menstrual bleeding without organic pathology. Further study of E(2)V/DNG compared with an active comparator is warranted. ClinicalTrials.gov identifier: NCT00307801.

Combined oral contraceptives and body weight: do oral contraceptives cause weight gain? A primate model.

BACKGROUND: The aim of this study was to determine if oral contraceptive (OC) use affects body weight, body composition and metabolism in primates. METHODS: Reproductive-age female rhesus monkeys of normal and obese BMI were studied to document baseline weight stability, then treated continuously with an OC (dosed to achieve equivalent human serum levels for a 30 µg ethinyl estradiol/150 µg levonorgestrel preparation) for 237 days. Monkeys were monitored for changes in body weight, levels of physical activity (measured by a triaxial Actical accelerometer), food/caloric intake, percent body fat (dual energy X-ray absorptiometry, DEXA) and metabolism (24 h metabolic rate and serum metabolic substrate and hormone concentrations). RESULTS: All 10 monkeys completed the study protocol with no adverse events. While body weight (-0.73% change) and percent body fat (-1.78% change) of the normal BMI group did not significantly decrease from baseline, obese monkeys showed a significant decrease in body weight (-8.58% change, P < 0.01) and percent body fat (-12.13% change P = 0.02) with OC treatment. In both the obese (P = 0.03) and the normal BMI (P = 0.01) groups, there was a significant increase in basal metabolic rate with OC use. No changes were seen in food intake, activity level or % lean muscle mass with OC use for either BMI-based group. CONCLUSIONS: Overall, OC use appears to cause a slight increase in basal metabolic rate in female monkeys, leading to a decrease in body weight and percent body fat in obese individuals.

Continuous versus cyclic use of combined oral contraceptives for contraception: systematic Cochrane review of randomized controlled trials.

BACKGROUND: With the recent US Food and Drug Administration approval of a combination oral contraceptive that causes a withdrawal bleed every 3 months instead of monthly, avoidance of menstruation through extended or continuous administration (>28 days of active pills) of combined oral contraceptives may become more commonplace for reasons of personal preference rather than limited to treatment of menstrual-associated medical disorders. METHODS: The review aimed to compare contraceptive efficacy, compliance, continuation, satisfaction, bleeding profiles, and menstrual symptoms of combined oral contraceptives with continuous dosing (>28 days of active pills) versus traditional cyclic dosing (21 days of active pills and 7 days of placebo). We searched five computerized databases as well as reference lists of relevant articles for randomized controlled trials (RCT) using continuous or extended combined oral contraceptives for contraception. Two reviewers independently extracted data from eligible articles. RESULTS: Six RCT met inclusion criteria and were of good quality. Contraceptive efficacy and compliance were similar between groups. Discontinuation overall, and for bleeding problems, was not uniformly higher in either group. When studied, participants reported high satisfaction with both dosing regimens. Five out of the six studies found that bleeding patterns were either equivalent or improved with continuous-dosing regimens. The continuous-dosing group had greater improvement of menstrual-associated symptoms (headaches, genital irritation, tiredness, bloating, and menstrual pain). CONCLUSIONS: The variations in pill type and time-interval for continuous dosing make direct comparisons between regimens unfeasible. To allow for comparisons, future studies should choose a previously researched pill and dosing regimen. More attention needs to be directed towards participant satisfaction and menstruation-associated symptoms.

Continuous or extended cycle vs. cyclic use of combined oral contraceptives for contraception.

BACKGROUND: The avoidance of menstruation through extended or continuous administration (greater than 28 days of active pills) of combination oral contraceptives (COCs) has gained legitimacy through its use in treating endometriosis, dysmenorrhea, and menstruation-associated symptoms. Avoidance of menstruation through continuous use of COCs for reasons of personal preference may have additional advantages to women, including improved compliance, greater satisfaction, fewer menstrual symptoms, and less menstruation-related absenteeism from work or school. OBJECTIVES: To determine the differences between COCs dosed continuously (greater than 28 days of active pills) compared with traditional cyclic dosing (21 days of active pills and 7 days of placebo). Our hypothesis was that continuously administered COCs have equivalent efficacy and safety but improved bleeding profiles, amenorrhea rates, adherence, continuation, participant satisfaction, and menstrual symptoms compared with cyclic COCs. SEARCH STRATEGY: We searched computerized databases (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, POPLINE, LILACS) for trials using continuous or extended COCs during the years 1966 to 2005. We also searched the references in review articles and publications identified for inclusion in the protocol. Investigators were contacted regarding additional references. SELECTION CRITERIA: All randomized controlled trials in any language comparing continuous (greater than 28 days of active pills) versus traditional cyclic administration (21 days of active pills and 7 days of placebo) of COCs for contraception. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified from the literature searches were assessed for potential inclusion. Data were extracted onto data collection forms and then entered into RevMan 4.2. Peto odds ratios with 95% confidence intervals were calculated for all outcomes for dichotomous outcomes. Weighted mean difference was calculated for continuous outcomes. The trials were critically appraised by examining the following factors: study design, blinding, randomization method, group allocation concealment, exclusions after randomization, loss to follow-up, and early discontinuation. Because the included trials did not have a standard treatment (type of pill and time length for continuous dosing), we could not aggregate data into meta-analysis. MAIN RESULTS: Six randomized controlled trials met our inclusion criteria. Study findings were similar between 28-day and extended cycles in regard to contraceptive efficacy (i.e., pregnancy rates) and safety profiles. When compliance was reported, no difference between 28-day and extended cycles was found. Participants reported high satisfaction with both dosing regimens, but this was not an outcome universally studied. Overall discontinuation and discontinuation for bleeding problems were not uniformly higher in either group in most studies. The few studies that reported menstrual symptoms found that the extended cycle group fared better in terms of headaches, genital irritation, tiredness, bloating, and menstrual pain. Five out of the six studies found that bleeding patterns were either equivalent between groups or improved with continuous-dosing regimens. Endometrial lining assessments by ultrasound were done in a small number of participants but all endometrial stripe measurements were less than 5 mm. AUTHORS' CONCLUSIONS: Evidence from existing randomized control trials comparing COCs given continuously (greater than 28 days of active pills) to traditional monthly cyclic dosing (21 days of active pills and 7 days of placebo) is of good quality. However, the variations in type of pill and time length for continuous dosing make direct comparisons between regimens impossible. Future studies should choose a previously described type of pill and dosing regimen. More attention needs to be directed towards participant satisfaction and menstruation-associated symptoms.

Transcervical polidocanol as a nonsurgical method of female sterilization: a pilot study.

We have studied the effects of transcervically administered polidocanol on uterine and fallopian tube morphology in Wistar rats and Rhesus monkeys. Polidocanol is a synthetic, long-chain fatty acid that is widely used as a sclerosing agent in Europe. The goal of the study was to determine whether polidocanol would safely cause tubal occlusion in an animal model. Twenty female Wistar rats and three female Rhesus monkeys underwent transcervical injection of polidocanol or physiological saline. The animals were followed for 30 days and then a lower laparotomy was performed, with excision of the entire upper reproductive tract. Specimens were subsequently examined for macroscopic and microscopic changes. Only cyclic changes were observed in the control animals of both species. Fifteen macroscopic and 37 microscopic changes were observed in the uterine horns of the 10 rats treated with polidocanol. There was no observed effect in the monkey fallopian tube. These results suggest that species differences that exist between rodents and primates may influence the effects of transcervical polidocanol. Experiments using a primate model are needed as proof of concept prior to human studies of candidate agents for transcervical tubal sterilization.

Eu3+ uptake by calcite: preliminary results from coprecipitation experiments and observations with surface-sensitive techniques.

A lack of information in databases for contamination risk assessment about the transport behaviour of the trivalent f-orbital elements in groundwater systems where calcite is at equilibrium motivated this study of Eu(3+) uptake. The free drift technique was used to examine the effects of Eu(3+) concentration, presence of Na(+) or K(+) and temperature, as well as calcite nucleation and precipitation kinetics, on the partitioning of calcite. Changes in surface composition and morphology resulting from exposure of single crystals of Iceland spar to Eu(3+)-bearing solutions were observed with X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). First results confirm that calcite has high affinity for Eu(3+). Rates of nucleation and precipitation strongly affect the extent of uptake but the presence of Na(+) and K(+) has no effect, suggesting formation of solid solution as CaCO(3)-EuOHCO(3). Surface-sensitive techniques prove that Eu(3+) is adsorbed to calcite even when the surface is dissolving and adsorption is not accompanied by precipitation of a separate Eu(3+)-solid phase. Adsorbed Eu modifies calcite's dissolution behaviour, roughening terraces and rounding step edges, and producing surface morphology where some surface sites appear blocked. Results imply that Eu(3+) concentrations in natural calcites are limited by Eu(3+) availability rather than by a lack of ability to fit into calcite's atomic structure. This behaviour can probably be expected for other trivalent rare Earth elements (REE), actinides and fission products whose behaviour is similar to that of Eu(3+). These elements are likely to be incorporated within the calcite bulk in systems where it is precipitating and the demonstrated strong partitioning ensures some uptake even where calcite is at or under saturation.

Phosphodiesterase 3 inhibitors selectively block the spontaneous resumption of meiosis by macaque oocytes in vitro.

BACKGROUND: The purpose of this study was to determine whether phosphodiesterase (PDE) 3 inhibitors selectively prevent the resumption of meiosis in primates. METHODS: Immature oocytes (intact germinal vesicles) obtained from large pre-ovulatory follicles following ovarian stimulation in rhesus macaques were incubated with or without various doses of the PDE3 inhibitors, Cilostamide, Milrinone or ORG 9935, or a selective PDE4 inhibitor, Rolipram. Oocytes were observed for germinal vesicle breakdown (GVBD) as an indicator of resumption of meiosis. RESULTS: At 24 h, 72 of 121 (60%) control oocytes progressed to GVBD compared with 9/34 (27%, P < 0.01), 4/36 (11.1%, P < 0.01) and 0/28 (0%, P < 0.01) oocytes incubated with ORG 9935 at 0.1, 0.5 and 1.0 micromol/l respectively. Similar results were achieved at 24 h with 1.0 micromol/l Cilostamide (2/24 oocytes, 8%, P < 0.01) and 100 micromol/l Milrinone (2/32, 6%, P < 0.01). In contrast, no significant difference in GVBD was noted between control oocytes and those incubated with up to 100 micromol/l Rolipram for 24 h (43/58, 74%) or 48 h (44/58, 76%). CONCLUSIONS: These experiments establish the specificity and dose-dependent ability of PDE3, but not PDE4, inhibitors to block resumption of meiosis in macaque oocytes in vitro. Thus, PDE3 inhibitors have potential use as contraceptives in primates.

Health benefits of oral contraceptives.

A sizeable literature corroborates the multiple health benefits of oral contraceptive use. The first estrogen/progestin combination pills were marketed to treat a variety of menstrual disorders. Although currently used oral contraceptives no longer carry FDA-approved labeling for these indications, they remain important therapeutic options for a variety of gynecologic conditions. Well-established gynecologic benefits include a reduction in dysmenorrhea and menorrhagia, iron-deficiency anemia, ectopic pregnancy, and PID. Although older, higher-dose pills reduced the incidence of ovarian cysts, low-dose pills suppress follicular activity less consistently. Nevertheless, cycle-related symptoms, including functional cysts, dysmenorrhea, chronic pelvic pain, and ovulation pain (mittelschmerz), generally improve. Women with polycystic ovary syndrome note improvement in bleeding patterns and a reduction in acne and hirsutism. Symptoms from endometriosis also improve with oral contraceptive therapy. Current data suggest that oral contraceptive therapy increases bone density and that past use decreases fracture risk. Oral contraceptives also improve acne, a major health concern of young women. Oral contraceptives provide lasting reduction in the risk of two serious gynecologic malignancies--ovarian and endometrial cancer. The data with respect to ovarian cancer are compelling enough to recommend the use of oral contraceptives to women at high risk by virtue of family history, positive carrier status of the BRCA mutations, or nulliparity, even if contraception is not required. Health care providers must counsel women regarding these benefits to counteract deeply held public attitudes and misconceptions regarding oral contraceptive use. Messages should focus on topics of interest to particular groups of women. The fact that oral contraceptives increase bone mineral density and reduce ovarian cancer is of great interest to women in their forties and helps influence use and compliance in this group. In contrast, the beneficial effects of oral contraceptives on acne resonates with younger women. Getting the good news out about the benefits of oral contraceptives will enable more women to take advantage of their positive health effects.

Acceptability of suction curettage and mifepristone abortion in the United States: a prospective comparison study.

OBJECTIVE: We sought to compare the acceptability of suction curettage abortion with that of medical abortion with mifepristone and misoprostol in American women. STUDY DESIGN: We performed a prospective, serially enrolled, cohort analysis. The study population consisted of 152 subjects receiving mifepristone and misoprostol and 174 subjects undergoing suction curettage abortion aged > or =18 years with intrauterine pregnancies of up to 63 days' estimated gestation. Questionnaires regarding expectations and experiences were administered before the abortion and at the 2-week follow-up visit. RESULTS: Subjects undergoing medical abortions reported significantly greater satisfaction than those undergoing surgical abortions (mean rank, 121 vs 149; P <.01) but were no more likely to recommend the method they had just experienced to a friend (97% vs 93.3%). If a future abortion was required, however, 41.7% of subjects undergoing surgical abortions indicated they would opt for a medical abortion, whereas only 8.6% of subjects receiving medical abortions would choose a surgical abortion (P <.001). Failure of the abortion decreased satisfaction in the medical group and increased the likelihood of choosing a surgical abortion for a subsequent procedure (P <.001). Surgical subjects who experienced more anxiety than expected during the abortion were more likely to choose a medical procedure for a subsequent abortion (P <.01). CONCLUSION: Women receiving mifepristone and misoprostol were more satisfied with their method and more likely to choose the same method again than were subjects undergoing surgical abortion. Failure of a medical abortion and increased anxiety during surgical abortion were associated with preference for the alternative technique in a future procedure.

Outcomes of suction curettage and mifepristone abortion in the United States. A prospective comparison study.

A prospective, nonconcurrent cohort analysis of 178 mifepristone/misoprostol and 199 suction curettage abortion subjects, ages > or = 18 years, with intrauterine pregnancies < or = 63 days estimated gestational age, was conducted to compare the outcomes of suction curettage abortion to those of medical abortion. The medical abortion subjects received 600 mg of mifeprisone orally, followed by 400 micrograms of oral misoprostol 2 days later. Surgical abortion subjects underwent electronic vacuum aspiration. All subjects were followed for 2 weeks or until the absence of clinical bleeding. Outcome measures included a successful abortion (complete abortion without a surgical intervention), duration of bleeding, and morbidity. Overall, 18.3% medical and 4.7% surgical patients failed their primary procedure and received an unanticipated suction curettage (RR 3.93, 95% CI 1.87, 8.29). Four mifepristone subjects required curettage for acute bleeding, nine to manage ongoing pregnancy, and five for incomplete abortion. Fourteen mifepristone and eight surgical subjects required curettage for persistent bleeding. The median time delay for therapeutic curettage was significantly longer in the medical abortion group (35 versus 8 days; Mann-Whitney U = 17.0, p = 0.008). Medical subjects experienced significantly longer bleeding (mean difference = 9.6 days, 95% CI 6.8, 12.4). No significant change in hemoglobin occurred in either group. Mifepristone patients reported significantly greater pain (77.1% vs 10.5%; RR 7.4, 95% CI 4.7, 11.5), and nausea or vomiting (68.6% vs 0.6%; RR 117.9, 95% CI 16.7, 834.7). Women receiving mifepristone/misoprostol are more likely to require an unplanned surgical intervention than women who undergo suction curettage. They experience more discomfort with their procedure and in the follow-up interval, bleed for a longer period, and remain at risk for surgical completion curettage for several weeks.

PIP: A prospective, nonconcurrent cohort analysis was conducted to compare the outcomes of suction curettage abortion to those of medical abortion in the US. The study included 178 mifepristone/misoprostol and 199 curettage abortion subjects, ages 18 years or older, with intrauterine pregnancies of 63 or fewer days. Medical abortion subjects received 600 mg of mifepristone orally, followed by 400 mcg of oral misoprostol 2 days later. Surgical abortion subjects underwent electronic vacuum aspiration. Results showed that 18.3% of medical and 4.7% of surgical patients failed their primary procedure and received an unanticipated suction curettage. Medical subjects experienced significantly longer bleeding; however, no significant change in hemoglobin occurred in either group. While, mifepristone patients reported significantly greater pain, nausea or vomiting. Thus, women receiving mifepristone/misoprostol are more likely to require an unplanned surgical intervention than women who undergo curretage. Medical abortion patients have more discomfort, they bleed longer, and remain at risk for surgical completion curettage for several weeks.

Localization of contraceptive implant capsules for removal.

Implanted contraceptive capsules occasionally cannot be removed by means of palpation with local dissection, and imaging guidance is necessary. The authors report obtaining a single antero-posterior radiograph of the upper arm followed by sonography to localize the capsule and to allow precise marking of the skin over the capsules. The method can be performed quickly and is inexpensive and effective, allowing the localization and removal procedures to be scheduled independently.

PIP: In Oregon, since some physicians could not remove contraceptive implant (Norplant) capsules, they referred three patients to Oregon Health Sciences University or the Kaiser Sunnyside Medical Center in Clackamas for implant removal. The physician was able to initially remove five of the six capsules in a 21-year-old mother of three. One month later, the physician tried again to remove the remaining capsule and did not succeed. Anteroposterior and lateral radiographs of the upper left arm could not detect the 6th capsule. The referral institution obtained a single anteroposterior radiograph (about 55 kVp and 10 mAs) that revealed the capsule in the subcutaneous tissue. Using landmarks on the radiograph, the capsule's location was estimated and scanned with a high frequency linear ultrasound probe that found the exact location of the capsule. The physicians marked the patient's skin along the length of the capsule and asked her to renew the mark every day until her own physician could remove it two days later. The complete imaging procedure lasted only 12 minutes. Two different surgeons attempted removal of three capsules in one woman. The second surgeon even used 15 minutes of intraoperative fluoroscopy. Another case was referred for imaging because her physician could not palpate one capsule. The referral institution used the same localization method (radiograph and ultrasound) to locate the capsule and mark its location. These cases show that clinicians can perform this inexpensive and effective localization method for undetectable implant capsules quickly. Localization of capsules and removal procedures can be scheduled at different times.

Hereditary angioneurotic edema in the puerperium. A case report.

Hereditary angioneurotic edema is a potentially fatal condition. Below is described the first reported case of the initial presentation of the condition precipitated by vaginal delivery.

Familial hypocalciuric hypercalcaemia. III: Bone mineral metabolism.

Bone mineral metabolism was studied in 10 subjects with familial hypocalciuric hypercalcaemia (FHH) and 10 age-, sex- and surface area matched healthy controls. Bone turnover was estimated by urinary calcium and hydroxyproline excretions relative to creatinine (Ca/Creat and OHPr/Creat, respectively), serum bone Gla-protein (S-BGP) and serum alkaline phosphatase (S-ALP). Bone status was evaluated by measurement of bone mineral content (BMC) on both forearms and X-ray examinations of the hands. Ca/Creat and OHPr/Creat (indices of bone resorption) were both significantly higher in the FHH group than in the controls. S-BGP and S-ALP (indices of bone formation) tended towards a higher level in the FHH subjects, but the differences were not significant. The BMC values were similar in the two study groups and did not change with time. We conclude that these patients with FHH might have a bone turnover higher than normal, and that the increased bone resorption must be paralleled by an increased bone formation.

Sclerosis and hyperostosis of the manubrium sterni.

Seven females and one male with almost identical sclerotic and hyperostotic changes of the manubrium sterni are reported. The clinical course was prolonged and characterized by intermittent periods of exacerbation followed by improvement. Malignancies, bacterial inflammatory processes, and Paget disease, which were first suspected, could be excluded. Pustulosis-palmoplantaris was present in four patients and one had psoriasis vulgaris. None of the patients had sacroiliitis or peripheral joint changes, but the three youngest patients had sclerotic changes of other bones, including the lumbar spine, the pubic bone, and the clavicle. This may indicate that this is an adult disease analogous to "chronic recurrent multifocal osteomyelitis", a disease mainly present in children and adolescents.

In situ localization of human fibronectin (FN) genes to chromosome regions 2p14----p16, 2q34----q36, and 11q12.1----q13.5 in germ line cells, but to chromosome 2 sites only in somatic cells.

The locations of the genes for fibronectin (FN) on chromosomes of human germ line and somatic cells were determined by in situ molecular hybridization with two 3H-labeled DNA probes, one for the region encoding the cell attachment domain of human FN, the other for the 3' noncoding and part of the coding region. Pachytene chromosomes of two males and lymphocyte chromosomes of one of these males and a female were used. Two regions of hybridization on pachytene and somatic chromosome 2 (p14----p16 and q34----q36) were found, but not in all individuals. A third region of hybridization was found at 11q12.1----q13.5 in meiotic, but not with significant frequency in somatic chromosomes. It is not clear if these differences between meiotic and somatic chromosomes, and the large differences between individuals at some of the other hybridization sites, resulted solely from technical factors. The differences between the findings in meiotic and somatic preparations might be due to the presence of four strands in pachytene chromosomes versus only one per somatic chromatid. Individual differences in DNA sequences in the chromosome segment containing the gene, differences in gene locations among individuals, or between meiotic and mitotic chromosomes might account for the other findings. The results confirm some of the earlier studies with cell hybrids that mapped FN genes to chromosomes 2 or 11. The combined findings suggest that some of these loci may be coding for the plasma form of FN and others for the cellular form. The expression of the different FN types by differentiated cells might then depend on the loci that are activated.