Recommendation to include hydroxyethyl (meth)acrylate in the British baseline patch test series.

BACKGROUND: (Meth)acrylates are potent sensitizers and a common cause of allergic contact dermatitis (ACD). The frequency of (meth)acrylate ACD has increased with soaring demand for acrylic nails. A preliminary audit has suggested a significant rate of positive patch tests to (meth)acrylates using aimed testing in patients providing a clear history of exposure. To date, (meth)acrylates have not been routinely tested in the baseline patch test series in the U.K. and Europe. OBJECTIVES: To determine whether inclusion of 2-hydroxyethyl methacrylate (2-HEMA) 2% in petrolatum (pet.) in the baseline series detects cases of treatable (meth)acrylate ACD. METHODS: During 2016-2017, 15 U.K. dermatology centres included 2-HEMA in the extended baseline patch test series. Patients with a history of (meth)acrylate exposure, or who tested positive to 2-HEMA, were selectively tested with a short series of eight (meth)acrylate allergens. RESULTS: In total 5920 patients were consecutively patch tested with the baseline series, of whom 669 were also tested with the (meth)acrylate series. Overall, 102 of 5920 (1·7%) tested positive to 2-HEMA and 140 (2·4%) to at least one (meth)acrylate. Had 2-HEMA been excluded from the baseline series, (meth)acrylate allergy would have been missed in 36 of 5920 (0·6% of all patients). The top (meth)acrylates eliciting a positive reaction were 2-HEMA (n = 102, 1·7%), 2-hydroxypropyl methacrylate (n = 61, 1·0%) and 2-hydroxyethyl acrylate (n = 57, 1·0%). CONCLUSIONS: We recommend that 2-HEMA 2% pet. be added to the British baseline patch test series. We also suggest a standardized short (meth)acrylate series, which is likely to detect most cases of (meth)acrylate allergy.

Mohs micrographic surgery for periocular skin tumours in Ireland.

OBJECTIVE: To describe the shared care and outcomes of patients with periocular skin tumours who underwent Mohs micrographic surgery (MMS) performed by dermatologists, followed by oculoplastic reconstruction undertaken by ophthalmologists at two teaching and one private hospital in Ireland. RESEARCH DESIGN AND METHODS: This was a retrospective chart review at the Royal Victoria Eye and Ear Hospital, St James Hospital and the Hermitage Clinic. RESULTS: One hundred and twenty seven patients had periocular Mohs surgery between November 2006 and January 2013 mainly indicated for basal cell carcinoma. The mean follow-up time was 2 years and to date there have been no local recurrences. CONCLUSIONS: MMS is available in Ireland and should be considered for patients with facial tumours in the ocular region.

Short-term blood pressure variability over 24 h and target organ damage in middle-aged men and women.

Blood pressure variability (BPV) has been associated with cardiovascular events; however, the prognostic significance of short-term BPV remains uncertain. As uncertainty also remains as to which measure of variability most accurately describes short-term BPV, this study explores different indices and investigates their relationship with subclinical target organ damage (TOD). We used data from the Mitchelstown Study, a cross-sectional study of Irish adults aged 47-73 years (n=2047). A subsample (1207) underwent 24-h ambulatory BP monitoring (ABPM). As measures of short-term BPV, we estimated the s.d., weighted s.d. (wSD), coefficient of variation (CV) and average real variability (ARV). TOD was documented by microalbuminuria and electrocardiogram (ECG) left ventricular hypertrophy (LVH). There was no association found between any measure of BPV and LVH in both unadjusted and fully adjusted logistic regression models. Similar analysis found that ARV (24 h, day and night), s.d. (day and night) and wSD were all univariately associated with microalbuminuria and remained associated after adjustment for age, gender, smoking, body mass index (BMI), diabetes and antihypertensive treatment. However, when the models were further adjusted for the mean BP the association did not persist for all indices. Our findings illustrate choosing the appropriate summary measure, which accurately captures that short-term BPV is difficult. Despite discrepancies in values between the different measures, there was no association between any indexes of variability with TOD measures after adjustment for the mean BP.

Inflammatory bowel disease and thromboembolism. Is inflammation at the centre of the clot?

Thromboembolic events are well recognised in patients with inflammatory bowel disease (IBD). We present three cases which highlight the need for vigilance with respect to this complication. We also propose that consideration be given to re-evaluating disease activity in those patients who develop thromboembolic complications.

Volumetric self-sampling of cervicovaginal fluid to determine potential fertility: a multicentre pre-effectiveness study of the Rovumeter.

The aim of this study was to assess how effectively the Rovumeter, designed for the volumetric self-sampling of cervicovaginal fluid (CVF), can be used to locate the minimum period of potential fertility (PPF) during ovulatory cycles. A multicentre, prospective study was undertaken of volunteers (attending natural family planning clinics) over three consecutive, apparently normal, menstrual cycles. All women collected daily samples of early morning urine and CVF and recorded the volumes (to the nearest 1.0 and 0.1 ml respectively). The concentrations of oestrone glucuronide (EG), luteinizing hormone (LH) and pregnanediol glucuronide (PG) were measured in all samples of early morning urine by immunoassay. A preliminary data set was used to optimize an algorithm to detect the start and end of potential fertility from the volumes of CVF. The end-points used were the normality of each menstrual cycle from its length, the length of luteal phase, and concentrations of EG, LH and PG, the start and end days of potential fertility from CVF volumes, and the minimum PPF, which was defined as the day of the LH peak minus 3 to day plus 2 inclusive. Overall, 72 women (median age 30 years, range 24-38) were recruited from three centres (23 from Birmingham, 24 from Milan, 25 from Santiago) and contributed data from 235 menstrual cycles (median length 28 days, range 23-44). The urinary LH peak was identified in 228 cycles (97%; median time, day 15 from day 1 of last menses, with range day 10 to day 35). The use of the Rovumeter gave start and end signals of potential fertility during 138 cycles (59%). The median length of the derived PPF was 8 days (range 4-18). The signals covered the defined, minimum PPF in 113 cycles [i.e. 50% of those with an LH peak; range 28% (Milan) to 62% (Birmingham)]. Overall 16/72 women (22%) had successful tests over three consecutive menstrual cycles [range 2/24 (8%; Milan) to 8/23 (35%; Birmingham)]. We conclude that signals from daily changes in the volume of CVF as determined by the use of the Rovumeter consistently locate the minimum period of potential fertility in only a small proportion of women.

Fertility of fully breast-feeding women in the early postpartum period.

OBJECTIVE: To examine bleeding between 6 and 8 weeks postpartum in fully breast-feeding women and its association with fertility as assessed by hormone analysis. METHODS: Seventy-two fully breast-feeding women were followed prospectively from 42 days postpartum. Vaginal bleeding was recorded daily. Women who experienced bleeding were compared with women who did not with respect to time of ovulation and time of first menses. RESULTS: Nearly half of the women experienced some vaginal bleeding or spotting between 6 and 8 weeks postpartum. These women eventually menstruated and ovulated earlier than the women who did not bleed, but the differences were not significant. The study had 34% and 45% power to detect a 20% difference in the proportion menstruating and ovulating, respectively, at 6 months postpartum, and 10% and 16% power to detect the same differences at 1 year. Seven women experienced ovarian follicular development before day 56, but neither bleeding nor follicular development was associated with ovulation in any woman in the first 8 weeks postpartum. CONCLUSIONS: It is unlikely that vaginal bleeding in fully breast-feeding women in the first 8 weeks postpartum represents a return to fertility.

Breastfeeding and the symptothermal method.

This prospective study was conducted among experienced users of periodic abstinence methods in Sydney, Montreal, and Birmingham (England) in order to describe the relationship between a laboratory measurement of ovulation and the natural symptoms of fertility during breastfeeding. Daily urinary estrogen and pregnanediol glucuronide assays were used to estimate the date of ovulation and to determine potentially fertile days. A standard set of Symptothermal Method (STM) rules was applied to daily STM records to assess the correspondence of the natural symptoms of fertility to the underlying hormonal profile. The STM symptoms and rules accurately identified 77-94 percent of the women's potentially fertile days, but abstinence was also recommended on about half of the days when the women were not fertile. An integrated set of common rules for STM use during breastfeeding is highly sensitive but not specific in its ability to screen for ovulation.

PIP: Periodic abstinence from sexual intercourse as a pregnancy prevention technique is sometimes the sole method used by women. The effectiveness of this technique is based on the woman's ability to fully understand her own menstrual cycle. Factors like breastfeeding and endocrine irregularities have been shown to interfere with a women's ability to determine periods of fertility. This article reports on a prospective study on the relationship between breastfeeding and hormonal levels, as a measurement of fertility, in women using periodic abstinence. The 73 women in this study were from England, Canada, and Australia. All women were breastfeeding. Daily symptothermal method (STM) records, which documented the cervical mucus conditions and basal body temperature, were kept. All women had experienced healthy pregnancies. Chi-square analysis and the analysis of variance (ANOVA) were the statistical methods employed. Significantly less abstinence is recommended by the STM rules during the anteovulation stage than during either of the later stages. Significantly less abstinence is also recommended during amenorrhea than after the first menstrual period. During the anteovulation stage, significantly fewer days were reported with fertile-type mucus than later stages. First ovulations were reported in 48 women (65%) during amenorrhea; of these, 25 (52%) were characterized as having adequate luteinization for conception. The STM method used in this study was considered to be sensitive but lacked specificity.

Symptothermal and hormonal markers of potential fertility in climacteric women.

One hundred seventy-seven menstrual cycles in 36 women between 45 and 53 years of age were studied prospectively. All the women were experienced in the symptothermal method of natural family planning. The objective was to determine the symptothermal and hormonal indices of potential fertility by measuring urinary estrone glucuronide and pregnanediol glucuronide. Thirty-three percent had regular cycles consistent with potential fertility, 19% had cycles consistent with infertility, and 47% had a mixture of both types of cycle.

PIP: The purpose of this study of 36 climateric women with 177 cycles and symtothermal markers of potential fertility are fivefold: 1) to determine the variation in menstrual cycle length during climateric, 2) to determine daily changes in urinary hormone secretion, 3) to define criteria for potential fertility, 4) to examine the relationship between the times of clinical and hormonal changes in ovarian events, and 5) to obtain the best indicators of potential fertility during climateric. Study participants were 45-54 years old and experienced symptothermal users of natural family planning (NFP). Self reporting of vaginal bleeding, basal body temperature, cervical and cervicovaginal mucus characteristics, and climateric symptoms (hot flashes, night sweats, breast tenderness, and dyspareunia) within the past 24 hours was provided. Early morning urine samples (daily) were analyzed for estrone glucuronide (EG) and pregnanediol glucuronide (PG) by time resolved theorescence immunoassay. Each menstrual cycle was retrospectively classified as potentially fertile or infertile from the changes in daily concentrations of EG and PG. The changes were determined to be with the presence of a rise, the presence of a peak, whether it was within specified limits, the class, the number, and the %. 61% of the cycles were potentially fertile based on normal criteria for PG and EG. 33% of the women were potentially fertile, while 47% were a mixture of fertile and infertile since ovulation need not necessarily accompany normal hormonal changes. It appears that there is a gradual transition over time of changes from fertile to infertile. The cycle length and clinical indicators are useful in predicting the start and finish of a defined period of fertility as used by younger women, but further research is being conducted to develop better differentiating markers, such as the dipstick for urinary metabolites.

Ultrasonographic patterns of ovarian activity during breastfeeding.

In this study, ultrasonography was used to detect follicular activity in lactating women, and these findings were related to the underlying hormonal profiles and to the mucus symptom. A number of different patterns of follicular development were seen before the women returned to normal fertile cycles during the period that was previously considered to be characterized by ovarian quiescence. Some of the transitory patterns of follicular activity were reflected in rising hormone levels and patterns of fertile mucus that were sometimes confusing for these lactating women who were using natural family planning.

PIP: The varieties of follicular development patterns seen on sonograms in lactating women before return to ovulatory cycles are described. 18 lactating women recorded mucus symptoms, basal body temperatures, breast and other feeds, and took timed urine samples for assay of estrogen, pregnanediol, and were scanned weekly. When follicular development or clinical symptoms suggested incipient ovulation, more frequent ultrasonography was done. There were several patterns of follicular development: multiple follicles, unruptured follicles, recurrent persistent follicles, and delayed ovulation. In many women early on, 3-20 small follicles developed in 1 of both ovaries, averaging 8 mm in diameter, with no release of estrogen or progesterone. 3 kinds of unruptured follicles were seen: luteinized unruptured follicles, atretic follicles and persistent follicles. Both luteinized and persistent unruptured follicles were accompanied by hormone release, and sometimes by long periods of wet cervical mucus. One women who breastfed intensively for 57 weeks had recurrent persistent follicles without any hormone or mucus symptoms. A scenario of apparently normal follicular development with an estrogen peak, but with ovulation delayed 2-3 days was also seen. Thus the previously held view that the ovary is quiescent during lactational amenorrhea is invalid. Use of the symptothermal method of natural family planning would be problematical urine prolonged lactation, given these findings.

The temporal relationship between vaginal fluid volumes obtained with the Rovumeter vaginal aspirator and the fertile phase of the cycle.

Recent trends in family planning demonstrate an increasing interest in natural methods of birth regulation. In their present form, however, these methods are highly subjective and individualistic. A further trend in fertility programmes has been a very rapid development of technological methods to detect fertility in the female cycle, some of which could possibly benefit natural family planning users. One such technique--that of changing volumes of cervico-vaginal fluid (CVF), which is a mixture of cervical mucus and vaginal transudate--has been tested in a pilot study to ascertain its reliability to demarcate the fertile phase of the cycle. Results show that in all cycles tested, it is possible using the Rovumeter aspirator to detect the beginning of the fertile phase by rapidly increasing volumes of CVF; this volume reaches a peak approximately 1 day before ovulation detected by ultrasound and demonstrates an abrupt fall after ovulation and the onset of the infertile phase. From the results of this pilot study, we believe that, by the use of suitable algorithms and larger studies, it should be possible to develop a CVF volume method which could be offered as an objective alternative method for users of natural family planning and programmes.

PIP: Natural family planning methods rely on clinical indicators to determine the onset of ovulation and the fertile period. Cervico-vaginal fluid volumes are known to change in different cycle phases. In 1985 a graduated vaginal aspirator, the Rovumeter, was developed, which enabled women to collect their own cervico-vaginal fluid. To test the feasibility of daily measurement of cervico-vaginal fluid volume as a method of natural family planning, 6 fertile women recorded for 13 cycles their daily cervico-vaginal fluid volumes. They also recorded, for comparison, urinary luteinizing hormone levels measured with a dipstick, cervical mucus changes, basal body temperatures, and changes in the uterine cervix. Follicular diameter measurements were tracked ultrasonically. Volumetric changes in the cervico-vaginal fluid corresponding to the fertile and infertile phases were detected in all 13 cycles, and they displayed a more precise relationship with the start of the fertile period than either mucus or cervix changes. The signal for the start of the fertile period is the 1st day of appreciable rise of the cervico-vaginal fluid, and the day of fall is the 1st of 2 consecutive days on which the cervico-vaginal fluid is equal or less than the threshold. The method is inexpensive and accurate and should offer a new objective approach to natural family planning.

Detection of the fertile phase from changes in cervico-vaginal fluid volume.

Characteristic changes in cervico-vaginal fluid (CVF) volume which occur during the menstrual cycle might be used to detect the fertile phase. Twenty-five normal women were asked to withdraw CVF and measure its volume at home using a small, disposable, graduated vaginal aspirator. In 16 cycles day 0 (ovulation) was defined as the day of maximum follicular diameter according to serial ultrasound examination. A rise in CVF volume occurred between day -9 and -2 and a peak between day -4 and 0. In these sixteen, and in a further 72 cycles, day 0 (time of maximum fertility) was taken as the day of peak cervical mucus secretion. CVF volume rose, on the average, on day -6.2 (range -17 to -2) and peaked on day -0.8 (range -5 to +2). In two cycles, no rise and peak were identified. Changes in CVF volume were easy to recognise and could be useful to couples wishing to achieve pregnancy.

Structural requirements for the neutralization of heparin-like saccharides by complement S protein/vitronectin.

S protein, a major inhibitor of the assembly of the membrane attack complex of complement, has recently been shown to be identical to the serum spreading factor vitronectin. It also neutralizes the anticoagulant activities of heparin. We have studied the structural requirements for the heparin neutralizing properties of S protein/vitronectin using heparin, heparan sulfate, and heparin oligosaccharides with well defined anticoagulant specificities. The abilities of heparin fractions, Mr 7,800-18,800, with high affinity for antithrombin, and of the International Heparin Standard, to accelerate the inactivation of thrombin and Factor Xa by antithrombin were readily neutralized by S protein/vitronectin. Binding and neutralization of heparin by S protein/vitronectin was inhibited by heparin with low affinity for antithrombin, indicating that S protein/vitronectin can interact with a region on the heparin chain that might serve as a proteinase binding site. S protein/vitronectin efficiently neutralized oligosaccharides of Mr 2,400-7,200, unlike the two other physiologically occurring heparin neutralizing proteins histidine-rich glycoprotein and platelet factor 4. Furthermore, S protein/vitronectin neutralized the anti-Factor Xa activity of a synthetic pentasaccharide comprising the antithrombin-binding sequence of heparin. High molar excess of a synthetic tridecapeptide corresponding to part (amino acids 374-359) of the proposed glycosaminoglycan binding domain of S protein/vitronectin neutralized high affinity heparin and some oligosaccharides, but failed to neutralize the synthetic antithrombin-binding pentasaccharide. Like platelet factor 4, but unlike histidine-rich glycoprotein, S protein/vitronectin readily neutralized the anticoagulant activities of heparan sulfate of Mr approximately 20,000. These findings suggest that S protein/vitronectin may interact through its glycosaminoglycan binding domain(s) with various functional domains of the heparin (heparan sulfate) molecule, including the antithrombin-binding pentasaccharide sequence. Furthermore, the results suggest that S protein/vitronectin may be a physiologically important modulator of the anticoagulant activity of heparin-like material on or near the vascular endothelium.

Neutralization of heparin-related saccharides by histidine-rich glycoprotein and platelet factor 4.

Heparin and heparin oligosaccharides prepared by nitrous acid depolymerization were fractionated by affinity chromatography on immobilized antithrombin and by gel chromatography. The anticoagulant activities of high affinity heparin of Mr greater than or equal to 7,800 could be readily neutralized by the plasma protein histidine-rich glycoprotein (see also Lijnen, H.R., Hoylaerts, M., and Collen, D. (1983) J. Biol. Chem. 258, 3803-3808), whereas oligosaccharides falling below 18 saccharide units (Mr 5,400) became increasingly resistant to neutralization. An octasaccharide with characteristic marked ability to accelerate the inactivation of Factor Xa by antithrombin retained greater than 50% of its activity even at a histidine-rich glycoprotein/oligosaccharide molar ratio of 500:1. Histidine-rich glycoprotein, like the platelet-derived heparin neutralizing protein platelet factor 4 (Lane, D.A., Denton, J., Flynn, A.M., Thunberg, L. and Lindahl, U. (1984) Biochem J. 218, 725-732), therefore requires interaction with saccharide sequences in addition to the antithrombin-binding pentasaccharide of heparin in order to efficiently express its antiheparin activity. Heparan sulfate isolated from pig intestinal mucosa (HS I, Mr approximately 20,000) and from human aorta (HS II, Mr approximately 40,000) exhibited anti-Factor Xa activities of 180 and 20 units/micromol [corrected], respectively. A fraction corresponding to about 5% of HS I bound with high affinity to immobilized antithrombin and contained all of the anticoagulant activity of the starting material. While these heparan sulfates were readily neutralized by platelet factor 4, they were relatively resistant to neutralization by histidine-rich glycoprotein, although complete neutralization could be attained in the presence of molar excess of this protein. These findings may be of importance in relation (a) to the functional role of endogenous anticoagulant polysaccharides at the vascular wall and (b) to clinical situations in which heparin or heparin-related compounds are administered as exogenous anticoagulants.

Natural methods of family planning.

Reliable indicators to detect the fertile and infertile phases in the menstrual cycle are now available, largely due to the intensive scientific research into fertility over the past decade. This means that couples who follow the rules of the different NFP methodologies have a highly effective means of birth control, without the introduction of hormones, chemicals or devices into the body. New scientific techniques can be expected within the next couple of years which will simplify the detection of the fertile phase and hopefully help to elucidate the grey area of the early fertile days, where most of the unplanned pregnancies occur. Fertility awareness by both partners is an important positive contribution to the whole sexual relationship and emphasizes that NFP is an educational delivery system rather than a technological one. The modification of sexual behaviour and the motivation of both partners for the successful use of NFP may initially present a problem to some couples. On the other hand, many partners find the discipline enhances their sexual relationship and dialogue. Whatever the motivation, today more and more couples are happier to be in autonomous control of their bodies and their fertility.

PIP: Recent scientific discoveries about the mechanisms of reproduction as well as growing concern about the adverse effects of modern contraceptive techniques have contributed to increased interest in natural family planning methods. Natural family planning encompasses both fertility awareness and the application of this knowledge to fertility control. Fertility detection can be achieved through biochemical methods, biophysical methods, or clinical indicators. In addition, there are several multiple index methods. Prospective studies aimed at assessing the efficacy of natural family planning have reached 3 general conclusions: 1) method-related failure rates are substantially lower than use failure rates; 2) the chances of an unplanned pregnancy are greatly reduced when intercourse is limited to the postovulatory infertile phase; and 3) all variations of the sympto-thermal method appear to have a significantly lower failure rate than the cervical mucus method. These studies further point to the importance of good quality teaching to the efficiency of natural methods. Postpartum women who select natural family planning should be alert to changes in the cervix rather than mucus to predict the return of ovulation. An inexpensive chemical kit to test urine to detect the changing concentration of estrogen and progesterone at the beginning of the fertile phase would make natural family planning more widely acceptable. New scientific techniques of this type are under development and can be expected within the next couple of years.

An automatic electronic device (Rite Time) to detect the onset of the infertile period by basal body temperature measurements.

Two trials of an electronic thermometer (Rite Time), designed to record and interpret basal body temperature (BBT) patterns in normal ovulating women, are described. A total of 140 menstrual cycles from 34 women, who used the thermal or symptothermal methods of natural family planning, were studied. Rite Time gave a signal for the start of the infertile period in 117 cycles, of which 114 (97%) appeared to have occurred at appropriate times. Further studies using hormonal and ultrasound reference points for ovulation were carried out in 21 cycles. Rite Time generally produced BBT patterns of quality acceptable for interpretation of the periovulatory BBT shift. About one-half of the volunteers said that they would be willing to replace their conventional charting methods with Rite Time.