Reliability and validity of the instrument for scoring clinical outcomes of research for epidermolysis bullosa (iscorEB).

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare and currently incurable genetic blistering disorders. As more pathogenic-driven therapies are being developed, there is an important need for EB-specific validated outcomes measures designed for use in clinical trials. OBJECTIVES: To test the reliability and construct validity of an instrument for scoring clinical outcomes of research for EB (iscorEB), a new combined clinician- and patient-reported outcomes tool. METHODS: We conducted an observational study consisting of independent 1-day assessments (six assessors) at two academic hospitals. The assessments consisted of iscorEB clinician (iscorEB-c), Birmingham Epidermolysis Bullosa Severity (BEBS) and global severity assessment for physicians; and iscorEB patient (iscorEB-p), Quality of Life evaluation in Epidermolysis Bullosa and Children's Dermatology Life Quality Index for patients. Construct validity and intraclass correlation coefficients (ICCs) for interobserver, intraobserver and test-retest reliability were calculated. RESULTS: Overall, 31 patients with a mean age of 19·5 years (1·8-45·2) were included. Disease severity was mild in 42% of cases, moderate in 29% and severe in 29%. The interobserver ICC was 0·96 for both the clinician-reported section of iscorEB-c and BEBS. The ICC for intraobserver reliability was 0·91 and 0·70 for the skin and mucosal domains of iscorEB-c, respectively. Cronbach's alpha for iscorEB-c was 0·89. The test-retest reliability of iscorEB-p was 0·97 and Cronbach's alpha was 0·84. The clinical score differentiated between subjects with mild, moderate and severe disease, and both clinical and patient subscores discriminated between recessive dystrophic EB and other EB subtypes. CONCLUSIONS: iscorEB has robust reliability and construct validity, including strong ability to distinguish EB types and severities. Further studies are planned to test its responsiveness to change.

Management of cutaneous squamous cell carcinoma in patients with epidermolysis bullosa: best clinical practice guidelines.

This article summarizes recommendations reached following a systematic literature review and expert consensus on the diagnosis and management of cutaneous squamous cell carcinomas in people with epidermolysis bullosa. The guidelines are intended to help inform decision making by clinicians dealing with this complex complication of a devastating disease.

Simple and Efficient Trap for Bark and Ambrosia Beetles (Coleoptera: Curculionidae) to Facilitate Invasive Species Monitoring and Citizen Involvement.

Bark and ambrosia beetles (Coleoptera: Curculionidae: Scolytinae & Platypodinae) are among the most damaging forest pests worldwide, and monitoring is essential to damage prevention. Unfortunately, traps and attractants that are currently used are costly, and agencies rely on limited field personnel for deployment. The situation can be greatly aided by 1) the development of cost-effective trapping techniques, and 2) distribution of the effort through the Citizen Science approach. The goal of this study was to test a simple, effective trap that can be made and deployed by anyone interested in collecting bark and ambrosia beetles. Three trap types made from 2-liter soda bottles and, separately, four attractants were compared. Simple, one-window traps performed comparably at capturing species in traps painted or with multiple windows. A comparison of attractants in two-window traps found that 95% ethanol attracted the highest number of species but that Purell hand sanitizer (70% ethanol) and then Germ-X hand sanitizer (63% ethanol) were also effective. A perforated zip-top plastic bag containing Purell hanging over a trap filled with automobile antifreeze attracted the fewest species and individual specimens. Overall, >4,500 bark and ambrosia beetles, including 30 species were captured, representing a third of the regional species diversity. More than three quarters of the specimens were nonnative, representing nearly half of the known regional exotic species. These results suggest that simple one-window soda bottle traps baited with ethanol-based hand sanitizer will be effective and inexpensive tools for large-scale monitoring of bark and ambrosia beetles.

Relationship of angiotensin converting enzyme gene polymorphism and hypertension in Yogyakarta, Indonesia.

AIM: To evaluate the association between ACE gene polymorphism I/D and hypertension in Yogyakarta population. METHODS: This study is a cross-sectional. Sample was taken by random sampling method from hypertensive, prehypertensve and normotensive subjects; from that were obtained 125 subjects, 97 subjects and 108 subjects, consecutively. ACE gene polymorphism I/D was examined by PCR. Genotype was classified as II, ID, or DD based on positive or negative insertion/delation allele. RESULTS: This study shows significant differences of three groups (ages, body mass index (BMI), and family history of hypertension) and total cholesterol level in blood, which tends to have greater value in the hypertension group. Frequency of genotype II, ID, DD are 85 (68%), 39 (31.2%), 1 (0.8%) in hypertension, 66 (61.1%), 38 (35.2%), 4 (3.7%) in normo-tension and 56 (57.7%), 37 (38.1%), 4 (4.1%) in pre-hypertension subject, consecutively. Chi-square analysis shows statistically significant association between ID+DD vs. II genotype and hypertension. Multiple logistic regression analysis shows four variables that significantly influence to hypertension, namely ages, family history of hypertension, BMI, and ACE gene polymorphism. CONCLUSION: ACE ID+DD genotype has significant relationship with hypertension in Melati population, Sleman, Yogyakarta, Indonesia.

The effects of soursop supplementation on blood pressure, serum uric acid, and kidney function in a prehypertensive population in accordance with the 2017 ACC/AHA guideline.

Soursop consumption is beneficial to health, but there have been few clinical studies observing its benefit in human subjects. We investigated the effects of soursop supplementation on blood pressure (BP), serum uric acid (SUA), and kidney function. A total of 143 subjects were included in this randomized controlled trial. Subjects were selected from a prehypertension population dataset (n = 4190) in the "Mlati Study Database" in 2007 (using the Joint National Committee (JNC) 7 guideline). After 10 years, 143 samples showed essential prehypertension combined with high-normal SUA levels. Subjects were randomly allocated into two groups, i.e., the treatment and control group. For a 3-month period, the treatment group was given 2 × 100 g soursop fruit juice per day and the control group was not treated. Using the JNC 7 guideline, the treatment group showed a significantly lower mean systolic BP after being adjusted by three times of examinations (baseline, week 6 and 12) compared with the control group. Furthermore, the control group was more likely to have prehypertension, hypertension, and high-normal and high SUA levels after 6 weeks, as well as after 12 weeks, compared with the treatment group. An additional analysis using the 2017 ACC/AHA guideline for subjects with stage 1 hypertension showed results similar to that using the JNC 7 guideline. Moreover, it indicated that mean of both systolic and diastolic BP of the treatment group was significantly lower compared with the control group after 12 weeks of treatment. We conclude that soursop supplementation can lower BP and SUA levels.

Epitestosterone: a potential new antiandrogen.

Epitestosterone (EpiT) is the 17 alpha-hydroxy epimer of testosterone (T) and a natural steroid metabolite. It has previously been shown to be a 5 alpha-reductase inhibitor. We have studied EpiT as an antiandrogen using the hamster flank organ model. One-centimeter silastic capsules of crystalline T or dihydrotestosterone (DHT) were implanted subcutaneously in female Golden Syrian hamsters to provide continuous androgenic stimulation. After 3 weeks, the pigmented spot was measured and the flank organs were fixed for histologic sectioning. The maximum surface area (SA) from a central section of the sebaceous gland and the diameter of hair follicles were measured using a computerized digitizing tablet. Following T and DHT, respectively, there was a significant increase in pigmented spot size (656/382%), sebaceous gland SA (210/315%), and mean hair follicle diameter (80/56%). A 1-cm capsule of EpiT alone had no androgenic effect. Five- and ten-fold doses of EpiT were implanted with T or DHT. Epitestosterone significantly inhibited the T-dependent stimulation of pigment, sebaceous gland, and hair follicle at either 5- and/or 10-fold excess doses. Additionally, a 10-fold dose of EpiT also inhibited DHT-dependent stimulation of all 3 cutaneous structures. We conclude that EpiT was effective as an antiandrogen and had no intrinsic androgenic activity in the hamster flank organ. It probably functions both as a competitive inhibitor of the androgen receptor and as a 5 alpha-reductase inhibitor. Pigment and sebaceous gland growth were more sensitive than the hair follicle to androgen inhibition by EpiT at the time and doses tested.

Autoradiographic localization of tritiated dihydrotestosterone in the flank organ of the albino hamster.

In the hamster flank organ, the growth of hair and growth of sebaceous glands are androgen-dependent functions. Although dihydrotestosterone (DHT) is known to be a potent stimulator of flank organ growth, there is no information about localization of DHT receptor sites in this organ. The purpose of this study was to use steroid autoradiography to localize DHT receptors in the hamster flank organ. Because steroid hormones are functional when translocated to nuclear receptors, nuclear localization by autoradiography defines receptor sites. In order to be able to visualize autoradiographic grains from radiolabeled androgens around hair follicles, albino hamsters were studied to avoid confusion between the grains and pigment granules which are abundant in the more common Golden Syrian hamster. Mature male hamsters castrated 24 hours earlier were given tritium-labeled dihydrotestosterone ( [3H]DHT). Using the technique of thaw-mount steroid autoradiography, 4-micron unfixed frozen sections were mounted in the dark onto emulsion-coated glass slides and allowed to develop for 4-6 months. [3H]DHT was found to be concentrated over sebocyte nuclei. The label was present peripherally as well as in differentiating sebocytes. There was no nuclear localization of [3H]DHT in animals pretreated with excessive quantities of unlabeled DHT. Steroid metabolites of [3H] DHT were assessed by thin-layer chromatography in paired tissue samples. Most of the label remained with DHT. Uptake was inhibited in the flank organ of hamsters pretreated with unlabeled DHT. Specific DHT receptors in the albino hamster flank organ are located in peripheral and differentiating sebocytes. Steroid autoradiography is a useful tool to study androgen interaction in the skin.

Hair follicle response of the golden Syrian hamster flank organ to continuous testosterone stimulation using silastic capsules.

The hamster flank organ has served as a model to study androgen-dependent responses of the skin, but the quantitative response of hair follicles to androgenic stimulation has been neglected. We assayed the hair follicle response to testosterone (T) and compared it to the response of the sebaceous glands and of the dermal pigment in the Golden Syrian hamster flank organ. Because of biologic variation in male animals and uneven absorption of hormone from parenteral injections, we implanted silastic capsules 0.25, 0.5, 1, and 2 cm in length filled with crystalline T subcutaneously into female hamsters for 6 weeks. Hair follicle response to T was more sensitive than sebaceous gland or pigment. Diameters of hairs under the sebaceous gland increased significantly from control values of 27.7 +/- 1.0 micron to 38.0 +/- 1.6 micron at the lowest dose of T tested, the 0.25-cm capsule (p less than 0.001). There was an increase in the absolute number of hairs under the sebaceous gland as the flank organ enlarged, from 27.9 +/- 9.9 control to 55.3 +/- 5.8 with the 2-cm T capsule. There was no concomitant increase in hair density, 14.4 +/- 3.5 hairs/mm control vs 12.5 +/- 1.1 hairs/mm with the 2-cm capsule. Hair follicles lateral to the sebaceous gland did not show the same response to androgen stimulation. Sebaceous gland and pigmentation responded in a dose-dependent fashion, the maximum effect being achieved with a 1-cm T capsule. We conclude that T affects hair by specifically stimulating growth of individual hairs physically under the sebaceous gland. As the whole flank organ enlarges more hairs are recruited to become larger but no new follicles appear. These studies also confirm that there are different sensitivities to androgen within the various androgen-dependent components of the hamster flank organ, with increase in hair diameter being highly sensitive. This model should be useful for the specific and quantitative assessment of androgenic and antiandrogenic substances on hair growth and ultimately by useful for therapy of hirsutism.

Plasma androgens in women with acne vulgaris.

We have studied a group of young adult women of mean age 23.8 +/- 6.5 (SD) years with only acne (A, n = 46), only hirsutism (H, n = 10), and acne plus hirsutism (A + H, n = 19) who sought dermatologic care. We measured the androgens, total and free testosterone (T), free 17 beta-hydroxysteroids (17-beta), dehydroepiandrosterone sulfate (DS), and the androgen precursors 17 alpha-hydroxypregnenolone (17-Preg) and 17 alpha-hydroxyprogesterone (17-Prog), as well as testosterone-estrogen binding globulin in all patients. Plasma hormone levels of the patients were compared to those of 23 controls of mean age 25.6 +/- 6.6 years who had neither acne nor hirsutism. Mean levels of all hormones measured, except 17-Preg, were elevated in the women with acne. Fifty-two percent of Group A, 60% of Group H, and 63% of Group A + H patients had at least one abnormal hormone level. The most frequently elevated plasma androgens in all the women with acne were: free T 25%, free 17-beta 23%, and DS 19%. Total T was high in only 12%. Elevations of plasma androgens were present in some women who did not have hirsutism or irregular menses. Identification of endocrine abnormalities in women with acne may potentially offer an opportunity for hormonal therapy.

Progesterone production by cultured preantral rat granulosa cells? Stimulation by androgens.

Progesterone (P) production by isolated rat granulosa cells from preantral follicles was enhanced by addition of androgens to the tissue culture medium. Testosterone (T) at 10(-7), 10(-6), and 10(-4)M as well as 10(-6)M dihydrotestosterone (DHT) increased P production 400 to 700% over paired control cultures. Human chorionic gonadotropin (100 mIU/ml) and 17beta-estradiol (7.8 X 10(-10M) had no effect on P production. P was identified by both a specific radioimmunoassay and sephadex LH-20 column chromatography. The stimulatory influence of T and DHT on these preantral follicular cells is consistent with a direct role for androgens in granulosa cell differentiation.

Dexamethasone preparation does not alter corticoid and androgen responses to adrenocorticotropin.

ACTH tests were performed with and without dexamethasone (dex) pretreatment to clarify the nature of the relationship between the absolute and incremental response (delta) to ACTH in normal men and women, hirsute women, adrenarchal children, and women heterozygous for congenital adrenal hyperplasia (CAH). The purposes were to test the effect of dex preparation on adrenal responsiveness to ACTH and the efficacy of the dex-pretreated ACTH test in detecting heterozygosity for CAH. Cosyntropin was given as a 10 micrograms/m2 iv bolus dose at 0800-1000 h; dex (1 mg/m2) was given at 2200-2400 h the night before. Dex did not alter the absolute plasma steroid levels achieved in response to ACTH. However, since post-dex baseline concentrations of adrenal steroids were lower, the delta to ACTH was significantly greater for the major adrenal secretory products, 17 alpha-hydroxypregnenolone (3 beta, 17 alpha-dihydroxypregn-5-ene-20-one), dehydroepiandrosterone, and cortisol (F). For example, for all paired tests, the mean plasma F values achieved 30 min post-ACTH were 26.0 +/- 4.4 (+/- SD) micrograms/dl without dex and 23.8 +/- 5.5 micrograms/dl after dex. In contrast, the mean delta of plasma F 30 min post-ACTH was less without (13.3 +/- 4.8 micrograms/dl) than after (19.4 +/- 3.3 micrograms/dl) dex (P less than 0.001). Apparent 21-hydroxylase efficiency, computed from dex-prepared tests, was found in follicular phase women to have a markedly skewed distribution without clear demarcation between 15% of the population and CAH heterozygotes. Luteal phase responses differed from follicular phase responses in dex-pretreated women in the magnitude of the 17-hydroxyprogesterone response. In the luteal phase, although the plasma 17-hydroxyprogesterone level at 30 min was higher, a response to ACTH was not consistently found, averaging only 22 +/- 26 ng/dl, in contrast to the consistent 52 +/- 15 ng/dl response in the follicular phase. These findings have practical implications for interpreting rapid ACTH test results. The absolute plasma F level achieved post-ACTH is more important as an index of adrenocortical reserve than the increment. Dex pretreatment appears to offer no practical advantage in ACTH testing for mild defects in 21-hydroxylation; we postulate that this is because of considerable normal variability in the efficiency of 21-hydroxylation.

Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche.

To determine the adrenal contribution to elevated plasma androgens in 31 young hyperandrogenemic women with acne and/or hirsutism, we compared their responses to ACTH with those of 14 normal women. Each subject was given a low dose (10 micrograms/m2) of synthetic ACTH-(1-24) (Cortrosyn) after administration of 1.5 mg dexamethasone the night before the test. Thirty and 60 min responses of plasma 17 alpha-hydroxypregnenolone (17-Preg), 17 alpha-hydroxyprogesterone, (17-prog), dehydroepiandrosterone (DHEA), androstenedione, 11-deoxycortisol, and cortisol were measured. Eighteen (58%) patients had increased responses of at least one 17-ketosteroid or adrenal androgen precursor. All patients had cortisol responses within the range of those of the 14 normal subjects. Nine patients (29%) had evidence of steroid biosynthetic enzyme deficiencies, either mild congenital adrenal hyperplasia or the heterozygote state; after ACTH, 4 of these patients had elevated 17-prog in the range of values in heterozygote carriers of 21-hydroxylase deficiency, 2 had elevated levels of 11-deoxycortisol compatible with 11 beta-hydroxylase deficiency, and 3 had elevated levels of 17-Preg and DHEA, suggestive of 3 beta-hydroxysteroid dehydrogenase deficiency. Another 9 subjects (29%) had 17-ketosteroid (DHEA and/or androstenedione) hyperresponsiveness to ACTH with associated elevated 17-Preg responses. As a group, their patterns suggested relatively deficient 3 beta-hydroxysteroid dehydrogenase and relatively hyperactive C lyase without impairment of cortisol secretion. This pattern resembles exaggerated adrenarche, and we postulate that these 9 patients have hyperplasia of the zona reticularis. Neither basal levels of plasma androgens (free testosterone and DHEA sulfate) nor menstrual history predicted which patients would have abnormal ACTH responses. Although 5 of 11 (45%) patients with acne alone had abnormal responses to ACTH, 10 of 14 patients with acne and hirsutism (71%) had abnormal responses to ACTH. We conclude that an adrenal contribution is found in about half of hyperandrogenemic women with acne and/or hirsutism. This adrenal androgen hyperresponsiveness is heterogeneous. Some patients may have mild forms of congenital adrenal hyperplasia. However, functional androgenic hyperresponsiveness to ACTH, which resembles an exaggeration of adrenarche, is the most common abnormality found. Such findings may provide an explanation for the clinical observation of exacerbations of acne with stress.

Pubertal progression in the presence of elevated serum gonadotropins in girls with multiple endocrine deficiencies.

Pubertal progression in the presence of abnormally elevated serum gonadotropins was followed over several years in two girls with multiple endocrine deficiencies and mucocutaneous candidiasis. Both had hypoparathyroidism and one had adrenal failure as well. A serum level of progesterone (8 ng/ml) consistent with ovulation was documented in the one girl who had regular monthly menses. High serum levels of FSH (30--60 mIU/ml) at times when serum estradiol was in the normal pubertal range (100--200 pg/ml) may indicate partial ovarian end-organ resistance or failure. Since premature menopause is associated with this syndrome, we postulate that we are observing puberty in girls whose ovaries are in the early stages of a destructive process which may eventually result in irreversible ovarian failure. A possible explanation could be the existence of increased resistance to gonadotropins at the ovarian level because of gonadotropin receptor antibodies or an inherent receptor defect.

Hormonal correlates of acne and hirsutism.

Acne is a multifactorial disorder reflecting the role of infection, abnormal keratinization and immunologic reaction, as well as hormonal influences, on the pilosebaceous unit. Clinical studies have correlated elevated levels of androgens, originating in both the adrenal glands and ovaries, with acne. These include total and free testosterone, delta 4-androstenedione, dehydroepiandrosterone and its sulfate, and low levels of sex hormone binding globulin. The pathogenesis of acne initiation in childhood has been linked to rising serum levels of dehydroepiandrosterone sulfate. Hirsutism has been more directly correlated with increased levels of serum androgens, notably free testosterone. Underlying causes of elevated androgens in both disorders include very rare tumors, partial or late-onset forms of congenital adrenal hyperplasia, developmental adrenal abnormalities and, most commonly, polycystic ovary syndrome. Early acne treatment may include topical benzoyl peroxide, antibiotics, and tretinoin. More severe disease can be treated systemically (with antibiotics and/or isotretinoin). Very-low-dose corticosteroids can be used to eliminate the adrenal component of hyperandrogenism. Oral contraceptives, especially those that contain low-androgenic progestins, can reduce excessive androgens from any source and specifically suppress the ovary in polycystic ovary syndrome. Gonadotropin-releasing hormone agonists, with or without estrogen supplementation, and systemic or topical antiandrogens may play a more important role in the future.

Acne, hirsutism, and alopecia in adolescent girls. Clinical expressions of androgen excess.

Hyperandrogenism must be considered in any girl with premature pubarche, unusual acne, hirsutism, or androgenetic alopecia. An association with menstrual irregularity or obesity should raise the index of suspicion. The most common causes of hyperandrogenism presenting in a teenage girl are functional ovarian hyperandrogenism, one manifestation of which is polycystic ovary syndrome, and functional adrenal hyperandrogenism, which usually seems to be due to an exaggeration of adrenarche. The plasma-free testosterone is a more sensitive indicator of hyperandrogenism than is the total testosterone concentration. The pattern of response of plasma free testosterone, DHEAS, and cortisol to dex-suppression testing can be diagnostic of the source of androgen excess. Treatment, including oral contraceptives, low-dose glucocorticoids, and antiandrogens, should be chosen according to the patient's symptoms and source of androgens and should be combined with traditional therapy for the specific dermatologic disorder.

Current status of the identification and management of tinea capitis.

Tinea capitis due to Trichophyton tonsurans has become a significant health problem affecting children and adolescents. This infection has several different distinctive clinical patterns which, if not recognized, may result in delayed diagnosis and therapy. This review is designed to emphasize the differences between tinea capitis caused by T tonsurans and that caused by other organisms. Current diagnostic and therapeutic measures are discussed.

Estradiol and testosterone effects on lipids in black and white boys aged 10 to 15 years.

Previous studies of lipids in adolescent males have shown greater increases in triglycerides and decreases in high-density lipoprotein cholesterol (HDL-C) in white boys compared with black boys, significant correlations between sex hormones and lipids, and complex body mass index (BMI) hormone-lipid associations. Within this frame of reference, we assessed race, BMI, and sex hormones as predictors of lipid parameters in 536 black and white boys recruited from area schools. Black boys were more advanced in puberty than white boys. After adjusting for pubertal stage, estradiol (E2) levels were higher in black boys but free testosterone (T) levels did not differ. Age, pubertal stage, race, BMI, free T, and E2 were entered as explanatory variables for lipids in backward stepwise regression analyses. The BMI and race were retained in every model. Black boys had lower triglycerides and apolipoprotein B (apo B) and higher HDL-C. E2 was inversely associated with total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), apo B, and the LDL-C/HDL-C ratio. Free T was inversely associated with HDL-C and positively associated with apo B. Given the increases in free T and E2 during adolescence and the association of these hormones with both atherogenic and protective lipid parameters, racial differences in E2 could contribute to the more atherogenic lipid profile found in white boys after puberty.

Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) appears to be due to a previously unrecognized type of steroidogenic abnormality, one in which hyperandrogenism arises from a regulatory abnormality (dysregulation) rather than from enzyme deficiency. It appears that PCOS typically arises from masculinized regulation of the androgen-forming enzyme (cytochrome P450c17 alpha) within ovarian thecal cells. This may arise by either excessive stimulation by luteinizing hormone (LH) or by escape from desensitization to LH. We review evidence which is compatible with the concept that the latter situation may result from an intrinsic intraovarian flaw in the paracrine feedback mechanism by which thecal androgen biosynthesis is inhibited and that coexistent adrenal 17-ketosteroid hyper-responsiveness to corticotropin (ACTH) may be due to a similar type of dysregulation of adrenocortical P450c17 alpha.