Severe epidermolysis bullosa/Kindler syndrome-like phenotype of an autoinflammatory syndrome in a child.

A 5-year-old boy presented with generalized cutaneous erosions, severe scarring, depigmentation and contractures affecting major joints. The lesions had initially affected his ears, nose, feet, and the genital and ocular mucosa, leading to significant depigmentation, scarring, contractures and mutilation. The whole of the trunk and limbs were involved at the time of presentation, with the exception of some islands of spared skin on the proximal thighs, legs, nipples and external genitalia. Electron microscopy revealed a split in the sublamina densa with the absence of anchoring fibrils, suggestive of dystrophic epidermolysis bullosa (EB). Immunofluorescence antigen mapping demonstrated a broad reticulate pattern of staining with collagen IV, VII, and laminin 332 in the floor of the blister, suggestive of Kindler syndrome. Next-generation sequencing revealed a de novo heterozygous missense mutation (a variant of unknown significance) in exon 22 of the phospholipase-C gamma 2 gene (PLCG2), which resulted in a substitution of serine by asparagine at codon 798 (p.Asp798Ser), a result that was validated using Sanger sequencing. The child was diagnosed with PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. The cutaneous and corneal erosions, inflammation and scarring of this magnitude, and the eventual result of death have not been described previously for the PLAID/APLAID spectrum previously. In conclusion, this was an unusual acquired autoinflammatory severe EB-like disease that may be associated with de novo PLCG2 mutation.

Use of cyproterone acetate/ethinylestradiol in polycystic ovary syndrome: rationale and practical aspects.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common, heterogeneous disorder characterised by hyperandrogenic skin symptoms, irregular menstruation and subfertility, increased risk of endometrial malignancy, and increased risk of preventable diseases associated with metabolic syndrome. Cyproterone acetate (CPA) 2 mg, combined with ethinylestradiol (EE) 35 µg, is indicated for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhea) and/or hirsutism, in women of reproductive age. OBJECTIVES: To review the present knowledge about PCOS and summarize the role of CPA/EE in the care of patients suffering from this condition for the practitioner. METHODS: Experts with clinical interest and experience in treating symptoms of androgen excess performed a non-systematic review to provide updated information regarding the use of CPA/EE in patients with PCOS. RESULTS: Polycystic ovary-related hyperandrogenic skin symptoms are effectively treated by CPA/EE, reducing not only the symptoms but also their negative impact on quality of life and mental health. Proven additional benefits for these patients include the treatment of menstrual irregularities and reduction in endometrial cancer risk. Possible benefits include preservation of fertility. Treatment increases the risk for venous thromboembolic complications. The nature of other metabolic and cardiovascular long-term effects i.e., whether positive or negative, are still to be investigated. CONCLUSIONS: Cyproterone acetate/ethinylestradiol provides effective treatment for PCO-related hyperandrogenic skin symptoms. This efficacy and additional benefits related to menstrual irregularities and endometrial cancer risk, have to be weighed against the risk of venous thromboembolic complications based on an individual benefit/risk evaluation.

Immunofluorescence mapping in inherited epidermolysis bullosa: a study of 86 cases from India.

BACKGROUND: Epidermolysis bullosa (EB) poses diagnostic challenges in infancy. In India, the diagnosis is largely clinical. There were no facilities to perform immunofluorescence mapping (IFM) until recently, and electron microscopy, which requires expertise to interpret, is limited to a few research laboratories. OBJECTIVES: To describe the patterns of IFM staining in the various forms of EB in Indian patients and to correlate these findings with clinical diagnosis. METHODS: We conducted a cross-sectional study of IFM findings in EB. Antibodies against type IV collagen, cytokeratin 14, laminin 332 and type VII collagen were used. Clinical correlation was performed in all cases, and concordance-discordance rates were calculated. RESULTS: Eighty-six patients with a diagnosis of EB were included in the study. There were 29 with EB simplex (EBS), 18 with junctional EB (JEB) and 15 with dystrophic EB (DEB). The remaining 24 cases included rare variants, cases with overlapping clinical features and cases where the type of EB was not known. On IFM diagnosis, there were 32 cases of EBS, 15 JEB, 17 DEB and two Kindler syndrome. Two cases were not EB and 18 were inconclusive. IFM could establish the type in 12 of 15 cases (80%) that had overlapping clinical features. Most of these cases were under 1 year of age. Overall the concordance was 57% and was seen best in cases of EBS. CONCLUSIONS: This is the first large study of IFM of the subtypes of EB in Indian patients. The study provides a framework for better understanding of EB in Indian patients and for better diagnosis and management, particularly in infancy.

Histopathological Diagnosis of Leprosy Type 1 Reaction with Emphasis on Interobserver Variation.

Upgrading typel lepra reaction or reversal reaction (RR) is an acute inflammatory complication of leprosy and a disparity exists between clinicians and pathologists for diagnosing a RR. Inter-observer variations among pathologists also compound this problem as no universally agreed diagnostic criteria exist. 120 biopsies and H&E stained slides were assessed by 3 pathologists. The pathologists were blinded to the clinical diagnosis and to each other's observations. Each pathologist assigned a likelihood of reaction by their histopathological observations as definitely reaction, probable reaction and no reaction. Clinicopathological correlation and interobserver agreement was analyzed statistically. Discordance between clinical and histopathological diagnosis was seen in 30.8% by pathologist 1 (P1), 23.7% by pathologist 2 (P2) and 34.5% bythe pathologist 3 (P3). Dermal edema, intragranuloma edema and epidermal erosion were consistent findings by all observers. Definite reaction was seen in 54.2% of cases by P1, 53.3% by P2 and 34.5% by P3. Kappa statistics for strength of agreement showed good agreement between 3 pathologists with P1 (κ = 0.83), P2 (κ = 0.61), P3 (κ = 0.62). RR are underdiagnosed on histopathological examination but this study shows that dermal edema, edema within the granuloma and partial obliteration of grenz zone by granuloma are reliable clues to diagnose a RR on histopathology.

Are significant numbers of abnormal cells lost on the discarded ThinPrep® broom when used for cervical cytology?

UNLABELLED: Are significant numbers of abnormal cells lost on the discarded ThinPrep® broom when used for cervical cytology? BACKGROUND: In view of a study with SurePath® showing that cells were lost on the broom if it was discarded, we decided to investigate whether cells were lost on the ThinPrep® (TP) broom, which is discarded according to the manufacturer's protocol. AIM: To determine whether significant amounts of cellular material are lost on the discarded TP broom, and whether the loss is operator dependent. METHODS: Three hundred and six women attending the Guy's Hospital Colposcopy Unit gave their consent for TP liquid-based cytology samples to be taken and the broom immersed in a second vial instead of being discarded. The cellularity of the first and second vials was compared by counting cells in 10 ×40 high-power fields (HPFs). The significance of cell loss was ascertained by correlating the likelihood of abnormal cells and transformation zone (TZ) material being present with the degree of cellularity of the two vials. RESULTS: More than 10 cells per HPF were seen in 3.2%, 19.4% and 35.8% of slides from the second vial taken by three experienced colposcopists, which was significantly different between them (P < 0.001); cellularity of the first vial was not significantly different between colposcopists but the one with highest cellularity in the first vial discarded most in the second. Abnormal cells were more likely to be seen in slides with more than 10 cells per HPF (P < 0.001) and with evidence of TZ sampling (P < 0.001), but there was no preferential loss of TZ material in the second vial. Of 126 slides with abnormal cells on the slides from the second vial, 113 (89.7%) were also present on the significantly more cellular first vial (P < 0.001). CONCLUSION: Abnormal cells were potentially lost on the broom, but were usually represented in the first vial. The likelihood of abnormal cells being discarded was operator dependent in this small study, but this did not affect the quality of the initial preparation. The likelihood of abnormal cells being seen on TP slides was dependent on their cellularity, which provided our laboratory with a criterion for the assessment of sample adequacy.

Panniculitis with vasculitis.

Panniculitides encompass a great number of different entities; however, once a vasculitis has been detected histopathologically within the subcutaneous tissue, the differential diagnosis is mainly restricted to polyarteritis (panarteritis) nodosa (PAN), nodular vasculitis (NV), and Bazin's erythema induratum (EI). Patients with PAN may have the disease confined to the skin, but must be followed over a long period because many of them develop late systemic disease. The NV/EI group represents by far the most common type of lobular panniculitis with vasculitis; we prefer keeping the distinction between the two entities by underlining the equation NV positive tuberculin skin test = EI. Other lobular panniculitides with vasculitis are exceedingly rare and set in a systemic background which can be infectious (lepromatous leprosy panniculitides) or autoimmune/dysreactive (neutrophilic lobular panniculitis in rheumatoid arthritis, lobular panniculitis in inflammatory bowel disease).

Invasive cervical cancer audit: why cancers developed in a high-risk population with an organised screening programme.

OBJECTIVES: To investigate why invasive cervical cancers developed in a high-risk urban population with an established screening programme and to place cancers in the context of high-grade cervical intraepithelial neoplasia (CIN) and cervical glandular intraepithelial neoplasia (CGIN) diagnosed during the same period of time. STUDY DESIGN: Observational study of CIN2+ (CGIN, CIN3 and CIN2) and invasive cervical cancer diagnosed at Guy's and St Thomas' NHS Foundation Trust in 1999-01, 2002-04 and 2005-07 and audit of screening histories of women with invasive cancer analysed according to route to diagnosis, histological type and International Federation of Obstetrics and Gynecology (FIGO) stage. RESULTS: There were 133 invasive cancers, 53 CGIN, 1502 CIN3 and 1472 CIN2. Screen-detected cancers in asymptomatic women comprised 48.9% of cancers and were successively more likely to be in younger age groups (P = 0.03); all except one were stage IA or IB1. Screen-detected IA cancers were more likely (P < 0.001) to be in women screened within 0.5-5.0 years (80.5%) than screen-detected fully invasive (58.3%) or symptomatic cancers (35.3%). Seventy-one (53.4%) women had been screened within 0.5-5.0 years; 11 had negative cytology within 0.5-3.5 years and two tests within 10 years. The other 60 had negative tests less frequently or had previous abnormal cytology, colposcopy or treatment. Potentially avoidable factors were often multiple, including false-negative cytology, high-grade cytology reported as low-grade and lapses in attendance either for routine or repeat screening, or for colposcopy or treatment. CONCLUSION: While often potentially avoidable, cancers in previously screened women tended to be early stage, detected by cytology and rare when compared with high-grade CIN.

Non steroidal anti-inflammatory drugs and colorectal cancer: is there a way forward?

Non steroidal anti-inflammatory drugs (NSAIDs) have diverse clinical applications through modulation of oxidative processes and cell signalling. Observations that these agents may inhibit human colorectal carcinogenesis have produced great excitement. However, comparative data relating to their chemopreventative effectiveness or to relevant mechanisms of action remains unclear. This review considers the clinical and epidemiological evidence for colorectal tumour prevention by NSAIDs against current concepts of drug mechanisms. We also propose areas of further research for potential therapeutic advancement.

Acid suppression in peptic ulcer haemorrhage: a 'meta-analysis'.

BACKGROUND: The use of acid-decreasing agents in the management of peptic ulcer haemorrhage continues to be controversial. Most clinical trials examining the efficacy of these drugs contain small numbers of patients, making it difficult to draw conclusions about their efficacy. METHODS: We report a meta-analysis that examined the effect of these drugs in the management of peptic ulcer haemorrhage. Included studies were located using a search of the Medline database between 1980 and 1999. Studies were published in English, randomized and controlled by a placebo group. Mantel-Haenszel and blinded random models were used in conducting the statistical processing of this meta-analysis. RESULTS: Twenty-one randomized placebo-controlled trials were included. The total number of patients was 3566 and the mean study size was 170 (range 20-1005). Seventeen of the papers assessed the efficacy of H2-antagonists, three assessed proton pump inhibitors and one was concerned with antacid therapy. The meta-analysis showed a significant reduction in re-bleeding rates (odds ratio, OR 0.727, 0.618-0.855, P < 0.001) and surgery rates (OR 0.707, 0.582-0.859, P < 0.001) when acid decreasing agents are used for acute peptic ulcer haemorrhage. Mortality rates appear to be unaffected (OR 1.140, 0.818-1.588, P=0. 49). CONCLUSIONS: This meta-analysis demonstrates a significant beneficial effect of acid-decreasing agents in lowering re-bleeding and surgery rates, but demonstrated no effect upon mortality.

The biochemistry of human endometrium after two regimens of postcoital contraception: a dl-norgestrel/ethinylestradiol combination or danazol.

A combination of 0.5 mg levonorgestrel (in 1 mg dl-norgestrel) and 0.1 mg ethinylestradiol was administered to eight volunteers 48 hours after the start of the luteinizing hormone surge. A second dose was given 12 hours later. Endometrial samples were obtained 24 hours after the first dose was given. The steroid receptor concentration was compared with ovulatory spontaneous cycles. The dl-norgestrel/ethinylestradiol combination caused a significant reduction in receptor concentration. Isocitrate dehydrogenase (a progestin-sensitive enzyme) was also altered, suggesting an effect on endometrial metabolism. Danazol was used in a similar fashion, with two doses each of 400 mg. Nine volunteers were studied. A similar pattern of alteration of endometrial biochemistry was demonstrated but did not reach statistical significance. The relevance to the postcoital use of hormones is discussed.

Gastric cancer distal to the cardia--prevention or cure?

Adenocarcinoma of the stomach distal to the cardia remains one of the most common cancers in the world. The interest in the aetiology of this disease has been rekindled because of recent epidemiological and molecular studies linking this cancer to H. pylori and certain dietary factors. The authors provide an updated review of the aetiology of gastric cancer. This review seeks to summarize the disease, to propose pathways of carcinogenesis and to suggest ways in which the "traditional" risk factors may be interpreted on the basis of evolving knowledge.

An update in the palliative management of malignant dysphagia.

BACKGROUND: Oesophageal cancer is generally associated with late presentation and poor prognosis. Therefore palliative surgery has been largely superseded by less invasive non-surgical techniques. Once palliation is indicated, the aims of the management should be: the maintenance of oral intake, minimizing hospital stay, relief of pain, elimination of reflux and regurgitation and the prevention of aspiration. METHODS: This study was a review of all published English language data on the palliation of malignant dysphagia between 1994-1999. The Medline and Bids databases were searched and other references were derived from the material perused. RESULTS AND CONCLUSIONS: Palliative treatment for oesophageal cancer should be individualized and relate to tumour stage, size and location, the patient's medical condition and his/her personal wishes. The palliative treatment largely includes self-expanding metal stents (SEMS), laser (including photodynamic therapy (PDT)) or a combination of the two to relieve symptoms, this may be employed with or without other treatments such as radiotherapy/chemotherapy (RT/CT) with the aim of reducing tumour bulk and possibly prolonging survival. A multi-disciplinary approach is vital in patients with advanced oesophageal cancer.

The outcome of urgent surgery for major peptic ulcer haemorrhage following failed endoscopic therapy.

OBJECTIVE: To review the outcome of patients who underwent emergency surgery for major peptic ulcer haemorrhage after failed endoscopic therapy. To address whether 'conservative' or 'aggressive' surgery is best. DESIGN: A retrospective analysis of emergency surgery for ulcer bleeding which could not be controlled by endoscopic therapy. SETTING: The four admitting units in the Lothian region of Scotland. PARTICIPANTS: Sixty-seven patients who failed endoscopic therapy for bleeding peptic ulcer and underwent emergency surgery between December 1990 and December 1995. Simple underrunning or excision of ulcer alone was done in 31 patients whilst 36 had more radical surgery. MAIN OUTCOME MEASURES: Rebleeding and 30-day mortality rates. RESULTS: Rebleeding was significantly higher in patients treated by underrunning (7 versus 1, P < 0.013). There were fewer deaths in the radically treated group (5 versus 7, not significant). CONCLUSION: Patients undergoing surgical operation for severe peptic ulcer haemorrhage after failed endoscopic therapy may be best served by a relatively aggressive approach.

A possible mechanism of action of danazol and an ethinylestradiol/norgestrel combination used as postcoital contraceptive agents.

Twenty-seven women requesting postcoital contraception were randomly allocated to take an ethinylestradiol/dl-norgestrel combination or danazol. Urine specimens were assayed for luteinising hormone (LH) and pregnanediol-3-glucuronide (P3G) levels from the day of the postcoital treatment to the next period. In addition, the urine samples of these recruits and 12 additional women were assayed for the Beta-subunit of human chorionic gonadotropin (B-hCG). A consistent pattern of alteration in urinary steroids was lacking, indicating a heterogeneous effect on ovarian function. There was no evidence of early pregnancy in successfully treated cases. We suggest that the main mechanism of action of these drugs is at the endometrial level.

New thinking in contraception.

PIP: Contraceptive research and development is currently addressing the preservation of female fertility through birth control, the promotion of birth control as an essential component of a healthy life-style, and prevention of the spread of sexually transmitted diseases. The combined oral contraceptive (OC) remains the most popular birth control method, and the introduction of new progestogens has lowered the incidence of cycle control problems and improved metabolic data. As protection against human immunodeficiency virus (HIV) transmission becomes a central concern among contraceptive users, the condom has increased in popularity. Recent innovations in the field of barrier methods include the female condom and cervical cap; plastic is being tested as a component of male condoms. Advances in IUD technology include Cu-safe 300 (a slim device with an anti-expulsion design), the flexigard (a frameless device associated with reduced pain and bleeding), and levonorgestrel-releasing devices. Among new contraceptive delivery systems are the vaginal ring, Norplant, and monthly combined injectables. Bioself 110, an electronic fertility indicator, refines the practice of natural family planning. For postpartum contraception, researchers are working on a delivery system for natural progesterone, and lactational amenorrhea has gained recognition as an effective method of pregnancy prevention.^ieng

The new contraceptives.

PIP: There are 3 new categories of contraceptives: contraceptive implant systems, new intrauterine contraceptives, and new barrier methods. The implant system Norplant (6 silastic rods each with 38 mg levonorgestrel) provides effective contraception for 5 years. Its 4-year pregnancy rate is 3.9/100 woman-years. Norplant prevents pregnancy by thickening the cervical mucus, suppressing the endometrium, and affecting the hypothalamic-pituitary-ovarian axis. Ovulation suppression also occurs in about 50% of Norplant acceptors during the first years of use. Fertility returns at about the same rate as that of other hormonal methods. Trained health personnel should insert the rods subdermally during the first 5 days of the menstrual cycle, immediately after an induced abortion, or during the 4th week postpartum. The rods must be removed no later than 5 years after insertion. Contraindications to Norplant are undiagnosed abnormal genital tract bleeding, confirmed or suspected pregnancy, steroid-dependent genital malignancy, severe or acute vascular disease, and acute liver disease. Irregular bleeding is the leading reason for discontinuation. Preinsertion counseling and postinsertion support increase the likelihood of continuation. The first-year continuation rate is about 75%. Norplant causes limited metabolic effects. UK centers provide services and training for Norplant. Another implant system is Norplant 2, a 2-capsule implant which protects against pregnancy for 2-3 years. Intrauterine contraception includes modified design or enhanced bioactivity of IUDs. A new IUD is the levonorgestrel-releasing IUD. Its pregnancy rate is the same as the combined pill. Its key side effect is irregular spotting. Condoms are now being made with natural rubber, polyurethane, or thermoplastic elastomer to alleviate the allergic reactions associated with latex. Other new barrier methods are the female condom and the nonlatex silicone rubber cervical cap.^ieng

Key developments in family planning.

PIP: Family planning services should try to continually improve patients' access to family planning information and services, in addition to achieving better success with issues of confidentiality, dignity, and privacy. The range of available contraceptive methods continues to widen, although standards set by the Royal College of Obstetrics and Gynecology Faculty of Family Planning are accepted as the gold standard. With regard to contraceptive choices, the long-acting methods of contraception are attracting renewed interest. In family planning clinics and general practice, nurses are being given the authority to provide systemic contraceptives, especially emergency contraception. Emergency contraception is so safe that many argue that it should be made available without prescription. Updated faculty guidelines on emergency contraception will be published by the end of the year. Progress is being made in the development of male systemic contraception. Persona is a miniature computerized device which accurately predicts a woman's fertile phase; efficacy studies suggest a failure rate of 6%. Combined oral contraceptives, IUDs, and monthly combined injectables are discussed.^ieng