Management of patients in a combined thyroid eye clinic in secondary care.

The European Group on Graves' Orbitopathy (EUGOGO) recommends the use of specialised multidisciplinary clinics for the management of thyroid eye disease (TED). In the UK, many patients with TED are managed outside of specialised clinics. We describe the organisation of a combined TED clinic in a secondary care setting and present the result of a prospective audit of the patient characteristics and outcomes during the first four years of a combined TED clinic. Of a total of 132 patients referred to the TED clinic, 114 (86 %) had TED (90 females, median age 56 years; range 17-90 years). At presentation, 77 (67 %) were current or ex-smokers and 99 (87 %) were biochemically euthyroid. Median duration of eye symptoms was 12 months. Fifty-two percent, 45 and 3 had mild, moderate-to-severe and sight-threatening TED, respectively. Only 18 % of patients had a clinical activity score (CAS) of ≥3. Sixty-nine patients (61 %) required follow-up appointments in the TED clinic. In those who required follow-up, 43 % (n = 30) received either immunosuppressive or surgical treatment. CAS improved from first to final visit, with 29 % (n = 20) having a CAS of ≥3 at the first visit and 1 % (n = 1) at the final visit (p = 0.0001). There was also a decrease in prevalence of smoking and thyroid dysfunction at the final visit. A multidisciplinary specialised TED clinic offers an optimal setting for managing patients with TED; however, patients are often referred late to a specialist TED clinic.

Refractive outcomes after cataract surgery with primary lens implantation in infants.

AIMS: To show the refractive outcomes, accuracy of intraocular lens power selection, and visual outcomes and complications in infants undergoing cataract surgery. METHODS: The refraction (spherical equivalent) of 14 operated eyes in 8 children aged <1 year was plotted over time. Preoperative and final recorded visual acuities were assessed. RESULTS: The median follow-up was 37.25 months. The median initial postoperative refraction was (+)6.75 dioptres. CONCLUSIONS: Refractive outcomes for each eye were not entirely predictable and were variable between infants. However, there was a consistent pattern in each infant who underwent bilateral surgery, with both eyes following a similar pattern of refractive change with time: a decreasing myopic shift was seen in 8 eyes, possibly demonstrating emmetropisation. The two unilateral cases appeared to show a linear myopic shift. 4 eyes in 2 patients did not follow a myopic shift curve and one of these patients showed an early trend towards increased hyperopia. Definite causes for this erratic refractive change were not identified. A postoperative refraction >4.5 dioptres avoided early onset myopia. The range of difference between postoperative and predicted refraction using SRK-T was (-)2.85 to 2.97 dioptres. Most of the visual results are encouraging compared with historical data in older children.

Modulation of host antimicrobial peptide (beta-defensins 1 and 2) expression during gastritis.

BACKGROUND: beta-Defensins are a newly identified family of antimicrobial peptides that are expressed by epithelia on mucosal surfaces where their production is augmented by infection or inflammation. Helicobacter pylori colonises the gastric epithelium causing persistent gastric inflammation leading to antral and corpus gastritis, and peptic ulcer disease. AIMS: To evaluate the role of beta-defensins in the innate immune response of the gastric epithelium to infection and inflammation, we have assessed mRNA expression and regulation of human beta-defensins 1 and 2 (hBD1, hBD2) by H pylori and proinflammatory stimuli. We have also compared gene and peptide expression of these bactericidal agents in H pylori induced gastritis with that in normal gastric mucosa. METHODS: Modulation of expression of hBD1 and hBD2 by various stimuli was studied in three (AGS, MKN7, MKN45) gastric epithelial cell lines by quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR). Defensin mRNA expression was measured by semiquantitative RT-PCR in gastritis tissue and compared with controls. Peptide localisation was assessed by immunohistochemistry. RESULTS: Cytotoxic H pylori and interleukin 1 beta (IL-1 beta) markedly upregulated expression of hBD2 in a dose and time dependent manner in both AGS and MKN7 cell lines. A modest increase in hBD1 expression was also noted during infection. Interestingly, induction of hBD1 gene expression by IL-1 beta was only observed in MKN7 cells. The magnitude of this response was delayed and reduced compared with hBD2 expression. In gastric biopsies, hBD2 was undetectable in normal gastric antrum but a marked increase was observed in H pylori positive gastritis compared with control tissue (p<0.001). Constitutive expression of hBD1 was observed in normal gastric mucosa and there was a significant increase in gastritis (p<0.05). Immunohistochemistry revealed a parallel increase in hBD1 and hBD2 peptide expression in gastritis tissue with positive staining confined to the surface epithelium of the gastric glands. CONCLUSIONS: Modulation of beta-defensin expression by pathogenic and/or inflammatory stimuli and their cellular localisation places these antimicrobial peptides in the front line of innate host defence in the human stomach.

Human beta defensin-1 and -2 expression in human pilosebaceous units: upregulation in acne vulgaris lesions.

A rich residential microflora is harboured by the distal outer root sheath of the hair follicle and the hair canal - normally without causing skin diseases. Although the basic mechanisms involved in the development of inflammation during acne vulgaris remain unclear, microbial agents might play an important role in this process. In this study we have analyzed by in situ hybridization and immunohistochemistry the expression patterns of two antimicrobial peptides, human beta defensin-1 and human beta defensin-2, in healthy human hair follicles as well as in perilesional and intralesional skin of acne vulgaris lesions such as comedones, papules, and pustules. Strong defensin-1 and defensin-2 immunoreactivity was found in all suprabasal layers of the epidermis, the distal outer root sheath of the hair follicle, and the pilosebaceous duct. Marked defensin-1 and defensin-2 immunoreactivity was also found in the sebaceous gland and in the basal layer of the central outer root sheath including the bulge region. The majority of acne biopsies displayed a marked upregulation of defensin-2 immunoreactivity in the lesional and perilesional epithelium - in particular in pustules - and a less marked upregulation of defensin-1 immunoreactivity. The upregulation of beta-defensin expression in acne vulgaris lesions compared to controls suggests that beta-defensins may be involved in the pathogenesis of acne vulgaris.

Traumatic rupture of the medial rectus muscle.

Traumatic rupture of an extraocular muscle, in the absence of significant injury to the globe and adnexa, is uncommon. We report the case of a patient with an isolated mid-belly rupture of the medial rectus muscle following ocular trauma and describe the technique of repairing the ruptured muscle by suturing the distal segment to the Tenon sleeve of the proximal segment. This was combined with postoperative botulinum toxin injection to the ipsilateral lateral rectus muscle. Good primary position alignment was achieved 7 months after surgery. The patient regained a useful horizontal field of binocular single vision totaling 27 degrees.

Are keloids really "gli-loids"?: High-level expression of gli-1 oncogene in keloids.

BACKGROUND: Keloids are a common lesion arising from sites of previous trauma and are a considerable source of morbidity because of continued growth of lesions, pruritus, and physical appearance. They consist of mesenchymal cells embedded in a stroma of disordered collagen matrix. Clinically, keloids are distinguished from scars in that keloids demonstrate continued growth over the borders of the original injury. Keloids appear with increased frequency in patients of African and Asian descent. Currently, no entirely satisfactory method of treatment exists for these lesions. Recently, a patient who was enrolled in a clinical trial of topical tacrolimus for atopic dermatitis applied this drug to a keloid and noted clearing. OBJECTIVE: Based on this clinical observation and the observation that rapamycin, a chemically similar compound to tacrolimus, is known to inhibit signaling from the gli-1 oncogene, we examined keloids and scars for expression of Gli-1 protein. METHODS: Skin sections from keloids and scars were examined by immunohistochemical staining for gli-1. To further confirm the presence of gli-1 expression in keloids, reverse transcriptase-polymerase chain reaction was carried out. RESULTS: Expression of gli-1 was strongly elevated in keloids compared with scars. CONCLUSION: These results provide a rationale for the treatment of keloids with topical rapamycin analogs, including tacrolimus. Clinical trials of topical tacrolimus are warranted.

Expression of the peptide antibiotics human beta defensin-1 and human beta defensin-2 in normal human skin.

Normal human skin is remarkably resistant to infection from the large numbers of microorganisms that routinely colonize its surface. In addition to the role of skin as a mechanical barrier, it has long been recognized that skin and other epithelia can produce a range of anti-microbial chemicals that play an important part in eliminating potential cutaneous pathogens. Anti-microbial peptides are an important evolutionarily conserved innate host defense mechanism in many organisms. Human beta defensin-1 and -2 are cysteine-rich, cationic, low molecular weight anti-microbial peptides that have recently been shown to be expressed in epithelial tissues. In this study, we describe the characterization of human beta defensin-1 and -2 mRNA and peptide expression in normal human skin. Using reverse transcription-polymerase chain reaction we demonstrate that human beta defensin-1 is consistently expressed in skin samples from various body sites. Human beta defensin-2 demonstrates expression that is more variable and is more readily detectable in facial skin and foreskin compared with skin from abdomen and breast. In situ hybridization localizes the human beta defensin-1 and -2 transcripts to keratinocytes within interfollicular skin. Using specific antibodies, we have shown that human beta defensin-1 and -2 peptides are localized to the Malpighian layer of the epidermis and/or stratum corneum and that there are interindividual and site-specific differences in intensity of immunostaining and the pattern of peptide localization. The localization of human beta defensins to the outer layer of the skin is consistent with the hypothesis that human beta defensins play an essential part in cutaneous innate immunity.

An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients.

Sebaceous carcinomas are rare cutaneous appendageal tumors that may occur sporadically or in association with an internal malignancy in Muir-Torre syndrome. In Muir-Torre syndrome microsatellite instability can often be demonstrated in tumor DNA as a result of an inherited mutation in one of several known mismatch repair genes; however, the role of microsatellite instability in sporadic sebaceous carcinomas has not been previously studied. In this report we describe the clinicopathologic characteristics of a series of unselected sebaceous carcinomas and examine them for the presence of microsatellite instability. Of 10 consecutive tumors identified over a 10 y period, only one was from a patient known to have Muir-Torre syndrome. Of the nine presumed sporadic cases, five were from four renal transplant recipients and four from otherwise healthy individuals. Microsatellite instability was demonstrable in three cases: in the Muir-Torre syndrome-associated tumor and in two tumors from transplant patients. Microsatellite instability was subsequently also found in a sebaceous carcinoma from a further transplant patient prospectively sought from another institution. The presence of microsatellite instability in post-transplant sebaceous carcinomas was associated with loss of expression of the mismatch repair protein hMSH2. In summary, sebaceous gland carcinomas, while characteristic of Muir-Torre syndrome, are commonly found outside this context. Among presumed sporadic cases, our data suggest they may be over-represented in immunosuppressed renal transplant recipients. The presence of microsatellite instability in transplant-associated lesions, together with loss of hMSH2 expression suggests that immunosuppression might unmask a previously silent Muir-Torre syndrome phenotype in some cases. Alternatively, there is experimental evidence to suggest that immunosuppressive drugs, most plausibly azathioprine, could select for the emergence of a mutator phenotype and thus predispose to the development of sebaceous carcinomas. The role of mismatch repair defects in other post-transplant skin malignancies remains to be established.

A prospective evaluation of anterior transposition of the inferior oblique muscle, with and without resection, in the treatment of dissociated vertical deviation.

BACKGROUND: Anterior transposition of the inferior oblique muscle (ATIO) has become a popular surgical treatment for dissociated vertical deviation (DVD), particularly in patients with coexisting inferior oblique muscle overaction (IOOA). We wanted to assess whether adding a resection improves the outcome compared with standard anteriorization. METHODS: We undertook a prospective, randomized evaluation of ATIO, with and without a 7-mm resection, in patients with DVD of at least 5 PD in one eye. We included 51 eyes of 30 patients, 26 eyes treated with the standard ATIO and 25 treated with a 7-mm resection added. We recorded the size of the preoperative and final DVD, grade of the preoperative and final IOOA, rates of reoperation, and complications. Mean follow-up was 15.4 months in the standard group and 25.0 months in the resection group, with a minimum of 4 months for all cases. RESULTS: The median preoperative and postoperative DVD was 12 PD and 4 PD in the standard group, respectively. This compared with 14 PD and 4 PD, respectively, in the resection group, representing no statistically significant difference in outcome. The presence or absence of IOOA did not influence the result of ATIO for either group. No significant complications of surgery occurred in either group. CONCLUSIONS: ATIO is an effective treatment for DVD and can be used to treat DVD in patients with or without IOOA, with few adverse effects. Our study revealed no advantage to adding a 7-mm resection to the standard procedure.

Microsatellite instability in benign skin lesions in hereditary non-polyposis colorectal cancer syndrome.

The coexistence of cutaneous and extra-cutaneous malignancies within one family could be explained by shared genetic mechanisms such as common tumor suppressor gene mutations or oncogene activation, as well as mutations in DNA repair genes. Hereditary non-polyposis colorectal cancer syndrome (HNPCC) and its variant Muir-Torre syndrome (MTS) are caused by germline DNA mismatch repair gene mutations. Colonic and endometrial tumors from HNPCC patients exhibit microsatellite instability (MSI), as do sebaceous lesions in MTS. We recruited individuals from cancer prone families to determine if MSI is found in benign and malignant skin lesions and to assess whether MSI in the skin is predictive of genomic instability with susceptibility to tumors characteristic of HNPCC. One hundred and fifteen benign, dysplastic, and malignant skin lesions from 39 cancer prone families were analyzed. Thirteen benign skin lesions from three individuals belonging to two HNPCC pedigrees showed MSI. No mutations in hMSH2 and hMLH1 were found in two of the three individuals with RER + skin lesions. We found MSI in non-sebaceous non-dysplastic skin lesions in HNPCC pedigrees. MSI was not found in skin lesions within other family cancer syndromes. These results have important clinical implications as the detection of MSI in prevalent readily accessible skin lesions could form the basis of noninvasive screening for HNPCC families. It may also be a valuable tool in the search for new mismatch repair genes.

Gli1 protein is expressed in basal cell carcinomas, outer root sheath keratinocytes and a subpopulation of mesenchymal cells in normal human skin.

Genetic studies of patients with the nevoid basal cell carcinoma syndrome have led to the recognition of the importance of the hedgehog signaling pathway in the development of basal cell carcinomas of the skin. Although hedgehog signaling is known to be important in hair follicle development, the function of this pathway in adult skin and the mechanism by which activation of this pathway leads to basal cell carcinoma development remain to be established. The Gli1 family of transcription factors mediates hedgehog signaling in mammalian cells and we have shown in previous studies that Gli1 mRNA is differentially expressed in basal cell carcinomas. Using antibodies to epitopes on the N and C terminal regions of Gli1 we show now that Gli1 protein is present in basal cell carcinomas and that the protein is mainly localized to the cytoplasmic compartment. Focal nuclear staining was seen in a small number of basal cell carcinomas with the C terminal antibody which suggest that nuclear localization is not dependent on loss of the C terminus of Gli1 due to proteolysis. Strong Gli1 immunostaining was seen in the outer root sheath keratinocytes of some hair follicles, a subpopulation of mesenchymal cells in the vicinity of the bulge region of adult hair follicles and the dermal sheath cells of developing hair follicles. Quantitation of Gli1 mRNA in basal cell carcinomas using northern blot analysis indicates that Gli1 is highly expressed in basal cell carcinomas. This suggests that the lower intensity of Gli1 immunostaining in basal cell carcinoma islands relative to outer root sheath keratinocytes is not simply a reflection of differences in gene expression. The continued expression of Gli1 in adult hair follicles and in the mesenchyme of adult human skin suggest that Hh signaling may play a part in hair cycling and in epidermal mesenchymal interactions important in normal skin maintenance.

Pediatric tetracycline-induced pseudotumor cerbri.

BACKGROUND: Tetracyclines have long been recognized as a cause of pseudotumor cerebri in adults, but the role of tetracyclines in the pediatric age group has not been well characterized in the literature and there have been few reported cases. We present 6 cases to better delineate the problem, the patient profile, the response to treatment, and the sequelae. METHODS: We retrospectively analyzed the records of all patients admitted with a diagnosis of pseudotumor cerebri who had documented usage of a tetracycline-class drug immediately before presentation at the Hospital For Sick Children in Toronto, Canada, from January 1, 1986, to March 1, 1996. RESULTS: Six patients (5 female, 1 male) who met all inclusion and exclusion criteria were identified; their ages ranged from 12 to 17 years. All were being treated for acne vulgaris. Duration of use before diagnosis was as short as 2 weeks and as long as 10 months, with a mean of 4.4 months. Duration of symptoms ranged from 0.57 to 4 weeks. Symptoms included headache (6 of 6), nausea (5 of 6), and diplopia (4 of 6). All for whom height and weight data were known (5 of 6) were in the upper quartile for body mass index. Visual acuity was 6/6 in all but 1 eye of one patient (6/9) at diagnosis, and final visual acuity was 6/6 in all patients. All had normal color vision, where this was recorded (5 of 6). The only recorded field defect was enlargement of the blind spot (4 of 6). All patients responded to treatment, with loss of symptoms in 1 day to 4 weeks. CONCLUSIONS: Pseudotumor cerebri as a result of tetracycline-class drugs does occur in the pediatric population. With prompt and appropriate medical treatment, long-term sequelae can almost always be avoided. Physicians who treat patients with tetracyclines need to be aware of the potential complications in children.

Basal cell carcinoma development is associated with induction of the expression of the transcription factor Gli-1.

Recent work has established that activation of Hedgehog/patched signalling plays a key role in the development of basal cell carcinomas (BCCs). In Drosophila the effects of hedgehog signalling are mediated by the transcription factor Cubitus interruptus, which is homologous to the mammalian Gli family of transcription factors. In order to investigate the downstream consequences of patched gene inactivation in BCCs, we have investigated the expression of Gli-1 and Gli-3 in normal skin and BCCs by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. Gli-3 was found to be expressed in both normal skin and BCCs by both RT-PCR and in situ hybridization using a Gli-3-specific probe. Using a sensitive RT-PCR assay we were unable to detect Gli-1 transcripts in normal skin. Gli-1 was expressed in 13 of 14 BCCs examined, and in situ hybridization confirmed that the transcripts were localized to the epithelial component of the tumours. Our results demonstrate that inactivation of the patched gene BCCs is associated with the accumulation of Gli-1 transcripts. These findings suggest that the Gli-1 transcription factor plays a key role in BCC development.

Management of cervical intraepithelial neoplasia during pregnancy with LOOP excision.

OBJECTIVE: Management of severe cervical dysplasia/possible microinvasive carcinoma during pregnancy is frequently associated with significant morbidity. The purpose of this study is to determine the efficacy of LOOP excision performed during pregnancy, and also to record the nature and frequency of complications of the procedure. METHODS: Twenty women underwent LOOP excision during pregnancy. The gestational age range was 8-34 weeks. Data concerning indications, complications, and histopathologic results were recorded. RESULTS: Fourteen of 20 (70%) had dysplastic changes in the LOOP specimen. Eight of 14 (57%) had involved margins. Nine of 19 (47%) had residual dysplasia 3 months postpartum, including 3 patients whose initial LOOP specimens were negative for dysplasia. Significant morbidity included 3 preterm births, 2 patients who required blood transfusion following LOOP, and 1 unexplained intrauterine fetal demise documented 4 weeks post-LOOP. The gestational age range of those patients who had significant morbidity was 27-34 weeks. CONCLUSIONS: LOOP excision of the cervix during pregnancy does not consistently produce diagnostic specimens and is associated with a significant rate of residual disease. Morbidity appears similar to that of cone biopsy during pregnancy and occurs primarily when the procedure is performed in the third trimester. Until refinements in technique occur, LOOP excision during pregnancy should be reserved for limited indications.