Sodium-glucose cotransporter 2 (SGLT-2) inhibitors and microvascular outcomes in patients with type 2 diabetes: systematic review and meta-analysis.

PURPOSE: The effect of the sodium-glucose 2 (SGLT-2) inhibitors on microvascular complications remains uncertain. We performed a systematic review to determine the efficacy of the SGLT-2 inhibitors on microvascular outcomes in patients with type 2 diabetes. METHODS: A comprehensive search was performed using Ovid, MEDLINE, EMBASE, Web of Science, and Scopus from inception to May 2019. Randomized trials comparing SGLT-2 inhibitors with placebo or other medication for type 2 diabetes for ≥ 4 weeks were included. Diabetes-related microvascular complications such as nephropathy, retinopathy, neuropathy, and peripheral vascular disease were evaluated. A random-effect model using mean differences for continuous outcomes and risk ratio for dichotomous outcomes was used to synthesize data. PROSPERO (CRD 42017076460). RESULTS: A total of 40 RCTs with overall moderate quality of evidence were included. SGLT-2 inhibitors reduced the risk of renal-replacement therapy (0.65; 95% CI 0.54-0.79), renal death (0.57; 95% CI 0.49-0.65), and progression of albuminuria (0.69; 95% CI 0.66-0.73). Conversely, they appeared ineffective in maintaining eGFR (0.33; 95% CI - 0.74 to 1.41) or reducing serum creatinine (- 0.07; 95% CI - 0.26 to 0.11), whereas urine albumin-creatinine ratio (- 23.4; 95% CI - 44.6 to - 2.2) was reduced. Risk of amputation was non-significant (1.30; 95% CI 0.93-1.83). No available data were found regarding neuropathy and retinopathy to perform a quantitative analysis. CONCLUSION: SGLT-2 inhibitors may reduce the risk of renal patient-important outcomes but fail to improve surrogate outcomes. Apparently, no increased risk of amputations was observed with these medications. No data were available regarding other microvascular complications.

Systematic review with meta-analysis: recurrence of Crohn's disease after total colectomy with permanent ileostomy.

BACKGROUND: Subtotal or total colectomy or proctocolectomy with permanent ileostomy (TC-PI) may be a treatment option for medically refractory colonic Crohn's disease (CD). AIM: To perform a systematic review and meta-analysis to evaluate the rate, risk factors and outcomes of CD recurrence after TC-PI. METHODS: In a systematic review ending 31 March 2016, we identified 18 cohort studies (1438 adults) who underwent TC-PI for colonic CD (median follow-up, 7.4 years; interquartile range, 5.3-9.0). We estimated pooled rates [with 95% confidence interval (CI)] of clinical and surgical recurrence, and risk factors for disease recurrence. RESULTS: On meta-analysis, the risk of clinical recurrence after TC-PI was 28.0% (95% CI, 21.7-35.3; 14 studies, 260/1004 patients), with a 5 and 10-year median cumulative rate of 23.5% (range, 7-35) and 40% (range, 11-60) respectively. The risk of surgical recurrence was 16.0% (95% CI, 11.1-22.7; 10 studies; 183/1092 patients), with a 5 and 10-year median cumulative rate of 10% (range, 3-29) and 18.5% (range, 14-34) respectively. The risk of clinical and surgical recurrence in patients without ileal disease at baseline was 11.5% (95% CI, 7.7-16.8) and 10.4% (95% CI, 4.5-22.5) respectively. History of ileal disease was associated with 3.2 times higher risk of disease recurrence (RR, 3.2; 95% CI, 1.8-5.6). Other inconsistent risk factors for disease recurrence were penetrating disease and young age at disease onset. CONCLUSIONS: Small bowel clinical recurrence occurs in about 28% of patients after total colectomy with permanent ileostomy for colonic Crohn's disease. Disease recurrence risk is 3.2 times higher in patients with history of ileal disease, and continued medical therapy may be advisable in this population. In patients without ileal inflammation at surgery, continued endoscopic surveillance may identify asymptomatic disease recurrence to guide therapy.

Systematic review with meta-analysis: faecal diversion for management of perianal Crohn's disease.

BACKGROUND: Temporary faecal diversion is sometimes used for management of refractory perianal Crohn's disease (CD) with variable success. AIMS: To perform a systematic review with meta-analysis to evaluate the effectiveness, long-term outcomes and factors associated with success of temporary faecal diversion for perianal CD. METHODS: Through a systematic literature review through 15 July 2015, we identified 16 cohort studies (556 patients) reporting outcomes after temporary faecal diversion. We estimated pooled rates [with 95% confidence interval (CI)] of early clinical response, attempted and successful restoration of bowel continuity after temporary faecal diversion (without symptomatic relapse), and rates of re-diversion (in patients with attempted restoration) and proctectomy (with or without colectomy and end-ileostomy). We identified factors associated with successful restoration of bowel continuity. RESULTS: On meta-analysis, 63.8% (95% CI: 54.1-72.5) of patients had early clinical response after faecal diversion for refractory perianal CD. Restoration of bowel continuity was attempted in 34.5% (95% CI: 27.0-42.8) of patients, and was successful in only 16.6% (95% CI: 11.8-22.9). Of those in whom restoration was attempted, 26.5% (95% CI: 14.1-44.2) required re-diversion because of severe relapse. Overall, 41.6% (95% CI: 32.6-51.2) of patients required proctectomy after failure of temporary faecal diversion. There was no difference in the successful restoration of bowel continuity after temporary faecal diversion in the pre-biological or biological era (13.7% vs. 17.6%, P = 0.60), in part due to selection bias. Absence of rectal involvement was the most consistent factor associated with restoration of bowel continuity. CONCLUSIONS: Temporary faecal diversion may improve symptoms in approximately two-thirds of patients with refractory perianal Crohn's disease, but bowel restoration is successful in only 17% of patients.

Dutogliptin, a selective DPP4 inhibitor, improves glycaemic control in patients with type 2 diabetes: a 12-week, double-blind, randomized, placebo-controlled, multicentre trial.

AIM: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. METHODS: This was a 12-week, multicentre, randomized, double-blind, placebo-controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2-week single-blind placebo run-in, patients aged 18-75 years with a body mass index of 25-48 kg/m(2) and baseline HbA1c of 7.3-11.0% were randomized 2:2:1 to receive once-daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. RESULTS: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by -0.52% (p < 0.001) and -0.35% (p = 0.006), respectively (placebo-corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of -0.82, -0.64 and -0.3%, respectively. The proportion of patients achieving an HbA1c < 7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo-corrected difference was -1.00 mmol/l (p < 0.001) for the 400 mg group and -0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC (0-2h) in both the 400 and 200 mg groups (placebo corrected values -2.58 mmol/l/h, p < 0.001 and -1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin-treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12-week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. CONCLUSIONS: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of < 7% than the 200 mg dose.

The dipeptidyl peptidase-4 inhibitor PHX1149 improves blood glucose control in patients with type 2 diabetes mellitus.

AIM: To determine the efficacy and tolerability of PHX1149, a novel dipeptidyl peptidase-4 (DPP4) inhibitor, in patients with type 2 diabetes. METHODS: This is a multicentre, randomized, double-blind, placebo-controlled, 4-week study in patients with type 2 diabetes with suboptimal metabolic control. Patients with a baseline haemoglobin A(1c) (HbA(1c)) of 7.3 to 11.0% were randomized 1 : 1 : 1 : 1 to receive once-daily oral therapy with either PHX1149 (100, 200 or 400 mg) or placebo; patients were on a constant background therapy of either metformin alone or metformin plus a glitazone. RESULTS: Treatment with 100, 200 or 400 mg of PHX1149 significantly decreased postprandial glucose area under the curve AUC(0-2 h) by approximately 20% (+0.11 +/- 0.50, -2.08 +/- 0.51, -1.73 +/- 0.49 and -1.88 +/- 0.48 mmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.002, 0.008 and 0.004 vs. placebo). Postprandial AUC(0-2 h) of intact glucagon-like peptide-1, the principal mediator of the biological effects of DPP4 inhibitors, was increased by 3.90 +/- 2.83, 11.63 +/- 2.86, 16.42 +/- 2.72 and 15.75 +/- 2.71 pmol/l x h, respectively, for placebo and 100, 200 and 400 mg (p = 0.053, 0.001 and 0.002 vs. placebo). Mean HbA(1c) was lower in all dose groups; the placebo-corrected change in the groups receiving 400 mg PHX1149 was -0.28% (p = 0.02). DPP4 inhibition on day 28 was 53, 73 and 78% at 24 h postdose in the groups receiving 100, 200 and 400 mg PHX1149, respectively. There were no differences in adverse events between PHX1149-treated and placebo subjects. CONCLUSIONS: Addition of the DPP4 inhibitor PHX1149 to a stable regimen of metformin or metformin plus a glitazone in patients with type 2 diabetes was well tolerated and improved blood glucose control.

Cytokine alterations in lichen sclerosus: an immunohistochemical study.

BACKGROUND: Although the histology of lichen sclerosus is characteristic, the precise nature of the inflammatory changes and the signals provoking them is uncertain. OBJECTIVES: To delineate the inflammatory changes in lichen sclerosus more accurately by studying cytokine changes. METHODS: An immunohistochemical study of 12 specimens of genital lichen sclerosus and one specimen of extragenital lichen sclerosus was undertaken using monoclonal antibodies to interferon (IFN)-gamma, IFN-gamma receptor, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-2 receptor (CD25), intercellular adhesion molecule-1 (ICAM-1) and its ligand CD11a. Control specimens were seven specimens of normal vulva obtained during gynaecological procedures, three specimens of normal skin, adjacent uninvolved thigh from three of the patients with lichen sclerosus, five specimens of nonvulval psoriasis, four specimens of nonvulval lichen planus and two specimens from chronic wounds. RESULTS: The lichen sclerosus specimens demonstrated slightly increased staining for IFN-gamma within the epidermis compared with the normal vulva and nonvulval skin. There was increased dermal staining for IFN-gamma both within the pale zone of the upper dermis and within the inflammatory zone below this. We confirmed our previous demonstration that in lichen sclerosus HLA-DR immunostaining is increased in association with vascular endothelium, the inflammatory cell infiltrate and around the keratinocytes. The areas of the epidermis with the strongest immunostaining for HLA-DR generally also had the strongest staining for IFN-gamma. In the lichen sclerosus specimens the zone of inflammation also demonstrated increased immunostaining for TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 while the zone of sclerosus demonstrated a smaller increase in immunostaining for IFN-gamma receptor, TNF-alpha, CD11a and ICAM-1, and the epidermis demonstrated increased staining for ICAM-1. CONCLUSIONS: The increased staining for IFN-gamma, TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 suggest that the cytokine response in lichen sclerosus shares characteristics of the cytokine response in lichen planus and chronic wounds.

FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248).

Somatic mutations of FLT3 resulting in constitutive kinase activation are the most common acquired genomic abnormality found in acute myeloid leukemia (AML). The majority of these mutations are internal tandem duplications (ITD) of the juxtamembrane region (JM). In addition, a minority of cases of AML are associated with mutation of the FLT3 activation loop (AL), typically involving codons D835 and/or I836. We hypothesized that other novel mutations of FLT3 could also contribute to leukemogenesis. We genotyped 109 cases of AML and identified two novel gain-of-function mutations. The first mutation, N841 H, is similar to previously described mutations involving amino-acid substitutions of codon 841. The other novel mutation, FLT3 K663Q, is the first AML-associated gain-of-function mutation located outside the JM and AL domains. Of note, this mutation was potently inhibited by Sunitinib (SU11248), a previously described FLT3 kinase inhibitor. Sunitinib reduced the proliferation and induced apoptosis of transformed Ba/F3 cells expressing FLT3 K663Q. The potency of Sunitinib against FLT3 K663Q was similar to its potency against FLT3 ITD mutations. We conclude that FLT3 mutations in AML can involve novel regions of the TK1. Future studies are needed to define the incidence and prognostic significance of FLT3 mutations outside the well-established JM and AL regions.

Childhood cicatricial pemphigoid confined to the vulva.

Cicatricial pemphigoid or benign mucous membrane pemphigoid is an autoimmune bullous disease predominantly affecting the mucosal surfaces and healing with scar formation. Localized cicatricial pemphigoid of the vulva in children is rare. We present a child with this rare condition who was initially investigated on suspicion of her being subjected to child sexual abuse, and discuss its management.

Intestinal bypass syndrome presenting as erythema nodosum.

Intestinal bypass was a popular surgical procedure for morbid obesity resulting, on average, in a 50 kg weight loss. We describe a 66-year-old woman who underwent the procedure 12 years earlier and subsequently presented with recurrent episodes of erythema nodosum-like lesions. Further investigations revealed hyperoxaluria, renal failure, deficiency of fat-soluble vitamins (causing night blindness, osteomalacia and easy bruising) and anaemia. Antibiotics led to only temporary remission and, as with 24-30% of similar cases, she underwent surgical reversal to prevent the complications from worsening.

Inhibitors of histone deacetylases promote hematopoietic stem cell self-renewal.

BACKGROUND: Histone deacetylases (HDAC) are associated with a variety of transcriptional repressors that control cellular differentiation and proliferation. HDAC inhibitors such as trichostatin A, trapoxin and chlamydocin could be useful tools to modulate these cellular processes. We investigated their effect on the self-renewal of hematopoietic stem cells (HSC) during ex vivo culture. METHODS: Purified murine HSC with the phenotype c-Kit+,Thy-1.1(lo), Lin(-/lo), Sca-1+ were cultured for 4 days with IL-3, IL-6 and c-Kit ligand without or with HDAC inhibitors, after which their degree of phenotypic differentiation in culture was assessed by flow cytometric analysis. To explore whether HDAC inhibitors could have a beneficial role in human HSC transplantation, mobilized peripheral blood CD34+ cells were cultured with thrombopoietin mimetic peptide, flt3 ligand, and c-Kit ligand, without or with various HDAC inhibitors. The fluorescent dye, carboxyfluorescein-diacetate succinimidylester (CFSE), was used to track division of cell subsets, and engrafting ability was evaluated in a non-obese diabetic (NOD) -SCID xenotransplantation model. RESULTS: Murine HSC cultured with HDAC inhibitors maintained a more primitive phenotype than control cultures. The number of human HSC expressing Thy-1 increased up to seven-fold during a 5-day culture with HDAC inhibitors compared with control cultures. Chlamydocin was the most effective of the HDAC inhibitors tested at promoting Thy-1 expression on human cells. CFSE tracking showed that the increase in Thy-1+ cells resulted from cell division. In a NOD-SCID repopulation assay, cells exposed to chlamydocin for 24 h displayed an average four-fold higher engrafting ability over control cells. DISCUSSION: Our studies suggest that HDAC inhibitors can induce ex vivo expansion of human HSC, and may improve engraftment in hematopoietic transplant patients when cell dose is limiting.

Kytococcus sedentarius, the organism associated with pitted keratolysis, produces two keratin-degrading enzymes.

AIMS: To determine characteristics of the extracellular enzyme activity of Kytococcus sedentarius on human callus. METHODS AND RESULTS: A concentrate of a continuous culture supernatant fluid of K. sedentarius, which had callus-degrading activity, was subjected to a series of chromatographic purification procedures. The enzyme activity was found to be attributable to two proteases. These were capable of degrading both native callus and extracted keratin polypeptides and were purified to homogeneity, as shown by SDS-PAGE with silver staining. The enzymes P1 and P2 were 30 kDa and 50 kDa in size with isoelectric points of 4.6 and 2.7, respectively. The optimum conditions for callus-degrading activity were 40 degrees C, pH 7.1 for P1 and 50 degrees C, pH 7.5 for P2. P2 displayed increased activity in the presence of 800 mmol l(-1) NaCl and both enzymes were inhibited by PMSF (1 mmol(-1) Phenylmethylsulphoryl fluoride) and 1 mmol l(-1) EDTA. The main enzyme cleavage sites were Lys-Trp, Val-Lys, Gly-Asp and Asp-Arg, as determined after incubation of P1 and P2 with the beta-chain of insulin. CONCLUSIONS: K. sedentarius produces two extracellular enzymes that independently degrade natural, insoluble human callus. Both enzymes are serine proteases and have cleavage preference sites that are present in a range of human keratins. SIGNIFICANCE AND IMPACT OF THE STUDY: The identification, in K. sedentarius cultures, of two enzymes which can degrade human callus strengthens the hypothesis that this organism is responsible for the pitting in human epidermis observed in pitted keratolysis. These enzymes may be of commercial use in the biodegradation of a range of keratin polymers, biological washing powders and in the treatment of unwanted callus on human skin.

Alterations in fibrillin as well as collagens I and III and elastin occur in vulval lichen sclerosus.

BACKGROUND: The clinical features of lichen sclerosus, which include atrophy, scarring, fragility and tendency to form ecchymoses with only slight trauma, suggest that there is an alteration in the extracellular matrix fibres that are responsible for the tensile strength of the dermis. However, the precise nature of these changes is poorly understood. METHODS: Biopsies from 16 patients with untreated, histologically confirmed, vulval lichen sclerosus were examined immunohistochemically using polyclonal antibodies to collagens I and III and a monoclonal antibody to elastin. Twelve of the lichen sclerosus specimens were also stained with a monoclonal antibody to fibrillin. Normal vulva tissue and patients' uninvolved thigh were used as controls. RESULTS: In the lichen sclerosus specimens, collagens I and III stained with a more homogeneous pattern than in the control tissues. Reduced numbers of elastin fibres were seen in the zone of sclerosus in 15 of the 16 lichen sclerosus specimens. In the control tissue fibrillin fibres were seen as a fine network of fibres in the upper dermis arranged at right angles to and inserting into the basement membrane and forming a fine network throughout the dermis. In the lichen sclerosus specimens, although fibrillin microfibrils were still seen inserting at right angles into the basement membrane, below this the fibrillin staining was reduced in the upper dermis in 11 of the 12 lichen sclerosus specimens. The zone of reduced fibrillin staining was greatest in those specimens where the band of inflammation was deep in the dermis. CONCLUSIONS: The distribution of collagens I and III, elastin and fibrillin are altered in lichen sclerosus and this is likely to contribute to the fragility, scarring and atrophy seen clinically in lichen sclerosus.

Distribution of transforming growth factor-beta isoforms TGF-beta 1, TGF-beta 2 and TGF-beta 3 and vascular endothelial growth factor in vulvar lichen sclerosus.

OBJECTIVE: To study the distribution of transforming growth factor beta (TGF-beta) isoforms TGF-beta 1, TGF-beta 2 and TGF-beta 3 and vascular endothelial growth factor (VEGF) in vulvar lichen sclerosus. STUDY DESIGN: Biopsies were obtained from 10 patients with vulvar lichen sclerosus, snap frozen and stained with polyclonal antibodies to TGF-beta 1, TGF-beta 2, TGF-beta 3 and VEGF. Control tissues used were uninvolved thigh tissue from two of the lichen sclerosus patients and normal vulvar tissue obtained from eight patients during gynecologic procedures. Two specimens of morphea were also examined. RESULTS: Weak TGF-beta 1 staining was demonstrated in the epidermis of all the lichen sclerosus, morphea, thigh and five of the eight normal vulvar specimens. Slight increase in TGF-beta 1 staining was seen in the upper and middermis in 6 of the 10 lichen sclerosus specimens and in the morphea specimens as compared to the control tissue, and this staining was localized within cells. TGF-beta 2 staining was present throughout the epidermis in all the normal thigh, normal vulva, lichen sclerosus and morphea specimens. TGF-beta 2 staining was increased within cells in the upper and middermis of the lichen sclerosus and morphea specimens. TGF-beta 3 staining occurred in the basal half of the epidermis of all the control, lichen sclerosus and morphea specimens, and only slight upper dermal staining of a few individual cells was seen in 3 of the 10 lichen sclerosus specimens. VEGF staining was similar in the normal tissues, lichen sclerosus and morphea. CONCLUSION: These results suggest that TGF-beta may.

A rapid flow cytometric assay to detect CD4+ and CD8+ T-helper (Th) 0, Th1 and Th2 cells in whole blood and its application to study cytokine levels in atopic dermatitis before and after cyclosporin therapy.

BACKGROUND: The immune response in atopic dermatitis (AD) is thought to be driven by T-helper (Th) 2 cytokines. Using flow cytometry, higher frequencies of peripheral blood CD4+ and CD8+ T cells producing interleukin (IL)-4 and correspondingly lower frequencies of CD4+ T cells producing interferon (IFN)-gamma have been found in patients with AD compared with healthy controls. It would be of interest to know whether other Th1 and Th2 cytokines such as IL-5, IL-13 and tumour necrosis factor (TNF)-alpha are similarly skewed in patients with AD and whether this immune skewing, detected via a simple blood assay, can be correlated with other clinical measurements or treatments in AD. OBJECTIVES: To use a rapid (4-h) flow cytometric assay to study a wide range of Th1 and Th2 cytokine patterns in peripheral blood lymphocytes from patients with AD, comparing them with non-atopic healthy controls. To correlate cytokine patterns with the degree of eosinophilia observed and in the case of one patient with severe disease, to observe the effect of cyclosporin therapy on peripheral blood cytokine patterns. METHODS: Peripheral blood from eight patients with AD and 23 healthy controls was examined for the frequencies of CD4+ and CD8+ T cells expressing IL-2, IL-4, IL-5, IL-13, IFN-gamma and TNF-alpha using flow cytometry. RESULTS: Significantly higher frequencies of CD4+/IL-4+ (P < 0.005) and CD4+/IL-13+ (P < 0.0001) and lower frequencies of CD4+/IFN-gamma+ (P < 0.002) and CD8+/TNF-alpha+ (P < 0.05) T lymphocytes were found in patients with AD compared with controls. There were significant positive correlations with the increased percentages of CD4+/IL-4+ and CD4+/IL-13+ T lymphocytes and the degree of eosinophilia observed (P < 0.05, P < 0.001) and a negative correlation between the percentage of CD4+/IFN-gamma+ T lymphocytes and eosinophilia (P < 0.05). In one patient examined before and 8 days after cyclosporin therapy, 50% or greater reductions were observed in percentages of peripheral blood CD8+/IL-5+, CD8+/IL-13+, CD4+/IL-4+ and CD4+/IL-5+ T lymphocytes following cyclosporin therapy. A smaller reduction of 15% after cyclosporin therapy was found in percentages of CD4+/IL-13+ T cells. CONCLUSIONS: These data strongly support a Th2 predominance in the peripheral blood of AD. The results suggest that administration of cyclosporin therapy in patients with AD may help to restore the Th2 cytokine imbalance seen in these patients.

Alterations in distribution of tenascin, fibronectin and fibrinogen in vulval lichen sclerosus.

BACKGROUND: The pathophysiology of lichen sclerosus remains uncertain. The clinical features, including increased fragility and scarring, and the histology suggest that significant reorganisation of the extracellular matrix is occurring. Tenascin, fibrinogen and fibronectin are extracellular matrix components that play a significant role in tissue remodelling, for example during wound repair. AIM: To examine the distribution of tenascin, fibrinogen and fibronectin in vulval lichen sclerosus. MATERIALS AND METHODS: Immunohistochemical staining was performed to study the distribution of tenascin, fibronectin and fibrinogen in 16 specimens of untreated vulval lichen sclerosus and 1 specimen of extragenital lichen sclerosus. Haematoxylin and eosin staining of the specimens was also performed to identify the position of the pale staining homogenous zone/zone of sclerosis and the inflammatory infiltrate below this. The control tissues studied included biopsies taken from the uninvolved thigh of 13 of the lichen sclerosus patients and 6 samples of normal vulva tissue obtained during gynaecological procedures from women of similar age to the lichen sclerosus women. RESULTS: All the lichen sclerosus specimens demonstrated increased immunostaining of tenascin in the upper dermis and comparing this with the haematoxylin and eosin staining this corresponded to the zone of sclerosis with relatively little tenascin staining associated with the inflammatory band. In 14 out of the 16 vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen fibrinogen immunostaining was increased in the upper dermis which corresponded--in haematoxylin and eosin staining --to the zone of sclerosis. There was also slightly increased fibrinogen staining in the mid dermis which corresponded to the inflammatory band. Fibronectin staining was reduced in the upper dermis of 12 of the vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen which corresponded to the zone of sclerosis. However, in 14 of the vulval lichen sclerosus specimens and the extragenital lichen sclerosus specimen, fibronectin was slightly increased in the mid and deeper dermis which corresponded to the zone of inflammatory cells and the area below this. There was also increased fibronectin staining around blood vessel walls both in the mid dermis and within the zone of sclerosis. CONCLUSION: The distribution of tenascin, fibrinogen and fibronectin is altered in lichen sclerosus and the alteration in these extracellular matrix components may be relevant to the initiation of scarring in lichen sclerosus and the associated increased skin fragility.

Optical imaging of bilingual cortical representations. Case report.

The organization of language in the brains of multilingual persons remains controversial. The authors investigated language representations in a proficient bilingual patient by using a novel neuroimaging technique, intraoperative optical imaging of intrinsic signals (iOIS), and a visual object naming task. The results indicate that there are cortical areas that are activated by the use of both English and Spanish languages (superior temporal sulcus, superior and middle temporal gyri, and parts of the supramarginal gyrus). In addition, language-specific areas were identified in the supramarginal (Spanish) and precentral (English) gyri. These results suggest that cortical language representations in bilingual persons may consist of both overlapping and distinct components. Furthermore, this study demonstrates the utility of iOIS in detecting topographical segregation of cognitively distinct cortices.

Genital lichen sclerosus associated with morphoea or systemic sclerosis: clinical and HLA characteristics.

Although patients with both morphoea and lichen sclerosus have been reported previously, in the majority of these reports the lichen sclerosus has been extragenital. We report nine patients in whom genital lichen sclerosus coexisted with scleroderma spectrum disorders including seven with morphoea, one with morphoea and lichen planus, and one with systemic sclerosis. The clinical features, associated autoimmune disease, autoantibodies and HLA type are reported. Antibodies to Borrelia burgdorferi were not detected in any of the patients. The coexistence of these diseases raises a number of intriguing questions about the relationship between them.

Do plasminogen activators play a role in lichen sclerosus?

The histological changes of lichen sclerosus suggest that significant remodelling of the extracellular matrix is occurring. As the proteases of the plasminogen activator system have been implicated in tissue remodelling, cell migration and tumour invasion, we performed an immunohistochemical study to look for evidence of alteration in the expression of plasminogen/plasmin, urokinase-type plasminogen activator, tissue-type plasminogen activator and alpha2-antiplasmin in biopsies of clinically typical vulval lichen sclerosus obtained from 11 untreated adult women. Normal vulva obtained from gynaecological procedures and samples of the patients' uninvolved thigh tissue were used as controls. No significant difference was seen in the staining pattern between the lichen sclerosus tissue and control tissue. However, although we found no immunohistochemical evidence that the plasminogen activator system is involved in the pathogenesis of vulval lichen sclerosus, it may be that other proteases are involved.

Characterization of optical intrinsic signals and blood volume during cortical spreading depression.

Cortical spreading depression (CSD) was imaged in vivo in a rodent model with optical intrinsic signals (OIS). This is the first study to identify a triphasic OIS response and to characterize the rate and timing of the response. The initial OIS phase had a highly uniform wavefront, which spread at a rate characteristic of CSD, 3.5 mm/min. Later phases were more diffuse and inhomogeneous. Blood volume changes, measured with intravascular fluorescent dye, correlated in time and location with the later phases of OIS response. This suggests that the inhomogeneity of the late OIS response may be due to complex residual hemodynamic contributions, as opposed to underlying cortical circuitry.

Optical intrinsic signal imaging in a rodent seizure model.

The authors studied seizure activity with optical intrinsic signal (OIS) imaging in a rat seizure model. OIS, which measures vascular and metabolic effects associated with neuronal activity, showed significant cortical reflectance changes from penicillin-induced seizures, and correlated well with EEG epileptiform discharges. Furthermore, OIS changes often preceded initial EEG spikes. These observations suggest that OIS is well coupled with seizure activity, and may provide sensitive cues for seizure detection.