Composite Hemangioendothelioma With Neuroendocrine Marker Expression: Report of a "Paraganglioma-Like" Paravertebral Case.

Composite hemangioendothelioma is a rare vascular tumor morphologically comprising several distinct vascular components and exhibits a borderline malignant potential. We described the case of a 53-year-old female who presented with an infiltrative mass in the paravertebral soft tissue. The tumor showed discrete nests of synaptophysin-expressing epithelioid cells accompanied by rich vasculature, features highly reminiscent of sympathetic paraganglioma. Further analysis revealed areas resembling spindle cell hemangioma, retiform hemangioendothelioma, cavernous hemangioma/lymphangioma, and epithelioid hemangioendothelioma without the myxohyaline matrix in the tumor, and a final diagnosis of composite hemangioendothelioma with synaptophysin expression was made. Critical appraisal of this recently described entity and its possible pathogenic relationship with retiform hemangioendothelioma were discussed.

MISSING THE OBVIOUS: A CASE OF UNDIAGNOSED GRAVES' DISEASE.

Undiagnosed hyperthyroidism has an estimated prevalence in the general population of 3.4 percent. Without adequate treatment, Graves' disease can lead to significant morbidity and result in potentially fatal conditions such as tachyarrhythmia induced heart failure or thyrotoxic crisis.

G-quadruplex DNA aptamers and their ligands: structure, function and application.

Highly specific and tight-binding nucleic acid aptamers have been selected against a variety of molecular targets for over 20 years. A significant proportion of these oligonucleotides display G-quadruplex structures, particularly for DNA aptamers, that enable molecular recognition of their ligands. G-quadruplex structures couple a common scaffold to varying loop motifs that act in target recognition. Here, we review DNA G-quadruplex aptamers and their ligands from a structural and functional perspective. We compare the diversity of DNA G-quadruplex aptamers selected against multiple ligand targets, and consider structure with a particular focus on dissecting the thrombin binding aptamer - thrombin interaction. Therapeutic and analytical applications of DNA G-quadruplex aptamers are also discussed. Understanding DNA G-quadruplex aptamers carries implications not only for therapeutics and diagnostics, but also in the natural biochemistry of guanine-rich nucleic acids.

Association between myasthaenia gravis and systemic lupus erythematosus: three case reports and review of the literature.

The coexistence of systemic lupus erythematosus (SLE) and myasthaenia gravis (MG) has been reported previously. Because of their shared clinical characteristics and autoantibody-mediated pathogenesis, an SLE expert panel decided to include MG as one of the 19 neuropsychiatric SLE syndromes. This study reports a cluster of three cases of SLE/MG overlap from our cohort and a review of the published data concerning this overlap of SLE and MG. A systematic Medline review revealed 13 cases described in eight publications from 1994 to 2009. In summary, 12 of the 16 patients (three from our cohort and 13 from the reported cases) were women with an average age of 34 years. The most common SLE manifestations were polyarthritis (15 out of 16 patients), skin rashes (5/16), serositis (5/16), and cytopaenias (10/16). All of the patients were anti-nuclear antibodies (ANA) positive and 15/16 were anti-dsDNA positive. Proximal muscle weakness was the most frequent MG-related symptom (9/16), while 11/16 patients were anti-acetylcholine receptor (anti-AChR) antibody positive and 9/16 had diagnostic electromyography (EMG). These data suggest that MG should to be included in the differential diagnosis of lupus patients with fatigue and muscular weakness together with inflammatory and drug-induced myopathy.

Occupational dermatitis related to chromium and cobalt: experience of dermatologists (EPIDERM) and occupational physicians (OPRA) in the U.K. over an 11-year period (1993-2004).

BACKGROUND: Chromium and cobalt (and their compounds) are well recognized as being important causes of occupational contact dermatitis (OCD), particularly of the hands, although their exact contribution to occupational hand dermatitis varies between different studies. In some European studies, cases of chromium-related dermatitis have decreased following the addition of ferrous sulphate to cement to reduce the amount of available chromium. OBJECTIVES: To examine, using data from the U.K. occupational skin surveillance schemes, the proportionate reported incidence and changing trends in OCD considered to be related to chromium and cobalt for the 11-year period from February 1993 to December 2004. METHODS: Surveillance data collected by the two British occupational health surveillance schemes, EPIDERM and OPRA, from February 1993 to December 2004 were studied. These are occupational health surveillance schemes in the U.K. to which physicians voluntarily and anonymously report new cases of skin disease suspected to be work related. RESULTS: Over the 11-year period, dermatologists reported 22 184 cases of OCD, comprising 77% of all types of occupational skin diseases that were disclosed. Chromium was recorded as being thought to play a role in 1226 (6%) of these, with cobalt identified as being likely to be implicated in 823 (4%). The numbers fluctuated on a year-on-year basis but there were no overall trends during the period of study. The male/female ratio was 5 : 1 for chromium and 1 : 1 for cobalt. Overall, the male/female ratio for OCD was 1.4 : 1. The rates of dermatitis believed to be related to both metals generally increased with age. In women, the highest rate for chromium was seen in the > 60 years age group, whereas conversely, for cobalt the rate decreased with age. For chromium-related OCD the most common occupations were builders and building contractors, bricklayers, construction workers and plasterers. For cobalt-related OCD, the commonest occupations were hairdressers/barbers, builders/building contractors, retail cash/checkout operators, machine operatives and domestic cleaners. Occupational physicians reported 15 016 cases of OCD (82% of all occupational skin diseases reported by them) for the period May 1994-December 2004. Of these, only 38 cases were thought to be related to chromium and 30 to cobalt (25 of the latter were processing labourers). CONCLUSIONS: In this series, chromium was reported by dermatologists as potentially being involved in 6% of all cases of OCD in the U.K., and cobalt in 4%. Our data support the view that chromium-related dermatitis has an onset in later working life and often affects those in the building trades, whereas cobalt-related dermatitis seems to have an earlier onset and may affect a wide range of employments.

Alopecia in association with severe seborrhoeic dermatitis following combination antiretroviral therapy for acute retroviral syndrome.

We present a case where alopecia occurred with severe seborrhoeic dermatitis associated with the commencement of combination antiretroviral therapy for acute retroviral syndrome. We postulate that the eruption could represent a novel manifestation in association with immunological response to antiretroviral therapy.

Occupational contact dermatitis to nickel: experience of the British dermatologists (EPIDERM) and occupational physicians (OPRA) surveillance schemes.

AIMS: To examine, from occupational surveillance reporting data, whether scheme reporters considered nickel exposure to play a role in occupational contact dermatitis (OCD) in the UK. METHODS: Data on occupational skin disease in the UK are collected by two occupational disease surveillance schemes, EPIDERM and OPRA. Cases of OCD believed to have relevant nickel exposure reported to EPIDERM or OPRA from February 1993 to January 1999 were studied. RESULTS: An estimate of 1190 cases of occupational contact dermatitis thought to have relevant nickel exposure (12% of total estimated OCD) was derived from reports by dermatologists, an average of 198 per year. The highest incidence rates were seen in hairdressers (23.9/100 000 workers/year), bar staff (4.7), chefs and cooks (4.4), retail cash and checkout operators (2.8), and catering assistants (2.5). From May 1994 to January 1999, 158 cases of nickel associated dermatitis (1.9% of total OCD cases) were estimated; the most frequently reported occupations were electronic assemblers, nurses, sales assistants, and general assemblers. From July 1997 to January 1999, 547 positive patch tests to nickel were reported; in 195 cases (36%), nickel was felt to be a relevant occupational allergen (for example, coin handling). In hairdressers, nurses, cooks, and beauticians, nickel was usually considered, if relevant at all, to be only one of several causes of dermatitis. CONCLUSIONS: Up to 12% of total estimated cases of OCD were thought to be due in part to nickel. Results suggest that nickel hypersensitivity is one of several contributors to OCD in subjects with multiple occupational exposures. Coin handling may be a source of OCD to nickel.

Effects of antecedent hypoglycemia, hyperinsulinemia, and excess corticosterone on hypoglycemic counterregulation.

This study aimed to differentiate the effects of repeated antecedent hypoglycemia, antecedent marked hyperinsulinemia, and antecedent increases in corticosterone on counterregulation to subsequent hypoglycemia in normal rats. Specifically, we examined whether exposure to hyperinsulinemia or elevated corticosterone per se could impair subsequent counterregulation. Four groups of male Sprague-Dawley rats were used: 1) normal controls (N) had 4 days of sham antecedent treatment; 2) an antecedent hypoglycemia group (AH) had 7 episodes of hyperinsulinemic hypoglycemia over 4 days; 3) an antecedent hyperinsulinemia group (AE) had 7 episodes of hyperinsulinemic euglycemia; and 4) an antecedent corticosterone group (AC) had 7 episodes of intravenous corticosterone to simulate the hypoglycemic corticosterone levels in AH rats. On day 5, hyperinsulinemic euglycemic-hypoglycemic clamps were performed. Epinephrine responses to hypoglycemia were impaired (P < 0.05 vs. N) after antecedent hypoglycemia and hyperinsulinemia. This correlated with diminished (P < 0.05 vs. N) absolute glucose production responses in AH rats and diminished incremental glucose production responses in AE rats. Paradoxically, norepinephrine responses were increased (P < 0.05 vs. N) after antecedent hypoglycemia. Glucagon and corticosterone responses were unaffected by antecedent hypoglycemia and hyperinsulinemia. In AC rats, incremental but not absolute glucose production responses were decreased (P < 0.05 vs. N). However, neuroendocrine counterregulation was unaltered. We conclude that both antecedent hypoglycemia and hyperinsulinemia impair epinephrine and glucose production responses to subsequent hypoglycemia, suggesting that severe recurrent hyperinsulinemia may contribute to the development of hypoglycemia-associated autonomic failure.

Occupational contact dermatitis has an appreciable impact on quality of life.

In this study, we examined the impact of occupational contact dermatitis on quality of life. 181 patients, diagnosed with occupational contact dermatitis over a period of 3 years (1996-1999 inclusive), were sent a questionnaire based on the Dermatology Life Quality Index (DLQI) and the Short Form-36 (SF-36). 60 (32%) patients were in industrial occupations and 27 (14%) in health care. An overall response rate of 39% (n=70) was obtained. The median DLQI score was 5, with a mean score 6.6 (SD 6.4), which is similar to that seen in Behçet's syndrome and urticaria. There was no statistically-significant difference between male and female median scores (p=0.98) and no significant correlation between age and DLQI score nor between DLQI score and time from diagnosis. The most problematic quality of life areas were symptoms and feelings. Males scored highest in problems associated with work, relationships and treatment, whereas females scored highest in problems associated with symptoms and feelings, daily activities and leisure. The SF-36 scores showed an association between physical problems and emotional problems affecting work. From this study, it can be seen that occupational contact dermatitis has an appreciable impact on quality of life.

The synthesis, testing and use of 5-fluoro-alpha-D-galactosyl fluoride to trap an intermediate on green coffee bean alpha-galactosidase and identify the catalytic nucleophile.

5-Fluoro-alpha-D-galactopyranosyl fluoride was synthesized and its interaction with the active site of an alpha-galactosidase from green coffee bean (Coffea arabica), a retaining glycosidase, characterized kinetically and structurally. The compound behaves as an apparently tight binding (Ki = 600 nM) competitive inhibitor, achieving this high affinity through reaction as a slow substrate that accumulates a high steady-state concentration of the glycosyl-enzyme intermediate, as evidenced by ESiMS. Proteolysis of the trapped enzyme coupled with HPLC/MS analysis allowed the localization of a labeled peptide that was subsequently sequenced. Comparison of this sequence information to that of other members of the same glycosidase family revealed the active site nucleophile to be Asp145 within the sequence LKYDNCNNN. The importance of this residue to catalysis has been confirmed by mutagenesis studies.

Effect of JTT-501 on net hepatic glucose balance and peripheral glucose uptake in alloxan-induced diabetic dogs.

JTT-501, a new insulin sensitizer, improves peripheral glucose uptake in insulin-resistant animals such as KK-Ay mice and Zucker fatty rats. However, the effect of JTT-501 on hepatic glucose metabolism has not been addressed. To investigate this effect, experiments were performed on 6 alloxan-diabetic dogs. Three experiments were conducted for each dog: the treatment experiment, which followed a 10-day oral treatment with JTT-501 30 mg x kg(-1) x d(-1), and 2 control experiments 2 weeks before and 2 weeks after the treatment experiment. A hyperinsulinemic-hyperglycemic clamp was performed with the tracer dilution method (intraportal insulin infusion rate, 18 pmol x kg(-1) x min(-1)). Arterial hyperglycemia (approximately 10 mmol/L) was maintained by adjusting the peripheral glucose infusion rate. After a 45-minute basal period (period I), portal glucose infusion (22.2 micromol x kg(-1)min(-1)) was administered for 120 minutes (period II). This was followed by a 90-minutes recovery period (period III). JTT-501 increased insulin-stimulated glucose utilization (P < .05) and enhanced insulin-mediated suppression of glucose production (P < .05) in periods I and III. Net hepatic glucose balance (NHGB) determined by the arterial-venous (A-V) difference method was increased by JTT-501 in period II (P < .01). We conclude that JTT-501 enhances both hepatic and peripheral insulin sensitivity and therefore may have important therapeutic effects in type 2 diabetes.

The British Association of Dermatologists audit of atopic eczema management in secondary care. Phase 3: audit of service outcome.

Service outcome was examined by a preconsultation (part 1) and a 6-week postconsultation (part 2) patient questionnaire in 29 hospital dermatology departments randomly selected from an original sample of 187 centres across the U.K. The outcome measures were: quality of life as measured by the Dermatology Life Quality Index (DLQI) and Children's DLQI (CDLQI), improvement in sleep loss, improvement in worse aspect of skin disease and return to work or school. Three hundred and fifty-two questionnaires (115 adults, 237 children) were completed for part 1, and 235 (67%) replied to part 2. The mean DLQI at initial consultation was 12.5, dropping to 9.7 at 6 weeks (P = 0.001). The mean CDLQI at initial consultation was 10.5, dropping to 8.7 at 6 weeks (P < 0.001). Forty-nine per cent of adults and 44% of children had a > 25% relative improvement in score, which did not meet the 60% working standard. Forty-four per cent of adults and 47% of children had an improvement in sleep loss at 6 weeks, falling short of the 70% working standard. Sixty-one per cent of adults and 59% of children had an improvement in the worst aspect of their skin condition at 6 weeks, falling short of the 80% working standard. Of the 20 adults and eight children off work/school during part 1, 70% of adults and 87.5% of children had returned to work/school by 6 weeks. This met the 80% working standard for children but not for adults. On a national scale, only one of the eight working standards for service outcome was met, although most of the working standards were met by at least one of the 11 National Health Service administrative areas. This study presents the first national data on the outcomes of a representative sample of atopic eczema patients seen in secondary care. Small sample sizes, instruments which may be insensitive to change, as well as local factors such as case-mix, baseline severity and staff to patient ratios need to be taken into account when interpreting these results. Nevertheless, the results of this baseline audit suggest that the outcome of patients with atopic eczema following secondary care consultation may not be as good as some doctors believe. This suggests that an improvement in practice, a re-evaluation of the working standards, or both, is needed and should be examined in future audit cycles.

The British Association of Dermatologists audit of atopic eczema management in secondary care. Phase 2: audit of service process.

An audit of atopic eczema management, conducted on behalf of the British Association of Dermatologists, examined service structure (phase 1), process (phase 2) and outcome (phase 3). In phase 2, an on-site case-note audit was conducted in 19 hospital dermatology departments randomly selected from the original sample of 187 centres across the U.K. In total, 630 sets of notes were examined for completeness of: (i) information given to general practitioners (GPs) in clinic letters and (ii) facts relevant to the management of atopic eczema recorded in the patients' notes. In general, the information given to GPs in the clinic letters was good, with the recording of diagnosis, treatment and follow-up approaching the 100% working standard. Factual information such as site and severity of eczema (83% and 74%), and presence or absence of asthma (53%) were better recorded than quality of life issues such as sleep loss secondary to itching (21%) and effect on school, work or social life (6%). On average, only 51% of all audit measures were recorded across all centres, with slight variation between centres (41-61%). The centre with the best recording had a purpose-designed data sheet for doctors to complete when seeing new patients with atopic eczema. Such data sheets may help improve case-note recording. Similar data sheets for patients to complete may be more time-efficient.

Drug delivery systems based on trimethyl lock lactonization: poly(ethylene glycol) prodrugs of amino-containing compounds.

A novel methodology for the synthesis of poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed which is based on the trimethyl lock lactonization reaction. These PEG-modified double prodrugs are water soluble, and by selective modification of the specifier or trigger, plasma half-lives can be adjusted at will to result in a wide range of values. Facile syntheses of ester, carbonate, and carbamate functionalities were accomplished and combined with greater or lesser degrees of steric hindrance in the spacer group, or on the aromatic framework, to achieve predictable ranges of drug concentration in plasma. In vivo screening of PEG prodrugs was done using a M109 syngeneic solid mouse tumor model. One of the PEG-daunorubicin prodrugs, with a half-life of 2 h, was evaluated in an in vivo solid tumor panel and found to be more efficacious against ovarian tumors (SKOV3) than equivalent amounts of daunorubicin.

A novel mutation in the 2B domain of keratin 2e causing ichthyosis bullosa of Siemens.

Ichthyosis bullosa of Siemens (IBS; MIM: 146800) is an autosomal dominant disorder of keratinization characterized by epidermolytic hyperkeratosis without erythroderma. The clinical features are less marked than those of bullous congenital ichthyosiform erythroderma with relatively mild hyperkeratosis usually limited to the skin flexures. Mutations in the epithelial cytokeratin 2e (K2e), which is expressed in a differentiation-specific fashion in the upper spinous and granular layers of the epidermis, have been shown to cause IBS. We detected a novel mutation in a three generation kindred with IBS (1448T-->A) within exon 7 of the KRT2E gene. This is predictive of an I483N substitution in the 2B domain of K2e. This extends the range of mutations reported to date and illustrates the usefulness of molecular genetics in the diagnosis of this disorder.

The British Association of Dermatologists audit of atopic eczema management in secondary care. Phase 1: audit of service structure.

This first comprehensive study of atopic eczema management describes an audit of service structure (phase 1), process (phase 2) and outcome (phase 3) in the U.K. This paper describes the phase 1 results. Service structure was audited by a single-page questionnaire containing 10 questions on outpatient facilities. This was sent to the lead dermatologist at 187 dermatology centres throughout the U.K., and a final response rate of 98% was achieved. Although the percentage of centres reporting the presence of recommended facilities did not reach the 100% working standard for any one specific criterion, about half of the recommended items, such as provision of height and weight measuring facilities, access to a dietician, patch testing and photochemotherapy, was reported in over 90% of centres. Areas of service structure which were infrequently reported to be in place were issuing of new appointment letters asking patients to bring their treatment details to clinic (52% of centres) and access to nurses with dermatology experience on paediatric wards (57% of centres). Some audit measures, e.g. access to counselling services, showed wide regional variation (range 33-94% of centres), and these variations could not be explained simply in terms of provision of specialists. Some of the elements of service structure, such as access to nurses with dermatology experience on paediatric wards, may be difficult to change in the short term because of funding and staffing constraints, but others, such as provision of growth charts, are easy to change at little cost. This preliminary audit serves as a framework for future audits of atopic eczema management.