Subungual squamous cell carcinoma presenting with minimal nail changes: A factor in delayed diagnosis?

Squamous cell carcinoma of the nail bed is a relatively uncommon tumour that may be diagnosed only after considerable delay. The first case presented is a 79-year-old man with a history of discomfort and discoloration affecting the right thumbnail of 3 years duration. The second case is a 70-year-old man who presented with a recurrent, offensive discharge from beneath the left thumbnail of 40 years duration. Clinical examination of the affected digits revealed minor nail abnormalities. The presence of tumour was fully apparent only after removal of the nail plate and inspection and biopsy of the nail bed. The cases demonstrate that subungual squamous cell carcinoma may present with prolonged symptoms and a deceptively benign appearance. The importance of consideration of the possibility of malignancy, removal of the nail plate for inspection of the nail bed and appropriate biopsy is emphasized.     

Serum 25-hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study)

OBJECTIVE

To examine whether serum 25-hydroxyvitamin D (25OHD) and dietary calcium predict incident type 2 diabetes and insulin sensitivity.

RESEARCH DESIGN AND METHODS

A total of 6,537 of the 11,247 adults evaluated in 1999–2000 in the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, returned for oral glucose tolerance test (OGTT) in 2004–2005. We studied those without diabetes who had complete data at baseline (n = 5,200; mean age 51 years; 55% were women; 92% were Europids). Serum 25OHD and energy-adjusted calcium intake (food frequency questionnaire) were assessed at baseline. Logistic regression was used to evaluate associations between serum 25OHD and dietary calcium on 5-year incidence of diabetes (diagnosed by OGTT) and insulin sensitivity (homeostasis model assessment of insulin sensitivity [HOMA-S]), adjusted for multiple potential confounders, including fasting plasma glucose (FPG).

RESULTS

During the 5-year follow-up, 199 incident cases of diabetes were diagnosed. Those who developed diabetes had lower serum 25OHD (mean 58 vs. 65 nmol/L; P < 0.001) and calcium intake (mean 881 vs. 923 mg/day; P = 0.03) compared with those who remained free of diabetes. Each 25 nmol/L increment in serum 25OHD was associated with a 24% reduced risk of diabetes (odds ratio 0.76 [95% CI 0.63–0.92]) after adjusting for age, waist circumference, ethnicity, season, latitude, smoking, physical activity, family history of diabetes, dietary magnesium, hypertension, serum triglycerides, and FPG. Dietary calcium intake was not associated with reduced diabetes risk. Only serum 25OHD was positively and independently associated with HOMA-S at 5 years.

CONCLUSIONS

Higher serum 25OHD levels, but not higher dietary calcium, were associated with a significantly reduced risk of diabetes in Australian adult men and women.Accumulating evidence suggests that vitamin D deficiency is associated with an increased risk of developing type 2 diabetes (1–3). Animal and human studies indicate that vitamin D can have a direct (via activation of the vitamin D receptor on pancreatic β-cells and insulin-sensitive organs) and indirect (via regulation of calcium homeostasis) positive effect on insulin secretion and sensitivity (3,4). Several prospective studies also support the hypothesis that low vitamin D status is a risk factor for the development of type 2 diabetes (1–3,5,6); however, these studies were limited by small study sample sizes (3), indirect measures of vitamin D status as a surrogate marker (6,7), and incomplete identification of incident diabetes cases (1,2,5). In addition, most did not include an assessment of dietary calcium, which may have an independent or synergistic effect with vitamin D on lowering type 2 diabetes risk (7). The aim of this study was to examine the relationship between serum 25-hydroxyvitamin D (25OHD), dietary calcium, and risk of developing type 2 diabetes as assessed by an oral glucose tolerance test (OGTT) in a large national, population-based prospective study: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study.     

Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival

The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma (MM) and to evaluate possible predictive factors for response rate and survival. Twenty-nine pretreated patients were enrolled, including 13 patients with a relapse after high-dose chemotherapy. The median number of relapses was 3 (range: 1–7). Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone. The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m² daily for 4 consecutive days every 3 weeks. Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved, whereas therapy with thalidomide was maintained until disease progression. Responses occurred in 62% of patients, including 5 (17%) complete remissions and 13 (45%) partial remissions. The median event-free survival (EFS) was 7.2 months and the median overall survival (OS) 26.1 months. In multivariate analysis, pretreatment serum levels of soluble interleukin-2 receptor (sIL-2R) were a significant prognostic factor for EFS, and those of ₂-microglobulin (2M) and sIL-2R for OS. Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide. Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone. Also, one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred. Other side effects were somnolence, peripheral neuropathy, and bradycardia occurring in 35, 55, 38 and 55% of patients, respectively. The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities. A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R.     

Milrinone use for hemodynamic instability in patent ductus arteriosus ligation

Objective: Determine if prophylactic milrinone improves cardiovascular or long-term clinical outcomes in preterm neonates who receive surgical patent ductus arteriosus (PDA) ligation.

Study design: Retrospective review of 45 infants over a 4-year period that received a PDA ligation at one institution. Data were collected on morbidity and mortality outcomes for all infants as well as milrinone therapy perioperatively.

Results: Of the 45 infants that were studied 15 received milrinone in the perioperative period of PDA ligation and the remaining 30 infants did not receive milrinone. The use of milrinone showed no statistically significant improvement in acute markers of hemodynamic stability. There was also no statistically significant difference in morbidity and mortality outcomes in milrinone group compared to the non-milrinone group.

Conclusion: Prophylactic milrinone use for premature infants following PDA ligation does not show a significant cardiovascular or long-term clinical benefit.     

Proteinase-activated receptor 2 activation in the airways enhances antigen-mediated airway inflammation and airway hyperresponsiveness through different pathways

BACKGROUND: Serine proteinases such as mast cell tryptase, trypsin-like enzymes, and certain allergens are important in the pathogenesis of asthma. These proteinases can activate the proteinase-activated receptor (PAR)-2, which has been shown to be upregulated in the airways of patients with asthma. OBJECTIVE: The purpose of this study was to investigate PAR-2 activation in the airways during allergen challenge and its effects on the 2 principle features of asthma, airway inflammation and airway hyperresponsiveness (AHR). METHODS: Proteinase-activated receptor 2 activating peptide SLIGRL-NH2 (PAR-2 activating peptide [ap]) or control peptide LSIGRL-NH2 (PAR-2 control peptide [cp]) was administered alone or in conjunction with ovalbumin intranasally to mice, and AHR and airway inflammation were evaluated. RESULTS: PAR2ap did not induce AHR or airway inflammation in ovalbumin-sensitized mice that had not been challenged with ovalbumin. When administered with ovalbumin, PAR-2ap enhanced AHR and airway inflammation compared with ovalbumin administered alone or with PAR-2cp. The enhanced AHR persisted for 5 days, whereas the enhancement to airway inflammation dissipated. Mice administered PAR-2ap alone during the 5 days after the final antigen challenge demonstrated an additional enhancement to airway inflammation compared with the control animals. PAR-2ap administered with allergen increased TNF and IL-5 mRNA in lung tissue and IL-13 and TNF in bronchoalveolar lavage fluid. CONCLUSION: Exogenous PAR-2 activation in parallel with allergen challenge enhances allergen-mediated AHR and airway inflammation through distinct mechanisms. PAR-2 activation can also enhance established airway inflammation even when dissociated from exposure to allergen. Therefore, PAR-2 activation may play a pathogenic role in the development of AHR and airway inflammation.     

Identification of loci determining susceptibility to the lethal effects of amyloid precursor protein transgene overexpression

Phenotypes produced by expression of human amyloid precursor protein (APP) transgenes vary depending on the genetic background of the mouse. FVB/N mice overexpressing human APP695 develop a central nervous system disorder and die prematurely, precluding development of Abeta peptide amyloid plaques. 129S6 mice are resistant to the lethal effects of APP overexpression, allowing sufficient levels of Abeta expression for the development of amyloid plaques and age-dependent memory deficits. To identify the genes that determine susceptibility or resistance to APP we analyzed crosses involving FVB/NCr and 129S6.Tg2576 mice that overexpress 'Swedish' mutant (K670N, M671L) APP695. APP transgene-positive FVB129S6F1 (F1) mice are resistant to the lethal effects of APP overexpression, so FVBxF1 backcross and F2 intercross offspring were produced. Analysis of age of death as a quantitative trait revealed significant linkage to loci on proximal chromosome 14 and on chromosome 9; 129S6 alleles protect against the lethal effects of APP. Within the chromosome 14 interval are segments homologous to regions on human chromosome 10 that have been linked to late onset Alzheimer's disease or to levels of Abeta peptide in plasma. However, analysis of plasma Abeta peptide concentrations at 6 weeks in backcross offspring produced no significant linkage. Similarly, elevation of human Abeta peptide concentrations by expression of mutant presenilin transgenes did not increase the proportion of mice dying prematurely, suggesting that early death reflects effects of APP or fragments other than Abeta.     

Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells

Anergic/suppressive CD4+CD25+ T cells have been proposed to play an important role in the maintenance of peripheral tolerance. Here we demonstrate that in humans these cells suppress proliferation to self antigens, but also to dietary and foreign antigens. The suppressive CD4+CD25+ T cells display a broad usage of the T cell receptor Vbeta repertoire,suggesting that they recognize a wide variety of antigens. They reside in the primed/memory CD4+CD45RO+CD45RB(low) subset and have short telomeres, indicating that these cells have the phenotype of highly differentiated CD4+ T cells that have experienced repeated episodes of antigen-specific stimulation in vivo. This suggests that anergic/suppressive CD4+CD25+ T cells may be generated in the periphery as a consequence of repeated antigenic encounter. This is supported by the observation that highly differentiated CD4+T cells can be induced to become anergic/suppressive when stimulated by antigen presented by non-professional antigen-presenting cells. We suggest that besides being generated in the thymus, CD4+CD25+ regulatory T cells may also be generated in the periphery. This would provide a mechanism for the generation of regulatory cells that induce tolerance to a wide array of antigens that may not be encountered in the thymus.