Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss.

BACKGROUND AND AIMS: We investigated the effect of different exercise modalities on high sensitivity-C reactive protein (hs-CRP) and other inflammatory markers in patients with type 2 diabetes and the metabolic syndrome. METHODS AND RESULTS: Eighty-two patients were randomized into 4 groups: sedentary control (A); receiving counseling to perform low-intensity physical activity (B); performing prescribed and supervised high-intensity aerobic (C) or aerobic+resistance (D) exercise (with the same caloric expenditure) for 12 months. Evaluation of leisure-time physical activity and assessment of physical fitness, cardiovascular risk factors and inflammatory biomarkers was performed at baseline and every 3 months. Volume of physical activity increased and HbA(1c) decreased in Groups B-D. VO(2max), HOMA-IR index, HDL-cholesterol, waist circumference and albuminuria improved in Groups C and D, whereas strength and flexibility improved only in Group D. Levels of hs-CRP decreased in all three exercising groups, but the reduction was significant only in Groups C and D, and particularly in Group D. Changes in VO(2max) and the exercise modalities were strong predictors of hs-CRP reduction, independent of body weight. Leptin, resistin and interleukin-6 decreased, whereas adiponectin increased in Groups C and D. Interleukin-1ß, tumor necrosis factor-α and interferon-γ decreased, whereas anti-inflammatory interleukin-4 and 10 increased only in Group D. CONCLUSION: Physical exercise in type 2 diabetic patients with the metabolic syndrome is associated with a significant reduction of hs-CRP and other inflammatory and insulin resistance biomarkers, independent of weight loss. Long-term high-intensity (preferably mixed) training, in addition to daytime physical activity, is required to obtain a significant anti-inflammatory effect.

Leflunomide-induced subacute cutaneous lupus erythematosus with erythema multiforme-like lesions.

Leflunomide is an immunosuppressive agent that acts by inhibiting pyrimidine synthesis in lymphocytes and other rapidly proliferating cells, as well as by suppressing tumor necrosis factor-alpha-induced cellular responses. A number of leflunomide-related adverse events have been reported. Among cutaneous side effects, a few cases of subacute cutaneous lupus erythematosus have been described. We report a previously undocumented reaction to leflunomide, manifesting as subacute cutaneous lupus erythematosus and erythema multiforme-like lesions, in a young woman treated with this drug for ankylosing spondylitis. Withdrawal of leflunomide combined with a short cycle of systemic corticosteroid led to the resolution of the patient's rash, indicating this drug as being responsible for the development of the disease. We conclude that leflunomide might have triggered the occurrence of both subacute cutaneous lupus erythematosus and erythema multiforme in a patient with pre-existing autoimmune diathesis. The suppressive effect of this drug on tumor necrosis factor-alpha-related mechanisms might have played a role in the induction of such a unique reaction to leflunomide.

Widespread idiopathic pyoderma gangrenosum evolved from ulcerative to vegetative type: a 10-year history with a recent response to infliximab.

Pyoderma gangrenosum (PG) is an infrequent neutrophilic dermatosis, which commonly presents with a limited number of ulcerative, pustular, bullous or vegetative lesions associated with an underlying systemic disorder. We report a 34-year-old man with ulcerative PG that was exceptionally widespread and not associated with any other condition. Moreover, it was resistant to steroid treatment and, after prolonged use of ciclosporin, it unexpectedly developed a vegetative pattern, further supporting the hypothesis that the different forms of PG are part of a single clinical spectrum. Finally, dramatic improvement of the condition occurred after treatment with infliximab, an antitumour necrosis factor-alpha monoclonal antibody; however, this produced circulating autoantibodies. Although this has not had any clinical consequence to date, accurate follow-up in patients treated with infliximab is essential to monitor the onset of a possible autoimmune disorder induced by the drug.

Cutaneous granulomatous reaction to injectable hyaluronic acid gel.

Injectable hyaluronic acid (HA) derivatives are the most used reabsorbable dermal fillers for soft tissue augmentation today and their utilization is considered safe. We report a cutaneous granulomatous reaction that developed in a woman 5 weeks after the first treatment with a nonanimal HA derivative for the correction of facial wrinkling. We describe the clinicopathological findings and course of the cutaneous reaction. The adverse reaction showed clinical and histopathological characteristics comparable to the few previously reported cases. All cutaneous lesions spontaneously disappeared without scars within 3 months. We conclude that even nonanimal injectable HA derivatives can be associated with delayed granulomatous reactions. The patient should be informed of this potential long-term complication.

The usefulness of clonality for the detection of cases clinically and/or histopathologically not recognized as cutaneous T-cell lymphoma.

BACKGROUND: The determination of clonality has proven to be a useful adjunct to the diagnosis of cutaneous lymphocytic infiltrates. It is considered particularly helpful for the distinction of mycosis fungoides (MF) and inflammatory dermatoses. OBJECTIVES: To verify the sensitivity of the polymerase chain reaction (PCR)-heteroduplex analysis of T-cell receptor gamma-chain gene (TCRgamma) rearrangements in patients with MF and to establish whether a clinicopathological re-evaluation of lesions previously unclassified or considered to be non-neoplastic entities but found to be monoclonal allowed the recognition of additional cases of MF. METHODS: Included in the study were 116 patients, seen at our Institute from April 2002 to September 2003 and tested for TCRgamma rearrangements. Thirty-six patients were affected by clinically and histopathologically proven MF, while the remaining 80 cases had not been classified or had been classified as non-neoplastic entities. The sensitivity of the molecular analysis was determined on the basis of the results obtained in the 36 patients with MF. The 29 cases of the second series of patients found to be monoclonal were clinically and histopathologically re-evaluated. RESULTS: Clonal rearrangements were found in 87.5% of patients with plaque stage MF and in 20% of those with patch stage MF. The clinicopathological re-evaluation allowed us to reclassify 15 of 29 monoclonal cases of the second series of patients as MF. CONCLUSIONS: The study showed that the PCR-heteroduplex technique can determine a high percentage of monoclonality only in plaque stage MF. However, in spite of the low sensitivity of the method, several cases previously unrecognized could be reclassified as MF when their clinical and histopathological features were re-evaluated taking into account the clonality of the lymphocytic infiltrate.

Sclerodermic linear lupus panniculitis: report of two cases.

Lupus erythematosus panniculitis is a rare disease characterized by deep subcutaneous nodules, most commonly localized on the upper limbs and face. Unique clinical presentations, such as linear configuration or 'overlap' forms between lupus erythematosus panniculitis and localized scleroderma have been reported. We present here the clinical characteristics, course and laboratory findings of 2 patients having linear lupus erythematosus panniculitis with localized scleroderma-like changes. The 2 patients (of the 14 patients with lupus erythematosus panniculitis seen by us since 1990) were females with a young age at the onset of disease (median, 25 years). In 1 case, evolution into systemic lupus erythematosus with severe renal involvement occurred whereas the other patient, who had a spontaneous abortion and exhibited anticardiolipin antibodies, should be followed and screened for the emergence of antiphospholipid syndrome. Thus, the clinical behavior of this variant seems to be more aggressive, as compared with the usual course of lupus erythematosus panniculitis, which is considered to be a benign disease, although some reports have suggested that its prognosis is not always favorable. The linear distribution could be the clinical hallmark of such a unique, 'sclerodermic' subset of lupus erythematosus panniculitis.

Keratosis lichenoides chronica and eruptive keratoacanthoma-like lesions in a patient with multiple myeloma.

We describe a 72-year-old woman with a 13-year history of a lichenoid dermatitis, who developed multiple, papular keratoacanthoma (KA)-like lesions and few crater-like nodules on the extremities over a period of 6 months before our observation. Her medical history also recorded multiple myeloma diagnosed a few years before. The long-standing dermatosis was diagnosed, clinically, as keratosis lichenoides chronica (KLC), although, histologically, a lichenoid tissue reaction pattern was not evident. On the other hand, histology from papular and nodular lesions of recent onset was consistent with a possible early phase of KA and spinocellular carcinoma, respectively. Oral acitretin induced regression of KA-like lesions and improvement of KLC but had no effects on crater-like nodules, which required surgical excision. KLC is a chronic disorder of keratinization characterized by lichenoid hyperkeratotic papules arranged in a linear pattern, erythematosquamous plaques and seborrhoea-like dermatitis. We emphasize in our case the association between KLC and multiple possible KAs, never previously reported, and speculate that these two rare conditions may represent here a 'continuum' from a pathogenetic point of view.

Elephantoid oedema of the eyelids.

We describe a male patient with rosacea who had a 2-year history of persistent bilateral oedema of the eyelids, leading to an elephantoid condition with blepharoptosis. An upper eyelid blepharoplasty was performed, but swelling progressively recurred over a few months. Based on the case history, clinical appearance and histological findings, rosaceous lymphoedema was considered to be the diagnosis. The latter is a bilateral, solid oedema of the mid-third of the face, regarded as a rare complication of rosacea. It is thought to occur as a result of chronic inflammation and lymphatic stasis, but its exact aethiopathogenesis remains elusive. Predominant eyelid involvement, causing severe visual impairment as in our patient, is unique.

Correlates of total homocysteine plasma concentration in type 2 diabetes.

BACKGROUND: Although well-defined in the general population, correlates of total homocysteine (tHcy) plasma concentration have not been sufficiently evaluated in diabetes. We investigated factors potentially associated with tHcy concentration in a cohort of type 2 diabetic subjects. MATERIALS AND METHODS: The common methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism, fasting tHcy, vitamin B12 and folate plasma levels were assessed in 312 diabetic subjects, whose clinical, metabolic and lifestyle information was also available. RESULTS: The MTHFR genotype distribution was comparable to the Hardy-Weinberg equilibrium, with an overall TT homozygous frequency of 22%. Fasting tHcy concentration was significantly higher in men than in women (P < 0.001). Multivariate-adjusted tHcy concentration was significantly different across the quartiles of age (P < 0.001), folate (P = 0.01), vitamin B12 (P = 0.03), creatinine concentrations (P = 0.001) and smoking (P = 0.02). Overall, significant trends were noted for creatinine clearance (P for trend = 0.02) and systolic blood pressure (BP) (unadjusted P for trend = 0.01), whereas no differences were noted according to BMI, diastolic BP, presence of hypertension, and diabetes-related variables, such as diabetes duration, fasting glucose and glycated haemoglobin concentrations, current treatment and diabetes long-term complications. Total homocysteine levels significantly correlated with age, systolic BP, vitamin B12, creatinine and creatinine clearance, but only age, creatinine, folate and vitamin B12 levels were independently associated with tHcy concentration in stepwise regression analysis. CONCLUSIONS: Age, creatinine, folate, vitamin B12, and to a minor extent, sex, smoking, TT genotype and systolic BP were significantly associated with Hcy plasma concentration in type 2 diabetes, whereas no significant associations were noted with diabetes-related variables.

5% Imiquimod cream for external anogenital warts in HIV-infected patients under HAART therapy.

The efficacy of imiquimod in the treatment of external genital warts in HIV positive subjects was compared to a group of patients with normal immune function. Imiquimod 5% cream was applied by patients three times a week until resolution for a maximum of 16 weeks. Assessment for response and the occurrence of side effects was performed every four weeks. Thirty-one per cent of 75 HIV positive patients achieved a complete clearance, a partial response was obtained in 24% of subjects while in 45% we observed no clinical response. In the control group a total clearance was obtained in 62% of subjects, a partial response in 24% and no response in 14%. Recurrences occurred in 4/23 HIV patients and 2/31 immunocompetent patients within three months of follow-up. Side effects were minor to moderate. We conclude that imiquimod 5% cream has an acceptable efficacy and safety on HIV patients.

Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen.

SUMMARY: Given the poor prognosis of patients with advanced cutaneous T-cell lymphoma and the high transplant-related mortality associated with conventional allogeneic bone marrow transplantation, we performed nonmyeloablative transplantation of allogeneic stem cells (ASCT) from HLA-identical siblings in three patients with this disease. All patients achieved full donor engraftment, clearance of clonal T cells leading to durable complete remissions but experienced high incidence of infections, which proved fatal in one case. These results suggest that nonmyeloablative ASCT is a novel and potentially curative therapy for patients with advanced T-cell lymphomas who have a histocompatible sibling.

Clonal CD8 infiltration of the skin in common variable immunodeficiency: a prelymphomatous stage?

Common variable immunodeficiency is a heterogeneous syndrome characterized by hypogammaglobulinemia and recurrent bacterial infections. Patients with this syndrome also have an increased incidence of autoimmune disease and malignancy, most notably lymphoproliferative disorders. The treatment for common variable immunodeficiency is supported by the use of intravenous infusion of immunoglobulins that allows for control of the disease and avoidance of recurrent opportunistic infections. This report describes a young patient having common variable immunodeficiency who presented with a clonal CD8(+) lymphocytic infiltration of the skin clinically manifesting as a widespread papulonodular eruption and resolving with intravenous immunoglobulin therapy. We speculate that such a unique cutaneous presentation may represent a prelymphomatous condition because of the development of an autonomous T-suppressor/cytotoxic cell clone, possibly also responsible for the impaired immunoglobulin production.

Congenital cutaneous multifocal kaposiform hemangioendothelioma.

Kaposiform hemangioendothelioma is a rare vascular neoplasm in children often associated with Kasabach-Merritt syndrome. The tumor usually presents in retroperitoneal location and is rarely present at birth. Cutaneous lesions manifest after birth and must be clinically differentiated from infantile hemangiomas and diffuse neonatal hemangiomatosis. Histologically, it bears similarities with Kaposi sarcoma. We present a case of congenital cutaneous multifocal kaposiform hemangioendothelioma (KHE).

Quality protein maize: a biochemical study of enzymes involved in lysine metabolism.

Quality protein maize (QPM) varieties have been produced by the introduction of opaque-2 modifier genes. Two QPM varieties, BR451 and BR473, a wild type and an opaque-2 variety, have been used to study key enzymes controlling lysine metabolism in the endosperm during development. Aspartate kinase and homoserine dehydrogenase enzymes, which are involved in lysine and threonine biosynthesis, respectively, exhibited identical activity patterns during endosperm development, with a maximum specific activity at 16 days after pollination. The QPM varieties exhibited higher levels of aspartate kinase activity in the endosperm, suggesting an increased rate of lysine biosynthesis when compared to the opaque-2 and wild-type genotypes. Similar results were observed for the lysine ketoglutarate reductase and saccharopine dehydrogenase enzymes, which form a single bifunctional polypetide involved in endosperm lysine degradation. Both enzyme activities were strongly reduced in the opaque-2 maize variety when compared to the wild-type maize, whereas the QPM varieties exhibited even lower levels of lysine ketoglutarate reductase-saccharopine dehydrogenase activities when compared to the opaque-2 variety. The developmental pattern of enzyme activity showed a different profile when compared to the enzymes involved in lysine biosynthesis, with activity being detected only 12-16 days after pollination (DAP) and maximum activities approximately 24 DAP. These results also suggest that the modifier genes have intensified the effect of the opaque-2 mutation on lysine ketoglutarate reductase-saccharopine dehydrogenase. These alterations lead to an increase in soluble lysine in the endosperm of the QPM varieties when compared to the opaque-2 and wild type.

Unilesional follicular mycosis fungoides.

Follicular mycosis fungoides (FMF) is an unusual clinical and histological variant of MF, characterized by selective involvement of hair follicles by atypical lymphocytes. We describe a female patient who had follicular papules located only on the medial aspect of her right thigh. To the best of our knowledge, this patient represents the first reported case of unilesional FMF.

Primary cutaneous B-cell lymphoma with a dermatomal distribution.

Primary cutaneous B-cell lymphomas (CBCLs) are indolent lymphoproliferative skin disorders with the only exception of the variant arising on the legs, which is characterized by a more aggressive clinical course. We report a case of CBCL unusual in that it presented with a dermatome-like distribution and showed early peripheral lymph node involvement. The other noteworthy finding is that rearrangement of the bcl-2 gene was detected by polymerase chain reaction in skin tissue samples. The bcl-2 rearrangement, which is usually absent in the classic CBCLs, is likely to play a role in the aggressive clinical behavior of the tumor, although further studies are necessary to confirm it. The hypothesis of a virus causing the dermatomal presentation is intriguing but there is no proof for such speculation at this point.

Erythema elevatum diutinum and HIV infection: a report of five cases.

Erythema elevatum diutinum (EED) is emerging as a specific HIV-associated dermatosis, 11 cases having so far been reported in the medical literature and five patients with the disease having been seen by us during the last 4 years. As the disease is poorly known, it is easily confused with Kaposi's sarcoma or bacillary angiomatosis, but the histopathological features are diagnostic. EED is considered to be an immune complex-mediated vasculitis. A streptococcal infection seemed to be the trigger factor in four of our patients. Partial control of the cutaneous lesions was achieved by the use of antibiotics.

Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior.

Cutaneous T cell lymphomas (CTCL) generally have the phenotype of CD3+, CD4+, CD45RO+ memory T cells. CTCL expressing a CD8+ T cell phenotype are extremely rare and ill-defined. To elucidate whether these CD8+ CTCL represent a distinct disease entity, the clinical, histological, and immunophenotypical features of 17 CD8+ CTCL were reviewed. None of the 17 cases expressed markers characteristic of natural killer cells or gamma/delta T cells. Nine of 17 cases showed the characteristic clinical and histological features as well as clinical behavior of well defined types of CTCL, such as mycosis fungoides (2 cases), pagetoid reticulosis (2 cases), lymphomatoid papulosis (2 cases), and CD30+ large T cell lymphoma (2 cases), all of which usually express a CD4+ T cell phenotype, and 1 case of subcutaneous panniculitis-like T cell lymphoma. The other 8 cases formed a homogeneous group showing a distinctive set of clinicopathological and immunophenotypical features, not consistent with that of other well defined types of CTCL. Clinical characteristics included presentation with generalized patches, plaques, papulonodules, and tumors mimicking disseminated pagetoid reticulosis; metastatic spread to unusual sites, such as the lung, testis, central nervous system, and oral cavity, but not to the lymph nodes; and an aggressive course (median survival, 32 months). Histologically, these lymphomas were characterized by band-like infiltrates consisting of pleomorphic T cells or immunoblasts, showing a diffuse infiltration of an acanthotic epidermis with variable degrees of spongiosis, intraepidermal blistering, and necrosis. The neoplastic cells showed a high Ki-67 proliferation index and expression of CD3, CD8, CD7, CD45RA, betaF1, and TIA-1 markers, whereas CD2 and CD5 were frequently lost. Expression of TIA-1 pointed out that these lymphomas are derived from a cytotoxic T cell subset. The results of this and other studies reviewed herein suggest that these strongly epidermotropic primary cutaneous CD8+ cytotoxic T cell lymphomas represent a distinct type of CTCL with an aggressive clinical behavior.

Dystrophic calcinosis cutis in subacute lupus.

Dystrophic calcinosis cutis is known to be associated with various connective tissue disorders but to the best of our knowledge has never been reported in subacute cutaneous lupus erythematosus (SCLE), a distinctive cutaneous subset in the spectrum of lupus erythematosus. It occurs without calcium and phosphorus metabolic abnormalities and may be localized or generalized. We report a patient with SCLE who developed calcinosis cutis and had normal serum calcium and phosphorus levels and, interestingly, a normal concentration of blood ionized calcium. This latter, which represents the active form in the total amount of blood calcium, is a parameter only rarely assessed in patients with dystrophic calcinosis cutis. Thus, other pathogenic factors should be investigated to clarify the pathophysiology of the dystrophic type of calcification.